Perchlorates in the treatment of hyperthyroidism and thyrotoxicosis: a comprehensive review.

INTRODUCTION: Perchlorates are ionic inhibitors antagonizing iodine transport into thyrocytes, hampering thyroid hormone synthesis. Nevertheless, perchlorates are not considered as first-line treatment in hyperthyroidism and thyrotoxicosis as compared to other pharmacological and non-pharmacological interventions. AIM: Reassessing the therapeutic role of perchlorates in hyperthyroidism and thyrotoxicosis throughout a systematic review of the Literature. METHODS: Guidelines were searched and examined to summarize current recommendations on the use of perchlorates in the management of hyperthyroidism. Randomized and non-randomized clinical trials were also searched and reviewed to summarize the efficacy/effectiveness and safety of perchlorates in hyperthyroidisms and thyrotoxicosis. RESULTS: The management of specific forms of hyperthyroidism was considered, including Graves' disease (GD) in non-pregnant adults, hyperthyroidisms in pregnancy, iodine media contrast-induced hyperthyroidism, amiodarone-induced hyperthyroidisms, and thyroid storm. Most of the reported studies had remarkable limitations in terms of study design (non-controlled trials, lack of blinding), low number of participants, and the lack of clinically relevant endpoints, such as cardiovascular events, cardiovascular mortality, and teratogenicity. Overall, perchlorates could be considered a second-line treatment after thionamides, radioiodine, and total thyroidectomy in both GD and hyperthyroidisms in pregnancy. The therapeutic potential of perchlorates alone or in combination with other agents could be considered a second-line treatment of iodine-related hyperthyroidisms and thyroid storm. CONCLUSION: Despite the low level of evidence, perchlorates could be considered in such specific forms of thyroid disorders, including iodine-induced hyperthyroidism and thyroid storm.

Lymph Node Ratio as a Predictive Factor of Persistent/Recurrent Disease in Patients With Medullary Thyroid Cancer: A Single-Center Retrospective Study.

OBJECTIVE: Thyroidectomy with neck lymph node dissection is curative for most patients with medullary thyroid cancer (MTC). Lymph node ratio (LNR, ie, the ratio between the metastatic and the removed lymph nodes) is a reliable parameter with which to estimate both disease extent and quality of neck dissection. The aim of this study was to investigate the prognostic role of LNR to predict persistent/recurrent disease in patients with MTC. METHODS: A single-center, retrospective study of a consecutive cohort of 95 patients with MTC treated with total thyroidectomy and neck dissection. Receiver operating characteristics curve analysis was performed to identify the LNR cut-off. RESULTS: LNR was positively associated with tumor size, preoperative and postoperative calcitonin values, postsurgery carcinoembryonic antigen values, persistent/recurrent disease, and the occurrence of distant metastases during follow-up. At multivariate analysis, persistent/recurrent disease was independently associated with the LNR value and was accurately predicted by a cut-off value of 0.12 (area under the curve = 0.85). Indeed, patients with LNR ≥0.12 had a higher probability of developing persistent/recurrent disease (79.3% vs 10.6%, odds ratio = 32.3, 95% CI = 9.8-106.4; P < .001) and distant metastasis (34.5% vs 3.0%, odds ratio = 16.8, 95% CI = 3.4-83.6; P < .001) than patients with LNR <0.12. The median time to progression was 15 months in patients with LNR ≥0.12 whereas it was not reached in patients with LNR <0.12 (hazard ratio: 7.18, 95% CI = 3.01-17.11, P < .001). CONCLUSIONS: LNR is a reliable prognostic factor to predict the risk of recurrence, persistence, and distant metastases in patients with MTC.

Effect of gluten-free diet on autoimmune thyroiditis progression in patients with no symptoms or histology of celiac disease: a meta-analysis.

Background: Hashimoto's thyroiditis (HT) is the most common autoimmune disease. HT may be associated with nonthyroidal autoimmune diseases, including celiac disease (CD) or other gluten-related conditions (GRC). In the last years, interest about gluten-free diet (GFD) has increased for its supposed extraintestinal anti-inflammatory effect; thus, many patients with HT initiate GFD on their own. Objectives: The aim of this meta-analysis is to examine all available data in literature about the effect of a GFD on TgAb, TPOAb, TSH, FT4, and FT3 levels in patients with HT and no symptoms or histology of CD. Methods: The study was conducted according to MOOSE (Meta-analysis Of Observational Studies in Epidemiology). The search was performed on databases PubMed and Scopus. The last search was performed on 7 February 2023. Quality assessment was performed. Meta-analyses were performed using the random-effect model. Hedges' g was used to measure the effect size (ES). Statistical analyses were performed using StataSE 17. Results: The online search retrieved 409 articles, and 4 studies with a total of 87 patients were finally included for quantitative analysis. The risk of bias was generally low. The mean period of GFD was almost 6 months. The meta-analyses showed reduction in antibody levels with ES: -0.39 for TgAb (95% CI: -0.81 to +0.02; p = 0.06; I² = 46.98%) and -0.40 for TPOAb (95% CI: -0.82 to +0.03; p = 0.07; I² = 47.58%). TSH showed a reduction with ES: -0.35 (95% CI: -0.64 to -0.05; p = 0.02; I² = 0%) and FT4 showed an increase with ES: +0.35% (95% CI: 0.06 to 0.64; p = 0.02; I² = 0%). FT3 did not display variations (ES: 0.05; 95% CI: -0.38 to +0.48; p = 0.82; I² = 51%). The heterogeneity of TgAb, TPOAb, and FT3 data was solved performing sub-analyses between patients with or without GRC (TgAb p = 0.02; TPOAb p = 0.02; FT3 p = 0.04) and only for FT3, performing a sub-analysis between patients taking and not taking LT4 (p = 0.03). Conclusion: This is the first meta-analysis investigating the effect of GFD on HT. Our results seem to indicate a positive effect of the gluten deprivation on thyroid function and its inflammation, particularly in patients with HT and GRC. However, current lines of evidence are not yet sufficient to recommend this dietary approach to all patients with a diagnosis of HT.

Levothyroxine therapy, calculated deiodinases activity and basal metabolic rate in obese or nonobese patients after total thyroidectomy for differentiated thyroid cancer, results of a retrospective observational study.

INTRODUCTION: Therapy for hypothyroid obese patients is still under definition since the thyrotropin-stimulating hormone (TSH) level is a less reliable marker of euthyroidism than nonobese patients. Indeed, TSH levels positively correlate with body mass index (BMI), and this increase may be a compensatory mechanism aimed at increasing energy expenditure in obese people. In contrast, the correlation of BMI with thyroid hormone levels is not completely clear, and conflicting results have been obtained by several studies. The L-T4 replacement dose is more variable in obese hypothyroid patients than in nonobese patients, and a recent study indicated that the L-T4 replacement dose is related to lean body mass in obese thyroidectomized patients. We aimed to study the correlations of L-T4-administered dose, thyroid hormone levels and TSH secretion with basal metabolic rate (BMR) and total calculated deiodinase activity (GD) in obese and nonobese athyreotic patients. We also looked for individualized L-T4 replacement dose set points to be used in clinical practice. METHODS: We studied retrospectively 160 athyreotic patients, 120 nonobese and 40 obese. GD was calculated by SPINA Thyr 4.2, the responsiveness of the hypothalamic/pituitary thyrotrope by Jostel's thyrotropin (TSH) index and BMR by the Mifflin-St. Jeor formula, the interplay of GD and BMR with L-T4, thyroid hormones and TSH index (TSHI) was also evaluated. RESULTS: In our study, the L-T4 dose was an independent predictor of GD, and approximately 30% of athyreotic patients under L-T4 therapy had a reduced GD; FT4 levels were higher and negatively modulated by BMR in obese athyreotic patients respect to nonobese, in these patients a T4 to T3 shunt, in terms of TSHI suppression is observed suggesting a defective hypothalamic pituitary T4 to T3 conversion and a resistance to L-T4 replacement therapy. CONCLUSIONS: L-t4 dose is the most important predictor of GD, BMR modulates T4 levels in obese athyreotic patients that are resistant to L-T4 replacement therapy.

Different FT3/TSH correlation in acquired and congenital hypothyroid patients reveals a different hypothalamic set-point.

OBJECTIVE: To understand differences in thyroid hormone replacement therapy with levo-thyroxine (l-T4) between acquired and congenital hypothyroid (CH) patients. DESIGN: We compared biochemical thyroid parameters between euthyroid subjects (EU) and both CH adult patients and thyroidectomized patients (TP) under replacement therapy. PATIENTS AND MEASUREMENTS: A retrospective analysis was performed on a series of 98 consecutive adult CH patients (27 males and 71 females) with a median age of 24 years (range 18-58). Serum TSH, FT3, FT4, l-T4 dose and body weight were assessed. For comparison purposes, large series of 461 TP for thyroid cancer and 1852 EU followed at our Thyroid Clinic were used as control groups. RESULTS: The daily weight-based l-T4 dose was significantly higher in CH than TP group (1.9 vs. 1.7 mcg/kg, p = .03). FT3/FT4 ratio was significantly higher in the EU group, intermediate in CH and lower in TP groups (0.32, 0.28 and 0.24, respectively). Linear regression analysis displayed an inverse correlation between FT4 and TSH in all the groups. An inverse correlation between FT3 and TSH was observed in the TP group, but not in the EU and CH group suggesting that CH patients, under replacement therapy, display biochemical thyroid parameters similar to EU subjects. CONCLUSIONS: Adult CH patients require a higher daily l-T4 dose than adult TP. However, the different correlation of TSH and FT3 values between CH and TP patients suggests an adaptive and different hypothalamic-pituitary-thyroid axis regulation that may depend on the early timing of the onset of hypothyroidism in CH.

Prognostic Effect of Lymph Node Metastases and Mesenteric Deposits in Neuroendocrine Tumors of the Small Bowel.

Well-differentiated, low-grade neuroendocrine tumors (NETs) are the most frequent tumor types of the small bowel. Despite their generally indolent growth patterns and grade, these tumors tend to metastasize; indeed, at presentation, approximately 50% show nodal metastases and 30% of patients have distant metastases, even though they potentially show long survival. Little is available in the literature concerning the optimal nodal yield in small-bowel resections, and the clinical significance of nodal metastases and lymph node ratio (LNR) at this site is still debated. The aim of this review, through a systematic literature search, is to explore and analyze data regarding nodal status, adequacy of lymphadenectomy, and LNR on the prognosis of small bowel NETs using defined end points (progression-free survival, recurrence-free survival, and overall survival). Some surgical series have demonstrated that extended regional mesenteric lymphadenectomy, together with primary tumor resection, is associated with improved patient survival, and LNR is proving a prognostically important parameter. The new feature of mesenteric tumor deposits (MTDs; neoplastic deposits found in the mesenteric perivisceral adipose tissue that are not LN associated) seems to be a better prognostic predictor in small-bowel NETs compared to nodal metastases, and this feature is explored and critiqued in this review. In particular, increasing number of tumor deposits is correlated with increased risk of disease-specific death, and MTDs seem to correlate with peritoneal carcinomatosis.

The Effects of Radioligand Therapy on Quality of Life and Sexual Function in Patients with Neuroendocrine Neoplasms.

Peptide receptor radionuclide therapy (PRRT), also called radioligand therapy, is an effective antitumoral treatment in patients with neuroendocrine neoplasm (NEN). It improves the patient's health-related quality of life (HRQoL), which is evaluated by self-assessment questionnaires. The aim of this narrative review was to report the current knowledge on the changes of HRQoL and sexual function in patients with NEN treated with PRRT. We conducted a literature search of the PubMed, Embase, and APA PsycInfo databases. We selected 15 studies (12 for HRQoL and three for sexual function). After treatment with PRRT, patients with NEN experienced a significant improvement in their global health status, disease-related worries, social and emotional functioning, and cancer-related symptoms such as fatigue and diarrhea. Other symptoms, such as nausea/vomiting, dyspnea, and constipation, as well as the economic impact, were unchanged by radioligand therapy. Data on sexual function were not equally promising; only a few studies investigated this issue by using appropriate questionnaires in patients treated with radioligand therapy. Therefore, additional studies are needed to draw a conclusion about the benefits from PRRT on sexual function.

Heavy Metals in the Environment and Thyroid Cancer.

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the "normal" range.

Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells dispersed in different organs. Receptor tyrosine kinases are a subclass of tyrosine kinases with a relevant role in several cellular processes including proliferation, differentiation, motility and metabolism. Dysregulation of these receptors is involved in neoplastic development and progression for several tumors, including NENs. In this review, we provide an overview concerning the role of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) system in the development and progression of NENs, the occurrence of fibrotic complications and the onset of drug-resistance. Although no specific FGFR kinase inhibitors have been evaluated in NENs, several clinical trials on multitarget tyrosine kinase inhibitors, acting also on FGF system, showed promising anti-tumor activity with an acceptable and manageable safety profile in patients with advanced NENs. Future studies will need to confirm these issues, particularly with the development of new tyrosine kinase inhibitors highly selective for FGFR.

Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.

BACKGROUND: Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome. CASE PRESENTATION: A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of 99mTc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of 99mTc-pertechnatate and the presence of a "cool" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion. CONCLUSION: We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or

The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer.

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.

Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression.

Previous reports indicate that selenium supplementation may be useful to reduce cell oxidative stress. In particular, selenium may decrease the level of thyroid autoantibodies in patients with Hashimoto's thyroiditis (HT). Recent studies also indicate that myo-inositol may have beneficial effects on thyroid function in patients with HT. Hence, the aim of the present study is to evaluate whether myo-inositol may enhance the protective effect of selenium on HT progression to hypothyroidism. The study was designed as observational and retrospective. Thyroid hormones were evaluated in patients with HT who were either euthyroid or subclinically hypothyroid. These patients were subdivided into three groups: untreated, treated with selenomethionine alone (Se-meth: 83 µg/day) and treated with Se-meth plus myo-inositol (Se-meth + Myo-I: 83 µg/day + 600 mg/day). Outcome evaluation was performed at baseline and after 6 and 12 months of treatment. High-resolution ultrasound of the thyroid gland was performed to evaluate changes in thyroid echoic pattern during the study. Compared to baseline, levels of thyroid-stimulating hormone (TSH) increased significantly in untreated patients but decreased by 31% and 38%, respectively, in those treated with Se-meth and Se-meth + Myo-I. Moreover, in the latter group the TSH reduction was observed earlier than in the Se-meth-treated group. Densitometric analysis of thyroid ultrasonography showed an echoic pattern improvement in both treated groups compared to untreated patients, although this difference was not statistically significant. Thus, Se-meth treatment is effective in patients with HT and its effect may be improved in combination with Myo-I through earlier achievement of TSH levels closer to physiological concentrations.

Corticosteroid Pulse Therapy for Graves' Ophthalmopathy Reduces the Relapse Rate of Graves' Hyperthyroidism.

Background: A course of anti-thyroid drugs (ATD) is the most common first line treatment for Graves' hyperthyroidism. However, hyperthyroidism relapse is frequent (30-70%). Due to the autoimmune nature of Graves' disease, the immunosuppressive treatment used for active Graves' orbitopathy (GO) may reduce the relapses after ATD discontinuation. Objective: To evaluate the recurrence rate in Graves' patients who, in addition to standard ATD, were treated or not treated with parenteral methylprednisolone (MPDS) for GO. Methods: Single-center retrospective study in a continuous series of 162 newly diagnosed Graves' patients, with or without GO, all gone into remission and followed-up until hyperthyroidism recurrence or at least 4 years after ATD discontinuation. Patients with moderate-severe active GO underwent middle dose MPDS treatment according to the EuGoGo guidelines. Cox proportional-hazard model was used to comparatively evaluate the risk of recurrence and the predictive factors in patients treated or not treated with MPDS pulse therapy. Results: MPDS treatment was the most significant factor that independently correlated with a reduced risk of hyperthyroidism relapse (HR = 0.53, 95% C.I. = 0.31-0.89). FT3 and female sex were also independent protective factors, while age almost reached the significance level, p = 0.062. The efficacy of MPDS was very high in patients aged <40 years (42.1% decrease in relapses, p < 0.01) but it was not significant in older patients. Discussion: Our study found that after ATD discontinuation the frequency of Graves' hyperthyroidism relapse was reduced in patients treated with MPDS pulse therapy for GO. This effect was more marked in young patients.

Increased Thyroid Cancer Incidence in Volcanic Areas: A Role of Increased Heavy Metals in the Environment?

Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause-effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

PURPOSE: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs. METHODS: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis. RESULTS: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis. CONCLUSIONS: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.

Fathoming the link between anthropogenic chemical contamination and thyroid cancer.

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.

Concentration of Metals and Trace Elements in the Normal Human and Rat Thyroid: Comparison with Muscle and Adipose Tissue and Volcanic Versus Control Areas.

Background: The concentration of trace elements and metals in the thyroid is the result of exposure, uptake, retention, and clearance. The specificity and selectivity of thyroid capacity to concentrate these elements relative to other tissues are not known. To obtain this information, we measured the tissue concentration of 26 elements in the thyroid, muscle, and fat of euthyroid human subjects and also in normal rats. Methods: At programmed surgery, small (<1 g) tissue fragments were collected in 77 euthyroid subjects. Macroscopically normal thyroid tissue, sternothyroid muscle, and neck subcutaneous fat samples were excised, and thyroid tissue was confirmed to be morphologically normal through microscopy. Tissue specimens (thyroid, hindlimb muscle, and abdominal fat) were also obtained from normal rats. Measurements of trace elements were performed on tissues using inductively coupled plasma mass spectrometry (DRC-ICP-MS). Results: Only 19 of the 26 investigated elements were measurable as 7 elements were below the limit of detection. The ranking concentration in human thyroid tissue, not considering iodide, indicated that Zn, Br, Cu, Cr, Se, and Mn represented over 95% of the measured elements. A similar ranking was observed in the rat thyroid. A comparison with other tissues indicated that in addition to I, also Br, Mn, Se, and Sn were significantly more concentrated in the thyroid, and this was also the case for the recognized carcinogens As, Cd, and Hg. As and Hg, but not Cd (which was not detectable in any of the rat tissues), were also more concentrated in the rat thyroid. Since human thyroid specimens were also obtained from residents of a volcanic area, where environmental pollution may cause human biocontamination, we compared the trace element concentration in specimens from the volcanic area with controls. Many trace elements were slightly, but not significantly, increased in the volcanic area specimens. Conclusions: In the normal human thyroid, many trace elements, including Br, Mn, Se, and Sn, and the recognized carcinogens, As, Cd, and Hg, are significantly more concentrated than in muscle and fat of the same individual. Similar data were observed in rats. The reason for the differential element accumulation in the thyroid is unclear; a better understanding may be useful to further clarify thyroid biology.

Combined use of sonographic and elastosonographic parameters can improve the diagnostic accuracy in thyroid nodules at risk of malignancy at cytological examination.

BACKGROUND: Thyroid nodules diagnosed as Thy3B at fine-needle aspiration biopsy have a relevant risk of malignancy (15-30%) and are usually addressed to surgery. However surgery will result unnecessary in most cases. The present study aims at evaluating the possible increase of diagnostic accuracy for predicting malignancy using novel sonographic and elastographic parameters. METHODS: In fifty patients undergoing thyroidectomy because of a Thy3B thyroid nodule, sonographic and elastosonographic evaluation was carried out by single operator before surgery. Five sonographic parameters (echogenicity, irregular margins, microcalcifications, intra-nodule blood flow and its irregularity) and two elastosonographic parameters (intra-nodule stiffness and its extension to adjacent tissue) were considered. After obtaining histological diagnosis, diagnostic accuracy was calculated. RESULTS: When the two procedures were analyzed separately, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were 100%, 85%, 63% and 100% for ultrasonography and 60%, 92.5%, 67%, 90% for elastrosonography, respectively. The newly introduced evaluation procedures increased sensitivity. When a combined sonographic and elastosonographic evaluation was introduced, diagnostic accuracy was significantly improved: when ≥4 out of the seven parameters indicated were present, the risk of malignancy was very high (sensitivity 100%, specificity 92.55%, PPV 77%, NPV 100%). CONCLUSIONS: A novel combined sonographic and elastosonographic parameter evaluation improved diagnostic accuracy for identifying thyroid nodules suspicious of malignancy.