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Adequate iodine intake is of crucial importance in pregnancy to meet the thyroid hormone needs of both mother and fetus. In the present study, undertaken as a part of the surveillance actions following the introduction in Italy of a national salt iodination program in 2005, the iodine intake was investigated in 123 pregnant women and 49 control women living in the same area of central Italy. All the participants were screened for urinary iodine concentration (UIC), serum level of thyrotropin, free-thyroxine, free-triiodothyronine, and thyroid volume. Moreover, they were provided with a questionnaire on the use of iodine-containing salt or supplements. Control women had a median UIC of 102 µg/L, consistent with an iodine sufficiency, while in pregnant women the median UIC value was 108 µg/L, lower than the endorsed UIC of 150 µg/L. In addition, pregnant women showed a significantly increased median thyroid volume compared to controls. Interestingly, the median UIC did not differ between pregnant women not using iodine-containing salt or supplements and those regularly consuming iodized salt alone, while pregnant women with a daily intake of iodine-containing supplements had an adequate median UIC (168 µg/L). In conclusion, the data reported here showed that pregnant women and their fetuses are still exposed to the detrimental effects of iodine deficiency and that the consumption of iodine-containing supplements should be recommended in pregnancy.

Benign and malignant thyroid diseases (TDs) have been associated with the occurrence of extrathyroidal malignancies (EMs), including colorectal cancers (CRCs). Such associations have generated a major interest, as their characterization may provide useful clues regarding diseases' etiology and/or progression, with the possible identification of shared congenital and environmental elements. On the other hand, elucidation of the underlying molecular mechanism(s) could lead to an improved and tailored clinical management of these patients and stimulate an increased surveillance of TD patients at higher threat of developing EMs. Here, we will examine the epidemiological, clinical, and molecular findings connecting TD and CRC, with the aim to identify possible molecular mechanism(s) responsible for such diseases' relationship.

Some human literature suggests a possible role of endocrine disruptors (EDs) exposure in thyroid cancer (TC) development. We investigated TC incidence in selected Italian National Priority Contaminated Sites (NPCS) with documented presence of EDs considered thyroid carcinogens. Adjusted Standardized Incidence Ratios (SIRs), with their 90% confidence intervals, were computed by gender, and age-specific groups (aged 15-39 years, and 40 years or over) for each NPCS in the period 2006 to 2013. In the age group of 15-39 years, a significant excess of TC risk was found in two NPCSs in males; non-significant excess risks were observed in four NPCSs in males, and in five in females. In the age group of 40 years and over, significant excess risks were found in six NPCSs in males and in seven NPCSs in females; non-significant excess risks were identified in two NPCSs in males and females. The findings of several excesses in incidence, mainly observed in adults aged 40 years or over, are suggestive of a possible adverse effect associated with residence in NPCSs, even if a role of other factors cannot be excluded, due to the adoption of an ecological study design. Future analytical studies are needed to clarify if EDs are a TC risk factor for individuals living in NPCSs.

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan-Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

The inhabitants of Lazio, similarly to those of other Italian regions, have been historically exposed to the detrimental effects of an inadequate intake of iodine. The latter is a micronutrient essential for the biosynthesis of thyroid hormones (TH). Iodine deficiency is responsible for a number of adverse effects on human health known as iodine deficiency disorders (IDD), the most common of which worldwide are goiter and hypothyroidism. In order to reduce IDD, a national salt iodination program was started in Italy in 2005. In this article we reviewed the available data regarding iodine intake in the Lazio population before and after the introduction of the national salt iodination program, in order to evaluate its efficacy and the eventual problem(s) limiting its success. On the whole, the information acquired indicates that, following the introduction of the program, the dietary iodine intake in the Lazio population is improved. There is, however, still much work ahead to ameliorate the iodine prophylaxis in this region. In fact, although a generally adequate iodine intake in school-age children has been observed, there are still areas where a mild iodine insufficiency is present. Moreover, two independent epidemiological surveys on pregnant women evidenced a low urinary iodine concentration with respect to the reference range conceived by the World Health Organization. These findings demonstrate the need for greater attention to the iodine prophylaxis by health care providers (i.e., obstetricians, gynecologists, pediatricians, etc.), and the implementation of effective advertising campaigns aimed at increasing the knowledge and awareness of the favorable effects of iodine supplementation on population health., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

Objective: The World Health Organization, the United Nations Children's Fund, and the International Council for the Control of Iodine Deficiency Disorders recommend a median urinary iodine concentration (UIC) in pregnant women between 150 µg/L and 249 µg/L. In the present study, we evaluated whether in the urban area of Cassino (central Italy), after a national salt iodination program (30 mg/kg) was introduced in 2005, the increased demand of iodine during pregnancy was satisfied., Methods: Between January 2016 and April 2017, 99 pregnant women were enrolled to evaluate UIC in spot urine samples, serum level of thyrotropin, free thyroxine, antithyroglobulin and antithyroperoxidase autoantibodies, and thyroid volume by ultrasonography. Eighty clinically healthy non-pregnant women were evaluated as controls., Results: The median UIC was of 97.7 µg/L and 110.3 µg/L, respectively, in control and pregnant women. A significant increase (P < 0.001) of median thyroid volume was found in pregnant women, relative to control women, being, respectively, 10.4 mL (range 3.68-19.49 mL) and 7.16 mL (range 2.57-14.00 mL). A positive correlation was found between thyroid volume and anthropometric parameters, and an inverse correlation was identified between free thyroxine serum levels and anthropometric parameters., Conclusions: This observational study found that the majority of pregnant women and their fetuses appear not to be protected from the detrimental consequences of iodine deficiency. Therefore, the identification of new strategies to increase the knowledge and awareness of the general population regarding the beneficial effects of iodine supplementation during pregnancy is highly required., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5-1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves' disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s).

Establishment and maintenance of the apical-basal cell polarity, required for proper replication, migration, specialized functions and tissue morphogenesis, relies on three evolutionary conserved complexes: PAR, CRUMBS and SCRIBBLE. Loss of cell polarity/cohesiveness (LOP/C) is implicated in cancer progression, and members of the polarity complex have been described as either oncogenes or oncosuppressors. However, no information on their role in thyroid cancer (TC) progression is available. In the present study, we evaluated the gene expression of the PAR complex members aPKCι, PARD3α/β and PARD6α/β/γ in 95 papillary TC (PTC), compared to their normal matched tissues and in 12 anaplastic TC (ATC). The mRNA and protein levels of investigated genes were altered in the majority of PTC and ATC tissues. In PTC, univariate analysis showed that reduced expression of aPKCι, PARD3β and PARD6γ mRNAs is associated with increased tumor size, and the reduced expression of PARD3β mRNA is associated also with recurrences. Multivariate analysis demonstrated that the presence of lymph node metastasis at diagnosis and the reduced expression of PARD3β are independent risk factors for recurrences, with hazard ratio, respectively, of 8.21 (p=0.006) and 3.04 (p=0.029). The latter result was confirmed by the Kaplan-Meier analysis, which evidenced the association between decreased PARD3β mRNA levels and shorter disease-free interval. In conclusion, we demonstrated that the expression of PAR complex components is deregulated in the majority of PTC and there is a general trend towards their reduction in ATC tissues. Moreover, a prognostic value for the PARD3β gene in PTCs is suggested.

Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p < 0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy ( p = 0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly ( p = 0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk.

Objective: It has been established that iodine prophylaxis prevents endemic goiter. In this study we reported the amount of iodized salt sold by the retailers of Cassino, a city of central Italy. The aim of the study was to evaluate the effects of an iodine prophylaxis program started in 2005 on urinary iodine concentration (UIC) and thyroid volume (TV), and their correlation with anthropometric parameters in a population of schoolchildren., Methods: The study included 234 schoolchildren (119 girls and 115 boys) ages 13 to 14 y. Each student provided a morning urine sample for UIC determination, and TV was evaluated by ultrasonography. Body weight and height also were measured. Each participant completed a questionnaire reporting the presence of thyroid disease and the consumption of iodized salt and iodine-rich food., Results: The percentage of iodized salt sold by local markets was 42.4%. Median UIC in schoolchildren was 133.9 μg/L (range 33.2-819.5 μg/L), with 71 children having mild (range 50.1-99.9 μg/L) and 10 moderate (range 33.2-48.8 μg/L) iodine deficiency. Eleven children showed excessive iodine intake (range 300.4-819.5 μg/L). Median UIC was higher in children using iodized salt or consuming milk. Goiter prevalence was 3.8%. A positive correlation between TV and body weight, height, and surface was observed., Conclusions: The data reported may suggest the presence of an adequate iodine intake in the population of Cassino despite the low percentage of iodized salt sold by local retailers. This indicates that silent iodine prophylaxis through the consumption of iodine-rich or iodine-enriched food is of importance in the prevention of iodine deficiency disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Measurement of thyroglobulin (Tg) protein in the washout of the needle used for fine needle aspiration biopsy cytology (FNAB-C) has been shown to increase the sensitivity of FNAB-C in identifying cervical lymph node (CLN) metastasis from well-differentiated thyroid cancer (TC). In this study, we evaluated whether routine measurement of Tg protein (FNAB-Tgp), Tg mRNA (FNAB-Tgm) and calcitonin (CT) mRNA (FNAB-CTm) in the FNAB washout of CLN increases the accuracy of FNAB-C in the diagnosis of suspicious metastatic CLN., Methods: In this prospective study 35 CLN from 28 patients were examined. Histology showed metastatic papillary TC (PTC) in 26 CLN, metastatic medullary TC (MTC) in 3 CLN, metastatic anaplastic TC (ATC) in 3 CLN and 3 metastatic CLN from extra-thyroidal cancers., Results: The overall accuracy of FNAB-C was 84.4%, reaching 95.7% when the analysis was restricted to PTC. Both FNAB-Tgp and FNAB-Tgm compared favorably with FNAB-C and shown diagnostic performances not statistically different from that of FNAB-C. However, FNAB-Tgp and FNAB-Tgm/FNAB-CTm were found useful in cases in which cytology results were inadequate or provided diagnosis inconsistent with patient's clinical parameters., Conclusions: We demonstrated that FNAB-C, Tg/CT mRNA and Tg protein determination in the fine-needle washout showed similar accuracy in the diagnosis of metastatic CLN from TC. The results of this study suggest that samples for Tg protein and Tg/CT mRNA measurements from CLN suspicious for metastatic TC should be collected, but their measurements should be restricted to cases in which FNAB-C provides uninformative or inconsistent diagnosis with respect to patient's clinical parameters.

Genetic instability, a hallmark of solid tumors including thyroid cancers, is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumour progression. Over the last few years, the knowledge of the molecular processes controlling the mitotic phase of the cell cycle has increased considerably, and different mitotic proteins, whose expression or function has been found altered in human cancer tissues, have been associated to tumour genetic instability and aneuploidy. These include the three members of the Aurora kinase family (Aurora-A, -B and -C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. The genes encoding the Aurora kinases have been shown to induce cell malignant transformation, and their overexpression has been detected in several tumor derived cell lines and tissues, being often associated with a poor prognosis. Over the last decade, specific inhibitors of Aurora kinases exhibited in preclinical and early phase clinical studies a good therapeutic efficacy against several tumour types, including the highly aggressive anaplastic thyroid cancer and the medullary thyroid cancer. In the present review we'll first focus on the Aurora mitotic functions in normal cells; then we shall describe the main implications of their overexpression in the onset of genetic instability and consequent aneuploidy. We shall finally discuss on the effects of the functional inhibition of Aurora kinases on thyroid cancer cells growth and tumorigenicity.

Fine needle aspiration cytology (FNAC) is the more accurate diagnostic method for cervical lymph node (CLN) metastasis from differentiated thyroid cancers (DTC). However, FNAC diagnosis of cystic CLN is, in most cases, uninformative due to inadequate cellularity. Recently, thyroglobulin (Tg) detection in FNAC needle washout fluid has been shown to improve the diagnostic accuracy of FNAC, and its routine association with cytology is recommended. We here describe the case of a 20 yr old girl complaining of the recent appearance of palpable non-painful laterocervical nodes in the neck. Ultrasound examination revealed the presence of 3 cystic CLNs and 2 mixed thyroid nodules, with the larger one showing irregular margins. On the latter, and on 2 larger CLNs, FNAC was performed, and both Tg protein and mRNA were determined in the needle washout. The cytological analysis was not diagnostic for the two CLNs, while that of the thyroid nodule reported the presence of colloid and groups of thyrocytes with normal morphology. Both CLNs showed, however, high levels of Tg protein and were positive for Tg mRNA, suggestive of metastatic DTC. Based on these findings, the FNAC analysis was performed on the second smaller thyroid nodule suggesting (Tir4) the presence of PTC. The patient was then subjected to total thyroidectomy with lymph nodes resection of the central and homolateral compartments. The histological diagnosis confirmed the presence of a PTC in the small nodule and metastatic lymph nodes. In conclusion, this case confirms that the cytological diagnosis of cystic lymph nodes is challenging, and that the measurement of Tg protein and/or mRNA in the needle washout may overcome this limitation.

Graves' orbitopathy (GO) is the most common and important extrathyroidal manifestation of Flajani-Basedow-Graves' disease, with autoimmune etiology. In most cases they are mild forms, in 3-5% they are severe and progressive. For therapeutic purposes, it is classified according to the severity (mild, moderate-severe or sight threatening), to the activity (active if clinical activity score is >=3), and to the impact on quality of life. The choice of medical or surgical therapy depends on the activity of the disease. Therapy for mild GO consists of abolition of risk factors, local treatments, oral administration of selenium. Therapy for moderate-severe and active GO consists of administration of intravenous, oral, topic and local (retrobulbar, peribulbar and subconjunctival) glucocorticoids (GC). The therapy of choice, after careful selection of patients, is pulse therapy with intravenous GC, with 79% of response. Orbital radiotherapy is effective in 60% of cases; diabetes mellitus and hypertension are absolute contraindications. Contemporary administration of oral GC and orbital radiotherapy are more effective than single therapies. Marginal and not validated therapies are cyclosporine, somatostatin analogues, TNF-a inhibitors and rituximab. The treatment for dysthyroid optic neuropathy (DON) consists of combination of steroids, orbital radiotherapy and, if necessary, orbital decompression surgery. The surgical therapies are orbital decompression and rehabilitative surgery.

The urokinase plasminogen activator (uPA) system (uPAS) comprises the uPA, its cell membrane receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. The tumor-promoting role of PAS is not limited to the degradation of ECM and BM required for local diffusion and spread to distant sites of malignant cells, but widens to tumor cell proliferation, adhesion and migration, intravasation, growth at the metastatic site and neoangiogenesis. The relevance of uPAS in cancer progression has been confirmed by several studies which documented an increased expression of uPA, uPAR and PAI-1 in different human malignancies, and a positive correlation between the levels of one or more of them and a poor prognosis. For these reasons, the uPAS components have aroused considerable interest as suitable targets for anticancer therapy, and several pharmacological approaches aimed at inhibiting the uPA and/or uPAR expression or function in preclinical and clinical settings have been described. In the present manuscript, we will first glance at uPAS biological functions in human cancer progression and its clinical significance in terms of prognosis and therapy. We will then review the main findings regarding expression and function of uPAS components in thyroid cancer tissues along with the experimental and clinical evidence suggesting its potential value as molecular prognostic marker and therapeutic target in thyroid cancer patients.

Objectives: Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated., Materials and Methods: The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar., Results: Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines., Conclusions: Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment.

Simple rat models of acute and chronic colonic inflammation were used to study the behaviour in serum and mucosa of transglutaminase (TG), an enzyme recently found to be reduced in serum of patients with inflammatory bowel disease (IBD) and related to the activity index of the disease. In the first model the intraluminal administration of 400 mM lactic acid in the colon caused an acute inflammation resembling that of florid ulcerative colitis in humans. In the second, intraluminal administration of the hapten 2,4,6-trinitrobenzenesulphonic acid (TNB) (10 or 30 mg) in 0.25 ml of ethanol as a 'barrier breaker' produced a chronic inflammatory disease. The results showed a reduced TG activity in colon of rats in both acute and chronic induced colitis (447 +/- 75 versus 1344 +/- 59 mU/g protein (p less than 0.001) and 484 +/- 59 versus 1204 +/- 75 mU/g protein (p less than 0.001)). This decreased activity was related to the severity of mucosal damage, which was dose-dependent. Moreover, in severe colitis the immunohistochemistry showed a TG location in repairing tissue. Serum TG activity was decreased after TNB administration (1.36 +/- 0.05 versus 3.44 +/- 0.20 mU/ml (p less than 0.001)) but not after lactic acid treatment (3.97 +/- 0.11 versus 3.78 +/- 0.16 mU/ml). In summary, the reduction of TG activity in both tissue and serum when the damage is stabilized reflects the altered morphofunctional integrity of the colon and suggests that serum assay of this enzyme could be a simple marker of intestinal mucosal status in IBD.