Iodine status and supplementation in pregnancy: an overview of the evidence provided by meta-analyses.

Iodine supplementation during pregnancy in areas with mild-moderate deficiency is still a matter of debate. The present study aimed at systematically reviewing currently available evidences provided by meta-analyses with the aim to further clarify controversial aspects regarding the need of iodine supplementation in pregnancy as well as to provide guidance on clinical decision-making, even in areas with mild-moderate deficiency. Medline, Embase and Cochrane search from 1969 to 2022 were performed. For the purpose of this review, only studies containing meta-analytic data were selected. A total of 7 meta-analyses were retrieved. Four meta-analyses evaluated the relationship between iodine status during pregnancy and neonatal and maternal outcomes suggesting the existence of a U-shaped correlation between iodine status and several maternal and neonatal consequences, especially if iodine status is evaluated at the beginning of pregnancy. Three meta-analyses evaluating the results of intervention trials failed to provide straightforward conclusions on the benefits of iodine supplementation in pregnant women in areas with mild-moderate iodine deficiency. Although evidence coming from meta-analyses suggests a role of iodine status during pregnancy in determining maternal and child outcomes, results of meta-analyses of intervention trials are still controversial. Several factors including, degree of iodine deficiency, and pooling studies conducted in areas with different iodine intake, may account for the lack of benefits reported by meta-analyses of intervention trials. More high-quality, randomized, controlled trials including information on timing, dose and regimen of iodine supplementation are needed to further elucidate this issue.

Determination of the quality of lipoproteins by Raman spectroscopy in obese and healthy subjects.

Lipoproteins (LPs) are multimolecular complexes of lipids and proteins responsible for transporting fatty acids, cholesterol, and micronutrients (carotenoids) through the body. The quantification of triglycerides and cholesterol carried by lipoproteins is a leading clinical parameter to assess the increased risk of cardiovascular events. However, in recent times, the study of the overall "quality" of lipoproteins, defined by their biochemical composition and oxidation state, has emerged as necessary to improve the definition of the cardiovascular risk. In this work, we present Raman spectroscopy (RS) as an effective method to immediately detect the functional groups relative to the principal biochemical components and the level of unsaturated lipids present in LPs. Furthermore, we show how RS can reveal the differences in the biochemical composition and oxidation state of LPs extracted from a cohort of obese patients (Ob) and a control group of healthy subjects (HC). In particular, RS revealed how low-density lipoproteins (LDLs) from obese patients are enriched in triglycerides and more oxidized than those from the control group, while high-density lipoproteins (HDLs) from Ob patients were depleted in cholesterol and phospholipids. RS analysis also allowed the study of the relationship between the levels of carotenoids present in the different classes of LPs highlighting how this parameter depends on the disease severity. Overall, these results demonstrated that RS is a viable approach for quickly and effectively gaining information on LPs' biochemical composition and oxidation state, providing an immediate measure of their quality. Besides, RS further proved the role of LPs in obesity and metabolic dysfunctions.

A unique presentation of Graves' disease in a pregnant woman with severe hypothyroidism.

BackgroundGraves' disease occurrence during pregnancy is not a frequent event, showing an incidence of 0.2-0.4% in unselected pregnant women. Depending on their functional properties, TSH-receptor antibodies can induce hypothyroidism or hyperthyroidism. Recognizing the signs of altered thyroid function is essential to prevent possible complications on the fetus.Materials and methodsThe case of a pregnant woman without previous history of thyroid disease presenting with severe overt hypothyroidism during the first trimester is reported. Levothyroxine therapy was started and 6 weeks later overt hyperthyroidism was observed. TRAb were detected at high titers. Levothyroxine was withdrawn and low dose methimazole was started. Serial obstetric ultrasound scans were negative for indirect signs of fetal thyroid dysfunctions and no fetal goiter was visualized throughout pregnancy. Spontaneous delivery occurred without complications at 39 weeks of gestation. In the post-partum, severe overt hypothyroidism recurred, thus methimazole was discontinued and levothyroxine was restarted. TRAb persisted at high levels. The infant experienced a transient thyrotoxicosis, which fully resolved in three months with normalization of thyroid function and negativization of TRAb levels.ResultsThe present case report allows us to overview the challenges related to the management of hypo and hyperthyroidism in patients with high TRAb levels, requiring strict monitoring aimed at early detection of both maternal and fetal consequences.ConclusionsThis case underlines the importance of close follow-up and the need of collaboration in a multidisciplinary team when Graves's disease is diagnosed in a pregnant woman to prevent adverse neonatal outcomes.

Risk factors, awareness of disease and use of medications in a deprived population: differences between indigent natives and undocumented migrants in Italy.

BACKGROUND: Undocumented migrants experience many health problems; a comparison with a suitable control group of natives living in the same socio-economic conditions is still lacking. METHODS: Demographic data and data on risk factors, chronic conditions and dietary habits were obtained for 6933 adults (2950 Italians and 3983 undocumented migrants) receiving medical assistance from 40 non-governmental organizations all over the country. RESULTS: Attributed to the fact that these were unselected groups, differences were found in their demographic features, the main ones being their marital status (singles: 50.5% among Italians and 42.8% among migrants; P < 0.001). Smokers were more frequent among Italians (45.3% versus 42.7% P = 0.03); the same happened with hypertension (40.5% versus 34.5% P < 0.001). Migrants were more often overweight (44.1% versus 40.5% P < 0.001) and reporting a chronic condition (20.2% versus 14.4% P < 0.001). Among those on medications (n = 1354), Italians were fewer (n = 425) and on different medications. Differences emerged also in dietary habits. CONCLUSIONS: Differences in health conditions exist between native-borns and undocumented migrants, not because of a bias related to socio-economic conditions. Further studies are needed to design sustainable health policies and tailored prevention plans.

Basal and longitudinal changes in serum levels of TSH in morbid obese patients experiencing failure or success of dietary treatment.

PURPOSE: The relationship between thyroid function and obesity is a widely investigated one. The impact of thyroid hormones in determining the outcome of dietary/lifestyle interventions remains to be fully elucidated. The aim of this study was to compare basal and post dietary-intervention circulating thyroid-function parameters, lipid profile and fasting-glucose in euthyroid obese patients according to a success or failure of a dietary intervention program. METHODS: In a retrospective longitudinal case-control study we enrolled 50 euthyroid obese patients who experienced a success in dietary intervention, as defined by a BMI reduction of at least 5% from baseline (Success Group) and 50 sex and age-matched euthyroid obese patients who experienced failure in dietary intervention as defined by either stable or increased body weight throughout the follow-up (Failure Group). Serum thyroid function parameters and metabolic profile at baseline and at the end of follow-up were collected. RESULTS: At baseline, the two groups showed similar BMI, total-cholesterol, HDL-cholesterol and fasting-blood-glucose, but patients in Success Group had a significantly higher TSH as compared with Failure Group (2.20 ± 0.97 vs 1.66 ± 0.73, respectively, p < 0.001). Throughout a mean follow-up of 21.4 months TSH significantly decreased in Success Group (2.20 ± 0.97 vs 2.06 ± 0.98; p = 0.029) and increased in Failure Group (1.63 ± 0.72 vs 2.01 ± 0.99; p < 0.001). Multiple regression analysis showed that the outcome of the dietary intervention was significantly and independently related to baseline BMI (0.925; 0.861-0.993), age (0.957; 0.922-0.993), TSH (0.531; 0.290-0.973) and TSH-changes (1.011; 1.000-1.022) during follow-up. CONCLUSIONS: Baseline serum TSH level is related to the final outcome of a dietary intervention program in obese patients. LEVEL OF EVIDENCE III: Evidence obtained from a retrospective cohort or case-control analytic studies.

TNF-α increases the membrane expression of the chemokine receptor CCR6 in thyroid tumor cells, but not in normal thyrocytes: potential role in the metastatic spread of thyroid cancer.

The chemokine receptor CCR6, selectively bound by CCL20, is involved in the metastatic spread of cancer cells. Tumor necrosis factor-α (TNF-α) displays a complex pro-tumorigenic actions, but it is unknown whether this cytokine could modulate the expression of chemokine receptors in thyroid tumors. The membrane expression of CCR6 was assessed by flow cytometry and immunofluorescence, in primary cultures of normal human thyroid (NHT) cells and in thyroid cancer cell lines (TPC-1 and BCPAP), both in basal conditions and after stimulation with TNF-α. In basal conditions, CCR6+ cells were virtually absent in NHT cells (0.4 ± 0.4 %), while they were detected in TPC-1 (23.6 ± 6.6 %) and in BCPAP (12.9 ± 9.4 %) tumor cells (ANOVA F: 10.534; p < 0.005). The incubation with TNF-α significantly increased the percentage of CCR6+ cells in TPC-1 (23.6 ± 6.6 % vs. 33.1 ± 8.7; p < 0.033) and in BCPAP (12.9 ± 9.4 % vs. 18.1 ± 11.5; p < 0.030), but not in NHT (0.4 ± 0.4 % vs. 0.2 ± 0.3; NS) cells. The magnitude of the TNF-α effect was similar for TPC-1 and BCPAP (∼40 % vs. baseline) cells. TPC-1 cells were characterized by a greater amount of CCR6 per cell as compared with BCPAP cells, both in basal conditions (148.3 ± 33.7 fluorescence intensity vs. 102.5 ± 22.1 p < 0.016) and after TNF-α stimulation (147.8 ± 46.3 fluorescence intensity vs. 95.3 ± 18.5; p < 0.025). Cell migration assays showed that TNF-α treatment significantly increased the rate of migrated cells in those cells in which it also increased the membrane expression of CCR6 (TPC-1 and BCPAP) as compared to basal condition (p < 0.05 for both TPC-1 and BCPAP cells). No effect was observed in NHT cells in which TNF-α stimulation had no effect in terms of CCR6 expression. We first report that TNF-α enhances the expression of CCR6 in thyroid tumor cells, thus providing evidence that TNF-α increases the metastatic potential of thyroid tumors.

GENDER INFLUENCES THE CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF GRAVES DISEASE.

OBJECTIVE: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD. METHODS: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated. RESULTS: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset. CONCLUSION: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD. ABBREVIATIONS: ATD = antithyroid drug FT3 = free triiodothyronine FT4 = free thyroxine GD = Graves disease GO = Graves orbitopathy RAI = radioiodine TRAb = thyroid-stimulating hormone-receptor antibody TSH = thyroid-stimulating hormone.

Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation.

CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.). Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL) alone or in combination with TNF-α (10 ng/mL) for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; p < 0.00001) and the TNFα-stimulated (ANOVA F: 15.309; p < 0.00001) CXCL8 secretions in BCPAP but not in TPC-1 cells (NS). On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP (p < 0.05) and TPC-1 (p < 0.05) cells. Transwell migration assay showed that (i) CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii) IFNγ significantly reduced the migration only of BCPAP cells; and (iii) CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line.

Anti-Mullerian hormone as a predictor of ovarian reserve in ART protocols: the hidden role of thyroid autoimmunity.

BACKGROUND: Protocols of controlled ovarian hyper-stimulation (COH) require, as a crucial step, the identification of reliable predictors of ovarian reserve. Anti-Mullerian hormone (AMH) is one of the most reliable predictors of ovarian reserve but other factors including autoimmune thyroid diseases (ATD) have been associated with reduced fertility and poor COH outcome. Aim of the present study was to evaluate the relationship between ATD and AMH, and their role on the outcome of COH. METHODS: The study group included 288 sub-fertile euthyroid women aged less than 40 years attending a single center for Reproductive Medicine. Among them, 55 were ATD-positive and 233 ATD-negative. The serum levels of AMH, FSH, LH, estradiol (E2), and TSH were measured before COH. The ratio between serum E2 concentration on the day of oocytes pick-up and the total dose of administered recombinant FSH (r-FSH) (E2/r-FSH ratio) was calculated. RESULTS: The serum levels of AMH were significantly related to E2/r-FSH ratio, total dose of r-FSH and number of M II oocytes, both in ATD-positive and ATD-negative women. Within the low stratum of AMH levels, the presence of ATD did not further affect the outcome of COH. When the serum levels of AMH were in the high stratum, the presence of ATD significantly affected the E2/rFSH ratio, the total dose of r-FSH and the number of M II oocytes. CONCLUSIONS: The probability of a poor response to COH is high, and independent from ATD, in women with low AMH serum levels. In women with a good ovarian reserve, as assessed by high AMH serum levels, the presence of ATD impairs the outcome of COH.

A male patient with acromegaly and breast cancer: treating acromegaly to control tumor progression.

BACKGROUND: Acromegaly is a rare disease associated with an increased risk of developing cancer. CASE PRESENTATION: We report the case of a 72-year-old man who was diagnosed with acromegaly (IGF-1 770 ng/ml) and breast cancer. Four years before he suffered from a colon-rectal cancer. Pituitary surgery and octreotide-LAR treatment failed to control acromegaly. Normalization of IGF-1 (97 ng/ml) was obtained with pegvisomant therapy. Four years after breast cancer surgery, 2 pulmonary metastases were detected at chest CT. The patient was started on anastrozole, but, contrary to medical advice, he stopped pegvisomant treatment (IGF-I 453 ng/ml). Four months later, chest CT revealed an increase in size of the metastatic lesion of the left lung. The patient was shifted from anastrozole to tamoxifen and was restarted on pegvisomant, with normalization of serum IGF-1 levels (90 ng/ml). Four months later, a reduction in size of the metastatic lesion of the left lung was detected by CT. Subsequent CT scans throughout a 24-month follow-up showed a further reduction in size and then a stabilization of the metastasis. CONCLUSIONS: This is the first report of a male patient with acromegaly and breast cancer. The clinical course of breast cancer was closely related to the metabolic control of acromegaly. The rapid progression of metastatic lesion was temporally related to stopping pegvisomant treatment and paralleled a rise in serum IGF-1 levels. Normalization of IGF-1 after re-starting pegvisomant impressively reduced the progression of metastatic breast lesions. Control of acromegaly is mandatory in acromegalic patients with cancer.

Maximal stiffness evaluation by real-time ultrasound elastography, an improved tool for the differential diagnosis of thyroid nodules.

OBJECTIVE: The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size. METHODS: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1, <1 cm; G2, 1-2 cm; G3, >3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. RESULTS: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P<.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P<.0001, respectively) and in the G1 and G2 subgroups. CONCLUSION: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.

Body weight changes in a large cohort of patients subjected to thyroidectomy for a wide spectrum of thyroid diseases.

OBJECTIVE: Patients undergoing thyroidectomy often complain of weight gain. The aim of this study was to longitudinally evaluate body-weight changes in patients thyroidectomized for euthyroid and hyperthyroid conditions in order to identify predictive factors. METHODS: Anthropometric data and thyroid function parameters were retrospectively reviewed for 267 thyroidectomized patients before and 40 to 60 days and 9 months after surgery. Presurgery diagnoses included benign (Graves disease, nodular toxic goiter, nodular nontoxic goiter) and malignant (differentiated thyroid cancer) conditions. RESULTS: Mean preintervention weight of the entire study group significantly increased (P<.0001) 9-months after thyroidectomy, from 70.8 ± 16.0 to 72.5 ± 16.4 kg. Body weight increased in 156 (58.4%) patients, decreased in 59 (22.1%) patients, and remained stable in 52 (19.5%) patients. A multiple regression model was constructed by entering the percentage of body-weight change 9 months postsurgery as the dependent variable and age, sex, presurgery body mass index, percentage of weight change 40 to 60 days postsurgery, presurgery thyroid-stimulating hormone (TSH) level, TSH level 40 to 60 days postsurgery, TSH level 9 months postsurgery, thyroid disease driving thyroidectomy, and type of surgical intervention as the covariates. No significant relationship was found for any of the covariates tested, with the exception of percentage of body-weight change at 40 to 60 days postsurgery (correlation coefficient, 0.869; [95% confidence interval, 0.692 to 1.046; P<.0001]). CONCLUSION: Thyroidectomy is associated with a significant increase in body weight, which is not limited to patients with Graves disease. Postsurgery TSH levels do not account for subsequent body-weight changes. Short-term changes (40 to 60 days postsurgery) in body weight are highly predictive of the outcome at 9 months, suggesting that early factors related to thyroidectomy per se might play a role.

Inflamm-ageing: How cytokines and nutrition shape the trajectory of ageing.

Population ageing is increasing in prevalence in most developed countries. Ageing is the decline of functional properties at the cellular, tissue, and organ level. Biochemical changes that occur in all organisms that experience biological ageing are referred to as the "Hallmarks of ageing". Inflammation is a common denominator of the hallmarks of ageing, being mechanistically involved in most age-related health consequences. Inflamm-ageing refers to age-related changes in the inflammatory and immune systems which somehow drive the ageing process towards healthy or unhealthy ageing. Current evidences, support that, reversing the age-related pro-inflammatory status of inflamm-ageing, is able to modulate most hallmarks of ageing. Inflamm-ageing is associated with increased levels of pro-inflammatory molecules (e.g. cytokines, chemokines), ultimately producing a chronic low-grade inflammatory state typically observed in older individuals. It is commonly accepted that, the balance between pro- and anti-inflammatory cytokines/chemokines is one of the factors determining whether healthy or unhealthy ageing occurs. Malnutrition and nutritional imbalances, are highly prevalent in the elderly, playing a role in driving the balance of pro- and anti-inflammatory immunoactive molecules. In particular, malnutrition is a major risk factor for sarcopenia, a phenomenon characterized by loss of muscle mass, which is often referred to as the biological basis for frailty. Given the close relationship between malnutrition and sarcopenia, there is also evidence for a link between malnutrition and frailty. Indeed, changes in cytokine/chemokine levels in elderly patients with malnutrition were demonstrated. The demonstration that specific cytokines play a role in modulating appetite and nutrient sensing and taste reception, provided further evidence for the existence of a link between inflamm-ageing, nutrition and cytokines in shaping the trajectory of ageing. The present review will overview current evidence supporting the role of specific circulating cytokines and chemokines in the relationship between ageing, inflammation, and malnutrition.

Do PFCAs drive the establishment of thyroid cancer microenvironment? Effects of C6O4, PFOA and PFHxA exposure in two models of human thyroid cells in primary culture.

BACKGROUND: Exposure to environmental pollutants is suspected to be one of the potential causes accounting for the increase in thyroid cancer (TC) incidence worldwide. Among the ubiquitous pollutants, per-polyfluoroalkyl substances (PFASs), were demonstrated to exert thyroid disrupting effects. Perfluoroalkyl carboxylates (PFCAs) represent a subgroup of PFAS and include perfluoro carboxylic acids (PFOA and PFHxA) and perfluoropolyether carboxylic acid (C6O4). The potential relationship between exposure to PFCAs and TC was not yet fully elucidated. This in vitro study investigated whether certain PFCAs (C6O4, PFOA, and PFHxA) can influence the composition of TC microenvironment. METHODS: Two models of normal thyroid cells in primary cultures: Adherent (A-NHT) and Spheroids (S-NHT) were employed. A-NHT and S-NHT were exposed to C6O4, PFOA or PFHxA (0; 0.01; 0.1, 1; 10; 100; 1000 ng/mL) to assess viability (WST-1 and AV/PI assay), evaluate spherification index (SI) and volume specifically in S-NHT. CXCL8 and CCL2 (mRNA and protein), and EMT-related genes were assessed in both models after exposure to PFCAs. RESULTS: PFHxA reduced the viability of both A-NHT and S-NHT. None of the PFCAs interfered with the volume or spherification process in S-NHT. CXCL8 and CCL2 mRNA and protein levels were differently up-regulated by each PFCAs, being PFOA and PFHxA the stronger inducers. Moreover, among the tested PFCAs, PFHxA induced a more consistent increase in the mRNA levels of EMT-related genes. CONCLUSIONS: This is the first evaluation of the effects of exposure to PFCAs on factors potentially involved in establishing the TC microenvironment. PFHxA modulated the TC microenvironment at three levels: cell viability, pro-tumorigenic chemokines, and EMT-genes. The results provide further evidence of the pro-tumorigenic effect of PFOA. On the other hand, a marginal effect was observed for C6O4 on pro-tumorigenic chemokines.

Canagliflozin reduces thyroid cancer cells migration in vitro by inhibiting CXCL8 and CCL2: An additional anti-tumor effect of the drug.

PURPOSE: Canagliflozin exert anti-cancer effects in several types of cancer including thyroid cancer (TC). However, whether it could modulate chemokines secreted in TC microenvironment is still unknown. The aim of the present study is to evaluate whether Canagliflozin could inhibit pro-tumorigenic chemokines CXCL8 and CCL2 and/or the TC cell migration induced by them. EXPERIMENTAL DESIGN: TC cell lines, TPC-1 and 8505C, HUVEC and normal thyroid cells NHT were treated with increasing concentrations of Canagliflozin. Viability was assessed by WST-1 and colony formation/proliferation by cristal violet. Chemokines were measured in cell supernatants by ELISA. mRNAs were evaluated by RT-PCR. TC migration (trans-well) and HUVEC proliferation (cristal violet) were assessed by treating cells with Canagliflozin alone or in combination with CXCL8 or CCL2. RESULTS: Canagliflozin reduced TC, HUVEC and NHT cells viability. The ability to form colonies of TC and the HUVEC proliferation (basal and CXCL8 or CCL2-induced) was also inhibited. mRNA and the secretion of CXCL8 was reduced in all cell types. The secretion of CCL2 was reduced by Canagliflozin in all cell types whereas its mRNA levels were reduced only in TPC-1. IL-6 was reduced in all cell types, while CXCL10 increased. More interestingly the CXCL8 and CCL2-induced TC cell migration as well as HUVEC proliferation was inhibited by Canagliflozin in both cell types. CONCLUSION: Canagliflozin exerts anti-cancer effects not only by reducing TC viability or colonies formation, but also by modulating two pro-tumorigenic chemokines resulting in reduced TC cells migration. These results expand the spectrum of canagliflozin-promoted anti-cancer effects.

In vitro study of the UV-filter homosalate effects on rat and human thyroid cells.

Homosalate is a UV-B filter, commonly used in sunscreens and personal-care products. Homosalate was shown to exert estrogenic and anti-androgenic effects in animal models, while few data are available on the effects of Homosalate on thyroid cells. The aim of this study was to evaluate if Homosalate exposure could exert adverse effect on thyroid cells in vitro. FRTL-5 and NHT were treated with increasing concentration of Homosalate for 24-48-72 h. Cell viability was assessed by WST-1. Cell proliferation was evaluated by cristal violet. Micronucleus staining was performed to assess genotoxicity. mRNA levels of thyroid-related genes (TSHR, TPO, TG, NIS, and PAX8) were evaluated by RT-PCR. Changes in ROS production by FRTL-5 and NHT were assessed with H2DCFDA. Homosalate significantly reduced cell viability after 72 h in FRTL-5 starting from the concentration 250 µM, while in NHT, Homosalate exposure significantly reduced cell viability after 48 and 72 h only at highest concentration (2000 µM). Cell proliferation was not modified by Homosalate at any concentration and time-point. Homosalate significantly up-regulated mRNA expression levels of TPO and Tg genes in FRTL-5, while a significant increase only in Tg mRNA expression was observed in NHT. No changes in ROS production was found in both cell types. The present study suggest that the effects of Homosalate exposure may differ according to the type of cell tested. The in vitro exposure of thyroid cells to Homosalate produces: i) cytotoxicity at high concentrations or after long time of incubation, ii) genotoxicity only in rat thyroid cells at the highest concentration, iii) upregulation of Tg mRNA in both thyroid cell types and of TPO mRNA in rat thyroid cells, iv) no changes in cell proliferation or oxidative stress. Further studies on the effects of Homosalate on thyroid cells should be encouraged.

Relationship between maternal obesity and first-trimester TSH in women with negative anti-TPO antibodies.

Objective: Obesity is associated with increased thyroid-stimulating hormone (TSH) in non-pregnant subjects, but this phenomenon has not been fully characterized during pregnancy. Our aim was to evaluate the impact of BMI on first-trimester TSH in a wide cohort of pregnant women with negative anti-thyroperoxidase antibodies (AbTPO) and its implications on uterine artery pulsatility index (UtA-PI), a marker of early placentation. Methods: The study included 2268 AbTPO-negative pregnant women at their first antenatal visit. Anamnestic data, BMI, TSH, anti-nuclear antibody (ANA) and extractable nuclear antigen (ENA) positivity and mean UtA-PI were collected. Results: A total of 1693 women had normal weight, 435 were overweight and 140 were obese. Maternal age, ANA/ENA positivity, history of autoimmune diseases and familiar history of thyroid diseases were similar in the three groups. TSH was significantly higher in obese women (1.8 (IQR: 1.4-2.4) mU/L) when compared to normal weight (1.6 (IQR: 1.2-2.2) mU/L) and overweight (median: 1.6 (IQR: 1.2-2.2) mU/L) ones (P < 0.001). BMI was significantly related with the risk of having a TSH level ≥4 mU/L at logistic regression, independently from non-thyroid autoimmunity, smoking or familiar predisposition for thyroid diseases (OR: 1.125, 95% CI: 1.080-1.172, P < 0.001). A restricted cubic splines regression showed a non-linear relationship between BMI and TSH. Women with a TSH ≥4 mU/L had a higher UtA-PI, independently from BMI. Conclusion: Overweight/obesity is significantly related with TSH serum levels in AbTPO-negative pregnant women, independently from the other risk factors for hypothyroidism during pregnancy. The increase of TSH levels could be clinically relevant, as suggested by its association with abnormal UtA-PI, a surrogate marker of abnormal placentation.

Proficiency in performing radiofrequency ablation procedure for non-functioning benign thyroid nodules: a qualitative rather than quantitative matter.

Objective: Radiofrequency ablation (RFA) is an emerging non-surgical treatment for benign thyroid nodules (BTN). Despite its proven safety profile, data on the learning curve (LC) required to achieve proficiency are still lacking. Materials and methods: The first 179 RFA procedures performed by a single operator in patients with non-functioning BTN were retrospectively analyzed. Six-month nodule volume reduction rate (VRR) ≥ 50% was regarded as reflection of proficiency. Multiple linear regression analysis has been performed to determine the relationship between the VRR and clinical variables. Cumulative sum (CUSUM) charts were plotted to assess LCs for all consecutive procedures and in relation to basal nodule size. In details, Group 1 (G1): 57 patients with small nodules (<10 ml); Group 2 (G2): 87 patients with intermediate nodules (10 - 25 ml); Group 3 (G3): 35 patients with large size (> 25 ml). Results: LC of all 179 procedures showed 3 phases: initial learning (1-39 procedures); consolidation (40-145 procedures); and experienced period (146-179 procedures). For G1 and G2 proficiency is achieved starting from the 10th procedure within the group (or 37th considering consecutively all procedures) and from the 59th procedure within the group (or 116th considering consecutively all procedures), respectively. LC of G3 did not detect operator proficiency. Conclusion: Specific LCs exist concerning the basal size of the nodule treated with RFA. In nodules with baseline volume > 25 ml suboptimal VRR has to be expected. Previously achieved experience on small-intermediate nodules does not seem to provide advantages in terms of higher VRR in the treatment of large nodules. Other potential and non-modifiable factors likely play a key role in the final volume reduction independently from the increased skill of the operator.

The American Thyroid Association risk classification of papillary thyroid cancer according to presurgery cytology.

OBJECTIVE: To compare the American Thyroid Association (ATA) risk staging of histologically proven papillary thyroid cancer (PTC) in patients who received a presurgery cytologic result of either indeterminate thyroid nodules (ITNs, Bethesda III/IV) or suspicious for malignancy/malignant (TIR 4/5, Bethesda V/VI). METHODS: Clinical, ultrasonographic, cytological data from patients with histologically diagnosed PTC were retrospectively collected. RESULTS: Patients were stratified according to the preoperative fine-needle aspiration cytology into 2 groups: 51 ITNs (TIR3A/3B) and 118 suspicious/malignant (TIR 4/5). Male/female ratio, age, and presurgery TSH level were similar between the 2 groups. At ultrasound, TIR 4/5 nodules were significantly more frequently hypoechoic (P = .037), with irregular margins (P = .041), and with microcalcifications (P = .020) and were more frequently classified as high-risk according to the European Thyroid Imaging and Reporting Data System (EU-TIRADS; P = .021). At histology, the follicular PTC subtype was significantly more prevalent among ITNs while classical PTC subtype was more frequent in TIR 4/5 group (P = .002). In TIR 4/5 group, a higher rate of focal vascular invasion (P < .001) and neck lymph node metastasis (P = .028) was observed. Intermediate-risk category according to ATA was significantly more frequent in TIR 4/5 group while low-risk category was more frequently found among ITNs (P = .021), with a higher number of patients receiving radioiodine in TIR 4/5 group (P = .002). At multivariate logistic regression, having a TIR 4/5 cytology was associated with a significant risk of having a higher ATA risk classification as compared to ITN (OR 4.6 [95% CI 1.523-14.007], P = .007), independently from presurgery findings (nodule size at ultrasound, sex, age, and EU-TIRADS score). CONCLUSIONS: Papillary thyroid cancers recorded among ITNs are likely less aggressive and are generally assessed as at lower risk according to ATA classification.