Polyphenol intake and differentiated thyroid cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow-up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country-specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval [CI] 0.77-1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80-1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55-2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p-trend = 0.019) and phenolic acids (p-trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.

Evaluation of the 2015 ATA Guidelines in Patients With Distant Metastatic Differentiated Thyroid Cancer.

CONTEXT: Current American Thyroid Association (ATA) Management Guidelines for the treatment of differentiated thyroid cancer (DTC) stratify patients to decide on additional radioiodine (RAI) therapy after surgery, and to predict recurring/persisting disease. However, studies evaluating the detection of distant metastases and how these guidelines perform in patients with distant metastases are scarce. OBJECTIVE: To evaluate the 2015 ATA Guidelines in DTC patients with respect to 1) the detection of distant metastases, and 2) the accuracy of its Risk Stratification System in patients with distant metastases. PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively included 83 DTC patients who were diagnosed with distant metastases around the time of initial therapy, and a control population of 472 patients (312 low-risk, 160 intermediate-risk) who did not have a routine indication for RAI therapy. We used the control group to assess the percentage of distant metastases that would have been missed if no RAI therapy was given. RESULTS: Two hundred forty-six patients had no routine indication for RAI therapy of which 4 (1.6%) had distant metastases. Furthermore, among the 83 patients with distant metastases, 14 patients (17%) had excellent response, while 55 (67%) had structural disease after a median follow-up of 62 months. None of the 14 patients that achieved an excellent response had a recurrence. CONCLUSIONS: In patients without a routine indication for RAI therapy according to the 2015 ATA Guidelines, distant metastases would initially have been missed in 1.6% of the patients. Furthermore, in patients with distant metastases upon diagnosis, the 2015 ATA Guidelines are an excellent predictor of both persistent disease and recurrence.

Iodine deficiency and thyroid nodular pathology--epidemiological and cancer characteristics in different populations: Portugal and South Africa.

BACKGROUND: The prevalence and pathology pattern of iodine deficiency (ID) related disorders are influenced by the dietary iodine intake: low iodine leads to thyroid nodular enlargement, to an increase in the incidence of thyroid cancer, an increase in anaplastic carcinomas and to an alteration in the papillary to follicular neoplasia ratio. This study aims at highlighting the effects of ID by comparatively evaluating the pattern of thyroid nodular pathology in different populations that, although geographically distant and heterogeneous, both had iodine deficiency at the time of data gathering and are at high altitude: Beira Interior (BI) in Portugal and Johannesburg (JHB) in South Africa. (S.A.) Mandatory salt iodization introduced in S. A. in 1995 has recently been shown to have resulted in the correction of ID. METHODS: Evaluation of thyroid histology reports over a 6 year period in BI and a 5 year period in the JHB area. RESULTS: Region of BI: 278 patients with histology reports-60 were malignancies (21.2 %): 31 papillary carcinomas, 22 follicular cancers (18 follicular carcinomas and 4 Hürthle cell tumours), 3 medullary carcinomas and 4 anaplastic carcinomas. Region of JHB: 136 histology reports- 33 were malignancies (24.3 %): 13 papillary carcinomas, 15 follicular cancers (10 follicular carcinomas and 5 Hürthle cell tumours), 1 medullary carcinoma, 3 anaplastic carcinomas and 1 metastatic carcinoma into the thyroid. There was an overlap in the frequencies of all histology types, of particular relevance in the relatively high anaplastic carcinoma incidences and in the papillary to follicular carcinoma ratios which was close to 1 in both areas- BI area ratio: 1.4 and JHB area ratio: 0.87, with overlapping 95 % CI's, also confirmed by the results of the chi-square calculations. CONCLUSIONS: During the study periods evaluated both study areas displayed pathology patterns usually found in ID. Public information regarding the negative consequences of ID combined with the availability of affordable iodized salt are likely to achieve the goal of the elimination of ID. Sea based nutrition, (naturally iodine containing), may also contribute to the elimination of ID, particularly at times when salt restriction tends to be generally advised.

Changing clinical characteristics of thyroid carcinoma at a single center from Turkey: before and after the Chernobyl disaster.

AIM: The aim of the study was to determine the possible role of Chernobyl disaster on changing clinical features of thyroid carcinoma (TC) in a moderately iodine deficient region. METHODS: We retrospectively reviewed demographical features, presenting symptoms, tumor size, histopathological diagnosis and distant metastates in 160 patients with TC diagnosed between 1990-2007. We compared our findings with the database of 118 TC patients diagnosed between 1970-1990 in the same center. RESULTS: There were 123 female (76.9%) and 37 (23.1%) male patients with a mean age of 44.89±14.84. Sex distribution and age at diagnosis were similar between 1970-1990 and 1990-2007 (P=0.77 and P=0.42, respectively). Histopathological diagnoses were papillary in 114 (73.1%), follicular in 22 (14.1%), medullary in 9 (5.8%), hurthle cell in 7 (4.5%) and anaplastic TC in 4 (2.6%) patients. We observed a marked increase in papillary TC (P<0.001) and marked decreases in follicular (P<0.001) and anaplastic TC (P=0.01) compared to the period between 1970-1990. Thyroid microcarcinomas accounted for 27.1% and 37.1% of carcinomas in 1970-1990 and 1990-2007, respectively (P<0.05). CONCLUSION: We showed that incidence of papillary TC increased and incidences of follicular and anaplastic TC decreased in a period that might be affected by Chernobyl fallout in a moderately iodine deficient area. Presenting symptoms of TC have changed and microcarcinomas are diagnosed more frequently compared to past. Further large scale trials are needed to find out whether Chernobyl disaster has role on changing characteristic of TC in countries that are not very near but also not very far from Chernobyl such as Turkey.

Thyroid cancer, thyroiditis and dietary iodine: a review based on the Salta, Argentina model.

Factors that should be considered when studying the effect of dietary iodine in the development of thyroid cancer include pathological criteria, diagnostic techniques, screening programs, radioactive fallout, and standard of medical care in the studied population. In most surveys, papillary carcinoma forms the largest group of thyroid malignancies, both before and after iodine prophylaxis where an increase in the papillary:follicular carcinoma ratio is also noted. Undifferentiated carcinomas decrease after salt prophylaxis. In Salta, Argentina, the increasing incidence of clinically significant papillary thyroid cancer and the decrease of undifferentiated carcinoma after iodine prophylaxis are probably due to better access to health centers and consequent earlier detection of differentiated precursor tumors. Autoimmune focal and diffuse or Hashimoto's thyroiditis are linked to dietary iodine. Pathological studies made in different regions indicate that these types of thyroiditis occur more frequently in areas of iodine sufficiency than in areas of iodine deficiency, and increase after iodine prophylaxis both in non-goitrous and iodine-deficient areas like Salta, Argentina. An increase of lymphocytic thyroiditis could be linked to an increased incidence of primary thyroid lymphoma, and thyroiditis is more commonly associated with papillary carcinoma than with other types of thyroid follicular or C-cell derived carcinomas regardless of iodine intake.

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.

B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF(V600E) specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF(V600E) patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf(V600E) induced a comparable reduction of viability in both wild-type and BRAF(V600E) mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF(V600E)-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf(V600E). We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf(V600E) may provide clinical benefit for patients with thyroid cancer.

Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation.

Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.

Association between malignant tumors of the thyroid gland and exposure to environmental protective and risk factors.

Risk factors for thyroid carcinomas and adenomas were investigated using a standard questionnaire in a case-control study in Southwestern Germany, a known iodine deficiency area. A clinical registry, set up after the Chernobyl accident at the University hospital Mannheim, served as the basis for 174 incident cases of each diagnostic group. Interview data were compared within and with prevalences from a population-based matched control group of equal size from the entire area. The protective role of coffee drinking and the consumption of cruciferous vegetables, such as broccoli, were confirmed for both genders. A high consumption of tomatoes (> 200/year) was associated with an elevated risk of > 2.5 for malignant tumors but not for benign tumors in both genders. In both genders, both treatment for goiter (hyperthyroidism) and decaffeinated coffee consumption were associated with an increased risk for malignant tumors, but less so for adenomas. In women, early menarche (< 13 years) and stillbirth after first pregnancy, as well as hysterectomy, were substantial risk factors. Occupational variables and radiation, including medical indications and mammography, did not reveal particular risks. We did not address the role of regular iodine substitution, but did analyze the consumption of freshwater fish and seafood. Multivariate analyses of the most prominent risk factors confirmed the persistence of tomato consumption as a risk factor. In view of experimental evidence on the carcinogenicity of organophosphates and the neurotoxicant effect of certain agrochemicals on neuroendocrinologically regulated organs, we postulate that in Germany, importing off-season tomatoes from areas with a known history of possible inexperienced use of agrochemicals may be associated with a promoting effect for malignant neoplasias of the thyroid gland in terms of promoting already existent proliferating tissue growth.

[Risk factors and prevention of thyroid carcinoma]. / Fattori di rischio e prevenzione del carcinoma della tiroide.

Thyroid carcinoma represents the most frequent endocrine tumor. Recent reports have documented an increase in the incidence of thyroid cancer. Its incidence varies geographically around the world from 0.9/ 100,000 men and 2.4/100,000 women in Great Britain to 8.8/100,000 men and 18.2/ 100,000 women in Hawaii. Radiation exposure has been strongly implicated as an aetiological factor. The greatest risk occurs with acute exposure to X and/or gamma rays, with a linear dose response curve, while the risk is inversely related to age at exposure with a latent period of 5-20 years. Together with irradiation, other factors (iodine, alcohol and calcium diet intake, hyperthyroidism, Hashi-moto's thyroiditis, Gardner syndrome, Cowden syndrome, pharmaceutical agents, hormonal factors, occupational exposure, activation of cellular oncogenes) have been associated with the risk of thyroid cancer. In prevention a policy should include regulations and methods for avoiding radiation exposure of the thyroid and for preventing nutritional deficiency and excess of iodine. Besides, early and continuous suppressive therapy of all patients affected by non-toxic goiter or treated previously with thyroidectomy, and a screening of medullary thyroid carcinoma (MTC) using pentagastrin stimulation test and restriction fragment length polymorphism analysis, in subjects with a familial history of MTC, are of paramount importance to prevent thyroid cancer.

Prophylactic external irradiation in differentiated thyroid cancer: a retrospective study over a 30-year observation period.

Following surgery which left no microscopic residue, 114 patients with differentiated thyroid cancer (58 papillary, 56 follicular) were subgrouped on the basis of the dose of externally applied prophylactic postoperative radiation: group 1 received an adequate dose of radiation (> or = 4,500 cGy of telecobalt, > or = 4,000 R of orthovoltage therapy), while group 2 received an inadequate dose of radiation (this group included non-irradiated patients). Local/regional-relapse-free survival (LRRFS), distant-metastatic-relapse-free survival (DMRFS) and total-cause-specific survival (TCSS) were calculated by means of life-table analysis for each histologic type. TCSS and LRRFS were significantly (p < 0.001) better for group 1 in papillary cancer. No difference was found in DMRFS. LRRFS was significantly (p < 0.001) better for group 1 in follicular cancer. No differences were found in TCSS and DMRFS. We conclude that (1) prophylactic postoperative external irradiation is an effective method for survival prolongation in papillary cancer, reducing local/regional recurrences, and (2) external irradiation should be considered in the postoperative management of follicular cancer, to diminish local/regional relapse.