Radioiodine therapy in the different stages of differentiated thyroid cancer.

Differentiated thyroid cancer is the most frequent type of thyroid cancer with an increasing incidence in the last decades. The initial management is represented by surgical treatment followed by radioactive iodine therapy that includes remnant ablation, adjuvant treatment or treatment of metastatic disease. Radioactive iodine treatment is performed only in selected cases based on the risk of recurrence and mortality during follow up, according to American Joint Committee on Cancer Union for international Cancer Control Tumor, Node, Metastasis (AJCC/TNM) staging system and the 2015 American Thyroid Association (ATA) risk stratification system. This article will review the key factors to consider when planning radioactive iodine therapy in differentiated thyroid cancer patients after surgery and during follow up.

Tackling Thyroid Cancer in Europe-The Challenges and Opportunities.

Thyroid cancer (TC) is the most common malignancy of the endocrine system that affects the thyroid gland. It is usually treatable and, in most cases, curable. The central issues are how to improve knowledge on TC, to accurately identify cases at an early stage that can benefit from effective intervention, optimise therapy, and reduce the risk of overdiagnosis and unnecessary treatment. Questions remain about management, about treating all patients in referral centres, and about which treatment should be proposed to any individual patient and how this can be optimised. The European Alliance for Personalised Medicine (EAPM) hosted an expert panel discussion to elucidate some of the challenges, and to identify possible steps towards effective responses at the EU and member state level, particularly in the context of the opportunities in the European Union's evolving initiatives-notably its Beating Cancer Plan, its Cancer Mission, and its research funding programmes. Recommendations emerging from the panel focus on improved infrastructure and funding, and on promoting multi-stakeholder collaboration between national and European initiatives to complement, support, and mutually reinforce efforts to improve patient care.

2022 ETA Consensus Statement: What are the indications for post-surgical radioiodine therapy in differentiated thyroid cancer?

Modern use of post-operative radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) should be implemented in line with patients' risk stratification. Although beneficial effects of radioiodine are undisputed in high-risk patients, controversy remains in intermediate-risk and some low-risk patients. Since the last consensus on post-surgical use of RAI in DTC patients, new retrospective data and results of prospective randomized trials have been published, which have allowed the development of a new European Thyroid Association (ETA) statement for the indications of post-surgical RAI therapy in DTC. Questions about which patients are candidates for RAI therapy, which activities of RAI can be used, and which modalities of pre-treatment patient preparation should be used are addressed in the present guidelines.

Calcitonin Levels in Thyroid Disease Are Not Affected by Autoimmune Thyroiditis or Differentiated Thyroid Carcinoma.

INTRODUCTION: Association between hypercalcitoninemia and pathological conditions such as autoimmune thyroiditis (AIT) or differentiated thyroid carcinoma (DTC) has been addressed, with conflicting results. We evaluated the prevalence and the clinical relevance of elevated basal serum calcitonin (CT) levels in non-neoplastic (nodular goiter [NG] and AIT) and neoplastic thyroid diseases (DTC). METHODS: We retrospectively evaluated 3,250 consecutive patients with thyroid nodular disease who underwent fine-needle aspiration cytology with adequate sample. After exclusion of medullary thyroid cancer (MTC) patients were divided according to the presence/absence of thyroid autoimmunity into NG or nodular autoimmune thyroiditis (N-AIT) and, according to cytological results, in benign or suspicious/malignant nodules. RESULTS: One hundred ninety-seven/3,250 patients (6.0%) showed CT level >10 pg/mL. In 11/3,250 (0.3%) cases, a final histological diagnosis of MTC was made, while the remaining 186/3,250 patients (5.7%) had non-MTC-related hypercalcitoninemia (CT > 10 pg/mL). According to cytological diagnosis, the rate of hypercalcitoninemia was similar in class II and class V-VI groups (5.4 vs. 6.9%, p = 0.4). The occurrence of hypercalcitoninemia was significantly higher in patients with NG (166/2,634 [6.3%]) than in patients with N-AIT (20/605 [3.3%]) (p = 0.004). However, after matching by sex, no difference was found between the 2 groups (NG and N-AIT). These results were confirmed in 598 patients submitted to surgery. CONCLUSIONS: AIT and DTC seem not to affect serum CT levels in patients with thyroid nodules. Therefore, hypercalcitoninemia, in these patients, should be submitted to the same diagnostic workup than patients without AIT or DTC.

Screening of Organ-Specific Autoantibodies in a Large Cohort of Patients with Autoimmune Thyroid Diseases.

Background: Autoimmune diseases tend to cluster in the same individual or in families. Four types of autoimmune polyglandular syndromes (APS) have been described based on the combination of endocrine and/or non-endocrine autoimmune diseases. In particular, type-3 APS is defined by the association of an autoimmune thyroid disease (ATD) and other autoimmune diseases and has a multifactorial etiology. The natural history of autoimmune diseases is characterized by three stages: potential, subclinical, and clinical. Methods: To determine the prevalence of organ-specific autoantibodies (anti-adrenal, anti-ovary [StCA], anti-pituitary [APA], anti-parietal cells [PCA], anti-tissue transglutaminase [tTGAb], anti-mitochondrial [AMA], anti-glutamic acid decarboxylase [GADA], anti-nicotinic acetylcholine receptor) in patients with ATD and to define the stage of the disease in patients with positive autoantibodies. From January 2016 to November 2018, 1502 patients (1302 female; age 52.7 ± 14.7 [mean ± standard deviation] years, range 18-86 years) with ATD (1285/1502 [85.6%] with chronic autoimmune thyroiditis and 217/1502 [14.4%] with Graves' disease) were prospectively enrolled. Results: The most common organ-specific autoantibodies were PCA (6.99%) and GADA (2.83%), while the prevalence of the remaining autoantibodies was ≤1%. All autoimmune diseases, but celiac disease, were predominant at the potential stage. Sex, ATD type, smoking habit, and coexistence of other autoimmune diseases correlated with the susceptibility to develop chronic atrophic gastritis (CAG) or autoimmune diabetes mellitus. Conclusions: The association between ATD and CAG was the most common manifestation of type-3 APS, mainly at the potential stage, that could lead to appropriate follow-up for early detection and timely treatment of the disease.

Validation of American Thyroid Association Ultrasound Risk-Adapted Approach for Repeating Cytology in Benign Thyroid Nodules.

Background: The 2015 American Thyroid Association (ATA) ultrasound (US) risk stratification system is used to identify thyroid nodules in which fine-needle aspiration cytology (FNAC) should be performed. In addition, this system is used to plan the long-term follow-up of patients with cytological benign thyroid nodules. The aim of our study was to evaluate the ATA US risk-adapted approach for repeating cytology in a large retrospective cohort of consecutive benign nodules with a second FNAC repeated after a median follow-up of 3.8 years (range 1.0-14.2 years). Methods: We retrospectively evaluated 1010 thyroid nodules, with an initial benign cytological diagnosis, that underwent at least one repeat FNAC during the follow-up. Results: The rate of missed cancer in the whole cohort of thyroid nodules was 1.0%, and it increased along by the US risk class (0.8% in very low/low-risk, 1.2% in intermediate-risk, and 3.1% in high-risk nodules). The 2015 ATA US risk stratification system showed a very high accuracy in selecting nodules that did not require a second FNAC (negative predictive value = 99.1%). In addition, the rate of missed cancer significantly increased along with the increase in the US risk class in nodules that showed an enlarged volume (0.4% in the low-risk class and 6.4% in the high-risk class, p = 0.005), while it was very low and not associated with the US features in the subgroup of thyroid nodules that did not grow during the follow-up (p = 0.96). Conclusions: Our results confirm the accuracy of the ATA recommendations in selecting benign nodules for FNAC repetition during the follow-up. An additional cytological evaluation maybe avoided in benign thyroid nodules with low-risk US features, regardless of the evidence of growth during the follow-up. While the utility of the routine repeat FNAC in all benign nodules with high-risk US features remains to be defined, based on our results, repetition of FNAC seems to be indicated in nodules with evidence of growth during the follow-up.

Long-Term Clinical Outcome in Familial and Sporadic Papillary Thyroid Carcinoma.

BACKGROUND: The definition and the behaviour of familial papillary thyroid cancer (FPTC) compared to the sporadic form (SPTC) are still debated. Some authors believe that only families with 3 or more affected members represent an actual example of familial diseases. OBJECTIVES: The objective of the study was to analyse the clinicopathological features and the outcome of sporadic and familial PTC patients also according to the number of affected members. METHODS: Among 731 patients, we identified 101 (13.8%) with familial diseases, 79 with 2 affected members (FPTC-2) and 22 with 3 or more affected members (FPTC-3) followed for a mean period of 10 years. RESULTS: FPTC patients had more frequently bilateral tumour (p = 0.007). No difference was found between the 2 groups for the other evaluated variables. At the time of the first follow-up (1-2 years after initial therapy), FPTC patients had a higher rate of persistent disease. However, at the last follow-up, the clinical outcome was not different between sporadic and familial patients. When the comparison between SPTC and FPTC was performed, according to the number of affected members, a significant trend between the 3 groups was observed for tumour diameter (p = 0.002) and bilaterality (p = 0.003), while we did not observe a significant trend for both response to initial therapy (p = 0.15) and last clinical outcome (p = 0.22). CONCLUSIONS: Our results suggest that, although the clinicopathological features of FPTC may be more aggressive, the long-term outcome is similar between FPTC and SPTC. A possible explanation is that PTC has a favourable prognosis, even when clinical presentation is more aggressive.

Long-term Effects of Radioiodine in Toxic Multinodular Goiter: Thyroid Volume, Function, and Autoimmunity.

CONTEXT: Long-term studies evaluating the treatment of toxic multinodular goiter (TMNG) with fixed activities of radioiodine (RAI) are lacking. OBJECTIVE: The objective of this work is to describe the effects of 15 mCi on thyroid volume, function, and autoimmunity in the long term. DESIGN AND SETTING: A population-based, retrospective analysis with up to 12 years of follow-up was conducted in Siena, Italy. PARTICIPANTS: Adult patients (n = 153) with TMNG, naive to RAI, were included. METHODS: Evaluation was performed of thyroid function, antithyroid antibodies, and ultrasound scans before and yearly after RAI. MAIN OUTCOME MEASURES: Evaluations included hyperthyroidism cure, hypothyroidism, volume reduction, nadir and regain, and antibody titer change. RESULTS: The study revealed mean volume reductions greater than or equal to 50% at 3 years after RAI; the greatest annual reduction was observed during the first year (30 ± 17.8%; P < .001). Most patients (60%) achieved their volume nadir 3 to 6 years after RAI. Although 22% patients showed volume regain, the net reduction was statistically significant as late as 9 years after RAI (P = .005). The mean time to hypothyroidism was 2.7 ± 2.4 years, and it was associated with greater reductions in volume (P = .01). During the first 3 years after treatment, hyperthyroid patients decreased approximately by 50% per year without additional RAI. There was no statistically significant association of antibody titers with thyroid function except for antithyrotropin receptor antibodies and hyperthyroidism (P = .004). At the end of follow-up there were 61.6% euthyroid patients, 11% hyperthyroid (4.8% overt), and 27.4% hypothyroid patients (2.7% overt). Hyperthyroidism was cured in 89%. CONCLUSIONS: The treatment of TMNG with 15 mCi of RAI induced low hypothyroidism rates while providing high cure rates and significant volume reduction, which was maintained in the long term.

Vemurafenib may overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in anaplastic thyroid cancer cells.

PURPOSE: Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206). METHODS: Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C). RESULTS: C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model. CONCLUSIONS: TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.

Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive form of thyroid cancer (TC) characterized by an aggressive behavior and poor prognosis, resulting in patients' death within a year. Standard treatments, such as chemo and radiotherapy, as well as tyrosine kinase inhibitors, are ineffective for ATC treatment. Cancer immunotherapy is one of the most promising research area in oncology. The PD-1/PD-L1 axis is of particular interest, in light of promising data showing a restoration of host immunity against tumors, with the prospect of long-lasting remissions. METHODS: In this study, we evaluated PD-L1 expression in a large series of TCs (20 cases) showing a progressive dedifferentiation of the thyroid tumor from well differentiated TC to ATC, employing two different antibodies [R&D Systems and VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody]. We also tested the anti PD-L1 mAb in an in vivo animal model. RESULTS: We found that approximately 70-90% of ATC cases were positive for PD-L1 whereas normal thyroid and differentiated TC were negative. Moreover, all analyzed cases presented immunopositive staining in the endothelium of vessels within or in close proximity to the tumor, while normal thyroid vessels were negative. PD-L1 mAb was also effective in inhibiting ATC growth in an in vivo model. CONCLUSIONS: These data suggest that immunotherapy may be a promising treatment specific for ATC suggesting the need to start with clinical TRIALs.

Safety and efficacy of two starting doses of vandetanib in advanced medullary thyroid cancer.

Vandetanib is an oral tyrosine kinase inhibitor approved for treatment of advanced symptomatic or progressive medullary thyroid cancer (MTC). The current study (Nbib1496313) evaluated the benefit-risk of two starting doses of vandetanib in patients with symptomatic or progressive MTC. Patients were randomized 1:1 to receive vandetanib 150 or 300 mg daily and followed for a maximum of 14 months (Part A), with the option to then enter an open-label phase (Part B) investigating vandetanib 100, 150, 200 and 300 mg daily doses. Efficacy was assessed in Part A, and safety and tolerability during Parts A and B up to 2 years post randomization. Eighty-one patients were randomized in Part A and 61 patients entered Part B, of whom 37 (60.7%) received 2 years of treatment. Overall, 25% of patients experienced an objective response (OR) at 14 months (OR rate, 0.29 (95% CI, 0.176-0.445) for 300 mg, and 0.20 (95% CI, 0.105-0.348) for 150 mg; one-sided P value approximately 0.43). The most common adverse events (AEs) included diarrhea, hypocalcemia, asthenia, QTc prolongation, hypokalemia and keratopathy, all at generally higher incidence with 300 vs 150 mg (Part A). Part B safety and tolerability was consistent with Part A. OR was observed with both vandetanib doses; the 300 mg dose showed a more favorable trend vs 150 mg as initial dose. Thus, for most patients, 300 mg vandetanib is the most appropriate starting dose; dose reductions to manage AEs and lower initial doses for patients with particular comorbidities can be considered.

Management of Subclinical Hypothyroidism in Pregnancy: A Comment from the Italian Society of Endocrinology and the Italian Thyroid Association to the 2017 American Thyroid Association Guidelines-"The Italian Way".

The 2017 American Thyroid Association guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum were published six years after the previous ones. They provide comprehensive clinical recommendations for the whole spectrum of thyroid diseases, as well as for optimal iodine intake during pregnancy, postpartum, and lactation. The present position statement mainly regards the recommended flow chart for therapeutic decision making in pregnant women being diagnosed with subclinical hypothyroidism. Here, we comment on the major biochemical and clinical situations and the corresponding therapeutic recommendations. In particular, we welcome the critical revision of the thyrotropin (TSH) reference range in pregnancy, and we agree that there is no need to treat thyroid peroxidase antibody-negative women with a serum TSH ranging from 2.5 µIU/mL to the upper limit of the reference range. This recommendation will hopefully reduce the huge proportion of healthy pregnant women in whom, according to the previous guidelines, levothyroxine therapy had to be initiated. On the other hand, we are concerned with the recommendation to only "consider treatment" in thyroid peroxidase antibody-negative pregnant women with a serum TSH ranging from the upper limit of the reference range to 10.0 µIU/mL. This is because thyroid antibodies may be falsely negative during gestation, and serum negative chronic autoimmune thyroiditis is a well-known clinical entity even outside pregnancy. Based on these and other arguments, we recommend treatment with levothyroxine in pregnant women with TSH levels ranging between the upper limit of the reference range and 10.0 µIU/mL independently from their thyroid antibody status.

Prospective Validation of ATA and ETA Sonographic Pattern Risk of Thyroid Nodules Selected for FNAC.

Context: Recently, the American Thyroid Association (ATA) and the European Thyroid Association (ETA) have proposed that thyroid ultrasound (US) should be used to stratify the risk of malignancy in thyroid nodules and to aid decision-making about whether fine-needle aspiration cytology (FNAC) is indicated. Objective: To validate and to compare the ATA and ETA US risk stratification systems of thyroid nodules in a prospective series of thyroid nodules submitted to FNAC. Setting: We prospectively evaluated 432 thyroid nodules selected for FNAC from 340 patients. Cytology reports were based on the five categories according to the criteria of the British Thyroid Association. Results: The proportion of Thy2 nodules decreased significantly, whereas the proportion of Thy4/Thy5 nodules significantly increased with increasing US risk class (P < 0.0001). The ability to identify benign and malignant nodules was similar between ATA and ETA systems. According to ATA and ETA US risk stratification systems, 23.7% and 56.0% nodules did not meet the criteria for FNAC, respectively. Considering only categories at lower risk of malignancy, the cumulative malignancy rate in these nodules was 1.2% for ATA and 1.7% for ETA US risk stratification systems. Conclusions: ETA and ATA US risk stratification systems provide effective malignancy risk stratification for thyroid nodules. In clinical practice, using this approach, we should be able to reduce the number of unnecessary FNAC without losing clinically relevant thyroid cancer.

Which patient with thyroid cancer deserves systemic therapy and when?

Distant metastases from differentiated thyroid cancer (DTC) are a rare event, occurring in less than 10% of patients with persistent or recurrent clinical disease. About 50% of these patients do respond to radioiodine (RAI) therapy, either with complete remission or stabilization of the disease on a long term period. Unfortunately, another 50% of these patients are refractory to the treatment with RAI, either from the first appearance of distant metastases or during follow-up. Overall, these patients represent 4-5 new cases/year/million. After the discovery of RAI-refractory disease, the 10-year survival rate is usually less than 10% and the mean life expectancy is 3-5 years (Durante et al., 2006). Tyrosine hinase inhibitors (TKI) have been introduced in the clinical practice based on the results of several phase III clinical trial, which brought to the approval from competent authorities in USA and Europe of two specific drugs: sorafenib and lenvatinib. Both of them, have shown objective response rates improving the progression-free survival rates, although no overall survival benefit has been demonstrated yet (Schlumberger et al., 2015; Brose et al., 2014) [2,3]. The most challenging issue in RAI-refractory thyroid cancer is when a patient should be considered RAI-refractory and when to initiate treatment with TKI.