Expressions of IL-17 and TNF-α in patients with Hashimoto's disease combined with thyroid cancer before and after surgery and their relationship with prognosis.

OBJECTIVE: This study aimed to investigate expressions and clinical significance of IL-17 and TNF-α after surgery in patients with Hashimoto's disease (HD) combined with thyroid cancer (TC). PATIENTS AND METHODS: From June 2010 to October 2012, 38 patients with HD combined with TC admitted to the oncology department of Tongji Hospital were selected as an experimental group, including three males and 35 females, aged 24-78 years. Forty adults undergoing physical examination during the same period were selected as a control group. All patients in the experimental group were given total endoscopic TC resection. Real-time fluorescence quantification (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression levels of serum IL-17 and TNF-α before and 14 days after surgery. Patients with HD combined with TC were divided into high and low expression groups according to the median values of preoperative IL-17 mRNA and TNF-α mRNA. The relationship between IL-17, TNF-α, and prognosis of patients was analyzed through K-M survival curve. RESULTS: The concentrations of IL-17 and TNF-α in serum were also higher than those in control group 14 days after surgery (p < 0.05). qRT-PCT showed that the relative expressions of IL-17 and TNF-α in serum 14 days after surgery were higher than those in control group (p < 0.05). According to the relative expression median of mRNA in IL-17 and TNF-α before surgery, they were divided into high and low expression groups. It was found that the survival rate of high expression groups of IL-17 and TNF-α was lower than that of low expression groups (IL-17, p = 0.028; TNF-α, p = 0.014). CONCLUSIONS: The protein and mRNA of IL-17 and TNF-α in serum of HD patients with TC are higher than those of healthy control group. Expressions of IL-17 and TNF-α can be reduced by surgical resection of focal tissue. IL-17 and TNF-α may be used as potential prognostic indicators of HD patients with TC.

Definition of the Response to Initial Therapy with Radioiodine in Patients with Differentiated Thyroid Carcinoma: Basal or Stimulated Thyroglobulin?

Basal thyroglobulin (b-Tg) measured with second-generation assay or stimulated Tg (s-Tg) can be used to define the response to therapy of differentiated thyroid carcinoma. However, they do not always define the same category and guidelines do not establish "if" or "when" s-Tg needs to be obtained. We studied 304 patients without clinically apparent disease or disease detected by neck ultrasonography and without anti-Tg antibodies 9-12 months after therapy. Based on b-Tg, 196 patients had an excellent response and 108 had an indeterminate response. Based on s-Tg, a change in category occurred in 10.2% of the patients with an initial excellent response (all to indeterminate response) and in half the patients with an initial indeterminate response (44.4% to excellent response and 5.5% to biochemical incomplete response). One case of recurrence was observed among patients with an initial excellent response but whose response changed to indeterminate after s-Tg, while no disease was detected among those who remained in the initial category; however, this difference was not significant. In patients with an initial indeterminate response, no recurrence was detected among those whose response changed to excellent after s-Tg, while 11.1 and 33.3% of those who remained in the initial category or whose response changed to biochemical incomplete, respectively, had structural disease. This study suggest that, in low- or intermediate-risk patients, s-Tg better defines the response to therapy with 131I when it is classified as indeterminate based on b-Tg using second-generation assay. However, s-Tg is not necessary when b-Tg defines the response as excellent.

Long-Term Follow-Up in Patients with Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) Without a Suspicion of Persistent Disease in Postoperative Assessment.

The objective was to determine whether negative assessment after surgery is a predictor of no relevant change of the results in subsequent evaluations in patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Six months after surgery, "absence of persistent disease" was defined when concentration of thyroglobulin (Tg) is ≤2 ng/ml in patients undergoing total thyroidectomy and ≤10 ng/ml in those undergoing lobectomy, in the absence of antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) without abnormalities. One hundred thirteen patients met the definition of "absence of persistent disease". The patients were followed up for 18-150 months. None of the patients developed structural disease. In the 56 patients undergoing total thyroidectomy, 380 Tg measurements were obtained and an increase in concentrations was not observed in any of them. During the same period, 332 US scans were performed and a suspicious lymph node was detected on only one occasion, but was not metastatic on fine needle aspiration (FNA). In the 57 patients undergoing lobectomy, 382 Tg measurements were obtained and increases or persistent concentrations>10 ng/ml were not observed in any patient. During the same period, 376 US scans were performed and nodules with an indication for FNA were detected in 4 patients, but malignancy was not confirmed in any of them. Finally, TgAb were not elevated in any of the 762 measurements obtained from the 113 patients. After complete resection of NIFTP, negative postoperative assessment can be used to exclude the need for long-term repetition of these tests.

Thyroglobulin levels before radioactive iodine therapy and dynamic risk stratification after 1 year in patients with differentiated thyroid cancer

ABSTRACT Objectives: We sought to assess the relationship between stimulated thyroglobulin (sTg) before radioactive iodine therapy (RIT), and the dynamic risk stratification 1 year after treatment, and to establish the utility of the sTg as a predictor of response to therapy in these patients. A retrospective chart review of patients with differentiated thyroid cancer (DTC) who underwent RIT after surgery and were followed for at least 1 year, was carried out. Subjects and methods: Patients were classified according to the dynamic risk stratification 1 year after initial treatment. The sTg values before RIT were compared among the groups. ROC curve analysis was performed. Results: Fifty-six patients were enrolled (mean age 44.7 ± 14.4 years, 80.7% had papillary carcinoma). Patients with excellent response had sTg = 2.1 ± 3.3 ng/mL, those with indeterminate response had sTg = 8.2 ± 9.2 ng/mL and those with incomplete response had sTg = 22.4 ± 28.3 ng/mL before RIT (p = 0.01). There was a difference in sTg between excellent and incomplete response groups (p = 0.009) while no difference was found between indeterminate and either excellent or incomplete groups. The ROC curve showed an area under the curve of 0.779 assuming a sTg value of 3.75 ng/mL. Conclusion: Our study results suggest that the higher the sTg before RIT, the greater the likelihood of an incomplete response to initial treatment. A sTg cut-off of 3.75 ng/mL was found to be a good predictor of response to initial treatment in patients with DTC.

Thyroglobulin levels before radioactive iodine therapy and dynamic risk stratification after 1 year in patients with differentiated thyroid cancer.

OBJECTIVES: We sought to assess the relationship between stimulated thyroglobulin (sTg) before radioactive iodine therapy (RIT), and the dynamic risk stratification 1 year after treatment, and to establish the utility of the sTg as a predictor of response to therapy in these patients. A retrospective chart review of patients with differentiated thyroid cancer (DTC) who underwent RIT after surgery and were followed for at least 1 year, was carried out. SUBJECTS AND METHODS: Patients were classified according to the dynamic risk stratification 1 year after initial treatment. The sTg values before RIT were compared among the groups. ROC curve analysis was performed. RESULTS: Fifty-six patients were enrolled (mean age 44.7 ± 14.4 years, 80.7% had papillary carcinoma). Patients with excellent response had sTg = 2.1 ± 3.3 ng/mL, those with indeterminate response had sTg = 8.2 ± 9.2 ng/mL and those with incomplete response had sTg = 22.4 ± 28.3 ng/mL before RIT (p = 0.01). There was a difference in sTg between excellent and incomplete response groups (p = 0.009) while no difference was found between indeterminate and either excellent or incomplete groups. The ROC curve showed an area under the curve of 0.779 assuming a sTg value of 3.75 ng/mL. CONCLUSION: Our study results suggest that the higher the sTg before RIT, the greater the likelihood of an incomplete response to initial treatment. A sTg cut-off of 3.75 ng/mL was found to be a good predictor of response to initial treatment in patients with DTC.

CD8+ tumour-infiltrating lymphocytes and COX2 expression may predict relapse in differentiated thyroid cancer.

BACKGROUND/OBJECTIVE: There is an increasing rate of papillary thyroid carcinomas that may never progress to cause symptoms or death. Predicting outcome and determining tumour aggressiveness could help diminish the number of patients submitted to aggressive treatments. We aimed to evaluate whether markers of the immune system response and of tumour-associated inflammation could predict outcome of differentiated thyroid cancer (DTC) patients. DESIGN: Retrospective cohort study. PATIENTS: We studied 399 consecutive patients, including 325 papillary and 74 follicular thyroid carcinomas. MEASUREMENTS: Immune cell markers were evaluated using immunohistochemistry, including tumour-associated macrophages (CD68) and subsets of tumour-infiltrating lymphocytes (TIL), such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69 and CD25. We also investigated the expression of cyclooxygenase 2 (COX2) in tumour cells and the presence of concurrent lymphocytic infiltration characterizing chronic thyroiditis. RESULTS: Concurrent lymphocytic infiltration characterizing chronic thyroiditis was observed in 29% of the cases. Among all the immunological parameters evaluated, only the enrichment of CD8+ lymphocytes (P = 0·001) and expression of COX2 (P =0·01) were associated with recurrence. A multivariate model analysis identified CD8+ TIL/COX2 as independent risk factor for recurrence. A multivariate analysis using Cox's proportional-hazards model adjusted for the presence of concurrent chronic thyroiditis demonstrated that the presence of concurrent chronic thyroiditis had no effect on prognostic prediction mediated by CD8+ TIL and COX2. CONCLUSION: In conclusion, we suggest the use of a relatively simple pathology tool to help select cases that may benefit of a more aggressive approach sparing the majority of patients from unnecessary procedures.

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer.

AIM: To evaluate the impact of genetic polymorphisms in uridine 5'-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4 ; 3,5,3',5'-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). METHODS: Patients (n = 268) submitted to total thyroidectomy and ablation by (131) I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables. RESULTS: A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage. CONCLUSION: UGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted.

Blood thyroglobulin and TSH receptor mRNA detection by RT-PCR in the follow-up of differentiated thyroid cancer patients.

OBJECTIVE: During the last years several groups have used the technique of RT-PCR for the detection of circulating thyroid cells, through the amplification of thyroglobulin (Tg) and TSH receptor(TSH-R) mRNA; however the published results are controversial. In this study we investigated the utility for the detection of Tg and TSH-R mRNA by RT-PCR in patients with differentiated thyroid cancer (DTC) during treatment with levothyroxine. SUBJECTS AND METHODS: We investigated the expression of Tg and TSH-R mRNA by single and nested RT-PCR in the blood of 3 groups of subjects: (A) 34 patients with DTC and no evidence of disease, (B) 8 patients with DTC and evidence of local or distant metastasis and (C) 13 normal subjects. Expression levels of Tg mRNA were also analysed by comparative semi-quantitative RT-PCR. RESULTS: Tg and TSH-R mRNA signals were detected in all subjects (patients with DTC with and without evidence of disease and in normal subjects) by single or nested RT-PCR. By semi-quantitative RT-PCR and densitometric analysis of PCR products, mean levels of circulating Tg mRNA of the 3 groups were: Group A 0.182+/-0.107, Group B 0.329+/-0.298 and Group C 0.305+/-0.217. CONCLUSIONS: Single or nested RT-PCR for Tg and TSH-R mRNA is not a suitable tool in the follow-up of patients with DTC. Lower levels of Tg mRNA in patients with DTC without evidence of disease, although not significant, may indicate that small numbers of thyroid cells may be normally present in the circulation or may represent an ectopic transcription of messengers from blood cells.

[Thyroid nodules and differentiated thyroid cancer: Brazilian consensus]. / Nódulos de tireóide e câncer diferenciado de tireóide: consenso brasileiro.

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.

Nódulos de tireóide e câncer diferenciado de tireóide: consenso brasileiro / Thyroid nodules and differentiated thyroid cancer: brazilian consensus

Os nódulos tireoidianos constituem a principal manifestação clínica de uma série de doenças da tireóide com uma prevalência de aproximadamente 10 por cento na população adulta. O maior desafio é excluir o câncer da tireóide, que ocorre em 5 a 10 por cento dos casos. Os carcinomas diferenciados respondem por 90 por cento dos casos de todas as neoplasias malignas da tireóide. A maioria dos pacientes com carcinoma diferenciado apresenta, geralmente, um bom prognóstico quando tratada adequadamente, com índices de mortalidade similares à população geral. No entanto, alguns indivíduos apresentam doença agressiva, desafiando o conhecimento atual e ilustrando a complexidade do manejo dessa neoplasia. No presente trabalho, reunimos 8 membros do Departamento de Tireóide da Sociedade Brasileira de Endocrinologia & Metabologia, para elaborarmos, por consenso, as diretrizes brasileiras no manejo dos nódulos tireoidianos e do câncer diferenciado da tireóide. Os membros participantes representam diferentes Centros Universitários do Brasil, refletindo diferentes abordagens diagnósticas e terapêuticas. Inicialmente, cada participante ficou responsável pela redação de determinado tema a ser enviado ao Coordenador, que, após revisão editorial e elaboração da primeira versão do manuscrito, enviou ao grupo para sugestões e aperfeiçoamentos. Quando concluído, o manuscrito foi novamente enviado e revisado por todos. A elaboração dessas diretrizes foi baseada na experiência dos participantes e revisão pertinente da literatura.

Thyroid nodules are a common manifestation of thyroid diseases. It is estimated that ~10 percent 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 percent). Differentiated thyroid carcinoma accounts for 90 percent 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.

Sonography in the diagnosis of cervical recurrence in patients with differentiated thyroid carcinoma.

OBJECTIVE: To determine the sensitivity of thyroglobulin (Tg), iodine scanning, and sonography in the diagnosis of cervical recurrence of thyroid cancer. METHODS: This prospective study assessed 81 patients with cervical metastases or extrathyroid invasion at first appearance who underwent clinical examination, scanning, measurement of Tg after thyroxine withdrawal, and sonography about 8 months after thyroidectomy followed by radioiodine treatment. Only patients without distant metastases and without anti-Tg antibodies were included. RESULTS: Fifty patients showed persistence of the disease in the cervical region, with only 16% of them having had a suspicion on clinical examination, 33 with Tg levels of 2 ng/mL or greater (66% sensitivity), and 29 with positive scan findings (58% sensitivity). A combination of the 2 methods detected disease in 40 (80%) of 50 patients but failed to show 20% of cases that were identified by sonography and confirmed by fine-needle aspiration. Sonography had sensitivity of 96%. Specificity values for Tg, iodine scanning, and sonography were 80.6%, 90.3%, and 87%, respectively. CONCLUSIONS: Classic follow-up methods may not detect cervical disease in some patients with differentiated thyroid carcinoma, and sonography is necessary even in patients apparently free of the disease.

Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer.

Serial weekly serum samples (for 3 weeks) were obtained from 42 patients with differentiated thyroid cancer (DTC, papillary no.=35, follicular no.=6, Hurthle cell no.=1) for serum thyroid hormone, TSH and TG before and after total thyroidectomy. Serum specimens were also obtained one month after radioiodine (131I) therapy followed by suppressive dose of L-thyroxine (L-T4, 2.5 microg/kg). The patients were subdivided into four groups: group I: the DTC was confined to a single solid nodule (no.=1 2); group II: thyroid malignancy invaded local cervical structures but there were no lymph node metastases (no.=8); group III: DTC with lymph node metastases (no.=6); and group IV: DTC with distant metastases (no.=16). In all group I patients serum TG remained undetectable in spite of elevated serum TSH levels at the 3rd week post-surgery (PS). Only one of group II patients had a detectable serum TG value of 5.2 ng/ml (3rd week PS). By contrast, 37.5% of group III patients had detectable serum TG levels, ranging from 3.4 to 16.8 ng/ml (3rd week PS). Lymph node metastases were detected in 5 of these patients by whole body scan (WBS) and removed surgically in 3. As expected, group IV patients had elevated serum TG values ranging 33.0-958.0 ng/ml and distant metastases were confirmed in all of them by WBS. From the calculations through univariate logistic regression comparing TG concentrations at the 3rd week PS from groups I and II vs groups III and IV, we obtained a cut-off value of 2.3 ng/ml with the following efficacy features: sensitivity=74.5%; specificity=95%; positive predictive value=92.3%; negative predictive value=65.5%; and accuracy=73.8%. After 131I and L-T4 suppressive therapy, only 5 out of 36 patients of groups I, II and III had detectable serum TG levels (3.1-7.0 ng/ml) whereas serum TG was detectable in all group IV patients (ranging 2.5-8.6 ng/ml). We concluded that serum TG concentrations above 2.3 ng/ml at the 3rd week PS could be suggestive of lymph node or distant metastases in patients with DTC. Patients with serum TG above this limit could be considered at risk for metastatic disease and higher doses of diagnostic iodine-131 (131I) may be indicated for actinic ablation.

Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood.

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.