Cardiovascular and metabolic comorbidities in patients with thyroid nodules: the impact of incidental diagnosis.

PURPOSE: The prevalence of thyroid nodules (TN) in the general population has increased as screening procedures are implemented and an association with metabolic and cardiovascular disorders has been reported. The aim of this study was to investigate the reason leading to the diagnosis of TN and to compare the clinical characteristics of patients diagnosed incidentally with those of patients diagnosed for thyroid-related reasons. METHODS: We designed a retrospective cross-sectional study including consecutive patients with TN from two high-volume hospital-based centers for thyroid diseases (Pavia and Messina) in Italy. Data regarding reason leading to TN diagnosis, age, sex, BMI, presence of cardio-metabolic comorbidities were collected. RESULTS: Among the 623 enrolled subjects, the US diagnosis of TN was prompted by thyroid-related reasons in 421 (67.6%, TD group) and incidental in 202 (32.4%, ID group) with a similar distribution in the two centers (p = 0.960). The ID group patients were more frequently males (38.6% vs 22.1%, p < 0.001) and significantly older (58.9 ± 13.7 vs 50.6 ± 15.5 years, p < 0.001) than the TD group ones, and had a higher rate of cardiovascular comorbidities (73.8% vs 47.5%, p < 0.001), despite having a similar BMI (27.9 ± 5.2 vs 27.8 ± 13.5, p = 0.893). CONCLUSIONS: Stratification of patients with TN according to the diagnostic procedure leading to diagnosis allows a better epidemiological characterization of this inhomogeneous and large population.

Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Predictors of thyroid adverse events during cancer immunotherapy: a real-life experience at a single center.

BACKGROUND: Thyroid dysfunction is among the most common immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) therapy. Data regarding potential predictors of the development of thyroid irAEs are still limited and sometimes conflicting. PATIENTS AND METHODS: We assessed potential risk factors and clinical outcomes associated with the onset of thyroid irAEs in a cohort of patients with different types of cancer treated with ICIs at a single center. Clinical and biochemical data, including thyroid function tests and autoantibodies at baseline and during treatment, were collected, and the onset of thyroid irAEs was recorded. Patients with thyroid dysfunction and/or under levothyroxine therapy before starting ICI were excluded. RESULTS: 110 patients (80 M, 30 F, aged 32-85 years; 56.4% non-small-cell lung cancer, 87% treated with anti-PD-1) with complete information were included in the study. Among them, 32 (29%) developed thyroid irAEs during ICIs therapy. Primary hypothyroidism was the most common irAEs, occurring in 31 patients (28.18% of the whole cohort), including 14 patients who experienced a transient thyrotoxicosis. About 60% of irAEs occurred within the first 8 weeks of therapy. At multivariate analysis, anti-thyroid autoantibodies positivity at baseline (OR 18.471, p = 0.022), a pre-existing (autoimmune and non-autoimmune) thyroid disorder (OR 16.307, p < 0.001), and a family history of thyroid diseases (OR = 9.287, p = 0.002) were independent predictors of the development of thyroid irAEs. CONCLUSION: Our data confirm the high frequency of thyroid dysfunctions (mostly hypothyroidism) during ICIs, and provide data on valuable predictors of thyroid toxicities that may help clinicians in identifying patients at risk for developing irAEs.

Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies.

PURPOSE: Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS: Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS: Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS: Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.

SARS-CoV-2 vaccine may trigger thyroid autoimmunity: real-life experience and review of the literature.

PURPOSE: SARS-CoV-2 infection can be associated with destructive thyroiditis and triggers thyroid autoimmunity. More recent evidence suggests that SARS-CoV-2 vaccines may also be associated with permanent or transient thyroid dysfunction in susceptible individuals. METHODS: We observed three patients who developed/exacerbated autoimmune thyroid diseases (AITDs) shortly after receiving mRNA-based vaccines against SARS-CoV2. Clinical histories are reported, and relevant literature in the field is summarized. RESULTS: Our case series gives a description of the full spectrum of autoimmune disorders that may occur after SARS-CoV-2 vaccines administration, ranging from a case of new-onset Graves' disease to autoimmune hypothyroidism in two patients with pre-existing AITDs. Our three patients had a personal and/or family history of autoimmune disorders, suggesting that genetic predisposition is an important risk factor for the development of AITDs following vaccination. Moreover, our real-life experience demonstrates that persistent hypothyroidism may occur in the long run and should be overlooked; subjects with a previous AITDs are at risk of developing it. Reviewing the pertinent literature up to date Graves' disease is the most common vaccine-related AITDs with up to 51 cases reported in the literature, occurring mainly in female patients with no personal history of AIDTs, while only a case of autoimmune hypothyroidism has been reported so far. CONCLUSIONS: SARS-CoV-2 vaccines can trigger autoimmune reactions and the present case series contributes to make clinicians aware of full spectrum of AITDs that may occur following vaccination. Thyroid function monitoring is recommended, mainly in subjects with a personal/family history of AITDs.

Iodine nutrition optimization: are there risks for thyroid autoimmunity?

Iodine deficiency is still the main cause of preventable thyroid disorders, worldwide. To optimize iodine intake, programs of voluntary or mandatory iodization of salt have been implemented in several iodine-deficient countries and iodine sufficiency has been achieved in many. Despite the clear beneficial effects on thyroid health, some concerns have been raised on the presumed detriment of iodine prophylaxis on thyroid autoimmunity. Very recent studies aimed at evaluating the long-term consequences of iodine supplementation on thyroid autoimmunity and related dysfunction, have clearly demonstrated that the early post-iodization increase in thyroid antibody positivity is largely transient and not clinically relevant, since the prevalence of overt thyroid dysfunction has remained reassuring low over two decades. The recommended iodine intake is therefore safe with regard to thyroid autoimmunity, the benefits largely outweighing the risks in a population with a stable median iodine concentration not exceeding 300 µg/L. Thus, a possible increase in thyroid autoimmunity should not represent a limitation to promoting iodine supplementation in the general population, also taking into account the steady rise in prevalence of autoimmune disorders which has occurred in the last few decades because of environmental factors other than iodine.

Obesity in Prader-Willi syndrome: physiopathological mechanisms, nutritional and pharmacological approaches.

Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main genetic subtypes are represented by paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defect. Clinical picture of PWS changes across life stages. The main clinical characteristics are represented by short stature, developmental delay, cognitive disability and behavioral diseases. Hypotonia and poor suck resulting in failure to thrive are typical of infancy. As the subjects with PWS age, clinical manifestations such as hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency due to hypothalamic dysfunction occur. Obesity and its complications are the most common causes of morbidity and mortality in PWS. Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. However, despite the advancement in the research field of the genetic basis of obesity in PWS, there are contradictory data on the management. Although it is mandatory to adopt obesity strategy prevention from infancy, there is promising evidence regarding the management of obesity in adulthood with current obesity drugs along with lifestyle interventions, although the data are limited. Therefore, the current manuscript provides a review of the current evidence on obesity and PWS, covering physiopathological aspects, obesity-related complications and conservative management.

Serum levels of advanced glycation end products (AGEs) are increased and their soluble receptor (sRAGE) reduced in Hashimoto's thyroiditis.

PURPOSE: Advanced glycation end products (AGEs) are increased in conditions of oxidative stress and promote inflammation by interacting with their receptor RAGE on cell membrane. By contrast, the soluble receptor sRAGE exerts protective effects by competing with RAGE for ligand binding. AGEs/sRAGEs interaction is involved in the pathogenesis of several diseases related to oxidative stress. In the present study, we evaluated the AGEs/sRAGEs oxidative balance in Hashimoto' thyroiditis (HT). METHODS: We measured the levels of sRAGE, by ELISA, and AGEs, by spectrophotometric method, in the serum of 50 HT patients (5 M, 45 F; mean age 38.5 ± 12 years) and 50 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. RESULTS: Serum sRAGEs were significantly lower (median 424 vs 738 pg/ml; p = 0.001) and AGEs higher (205 vs 114 AU/g prot; p = 0.001) in HT patients compared to controls, and the two parameters were inversely correlated (p = 0.016). Accordingly, the AGEs/sRAGEs ratio was threefold higher in HT patients than controls (0.48 vs 0.15; p = 0.0001). In regression analysis models, serum TPO-Ab were the main predictors for AGEs and sRAGEs levels and AGEs/sRAGEs ratio (p < 0.0001), irrespective of TSH and/or FT4 values. CONCLUSION: sRAGEs were decreased and AGEs increased, suggesting a dysregulation of AGE/sRAGEs-related oxidative homeostasis in HT patients, even when in euthyroid status. Autoimmunity per se seems to play an important role in AGEs/sRAGE imbalance, irrespective of thyroid function alterations.

Non-specific rheumatic manifestations in patients with Hashimoto's thyroiditis: a pilot cross-sectional study.

PURPOSE: Hashimoto's thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. METHODS: 500 HT patients (467 F, 33 M; median age 41 years, range 14-69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took L-thyroxine. EXCLUSION CRITERIA: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. RESULTS: In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P < 0.001). There were minimal differences between the manifestations recorded in the two groups, the most common being polyarthralgias and myalgias/fibromyalgia, but non-specific RMs occurred threefold more in HT patients. Comparing HT patients with RMs (96 F and 4 M) with those affected by HT alone, female sex was prevalent (F:M ratio 24:1 vs 5:1) with higher age at diagnosis (median 43 vs 37 years; P < 0.001). HT patients with RMs (62%) were mostly euthyroid (median TSH 2.0 µIU/L) and only 7% overtly hypothyroid, discouraging a possible causal relationship between thyroid dysfunction per se and RMs. CONCLUSIONS: A significant percentage of HT patients complains of non-specific rheumatic signs and symptoms, in the absence of other diagnosed systemic comorbidities and regardless of thyroid functional status, deserving careful evaluation and prolonged follow-up.

Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis.

PURPOSE: Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust evidence on prevalence and outcome of the spectrum of alemtuzumab-induced autoimmune thyroid events in patients with multiple sclerosis. METHODS: PubMed and Scopus were systematically searched through July 2019. Studies dealing with patients without personal history of thyroid dysfunctions and affected by MS treated with ALZ and reporting ATEs were selected. Data on prevalence and outcome of ATEs were extracted. A proportion of meta-analysis with random-effects model was performed. RESULTS: Considering the overall pooled number of 1362 MS patients treated with ALZ (seven included studies), a 33% prevalence of newly diagnosed ATEs was recorded. Among all ATEs, Graves' disease (GD) was the most represented [63% of cases, 95% confidence interval (CI) 52-74%], followed by Hashimoto thyroiditis (15%, 95% CI 10-22%). Interestingly, GD showed a fluctuating course in 15% of cases (95% CI 8-25%). Of all GD, 12% (95% CI 2-42%) likely had spontaneous remission, 56% (95% CI 34-76%) required only antithyroid drugs, 22% (95% CI 13-32%) needed additional RAI, and 11% (95% CI 0.9-29%) underwent definitive surgery. CONCLUSION: Among different categories of ATEs, Graves' hyperthyroidism was the most common thyroid dysfunction, occurring in more than half of cases. Antithyroid drugs should represent the first-line treatment for ALZ-induced GD patients. However, alemtuzumab-induced GD could not be considered as having a more favourable outcome than conventional GD, given the substantial chance to encounter a fluctuating and unpredictable course.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know).

Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto's thyroiditis.

PURPOSE: Interleukin-37 (IL-37), member of the IL-1 family, is a natural suppressor of immune and inflammatory responses. Increased serum IL-37 levels were observed in several autoimmune diseases, including Graves' disease. To our knowledge, no data on Hashimoto's thyroiditis (HT) are available in the literature. METHODS: Aim of our study was to measure serum IL-37 levels and evaluate their relationship, if any, with oxidative stress markers in HT patients. We enrolled 45 euthyroid HT patients (5 M e 40 F, median age 40 years) and 50 age- and sex-matched healthy controls. None was under L-thyroxine therapy. Serum IL-37 levels were measured by ELISA. Specific serum tests, such as derived reactive oxygen metabolites (d-ROMs), and biological anti-oxidant potential (BAP) test were performed in all subjects to investigate the changes in oxidative balance, and advanced glycation end products (AGEs) were determined as a specific marker of oxidative stress. RESULTS: IL-37 levels were significantly higher in HT than in controls (median 475 vs. 268 pg/ml, P = 0.018). In the same patients, serum oxidants (d-ROMs) were increased and anti-oxidants (BAP) decreased compared with controls (P = 0.011 and < 0.0001, respectively), clearly indicating an enhanced oxidative stress. In addition, AGEs levels were higher in HT patients than in controls (210 vs. 140 AU/g prot, P < 0.0001) and directly correlated with IL-37 levels (P = 0.048). At multivariate analysis, the main independent predictors that influenced IL-37 levels were both anti-thyroid antibodies (P = 0.026) and AGEs levels (P = 0.001). CONCLUSIONS: IL-37 is up-regulated in HT and may exert a protective role by counteracting oxidative stress and inflammation.

Multicentre clinical evaluation of the new highly sensitive Elecsys® thyroglobulin II assay in patients with differentiated thyroid carcinoma.

OBJECTIVE: A highly sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here, we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, CA, USA). DESIGN: Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management. PARTICIPANTS: All DTC cases diagnosed, treated and followed up in four tertiary referral centres for thyroid cancer since January 2005 (n = 1456) were retrieved, and predefined selection criteria were applied to prevent relevant enrolment biases. A series of 204 patients was finally selected for this study. MEASUREMENTS: Samples had been stored at -80°C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory. RESULTS: Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC), and 81.4% showed no evidence of disease (NED) at the end of follow-up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH-stimulated Tg cut-offs to detect sREC were 0.41 µg/L and 1.82 µg/L for Elecsys® and 0.36 µg/L and 1.62 µg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse. CONCLUSIONS: Using appropriate assay-specific cut-offs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well-established Access® Tg assay.

Combined BRAFV600E analysis and 99mTc-MIBI scintigraphy can be a useful diagnostic tool in differentiated thyroid cancer patients with incomplete bio-chemical response to first radioiodine therapy (RAIT): a pilot investigation.

PURPOSE: The aim of the present study was to evaluate the possible diagnostic role of the combined performance of BRAF mutation analysis and MIBI scintigraphy in papillary thyroid cancer (PTC) patients with incomplete bio-chemical response to first radioiodine therapy (RAIT) performed for thyroid remnant ablation. METHODS: The records of 15 PTC patients with bio-chemical incomplete response to first RAIT were retrospectively analyzed. BRAFV600E analysis on primary tumor samples was obtained in all cases along with neck ultrasonography and 99mTc-MIBI scintigraphy of the neck-thorax regions at first follow-up. All patients then underwent RAIT with high radioiodine activities. A post-therapy whole-body scan (pT-WBS) was acquired 5-7 days after RAIT. RESULTS: Abnormal radioiodine uptake was found in 10 out of the 15 patients (67%, 131I+ve), while in the remaining 33%, no abnormal radioiodine uptake was detected (5/15, 131I-ve). Abnormal tracer uptake was found in 6 out of 10 131I+ve patients at 99mTc-MIBI scintigraphy (MIBI+ve). BRAFV600E mutation was not found in the majority of 131I+ve patients (9 out of 10 BRAFV600E-ve). On the contrary, in the 5 131I-ve patients, 99mTc-MIBI scintigraphy did not show any abnormal tracer uptake (MIBI-ve), while BRAFV600E mutation was present (BRAFV600E+ve). Thus, in our series, the association between MIBI-ve scintigraphy and BRAF+ve mutation was a useful diagnostic tool in predicting negative pT-WBS outcome. CONCLUSION: Albeit obtained in a small retrospective series, our results suggest that the combination of BRAFV600E+ve mutation and MIBI-ve scintigraphy may be considered a negative prognostic clue, which predicts the absence of radioiodine uptake at pT-WBS in DTC patients with incomplete bio-chemical response to first RAIT.

Correlation of cardio-metabolic parameters with vitamin D status in healthy premenopausal women.

PURPOSE: Vitamin D has been associated with metabolic disorders and increasing risk of cardiovascular diseases, with conflicting results. Aim of our study was to evaluate the relationship, if any, between cardio-metabolic risk factors and serum 25(OH)D concentrations in healthy women in premenopausal age. METHODS: We enrolled 200 healthy women, aged 19-50 years (mean age ± SD, 38 ± 11 years). In each subject, we measured serum 25(OH)D in relation to metabolic biomarkers and cardiovascular parameters. RESULTS: A status of vitamin D deficiency was found in 48% of the study population, while 38% showed levels higher than 30 ng/ml. Fasting glucose and insulin levels were significantly higher in subjects with vitamin D deficiency/insufficiency (P = 0.034 and P = 0.049, respectively) as well as HOMA-IR (P = 0.05). HDL cholesterol was significantly lower (P = 0.024) and intima-media thickness (IMT) higher (P = 0.014) in the vitamin D deficient/insufficient subjects. Moreover, serum 25(OH)D levels inversely correlated with insulin levels (P = 0.0001) and intima-media thickness (P = 0.015), and directly with serum HDL cholesterol (P = 0.010). At univariate regression analysis, the parameters that were significantly associated with vitamin D levels were insulin (P = 0.050), HDL cholesterol (P = 0.016), and intima-media thickness (P = 0.015). At multivariate analysis adjusted for age and BMI, vitamin D was still significantly associated with HDL cholesterol and intima-media thickness. CONCLUSIONS: A positive association between vitamin D and HDL cholesterol was found in healthy women without any evidence of metabolic disorders, with a significant inverse correlation between vitamin D and IMT. These results suggest a possible protective role of 25(OH)D in cardiovascular disorders.

TP53 polymorphism may contribute to genetic susceptibility to develop Hashimoto's thyroiditis.

PURPOSE: p53, which is encoded by the tumor suppressor gene TP53, plays a crucial role in the regulation of mechanisms of cell cycle arrest and apoptosis. Some SNPs of TP53, involving a different apoptotic ability of p53, have been associated with increased susceptibility to develop autoimmune diseases as well as cancer. We investigated the genotypic distribution of TP53 exon 4 SNPs in a cohort of Caucasian patients affected by Hashimoto's thyroiditis (HT). METHODS: Peripheral blood for DNA extraction was collected from 109 Caucasian unrelated subjects, 79 HT patients and 30 healthy controls. SNPs analysis was carried out by amplification and sequencing of exon 4 TP53. RESULTS: For the Pro72Arg (rs 1042522) SNP we found these rates in HT patients: 11.4% wild-type C/C (Pro72Pro), 24.0% heterozygous G/C (Pro72Arg), 64.6% homozygous G/G (Arg72Arg). The corresponding rates in healthy controls were 10, 46.7 and 43.3%, respectively. Thus, significantly different were G/C heterozygosity (24.0 vs 46.7 %, p = 0.039) and G/G homozygosity (64.6 vs 43.3%, p = 0.042). These differences were also confirmed when comparing our study population to published Caucasian control groups. The other described SNPs (Pro34Pro rs 11575998, Pro36Pro rs1800370, Pro47Ser rs1800371, and Arg110Leu rs 11540654) were absent or very rare in our study population. CONCLUSIONS: Our preliminary data, the first on a Caucasian population, indicate an increased prevalence of the homozygous genotype Arg/Arg and a decreased prevalence of heterozygous genotype Arg/Pro of rs 1042522 in HT patients compared to controls, suggesting that such SNP may contribute to confer susceptibility to HT.

Increased frequency of the rs2066853 variant of aryl hydrocarbon receptor gene in patients with acromegaly.

CONTEXT: Aryl hydrocarbon receptor (AHR) pathway has a key role in cellular detoxification mechanisms and seems implicated in tumorigenesis. Moreover, polymorphisms and mutations of AHR gene have been associated with several human and animal tumours. Although AHR has been found differently expressed in pituitary adenomas, AHR gene mutation status has never been investigated in acromegalic patients. DESIGN: In this study, we evaluated patients with apparently sporadic GH-secreting pituitary adenoma for AHR gene variants. PATIENTS AND METHODS: Seventy patients with sporadic GH-secreting pituitary adenoma (M = 27, age 59.1 ± 1.6 years) and 157 sex- and age-matched controls were enrolled in the study. In all patients and controls, the exons 1, 2, 3, 5 and 10 of AHR gene were evaluated for nucleotide variants by sequencing analysis. RESULTS: The rs2066853 polymorphism was identified in the exon 10 of 18/70 acromegalic patients and 9/157 healthy subjects (25.7 vs. 5.7%, χ(2) = 18.98 P < 0.0001), in homozygosis in one patient and in heterozygosis in the other 17 and in the 9 healthy subjects. Moreover, a heterozygous rs4986826 variant in exon 10 was identified in a patient with heterozygous rs2066853 polymorphism, and in the patient with homozygous rs2066853 variant. This second polymorphism was not detected in the control group. Patients with rs2066853 polymorphism showed increased IGF-1 ULN (P < 0.05) and prevalence of cavernous sinus invasion (P = 0.05), thyroid (P = 0.02), bladder (P = 0.0001) or lymphohematopoietic (P < 0.05) tumours. CONCLUSIONS: AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects and is associated with increased disease aggressivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared.

Increased serum interleukin-22 levels in patients with PRL-secreting and non-functioning pituitary macroadenomas.

Cytokines' involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8 ± 14.4 years) and 30 healthy controls (19 males, mean age 50.4 ± 8.4 years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29-70.12) vs. 5.58 (0.19-21.46) pg/mL, p < 0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82-70.12) vs. 21.29 (11.29-56) pg/mL, p = 0.039]. IHC revealed a strong IL-22R staining in 100 % of PRL-omas and 60 % of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60 % of NFPAs.