Efficacy and tolerability of somatostatin analogues according to gender in patients with neuroendocrine tumors.

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome.

PURPOSE: Multiple endocrine neoplasia type 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome, associated with a wide tumor spectrum but hallmarked by primary hyperparathyroidism, which represents the most common clinical feature, followed by pituitary (functional and non-functional) adenomas, and neuroendocrine tumors. MEN4 clinically overlaps MEN type 1 (MEN1) but differs from it for milder clinical features and an older patient's age at onset. The underlying mutated gene, CDKN1B, encodes the cell cycle regulator p27, implicated in cellular proliferation, motility and apoptosis. Given the paucity of MEN4 cases described in the literature, possible genotype-phenotype correlations have not been thoroughly assessed, and specific clinical recommendations are lacking. The present review provides an extensive overview of molecular genetics and clinical features of MEN4, with the aim of contributing to delineate peculiar strategies for clinical management, screening and follow-up of the last and least known MEN syndrome. METHODS: A literature search was performed through online databases like MEDLINE and Scopus. CONCLUSIONS: MEN4 is much less common that MEN1, tend to present later in life with a more indolent course, although involving the same primary organs as MEN1. As a consequence, MEN4 patients might need specific diagnostic and therapeutic approaches and a different strategy for screening and follow-up. Further studies are needed to assess the real oncological risk of MEN4 carriers, and to establish a standardized screening protocol. Furthermore, a deeper understanding of molecular genetics of MEN4 is needed in order to explore p27 as a novel therapeutic target.

Evaluation of paraoxonase activity and association with serum advanced glycation end products as reliable markers of oxidative stress in Hashimoto's thyroiditis.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of autoimmune thyroiditis, also referred to as Hashimoto's thyroiditis (HT), and several biomarkers have been measured to evaluate the impact and clinical relevance of oxidative stress in this setting. Recently, advanced glycation end products (AGEs) have been proposed as reliable markers of oxidative stress in HT. In the present study, we investigated the relationship of AGEs with antioxidant paraoxonase (PON-1) activity as potential combined markers of oxidative stress. MATERIALS AND METHODS: We measured the levels of AGEs, and advanced oxidation protein products (AOPPs) and PON-1 activity by spectrophotometric methods, in the serum of 40 HT patients (36 F; mean age 35.4 ± 11.5 yr) and 38 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. RESULTS: Serum levels of AGEs were significantly higher (median 378 vs 290 AU/g protein; P<0.001), while PON1 activity was significantly lower (median 165 vs 201 U/L; P<0.05) in HT patients compared to controls: the two parameters were inversely correlated (P<0.01), clearly indicating a pro-oxidant imbalance in HT patients. At stepwise regression analysis, TPOAb positivity was an independent predictor of both PON-1 activity (P = 0.002) and AGEs levels (P = 0.000). CONCLUSIONS: Increased formation and accumulation of AGEs contribute to enhanced oxidative stress, along with a decrease in PON-1 activity in HT. As a consequence, AGEs levels and alteration in PON 1 may serve as useful markers for monitoring the levels of oxidative stress in this disorder.

Sex differences in carcinoid syndrome: A gap to be closed.

The incidence of neuroendocrine neoplasms and related carcinoid syndrome (CS) has markedly increased over the last decades and women seem to be more at risk than men for developing CS. Nevertheless, very few studies have investigated sex differences in clinical presentation and outcomes of CS. However, as per other tumours, sex might be relevant in influencing tumour localization, delay in diagnosis, clinical outcomes, prognosis and overall survival in CS. The present review was aimed at evaluating sex differences in CS, as they emerge from an extensive search of the recent literature. It emerged that CS occurs more frequently in female than in male patients with NENs and women seem to have a better prognosis and a slight advantage in overall survival and response to therapy. Moreover, the disease likely impacts differently the quality of life of men and women, with different psychological and social consequences. Nevertheless, sex differences, even if partially known, are deeply underestimated in clinical practice and data from clinical trials are lacking. There is urgent need to increase our understanding of the sex-related differences of CS, in order to define tailored strategies of management of the disease, improving both the quality of life and the prognosis of affected patients.

Prevalence of thyroid dysfunction in patients with COVID-19: a systematic review.

PURPOSE: Currently, there is an increasing interest regarding the impact of COVID-19 on the thyroid function. As several recent reports have described the onset of thyroid dysfunction in patients diagnosed with COVID-19, we performed a systematic review to assess the prevalence of thyroid dysfunction in patients with COVID-19 as this information could be clinically relevant for the management of these patients. METHODS: A comprehensive computer literature search using PubMed/Medline and Cochrane databases was performed until November 14, 2020 to search original articles evaluating thyroid dysfunction in COVID-19 patients. Information about thyroid dysfunction assessed by thyroid function test was retrieved by the eligible articles. Qualitative analysis (systematic review) only was performed whether a significant heterogeneity of data was detected. RESULTS: Seven studies including 1237 patients with COVID-19 were included. A significant heterogeneity across the studies was found. Most COVID-19 patients were euthyroid with TSH levels in the normal range (from 44 to 94% of the COVID-19 patients assessed in the included studies). The prevalence of thyroid dysfunction in COVID-19 patients (defined as abnormal thyroid function tests) largely varies among the included studies between 13 and 64% of COVID-19 patients as well as clinical presentation. A positive correlation between thyroid dysfunction and clinical severity of COVID-19 was reported. CONCLUSION: Literature data show that thyroid dysfunction is present in a significant percentage of patients with COVID-19. Assessment of thyroid function may be considered in symptomatic COVID-19 patients to have a baseline before introducing thyroid-interfering drugs and those requiring high-intensity care. Further, well-designed studies are needed to better elucidate the impact of COVID-19 on thyroid function and inform thyroid function testing and thyroid dysfunction management in COVID-19 patients.

BRAFV600E mutation is associated with increased prevalence of contralateral lymph-node metastases in low and low-to-intermediate risk papillary thyroid cancer.

OBJECTIVE: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Despite good prognosis being generally associated with PTC, persistent/recurrent disease can be observed in a not negligible number of patients. Accurate postoperative management can lead to a significant improvement of risk stratification/staging of PTC patients identifying those at higher risk of a more aggressive clinical course. Molecular tests were introduced at the beginning of the 2000s to improve PTC risk stratification. METHODS: We reviewed the records of 354/1185 patients affected by low or low-to-intermediate risk unilateral-PTC. In these patients, BRAFV600E mutation was looked for and 131-radioiodine therapy was performed 3 months after thyroid surgery. A radioiodine post-therapeutic imaging was obtained in all patients. RESULTS: BRAFV600E mutation was found in 170/354 PTC patients (female = 126). Forty-two out of 170 BRAFV600E mutation +ve patients (female = 27) had ipsilateral (n = 24) or contralateral (n = 18) loco-regional metastases at post-therapeutic imaging. Significant differences in terms of 2015 American Thyroid Association risk stratification, Hashimoto thyroiditis prevalence, tumor size, multifocality, disease staging and aggressive variant were observed between BRAFV600E mutation +ve and BRAFV600E mutation -ve patients (P ≤ 0.001;P = 0.001; P ≤ 0.001; P = 0.026; P ≤ 0.001; P ≤ 0.001). Interestingly, the prevalence of contralateral lymph-node metastases was significantly higher in BRAFV600E mutation +ve than BRAFV600E mutation -ve patients (18/42 vs. 2/22, respectively; P = 0.013). CONCLUSION: This study suggests that BRAFV600E mutation represents a significant risk factor for developing contralateral lymph-node metastases and confirms that BRAFV600E mutation is associated with more aggressive PTC features and a higher prevalence of metastatic disease also in low or low-to-intermediate-risk PTC patients.

Oxidative stress as a key feature of autoimmune thyroiditis: an update.

INTRODUCTION: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported. EVIDENCE ACQUISITION: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated. EVIDENCE SYNTHESIS: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis. CONCLUSIONS: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.

Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications.

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient's quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.

Selenium exerts protective effects against oxidative stress and cell damage in human thyrocytes and fibroblasts.

PURPOSE: Selenium, incorporated into specific seleno-enzymes, is essential to proper thyroid function and protect cells from oxidative damage induced by H2O2 during thyroid hormone synthesis. Several studies indicated that low selenium levels are associated with thyroid autoimmunity and related disorders, but real effectiveness of selenium supplementation in such diseases is still controversial. We evaluated the effect of selenium on oxidative damage in human thyrocytes and thyroid fibroblasts in vitro. METHODS: To induce oxidative stress, primary cultures were exposed to H2O2, in the presence or the absence of selenium, as either selenomethionine or selenite. We performed the following assays: cell viability, caspase-3 activity, BCL-2/BAX gene expression, DNA fragmentation, malondialdehyde levels, and glutathione peroxidase (GPx) activity measurements. RESULTS: Thyrocytes and thyroid fibroblasts exposed to H2O2 and preincubated with both selenocompounds displayed a significant dose-dependent increase in cell viability compared to cells incubated with H2O2 alone. Pretreatment with selenomethionine and selenite significantly reduced caspase-3 activity and BAX mRNA levels and increased BCL-2 mRNA levels in a dose-dependent manner. Accordingly, H2O2 induced a diffuse pattern of DNA degradation and an increase in malondialdehyde levels, which was prevented by the pretreatment with both selenomethionine and selenite. Both selenocompounds induced an increase in GPx activity, suggesting that these protective effects may be, almost in part, mediated by these selenoproteins. CONCLUSION: In human thyrocytes and fibroblasts in vitro, selenium exerts protective effects against H2O2 in a dose-dependent manner, being selenite effective at lower doses than selenomethionine.

Autoimmune endocrine diseases.

The endocrine system is interested by several autoimmune diseases, characterized by different impact and severity, according to the organs involved. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders, while hypophysitis, adrenalitis (90% of cases of primary hypocortisolism or Addison's disease), POF and hypoparathyroidism represent quite rare conditions. Autoimmune endocrine diseases can also coexist in the same individuals and cluster in families. Some of these associations are nosologically codified in the so-called autoimmune polyglandular syndromes, but autoimmune endocrinopathies can also be accompanied by other non-endocrine autoimmune disorders (i.e. connective tissue, skin or gastrointestinal diseases). Pathophysiology generally results from a complex interplay among genetic predisposition and environmental/endogenous factors. In the diagnostic process, measurement of organ-specific autoantibodies, both with a causative role or as an epiphenomenon, is often fundamental and integrates the assessment of hormone axes and the targeted imaging studies.

HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin.

The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes (p = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy.

Treatment of hyperthyroidism with radioiodine targeted activity: A comparison between two dosimetric methods.

Radioiodine therapy is an effective and safe treatment of hyperthyroidism due to Graves' disease, toxic adenoma, toxic multinodular goiter. We compared the outcomes of a traditional calculation method based on an analytical fit of the uptake curve and subsequent dose calculation with the MIRD approach, and an alternative computation approach based on a formulation implemented in a public-access website, searching for the best timing of radioiodine uptake measurements in pre-therapeutic dosimetry. We report about sixty-nine hyperthyroid patients that were treated after performing a pre-therapeutic dosimetry calculated by fitting a six-point uptake curve (3-168h). In order to evaluate the results of the radioiodine treatment, patients were followed up to sixty-four months after treatment (mean 47.4±16.9). Patient dosimetry was then retrospectively recalculated with the two above-mentioned methods. Several time schedules for uptake measurements were considered, with different timings and total number of points. Early time schedules, sampling uptake up to 48h, do not allow to set-up an accurate treatment plan, while schedules including the measurement at one week give significantly better results. The analytical fit procedure applied to the three-point time schedule 3(6)-24-168h gave results significantly more accurate than the website approach exploiting either the same schedule, or the single measurement at 168h. Consequently, the best strategy among the ones considered is to sample the uptake at 3(6)-24-168h, and carry out an analytical fit of the curve, while extra measurements at 48 and 72h lead only marginal improvements in the accuracy of therapeutic activity determination.

(99m)Tc-Methoxy-Isobutyl-Isonitrile Scintigraphy Is a Useful Tool for Assessing the Risk of Malignancy in Thyroid Nodules with Indeterminate Fine-Needle Cytology.

BACKGROUND: Thyroid nodular disease is a very common clinical problem. The diagnostic algorithm includes laboratory tests, thyroid ultrasound (US), thyroid scintigraphy, and, if necessary, US-guided fine-needle aspiration cytology. However, cytology results are reported as indeterminate in a not negligible number of patients. This is a central problem in the workup of patients, since about 55-85% of those undergoing surgery do not have thyroid cancer at final histology diagnosis. The aim of this study was to evaluate prospectively the role of (99m)Tc-methoxy-isobutyl-isonitrile ((99m)Tc-MIBI) thyroid scintigraphy in differentiating malignant from benign thyroid nodules with indeterminate cytology using quantitative analysis. METHOD: One hundred five patients affected by nodular thyroid goiter and with a euthyroid or hypothyroid functional status were prospectively evaluated. All patients had a suspicious nodule ≥15 mm in maximal diameter on US. All nodules were "cold" on (99m)Tc-pertechnetate scintigraphy and had a cytological diagnosis of class III or IV according to the Bethesda system. Planar images of the thyroid were acquired 10 and 60 minutes after (99m)Tc-MIBI administration. All cold nodules were MIBI-positive. Using quantitative analysis, the MIBI washout index (WOind) was calculated as a percentage reduction value of mean MIBI nodular uptake between early (+10 minutes) and late (+60 minutes) scans. RESULTS: Subdividing the patients into positive and negative for malignancy (either including or excluding patients with Hürthle cell adenoma) and performing receiver operating characterist curve analysis, the optimal WOind cutoff in differentiating malignant from benign follicular lesions was set at -19%. The overall sensitivity and specificity of (99m)Tc-MIBI quantitative analysis in identifying patients with malignant lesions was 100% and 90.9%, respectively. However, after excluding patients with Hürthle cell adenomas from the negative patient group, the overall sensitivity and specificity both reached 100%. CONCLUSION: The use of MIBI scintigraphy using quantitative analysis in the workup of cold nodules with indeterminate cytology is suggested in order to stratify patient risk for a malignant lesion better, thus reducing the number of patients referred to surgery. Surgical treatment should be planned in those patients with a WOind up to -19%.

Oxidative Stress and Advanced Glycation End Products in Hashimoto's Thyroiditis.

BACKGROUND: Oxidative stress, which occurs as a result of an imbalance between free-radical production and antioxidant defense mechanisms, has been implicated in the pathogenesis of several autoimmune disorders, including thyroid diseases. Importantly, it has been correlated to thyroid dysfunction. This study investigated the changes in oxidative balance in euthyroid Hashimoto's thyroiditis (HT) by means of specific serum tests, such as derived reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) test. In addition, advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs)--compounds formed by the transformation of proteins--were evaluated as potential new markers of oxidative stress in this disease. METHODS: This study included 134 euthyroid subject: 71 newly diagnosed HT patients (63 females; M age = 38 ± 13 years) and 63 age and sex-matched healthy controls. None of them were on thyroxine therapy. RESULTS: Serum d-ROMs were elevated, and BAP decreased in HT patients compared with controls (p < 0.001), and the two parameters were inversely correlated (r = -0.211; p = 0.027), clearly indicating an enhanced oxidative stress. Furthermore, AGE levels were higher in HT patients (M = 223.18 AU/g prot) than in controls (M = 189.636 AU/g prot; p = 0.020) and inversely correlated with BAP levels (r = -0.196; p = 0.037). In uni- and multivariate analysis, serum antithyroperoxidase antibodies were the main predictors for d-ROMs (p = 0.006), BAP (p < 0.001), and AGEs (p = 0.014), irrespective of thyrotropin and/or free thyroxine values. No differences in AOPPs levels were found between patients and controls (p = 0.923). CONCLUSIONS: Oxidants are increased and antioxidants decreased in euthyroid HT patients. As a result, the oxidative/antioxidative balance is shifted toward the oxidative side. Moreover, this study reports on a possible significant involvement of AGEs in HT, thus contributing to a better definition of the redox homoeostasis dysregulation in HT.

Abnormal radioiodine uptake on post-therapy whole body scan and sodium/iodine symporter expression in a dermoid cyst of the ovary: report of a case and review of the literature.

In patients affected by differentiated thyroid cancer, the whole-body scan (WBS) with 131-radioiodine, especially when performed after a therapeutic activity of 131I, represents a sensitive procedure for detecting thyroid remnant and/or metastatic disease. Nevertheless, a wide spectrum of potentially pitfalls has been reported. Herein we describe a 63-year-old woman affected by follicular thyroid cancer, who was accidentally found to have an abdominal mass at post-dose WBS (pWBS). pWBS showed abnormal radioiodine uptake in the upper mediastinum, consistent with lymph-node metastases, and a slight radioiodine uptake in an abdominal focal area. Computed tomography revealed an inhomogeneous mass in the pelvis, previously unrecognized. The lesion, surgically removed, was found to be a typical dermoid cyst of the ovary, without any evidence of thyroid tissue. By immunohistochemistry, a moderate expression of the sodium-iodine symporter (NIS) was demonstrated in the epithelial cells, suggesting a NIS-dependent uptake of radioiodine by the cyst.

Thyroid remnant ablation in differentiated thyroid cancer: searching for the most effective radioiodine activity and stimulation strategy in a real-life scenario.

OBJECTIVE: Differentiated thyroid cancer is rare, but the incidence has been increasing in the last few decades. Early treatment is based on surgery and thyroid remnant ablation (TRA) by means of radioiodine therapy. Despite radioiodine being widely used for decades, the choice of ablative activity is generally empirical and no consensus has been reached to date. The aim of our study was to compare the efficacy and safety of different radioiodine activities. In addition, we compared the ablation rate in patients treated in the hypothyroid state or after recombinant human thyroid-stimulating hormone (rhTSH) administration, retrospectively reviewing the records of 471 patients affected by differentiated thyroid cancer. PATIENTS AND METHODS: Patients were subdivided into three groups on the basis of the different activities of radioiodine administered and taking into account the different approaches used to perform the therapy: thyroid hormonal withdrawal or rhTSH stimulation. RESULTS: The success of TRA was evaluated 12 months later. TRA was obtained in 62/79 (78.5%) in group A (1110 MBq in the hypothyroid state), 183/190 (96.3%) in group B [2220 MBq in the hypothyroid state or after rhTSH administration: 87/90 (97%) and 96/100 (96%) patients, respectively], 199/202 (98.5%) in group C [3700 MBq in hypothyroid state or after rhTSH administration: 98/100 (98%) and 101/102 (99%) patients, respectively]. CONCLUSION: Our data demonstrate that 2220 and 3700 MBq radioiodine are more effective compared with 1110 MBq in TRA, without significant differences between 2220 and 3700 MBq or between hypothyroidism and euthyroidism. We suggest rhTSH-aided TRA with 2220 MBq iodine-131, as this approach permits efficacious treatment, thereby reducing side effects, absorbed dose to body and hospital stay.