Short Call Abstracts

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We used six different thyroid cell lines, human primary cultures and SCID mouse xenograft models to explore how PDGFRα alters follicular cell differentiation as defined by TTF1, Pax8 expression and iodide transport. Confocal microscopy, invasion assays and 3D culture defined TTF1 subcellular targeting and cell phenotype. Immunohistochemistry on patient tissue arrays (n = 287) with matching clinical data (follow‐up period 11 years) were used to map out recurrence rates as a function of PDGFRα and cytoplasmic TTF1 expression. We reveal that PDGFRα has a unique role in driving aggressive disease in PTC through a double‐hit on follicular cells. First, PDGFRα specifically drives dedifferentiation by disrupting the transcriptional activity of TTF1. PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. Disrupted TTF1 function creates an invasive phenotype that lacks thyroglobulin production and sodium iodide symporter function. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5 years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. Secondly, PDGFRα transforms PTC cell lines as documented by cytoskeletal rearrangement, increased migratory potential, the formation of invadopodia and through the epithelial‐mesenchymal transition by impressive augmentation of Snail and Slug expression. Crenolanib, a small molecule inhibitor of PDGFRα reverses these phenotypic changes. Moreover, we demonstrate in SCID xenografts that crenolanib treatment restores iodide transport and decreases tumor burden by more than 50%. We demonstrate that PDGFRα drives PTC metastases by disrupting TTF1 function and mediating the epithelial‐mesenchymal transition. Focused inhibition of PDGFRα, combined with radioactive iodine, represents a new avenue for treating patients with aggressive variants of PTC.

A new paradigm has reclassified the non‐invasive encapsulated follicular variant of papillary thyroid cancer (EFVPTC) as a non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) without a significant risk for malignancy. Increased expression of programmed death ligand 1(PD‐L1) on tumor cells has been associated with poor prognosis in some human cancers. The aim of this study was to determine whether PD‐L1 expression could be a useful biomarker to distinguish invasive EFVPTC from NIFTP patients. In a retrospective study, immunohistochemical analysis of PD‐L1 expression was performed in 157 cases (50 reclassified NIFTP, 45 invasive EFVPTC, 26 benign lesions and 36 benign lesions with lymphocytic thyroiditis). Formalin fixed and paraffin embedded tissue sections were immunostained with anti‐PDL‐1 antibody (E1L3N), and detected using Vectastain ABC system. Immunostaining in subcellular compartments of tumor cells was scored manually and compared with digital image analysis (DIA) using Visiopharm system. Statistical analyses were performed using independent samples t‐test and ANOVA. Cytoplasmic and membranous PD‐L1 expression was significantly increased in invasive EFVPTC as compared to NIFTP (p < 0.001; p = 0.008 respectively), and in EFVPTC vs benign neoplasms (p < 0.001; p < 0.001). ANOVA revealed significant difference in PD‐L1 expression between NIFTP and EFVPTC, but not in the benign group. The presence of lymphocytic thyroiditis enhanced PD‐L1 expression in benign nodules indicating that concurrent lymphocytic infiltration needs to be interpreted with caution. Automated DIA confirmed the manual scoring findings thereby validating the utility of PD‐L1 as a biomarker in distinguishing NIFTP from invasive EFVPTC. PD‐L1 expression is increased in invasive EFVPTC as compared to NIFTP and benign thyroid nodules suggesting that it could be a useful test in distinguishing NIFTP from invasive EFVPTC. To our knowledge this is the first report using a protein biomarker such as PD‐L1to support the conclusion that the majority of NIFTP are benign tumors.

Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto‐oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death. We hypothesized that loss of function of ATF4 could play a role in initiation of MTCTargeted deletion of ATF4 in mice was used to assess ATF4 function in the thyroid gland. ATF4 overexpression was achieved by adenoviral and lentiviral vectors. We used immunohistochemical analysis and western blotting of MTC tumors to determine protein levels of RET and ATF4 and the Kaplan‐Meier method to determine the association with clinical outcomeTargeted deletion of ATF4 in mice causes C‐cell hyperplasia, a precancerous lesion preceding MTC. Forced ATF4 expression decreased survival of MTC cells and blocked the activation of RET downstream signaling pathways (phosphorylated ERK, phosphorylated AKT, and p70s6k/pS6). ATF4 knockdown decreased sensitivity to sunitinib‐induced apoptosis. Moreover, ATF4 expression decreased RET protein levels by promoting RET ubiquitination. We found decreased or loss of ATF4 in 52% of MTC tumors (n = 40) compared with normal thyroid follicle cells. A negative correlation was observed between RET and ATF4 protein levels in MTC tumors, and low ATF4 expression was associated with poor overall survival in MTC patients. ATF4 was identified as a negative regulator of RET, a candidate tumor suppressor gene, and may be a molecular marker that distinguishes patients at high risk of MTC from those with a longer survival prognosis.

The intracerebral availability of thyroid hormones is partly regulated by the local type II deiodinase (DIO2) and the cellular membrane transport‐facilitating monocarboxylate transporter (MCT10). Previous prospective randomized studies of hypothyroid patients have indicated that around half of patients preferred T4+T3 combination therapy. We now studied DIO2 and MCT10 gene polymorphisms in relation to such preference. 44 previously hypothyroid patients now with long‐time stable (≥6 months) euthyroidism on T4 therapy participated in a prospective double blind cross‐over study. Half of the patients were randomized into continuous three months T4 therapy followed by 3 months T4‐T3‐combination therapy, the rest into combination therapy followed by T4‐therapy. In both periods, 50 mg of T4 was blindly replaced by either identical 50 mg T4 or by 20 mg T3. We investigate four single‐nucleotide polymorphisms (SNPs) with predesigned TaqMan assay (Applied Biosystems, Foster City, CA) in two genes: DIO2 (rs225014, rs12885300, rs502215) and MCT10 (rs17606253). We further asked in which of the two treatment periods patients felt better (which treatment was preferred). Overall, 27 out of 45 patients (60%) preferred the combination therapy. Patients preferring the combination therapy had a 6.40 (1.06–49.7) higher odds for harboring polymorphism in the rs17606253 (MCT10) gene (p = 0.018), and a 2.80 (0.66–12.3) borderline higher odds for harboring polymorphism in the rs225014 (DIO2) gene (p = 0.11). Accordingly to standard procedures, we combined the two gene polymorphisms, and 8/19 (42%) of patients with no polymorphism, 12/19 (63%) of patients harboring one of the two polymorphisms, and all 7 of those with polymorphisms in both genes (100%) preferred the combined T3+T4 treatment (linear‐by‐linear association, p = 0.011; Jongheere‐Terpstra test, p = 0.009). The present study indicated that the combination of two polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients' preference for T4+T3 replacement therapy. If future studies can confirm these results, combination therapy may be restricted to specific individuals harboring certain polymorphism patterns.

This study examined whether the prevalence of an anomaly called methimazole (MMI) embryopathy (single or multiple existence of choanal atresia, esophageal atresia, aplasia cutis, umbilical defects, or omphalocele) increases with MMI exposure in the first 12 gestational weeks. We performed a prospective, multicenter, observational study from 2008 to 2015. Women with Graves' disease who became pregnant were registered from thyroid clinics at the Japan Drug Information Institute in Pregnancy (JDIIP). The MMI group comprised women who took any dose of MMI regardless of taking propylthiouracil (PTU) during the first trimester; the PTU group comprised women who took any dose of PTU, but not MMI; and the non‐antithyroidal drug (ATD) group comprised women who took neither PTU nor MMI. Pregnancy outcomes were collected from participants and medical institutes by mail or phone and compared with matched controls who consulted at JDIIP during the same period with known non‐teratogenic drugs or diseases. Nine hundred ninety‐nine women with Graves' disease and 2,869 controls were registered, and 884 cases and 2,010 controls were finally analyzed. In the MMI group, the incidence of MMI‐related embryopathy was 2.7% (95% CI: 1.1–5.4%; 7 cases in 263 live births), which was markedly higher than the control incidence of 0.05% (1 case in 1837 live births). However, no MMI‐related embryopathy cases were found among the 319 PTU group live births or the 276 non‐ATD group live births. Five MMI embryopathy cases were exposed to MMI during the entire organogenetic period, while the other 2 cases were exposed till 7 and 8 gestational weeks, respectively. The incidence of MMI embryopathy was very high at 7.6% when MMI was discontinued after 8 gestational weeks, while embryopathy was not observed if MMI was stopped before 6 gestational weeks. The 5.7% incidence of general malformation in the MMI group was significantly higher than in the non‐ATD (1.4%) and control (2.2%) groups, while the 3.1% incidence in the PTU group was similar to these other groups. We recommend that pregnant women with Graves' disease avoid exposure to MMI during the organogenesis period. Cessation of MMI prenatally or during early pregnancy is recommended.

ESTIMABL 1, a non‐inferiority randomized phase III trial showed an equivalent ablation rate at 8 months in low risk thyroid cancer patients with a low (1.1GBq) or a high (3.7GBq) 131‐I activity and after preparation with either rhTSH or prolonged thyroid hormone withdrawal (THW) (NEJM 2012). We provide here outcome data on the 711 patients who were still on trial with a mean follow‐up of 61.7 months (follow‐up >3 years for 91%), according to disease status at ablation and at 8 months. Among 27 patients with persistent disease at ablation, 16 were retreated with 131‐I and 8 with surgery. At last follow‐up, 25 achieved a complete remission, and two had persistent disease.

Among 53 patients with an incomplete ablation at 8 months, 13 were retreated with 131‐I and 5 with surgery. At last follow‐up, one patient had persistent lung disease, 6 had elevated serum Tg (>1ng/mL) on LT4 treatment and no other evidence of disease and 46 were in complete remission.

Among 631 patients with no evidence of disease and a complete ablation at 8 months, 614 remained in complete remission and 17 had abnormalities during follow up (either abnormal US or/and serum Tg >1ng/mL on LT4 treatment). At last follow‐up, 15 were in complete remission without any further treatment and two had a lymph node recurrence.

At last follow‐up, 11 patients had either persistent structural disease (n = 5) or serum Tg level >1ng/mL (n = 6). Seven received initially 1.1 GBq (4 after rhTSH and 3 after THW) and four 3.7 GBq (2 after rhTSH and 2 after THW). No thyroid cancer related death was observed. Long term recurrence rate is low and does not seem dependent on the strategy of initial ablation. These data validate the use of 1.1 GBq following rhTSH for post‐operative ablation in low risk thyroid cancer patients, when ablation is indicated.

While an active surveillance management approach to low risk thyroid cancer has been pioneered and effectively implemented in Japan, it remains uncertain whether or not a similar approach would be accepted and successful in a US population. Using careful risk stratification, the thyroid cancer disease management team at MSKCC has offered an observational management approach to selected patients with low risk papillary thyroid cancer for many years (usually with ultrasound q 6 months for 2 years, then yearly without levothyroxine suppression). As of August 2016, 278 low risk patients are being followed with an active surveillance management approach [84% (n = 234) Bethesda VI, 16% (n = 44) Bethesda V cytology]. Overall, 75% are female, the median age at diagnosis is 52 yrs, the median tumor size is 8 mm (range 3–22 mm, 22% > 1 cm), and the median follow‐up is 20 months. At last follow‐up, 96% (n = 267) continue on AS without evidence of structural disease progression, 2.2% (n = 6) demonstrated an increase in the size of the primary tumor >3 mm [ median diameter increased from 9.5 mm to 11.5 mm during 23 months of observation, range 10–54 months], 1.1% (n = 3) elected to have surgery without evidence for structural disease progression, and 0.7% (n = 2) transferred their care back to the community. No patient developed lymph node metastases. Neither the size of the primary tumor, gender, nor the duration of follow up predicted tumor growth. However, patients showing an increase in tumor size during observation tended to be younger than those with stable disease (41 ± 12 yrs vs. 53 ± 15 yrs, p = 0.057). Consistent with the data reported from the Kuma Clinic in Japan, our data show that an active surveillance management approach to low risk thyroid cancer can be effectively employed in the US population.

Despite recent advances, treatment options for advanced thyroid cancer remains limited. Aberrant mTOR pathway and somatostatin receptor signaling is implicated in thyroid cancer and offers potential targets of therapy. This study assessed the clinical efficacy of everolimus and pasireotide in patients with differentiated and medullary thyroid cancer. Adult patients with progressive medullary (MTC) and iodine refractory differentiated thyroid cancer (DTC) previously untreated or treated with one systemic therapy were eligible. Patients were randomized to receive everolimus (Arm A), pasireotide (Arm B), or the combination of both drugs (Arm C). At progression, patients in Arm A or B switched to the combination of both agents. Treatment continued until progression or intolerable toxicity. The co‐primary endpoints were response rate and 1‐year progression free survival. The trial employed a Simon 2‐stage enrolment with 18 and 10 patients in stage I and II for each arm of the study. Efficacy was measured by RECIST criteria and toxicity was monitored and graded according to NCI CTCAE v. 4 The study enrolled a total of 42 patients. Interim analysis was conducted after enrolling 34 patients (27 DTC and 7 MTC) randomized to Arm A (11), B (11) and C (12); the interim analysis result is reported herein. The most frequent adverse events (AE) were anemia, stomatitis, fatigue, hyperglycemia and hypercholesterolemia. AEs were most frequent in Arm C followed by Arm A and then Arm B. There was no objective response by RECIST criteria across the three arms of the study. The 1‐year PFS rate was 54.5%, 43.6% and 50.0% while the median PFS was 23, 8 and 12.5 months for Arms A, B and C respectively. There was a noticeable difference in efficacy by histology with 1‐year and median PFS of 52.6% vs. 26.8% and 13 vs. 8 months for DTC and MTC respectively. Everolimus followed by the delayed combination of everolimus and pasireotide LAR was identified as the best arm on study. This sequential combination strategy offers improved tolerability and efficacy over immediate combination strategy. Updated data from all 42 enrolled patients will be presented at the meeting.

Isolated central hypothyroidism(ICH) is a rare entity in the pediatric population, characterized by delayed diagnosis and treatment due to its variable presentation and subclinical onset. It is often missed on TSH based screening. Undiagnosed central hypothyroidism(CH) can be detrimental to cognition and metabolism. Herein, we present a case of ICH in an adolescent with Narcolepsy. A 15 year old obese male was evaluated for excessive daytime somnolence and snoring. No other symptoms. Denied cataplexy or hypnogogic hallucinations. Besides obesity, he was healthy. No family history of similar presentation. Sleep study showed mild obstructive sleep apnea. Multiple Sleep Latency Test was consistent with narcolepsy and he was started on Modafinil. Due to persistent weight gain and daytime somnolence, thyroid function tests (TFT) were sent [TSH: 0.6 uIU/ml (inappropriately normal) and Free T4: 0.56 ng/dl (low) with negative thyroglobulin and anti‐peroxidase antibodies]. Serial TFT confirmed CH. MRI of brain and pituitary was normal as well as the rest of the pituitary hormones. ICH was diagnosed and he was started on thyroxine replacement with improvement in weight and sleep symptoms in the following months. Central hypothyroidism presentation may be subtle and with overlapping symptoms with other conditions. Even on patients with diagnosed Narcolepsy, TFT should be done routinely. Moreover, when symptoms don't improve as expected on Narcolepsy medications, thyroid functions tests are warranted. Both, CH and Narcolepsy are rare conditions in pediatrics and difficult to diagnose due to their variable presentations and severity. Theoretical association between the two conditions can exist due to their association with hypothalamus and pituitary gland, however clinical association as seen in our case has not been described in the literature, to the best of our knowledge. Isolated central hypothyroidism can often be subclinical and undiagnosed hence a thorough knowledge of various presentation and associations is detrimental in early diagnosis and treatment. Presence of narcolepsy should prompt towards screening for central hypothyroidism in appropriate clinical settings.

The diagnosis of adenomas secreting of multiple pituitary hormones can be challenging. Our case summarizes the clinical and pathology features of a patient with a plurihormonal pituitary adenomac64 yo man was seen in the clinic for palpitation and sleeping difficulty for 6 months. He reports 10 lb weight fluctuation and improvement in libido, denied symptoms of hyperthyroidism. He denied taking thyroid medications, supplements or excessive caffeine intake. No family history of pituitary or thyroid abnormalities. Exam was remarkable for tachycardia with no features of Cushing or Acromegaly. Labs: TSH 6.716 H uIU/mL, FT4 1.61 ng/dL (0.7–1.48), Free T3 4.19 pg/mL (1.5–4.2) Reverse T3 35 ng/dL (8–25), Thyroglobulin 50.2 ng/mL, Thyroglobulin Ab negative, Anti‐TPO Ab negative, Alpha subunit 1.8 ng/mL (<0.6), Thyroxine 11.33 ug/dL (5.1–14.1), Thyroxine binding globulin 10.6 ug/mL (13–30), Free T4 by dialysis 5 ng/dL (0.8–2.7) Total testosterone 1309 H ng/dL, Free testosterone 80.5 pg/mL, Bioavailable testosterone 165.5 ng/dL, SHBG 75 nmol/L, Albumin 4.5 g/dL, FSH 11.22 mIU/ml, LH 8.62 mIU/mL, PRL 6.7 ng/mL confirmed by dilution, am Cortisol: 9.7 ug/dL, ACTH 30 pg/mL, IGF‐I: 144 ng/mL Z‐score 0.4. Pituitary MRI: 12 mm pituitary macroadenoma without impingement upon optic chiasm or extension into cavernous sinuses. Repeated labs confirmed the finding of inappropriately high‐normal gonodotropins and thyrotropin with high‐normal testosterone and FT4. Patient could not tolerate T3 suppression testing nor MMI. He underwent frameless stereotactic transnasal transsphenoidal microsurgery excision of pituitary macroadenoma. Immunostaining of tumor tissue demonstrated positivity for TSH, GH, FSH, PRL and α‐subunit. Negative for LH, FSH and ACTH. MIB‐1 2.8%. Post‐op course was complicated by transient SIADH. Follow up labs and pituitary MRI are normal up to 1‐year post‐op. He is not on hormonal replacement Thyroid‐stimulating hormone‐secreting pituitary lesions are frequently macroadenomas and can co‐secrete pituitary hormones. Plurihormonal adenoma can have a heterogeneous clinical picture and be more challenging. In our case the surgical management was curative, but close monitoring is recommender due to the recurrence risk.

Whether subclinical hypothyroidism adversely impacts pregnancy outcomes was inconclusive, and little data were available on the optimal thyroid stimulating hormone (TSH) range in women planning a conception. Our objective was to investigate the association between preconception TSH levels and pregnancy outcomes. The cohort was nested in the free National Pre‐pregnancy Checkups Project during 2010–2012 in China. A total of 183923 women with singleton live‐birth infants were eligible in the present study. Maternal serum samples were obtained within six‐month before conception. Participants were grouped by two TSH cutoffs, namely first‐trimester specific upper limit 2.5 mIU/L and non‐pregnant upper limit 4.29 mIU/L. Outcomes included gestational age, modes of delivery, birth weight. A multinomial logistic regression model was used to adjust odds ratio (OR). The incidence of preterm birth, postterm birth, caesarean section (CS) and operative vaginal delivery was 4.7%, 0.2%, 38.1% and 4.8%. The incidence of small for gestational age, large for gestational age (LGA), low birth weight and macrosomia infants was 11.1%, 11.9%, 4.9% and 5.8%. High TSH levels carried increased risk of preterm birth, CS and LGA, regardless of which upper limit adopted. Compared with TSH 0.48–2.5 mIU/L, preconception TSH 2.5–4.29 mIU/L was associated with increased risk of early preterm birth (OR 1.16, 95% CI 1.05–1.27), late preterm birth (OR 1.07, 95% CI 1.00–1.13) and operative vaginal delivery (OR 1.15, 95% CI 1.09–1.21), while TSH 4.29–10 mIU/L was correlated with early preterm birth (OR 1.14, 95% CI 1.10–1.62), late preterm birth (OR 1.15, 95% CI 1.01–1.30), CS (OR 1.15, 95% CI 1.10–1.22) and LGA (OR 1.12, 95% CI 1.04–1.21). No difference was observed regarding other pregnancy outcomes. Differences were consistently significant when we compared TSH 2.5–4.29 mIU/L group with TSH 4.29–10 mIU/L group, as to preterm birth (OR 1.13, 95% CI 1.01–1.26), CS (OR 1.18, 95% CI 1.11–1.24) and LGA (OR 1.09, 95% CI 1.02–1.19). Preconception high TSH levels were associated with increased risk of preterm birth, CS delivery and LGA infants, even within normal non‐pregnant reference range.

We have analyzed liver‐spleen SPECT with fractal slopes, Sb, positive, and Sw, negative, for areas of best and worst liver function. As the absolute value of S increases, liver function is more heterogeneous and more compromised. Liver‐spleen SPECT used Tc‐99m‐sulfur colloid IV and high resolution collimators. Modified fractal analysis used plots of Ln(Is) vs. Ln(Av/Pk), for peak, Pk, and average, Av, liver counts in isocontours, Is. Sb >0 is the limiting slope as both Av/Pk and Is approach 1, at Is near 100% of Pk. Similarly, Sw <0 is from plots of Ln[(100+B)‐(Is)] vs. Ln (Av/Mn), where Mn is the least liver count and B is the Is value for the liver boundary. Sn was Sb normalized for body and liver‐spleen size. Uncertainties noted are standard deviations and abnormal >2 Std dev from mean. Among 744 patients, 163 (22%) had thyroid disease and Sn was abnormal in 724 (97%), among whom 163/596 (27%) had abnormal serum ALT or AST. Limiting slopes were linear for Sb and fit a binomial or trinomial for Sw. Euthyroid patients without liver disease due to hepatotoxins, viral hepatitis, cholecystitis or cysts had Sn 0.96+‐0.13; Sw −0.94+‐0.11 (p 0.6, NS) for 20 near normal; Sn 1.88+‐0.31 for 123 NAFL; Sn 2.89+‐0.56 for 88 NASH and Sn 3.82+‐0.87 for 25 hepatic fibrosis patients. In each group, dysthyroid patients had Sn > and/or Sw < their group average Sn, often near average Sn for the next more abnormal group. The highest Sn in a thyroid patient was 5.01, post thyroid storm, similar to Sn 5.27 with HbA1c > 10% or Sn 6.30 in fatal liver metastases. Mild hypothyroidism led to NAFL in 3 lean, type 1 diabetics (not NAFL prone) with no other liver disease. In insulin resistant patients, thyroid and glycemic status effects were nearly additive. Subclinical thyroid disease in 5 near normal cases had only Sw abnormal in 4 and Sb in 1. In treated thyroid patients with 86 follow‐up studies at 3 to 40 months, Sn was worse in 27 (31%), unchanged in 17 (20%) and better in 42 (49%). Quantitative analysis of high resolution liver SPECT reveals that thyroid status critically affects hepatic function and directly impacts hepatocentric pathogenesis, such as insulin resistance.

Given the complex action and role of the thyroid in metabolism and control of weight gain/loss, it is important to understand how this treatment may affect weight loss, beyond the standard measures of changes in % body weight and BMI. For the first time, here we present data collected over the past 18 months from the 20 Lighter Program (T20LP), a 3‐phase (9 wk) intensive weight reduction program. This abstract focuses on the differences between participants taking/not taking prescription thyroid replacement over the first 2 phases (6 wk) between Jan 2015 and June 2016. T20LP, a doctor supervised 3‐phase program includes a loading day, 6 wk of VLCD (500–520 calorie/day), and 3 wk transition back to a normal dietary intake. T20LP includes daily home weigh‐ins, daily texting with the doctor, proprietary vitamin/mineral supplementation, daily journaling, and requires 3 in‐person office visits (Initial baseline, ∼Day42, and ∼Day63). T20LP uses body composition analysis via Bioelectrical Impedance Analysis with bipolar foot electrodes at each office visit to monitor participant progress. Of 602 participants completing the first 6 wk of T20LP by July 31, 2016, 60 reported taking prescription thyroid hormone replacement. Baseline age, comorbidities, history and prescription medications were similar between those taking and not taking thyroid medications, and typical of metabolic syndrome. From initial baseline to 6 wk, T20LP participants from both groups showed statistically significant and clinically meaningful reductions in body weight, BMI, body fat %, visceral fat, basal metabolic rate, metabolic age; and increases in body water %. However, we found a significant divergence in mean changes in body fat, visceral fat, muscle mass, and basal metabolic rate between the two groups favoring those not on thyroid hormone. At first glance the improvements in weight and BMI between participants on/not on thyroid hormone are the same, but when more detailed measures of body composition and metabolism are examined there are notable differences. While still statistically significant and clinically meaningful, there is a difference that clinicians should be aware of.

No data are present in literature about the effectiveness of levothyroxine (L‐T4) soft gel capsule formulation in patients recently submitted to total thyroidectomy. The aim of this study was to compare the effectiveness of L‐T4 gel capsule, with L‐T4 tablets, in patients recently submitted to total thyroidectomy for euthyroid benign nodular goiter (without malabsorption or drug interference).

Thirty‐two patients were consecutively recruited: 16 patients were treated with L‐T4 therapy in tablets, while 16 with gel capsule L‐T4 at the same dosage (1.5 mcg/kg/day), 30 min before breakfast, starting the day after thyroidectomy. Serum thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were re‐evaluated after 6 weeks (first control) and 12 weeks (second control) in both groups.

TSH values were significantly lower in the L‐T4 gel capsule group, than in L‐T4 tablet group, both at the first control (P < 0.01) and at the second control (P < 0.01); FT4 and FT3 levels were not significantly different. The prevalence of patients in the hypothyroid range (TSH >3.6 mcU/ml) was significantly higher in the L‐T4 tablet group.

These results suggest that soft L‐T4 gel capsule is more effective than L‐T4 tablets in controlling TSH levels in thyroidectomized patients without malabsorption, gastric disorders, or drug interference. However a larger number of studied patients is necessary to obtain a definitive result.

Few data are present in literature about the effectiveness of levothyroxine (L‐T4) liquid formulation in patients recently submitted to total thyroidectomy. The aim of this study was to compare the effectiveness of L‐T4 liquid formulation, with L‐T4 tablets, in patients recently submitted to total thyroidectomy for euthyroid benign nodular goiter (without malabsorption or drug interference).

One hundred patients were consecutively recruited: 51 patients were treated with L‐T4 therapy in tablets, while 49 with liquid L‐T4 at the same dosage (1.5 mcg/kg/day), 30 min before breakfast, starting the day after thyroidectomy. Serum thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were re‐evaluated after 6 weeks (first control) and 12 weeks (second control) in both groups.

TSH values were significantly lower in the liquid L‐T4 group, than in the tablet L‐T4 group, both at the first control (P < 0.05) and at the second control (P < 0.01); FT4 and FT3 levels were not significantly different. The prevalence of patients in the hypothyroid range (TSH >3.6 mcU/ml) was significantly higher in the L‐T4 tablet group.

These results suggest that liquid L‐T4 is more effective than L‐T4 in tablets in controlling TSH levels in thyroidectomized patients without malabsorption, gastric disorders, or drug interference.

Dairy products contribute over 60 percent of the iodine nutrition in the US population and most likely plays a contributing role in the different iodine levels, found in the four regions. We recently evaluated the iodine content in dairy products and some nondairy substitutes. There Many factors including iodine content in the cow's feed and sanitizers used, as well as the region and season of milk collection affect iodine content in dairy products The Centers for Disease Control and Prevention (CDC) used recent analysis of data from the restricted National Health and Nutrition Examination Survey (NHANES) data sets to evaluate the geographic distribution of NHANES iodine status by region, to help identify the populations that are at risk of insufficient iodine intake.

We recently evaluated the iodine content in dairy products and some nondairy substitutes. There is little current data available regarding the iodine content in dairy products in the US. Many factors including iodine content in the cow's feed and sanitizers used, as well as the region and season of milk collection affect iodine content in dairy products. We analyzed the iodine content in 55 dairy products. We also analyzed the iodine content of nondairy products (soy, rice, hemp and others). Factors that can affect the iodine content in these products includes soil iodine content or use of fertilizers that contain iodine. The data indicate that pregnant women in the NHANES 2001–2010 from the Midwest have significantly low levels of urine iodine (UI). While pregnant women from the other three regions have adequate levels of iodine nutrition. The range of iodine concentrations for dairy products fell between 30 ug/L to 2459 ug/L. Nondairy products had considerably less iodine concentration range of <1 ug/L to 105 ug/L. There are geographical differences in the UI concentration of pregnant women in the US. Our initial study indicates the need for further outreach to the dairy industry, health professionals and consumers to work together to ensure adequate iodine nutrition for the US population.

The common carotid artery is the lateral landmark of dissection during thyroidectomy. When performing a thyroidectomy, knowledge of normal anatomy as well as possible anatomic variants is vital to avoid injuring nearby structures. In normal cervical anatomy, the bilateral carotid arteries are found coursing posterolaterally to the thyroid gland and deep to the visceral layer of pretracheal fascia which envelopes the thyroid. This case report describes an exceedingly rare variant of an intra‐thyroidal common carotid artery, not previously described in the literature. A 23 year old Caucasian female presented to our institution for workup for multinodular goiter. Family history was positive for papillary thyroid cancer in her mother and thyroid disease (goiter) in her grandmother and great‐grandmother. Her past medical history was significant for cutaneous melanoma. Ultrasound demonstrated multinodular thyroid as well as a large solid cystic mass in the left thyroid lobe and fine needle aspiration was positive for papillary thyroid carcinoma. During total thyroidectomy, the carotid artery was found to course centrally through the parynchyma of the right lobe and was associated with an ipsilateral lower non‐recurrent recurrent laryngeal nerve (RLN) coursing superolaterally to enter the cricothyroid joint. The common carotid artery was dissected free from within the substance of the gland, the non‐recurrent nerve was found and preserved and the thyroidectomy was completed without complications. This is, to our knowledge the first report of such an anatomic variant in the literature. An aberrant carotid artery anatomy has the potential to cause life threatening surgical complications and recognition of this anatomic variant should be taken into consideration when performing a thyroidectomy. Furthermore, recognition of the concurrence of RLN anomalies with vascular variations will allow identification of non‐recurrent nerves and prevent nerve damage.

The association between surgeon volume and outcomes is well established for thyroid procedures but few reports focus on parathyroid surgery. The purpose of this study was to test our hypothesis that high surgeon volume is associated with improved surgical efficiency, 30‐day outcomes, and lower hospital utilization for parathyroid procedures.

547 patients with parathyroidectomy performed by a high‐volume surgeon (> 40 cases per year) were propensity score‐matched to 547 patients with the same procedure performed by a low‐volume surgeon (≤ 20 cases per year). Matching variables included demographics, health care use in the year before surgery, DxCG risk score and Charlson comorbidity index, and 26 thyroid‐specific and general comorbidities. We assessed a composite outcome of 25 complications that included thyroid‐specific surgical complications (hematoma, stridor, transient hypocalcemia, and vocal cord paralysis/paresis) and general surgical complications. We also assessed mortality, readmission, and emergency department visit rates, proportion of outpatient procedures, cut‐to‐close time, and length of stay.

Compared to patients undergoing parathyroidectomy performed by low‐volume surgeons, those undergoing parathyroid surgery performed by high‐volume surgeons had a lower rate of vocal cord paralysis (0.2% vs. 1.6%, p < .05). No differences were observed for hematomas or hypocalcemia. High‐volume surgeons had a greater proportion of outpatient procedures for parathyroidectomies than did low‐volume surgeons (60% vs. 34%, p < .05). No other differences in 30‐day outcomes and utilization and surgical efficiency were observed.

Surgeon volume is associated with outcomes to a limited degree in parathyroid surgery. However, experienced surgeons contributed to organizational efficiency by conducting more procedures on an outpatient basis.

Our lab has shown Src is a key mediator of tumorigenesis in thyroid cancer; however, Src inhibitors have had limited efficacy in solid tumors. To more effectively target Src in the clinic, our lab generated 4 thyroid cancer cell lines (BCPAP, SW1736, Cal62, C643) resistant to dasatinib (Beadnell et al 2016). We have shown the dasatinib‐resistant (DasRes) cells are also resistant to saracatinib, but sensitive to the Src inhibitor bosutinib, suggesting unique off‐targets of bosutinib play an important role in mediating dasatinib resistance. We used compound centric chemical proteomics to identify bosutinib specific kinases (BSKs). Using the STRING database we identified mTOR as a potential network breaker among the BSKs. The effects of AKT/mTOR pathway inhibition on thyroid cancer cell growth was tested using Sulforhodamine B assays and signaling was evaluated by immunoblotting. Treatment with the AKT/p70S6 inhibitor, AT7867, or the mTOR inhibitor, everolimus, inhibited the growth of control and DasRes cells. Interestingly, maintaining the DasRes cells in dasatinib increased the sensitivity to AT7867 3–8 fold, but did not affect sensitivity to everolimus. Accordingly, immunoblot analysis showed that sensitivity to the combination of AT7867 and dasatinib completely inhibited S6 ribosomal protein (S235/236, S240/244), while single agent treatment only partially inhibited S6. Single agent mTOR inhibition with everolimus was sufficient to shut down S6, correlating with no increase in sensitivity when the DasRes cells are maintained in dasatinib. Increased activation of AKT(T308) and ERK(T202/Y204) was observed in response to everolimus or AT7867 treatment, suggesting that inhibition of this pathway promotes a feedback loop to try to activate the MAPK pathway. This increase in pERK is attenuated when the DasRes cell lines are maintained in dasatinib, suggesting the combination of dasatinib and AKT/mTOR inhibition is the most effective at shutting down escape signaling pathways. These results indicate that activation of S6 may be a biomarker of Src inhibitor resistance, and provides important information on how targeting different components of the AKT/mTOR pathway affect bypass signaling mechanisms in DasRes cells.

Primary thyroid lymphoma is rare, comprising only 1–5% of thyroid neoplasms and mostly of the non‐Hodgkin type. Tuberculosis (TB) in the head and neck represents about 15% of cases of extra pulmonary TB. Several reports have described the coexistence of TB and non‐Hodgkin lymphoma in lymph nodes. a case rportA 70‐year‐old male presented with a huge goiter of one year duration, progressively increasing in size with compressive symptoms over the last two months with reported night sweating, fever and weight loss. He has ischemic heart disease, hypertension and longstanding hypothyroidism.

On physical exam, looks unwell, tachypnea, febrile with normal pulse.

Neck exam revealed huge goiter with retrosternal extension and palpable multiple bilateral cervical lymphadenopathy, largest measure 3 cm. other system examination were unremarkable.

Initial blood test showed FT4 16.3 (12.0 − 22.0 pmol/L), TSH 9.78 (0.270 − 4.200 uIU/mL), normal WBC with lymphopenia, Lactate Dehydrogenase 320 (135 − 225 U/L), Albumin 27 (38 – 51 g/L) with normal liver function and calcium. ESR 24 mm/hr. and CRP 132 (0 − 6 mg/L).

Neck ultrasound revealed Thyroid gland is marked heterogeneous and diffusely enlarged and bilateral cervical lymphadenopathy. CT scan showed large heterogeneous necrotizing thyroid with retrosternal extension, extensive necrotizing cervical lymphadenopathy.

FNA of thyroid showed malignant lymphoma.

FNA of cervical lymph node revealed diffuse large B‐cell lymphoma with Ki67 90%. Also positive for acid‐fast bacilli were seen on smear. The culture showed Mycobacterium Tuberculosis complex. He was started on Anti‐TB treatment; three cycles reduced dose CHOP‐R chemotherapy and radiotherapy.

The patient developed re‐accumulating right pleural effusion together with renal shutdown became hemodynamically unstable and eventually cardiac arrest and death occurred. It has been reported that the risk of non‐Hodgkin lymphoma is significantly increased (OR 1.8) in individuals with a history of TB mainly with severe forms of TB and have not received proper treatment. Therefore, clinicians need to be aware of the manifestations of TB and lymphoma and maintain a high index of suspicion for simultaneous and/or misleading presentations.

Anaplastic thyroid cancer (ATC) is a rare and lethal form of thyroid cancer. A 40‐year‐old female patient underwent a total thyroidectomy with central lymph nodal dissection in July 2011. Histology showed an 80 mm nodule (90% with ATC component and 10% papillary carcinoma) without angioinvasion or lymph node metastases. Imaging studies excluded macroscopic locorregional or systemic disease. Thyroglobulin (Tg) was 2.1 ng/mL. Adjuvant systemic chemotherapy with docetaxel and doxorubicin and radiotherapy was started. On March 2012 neck and chest CT imaging showed absence of disease.

In March 2013, Tg rose to 13,4 ng/mL and a PET‐CT scan showed two lung metastasis (left superior and middle lobe with 28 and 30 mm). Bronchial brushing was compatible with PTC. In May 2013 serum Tg was 21,8 mg/mL and the patient started sunitinib 50 mg. A reduction of Tg to 7,9 ng/mL was documented. On August 2013 150 mCI of radioiodine was administered based on the PTC origin of lung metastasis. Serum basal Tg was 7,9 ng/mL. Over time the dosage of sunitinib was reduced to 25 mg due to side effects.

In February 2014 a partial response was observed with a suppressed Tg of 5.3 ng/mL and a reduction in both lung lesions to 11 and 10 mm. Nevertheless the disease progressed until July 2015: Tg rose to 22,4 ng/mL and on PET‐CT an increase in size of the lung lesions to 48 and 35 mm was documented. A new lesion in the left lower lobe with 13 mm was observed. Sunitinib was switched to sorafenib (800 mg daily). In December 2015, there was a significant progression of the pulmonary left superior, left lower and middle lobe disease to 59, 36 and 55 mm with a rise in Tg levels to 117 ng/mL. In February 2016, chemotherapy with paclitaxel and carboplatin was added to sorafenib until June 2016 (6 treatment cycles). At the end of treatment, the Tg decreased to 3,9 ng/mL.

In July 2016, a pneumothorax secondary to the necrosis of a left lung lesion was diagnosed. Chest CT showed a reduction in size of the left superior and middle lobe lesions to 52 and 40 mm and an increase in size of the left lower lobe metastasis to 45 mm. While multimodal therapy can increase the survival of ATC, new challenges such as treatment iatrogeny are more likely to occur.

Clinical decision making for patients with cytologically indeterminate thyroid nodules can be challenging. Thyroseq v2 is a next generation gene sequencing diagnostic test that may aid in risk stratifying patients as low risk or high risk for thyroid cancer when cytology falls into Bethesda cytology category III‐V (AUS/FLUS, SFN or SFM respectively). The standard practice at the Colorado Permanente Medical Group is to use Thyroseq v2 to risk stratify indeterminate cytology as an aid to recommending surgery or monitoring. This retrospective review evaluated the clinical outcomes of patients with cytology samples sent for ThyroSeq v2 testing from 10/2013 to 4/2016. The overall indeterminate rate was 18%, with 70% reported as AUS. There were 337 nodules representing 325 unique individuals, with 93% of nodules having sufficient genetic material for analysis. Sixty‐nine nodules had high risk mutations and 18 had low risk mutations. Ninety‐seven percent of patients with high risk mutations went to surgery. The positive predictive value (PPV) for malignancy for all high risk mutations was 61%: 46% for AUS (18 out of 39), 78% for SFN (14 out of 18), and 90% for SFM (9 out of 10). An NPV cannot be accurately calculated since most mutation negative or low risk lesions did not go to surgery. However, overall 9 of 38 (24%) mutation negative nodules that went to surgery were malignant (6 of 27 diagnosed as AUS, 3 of 10 diagnosed as SFN, and 0 of 1 diagnosed was SFM). Additionally, the PPV for cancer in all indeterminate nodules with mutations described as low risk (primarily due to low allelic frequency) was 45% (5 out of 11 cancers). In summary, this retrospective review of indeterminate thyroid nodules that had Thyroseq v2 testing showed a lower than expected PPV for malignancy and a higher than expected number of malignancies among mutation negative nodules. Additionally, reported low risk mutations had an unexpectedly high rate of malignancy on final histopathology. In conclusion, high risk Thyroseq v2 mutations aid in recommending surgery, but the absence of mutations and low risk mutations may not adequately rule out thyroid cancer.

Well‐differentiated thyroid carcinoma (WDTC) is considered to have a favorable prognosis, but studies have shown that patients with multiple treatment failures and/or recurrences have significantly lower survival. Consequently, identifying individuals who are more likely to experience poor outcomes is of high importance. People of Filipino heritage (hereafter, Filipinos) are known to have increased thyroid cancer prevalence and risk of recurrence. It remains unclear whether this leads to a difference in mortality due to thyroid cancer between Filipino and non‐Filipino patients. Cause of death and race/ethnicity were identified for decedents included in the U.S. mortality records from the National Center for Health Statistics (NCHS) Multiple Cause of Death mortality files from 2003–2012 for all states (N = 24,188,105). Contingency table analysis was used to estimate the relative risk of death due to thyroid cancer comparing Filipinos to all other racial/ethnic groups.87,451 decedents were of Filipino ethnicity. Among Filipinos, 0.31% died of thyroid cancer. Among non‐Filipinos, 0.08% died of thyroid cancer. The risk of death due to thyroid cancer among Filipinos was 3.8 (CI: 3.4 – 4.3; p < 0.0001) relative to non‐Filipinos. Building on earlier studies showing that Filipino patients have a higher rate of recurrent WDTC, we have shown that Filipinos are about four times more likely to die from thyroid cancer than non‐Filipinos. These results may suggest that Filipino patients tend to have more aggressive thyroid tumors and/or face environmental factors that lead to higher rates of death. Future studies will examine the root causes behind this difference in outcomes.

DNA sequencing has identified the RET gene as being mutated in familial syndromes associated with medullary thyroid carcinoma (MTC). Unfortunately, 75 percent of MTC cases are sporadic and 60 percent of these do not harbor RET mutations. Our lab has determined that cyclin dependent kinase 5 (Cdk5) promotes growth in MTC and has established a transgenic mouse model of MTC that is driven by Cdk5 activity. Phosphoproteomic analysis of mouse tumors revealed elevation of over 200 phosphorylation sites. Phosphorylation state‐specific antibodies were generated to a set of these sites and the sites were confirmed to be upregulated in growing mouse tumors and dependent on Cdk5 activity. The objective of the current study is to evaluate blockage of these phosphorylation sites as a potential therapeutic strategy. Short interfering peptides (SIPs) were designed to inhibit newly identified phospho‐proteins. The MTC‐SK human cell line was treated with SIPs and monitored for effects on the phosphorylation state of these proteins and cell growth. Leukosomes, a biomimetic nanoparticle drug delivery system, were evaluated as a method to target SIPs to MTC tumors in vivo. Rhodamine (Rd) labeled SIPs were encapsulated in leukosomes and injected retro‐orbitally into MTC mice. Bi‐lateral tumors were harvested at indicated timepoints. One tumor was fixed in 4% PFA, embedded in paraffin, cut into 5 micron sections, and analyzed via IHC for Rd. The second tumor was lysed and Rd levels quantitated by measuring fluorescence. SIPs inhibit proliferation of human MTC cells in a concentration dependent manner. SIPs block phosphorylation of newly identified growth promoting proteins. Using leukosomes, Rd‐SIPs are successfully delivered to MTC tumors within 30 mins. However, Rd fluorescence is lost after 24 hours suggesting that SIPs are rapidly metabolized within tumors. These studies demonstrate that SIPs have anti‐proliferative activity and can be successfully delivered in vivo. Future work will investigate methods to decrease rates of SIP clearance from tumors and investigate the potential of SIPs as targeted therapeutics for subgroups of MTC patients that are dependent on Cdk5 activity for growth and/or survival.

Src has been shown to be a promising clinical target in advanced thyroid cancer, however, heterogeneous mechanisms of resistance to targeted therapies continue to hinder effective treatment options. In this current study we hypothesized that identifying and targeting a poly‐network regulator would prevent and/or reverse the heterogeneous survival response seen in thyroid cancer cell lines in response to Src inhibition. An shRNA kinome library screen was performed in a panel of 2 dasatinib‐sensitive (SW1736, Cal62) and 2 dasatinib resistant cell lines (8505C, C643) to identify synthetic lethal targets of dasatinib. Bioinformatic analysis was used to identify synthetic lethal targets. Cell growth, clonogenic growth, and apoptosis were measured using sulforhodamine B‐, clonogenic outgrowth‐ and cleaved caspase 3/7‐assays, respectively. Our studies identified the bromodomainand extra‐terminal (BET) protein family members, Brd3 and Brd4, as synthetic lethal targets in response to Src inhibition in the RAS‐mutant cell lines (C643, Cal62; p < 0.006). Interestingly, both the BRAF‐ and RAS‐mutant cell lines were sensitive to Brd3/4 inhibition with JQ1 (300 nM), resulting in decreased cell growth (2‐fold in BRAF‐, 3‐fold in RAS‐mutant) and reduced clonogenic outgrowth (3‐fold in BRAF‐, 2‐fold in RAS‐mutant) compared to controls. Combination therapy using dasatinib and JQ1 (at IC50 values for each cell line) resulted in increased sensitivity to Src inhibition, leading to an enhanced suppression in cell growth (BRAF‐, CI = 0.38; RAS‐, CI = 0.76) as well as clonogenic outgrowth. Finally, neither dasatinib nor JQ1 alone caused a significant increase in apoptosis, however, the combination therapy led to a marked increase (>5 fold) in apoptosis in both the BRAF‐ and RAS‐ mutant cell lines compared to controls. Taken together our data show that inhibition of Brd3/4 sensitizes both BRAF‐ and RAS‐ mutant thyroid cancer cell lines to Src inhibition by dasatinib, and that targeting these BET proteins may represent a network break approach that can overcome the heterogeneous mechanisms of resistance to Src inhibition.

Deregulations of microRNAs and mRNAs play critical roles in tumorigenesis and progression in different types of cancers. We aim to identify microRNAs and mRNAs differentially expressed in papillary thyroid cancer that correlate with clinical characteristics of the disease. Level 3 miR‐Seq and mRNA‐Seq data of thyroid cancer from The Cancer Genome Atlas (TCGA) were downloaded and analyzed. The expression level of microRNAs and mRNAs between normal and primary tumor samples were compared. The correlation between differentially expressed miRNAs/mRNAs and patients' clinical characteristics, including tumor size (T1/2 vs. T3/4), lymph node status, metastatic status, extrathyroidal extension (ETE), BRAF mutation, and AJCC tumor stage (TI/II vs. TIII/IV) were tested. We identify 65 miRNAs differentially expressed with more than 2‐fold changes in papillary thyroid tumors (PTC), which include previously‐reported miRs. Many differentially expressed miRs were significantly correlated with lymph node involvement, ETE, BRAF mutation, tumor stage, but not with tumor size. The mir‐551b was the second upregulated miRs in primary tumor compared to normal tissues (7.6 fold, p < 0.0001), and was further increased in tumors from patients with lymph node metastasis or BRAF mutation. Among differentially expressed mRNAs, SEMA3D expression was significantly decreased (31.7 fold, p < 0.0001) in PTC, and was further decreased in tumors from patients with lymph node metastasis, tumor stage III/IV, ETE, or BRAF mutation. SEMA3D shows significant negative correlation with miR‐551b in PTC patients (r =  −0.66 and p < .0001), and miRDB predicts SEMA3D as a target of miR‐551b. Both miR‐551b and SEMA3D has been reported as a potential therapeutic target in other cancers and SEMA3D was implicated in tumor progression in various types of cancers. Recently, SEMA3D was included in a 15‐gene biomarker panel to identify malignancy among cytologically indeterminate thyroid tumors. Therefore, miR‐551b and SEMA3D may play a critical role in thyroid cancer tumorigenesis and/or progression. Deregulated miR‐551b and SEMA3D may play a critical role in tumorigenesis and/or progression and they may serve as potential therapeutic targets in PTC.

Thyroid hormone (TH) secretion from the thyroid gland plays a key role in maintaining circulating thyroid hormone levels. Importantly, the mechanisms governing thyroid hormone secretion are not fully understood. Recently, we have been examining the role of TH in the regulation of metabolite production systemically and determined that TH controls the trans‐sulfuration pathway and the production of cystathionine, cysteine and hydrogen sulfide via the enzyme cystathionine gamma‐lyase (CTH).

To determine if trans‐sulfuration pathway impacts TH action we utilized mice that lack CTH in all tissues (CTH KO).

At baseline CTH KO mice had slightly reduced total T4 levels with normal TSH production in the pituitary when compared to littermate controls. Remarkably, when placed on a PTU/low iodine diet for 3 weeks CTH KO mice were resistant to the development of hypothyroidism in that their T4 levels only fell by 50% over 3 weeks. In contrast, WT mice develop over a 90% drop in T4 levels after just two weeks on this diet. To rule out an issue with the absorption of the diet we developed a serum PTU assay and found no difference. To better understand this phenotype we examined thyroid histology in both CTH KO and WT mice. In the euthyoid setting CTH KO mice had extensively enlarged thyroid follicles with increased stored T4 in the gland. When exposed to PTU for 3 weeks WT mice lost all follicular structure and their glands were depleted of T4. In contrast, CTH KO mice retained many thyroid follicles and significant T4 was still present in the gland. Similarly when challenged with a prolonged fast T4 levels fell in WT mice but did not fall in CTH KO mice.

These data demonstrate that the trans‐sulfuration pathway is necessary for normal TH secretion from the gland and in the absence of CTH T4 is synthesized normally but cannot be secreted appropriately from the gland. It is tempting to speculate that this defect may either involve the proteolysis of T4‐thyroglobulin moieties or MCT8 function and T4 secretion.

The 2015 American Thyroid Association (ATA) guidelines for management of thyroid nodules present a novel tool by which nodules are assigned a categorical risk of malignancy based upon a pattern of sonographic features. An estimation of risk for each pattern was based on prior studies and observations, however, to our knowledge, the patterns have not yet been validated. We sought to assess the performance of these patterns for predicting malignancy in our database of thyroid nodules. We reviewed all thyroid nodules biopsied from April 2013 through October 2015. The nodule images were de‐identified and assigned a random number. Two endocrinologists, both of whom perform high volume neck sonograms, then reviewed the de‐identified images. A sonographic pattern, according to the construct outlined in the guidelines, was assigned for each nodule: benign(B), very low suspicion (VLS), low suspicion (LS), intermediate suspicion (IS), high suspicion (HS). Nodules which could not be categorized were labeled non‐categorizable (NC).325 nodules were selected for analysis.

B n = 1(<1%): IV 1(100)

VLS n = 49(15): I 5(10), II 40(82), III 2(4), IV 1(2), V 0(0), VI 1(2)

LS n = 131(40): I 2(2), II 87(66), III 30(23), IV 8(6), V 1(<1), VI 3(2)

IS n = 61(19): I 3(5), II 31(51), III 14(23), IV 8(13), V 1(2), VI 4(7)

HS n = 51(16): I 2(4), II 25(49), III 11(22), IV 6(12), V 1(2), VI 6(12)

NC n = 32(10): I 3(9), II 18(56), III 6(19), IV 0(0), V 2(6), VI 3(9)

Of the NC nodules, 28(88) were isoechoic, 13 were taller than wide (41), 11(34) contained microcalcifications, and 8(25) had macrocalcifications. As expected, rate of malignancy increased as the pattern progressed from VLS to HS. However, the rate of malignancy among nodules assigned the HS pattern was lower (12%) than that predicted in the guidelines (70–90%). 10% of nodules were non‐categorizable, most due to a suspicious feature in an isoechoic nodule. The distribution of cytology findings among the NC nodules was similar to that seen in the HS nodules, with 15% of NC nodules having Bethesda V or VI cytology. This suggests that the presence of a suspicious feature in a non‐hypoechoic nodule may merit the monitoring and biopsy cutoff recommendations given for HS nodules.

72yo man with melanoma was discovered to have a PET hypermetabolic (SUV 4.9) right thyroid nodule. He denied any aero digestive compressive signs or symptoms. No signs or symptoms of thyroid hormone excess or deficiency. No risk factors for thyroid cancer or suggestion of thyroid cancer predisposition syndrome. On physical examination a 3 cm firm right thyroid nodule is palpated. He is biochemically euthyroid. Underwent a right thyroid nodule FNA reported as suspicious for malignancy unfortunately no cellblock could be obtained. The differential diagnoses included: Hurthle cell neoplasm, medullary carcinoma, oncocytic papillary thyroid carcinoma and malignant melanoma. ThyroSeqV2: BRAFv600 and TERT mutation positive. Based on the above the patient had a second FNAB reported as melanoma. He then underwent total thyroidectomy with surgical pathology reported as metastatic malignant melanoma (3.5 cm) involving the right thyroid lobe with surgical margins free of tumor. Metastasis to the thyroid is infrequently sought and even less common is melanoma metastatic to the thyroid. Our case had a suspicious for malignancy pathology from FNAB and also molecular markers positive for BRAF and TERT mutations; found in thyroid cancer and melanoma. The prevalence of metastasis to the thyroid in autopsy is 2 to 39%. The most common sites of metastasis to the thyroid are the kidney, breast and lung. Melanoma metastasize to almost every organ, most commonly lungs, liver, and brain. Therefore it should not be uncommon the propensity for the thyroid given its vascularity. TERT mutation is present in70% of melanomas and 50 % of melanomas harbor BRAF mutations. The BRAF V600E mutation is the most common mutation in PTC. TERT mutations are in 10–20% of DTC and 30–50% of dedifferentiated thyroid cancers. Our case allows for discussion of the diagnosis and management of thyroid metastases and brings awareness of the condition. Patients with a history of malignancy and a thyroid nodule present a conundrum. We propose that any patient who has a history of malignancy and presents with a thyroid nodule should be considered as having a metastasis until proven otherwise.

Fine‐Needle Aspiration Biopsy (FNAB) is important in predicting the risk of thyroid malignancy. Molecular markers can potentially improve the diagnostic accuracy of FNAB and reduce the number of operations. In this large prospective study we evaluated the performance of the ThyroSeq2^® analysis to detect oncogenic mutations in thyroid cancers.469 FNAB, performed between 02/15 ‐ 02/16, were evaluated. 59 cases were excluded because of poor cell yield and 408 were sent for oncogenic mutational analysis with ThyroSeq2^® multigene next‐generation sequencing analysis (NGS). Of the 156 indeterminate cytologies (Bethesda III‐V), 148 (95%) underwent genetic analysis. Oncogenic mutations were detected in 51 patients (35%), of whom 29 (57%) had a thyroidectomy. Of the 29 patients, 19 (66%) had thyroid cancer and 10 had benign nodules (34%). The most frequently mutated genes were NRAS (p.Q61K, c.181C>A) in the benign nodules (45%), NRAS (p.Q61R, c.182 A>G) in the follicular variant of papillary thyroid cancers (43%), BRAF (P.V600e, c.1799 T>A) in the papillary thyroid cancers (37%), and calcitonin gene in the medullary thyroid cancers (100%). Of the 92 patients with negative genetic markers, 16 had surgery (31%), of whom 15 were benign (94%) and 1 had thyroid cancer (6%). ThyroSeq2^® showed a sensitivity to detect cancer of 95.0% [confidence interval (CI) 75.1% −  99.9%], specificity of 60.0 % [CI 38.7% − 78.9%], positive predictive value of 65.5% [CI 45.7–82.1], and negative predictive value of 93.7% [CI 69.8–99.8], with an overall accuracy of 75% [CI (67.6% − 91.5%)]. ThyroSeq2^® provides a high sensitivity to detect thyroid malignancy in nodules with indeterminate cytology but the specificity was low due to the detection of an array of mutations in benign nodules. ThyroSeq2® is useful to reduce unnecessary operations, but the current assay is not a “positive predictor” of malignancy because of the large number of mutations in benign nodules. Further studies will determine if the use of imaging studies in addition to cytology and oncogenic mutations will better define which patients need surgery for thyroid cancer.

TPO autoantibodies (TPO‐Ab) and TRAb are biomarkers of autoimmunity in hypothyroidism and hyperthyroidism, resp.. Here, we measured biological activity of thyroid autoimmunity (TA) by a TSH receptor bioassay in sera from patients with HD.

fT4, fT3, TSH, TPO‐Ab, TRAb (Brahms GmbH) and sTRAb [1] were tested to confirm the diagnosis. Stimulating (sBIO positive>ca. 1.2–1.3 SI) and blocking (bBIO positive <0.7–0.8 SI) activity were measured by a TSH receptor TRE reporter gene bioassay in HEK (Human Embryonic Kidney 293) cells [2]. Groups of patients with TA: 1. Hypothyroid and only TPO extremely (a) or moderately (b) positive; 2. Hypothyroid and TPO‐Ab, TRAb and sTRAb positive. Statistical distributions were compared with Welch's t test and Pearson's correlation.

Means ± SEMs were: G1a: TPO‐Ab = 7713.9 ± 1403 U/ml, TRAb <1 IU/L, sTRAb = 0.16 ± 0.161 IU/L, bBIO = 0,495 ± 0.055 SI (n = 10). G1b: TPO‐Ab = 2355.1 ± 264.4 U/ml, TRAb = 3.3 ± 2.7 IU/L, sTRAb =  2.2 ± 2.1 IU/L, bBIO = 1.022 ± 0.08 SI (n = 20). G2: TPO‐Ab = 2544 ±  625.2 U/ml, TRAb = 26.8 ± 14.3 IU/L, sTRAb = 24.7 ± 7.6 IU/L, sBIO =  1.32 ± 0.28 SI (n = 5).

Signal transduction was impaired in sera with high TPO‐Ab titers in G1a (p < 0.001) compared to G1b with lower TPO‐Ab titers and there was a significant negative correlation between TPO Ab titers and inhibition of TSH signaling in the blocking assay in G1 (r^2 = 0.22, p < 0.05). Interestingly, in G1a TRAb and sTRAb were negative, however positive in G1b. CRE signaling could be stimulated in sera containing TRAb (p < 0.001).

These data show that sera with TPO‐Ab in HT at high titers inhibit cAMP accumulation. It might be suggested that in vivo this pathway brings about inhibition of TPO activity involved in the pathogenesis of hypothyroidism. Furthermore, stimulatory character of coexisting TRAb values was detected.

Although thyroid autoimmunity is generally considered to be progressive, Hashimoto's thyroiditis is not always permanent ‐ particularly in children and adolescents and one third will not need long term therapy. To describe an interesting case of a young woman with history of Hashimoto's hypothyroidism who went into remission following years of levothyroxine therapy. 20 year old woman with a history of Hashimoto's thyroiditis since age 7. At diagnosis, her TSH was 64 (normal 0.360–5.8 UIU/ML), free T4 0.9 (normal 1.2–4.9 ug/dl), and Anti Thyroid Peroxidase Antibody was 55 (normal 0–40 IU/mL). She had difficulty with medication and follow‐up adherence. She initially presented to transition to adult care endocrinology after having not followed up with her pediatric endocrinologist for two years. She had not taken her Levothyroxine for more than a year prior to her initial visit because she had run out of refills, had moved out of her mother's house, and had been busy with work. She reported an unintentional 35‐pound weight loss, hyperpigmentation of sun exposed skin, as well as lightheadedness when standing. Otherwise, she felt well. She denied changes in her bowel movements, changes in her menstrual cycle, symptoms of polyuria, polyphagia, or polydipsia. Thyroid was diffusely enlarged and nontender on exam. Orthostatics were negative.

Surprisingly, her TSH was 4.7 (0.45–4.50 UIU/ML) and Free T4 was 0.8 (0.60 − 1.30 NG/DL). Screen for other autoimmune disorders such as diabetes and adrenal insufficiency was negative; CBC and cmp were normal. Patient remained off of Levothyroxine at that time. Follow‐up visit two months later, patient reported to continue to feel well. TSH was 2.5, FreeT4 was 1.1, and Thyroid Stimulating Immunoglobulin was 38% (normal 0–139). A watchful approach was pursued and patient has remained off of levothyroxine treatment. Hypothyroidism caused by Hashimoto's thyroiditis is not always permanent. This case is interesting in that this young woman with once severe, longstanding hypothyroidism, is now in remission; this case further exemplifies the reversibility of autoimmune thyroid disease.

Papillary thyroid microcarcinomas (PTMC) measure 10 mm or less and are being identified with greater frequency due to increased use of thyroid ultrasound and other neck imaging modalities that can identify nodules too small to be palpated. Lymph node metastases in PTMC occur 15–50% of the time. A small subset of patients with PTMC present with macroscopic neck node metastasis, which then leads to the diagnosis of papillary thyroid carcinomas that were initially not apparent. To describe an interesting case of PTMC incidentally revealed following discovery of an unexpected metastatic lymph node53 year old man who had a preventative carotid ultrasound, was found to have a right midjugular cystic lymph node which was further visualized on CT scan to be 4 × 1.6 cm in size. CT scan initially showed a normal thyroid without any nodules. Further evaluation with dedicated thyroid ultrasound showed a solitary 7 × 6 × 4mm hypoechoic right thyroid nodule. No history of radiation exposure or family history of thyroid cancer. Right neck exploration and lymph node dissection showed a black multiloculated cyst with pathology positive for papillary thyroid cancer and five benign adjacent jugular and auricular lymph nodes. Thyroid nodule biopsy was nondiagnostic. Near total thyroidectomy was performed with pathology showing three foci of papillary microcarcinoma in the right lobe, 0.6 cm in greatest dimension. He was started on suppressive dose of Levothyroxine. Thyrogen stimulated whole body scan was performed revealing three focal areas of uptake of 0.5% in the central neck and no evidence of distant metastatic disease. He received 150 mCi of 1–131. The year following, repeat thyrogen stimulated whole body scan showed no metastasis with thyroglobulin of <0.1 ng/mL and anti‐thyroglobulin antibody of <1.8 IU/mL (normal <4.0 IU/mL). Patient remains on suppressive doses of levothyroxine and is being followed biyearly for surveillance. PTMC can rarely present as lymph node metastasis. This case is one of very few cases reported of PTMC presenting as an incidentally found solitary lymph node metastasis without initial evidence of primary thyroid tumor until dedicated thyroid ultrasound and confirmatory tissue diagnosis was made.

Hashimoto's encephalopathy associated with autoimmune thyroiditis is a rare form of acquired autoimmune encephalopathy which is more common in women with average age of onset between 45–55 years old. It is a diagnosis of exclusion. Thyroid hormone abnormalities do not play a role in the symptoms of Hashimoto's encephalopathy and thyroid status can vary. Immunosuppressive therapy with corticosteroids is mainstay of therapy. Case ReportAn 84 year old female with PMH of HTN and osteoporosis presented to ED with altered mental status. For the two weeks prior to admission she was noted to be increasingly confused, fatigued with occasional visual hallucinations. On presentation, her vital signs were stable. Neurologic examination did not show any focal deficits except for altered mental status. Her initial workup for etiology was negative. During her hospitalization, her mental status continued to worsen requiring more extensive testing. TSH 4.5 (N 0.35–5.5 uIU/ml), FT4 1.0 (N 0.80–1.8 ng/dl), FT3 190.4 (230–420 pg/dl). Her thyroglobulin antibodies were normal at 41.9 (0–60 u/ml) and TPO antibodies were mildly elevated at 92.1 (normal 1.0–60.0 IU/ml). There were no bacterial, viral, fungal nor parasitic growth in the CSF. Paraneoplastic antibodies were also negative. Brain MRI with and without contrast showed no acute intracranial abnormality. EEG was suggestive of moderate diffuse encephalopathy with some evidence of seizure focus on right hemisphere but no ongoing seizure activity. The patient was initially started on Keppra based on EEG findings however there was no change in her clinical status. She was eventually started on 1g of IV solumedrol with rapid improvement of her mental status. She was then tapered to prednisone 60 mg however her mental status worsened, so the dose was increased to 120 mg with clinical improvement. Hashimoto's encephalopathy or steroid responsive encephalopathy associated with autoimmune thyroiditis is a rare and therefore poorly understood disease. It can present with a myriad of neuropsychiatric abnormalities. It is often unrecognized especially in an elderly but it is important for a clinician to consider it since it is a highly treatable form of encephalopathy.

Methimazole induced agranulocytosis is a rare and life threatening toxicity with reported incidence as 0.1–0.5%. The underlying mechanism is thought to be either immune mediated neutrophil destruction or inhibition of granulopoiesis. It can occur 1 month to 1 year after methimazole treatment. The risk is higher in older patients treated with methimazole doses greater than 40 mg daily. Granulocyte colony stimulating factor (GCSF) therapy for severe agranulocytosis has not been documented to be effective for treating this complication. Our case supports total thyroidectomy as the treatment of choice in case of methimazole induced severe agranulocytosis.

Case Report: An 81 year old man was seen in the clinic for evaluation of Graves' disease with TSH 0.005 uIU/ml (045–4.5), FT4 5.94 ng/dl (0.82–1.77), TT3 409 ng/dl (71–180) and thyroid stimulating immunoglobulin 290% (normal 0–139). Baseline white blood cell count (WBC) was 4000/μL (normal 3400–10800) and absolute neutrophil count (ANC) 2200/μL (normal 1400–17000). He was started on methimazole 20 mg three times daily and the dose was titrated to 30 mg three times daily after 2 weeks based on TSH 0.005 uIU/ml, FT4 2.87 ng/dl and TT3 182 ng/dl. Repeat labs 4 weeks after treatment initiation revealed severe agranulocytosis with WBC 700/μL, ANC 0/μL, hemoglobin 12.8 g/dl (normal 12.6–17.7) and platelets 224000/μL (normal 150000–379000). Thyroid function test that time were, TSH 0.02 uIU/ml, FT4 0.99 ng/dl and TT3 69.7 ng/dl. He was admitted to intensive care unit with neutropenic fever, oral thrush and new onset atrial fibrillation with rapid ventricular rate. Methimazole was discontinued and Filgastrim (GCSF) was started at 480 μg daily. Based on the rising FT4 1.89 ng/dl with inadequate response to Filgastrim (ANC 400/μL), lithium was initiated at a dose of 300 mg three times a day and patient had a total thyroidectomy on day four of hospitalization.

Discussion: GCSF has been used successfully to treat mild to moderate methimazole induced agranulocytosis. Our case demonstrates that in setting of severe agranulocytosis with underlying thyrotoxicosis, total thyroidectomy should be the preferred treatment.

Thionamide‐derived medications can rarely cause agranulocytosis (approximately 0.17% of patient). Agranulocytosis can lead to life‐threatening infectious sequlae.

Case Report: 26F presented with 3‐day history of fever (39.2 C), dry cough and dysphagia. She also had 2‐day history of vomiting and diarrhea. She was recently diagnosed with hyperthyroidism secondary to Graves' disease (90% RAI uptake at 24 hr) 2 months prior to admission and has been on methimazole 5 mg bid for 4 weeks. At the time of presentation she was in sinus rhythm (146 bpm). Initial investigations showed Hb of 108 g/L, WBC 0.81 E9/L, Abs Neut 0.03 E9/L and Plt 120 E9/L. TSH was undetectable, free T3 was 21.5 pmol/L and free T4 was 65.3 pmol/L. Oral candidiasis was diagnosed, initial infectious work up was ordered and methimazole was discontinued. She was treated with IV hydration, empiric antibiotics and propranolol.

After discussing the option of surgery and RAI ablation with patient, decision was made to proceed with RAI 131 ablation with 10 mCi 11 days after her initial presentation. In consultation with Infectious Disease team, she was treated with prednisone to prevent worsening of underlying mild orbitopathy. Thyroid indices remained elevated 1 ½ months post RAI ablation (fT3 38.2 and fT4 69.3). She required a second dose of 20 mCi 131 iodine. Subsequently, her thyroid indices improved and she started to feel significantly better. Her TSH 6 months later was 19.7 pmol/L, fT4 4.9 pmol/L and fT3 2.9 pmol/L. She was started on levothyroxine replacement. Methimazole‐induced agranulocytosis is a rare, life‐threatening adverse event. Measuring WBC count during febrile illness and at onset of pharyngitis in recommended (ATA 2015). Educating patients about symptoms my help identify affected individuals early. Treatment with appropriate antibiotics, beta blockade and close follow up is necessary. Definitive treatment with 131 Iodine or thyroidectomy should be undertaken.

Graves' Disease is a common cause of hyperthyroidism. This is a case of a patient presenting with uncommon manifestations of Graves' disease that presented after radioactive iodine ablation.

A 34 year old African American female was diagnosed with hyperthyroidism due to Graves' Disease in 1996 and was also found to have a multinodular goiter. Four months after radioactive iodine ablation, she developed edema in her legs and feet along with bilateral exophthalmos and loss of vision in the right eye that required emergency decompressive surgery with sight recovery after surgery. The lower leg edema continued to worsen over the next year from scaly skin patches to prominent cobblestone nodularity becoming so large she was unable to fit her shoes. She also developed bilateral clubbing with tender swelling of the dorsal middle phalanges (thyroid acropachy). Skin biopsy showed hyperkeratosis, fibrotic dermis and abundant interstitial mucin, consistent with pretibial myxedema. Nine months following RAI ablation, she became hypothyroid and was started on levothyroxine. In 2007, her hyperthyroidism recurred, so levothyroxine was discontinued. She was started on methimazole; however, she was poorly compliant with methimazole. In 2011, she was placed on hemodialysis due to ESRD. She remained off any thyroid medication until 2012 when she developed T3 toxicosis with thyroid scan and uptake in 2012 revealing four cm hyperfunctioning right thyroid nodule. She declined radioiodine treatment and restarted methimazole. She subsequently developed secondary and tertiary hyperparathyroidism for which she had subsequent four gland parathyroidectomy with autotransplantation at which time she also underwent total thyroidectomy. Swelling in her bilateral lower extremities and fingers have decreased over time but remained prominent. We present images of our patient's thyroid acropachy and pretibial edema that meets criteria for elephantiasis nostras verrcuosa, all of which are uncommon in patients with Graves' Disease and even more rare to see concomitantly in the same patient.

A 36 year old female with history of Turner's syndrome and severe pulmonary hypertension presented to her primary care physician with enlarged eyes, tremor and anxiety. She was found to be hyperthyroid on laboratory evaluation with undetectable TSH, elevated T3 and T4, with positive antibodies. She was started on Methimazole 30 mg daily. One month later, she presented to the hospital with fever and cough, was diagnosed with severe sepsis secondary to pneumonia, typhlitis, and thrush. She was diagnosed with severe leukopenia with total WBC count of 0.1 k/uL (4.5 − 11.0 k/uL). Methimazole was discontinued, and the patient became hyperthyroid again. She was unable to have radioactive iodine ablation because of a recent CT scan of the chest with contrast. She was unable to have a thyroidectomy because she had a high surgical risk with severe uncontrolled pulmonary hypertension and hyperthyroidism. The decision was made to try Propylthiouracil 50 mg TID twenty‐one days after Methimazole was discontinued, and closely monitor for recurrence of adverse effect of agranulocytosis. The patient was maintained on Propylthiouracil for months until she was able to have a radioactive iodine ablation for definitive treatment of her Graves' disease. She had no recurrence of agranulocytosis while on Propylthiouracil.

The adverse effects of anti‐thyroid drugs are well known. Common reactions are urticaria, low‐grade liver dysfunction and arthralgia. Severe reactions are agranulocytosis (granulocyte count <500/μL), myeloperoxidase ANCA‐related vasculitis, and severe hepatotoxicity. Agranulocytosis can occur on 0.1–0.5% of patients with Graves' disease receiving anti‐thyroid drug therapy. Given the life‐threatening nature of agranulocytosis, this adverse effect is a contraindication to resuming an anti‐thyroid drug for a patient with Graves' disease. However, our patient had no alternative to treatment with anti‐thyroid drug therapy, as radioactive iodine ablation and surgery were contraindicated. This case is interesting because it gave us an opportunity to diagnose a rare adverse effect of anti‐thyroid drug therapy and to treat a patient in unique clinical circumstances.

Association of Primary Hyperparathyroidism (pHPT) with Differentiated Thyroid Carcinoma has been reported to range from 1.7% in surgical cases to 17.6% in larger cohorts. Currently, minimally invasive surgical approach is favored for treatment of pHPT, therefore significant dual disease may be missed. Standardized protocol for detecting silent thyroid disease may be warranted. In a period of 5 years (2010–2015), 37 cases of pHPT underwent surgical excision by a single surgeon. Concomitant thyroid disease was found in 43% (16 cases). Differentiated thyroid carcinoma was confirmed by pathology in 4 cases. As per institutional protocol, all cases had intact PTH levels, serum calcium, parathyroid scintigraphy with Tc99‐MIBI, thyroid function tests and preoperative thyroid ultrasonography. FNAB was performed as per ATA guidelines.11% (n = 4) of primary hyperparathyroidism cases had concomitant papillary thyroid carcinoma, classic variant. These cases were diagnosed pre‐operatively by FNAB as suspicious for malignancy (Bethesda V/VI). All cases were females, mean age 59.2 years, and underwent total thyroid resection at the time of parathyroidectomy. Histology confirmed three Papillary Thyroid Carcinomas (75%), and one Micropapillary Thyroid Carcinoma (25%). Intraoperative PTH measurements were performed. Two cases of papillary carcinoma were located on the contralateral lobe of the parathyroid adenoma and two on the ipsilateral lobe. Neither presented locoregional metastasis. There was no previous history of head/neck radiation. One patient presented transient hypocalcemia, which corrected few days postoperatively. Concomitant thyroid and parathyroid pathology are common and can be treated in a single intervention. Therefore, it is important to include complementary thyroid studies as part of hyperparathyroidism evaluation.

While the time course of structural disease recurrence has been described in patients with an excellent response to therapy, the time to identification of structural disease has not been well characterized in patients demonstrating either an indeterminate or biochemical incomplete response to therapy. The goal of this study was to characterize the time course of structural disease recurrence within each of the response to therapy categories. A retrospective data analysis included 383 patients with differentiated thyroid cancer (thyroidectomy and radioactive iodine) of all ATA risk categories who had no structurally identifiable disease at the 6 months followup visit. Time to identification of structural disease recurrence was the primary endpoint. Over a median of 14 years, 33 patients (8.6%, 33/383) developed structurally identifiable disease (22 with local recurrence, 15 with distant metastases, 4 with both).

An excellent response (n = 205) was associated with local recurrence in 0.1% (1/205 at 8.3 years) and distant metastases 1.5% (3/205, at 7–13 years after initial therapy).

An indeterminate response (n = 149) was associated with local recurrence in 6% (9/149) after a median of 2.8 years) and distant metastases in 4% (6/149, median 4.1 years).

A biochemical incomplete response (n = 29) was associated with local recurrence in 41% (12/29, median 3.8 years) and distant metastases in 21% (6/29, median 2.3 years).

In patients with an indeterminate or a biochemical incomplete response to initial therapy, 95% of the local recurrences occurred in the first 5 years of followup while only 67% of the distant metastases were identified in the first 5 years of followup. The highest risk of local disease recurrence is seen in the first 5 years of followup in patients with an initial indeterminate or biochemical incomplete response to therapy. After 5 years of followup, local disease recurrence is rare although late distant metastases may still be identified. These data should be used to guide individualized recommendations in different response to therapy categories regarding the timing and site specific selection of imaging modalities for timely detection of structural disease recurrence during followup.

Programmed death ligand 1 (PD‐L1) expression has been reported in several malignancies, but the expression of PD‐L1 in papillary thyroid cancer (PTC) is rarely defined. The aim of this study was to assess the significance of PD‐L1 expression and its associations with clinicopathological factors and disease outcome in PTC. Immunohistochemistry staining was conducted retrospectively to evaluate the expression of PD‐L1 in a total of 260 PTC tumor and corresponding non‐tumor tissues. The correlations between PD‐L1 expressions with clinicopathological features and recurrence‐free survival (RFS) were analyzed. PD‐L1 expression was positive in 52.3% PTC tumor tissues (136/260), which was significantly higher than in corresponding non‐tumor thyroid tissues. In clinicopathological analyses, this positive staining of PD‐L1 was positively linked to multifocality (p = 0.001) and extrathyroidal extension (ETE) (p = 0.001). In multivariate Cox regression analysis, positive PD‐L1 expression in tumor tissue was significantly associated with worse RFS (hazard ratio 2.825, 95% confidence interval 1.149–6.943, p = 0.024). In subgroup analyses based on clinicopathological factors, positive PD‐L1 staining of tumor tissue was associated with worse RFS in the males (p = 0.001), the elders (≥45 years, p = 0.001), and patients with primary tumor size >4 cm (p = 0.002), multifocal tumors (p = 0.031), ETE (p = 0.012) and lymph node metastasis (p = 0.004). In contrast, positive PD‐L1 staining predicted worse RFS in subgroup of patients without Hashimoto's thyroiditis (p =  0.001) and treated with total thyroidectomy (p = 0.019). PD‐L1 is important in determining aggressiveness of PTC and could predict the prognosis of patients with it. Therefore, we suggest inhibition of PD‐L1 as a potential strategy for the treatment of advanced PTC with high expression of PD‐L1.

DTC cells express TSH receptors and may grow if exposed to elevated TSH. ATA Guidelines recommend TSH suppressive thyroid hormone therapy in patients with advanced metastatic disease. The VERIFY study found a numerically greater progression free survival (PFS) for pts treated with vandetanib (V, 10.0 months) compared to pts treated with placebo (P, 5.7 months); however the result did not reach statistical significance (p = 0.080). We report here a post hoc analysis of the effect of TSH level on PFS observed in this study. This multinational, double‐blind, randomized, phase III study (NCT01876784) enrolled pts with advanced DTC (n = 238) not previously treated with a TKI. Patients were randomized 1:1 to V 300 mg (n = 119) or P (n = 119). The primary end point was PFS. Inclusion criteria required TSH <0.5 mU/L at baseline (BL). Per protocol, TSH levels were monitored at BL, wks 4, 8, 12, and q12 wks thereafter. The protocol did not provide specific direction for TSH management during the study. Mean TSH levels for pts with ≥1 post‐BL TSH value during the treatment period were 1.48 mU/L for V (n = 113) and 0.34 mU/L for P (n = 116). Median PFS was 10.8 months for V and 5.8 months for P. For pts with mean TSH <0.5 mU/L, median PFS was 10.9 months for V (n = 59) and 5.7 months for P (n = 103). For pts with mean TSH <0.1 mU/L, median PFS was 11.1 months for V (n = 37) and 8.1 months for P (n = 69). In a Cox proportional hazards model, adjusting for most recent TSH >0.1, the HR for V compared to P is 0.62 (95% CI: 0.44–0.87, p = 0.005). Overall, a trend was observed that pts treated with V had a longer estimated median PFS compared to patients treated with P by approximately 5 months. With the use of a kinase inhibitor, serum TSH level may increase and contribute to DTC tumor growth. When TSH >0.1 mU/L was accounted for in a Cox proportional hazards model, the HR comparing V to P was statistically significant. Thus, TSH levels must be assessed when therapy is initiated and monitored at frequent intervals, with modification of levothyroxine doses where indicated, with the goal of a suppressed TSH level (as tolerated/in the absence of medical contraindication).

Follicular variant of papillary thyroid carcinoma (FVPTC) comprises 22–43% of all PTCs. FVPTC can be separated into 2 subtypes: invasive (IFVPTC) and encapsulated (EFVPTC). It has been proposed to replace the EFVPTC with a non‐malignant NIFTP classification because of its indolent behavior. Although it has been suggested that NIFTP occurs in about 13.6–36% of PTCs, a prospective study has not been confirmed this estimation. From February 2015 – January 2016, 469 sequential fine needle biopsies were prospectively evaluated and specimens with indeterminate results had a Thyroseq2^® Next Generation Sequencing Panel Analysis. Thyroid surgery was recommended for Bethesda V or VI cytology, positive Thyroseq2^® panel, suspicious Afirma^® analysis, obstructive symptoms or high risk ultrasound characteristics. 94 patients had thyroid cancer (CA) by pathology: 2 follicular thyroid CA, 61 classic PTC, 27 FVPTC and 4 medullary thyroid CA. Of the FVPTC, 16 had no or partial capsule or invasion (IFVPTC) and 11 were noninvasive EFVPTC or NIFTP. 3 of the 11 EFVPTC were incidental <1 cm in size. When tested, 3/3 NIFTP tumors contained mutations (RAS, THADA/IFG2BP3 fusion) while 8/12 IFVPTC contained mutations (RAS, BRAF). All of the EFVPTC were ATA low risk but 5/16 IFVPTC were ATA higher risk (metastatic nodes and pulmonary nodules). 6 patients with IFVPTC (invasion, metastatic nodes, pulmonary nodules) and none of the EFVPTC received radioactive iodine therapy. Thyroglobulin levels obtained >6 weeks postoperatively were lower for EFVPTC (n = 10) 0.51 ng/mL ±0.55 (mean±SD) than IFVPTC (n = 13) 1.65 ng/mL ±1.4 (mean±SD). Our series suggests that the absence of oncogenic mutations cannot differentiate between NIFTP and IFVPTC and the diagnosis of NIFTP requires surgical resection and careful pathological examination. Contrary to prior estimations, focal invasion or incomplete capsules were frequently found in >1 cm FVPTC leaving only 9.1% (8/88) of the PTC with the possible diagnosis of a NIFTP. The NIFTP tumors in this study did not have metastases. There are limitations of our study that warrant caution. Our study was conducted over a relatively short time with a limited number of cases from a single academic center.

Molecular testing of FNA samples was introduced as a tool to further asses the risk of malignancy in indeterminate thyroid nodules. ThyroSeq 2.0 has been used at Mayo Clinic Florida since January 2015. A retrospective analysis to evaluate the use ThyroSeq at our institution.611 thyroid nodule FNAs were performed from January 1, 2014 to May 7, 2016. 28 patients had nodules categorized as Bethesda III and 31 as Bethesda IV, suspicious for follicular neoplasm (SFN).

Of the 28 Bethesda III nodules, 8 had ThyroSeq testing, 5 had detectable mutations. Four underwent thyroidectomy (TDX), 2 of which had thyroid cancer (50%). 1 is scheduled for TDX. 3 patients did not have mutations and are being followed with US. 20 patients had no molecular testing; 13 had TDX, 5 are being followed with US and 2 have no follow up. Of the 13 who had TDX, 7 had thyroid cancer (53%), 5 did not.

Of the 31 Bethesda IV nodules, 20 had ThyroSeq testing, 6 had detectable mutations, all 6 underwent TDX and all had thyroid cancer (100%). 13 patients did not have mutations and are being followed with US. One result was pending at the time of data collection. 11 patients had no molecular testing, 9 had TDX and 2 are being followed with US. Of the 9 who had TDX, 5 had thyroid cancer (55%), 4 did not.

The cost of TDX with frozen section is $24,000 (government rate); the cost of ThyroSeq testing is $1,500.

The cost of thyroid cancer treatment per patient with Bethesda III category nodules is $54,000 and $44,570 using and not using ThyroSeq, respectively. Three patients did not have mutations and were able to avoid TDX resulting in cost saving of $67,500.

The cost of thyroid cancer treatment per patient with Bethesda IV, SFN category nodules is $29,000 and $43,200 using and not using ThyroSeq, respectively. 12 patients did not have mutations, of which 11 did not have TDX, resulting in cost saving of $84,000. ThyroSeq 2.0 is a cost effective tool to diagnose thyroid cancer compared to TDX without molecular testing in patients with nodules categorized Bethesda IV, SFN. ThyroSeq minimizes overall costs of management of indeterminate nodules and avoids unnecessary exposure to surgical risk and morbidity related to TDX.

Increased suicidal tendencies among cancer patients have been well documented. To date, there has been no specific examination of suicide rates and factors associated with suicide in thyroid cancer. The aim of this study is to examine suicide incidence and associated factors in thyroid cancer patients from 1973 to 2013. The Surveillance, Epidemiology, and End Results (SEER) Database of the National Cancer Institute was queried to identify patients with thyroid cancer. The study included mortality and demographic data from 1973 to 2013. Comparison data with the general United States population was derived from the Centers for Disease Control and Prevention's National Center for Injury Prevention and Control using the Web‐based Injury Statistics Query and Reporting System. Standardized mortality ratios (SMR) and their 95% confidence intervals (CI) were calculated, and multivariable logistic regression models generated odds ratios (OR) for the identification of factors associated with suicide in thyroid malignancy. Overall, 154 suicides among 168,339 patients were identified. There was no statistically significant difference in suicide rate with respect to age, marital status, median household income, surgical intervention, histologic subtype, or stage at diagnosis. The SMR's for females with thyroid cancer was 2.17 (95% CI, 1.64 − 2.78), 0.85 for males (95% CI, 0.69 − 1.03), and 0.71 for whites (95% CI, 0.60 − 0.83). On multivariable analysis male gender and Caucasian race were associated with increased risk of suicide with odds ratios of 5.39 (95% CI 3.89 − 7.49) and 3.17 (95% CI 1.67–6.02) respectively. Identification of evidence‐based risk factors associated with suicide among patients with thyroid cancer is an important step in the development of screening strategies and management of psychosocial stressors. Race and gender appear to influence suicide rates in patients with thyroid cancer. While SMR was <1 in most sub‐groups, females with thyroid cancer demonstrated approximately twice the suicide rate of the gender‐matched population. These results, coupled with further studies and analyses, could be used to formulate a comprehensive suicide risk factor scoring system for screening all cancer patients.

Thyroid cancer is generally associated with a favorable prognosis and excellent surgical outcomes. Consequently, its treatment tends to be medically focused and interdisciplinary care recommended for complex cases alone (ATA Guidelines, 2016). To date, no studies have evaluated the need for and impact of an interdisciplinary team based care approach (ITCA‐ThyCa) for thyroid cancer patients at large, including a dedicated nurse as well as patient‐reported outcomes as promoted worldwide in cancer care. Our aim was to evaluate such a program. ITCA‐ThyCa was evaluated using the Centers for Disease Control (2014) Framework, including process and outcome measures. Patients were eligible if they: were adults; had received biopsy results indicating confirmed or highly suspicious thyroid cancer (TNM classification+Bethesda V or VI); were awaiting treatment; and were capable of giving free and informed consent. The Experimental Group (EG) received ITCA‐ThyCa provided during their treatment trajectory and the Control Group (CG) received usual care alone. Patients were recruited from large urban university‐affiliated hospitals following full ethics approval. Our sample comprised a representative 200 participants (122 EG; 78 CG); with EG and CG presenting similar sociodemographic and medical profiles. ITCA‐ThyCa patients showed significantly better outcomes than CG patients, namely: higher levels of overall wellbeing (p = 0.001), less physical problems (p = 0.003), and less practical concerns (p = 0.003). They were more satisfied with their overall care (p = 0.028), reported their doctor as more approachable (p = 0.007), trustworthy (p = 0.077;trend), and respectful (p = 0.005), were more satisfied with their care coordination (p = 0.049), and more likely to recommend their doctor (p = 0.020). Ninety‐eight percent of EG patients recommended ITCA‐ThyCa. Mechanistic models show patient profiles most likely to benefit from ITCA‐ThyCa. Overall, the data indicates that thyroid cancer patients have important needs commanding attention in the context of an interdisciplinary team. We will present ITCA‐ThyCa and how it can be widely implemented at low cost. We will also discuss proposed ways to reform ATA Management Guidelines accordingly.

Although (DTC) has an excellent long term prognosis, in approximately 5–15% of patients it becomes refractory to RAI and might progress with much worse survival and complications.

Sorafenib a multiple kinase inhibitor was approved for treatment of progressive DTCAs a part of phase 3 larger multicenter trial, our center participated with enrollement of 5 subjects who met the criteria for RAI refractory, progressive DTC and were randomized for Placebo or Sorafenib in double blind fashion. Patients were followed periodically with clinical, radiological and biochemical assessment of disease stability, Quality of life and presence of side effects. If patient progressed using RECIST criteria then patient on placebo was offered to switch to sorafenib. Five females were enrolled with mean age of 63 y. Three were randomized to Sorafenib and two to placebo. The mean duration of DTC was 6.4 y and duration from first progression was 5.9 y. All had PTC histology type, one FV and one with PD pattern. Stages at diagnosis were I to IV. All had total thyroidectomies, avaerge 280 mci of I131 treatment (150–562 mci), with mean duration of 4.4 y since last treatment. 4/5 patients had negative uptake and 4/5 had positive FDG PET scans.

Of the 3 patients on active treatment, one showed PR from cycle 1–7 with nadir response at cycle 3 and 2 had SD from cycle 1–37 and 1–35 respectively with nadir at cycles 4 and 31 respectively. The second stable patient progressed at cycle 37.

The 2 patients on placebo progressed further at 4 and 8 months respectively. One crossed to sorafenib and was stable till cycle 37 on treatment.

Progression free survival (PFS) was 4.4 month in placebo and 26.6 mo in active treatment.

There were significant side effects with one patient withdrawing. The other 3 patients on treatment tolerated the treatment in spite of the adverse events and continued on sorafenib in an open label extension. All patients on sorafenib underwent transient dose modification and one had permanent dose reduction. Sorafenib can be an effective stabilizing therapy in advanced refractory DTC.

The use of Sorafenib is associated with significant AEs and lower QOL score, but long duration of tolerance to therapy was noted in our patients.

Many years patients with a differentiated thyroid cancer after realization of a radical surgical procedure (total thyroidectomy) passed to treatment to nuclear medicine specialists. They carried out treatment by a radioiodine and follow‐up. After development of a radioactive iodine (RAI) ‐refractory patient directed to the oncologist who had no opportunity to help the patient, except symptomatic therapy. Introduction to clinical practice of Lenvatinib gave prospects to this group of patients. In our work we present group of patients with a RAI‐refractory high‐differentiated thyroid cancer, treatment by which it was carried out with use of Lenvatinib. On treatment were 8 patients. Histologically – papillary thyroid carcinoma. Provisions of national clinical recommendations were considered as criteria of a RAI‐refractory status. Existence of a symptomatic progression of a tumor or existence of the tumor lesions sizes more than 1,5 cm were main criteries. Three patients stopped treatment after 1 month of therapy because of 3–4 degrees of toxicity of the adverse effects. Other five patients received from 3 to 6 months of treatment. At these patients partial regression of the tumor lesions by PET‐FDG‐CT and the expressed decrease of level of a thyroglobulin is noted. The adverse effects were controllable. At all patients development of the expressed arterial hypertension is noted. Before correction of a dose of a drug increase of arterial pressure more than 160/100 mm Hg is noted. Arterial pressure managed to be corrected the triple scheme of therapy. Correction of a dose of lenvatinib is made at 4 patients to 20 mg daily. Application of a lenvatinib is very successful in routine clinical practice. We consider as a condition of successful use of a lenvatinib accurate expert selection of patients for treatment after establishment of a condition of a RAI‐refractory, competent correction of the adverse effects (arterial hypertension) and well‐timed correction of a dose of a lenvatinib.

Thyroid cancer accounts for the majority of endocrine‐related cancers and cancer‐related deaths. One in twelve premenopausal women have thyroid nodules in the US, only 5–10% of these nodules are malignant and rests are benign those are confirmed after surgery. A minimally invasive, highly specific, and cost‐effective molecular marker is needed to distinguish benign from all subtypes of malignant nodules before a treatment decision is made. Follicular cell‐derived thyroid carcinomas constitute a biological continuum progressing from the highly curable well‐differentiated papillary thyroid carcinoma (PTC) to undifferentiated or anaplastic thyroid carcinoma (ATC) (1, 2). ATC is the deadliest despite aggressive treatment and patients die within a year (1). Enigma, also known as PDLIM7, a known bone formation protein, recently gained attention to cancer due to its oncogenic properties (3). In this study, we have investigated Enigma and its interacting partners in different subtypes of thyroid cancers. We collected PTC (n = 200), follicular thyroid cancer (FTC) (n = 10), poorly differentiated phenotypes (PDTC) (n = 10), and ATC (n = 10) from paraffin embedded tissue sections and immunostained with antibodies. Enigma was shown to be sequentially overexpressed in early PTC, FTC, PDTC, and ATC. We also found that Enigma and bone morphogenetic protein‐1 (BMP‐1) were differentially expressed and colocalized in PTC with and without calcifications. Conversely, Enigma colocalized with RET in FTCs. Interestingly, differential expressions and colocalizations of Enigma and MDM2/p53 were observed in PDTC and ATC. We conclude that Enigma is a key player in thyroid oncogenesis and may potentially regulate the progression from differentiated to undifferentiated or poorly differentiated PTC and ATC phenotypes. We are optimizing Enigma by PCR analysis in a minimally invasive fine needle aspiration (FNA) tissue samples. So far Enigma detection by PCR will be the most cost‐effective, easy‐to‐do molecular biomarker to discriminate between benign and malignant cells in a scanty FNA sample.

Introduction: Previously, we reported on the clinical validation of a combined diagnostic approach using mutation detection (ThyGenX) and microRNA classifier profiling (ThyraMIR) for thyroid nodule FNAs with 74% PPV and 94% NPV at 32% disease prevalence. Here we report the suitability of cytology smear slides for use with the combined ThyGenX + ThyraMIR test when FNA samples are unavailable for analysis.

Methods: Combined molecular analysis (NGS‐mutational and miroRNA testing) was carried out on 47 dedicated FNA aspirates, stored either as air‐dried smears on cytological slides or in a RNA protective buffer to show equivalence of FNA in buffer with cytology smears. In a prospective study, 107 cytology smear specimens were tested with the combined ThyGenX + ThyraMIR panel and the molecular analysis results were correlated with the histopathological evaluation of the surgically resected nodules.

Results: For matching FNA samples (n = 47) from the same patient, either stored in RNA protective solution or as air‐dried smears on the cytology slides, the concordance observed between ThyGenX calls from the two specimen types was 98% (46/47) and from ThyraMIR calls was 89% (42/47). For the prospective study using 107 cytology smear specimens, we found assay sensitivity of 82% and specificity of 82%, resulting in 66.3% PPV and 91.5% NPV at 30% cancer prevalence.

Conclusions: These results clearly demonstrate that the combined ThyGenX + ThyraMIR test can be carried out from FNA material stored on cytology slides. The performance of the combined test in FNA in protective buffer was found to be slightly superior to cytology smears. Thus, cytology smears are an adequate sample type for the molecular profiling, for both NGS and microRNA testing, when FNA in preservative buffer is unavailable or insufficient for analysis. These results also suggest that archived cytology smears are a suitable sample type for retrospective molecular analysis.

Introduction: Non‐diagnostic cytology (NDC) (Insufficient) occur in 5–10% of thyroid nodule needle aspirates, often resulting in repeat FNAs. The NDC topic tends to be overlooked but is potentially addressable by molecular analysis. To better understand efficacy of molecular testing in NDC samples, we reviewed our experience with correlative parallel needle aspirates, using mutational and microRNA (miR) analysis.

Methods: We reviewed 4,503 consecutive thyroid nodule needle aspirates submitted for combined NGS‐ mutation (ThyGenX) and microRNA expression (ThyraMIR) classifier analysis correlated with cytology diagnosis. Sample adequacy criteria for combined molecular testing included supra‐threshold levels of thyroid follicular epithelial cell mRNA, total extracted nucleic acid concentration and DNA copy number.

Results: 201 (4.5%) of 4,503 needle aspirates cytology samples were non‐diagnostic. 137 of these 201 (68.2%) NDC cases met molecular criteria for adequacy and were successful for both mutational change and miR classifier determination. The remaining 64 NDC cases (31.8%) failed miR testing with 37 (18.4%) also failing mutational analysis. 279 (6.2%) of 4,503 total cases failed miR testing however 64 were NDC for a true miR failure rate of 215 cases (4.7%). 129 of 279 cases also failed mutational analysis (3.9%) however 64 represented correlative NDC for a true mutational failure rate of 65 cases (1.4%). Patients with unsuccessful FNA molecular testing in the context of adequate cytology diagnosis were offered direct cytology slide/cell block testing which further lowered the overall failed molecular testing rate precluding the need for repeat needle aspiration.

Conclusions: Needle aspirate molecular analysis shows a very low true nucleic acid testing failure rate equivalent to that seen for cytology (4.7%). Successful testing, achievable in the majority of patients (68.2%), utilizes both cell‐free and cellular nucleic acid. Direct molecular analysis of the aspirate followed by testing of residual cytology material (stained slide/cell block) represents an effective approach to be considered for non‐diagnostic thyroid nodule cytology sample before resorting to repeat aspiration.

Thyroid nodules are extremely common, yet thyroid cancer is a relatively rare condition. The identification of a nodule as benign or malignant has important surgical and therapeutic implications. The evaluation of FNA cytology leads to a definitive benign or malignant diagnosis in the majority of cases. However, as much as a third of thyroid aspirates yield indeterminate cytology with an estimated malignancy rate ranging from 5% to 75%. We developed a microRNA‐based assay, RosettaGX Reveal that can diagnose indeterminate thyroid nodules utilizing stained FNA smears prepared for cytopathological evaluation. In the present study, we assessed our microRNA classifier on pairs of FNA stained smears and liquid‐based cytology samples from the same nodule in order to validate the assay for use on these samples. Study results demonstrate full classification concordance. Thirty thyroid FNA liquid‐based cytology samples (prepared using the ThinPrep^® system) with corresponding stained smears were collected. Using proprietary protocols, high‐quality RNA was extracted from the samples and the expression levels of the assay's microRNA biomarkers were measured by qRT‐PCR. Using the miRNA classifier, the samples were classified as benign or suspicious for malignancy. Total RNA was extracted from 30 paired samples yielding 0–500 ng RNA/sample. Twenty‐one liquid‐based cytology‐smear pairs passed QC criteria. 8 out of the 9 samples that did not pass QC, failed due to low expression of assay microRNAs (7 of them in the thin layer sample alone or in both the liquid‐based and corresponding smear samples and one in the smear sample alone). For the 21 samples that passed QC, there was a 100% concordance in the classification of the matched liquid‐based and smear samples by the assay. Seven samples were classified as benign and 14 were classified as suspicious by the assay on the matched smear and liquid‐based cytology samples. Liquid‐based cytology samples are widely used for evaluation of thyroid aspirates. Here we show that our microRNA‐based diagnostic assay, developed to classify indeterminate thyroid nodules, utilizing stained smears, is suitable for the diagnosis of liquid‐based thyroid FNAs.

A mouse with selective inactivation of Dio2 in the liver (Alb‐D2KO) is resistant to diet‐induced liver steatosis and exhibits a 60% reduction in liver Zfp125 mRNA levels, a gene that we found to be increased by fasting (2‐fold; p < 0.05) and inhibited by insulin (25–60%, p < 0.05). To understand its role, the mouse hepatocyte line AML12 stably expressing Zfp125 was analyzed and found to accumulate lipids (2–4 fold, p < 0.001), triglycerides and cholesterol (10–60%; p < 0.001), while differentially expressing 152 genes (>1.5‐fold; p < 0.001) and 182 gene sets (microarray and RT‐qPCR). Overall, expression of Zfp125 was associated with decreased expression of genes involved in hepatocyte lipid binding and transport (40–90%; p < 0.05). In contrast, the opposite phenotype was observed in AML12 hepatocytes with Zfp125 siRNA. A very similar scenario was observed in hepatocytes stably expressing ZNF670, the Zfp125 human homologue, i.e. lipid accumulation and down‐regulation of genes involved in lipid binding/transport. Chip assays performed in AML12 cells stably expressing Flag‐tagged ZNF670 identified a 3.5‐fold increased binding (p < 0.05) to the Mttp promoter. Next, mice with liposome‐mediated transient liver expression of Zfp125 or ZNF670 were found to have the expected hepatic changes in gene expression by RT‐qPCR and increased levels of serum VLDL/LDL cholesterol (19‐fold; p<0.001). Likewise, selective Zfp125 knockdown in liver led to increased expression of genes involved in hepatic lipid binding and transport, with no differences in serum cholesterol profile. In humans, ZNF670 mRNA levels were decreased in liver of our obese patients with no DM (20%; p < 0.05) and in publically available liver data of obese healthy patients (28%; p < 0.03). Furthermore, ZNF670 SNP rs2172795 (p = 0.006) is negatively associated with serum levels of LDL cholesterol in publically available GWAS data from HapMap CEU cohort. In conclusion, D2‐sensitive Zfp125 and ZNF670 are transcriptional repressors that promote hepatic steatosis and elevate the serum cholesterol.

In 2015, the American College of Radiology (ACR) introduced its own Thyroid Imaging, Reporting, and Data System (ACR‐TIRADS) in order to standardize descriptions of ultrasound (US) findings. The aim of this study was to assess the ability of practicing radiologists to correctly apply ACR‐TIRADS without a prior dedicated training devoted to this new system. In an IRB‐approved study, the performance of 10 radiologists with an average of 9 years (1–34) of US experience was tested. US images of 20 thyroid nodules were taken from the MCMC archive and incorporated into a computerized survey. We assessed the identification of 5 ACR‐TIRADS features (composition, echogenicity, orientation, echogenic foci, margins) using the proposed descriptors. In addition, round orientation and anechoic echogenicity were added to the survey, as these were not a part of ACR‐TIRADS but are required for precise reporting. The subsequent identification of 5 suspicious US features (hypoechogenicity, marked hypoechogenicity, microcalcifications, taller‐than‐wide orientation, suspicious borders [irregular, lobulated, and ill‐defined]) was analyzed. Diagnostic accuracy was calculated utilizing the new 2015 ACR‐TIRADS for all 10 readers combined: 66% for nodule composition, 72% for echogenicity, 76% for orientation, 66% for identification and characterization of echogenic foci, and 68% for nodule margins. The sensitivity and specificity, respectively, for suspicious features were as follows: 68% and 83% for nodule hypoechogenicity, 60% and 96% for marked hypoechogenicity, 78% and 76% for microcalcifications, 62 and 96% for solid composition and 70% and 88% for taller‐than‐wide orientation, and 88% and 71% for suspicious margins.

1. Although ACR‐TIRADS provides a strong background for US description of thyroid nodules, our study showed that the accuracy of interpretation without a dedicated training ranged from 63 to 76%, with 60–88% sensitivity and 71–96% specificity.

2. The performance of radiologists may benefit from training devoted to this system.

3. Round orientation and anechoic echogenicity should be included in the ACR‐TIRADS descriptors; they were not initially part of the system, but they are necessary for precision in reporting.

Cystic cervical lymphadenopathy justifiably raises the suspicion for metastatic papillary thyroid cancer (PTC). Even in the absence of a malignant cytology, an elevated thyroglobulin level frequently prompts cervical lymph node dissection and total thyroidectomy for presumed metastatic thyroid cancer. Hemangiomas are benign vascular tumors that present relatively frequently in the skin and soft tissue of the head and neck. However, hemangiomas arising from within a lymph node are rare, and only one prior case of a cervical intranodal hemangioma has been reported. We present a case of a cystic cervical lymph node with high thyroglobulin levels that turned out to be a primary nodal hemangioma rather than metastatic PTC. A case report from a tertiary care academic center. A 30‐year‐old euthyroid female presented with a left thyroid nodule and ipsilateral cervical lymphadenopathy. Ultrasonography revealed a left 2.1 cm thyroid nodule with microcalcifications and an ipsilateral 3.0 cm level III lymph node with multiple irregular cystic areas, suspicious for malignancy. Fine needle aspiration cytologies of the nodule and the lymph node were negative for malignancy. A thyroglobulin level measured from the lymph node aspirate was 97.5 IU/mL against a serum background of 10.6 IU/mL, consistent with metastatic thyroid cancer. An ultrasonographically‐guided excisional lymph node biopsy was performed. The lymph node was encapsulated and easily resected. Frozen section pathology revealed a benign intranodal hemangioma and plans for thyroidectomy were aborted. At follow‐up, there was no sign of persistent or recurrent tumor. Primary intranodal hemangiomas are rare and can mimic other tumors. Unlike the infiltrative nature of skin and soft tissue hemangiomas, nodal hemangiomas are well‐circumscribed and easily separated from surrounding tissues. Intranodal benign vascular tumors may present as cystic cervical lymph nodes and may concentrate thyroglobulin so as to mimic metastatic PTC. In the absence of definitive malignant cytology, frozen section pathology should be obtained on excisional cervical lymph node biopsies prior to proceeding with thyroidectomy and cervical lymph node dissection for presumed metastatic PTC.

Autoimmune Polyglandular Syndrome (APS) is a rare polyendocrinopathy characterized by insufficiency of at least two endocrine glands through an autoimmune mediated process. APS type II is defined by primary adrenal insufficiency as its principal manifestation and can be associated with autoimmune thyroid disease and/or type 1 diabetes mellitus. Typically the autoimmune thyroid disease most commonly associated is chronic thyroiditis, but here we describe a patient presenting with Graves' thyrotoxicosis. n/aA 42 year old female presented with 20 lb weight loss associated with fatigue, palpitations, and profound weakness. She had tachycardia, tremors, and a thyroid bruit and was found to have thyrotoxicosis secondary to Graves' disease (TRAB 17 IU/L [ref 0–1.75], TSI index 3.5 [ref <1.3]). She was started on methimazole, hydrocortisone, and propranolol with improvement in symptoms but developed agranulocytosis requiring discontinuation of methimazole and urgent thyroidectomy. After thyroidectomy and steroid taper she continued to have fatigue, relative hypotension, and hyponatremia. ACTH stimulation test showed baseline cortisol 1.5 mcg/dL, 60 minute cortisol 2.4 mcg/dL and an elevated ACTH of 199 pg/mL (ref range 6–50 pg/mL). She also had elevated 21 hydroxylase antibodies, all consistent with primary adrenal insufficiency. She was restarted on hydrocortisone and had significant improvement in symptoms. As clinicians we should maintain suspicion of other endocrinopathies following the diagnosis of one endocrine gland dysfunction. The glucocorticoids used to treat this patient's thyrotoxicosis likely masked her underlying adrenal insufficiency and delayed the diagnosis. It is crucial to remember that the autoimmune thyroid disease associated with APS type II is not limited to chronic thyroiditis but includes Graves' disease as well. A review published by Betterle et al in 2004 reported that in patients with APS type II, autoimmune thyroid disease was present in 88% of patients and the prevalence of Graves' disease was 21.2%. It is critical to consider primary adrenal insufficiency in a patient presenting with Graves' disease, especially because thyrotoxicosis can precipitate an Addisonian crisis.

Background: Primary hypothyroidism is generally considered a stable or gradually progressing condition requiring life‐long thyroid hormone replacement therapy. It is not uncommon to observe hyperthyroidism reverse to hypothyroidism. However, there are few case reports in the literature of switching from hypothyroidism to hyperthyroidism.

Case Presentation: We report a 32‐year‐old G2P2 female who developed hypothyroidism during her pregnancies in 2010 and 2014. She was treated with levothyroxine during both pregnancies which were otherwise uncomplicated, and remained euthyroid between pregnancies. Levothyroxine was discontinued in June 2015, one year after the birth of her second child.

After unsuccessful attempts to conceive a third child, she was diagnosed with hyperthyroidism in March 2016. Other than fatigue and weakness she felt well, and there was no thyroid associated orbitopathy. A thyroid scan on March 30, 2016 demonstrated homogenous increased uptake, in keeping with Graves' disease. However, as thyroid indices were not available at the time of the scan, and since subsequent thyroid indices in July 2016 were normal, the differential diagnosis would include recovering thyroiditis. A thyroid ultrasound revealed a heterogeneous, nodular and hypervascular gland of normal size. TSH receptor antibodies and anti‐thyroid peroxidase antibodies were negative. Thyroid function tests in table format, thyroid scan, and thyroid ultrasound are available as images.

Discussion: Conversions from primary hypothyroidism to hyperthyroidism have been infrequently reported. There are several possible explanations for such a phenomenon. Some patients can have concurrent Hashimoto's disease and Graves' disease; others can have Graves' disease with swinging dominance between TSH‐stimulating autoantibodies (TSAb) and TSH‐blocking autoantibodies (TBAb). Thyroid hormone replacement, anti‐thyroid drugs, and pregnancy can influence TSAb and TBAb levels. It is important for clinicians to be aware of this clinical entity to allow for prompt diagnosis and treatment.

Methimazole‐induced Agranulocytosis (MIA) is a rare treatment complication in patients with Graves' disease (GD). The Lack of a standardized treatment makes this entity a medical challenge. We aimed to evaluate socioeconomic and clinical characteristics in a group of Peruvian patients with MIA and to assess its in‐hospital mortality rate. We conducted a retrospective study in patients with diagnosis of GD who were hospitalized secondary to MIA in a Peruvian National Hospital for the last six years. Numeric variables were reported as medians (percentiles: 25^th‐75^th) and categorical variable, as frequencies. Association between variables and in‐hospital mortality were evaluated by Mann‐Whitney U‐test and Fisher's exact‐test. Finally, long‐rank test was used to assess survival rate in Granulocyte colony‐stimulating factor users (G‐CSF) vs non‐user (NG‐CSF). A total of 29 medical records were included in the study. Median age was 34(29–43) years, female 25(86.2%) patients; median time‐of‐disease was 5(3–23) months. Eighteen(62.1%) patients received 15–30 mg of methimazole compared to 11(37.9%) patients who received 40–60 mg. G‐CSF groups was 12(41.45%) and NG‐CSF was 17 (58.6%) patients. MIA death rate during hospitalization was 10% (n = 3). In‐hospital mortality was associated with higher methimazole‐dose (p = 0.045). The only three deaths occurred in NG‐CSF compared to G‐CSF which had no death, although no significant association has been found. Median time since MIA diagnosis until total recovery was 9.5(7–15) days for G‐CSF and 9(7–14) days for NG‐CSF and log‐rank test did not reveal significant difference between survival groups (p = 0.550).

Similarly to previous literature, higher methimazole's dose was associated with mortality. This early mortality could be explained by immune‐mediated mechanisms which proceed rapidly compared a toxic mechanisms. The role of G‐CSF in patient with MIA remains controversial although all of deaths occurred in NG‐CSF group. We hypothesis opportunistic infection may have played a role in setting of a low‐income hospital. Identifying GD candidates for methimazole through careful risk‐factor assessment or considering other therapies (e.g. 131‐Iodine) are needed.

Preeclampsia is defined as the association of hypertension and proteinuria and occurs after 20 weeks of amenorrhea. It is also an important cause of morbidity and mortality in pregnancy. Some previous studies associated gestational thyroid dysfunction and preeclampsia. Nevertheless, the aim of our study is to find differentially expressed genes in preeclampsia pregnant patients and gestational hypothyroid patients.

Methods: We selected eight euthyroid pregnant women, four with gestational hypothyroidism and four with preeclampsia for transcriptome analysis. Peripheral blood was collected in PAXgene blood RNA preservation tubes, and PAXgene Blood RNA kit (Qiagen) was used in the extraction. NGS platform Ion Proton System was used for transcriptome analysis following the Ion AmpliSeq transcriptome Human Gene Kit protocols (Thermo Fisher Scientific Manufacturer). Two independent libraries were generated: one with four euthyroid/four hypothyroid pregnant women and the second library with four independent euthyroid/four preeclampsia women. All the data was analyzed in rstudio 0.99.491 software, Package Edger 3.12.0 of Bioconductor (Robinson MD, DJ McCarthy and Smyth GK, 2010).

Results: We sequenced 22,786 transcripts in the sixteen pregnant women. The differential expression analysis revealed 1867 genes altered in the hypothyroid group (981 under‐expressed and 886 overexpressed genes) and 19 genes in the preeclampsia group (all of them with under‐expression). Interestingly, we identified the transcript of Homo sapiens olfactory receptor family 10 subfamily G member 7 (OR10G7) mRNA as the link between the two diseases.

Conclusion: This gene and probably its protein may represent a good biomarker to preeclampsia pregnancy complication in a gestational hypothyroid patient or even in general population.

Iodine is an essential micronutrient for thyroid hormone production. Adequate maternal thyroid hormone in pregnancy is critical for proper fetal development. The American Thyroid Association (ATA) recommends that U.S. women take supplements containing 150 μg of iodine daily preconception, during pregnancy, and lactation. A 2009 study showed that only 51% of commercially available prenatal vitamins (PNVs) in the U.S. listed iodine on their product labels. In early 2015, the Council for Responsible Nutrition (CRN) issued a recommendation for all multivitamin or mineral supplements intended for pregnant or lactating women in the U.S. to include at least 150 μg of iodine per daily dose in their supplements. In this study, we assessed the current status of iodine contents of the commercially available PNVs in the U.S.A list of commercially available PNVs was assembled from sources including the National Institute of Health Dietary Supplement Label Database, the Natural Medicines Database, and the U.S. National Library of Medicine DailyMed Database. Information regarding iodine content was obtained from product labels. A total of 386 PNV products (234 nonprescription and 152 available by prescription) were identified. Of these, only 237 (61%) PNVs contained iodine (71% of nonprescription PNVs and 46% of prescription PNVs). The majority of PNVs with iodine (212, 89%) contained at least 150 μg of iodine per daily dose, with iodine content ranging from 10–450 μg per daily dose. The most common source of iodine was potassium iodide (151, 64%), followed by kelp (61, 26%). Fifty‐four PNVs were marketed by CRN member companies, 93% (50) of which contained iodine. Compared to 2009, there has been a modest increase in the proportion of PNVs that contained iodine, from 51% to 61%, despite recent recommendations by the CRN and the ATA. Almost all PNVs marketed by CRN members companies contained iodine. More effort is needed to ensure adequate iodine content of U.S. PNVs in order to protect developing fetus.

Autoantibodies against thyroid‐stimulating hormone receptor (TSHR) have been used as specific biomarkers of autoimmune thyroid diseases (AITD). There are two distinct types of autoantibodies to the TSHR which have been characterized as thyroid stimulating antibody (TSAb) and thyroid blocking antibody (TBAb). Two bioassays, named as QTSI and TBI, have been developed that are able to either quantitatively detect only TSAb or qualitatively detect only TBAb in ATID patient sera. The purpose of this study was to demonstrate the high specificity of both the QTSI assay and the TBI assay. Human TSHR stimulating antibody (M22) and blocking antibody (K1–70) were serially diluted and tested by both QTSI and TBI assays concurrently following the manufacturer's instructions (Quidel). The two antibodies were also mixed at different ratios and tested by the two assays. The TSAb concentration (mIU/L) for each sample was calculated based on the standard curve generated in the QTSI assay. The % Inhibition of luciferase expression for each sample was calculated using the assay Reference Control included in the TBI assay. Twenty archived clinical samples obtained from AITD patients were also analyzed by the two assays using the same method. To further demonstrate the high specificity of the two bioassays, a commercial available TSH Receptor Autoantibody (TRAb) ELISA Kit (Kronus) was used to test the same samples as a comparison. All M22 stimulating antibody dilutions and nine clinical samples were positive (≥ 200 mIU/L) only by the QTSI assay. All K1–70 blocking antibody dilutions and 11 other clinical samples were positive (≥ 34% Inhibition) only by the TBI assay. When testing mixtures of the two TSHR antibodies (M22 and K170), the interaction between the two antibodies can be detected by the two bioassays but not by the Kronus Kit. Both the QTSI assay and the TBI assay showed 100% specificity when testing M22 stimulating antibody and K1‐70 blocking antibody concurrently. The bioassays also exhibited 100% specificity when testing 20 archived clinical samples from AITD patients. The diagnostic accuracy for the AITD patients will be increased substantially by using the two unique, highly specific and sensitive bioassays.

Parathyroid gland (PG) identification during thyroid and parathyroid surgery is challenging. Accidental parathyroidectomy increases the rate of post‐operative hypocalcemia. Recently, the use of autofluorescence (AF) with near infrared light (NIRL) has been described as a useful method for PG visualization. The aim of this study is to analyze the increased rate of visualization of PG with the use of NIRL compared to white light (WL) in order to improve patient's post‐operative hypocalcemia. All patients undergoing thyroid and parathyroid surgery were included in this study. During the procedure, the surgical field was illuminated with WL and NIRL with a laser system. PGs were identified with both wavelength lights by experienced head and neck surgeons. The number of PGs identified with NIRL and WL were compared. The identification of PGs was correlated to age, sex, and histopathological diagnosis.

One hundred and seventy patients, 72.9% (n = 124) female and 27.1% (n = 46) male, were included in the study. The mean age was 52 (SD ± 14) years old. The mean fluorescence intensity of PGs (57.2) was significantly higher than fluorescence intensity of thyroid glands (TGs) (21.5) and background (9.27) (p < 0.0001). The mean number of PGs identified with NIRL and WL were 3.7 and 2.5, respectively (p < 0.001). The number of PGs identified with NIRL compared to WL was higher in 137 (81.1%) patients, the same in 30 patients (17.6%), and lower in two patient (1.3%). The difference in the number of PGs identified with NIRL and WL was not related to age, sex or histopathological diagnosis with the exception of the diagnosis of thyroiditis.

Fluorescence intensity of the PGs was not dependent on gender, age or pathological diagnosis. No post‐operative hypocalcemias were reported in this series.

The use of NIRL for PG visualization significantly increased the identification in the number of PGs during thyroid and parathyroid surgery and the difference in fluorescent intensity between PGs, TGs and background were not affected by age, sex and histopathological diagnosis. Autofluorescence visualization of PGs resulted in a promising method to decrease the morbidity in thyroid surgery.

Acromegaly increases the incidence of goiters and Thyroid Cancer (TC). There is a possible link between Acromegaly and other solid cancers, though the evidence is mixed. I‐131 is the standard treatment for Thyroid Cancer, though long‐term complications may include increasing incidence of leukemia. A 76 year old man presented with bilateral complex thyroid nodules, benign by repeated UG‐FNA (2009–2013); surgery was recommended but refused. Features suggestive of Acromegaly. IGF‐1 and failure to suppress GH with glucose load confirmed diagnosis; pituitary micro‐adenoma treated with gamma knife. UG‐FNA was unchanged until nodules enlarged (2013) and at that time revealed FTC, and CT of the neck and chest showed pulmonary nodules and metastatic FC. A total thyroidectomy showed FTC, pT3NxM1. I‐131,150 mCi given and Thyroglobulin (TG) 11,352 ng/mL was noted. Octreotide started when IGF‐1 levels increased but was discontinued after the patient developed symptoms of cholelithiasis. Two more I‐131 treatments were given and Sorafenib was added

During third I‐131 treatment, patient complained of abdominal pain, EGD showed gastric ulcer, biopsy revealed primary gastric adenocarcinoma. The patient's gastric cancer was treated with Folinic Acid, 5FU, and Oxaliplatin every two weeks in preparation for surgery. There is a known increase in the risk of TC in patients with Acromegaly (even after successful treatment), but it is unclear if there is a link between Acromegaly and subsequent gastric cancer—some studies show elevated rates of gastric cancer and polyps and others do not. There is a controversial link between I‐131 and secondary primary malignancies, but to our knowledge, I‐131 is not associated with gastric cancer. Long‐term follow up studies on pediatric patients treated with I‐131 for PTC have shown no increased risk of any cancers. Prior radiotherapy, along with previously active acromegaly, may have played a role in the genesis of gastric cancer. Guidelines on acromegaly should recommend surveillance with periodic thyroid US and surgery for suspicious nodules even with negative UG‐FNA. This case is the rare combination of FTC, acromegaly and a primary gastric cancer discovered after treatment of DTC with I‐131.

Mutations in the promoter region of the telomerase‐reverse‐transcriptase (TERT) gene are known to occur in cancer. Two currently known mutation hotspots, −124C>T (C228T) and −146 C > T (C250T), have been reported in a subset of follicular‐cell derived thyroid cancers. These mutations generate de novo consensus binding sites for ETS transcription factors causing increased TERT transcription. However, other regions of TERT promoter have not been thoroughly studied. The aim of this study was to analyze an extended TERT promoter region in all main types of thyroid cancer to search for novel functional TERT mutations.

We studied 193 papillary thyroid carcinomas (PTC), 23 follicular thyroid carcinomas (FTC), 31 Hürthle cell carcinomas (HCC), 7 poorly differentiated/anaplastic thyroid carcinomas (PDTC/ATC), and 15 medullary thyroid carcinomas (MTC) using PCR and Sanger sequencing for mutations in a 489 bp region upstream of the first cDNA codon of TERT. TERT expression was analyzed using targeted amplification‐based next‐generation sequencing assay. The most common TERT mutation, −124C>T (C228T), was found in 11 (5.7%) PTC, 3 (13%) FTC, 2 (13.3%) HCC, 5 (71.4%) PDTC/ATC, but not in any MTC. TERT −146 C > T (C250T) mutation was detected in 4 (2.1%) PTC and 2 (28.6%) PDTC/ATC. Further, we identified a novel mutation, also C > T substitution, located at −332 base pairs (Chr 5:1,295,436 hg19 position) from the ATG initiation site, in one tumor. This tumor was diagnosed as MTC and had no known hotspot TERT mutations. The −332C>T mutation creates GGAT sequence, which is a putative consensus ETS transcription factor binding site and could lead the activation of TERT. Indeed, on TERT expression analysis, this tumor showed TERT expression >100 fold higher compared to other thyroid cancers.

The results of this study confirm the presence of common hotspot TERT mutations in the follicular cell‐derived thyroid cancer, but show that they do not occur in MTC. Further, we report a novel mutational hotspot, −332C>T, located on a significant distance upstream of the two known and typically studied TERT promoter mutation sites, which leads to high levels of TERT gene expression.

This pilot study aims to assess the short‐term efficacy after apatinib, a novel tyrosine kinases inhibitor (TKI) targeted VEGFR2, in radioiodine refractory differentiated thyroid cancer (RAIR‐DTC) via different assessing modality including thyroglobulin (Tg), RECIST, and glucose metabolism. This study was approved by the institutional review board of Peking Medical College Hospital Ethics Committee. Patients with RAIR‐DTC aged 18 or older were enrolled, who received oral apatinib 750 mg once daily with a cycle defined as 4 weeks. Within 8 weeks of apatinib, Tg level was monitored every 2 weeks. CT and PET/CT were performed every 4 weeks. Therapeutic responses were evaluated in terms of biochemistry, RECIST and glucose metabolism. Meanwhile, the adverse events (AE) were also observed during the therapy. Ten patients were involved in this study with mean age of 54.9 years, confirmed with papillary thyroid cancer.

A mean Tg decline of 21% can be observed as early as 2 weeks after apatinib treatment, indicating a quick biochemical response. After 8 weeks' treatments, the mean Tg decreased by 81.4% from 1583.5 ng/mL to 294.6 ng/mL. Totally 90% (9/10) patients achieved partial response and 1 patient of stable disease. At baseline, the mean diameter of target lesions was 21.6 mm. After 8 weeks' treatment, the mean diameter shrunk to 12.7 mm. The mean diameter diminished 34% from 22.4 to 14.8 mm after 4 weeks, indicating a rapid structural response. Meanwhile, a significantly decrease of 60.8% on mean SUVmax revealed by PET/CT was observed after 4 weeks' treatment, implying the earlier and more substantial metabolic response than the structural change.

The common grade 3 AEs including hand‐foot‐skin reaction, hypertension, hypocalcemia, accounted for 50%, 30%, and 20%, respectively. No severe AE related to apatinib was observed within 8 weeks observation. Rapid response and high PR rate in terms of biochemistry, RECIST1.1 and metabolism could be observed in RAIR‐DTC within 8 weeks' apatinib treatment. Tg and PET/CT are indispensible in assessing the early response of TKI in RAIR‐DTC. Our study indicated the promising efficacy of apatinib with an acceptable safety profile in patients with RAIR‐DTC.

The optimal time to initial radioactive iodine (RAI) therapy after surgery remains unclear. We tried to use therapeutic response system to evaluate the impact of intervals to initial RAI therapy after operation in patients with non‐high risk differentiated thyroid cancer (DTC). A total of 140 consecutive non‐high‐risk patients were retrospectively reviewed, including their age, gender, the surgery time, TNM stage, ATA recurrence risk and the initial RAI treatment time. The intervals between the initial RAI treatment and surgery were calculated and denoted as T. Patients were divided into 4 groups according to the different T period, Group 1: T <28d (n = 31), Group 2: 28d≦T<43d (n = 38), Group3: 43d≦T<95d (n = 35) and Group4: T≧95d (n = 36). Responses to RAI therapy were evaluated as excellent, indeterminate, biochemical incomplete, or structural incomplete response (ER, IDR, BIR, or SIR) according to the new ATA therapy response system after a mean follow‐up of 588 ± 231 days. ANOVA, chi‐square test, K‐W test were used for statistical analysis. There were no significant differences of age, gender, TNM stage, time of follow‐up among 4 groups (all P > 0.05). The therapy response was different among these 4 groups (H = 11.34, P = 0.01), the ER rates were 93.5%, 78.9%, 71.4%, 58.3% (c² = 11.95, P = 0.007) in group 1 to 4, respectively. Further comparison in each 2 groups showed significant different ER rates between group 1 and 4(93.5% vs 58.3%) (c² = 10.91, P = 0.001, corrected α = 0.008) The therapeutic response was influenced by the intervals between surgery to RAI in intermediate to low risk

DTC patients. The sooner the time to RAI therapy, the more favorable response would be expected, which indicating RAI therapy should be managed as early as possible.

The post‐thyroidectomy population poses a unique challenge for venous thromboembolism (VTE) prophylaxis management. Current VTE risk assessment models place many thyroidectomy patients at high risk for VTE based primarily on the length of the procedure and the presence of various comorbidities.¹ However, the published incidence in this subpopulation does not reflect this theoretical risk.² To evaluate the utility of pharmacologic prophylaxis in this specific population, we conducted a retrospective chart review of all patients undergoing a total thyroidectomy, thyroid lobectomy, and completion thyroidectomy at a single military treatment facility over a four year period. For initial validation purposes, a pilot study was performed of solely the total thyroidectomy population. Basic demographics were collected and preoperative Caprini risk assessment scores were calculated for individual patients. The administration of chemical prophylaxis was documented and the primary events (VTE, bleeding events) were compared between those that received prophylaxis and those that did not.263 patients were included in our pilot study, 73% of whom were female with an average age of 44. Seventy‐five percent of patients underwent a total thyroidectomy for a benign etiology, most commonly for multinodular goiter. The remaining 25% had a preoperative diagnosis of malignancy. The average preoperative Caprini score was 4.4, placing the patients at high risk and warranting chemical prophylaxis. However, only two patients received prophylaxis (0.76%) and moreover, there were no documented VTEs in our study. Three patients did, however, suffer a postoperative bleeding event (1.1%). In conclusion, post‐thyroidectomy patients exhibit a low incidence for VTE despite the high theoretical risk suggested by the Caprini risk assessment model. Moreover, our data demonstrates that this subpopulation possesses a higher baseline incidence of postoperative bleeding than for VTE, suggesting that administration of prophylaxis is unwarranted. The next phase of our study will include lobectomy and completion thyroidectomy patients at our institution, as well as up to five additional military treatment facilities.

Objective: The aim of this study was to explore what a diagnosis of papillary thyroid cancer means to patients and how they derive these assessments.

Methods: Subjects for this qualitative study were papillary thyroid cancer patients enrolled in a randomized clinical trial who were interviewed using a semi‐structured interview guide. Interviews were transcribed verbatim and thematically coded in Nvivo using modified grounded theory. The present study included data from pre‐operative interviews from 37 patients who addressed topics related to how they conceptualize thyroid cancer.

Results: Analysis of interviews revealed that patients varied in the meanings they gave a thyroid cancer diagnosis: 41% percent viewed it as a “bump in the road,” 23% percept described thyroid cancer as “life‐changing,” and 36% straddled both domains. The primary driver behind an assessment of thyroid cancer as “a blip on the radar” was knowledge of thyroid cancer, which many described as a “very curable” cancer that only requires “surgery and a pill.” Other factors that influenced this assessment included exposure to thyroid cancer survivors and experience with chronic health conditions. Those that interpreted thyroid cancer as life‐altering were influenced by negative experiences with cancer or “the ‘C’ word,” anxiety about treatment and “not knowing when it's working,” and concern that thyroid cancer would disrupt daily life because, according to one patient, “[no one] has time for cancer.”

Conclusion: The data in this study revealed that thyroid cancer patients are extremely diverse in the meanings they assigned to thyroid cancer. Some view their disease as inconsequential, others understand it as a worst‐case scenario, and a sizeable number describe it in both ways. Certain factors that influence a patient's appraisal of their disease are predetermined and cannot be changed, such as prior experiences with cancer and personal co‐morbidities. However, doctors may be able to mitigate the influence of these experiences and assuage patient anxiety by comprehensively discussing thyroid cancer's prognosis and educating them about what they can expect from treatment.

Reported results for thyroid nodule fine needle aspiration cytology (FNACs) mainly originate from tertiary centers. However, thyroid nodule FNA cytology is mainly performed in primary care settings for which the distribution of FNAC Bethesda categories and their respective malignancy rates are largely unknown. Moreover, in several European countries preoperative FNA rates for patients with thyroid nodules are low and the majority of thyroid cancers are not detected by FNAC.

In a primary care setting we therefore retrospectively analyzed 9460 FNAC of thyroid nodules from 8380 patients evaluated by one cytologist (I.R.) during a period of two years. The 8380 FNACs were performed by 64 physicians in different private practices throughout Germany in primary care settings. The cytopathology results were classified according to the Bethesda System as non‐diagnostic in 19%, cyst/cystic nodule in 21%, benign (including thyroiditis) in 48%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 6%, follicular neoplasms (FN) in 4%, suspicious for malignancy ((SFM) including suspicious for PTC, MTC, lymphoma in 1%, malignant including PTC, MTC, anaplastic carcinoma, poorly differentiated carcinoma, metastasis of non‐thyroidal cancer and lymphoma in 1%. The proportion of patients proceeding to surgery and the observed risks of malignancy were 71%/98% for malignant, 78%/86% for suspicious, 22%/12% for AUS/FLUS, 69%/21% for FN. For 112 suspicious and malignant FNACs there were 102 true positives and 10 false positives, considering histology as gold standard. At variance with predominant other data mostly originating from tertiary centers these data demonstrate low percentages for malignant, SFM, FN and AUS/FLUS and high percentages for cysts/cystic nodules in this primary care setting in Germany. The risks of malignancy for malignant, SFM, AUS/FLUS and FN FNACs are according to Bethesda recommendations.

Consumption of artificial sweetener (AS) has increased over the past three decades. Studies have linked saccharin and cyclamates to bladder cancer in laboratory rats. However, no definitive studies are available in human beings. The National Cancer Institute Surveillance Epidemiology and End Results has reported an increase in the prevalence Well Differentiated Thyroid Cancer (WDTC). The cause of this increase is not known.

As the incidence of AS consumption and thyroid cancer are both increasing, our study would focus on determining any possible association between them. A retrospective study that included 50 patients with age 18 years and above who have been diagnosed with WDTC between Jan 1, 2004 – Aug 31, 2014 at our was performed. A telephonic survey questionnaire was conducted pertaining to the use of AS in their diet. Age, gender, ethnicity, history of radiation exposure were also included. Based on the data collected, the average number of AS packets consumed per user was calculated. And a statistical analysis using proportionate testing was conducted. 38 out of 50 patients (76%) took sugar substitutes while 12 patients (24%) did not take any such products. The average number of packets consumed per user was 2 per day and the average duration of use was 3 years. An analysis done with proportionate testing showed a statistically significant (p ‐ 0.01) number of AS consumers in thyroid cancer patients.

Aspartame, Sucralose and Saccharin, the main ingredients of AS are known to cause cancers in animals. A previous report suggested that AS can be associated with Hashimoto's thyroiditis. It has been found in different studies that heavy AS (>1680 mg/day) use leads to an increased relative risk of 1.3 for bladder cancer in humans. Based on our analysis, there was a significant correlation between use of AS and WDTC. This study suggested that use of average of 2 packets (2 grams) of AS for an average duration of 3 years is associated with WDTC. Further analysis to be done in comparison with the control group.

This study emphasizes the significance of AS consumption as a potential risk factor for WDTC and increase public awareness for it.

Anaplastic thyroid carcinoma (ATC) is a rare cancer representing only 1–2% of thyroid carcinomas and considered the most lethal thyroid cancer, accounting for up to fifty percent of all thyroid cancer mortality. TCGA data reports mutational alterations of TP53, beta‐catenin, EFGR, PIK3CA, PTEN, and in lesser extent KRAS, HRAS, NRAS, and BRAF genes in ATCs. However currently there is no specific molecular marker for diagnosis of this cancer. In this pilot study we examined gene fusion abnormalities among patients with ATC. Formalin‐fixed paraffin‐embedded tissues (FFPE) of 11 cases of thyroid cancers, 5 papillary thyroid carcinomas (PTC) and 6 anaplastic thyroid carcinomas (ATC), were tested with a 53‐gene fusion assay by NGS using the Archer™ Universal RNA Reagent Kits v2. Fusion gene product for WHSC1L1‐NUTM1 was detected only in one of the six ATC patients. The WHSC1L1‐NUTM1 fusion positive patient is alive for 3 years after extensive neck surgery and chemo sensitization radiotherapy. Only one of the other five fusion negative patients is still alive, 7 years after his extensive surgery and chemosensitization radiotherapy. Among five PTC patients with no known mutations, two were positive for CCDC6‐RET fusions, one was positive for the NCOA4‐RET fusion with a novel breakpoint in NCOA4 gene, and the other one found to have a novel fusion PEX14‐BRAF. This is one of the first principle studies demonstrating the feasibility of performing 53 fusion genes in a single sequencing assay using FFPE tissue. Our goal is to use this fusion data in combination with mutation and copy number variation results to bring new insight towards understanding the genomic landscape within ATC. The WHSC1L1‐NUTM1 fusion has not been reported in any anaplastic thyroid carcinoma to our knowledge. We need to study a bigger sample size to establish the use of the molecular findings as diagnostic, prognostic, or potential therapeutic targets for this aggressive disease.

Thyroid nodules are a common medical problem in China and worldwide. Ultrasound (US) is the first evaluation tool to assess thyroid and cervical lymph node, while it is a relatively subjective diagnostic method, highly dependent on the skill of the performer. Assessment and improvement of inter‐observer reliability might contribute to solving this problem as it leads to more uniformity. The current study was conducted among 45 participants from Peking Union Medical College Hospital (PUMCH) from April to October 2015. Four of them received intensity training course and 26 of them received precision training course. The analyses were in accordance with the guidelines proposed by 2015 American Thyroid Association(ATA) guideline. Inter‐ observer variabilities were calculated using Cohen's kappa statistics. In the pre training, the kappa value of inter‐observer agreement was 0.15 to 0.43 and 0.13 to 0.48 for US features of thyroid nodule and cervical lymph nodes. Post intensity training improved with the kappa value of 0.11 to 0.65 and 0.09 to 0.66. Post precision training significantly improved with the agreement was 0.43 to 0.70 and 0.32 to 0.79. Intensity training might be effective in some features easily figured out, while precision training was more effective in those features which were difficult to be accurately judged and mastered.