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BACKGROUND: Preoperative predictors for the need of prophylactic lymph node dissection in the lateral neck have been studied in patients with medullary thyroid carcinoma (MTC). OBJECTIVES: To evaluate the ability of serum calcitonin to predict the extent of surgery needed in the lateral neck. METHODS: This retrospective population-based cohort study includes data from 94 of 139 patients with MTC surgically treated in Norway from 2003 to 2016. Patients were identified in the 4 regional centers treating MTC and by the Cancer Registry of Norway, and grouped according to calcitonin levels. In 58 patients without distant metastases or disease progression to the next tumor level (NPNL), data were compared in prognostic groups (N0-NPNL), (N1a-NPNL), and (N1b-NPNL). RESULTS: At calcitonin levels ≤500, 501–1,000, and >1,000 pmol/L, metastatic lymph nodes in the lateral neck were found in 16, 50, and 71% of the patients, respectively. In the prognostic groups, 19% of N0-NPNL patients had calcitonin >500 pmol/L and 17% of N1b-NPNL patients had calcitonin ≤500 pmol/L. In multivariate analysis, factors predicting biochemical cure and calcitonin level ≤500 pmol/L were no metastatic lymph nodes in the lateral neck (p = 0.030) and tumor diameter ≤20 mm (p < 0.001), respectively. Factors related to metastatic lymph nodes in the lateral neck were extrathyroidal extension (p = 0.007) and no biochemical cure (p = 0.028). CONCLUSIONS: Basal calcitonin cannot predict the need for prophylactic lateral lymph node dissection in patients with MTC. Further prospective, randomized studies are warranted.

Guidelines suggest that subclinical hypothyroid (SCH) patients with thyrotropin (TSH) between 4 and 10 mU/L and symptoms associated with hypothyroidism should receive L-T4 substitution treatment, be evaluated, and continue treatment if symptoms subside. The latter requires detecting a true change in symptoms, which can be calculated from within-person variation in symptom evaluation tools. This led us to assess within-person variation in hypothyroid symptoms, in mood-related symptoms, and quality of life in patients with untreated SCH in order to support the recommended evaluations. Method: The within-person coefficient of variation (CV) was estimated from 13 consecutive monthly evaluations in 15 patients with initial TSH between 5 and 12 mU/L and no trend in TSH. Results: The within-person CV was rather large for the Hospital Anxiety and Depression Scale (HADS) and Zulewski hypothyroid score at 41.6 and 60.9%, respectively. For quality of life the within-person CV was lower at 8.0% for the physical component summary and 8.7% for the mental component summary from the SF-36 questionnaire. The difference required between two measurements to detect a true change was 97% for mood-related symptoms (HADS) and 140% for hypothyroid symptoms. For quality of life (SF-36) the required difference was 20%. Conclusion: Score differences of almost 100% and higher were required to support a true change in mood (HADS) and hypothyroid symptom scores in untreated SCH patients. For quality of life a true change was detected at a 20% difference in SF-36 scores. The hypothyroid score and HADS questionnaire do not seem useful for the evaluation of individuals.

A 73-year-old female presenting with haemoptysis and dyspnoea was found to have a locally advanced left thyroid mass and vocal cord palsy. A CT scan of the neck and thorax and endoscopy demonstrated invasion into the tracheal lumen. Histopathology of the intraluminal tracheal mass confirmed a papillary thyroid cancer (PTC). The tumour was deemed unresectable due to local extent and patient comorbidities. TKI therapy with lenvatinib was used for 14 months. On serial scanning, a marked reduction in tumour volume from 31 × 59 × 32 mm to 17 × 28 × 22 mm was noted. This subsequently allowed a successful surgical resection with a total thyroidectomy and central neck dissection with no evidence of residual macroscopic disease. Histopathology confirmed a well-differentiated PTC with features of tumour regression. In this case, TKI therapy in a locally advanced unresectable DTC reduced tumour size and infiltration to a degree that surgical resection of macroscopic disease was possible, without requiring airway resection. This raises the possibility that TKIs may have a neoadjuvant role in selected cases of locally advanced DTC to reduce tumour volume and therefore morbidity of subsequent surgical resection.

Background Although body weight change (BWC) is a common manifestation of thyroid dysfunction, solid evidence for whether to perform or on whom to perform thyroid function test in subjects complaining of BWC is lacking. Objective To evaluate the association between thyroid dysfunction and BWC using a nationwide survey. Method Data was obtained from the Korea National Health and Nutrition Examination Survey VI 2013-2015 and 5,456 subjects without previous thyroid disease were included. Serum thyroid-stimulating hormone (TSH), free T4, and self-reported BWC during the previous year were used for the evaluation. Weight loss or gain was defined as weight change of at least 3 kg. Results In total, 1,017 men (37.3%) and 1,175 women (43.0%) reported BWCs during the previous year. The overall weighted prevalence of thyroid dysfunction was not significantly associated with the extent of BWC in men (p = 0.705) or women (p = 0.094). However, when the impact of TSH levels on weight change was separately evaluated for weight gain and loss after adjusting for age and body mass index in each sex, weight loss in women was significantly associated with TSH levels (hazard ratio 0.64, 95% CI 0.47-0.85, p = 0.03). No association of thyroid dysfunction was observed for weight gain in women (p = 0.23) or any changes in men (p = 0.875 in weight gain, p = 0.923 in weight loss). Conclusions This study highlights the necessity of performing thyroid function testing in women who complain of weight loss, but such testing may be less vital in women with weight gain or men with any changes in weight.

BACKGROUND: While the effects of thyroxine (T4) replacement on improving gonadal function in hypothyroid men has been well documented, the same has not been adequately studied in hypothyroid premenopausal women. METHODOLOGY: Premenopausal women with overt hypothyroidism (thyroid-stimulating hormone [TSH] > 15 IU/L) were tested in the early follicular phase of their natural menstrual cycles or after a progesterone challenge for gonadotropins, estradiol (E2), and prolactin (PRL). They were then treated adequately with T4 replacement and retested under similar circumstances for the same parameters ≥2 months after the restoration of euthyroidism. RESULTS: Forty premenopausal hypothyroid women were evaluated at baseline and ≥2 months after adequate T4 replacement. At baseline, there was an inverse correlation of the gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and TSH, prolactin (PRL) and free T4 (fT4), and E2 and PRL. After normalization of the thyroid function, there was a significant fall in PRL (p < 0.001) accompanied by a rise in serum E2 (p < 0.001). There were no changes in the levels of the gonadotropins LH and FSH. The proportion of patients with hyperprolactinemia fell 5-fold, from 5/40 to 1/40. While there were 5 patients with low estrogen prior to treatment, there were none with hypoestrogenemia after treatment. CONCLUSION: Hypothyroidism is associated with a reversible partial suppression of the hypothalamo-pituitary-gonadal axis in premenopausal women, demonstrated by lower E2 along with a mild elevation of PRL. Treatment of hypothyroidism improves the level of estrogen and lowers the level of PRL.

Objectives The majority of thyroid nodules are discovered incidentally, and the management may be a challenge if the fine needle aspiration specimen yields indeterminate findings. Our aim was to develop an individualized risk prediction model to provide an accurate estimate of cancer risk in patients with cytologically indeterminate thyroid nodules. Materials and methods Clinical records, ultrasound images, and cytopathology reports of patients who underwent thyroidectomy were retrospectively reviewed. Logistic regression analysis was used to identify the predictive ability of each variable for malignancy, and a nomogram was built by integrating patients' age, multiplicity of nodules, cytology results, and suspicious ultrasound features, such as microcalcifications and irregular margins. Results For the 233 indeterminate nodules according to the Bethesda System for Reporting Thyroid Cytopathology, the malignancy rates of the subgroups "atypia of undetermined significance," "suspicious follicular neoplasia," and "suspicious for malignancy" were 44.3, 47.7, and 88.0%, respectively. It was found that the Bethesda category "suspicious for malignancy," microcalcifications, and irregular margins were independent risk factors for malignancy. The area under the receiver operating characteristics curve was 0.784, which suggested that the presented nomogram had considerable discriminative performance. Conclusions The nomogram developed in our study accurately predicts the malignancy risk of thyroid nodules with indeterminate cytology by using clinical, cytological, and ultrasonographic features.

BACKGROUND: An unprecedented rise in the prevalence of low-risk well-differentiated thyroid cancer (TC) has been reported in several countries, which is partly due to an increased utility of sensitive imaging techniques. The outcome of these cancers has generally remained excellent and the overall 5-year survival is almost 100%. However, the extended follow-up strategy for these patients remains unclear and while the initial management is done in specialist centres some experts opt to follow them on a long-term basis while others discharge them to primary care after the initial management. The effectiveness of one strategy versus the other has not been studied. METHODS: We conducted a real-world comparison to assess the outcome of low-risk TC (AJCC stage I) with undetectable thyroglobulin (TG) 2 years after radio­iodine (I-131) therapy. The outcome from Halifax (NS, Canada) and London (ON, Canada), where all TC patients are routinely followed by the tertiary care team, was compared with that from Edmonton (AB, Canada), where patients are routinely discharged to primary care. RESULTS: All patients were diagnosed between January 1, 2006, and December 31, 2011. The mean follow-up in primary care after discharge was 62.2 months and in tertiary care it was 64.6 months (p = 0.43). Rates of recurrence were similar in both groups, i.e., 1.1% in primary care and 1.3% in tertiary care (p = 0.69). Ultrasound surveillance was conducted in 56.5% of the patients in primary care and 52.6% of the tertiary care group (p = 0.26). The rate of annual unstimulated TG testing per patient was 0.58 (range 0–14) in primary care and 0.96 (range 0–6) in tertiary care (p = 0.06). More patients in primary care (86%) than in tertiary care (29.9%) consistently had thyroid-stimulating hormone levels within the target range (p < 0.001). The mean healthcare cost, based on a single follow-up visit with a blood test and ultrasound in the primary care group was CAD 118.01 and in the tertiary care group it was CAD 164.12. CONCLUSION: Our study shows that extended follow-up of low-risk TC patients is perfectly feasible in primary care and provides significant economic benefit for the healthcare system.

BACKGROUND: Periodic ultrasonography (US) examination is recommended in many patients with papillary thyroid carcinoma (PTC) after treatment with radioactive iodine (RAI), but recurrences are confirmed in few cases. This study determined whether the indication of US in the first years after treatment with RAI can be selective when postoperative US and posttherapy whole-body scanning (RxWBS) ruled out persistent neck disease. METHODS: This was a prospective study. Two hundred and fifty-four patients with PTC (242 of intermediate risk) undergoing thyroidectomy and RAI, who had no apparent disease at the time of initial therapy (including negative postoperative US and RxWBS), were studied. The patients were followed up for 5 years after treatment with RAI by annual US. RESULTS: At the end of 5 years, 47 patients (18.5%) had at least one suspicious US, but neck recurrence was confirmed in only 4 patients (1.5% of all patients and 8.5% of those with suspicious US). The remaining cases were considered false-positives. US did not reveal disease in the first or second year after treatment with RAI in any patient. In the third, fourth, and fifth year after treatment with RAI, considering only patients with unstimulated Tg < 1 ng/mL in these assessments, US revealed disease in 0, 1 (0.4%), and 1 (0.4%) patient, respectively. CONCLUSION: The results suggest that low- or intermediate-risk patients with PTC without persistent disease after thyroidectomy (including negative postoperative US and RxWBS) do not require repeat US examination in the first two years after treatment with RAI. In the following years until the fifth year, US can be restricted to patients with Tg ≥1 ng/mL.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare cancer and has a poor prognosis. Several radiation protocols have been reported, but the results were not satisfactory. OBJECTIVE: The aim of this study was to determine the effect of hypofractionated radiotherapy. METHODS: Thirty-three patients who received radiotherapy for ATC between January 2000 and December 2014 were retrospectively included. We defined hypofractionated radiotherapy as a single dose ≥5 Gy. RESULTS: Nineteen patients were treated with hypofractionated radiotherapy. Twenty-eight patients died, and 27 of those patients died from ATC. Sixteen patients died from distant metastasis and 6 from local recurrence. In the hypofractionated radiotherapy group, local recurrence occurred in 5 patients and 1 of them died from active bleeding from a local tumor. There was local recurrence in 7 patients who received the other protocol, and 5 of them died from asphyxiation, active bleeding, or uncontrollable growth of a local tumor on the neck. The median overall survival (OS) was 5 months. In multivariate analysis, patients who received an equivalent dose in 2-Gy fractions (EQD(2)) ≥50 Gy had significantly better OS (p = 0.016). In univariate analysis, patients who received hypofractionated radiotherapy did not have significantly better OS (p = 0.872) or local control (p = 0.090). The χ(2) test showed that significantly fewer patients died from local recurrence in the hypofractionated radiotherapy group (p = 0.025). CONCLUSIONS: Multivariate analysis showed that an EQD(2) ≥50 Gy resulted in better OS, and hypofractionated radiotherapy decreased the rate of mortality from local recurrence.

Aim: Based on the response criteria of the 2015 American Thyroid Associations guidelines, our objectives were to ­determine the response rate when using a low dose of ­131-I GBq in patients with low-risk differentiated thyroid cancer (LRDTC) and the influence of clinical and analytical variables on the prediction of complete response. Methods: We performed a multicentre and longitudinal study, including patients who were operated for LRDTC and who underwent radioiodine remnant ablation with a low-dose of 131-I. All patients were assessed at 6–12 months, and their status was classified as complete (excellent response) or incomplete response (structural incomplete, biochemical incomplete or indeterminate response). Various factors including age, gender, histology, tumour focality and size, stage, time from surgery to treatment, type of thyroid-stimulating hormone (TSH) stimulation, preablation serum thyroglobulin (pTg), antiTg antibodies (pAntiTgAb) and TSH (pTSH) levels were also analysed in order to predict the complete response rate. Results: Of 108 patients, 79.6% achieved complete response and the remaining showed incomplete response (2.9, 5.5 and 12% due to biochemical incomplete, structural incomplete and indeterminate response respectively). Six patients received a new dose of 131-I. Tumour size and pAntiTgAb were the only factors related to therapeutic response (p = 0.03 and p < 0.01, respectively). However, pAntiTgAb was the only independent factor related to complete ­response. Patients with complete response showed lower pTg than those with incomplete response (5.1 ± 12.9 vs. 11.2 ± 25 ng/mL) although without statistical significance (p = 0.14). There was no significant difference in the response rate depending on the thyrotropin stimulation methods. Conclusions: A low dose of 131-I was sufficient for reaching a complete response at 6–12 months of follow-up in the majority of patients with LRDTC. Tumour size and pAntiTgAb variables were related to therapeutic response.

Background Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has an anticancer action in patients with differentiated thyroid cancer that is refractory to radioiodine. Knowledge of the efficacy and safety of lenvatinib in patients with anaplastic thyroid cancer (ATC) is limited. Tyrosine kinase inhibitors frequently cause hypothyroidism, but the incidence of hypothyroidism with lenvatinib is unclear. Objectives We conducted a retrospective study to investigate the efficacy and safety of lenvatinib in ATC. Methods Five patients with unresectable ATC were enrolled. Lenvatinib 24 mg once daily was administered until disease progression, unmanageable toxicity, withdrawal, or death occurred. We retrospectively analyzed the objective response rate (ORR), time to progression (TTP), overall survival, and safety. Results Three of the 5 patients (60%) had a partial response, and 5 (40%) had stable disease. The ORR was 60%. Median TTP was 88 days, and overall survival was 165 days. Hypothyroidism was a common treatment-related adverse effect; 4 patients (80%) had hypothyroidism of any grade. These 4 patients had not undergone total thyroidectomy prior to lenvatinib administration, and the other patient had undergone total thyroidectomy. Treatment-related adverse effects of any grade were hypertension in 80% of patients, diarrhea in 40%, fatigue in 80%, and decreased appetite in 80%. Conclusions Lenvatinib is an effective treatment and may improve the prognosis of unresectable ATC. Four of the 5 patients had hypothyroidism, which may have been associated with treatment-induced injury of the thyroid gland. There were many treatment-related adverse effects, most of which were manageable by dose modification and medical therapy.

BACKGROUND: International best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1–4 cm. A personalised approach to decision-making is recommended. OBJECTIVES: This study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1–4 cm tumour cohort on contemporary practice patterns. METHODS: Data were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed. RESULTS: Ninety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA. CONCLUSIONS: Management of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to ratio­nalise management strategies.

INTRODUCTION: Thyroid hormones are involved in the regulation of body composition, lipid metabolism, and insulin resistance. Thus, it is possible that they might play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of thyroid function on NAFLD is not well defined. In this study, we evaluated the relationship between thyroid-stimulating hormone (TSH) levels, within the reference range, and presence of NAFLD in asymptomatic individuals. STUDY DESIGN: We included all individuals evaluated at a preventive clinic of the Hospital Israelita Albert Einstein, between 2014 and 2015. The prevalence of NAFLD (analyzed by abdominal ultrasound), according to TSH quartiles, within the reference range, was determined. The association between TSH quartiles and NAFLD was analyzed by logistic regression adjusted for possible confounders. ­ RESULTS: We evaluated 10,539 individuals (73% male, age 43.4 ± 9.4 years). The prevalence of NAFLD was 34, 38, 38, and 39% in the first to the fourth TSH quartiles (0.46–1.44, 1.45–1.97, 1.98–2.68, and 2.69–4.68 mUI/L, respectively, p for trend < 0.001). At univariate analysis, higher TSH levels were associated with the diagnosis of NAFLD. When data were adjusted for the metabolic syndrome characteristics (waist circumference, HDL-cholesterol and triglycerides levels, presence of diabetes, and systemic arterial hypertension), the association was no longer significant. CONCLUSIONS: Although the TSH variability within the reference range is associated with NAFLD in univariable models, once adjusted for metabolic syndrome factors no significant association is noted.

Introduction Nivolumab is a promising treatment in patients with advanced malignancies. Among immune-related adverse events, autoimmune thyroid disorders are frequently reported. Patient A 61-year-old male patient had no history of familial or personal thyroid disease. In 2012, this patient, a heavy smoker, presented with non-small-cell lung cancer that was treated with radiotherapy and chemotherapy. In 2015, the cancer progressed with cervical compressive symptoms, and the patient was treated with nivolumab. Results After 3 infusions, bilateral eyelid ptosis and bilateral conjunctival redness with chemosis were observed. Ophthalmologic examination revealed severe proptosis with complete ophthalmoplegia but with normal vision, color test, and optic disk. Thyroid function tests were normal (TSH = 0.65 mU/L, free T4 = 15.4 pmol/L) without anti-thyroperoxidase or anti-TSH receptor antibodies. CT scan of the orbits confirmed marked bilateral proptosis with expansion of the orbital adipose tissue without significant thickening of extraocular muscles. T2-weighted MRI showed inflammation of orbital adipose tissue. Nivolumab treatment was withdrawn, and the patient received weekly intravenous high-dose methylprednisolone (1 g for 2 weeks, 500 mg for 4 weeks, and 250 mg for 5 weeks). After the first 3 cycles, significant improvement of left chemosis was observed whereas bilateral ptosis and ophthalmoplegia were unchanged. The patient was euthyroid without thyroid autoimmunity 1 week prior to his death due to massive hemoptysis. Conclusion We report severe inflammatory ophthalmopathy in a euthyroid patient with non-small-cell lung cancer during nivolumab therapy. The occurrence of such ophthalmic adverse events is likely to increase during nivolumab therapy in patients with advanced malignancies.

PURPOSE: The role of thyroglobulin (Tg) in predicting death and recurrence risk in patients with poorly differentiated thyroid carcinoma (PDTC) is not well established. We aimed to analyze Tg levels following total thyroidectomy and adjuvant radioiodine treatment (RAI) in PDTC patients and correlate Tg levels with survival and recurrence. METHODS: A retrospective analysis was conducted on 101 patients with PDTC who were treated between 1986 and 2010. Among them, 38 had no distant metastases at presentation, were managed by total thyroidectomy and adjuvant RAI, and had negative anti-Tg antibodies. An unstimulated Tg level < 1 ng/mL was used as a cut-off point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ(2) test. Overall survival, disease-specific survival (DSS), and recurrence-free survival (RFS), stratified by Tg levels, were calculated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Compared to patients with undetectable Tg, cases with detectable Tg had a lower probability of achieving free surgical margins (21.7 vs. 46.7%; p = 0.04), higher node status (73.3 vs. 21.8%; p = 0.005), decreased 5-year DSS (65 vs. 100%; p = 0.009), and worse 5-year RFS (32 vs. 84%, p = 0.010), with a significant number of patients having a recurrence in the first year (50 vs. 12.5%; p = 0.021). Patients with detectable Tg levels also showed worse locoregional (55.6 vs. 90.9%; p = 0.014) and distant control (5-year distant control of 46.9 vs. 91%; p = 0.017). CONCLUSIONS: Our results suggest that detectable Tg levels after surgery and RAI in a subset of PDTC patients appear to predict a higher rate of death and recurrence.

OBJECTIVES: Pregnancy induces changes in thyroid function, and thyroid dysfunction during gestation is associated with adverse outcomes. We examined the management of subclinical hypothyroidism and chronic autoimmune thyroiditis in pregnancy among Italian and Romanian endocrinologists. METHODS: Members of the Associazione Medici Endocrinologi (AME) and Romanian Society of Endocrinology (RSE) were invited to participate in a web-based survey investigating the topic. RESULTS: A total of 902 individuals participated in the survey, 759 of whom completed all sections. Among the respondents, 85.1% were aware of the 2017 American Thyroid Association guidelines about thyroid disease and pregnancy, and 82.9% declared that thyroid-stimulating hormone (TSH) screening at the beginning of pregnancy should be warranted. In a patient negative for peroxidase antibodies, 53.6% considered 2.5 mIU/L and 26.2% considered 4.0 mIU/L as the upper normal limit of TSH, and 50% would treat a patient with TSH 3.5 mIU/L with levothyroxine. About 20% did not suggest iodine supplementation. Isolated hypothyroxinemia detected in the first trimester would be treated by 40.8%. In patients undergoing ovarian stimulation, a TSH < 2.5 mIU/L would be targeted by 70%. CONCLUSIONS: Respondents globally appeared well informed about the management of thyroid autoimmunity and subclinical hypothyroidism in pregnancy. A more aggressive attitude in implementing iodine supplementation would be desirable. Most endocrinologists were convinced about an evident association between mild thyroid impairment and adverse outcomes in pregnancy, thus using a TSH value of 2.5 mIU/L as the threshold for diagnosing hypothyroidism and starting levothyroxine in pregnant women.

Background: Sorafenib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma, and recently for radioactive iodine (RAI)-refractory metastatic differentiated thyroid carcinoma (DTC). Several side effects have been described including alterations in amylase and lipase levels. Nonetheless, only a few cases of pancreatitis during renal carcinoma and hepatocellular carcinoma treatment have been described. Objective: To describe the first case report of sorafenib-induced acute pancreatitis during the treatment of thyroid carcinoma. Methods and Results: In a 60-year-old Latin woman with RAI-refractory papillary thyroid carcinoma, T4bN1bM1, sorafenib was indicated due to locally recurrent, metastatic, and progressive lung involvement without iodine uptake. Therapy was initiated (200 mg) every 8 h. Three days after starting the medication, abdominal pain, nausea, and emesis appeared. A blood test revealed elevated amylase (343 U/L RV: 28–100) and lipase (1,969 U/L RV: 23–300) levels, but no other findings, confirming acute mild pancreatitis. Hypertriglyceridemia, hypercalcemia, and alcohol and biliary etiologies were ruled out and sorafenib-acute pancreatitis was concluded. Two weeks later, sorafenib was resumed without recurrence. To date, this is the tenth sorafenib-related pancreatitis report and the first in a patient with RAI-refractory metastatic DTC. Conclusions: Sorafenib-acute pancreatitis may develop in patients with RAI-refractory thyroid cancer. This adverse event seems to be inde­pendent of the treatment duration and administered dose. Resuming the medication with an adjusted dose after pancreatitis resolution may be safe.

Background Differentiating between dysthyroid optic neuropathy (DON), which requires urgent therapy to prevent blindness, and moderate-to-severe Graves orbitopathy (GO) remains challenging. There is no pathognomonic feature of DON in either ophthalmological or radiological examinations. Objectives Our aim was to investigate the prevalence of radiological signs of DON in magnetic resonance imaging (MRI) in patients with moderate-to-severe and very severe GO. Methods Two researchers reassessed MRI scans of 23 consecutive patients (46 eyes) with active, moderate-to-severe GO and 14 patients (23 eyes) with very severe GO. Typical signs of DON in MRI include apical crowding and optic nerve stretching. These were evaluated in the eyes of both groups of patients. Lack of cerebrospinal fluid in the optic nerve sheath as well as muscle index values were also studied. These clinical evaluations and laboratory results were then compared between groups. Results At least one of the typical radiological features of DON was found in 22 (96%) and 16 (35%) eyes with very severe and moderate-to-severe GO, respectively. Each occurred statistically more often in patients with very severe GO. There were no ophthalmological signs of very severe GO observed in the group of patients with moderate-to-severe GO during the study or its subsequent follow-up (234 weeks). Conclusions MRI is a useful tool in evaluating very severe GO. However, features typical for DON are also found in up to 35% of eyes in patients with active, moderate-to-severe GO. Therefore, ophthalmological evaluation seems to be most important in the recognition of very severe GO.

Background Patients with small papillary thyroid carcinomas (PTC) can currently be maintained under active surveillance (AS). The recommended criteria are the following: adult individual, tumor ≤1 cm and not adjacent to the trachea or recurrent laryngeal nerve, cytology non-suggestive of the aggressive subtype, absence of lymph node (LN) involvement and extrathyroidal extension (ETE) on ultrasonography (US), and absence of clinical distant metastases. This study aimed to evaluate the frequency of the following peri- and postoperative findings in patients who met the criteria for PTC being candidate for AS: tumor > 1 cm, aggressive subtype or vascular invasion, ETE, clinical LN metastases (cN1), and distant metastases. Methods We reviewed the results of peri- and postoperative evaluation and histology of patients with a preoperative diagnosis of PTC who would currently be candidates for AS. Results There were 124 patients (102 women) with nodules ≤1 cm (range 4-10 mm). All nodules corresponded to papillary microcarcinomas on histology and none of them were > 1 cm. Only one microcarcinoma (0.8%) was of the tall-cell subtype. Vascular invasion was found in 10 microcarcinomas (8%). None of the microcarcinomas were staged as T3b or T4, although microscopic ETE was observed in 25 tumors (20%). In 8 patients (6.4%), central LN involvement was suspected during perioperative evaluation and was confirmed by histology (cN1a). None of the patients had distant metastases (M0). Conclusion Findings that define an intermediate risk of recurrence and favor total thyroidectomy were observed in 31.5% of patients with PTC who are candidates for AS.

Liposarcoma of the thyroid gland is a pathology that is rarely encountered in clinical practice, given the paucity of these cases. For the same reason, a definite treatment protocol has not been established for these cases. We present a case of a 49-year-old man who presented with a thyroid mass that was found to be a well-differentiated liposarcoma and was treated surgically with no adjuvant therapy other than close surveillance with clinical examination and MRI scans. On his most recent clinical visit, 9 months after surgery, there was no clinical or radiologic evidence of recurrence and the patient is doing well with good speech and swallow functions and no new symptoms. We also summarize all the cases of this rare pathology presented thus far to the best of our knowledge.

Cabozantinib and lenvatinib have been approved for the treatment of progressive medullary thyroid cancer and radioiodine-resistant thyroid cancer, respectively. Both phase III trials of cabozantinib and lenvatinib reported that renal adverse events (AEs) rarely occurred. The cabozantinib phase III study reported no AEs related to renal toxicity. In the lenvatinib phase III trial grade 3 (CTCAE), proteinuria (urinary protein ≥3.5 g/24 h) was found in 10.0% of the lenvatinib and 0.0% of the placebo patients. We report a 23-year-old patient with metastatic medullary thyroid cancer who was enrolled in the phase III trial, comparing cabozantinib to placebo and a 67-year-old patient with metastatic, papillary thyroid carcinoma who was undergoing treatment with lenvatinib during his enrollment in the phase III trial. The first patient had a normal kidney function initially, but developed end-stage chronic kidney disease unexpectedly on cabozantinib and additional zoledronate infusion. Whereas the second patient suffered from a dramatic aggravation of his known mild chronic renal insufficiency (KDOQI stage 2) due to long standing hypertension and atherosclerosis during the treatment with lenvatinib. These severe AEs due to anti-VEGF tyrosine kinase inhibitor treatment were unknown so far. In conclusion, these 2 cases argue for increased awareness for the possibility of renal failure as a consequence of anti-VEFG treatment. Predisposing conditions like known mild chronic renal insufficiency with only mild proteinuria and with atherosclerosis or precipitating co-medications like zoledronate infusion need to be accounted for to prevent these severe AEs.

Objective: The aim was to compare the vitamin D levels in patients with Graves disease (GD) with the general population and to correlate the vitamin D levels with laboratory and clinical parameters in GD. Moreover, we examined the genetic variation in genes involved in the vitamin D metabolism and their association with GD.Methods: The levels of vitamin D were compared in 292 patients with newly diagnosed GD and 2,305 controls. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1-α-hydroxylase (CYP27B1) were examined for association with GD and/or Graves ophthalmopathy (GO) in 708 patients and 1,178 controls.Results: Patients with GD had significantly lower vitamin D levels compared to controls (55.0 ± 23.2 vs. 87.2 ± 27.6 nmol/L, p < 0.001). In patients with GD (n = 219), there was no association between the levels of vitamin D at diagnosis and free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin receptor antibodies (TRAb), GO at diagnosis, or relapse after terminating treatment with antithyroid drugs. Two SNPs in VDR were associated with GD: rs10735810 (OR = 1.36, 95% CI: 1.02-1.36, p = 0.02) and rs1544410 (OR = 1.47, 95% CI: 1.03-1.47, p = 0.02). There was no difference in the mean vitamin D level between genotypes in either rs10735810 or rs154410.Conclusions: Patients with GD had lower vitamin D levels compared to the general population; however, the vitamin D levels did not affect the laboratory or clinical parameters of GD. SNPs in the VDR influenced the risk of GD through mechanisms other than reducing the vitamin D levels.

Whether hypothyroidism is related to nonalcoholic fatty liver disease (NAFLD) is unclear. Thyroid dysfunction is closely related with components of metabolic syndrome. Given the hepatic manifestation of metabolic syndrome, several studies have investigated the association between NAFLD and thyroid dysfunction and have demonstrated inconsistent results. Thus, we conducted a systematic review and meta-analysis to better characterize the association between NAFLD and thyroid dysfunction.MEDLINE and Embase were searched through July 2016. The primary outcome was the association between NAFLD and subclinical, overt, and overall hypothyroidism. The secondary outcome was the difference in thyroid hormone levels (free triiodothyronine [FTData were extracted from 14 studies involving 7,191 NAFLD patients and 30,003 controls. NAFLD was not associated with subclinical, overt, or overall hypothyroidism compared with non-NAFLD controls. Patients who had NAFLD did not show a significant difference in FTOur meta-analysis demonstrates no significant association between NAFLD and subclinical, overt, or overall hypothyroidism, and we also found no significant difference in thyroid hormone levels between participants with and without NAFLD.

Background: Despite biochemical euthyroidism, some levothyroxine (L-T4)-treated hypothyroid patients report persisting symptoms and some of these patients are tentatively treated with a combination of L-T4 and liothyronine (L-T3). Combination therapy and the appropriate choice of blood tests to monitor treatment are highly debated among specialists and patients. Aim: To evaluate whether measuring serum triiodothyronine (S-T3) at baseline or during combination therapy can be used as an indicator of a positive effect from L-T4/L-T3 combination therapy. Materials and Methods: Observational retrospective study of patients (n = 42) with persisting symptoms of hypothyroidism despite L-T4 therapy who had normal TSH levels and did not have any comorbidities that could explain their symptoms. All were then treated with L-T4/L-T3 combination therapy at a dose ratio of 17/1 according to European Thyroid Association guidelines. Based on patient-reported outcome, they were divided into responders and nonresponders. Results: Five patients were lost to follow-up and thus excluded. At the 3-month follow-up, 11 were classified as nonresponders and 26 as responders. At 12 months these figures had changed to 13 (35%) and 24 (65%), respectively. When comparing responders versus nonresponders, no differences were seen at baseline or during follow-up in S-T3 and in free T3 estimates. Further, logistic regression showed no correlation between S-T3 and free T3 estimates and responder/nonresponder status. Conclusion: Our data indicate that serum T3 measurements are not suitable to predict which patient will benefit from L-T4/L-T3 combination therapy, and treatment response cannot be followed by repeated T3 measurements either.

Considerable variations in diagnosis and therapeutic practices are reported for hyperthyroidism (HT) between countries.A clinical study was conducted among a representative sample of 263 endocrinologists in France. All consecutive patients seen for HT during the study period were included. Diagnosis and treatment modalities were recorded from hyperthyroid patients with Graves disease (GD,Antithyroid antibodies were measured in half of the population (anti-TPO in 48.5% and anti-TSH receptor in 57.8%). Patients had thyroid ultrasonography and scintigraphy in 93.8 and 40.3%, respectively. Therapeutic management depended on the etiology: for the first episode of GD, antithyroid drugs (ATDs) were the first-line treatment in 91% of the patients, combined with surgery in 6.1% and with radioiodine in 2.9%. Surgery was preferred to radioiodine in MNG (52.6 vs. 22.4%) and TA (59.1 vs. 24.2%). Euthyroid status was achieved after 3 months in 64.4% of GD. A "block and replace" protocol was used in 41.2% of patients. After 3 months, 73% of patients were euthyroid in the "block and replace" group compared to 56.2% in the group with ATDs alone (Large discrepancies remain between clinical practice and international guidelines. These results should boost efforts to improve adherence to these guidelines.

Objective: A large goiter may cause compression of the trachea. The aim of this study was to investigate the impact of thyroidectomy on tracheal anatomy and airflow and to correlate this with changes in health-related quality of life (HRQoL) in patients with benign nodular goiter. Methods: Magnetic resonance images of the neck and respiratory flow-volume curves, including both inspiration and expiration, were performed prior to and 6 months following surgery. HRQoL was measured by selected scales from the thyroid-specific patient-reported outcome (ThyPRO). Cohen’s effect size (ES) was calculated as mean change divided by standard deviation at baseline. ES of 0.2–0.5 were defined as small, 0.5–0.8 as moderate, and values >0.8 as large. Results: Sixty-five patients completed all examinations. Median goiter volume was 58 mL (range, 14–642 mL) before surgery with surgical removal of a median of 43 g (range, 8–607 g). Six months after surgery, tracheal narrowing and deviation were diminished by a median of 26% (ES = 0.67, p < 0.001) and 33% (ES = 0.61, p < 0.001), respectively. Correspondingly, each 10% decrease in goiter volume resulted in 1.0% less tracheal narrowing (p < 0.001). Concomitantly, a small improvement was seen in forced inspiratory flow at 50% of forced vital capacity (ES = 0.32, p < 0.001). A reduction in tracheal narrowing was associated with improvements in the Impaired Daily Life scale (0.33 points per 1% decrease in tracheal narrowing, p = 0.03) of the ThyPRO questionnaire. Conclusions: In patients with symptomatic benign nodular goiter, thyroidectomy resulted in substantial improvements in tracheal anatomy and improvements in inspiratory flow, which were followed by gains in HRQoL. This information is pertinent when counseling patients before choice of treatment.

To evaluate the influence of age at diagnosis on the frequency of structural incomplete response (SIR) according to the modified risk of recurrence (RR) staging system from the American Thyroid Association guidelines.We performed a retrospective analysis of 268 patients with differentiated thyroid cancer (DTC) followed up for at least 3 years after initial treatment (total thyroidectomy and remnant ablation). The median follow-up in the whole cohort was 74.3 months (range: 36.1-317.9) and the median age at diagnosis was 45.9 years (range: 18-87). The association between age at diagnosis and the initial and final response to treatment was assessed with analysis of variance (ANOVA). Patients were also divided into several groups considering age younger and older than 40, 50, and 60 years.Age at diagnosis was not associated with either an initial or final statistically significant different SIR to treatment (When patients are correctly risk stratified, it seems that age at diagnosis is not involved in the frequency of having a SIR at the initial evaluation or at the final follow-up, so it should not be included as an additional variable to be considered in the RR classifications.

Background: We present a case of a cervical schwannoma, likely originating from the pharyngeal plexus of the vagal nerve. The lesion masqueraded as a thyroid nodule and magnetic resonance imaging (MRI) assisted in preoperative diagnosis. We review the radiographic characteristics of nerve sheath tumors on MRI as well as the diagnostic cytologic stains which can enhance the possibility of a correct preoperative diagnosis. Case: We describe a 60-year-old female with dysphagia and a neck mass consistent with a nodular goiter. The patient's history, diagnostic images, cytology, pathology, and surgical management are presented and analyzed. The preoperative diagnosis of a cervical schwannoma was suspected by the use of MRI which led to additional specialized cytologic stains. Conclusion: Pharyngeal wall schwannomas are important to consider in the differential diagnosis of thyroid nodules when fine needle aspiration cytology indicates cells of neural origin. Imaging by MRI can assist in identifying lesions of neural origin masquerading as thyroid nodules.

Postoperative hypoparathyroidism is a common complication following total thyroidectomy. The aim of this study was to investigate the incidence of both transient and permanent hypoparathyroidism in patients undergoing total thyroidectomy in a tertiary referral centre and, furthermore, to identify early predictive risk factors.Based on a single-institution retrospective review, we identified 582 patients who underwent total thyroidectomy between January 2010 and March 2015. Information on age, gender, pathological diagnosis, duration of surgery, autotransplantation of parathyroid glands, neck dissection, and experience and position of the surgeon was retrieved from the medical records. Furthermore, serum levels of parathyroid hormone and calcium were registered pre- and postoperatively and after 3 and 12 months.The incidence of transient hypoparathyroidism during the first 24 h and 3 months after surgery was 47.8 and 17.8%, respectively. Furthermore, the incidence of permanent hypoparathyroidism 1 year after surgery was 10.7%. A prolonged duration of surgery was significantly associated with hypoparathyroidism. Moreover, autotransplantation of parathyroid glands was a significant predictor of transient hypoparathyroidism after 24 h and 3 months, but was not associated with permanent hypoparathyroidism.Transient and permanent hypoparathyroidism is common among patients undergoing total thyroidectomy in a tertiary referral centre. A duration of surgery120 min constitutes an independent risk factor due to the risk of ischaemic damage. Regain of function of devascularized parathyroid glands must be expected to last at least 1 year postoperatively. Furthermore, the recovery of autotransplanted parathyroid glands should not be evaluated within 1-3 months after surgery.

Introduction In the last few years, immune checkpoint inhibitors (ICPis) have become a common treatment of cancer. ICPis are associated with peculiar immune side effects, termed immune-related adverse events (irAEs). Thyroid disfunction is a common irAE, but clinical manifestation, severity, and pathogenesis can be variable. While destructive thyroiditis and hypothyroidism are the most common thyroid irAEs induced by ICPis, autoimmune hyperthyroidism (Graves' disease) is rare. We describe a case of a Graves' disease induced by anti-PD-1 therapy and we review the previous reports on this issue. Case presentation A 51-year-old man developed an overt autoimmune hyperthyroidism 2 months after he had started nivolumab (anti-PD-1) therapy for a metastatic non-small cell lung cancer. Although TSH-receptor autoantibodies (TRAb) were negative, the persistence of hyperthyroidism, the hypervascular pattern at thyroid ultrasound, and the high uptake at thyroid scintigraphy were all features suggestive of Graves' disease. Methimazole was started with the prompt restoration of euthyroidism. TRAb remained undetectable during the entire follow-up. Conclusions Autoimmune hyperthyroidism can be induced by anti-PD-1 treatment. TRAb were negative in both cases of nivolumab-induced Graves' disease described to date. A correct differential diagnosis between destructive thyroiditis and autoimmune hyperthyroidism is crucial for the appropriate treatment.

Background/aims Few data exist on reference thyroid volumes (Tvols) for Spanish children. The standard tables of the World Health Organization (WHO) are only for children older than 6 years. The present cross-sectional study reports the normal Tvols of 3-14 year-old girls and boys living in Madrid (Spain). Methods The study subjects were 217 children aged 3-14 years. Urinary iodine was determined, and, on the same day, cervical ultrasound examinations were performed by a single, experienced paediatric radiologist. The sex-specific, upper normal limits for Tvol were then determined, based on age and body surface area (BSA). Results The median urinary iodine concentration was 120 µg/L (interquartile range 80-184); the population was therefore deemed to fall within the optimum range for iodine nutritional status. Eight children with heterogeneous glandular parenchyma were detected, as were 6 with increased vascularity, and 22 with intrathyroid cysts. Tvol increased with age and BSA in both sexes from the age of 3 years. In girls aged 11-12 years, Tvol was significantly larger than that in boys of the same age. When comparing children 6 years old and above, the 97th percentile Tvols with respect to gender/BSA were similar to WHO reference values, but by gender/age they were 30% larger. Conclusions This work proposes reference ultrasound-determined Tvols for 3-14-year-old children living in Madrid.

BACKGROUND: Orbital radioiodine uptake in patients with thyroid cancer is very uncommon with only a few reported cases, most of them being metastasis. The accumulation of 131I in nonthyroidal tissues and body fluids can lead to false-positive results in scintigraphy, which are sometimes difficult to differentiate from true metastases. CASE REPORT: A post-therapy 131I whole-body (WBI) scintigraphy in an asymptomatic 57-year-old female with papillary thyroid carcinoma (PTC) previously treated with total thyroidectomy and 6 ablative radioiodine doses showed a focal uptake in the right eyeball region. The lesion, placed in the orbital space, was surgically removed, and histology revealed a conjunctival inclusion cyst. DISCUSSION: Ocular and orbital metastases from thyroid cancer, as well as some non-neoplastic disorders or contamination, are possible causes for 131I uptake in the orbital region in scintigraphy. Conjunctival inclusion cyst is a condition associated with incidental 131I uptake that had not been reported before and should be ruled out as a non-metastatic cause of orbital radioiodine uptake in patients with PTC.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a common and deleterious side effect of amiodarone use. There are two types of AIT, characterized by distinct pathogenic mechanisms and, hence, different treatments. Discriminating between type 1 (AIT1) and type 2 (AIT2) AIT is often very challenging. Beta-glucuronidase (β-G) is a lysosomal enzyme released into the extracellular fluid during inflammation. OBJECTIVES: To examine whether the determination of the plasma activity of β-G is useful in distinguishing AIT1 from AIT2. METHODS: The study included 67 subjects: 9 with AIT1, 9 with AIT2, 14 with hyperthyroidism due to Grave's disease or toxic multinodular goiter, 14 with subacute thyroiditis, and 21 euthyroid controls. Thyroid function tests and plasma β-G activity were determined in all participants, while thyrotoxic patients also underwent thyroid ultrasound/scintigraphy and urine iodine excretion assessment. RESULTS: Plasma β-G activity (expressed as mean ± SD in nmol 4-methylumbelliferone [4-MU]/mL plasma/h) in AIT2 was higher compared to AIT1 (2,263.6 ± 771 vs. 1,101.8 ± 201.9, p < 0.05) and similar to subacute thyroiditis (2,263.6 ± 771 vs. 2,083.2 ± 987.5, p = ns). β-G activity did not differ significantly between AIT1 and controls (1,101.8 ± 201.9 vs. 954.6 ± 248.6, p = ns). ROC curve analysis revealed that β-G activity had a high predictive value for destructive processes, namely AIT2 and subacute thyroiditis (AUC 0.846, 95% CI 0.748–0.943) and a cut-off value of 1,480.5 nmol 4-MU/mL plasma/h was able to discriminate between destructive and non-destructive thyroid conditions with 74% sensitivity and 82% specificity. CONCLUSION: In our study, plasma β-G activity performed well in distinguishing AIT1 from AIT2. Further studies are warranted to establish its usefulness as a discriminator between the two AIT types.

Background: In Graves' disease (GD), immunocompetent cells infiltrate thyroid tissue with release of TSH-receptor antibodies (TRAb), and radioiodine treatment is known to elicit an immune response with an increase in TRAb. Objectives: The aim was to study if all patients treated with radioiodine respond with a release of TRAb, anti-thyroperoxidase (anti-TPO), and anti-thyroglobulin (anti-TG). Methods: This is a prospective observational study. GD patients (n = 131) were admitted for treatment with radioiodine. Thyroid antibodies were measured before and 3 months after iodine-131 treatment. Results: After 3 months, a fold change > 1.1 was found in 66% of the GD patients, while the remaining 34% did not have a change or decrease in in TRAb. Anti-TPO and anti-TG also increased; the former showed an increase in 73% and the latter of 52%, while 27 and 48% decreased/were unchanged. A significant positive correlation was found between TRAb and anti-TPO, but not between TRAb and anti-TG. In the group with an increase in TRAb, the median fold change was 5.1, but there were no additional effects of tobacco smoking. The proportion of females below the median age (51.5 years) was significantly higher in the group that increased in TRAb compared to the one that decreased/was unchanged (66 vs. 34%). Conclusions: Treatment with radioiodine elicits an increase in thyroid antibodies, but not in all GD patients. The proportion of responders varied and was affected by age, resulting in a stronger immune response at younger age. However, there were no additional effects of smoking. (Less)

Background Oculocutaneous albinism (OCA) is a heterogeneous autosomal recessive disorder characterized by reduced or absent melanin synthesis. Its prevalence is approximately one in 17,000 individuals worldwide. OCA causes a complete or partial absence of pigment in the skin, hair, and eyes. Reduction of melanin in the eyes results in reduced visual acuity, photophobia, and nystagmus. To our knowledge, the coexistence of albinism and thyroid autoimmune diseases has not been reported. Case report A 37-year-old male with OCA came to our observation for a familial history of autoimmune thyroiditis. He complained with mild asthenia. His brother was affected by OCA and autoimmune thyroiditis. Physical examination revealed the presence of fair skin, platinum white hair, and hypopigmentation of the iris. Laboratory data revealed the presence of subclinical hypothyroidism with positive serum anti-thyroid antibodies. Neck ultrasonography showed a markedly heterogeneously hypoechoic pattern of the thyroid, with a honeycomb-like appearance. Discussion In the majority of cases, OCA in Caucasians is caused by mutations in the tyrosinase gene. The tyrosinase peptide is normally expressed on the surface of melanocytes, although recent studies have shown its presence in thyroid follicular epithelial cells of patients with Hashimoto's thyroiditis. Therefore, although the mechanism is unclear, the present case report may suggest a pathogenetic link between OCA and Hashimoto's thyroiditis.

Introduction: Benign nodular goiter may be associated with swallowing difficulties, but insight into the associated pathophysiology is limited. The aim of this study was to investigate the effect of surgery on the degree of esophageal compression, and its correlation to swallowing difficulties.Methods: Esophageal compression and deviation were evaluated blindly on magnetic resonance imaging (MRI) of the neck, prior to and 6 months after thyroid surgery for symptomatic benign goiter. Goiter symptoms and swallowing difficulties were measured by the Goiter Symptom Scale of the Thyroid-Specific Patient-Reported Outcome (ThyPRO) questionnaire. Cohen's d was used for evaluating effect sizes (ES). Results: Sixty-four patients completed the study. Before surgery, median goiter volume was 57 (range 14-642) mL. The smallest cross-sectional area of the esophagus (SCAE) increased from a median of 95 (47-147) to 137 (72-286) mm 2 (ES = 1.31, p < 0.001). Median esophagus width increased from 15 (range 10-21) to 17 (range 12-24) mm (ES = 0.94, p < 0.001) after surgery, while no statistically significant change was observed for the sagittal dimension (anterior-to-posterior), thus reflecting an increasingly ellipsoid esophageal shape. Median esophageal deviation decreased moderately after surgery from 4 (0-23) to 3 (0-10) mm (ES = 0.54, p = 0.005). The goiter symptom score improved considerably from (mean ± SD) 40 ± 21 to 10 ± 10 points (ES = 1.5, p < 0.001) after surgery, and the improvements were associated with improvements in SCAE ( p = 0.03). Conclusions: In patients with goiter, thyroidectomy leads to substantial improvements in esophageal anatomy, as assessed by MRI, and this correlates with improved swallowing symptoms. This information is valuable in qualifying the dialogue with goiter patients, before deciding on the mode of therapy. Clinicaltrials.gov (NCT03072654).

Background: While thyroid nodules are frequent in endocrine clinical practice, patients are often asymptomatic and euthyroid, and death is rare in cases of malignancy. Objectives: To evaluate the perception of current international guidelines regarding thyroid nodule management among Italian endocrinologists, and to compare daily clinical practice with suggested recommendations. Methods: Italian Association of Clinical Endocrinologists (AME) members were invited to participate in a Web-based survey. Results: A total of 566 physicians responded. About 50% had read the full text of the guidelines. Over half appreciated the suggested ultrasound (US) risk categories. Fine-needle aspiration (FNA) was obtained more frequently than recommended. Follow-up of a cytologically benign nodule was largely performed according to the guidelines. Molecular testing would be most commonly requested when cytology reports showed atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (TIR3A for Italian System). Iodine and/or levothyroxine were largely prescribed for cytologically benign asymptomatic nodules. Laser/radiofrequency ablation and percutaneous ethanol injection were commonly considered as alternatives to surgery (46.2 and 71.4%, respectively). Conclusions: Efforts are needed to make the guidelines more user-friendly and to encourage the use of codified risk categories in thyroid US reports. FNA indications remain a matter of debate as FNA is obtained in clinical practice more often than is recommended. Current US follow-up modalities for a benign nodule are correct, but probably could be performed less frequently without any harm. Molecular testing, if accessible, would be helpful in guiding clinicians' strategies in cases of AUS/FLUS-TIR3A cytologic results. Nonsurgical procedures are favorably embraced.

Background: It is generally considered impossible to differentiate follicular carcinomas from follicular adenomas by means of ultrasonography or cytology before surgery. Therefore, follicular carcinoma is histopathologically diagnosed by verifying capsular and/or vascular invasion after surgery. However, ultrasonography may play an important role in diagnosing follicular carcinoma preoperatively in a small number of cases. Case Description: Four cases of follicular carcinoma or follicular neoplasm that transformed from a benign thyroid tumor and demonstrated a “nodule in nodule” appearance on ultrasonography are presented in this report. Characteristic ultrasound features of such patients are: (1) a “nodule in nodule” appearance, (2) a well-defined boundary line between the nodules, and (3) separate distribution of blood signals within each nodule. Conclusion: A small number of patients with follicular carcinomas or follicular neoplasms may present with a “nodule in nodule” appearance on ultrasonography. It was suggested a long time ago that follicular carcinomas may develop from benign thyroid tumors. The fact that follicular carcinomas appear within benign tumors may be evidence of thyroid tumorigenesis.

Background: Hypothyroidism due to non-compliance with levothyroxine therapy (pseudomalabsorption) is rare. The diagnosis is considered in patients with persistent severe hypothyroidism despite treatment with large doses of levothyroxine. Intestinal malabsorption, drug and dietary interference with levothyroxine absorption and nephrotic syndrome should be excluded. The diagnosis of pseudomalabsorption can be demonstrated by using “an oral 1,000 µg of levothyroxine test” showing a rapid decrease in thyroid-stimulating hormone and increase in thyroxine. There are however few data on the sensitivity and specificity of the test in large cohorts of hypothyroid patients. Treatment of pseudomalabsorption is controversial, with reports using parenteral, intramuscular or single weekly oral dosing of levothyroxine. Cases: We report 3 patients who presented with persistent clinical and biochemical signs of hypothyroidism despite replacement therapy with high doses of levothyroxine. Pseudomalabsorption was diagnosed by a systematic approach, including prior exclusion of digestive, liver and kidney diseases. A peroral challenge test was positive in all cases. Patients denied non-compliance, and a psychiatric approach was elusive. Two of the patients were treated successfully with a single supervised weekly 1,000-µg administration of levothyroxine, while non-supervised weekly administration resulted in hypothyroidism confirming pseudomalabsorption. Conclusions: Non-compliance with medical therapy should be considered in patients with treatment-refractory hypothyroidism. Supervised once weekly levothyroxine treatment is a safe and well-tolerated treatment option, obviating the need for parenteral administration of the drug. Apart from the medical treatment, there is also a need for psychiatric evaluation and care.

Background: Van Wyk-Grumbach syndrome (VWGS) is a rare presentation of juvenile hypothyroidism which manifests in females as chronic autoimmune hypothyroidism, isosexual pseudoprecocious puberty, and multicystic ovaries. It uniquely presents with short stature and delayed bone age unlike other causes of precocious puberty. Kocher-Debre-Semelaigne (KDSS) is a rare presentation of juvenile hypothyroidism manifesting as calf muscle pseudohypertrophy, delayed contraction and relaxation of reflexes, and percussion myxedema. Objectives: To diagnose the rare association of VWGS and KDSS and to conduct a follow-up of the patient on replacement therapy. Methods: We present a case of a 9-year-old female child who presented to the endocrine department with complaints of intermittent vaginal bleeding, short stature, and difficulty in walking. On evaluation she was found to be having autoimmune hypothyroidism, FSH-dominated isosexual pseudoprecocious puberty, delayed bone age, secondary pituitary macroadenoma, delayed relaxation of deep tendon reflexes, and pseudohypertrophy of calf muscles. The diagnosis of VWGS associated with KDSS was made. The patient was initially put on 25 μg thyroxine replacement, which was titrated accordingly, and was followed up after 6 months and 1 year. Results: All the features of the syndrome improved after 12 months of adequate thyroxine replacement. Conclusions: VWGS and KDSS are rare presentations of juvenile hypothyroidism, and their association is even rarer. Early diagnosis and prompt replacement therapy can avoid unnecessary investigations and surgical interventions.

Background: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT4) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT4 within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. Methods: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1: 4. We evaluated the association between preoperative FT4 levels and the risk of major bleeding by logistic regression. Results: Seventy-two cases (2.5%) with major bleeding were identified and 288 controls were selected. The median plasma level of FT4 was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT4 on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT4 level

Background: Struma ovarii (SO) is a specialized monodermal teratoma predominantly composed of mature thyroid tissue, accounting for approximately 5% of all ovarian teratomas. Thyrotoxicosis is seen in about 8% of patients with SO. Most SO cases are benign with only 5-10% being malignant, and malignant SO causing thyrotoxicosis is very uncommon. Case: A 64-year-old woman had been diagnosed with thyrotoxicosis 2 years previously. The thyroid gland was palpable with a micronodular texture, and the patient was euthyroid under carbimazole. She presented with abdominal pain and progressive enlargement of the abdomen over a 2-month period. An abdominal ultrasonography revealed a pelvic mass and a large fluid collection. Additional imaging confirmed the presence of a complex right ovarian mass measuring 13 cm. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy and appendectomy. The histological examination revealed the presence of ‘follicular thyroid-type carcinoma arising in an SO of the right ovary, with metastatic infiltration in the tissue fragments from the pouch of Douglas'. Antithyroid treatment was discontinued 1 month after surgery in light of the pathology result. During the 4-year follow-up, the patient remained euthyroid. Conclusion: There has been controversy about the management of malignant SO, which is a rare entity. Malignant SO causing thyrotoxicosis is even more uncommon. As clinical signs are nonspecific, other causes of thyrotoxicosis must be considered for a differential diagnosis. Our case is one of the very few cases ever reported.

Background: Subclinical hypothyroidism (SCH) is associated with an increased cardiovascular risk, but little information is available about its association with high-sensitivity C-reactive protein (hs-CRP). Objectives: This study aims to analyze the association between SCH and hs-CRP using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: The study has a cross-sectional design. We included subjects with normal thyroid function (thyroid-stimulating hormone, TSH, 0.4-4.0 μIU/ml and normal free thyroxine, fT4, 10.3-24.45 pmol/l) and SCH (TSH >4.0 μIU/ml and normal fT4) who were evaluated for hs-CRP. We excluded individuals on medications that affect thyroid function and those who had prevalent cardiovascular disease. Multivariate linear regression evaluated hs-CRP and TSH as continuous variables, and logistic regression models assessed hs-CRP ≥19.05 nmol/l as the dependent variable and crescent quintiles of TSH as the independent variables adjusted for demographic and cardiovascular risk factors. Results: We included 12,284 subjects with a median age of 50 years (interquartile range = 45-57); 6,408 (52.2%) were female, 11,589 (94.3%) were euthyroid, and 695 (5.7%) had SCH. Bivariate analyses of participants stratified into quintiles of TSH revealed differences according to hs-CRP but not the Framingham risk score. The fifth quintile of TSH was not associated with elevated hs-CRP, odds ratio = 1.11 (95% confidence interval = 0.98-1.26), p = 0.102, in a fully adjusted logistic model, also consistent with the linear model (β = 0.024, p = 0.145). Conclusions: TSH is not associated with hs-CRP. Obesity and insulin resistance are very important confounders in the study of the association between SCH and hs-CRP.

Papillary thyroid microcarcinoma (MPTC) has an excellent prognosis. We aimed to evaluate the evolution of therapeutic strategies over time and the clinical outcome of MPTC.In this retrospective multicenter observational study in a northwest Italian region, patients with intrathyroidal, unifocal tumor ≤1 cm in size, incidentally found at histology or preoperative cytology diagnosis, were included. Exclusion criteria were a previous head-and-neck irradiation and/or node metastases.From 1985 to 2012, 437 patients had an MPTC diagnosis, which was incidental in 85% and preoperative in 15%. Patients with a preoperative diagnosis were younger at the time of diagnosis (47.6 ± 12.7 years, p0.01) and had a larger tumor (7.0 ± 2.5 mm, p0.0001) than patients with an incidental diagnosis (age 52 ± 13.5 years, size 4.4 ± 2.8 mm), but there were no differences in clinical outcome between both groups. We observed a significant (p0.001) reduction in radioiodine remnant ablation during the years. TSH levels were:0.1 mIU/l in 27.5%, 0.1-0.5 mlU/l in 33.7%, 0.5-2.5 mlU/l in 32.6%, 2.5-4.2 mlU/l in 3.9%, and4.2 mlU/l in 2.3% of patients. Six patients (1.37%) had nodal recurrence; 5 of them were cured after therapy. MPTC-linked mortality was null.We confirmed the favorable clinical outcome of MPTC. Despite the reduction in radioiodine ablation, overtreatment of MPTC is still observed.

The aim of this study was to compare the TNM staging system and the American Thyroid Association (ATA) recurrence risk classification in predicting radioiodine refractory disease (RRD) in differentiated thyroid cancer (DTC) and to analyze the correlation of stimulated thyroglobulin (Tg) levels and rate of Tg elevation with the standardized uptake value onRRD was indicated through the retrospective analysis of consecutiveFifty-eight of 636 subjects developed RRD: 52 papillary and 6 follicular thyroid cancer. The median time between diagnosis and a negative WBS was 24 months (range 12-240). RRD developed in 11 low-risk, 32 intermediate-risk and 15 high-risk patients. A better response to therapy was seen in the low-risk versus the intermediate- and high-risk groups.The TNM and ATA staging systems show no significant difference in predicting the development of RRD. RRD is less likely in stage I, II and low-risk patients. There is no correlation between the level or rate of Tg rise and a positive

Beginning in 2011, the Food and Drug Administration (FDA) approved the use of multikinase inhibitors (MKIs) for medullary thyroid cancers (MTCs), and in 2013 MKIs were approved for metastatic differentiated thyroid cancers (DTCs). However, little is known about the use of chemotherapy in thyroid cancer patients. Thus, the goal of our study was to describe patterns of chemotherapy use, including MKIs, among DTC and MTC patients in the National Cancer Database (NCDB).Chemotherapy use, along with other treatment types (surgery and radiation), was assessed between 2004 and 2013. The primary predictor was the year of diagnosis (2004-2010 and 2011-2013), based on the FDA's approval of chemotherapy for MTC (2011). Baseline use of MKIs in DTCs in 2013 was also examined. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% CI of receipt of chemotherapy.Overall, 199,654 patients were included in our analytic sample with 194,667 nonmetastatic DTCs, 1,633 metastatic DTCs, and 3,354 MTCs. Among MTCs, chemotherapy use significantly increased from 3.1% in 2004-2010 to 5.0% in 2011-2013 (p = 0.018) in unadjusted and adjusted (OR = 1.54, 95% CI: 1.00, 2.36) analyses. In metastatic DTCs, 4.9% of patients received chemotherapy in 2013, which was not significantly higher than in previous years (p = 0.755).Overall, chemotherapy use among MTCs increased marginally following the FDA's approval of MKIs in 2011, although their use remains very low. MKIs were infrequently used in metastatic DTCs in 2013. Future studies examining patterns of chemotherapy in thyroid cancer patients are warranted.

Objective: To assess the reliability of thyroglobulin (Tg) as a marker of iodine status during pregnancy. Design: 299 women aged 30.5 ± 4.8 years (mean ± SD) were studied. Methods: In every subject, we measured urinary iodine concentration (UIC), serum thyrotropin (TSH), Tg, free thyroxine (fT4), Tg autoantibodies (TgAbs) and human chorionic gonadotropin (hCG) levels. We excluded samples with increased TgAbs from the analysis. Results: According to WHO criteria, the study population was iodine deficient in every trimester. Serum Tg levels did not differ during the three trimesters of pregnancy. Serum hCG levels fell significantly as pregnancies advanced. A weak, significantly negative correlation (limited to the 3rd trimester) was found between Tg and UIC (ρ = -0.187, p = 0.039). Serum fT4 decreased as pregnancies advanced and TSH increased. Serum fT4 was negatively correlated with TSH (ρ = -0.161, p = 0.006) and positively with hCG (ρ = +0.165, p = 0.005). The multiple regression equation of Tg based on hCG, TSH, UIC and trimester of pregnancy was significant but weak (F = 4.057, p = 0.003; R2 = 0.055), with hCG as a significant predictor Tg (p for log hCG = 0.041). Conclusions: Tg cannot be considered as a valid marker of iodine deficiency in pregnancy, at least in a mildly iodine-deficient environment. Further studies in a larger patient cohort with differences in iodine status, as well as studies on Tg changes after improving iodine status in pregnant women, are needed in order to corroborate these results.

Objective: To investigate the association between reproductive history and later development of various nosological subtypes of overt hyperthyroidism. Study Design: From the Danish population, we included incident hyperthyroid women, and for each case we recruited 4 euthyroid age-sex-region-matched controls from the same sub-population. Hyperthyroid cases/controls were: Graves' disease (GD, n = 232/928), multinodular toxic goitre (MNTG, n = 91/364), solitary toxic adenoma (STA, n = 21/84). Patients diagnosed with hyperthyroidism within 1 year after delivery including post-partum GD were excluded. In multivariate conditional regression models (reference: no reproductive events), we analysed the association between development of GD/MNTG/STA and reproductive factors such as age at menarche/menopause, reproductive span, number of pregnancies/childbirths/abortions, investigations for infertility, and years on oral contraceptives. We adjusted for possible confounders such as alcohol intake, smoking, co-morbidity, and education. Age was studied as a potential effect measure modifier. Results: GD patients diagnosed before the age of 40 years had given births more often than control subjects (OR [95% CI] for 1/2/3+ births [ref.: nulliparous] were 1.57 [0.80-3.11]/2.06 [1.001-4.22]/3.07 [1.50-6.26]), and they had induced abortions performed more often (OR for 1/2+ induced abortions [ref.: no: events] were 0.99 [0.54-1.84]/2.24 [1.12-4.45]). No associations were observed between any reproductive factor and the development of MNTG or STA. Conclusions: Childbirths and induced abortions may be followed by development of Graves' hyperthyroidism after the post-partum period. This was not the case for the non-autoimmune subtypes of hyperthyroidism.

Background/aims Overall, 2-13% of patients with thyroid cancer develop bone metastases (BM). In addition to decreased survival, patients with BM may present skeletal-related events (SRE) that impair the quality of life. Our objectives were to characterize clinical features, treatment approaches, and outcomes of patients with thyroid cancer and BM. Material and methods We identified patients diagnosed with thyroid carcinoma of follicular origin and BM followed at the Instituto Portugues de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal, from 1991 to 2017. SRE were defined as the need for bone irradiation, bone surgery, spinal cord compression, or pathologic fractures. Results The final cohort consisted of 86 patients, with a median follow-up time of 54 months (IQR 22.8-82.8), mainly women (67.4%), and a median age of 64 years (IQR 53.6-71.2). BM was the initial presentation of thyroid cancer in 36.0% of the patients. Bone involvement was multiple in 59.3% of the cases. Papillary carcinoma was the most frequent histological type, present in 47.7% of the patients, of which 56.1% presented the follicular variant. SRE were found in 76.7% of the patients. The most frequent SRE was radiotherapy (66.3%). Treatment with bisphosphonates was initiated in 19.8% of the patients. The 5-year specific survival was 60%, whereas the 10-year specific survival decreased to 50%. There were no differences in 5- or 10-year specific survival regarding gender, the occurrence of SRE, or histological type. However, patients with initial radioiodine non-avid lesions had a lower 5- and 10-year specific survival (p = 0.002). Discussion The high frequency of patients with SRE was notable. The follicular variant of papillary thyroid cancer was the variant most commonly associated with BM, reflecting a more similar behavior to follicular carcinoma than the classic variant.

Background: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer originating from parafollicular, calcitonin (Ctn)-producing C-cells. Prognosis correlates with primary tumor stage and Ctn levels. Patient: We describe a case of MTC involving a mass 7 cm in its largest dimension, associated with high Ctn concentrations (> 5,000 pg/mL), but normal carcinoembryonic antigen levels, and with no lymph nodes or distant metastases, in complete remission after thyroid surgery. The MTC had very peculiar histological features, with an expansive, noninfiltrating growth around the thyroid follicles, and no signs of invasion. These histopathological characteristics are reminiscent of the C-cell adenoma described in animals. The tumor also revealed an ossifying extracellular matrix unlike the classical amyloid. Despite the size of the tumor and the patient’s high Ctn levels at diagnosis, the case described here reached complete remission after surgery. Conclusions: Further studies are needed to clarify the characteristics of MTC and better predict its behavior at diagnosis.