88 th Annual Meeting of the American Thyroid Association

Thyroid ultrasound screening has been involved in routine physical examination at hospitals. However, due to the uneven development of medical resources, the diagnostic accuracy for thyroid nodules varies greatly. The aim of this study was to explore a novel artificial intelligence-assisted ultrasound diagnostic system to improve the diagnosis efficiency and accuracy for thyroid nodules. The artificial intelligence-assisted ultrasound diagnostic system was developed based on computer deep learning, training and multi-frame dynamic image recognition techniques. In order to validate the accuracy of the system, 500 pathologically confirmed thyroid nodules were selected, including 208 benign and 292 malignant. The images of all nodules, acquired from 10 different types of ultrasound equipment, were dynamically stored in the form of the consecutively longitudinal and transverse sections. Then the AI-assisted diagnostic system automatically recognized and analyzed the features of the images, and gave recommendations for diagnosis. The diagnostic accuracy of the system was compared with that of junior and senior physicians. The results showed that the sensitivity of the AI-assisted diagnostic system, junior physicians, senior physicians, combo of junior physicians and the AI-assisted system was 82.9%, 52.6%, 87.4% and 98.6%, respectively; and the specificity was 70.2%, 95.7%, 83.2% and 83.7%, respectively. The diagnostic accuracy of the AI-assisted system alone was higher than that of junior physicians (77.6% vs. 70.5%), however, the accuracy can reach 92.4% when the junior physicians was assisted by the AI-assisted system, which was higher than that of the senior physicians (85.6%). At the same time, the diagnostic tests on thyroid nodules of different sizes (<1cm, 1-2cm, and >2cm) were performed using the system. The results showed that there was no significant difference in the diagnostic accuracy among the three groups (P < 0.05). The AI-assisted ultrasound diagnostic system can effectively assist ultrasound physicians in the diagnosis of benign and malignant thyroid nodules, reduce unnecessary puncture and over-treatment, and help the junior physicians to improve the diagnosis efficiency and accuracy.

Results from a 24-week randomized, double-masked, placebo-controlled treatment trial of teprotumumab, an insulin-like growth factor 1 receptor inhibitory antibody, in 88 patients with active and moderate-to-severe thyroid-associated ophthalmopathy (TAO) have been reported (NEJM2017;376:1748). The primary endpoint response (≥2 points reduction in clinical activity score, CAS and ≥2 mm reduction in proptosis at 24 weeks) was achieved in 69% of patients receiving teprotumumab compared to placebo (20%), p < 0.001 with no deterioration in the non-study eye. The effects were rapid: at week 6, 43% of patients receiving teprotumumab responded vs. 4% of placebo patients (p < 0.001). Teprotumumab reduced proptosis significantly beginning at week 6 of treatment, effects that continued over 24 weeks as compared with placebo. Proptosis response was greater among the teprotumumab group at week 24 (71.4% vs. 20.0%, p < 0.001) We now report results assessing clinical status following multicenter treatment at week 28 and 72. Proptosis is relevant from clinical and regulatory agency perspectives since it reflects tissue remodeling in patients with TAO. At week 28 (4 weeks following treatment period), proptosis response was 73.8% in the teprotumumab group vs. 13.3% in controls (p < 0.001). 53% of week 24 teprotumumab proptosis responders maintained ≧2 mm improvement relative to baseline at week 72 (48 weeks following treatment period). Compared to baseline and placebo, CAS further decreased at week 28, mean (SE) -4.44 (0.23) vs. -2.54 (0.22), p < 0.001 and remained relatively unchanged in the teprotumumab group at week 72. These results indicate no acute rebound of disease following the 24-week treatmentTeprotumumab could represent a disease modifying therapy in TAO by reducing proptosis and CAS with sustained effects seen in the majority of patients 48 weeks following the completion of the study treatment phase. Considering the variable duration of activity in TAO (typically 2-3 years), patients might benefit from longer treatment or re-treatment with teprotumumab. These possibilities are currently being studied in an ongoing phase 3 trial.

Patients with mutations of the THRA gene show growth retardation, delayed bone development, and anemia. These symptoms are due to the dominant negative action of TRa1 mutants. However, little is known about how TRa1 mutants exert their deleterious effects during early development. To understand the action of TRa1 mutants in early development, we created zebrafish expressing mutated thra genes (gene duplication in zebrafish: thraa and thrab) by CRISPR/Cas-9 mediated targeted mutagenesis. We obtained 2 fish lines expressing mutated thraa (8-base pair insertion: L405EfsX6) or thrab (1-base pair insertion: E394X), encoding C-terminal truncated TRa1 proteins, similar to those in patients. We used biochemical methods to characterize phenotypes of the mutant fish. We found that ThraaL405EfsX6 and ThrabE394X lost T3 binding activity and transcriptional capacity, showing potent dominant negative activity by inhibiting transcriptional activity of wild-type TR. Adult mutant fish had impaired growth, like patients. ThrabE394X mutant fish had more severe and persistent impaired growth than ThraaL405EfsX mutants. Expression of the growth hormone gene (gh1) in the pituitary was suppressed 96% in ThrabE394X mutants. Analysis revealed decreased ossification and abnormal shape in the cleithrum in ThrabE394X day-5 embryos, indicating delayed bone development. Interestingly, ThraaL405EfsX6 mutants exhibited abnormal patterns in blood smears versus wild-type fish, indicative of erythroid disorders as in patients. Whole mount in situ hybridization analysis revealed that the expression of erythroid-related genes such as gata-1 and alpha-globin was suppressed in 1 day-embryos, but not in ThrabE394X mutant fish. These data indicated that ThrabE394X mutant impaired growth, whereas ThraaL405EfsX6 mutant caused erythroid disorders. These two lines of mutant zebrafish reproduce growth abnormalities and erythroid disorders detected in patients. The novel zebrafish model is useful not only to understand the in vivo pathogenic actions of TRa1 mutants in early development of human disease, but also to provide a platform for rapid screening of drugs to treat abnormalities at early development.

Tumour angiogenesis requires recruitment and interaction of various different cells, including endothelial cells and mesenchymal stem cells (MSCs). Thyroid hormones (TH) T3 and T4 act as proangiogenic modulators mediated by non-genomic mechanisms via cell surface receptor integrin αvβ3. The aim of this study was to evaluate the effects of T3 and T4 versus tetrac, a specific inhibitor of TH action at the integrin, on MSCs in the context of angiogenesis. Treatment of MSCs with TH in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium resulted in stimulation of expression of genes associated with angiogenesis as determined by qPCR and ELISA, while tetrac reversed these effects. Adding supernatant from these MSCs to endothelial cells (HUVECs) in a Matrigel tube formation assay significantly enhanced tube formation with potent inhibition by tetrac. We further established an angiogenesis reporter gene system by placing the sodium iodide symporter (NIS) gene under control of the vascular endothelial growth factor (VEGF) promoter. MSCs transfected with this construct (VEGF-NIS-MSCs) showed enhanced perchlorate-sensitive NIS-mediated iodide uptake activity after stimulation with HCC cell-conditioned medium and either T3 or T4 that was blocked by tetrac, the PI3K pathway inhibitor LY294002 and the ERK1/2 pathway inhibitor RAF265, and tetrac and RAF265, respectively, supporting integrin αvβ3-dependency. In vivo effects were evaluated by ¹²⁴I PET in an orthotopic HCC xenograft mouse model. Tumoural radioiodide uptake demonstrated successful recruitment of VEGF-NIS-MSCs after systemic application followed by VEGF promoter-driven NIS expression. In hyperthyroid animals, a strongly enhanced radioiodide signal was detected compared to euthyroid and hypothyroid mice, while treatment with tetrac markedly reduced the signal. These data confirm the in vitro data suggesting TH-mediated stimulation of VEGF that is inhibited by tetrac. Our data suggest that TH influence angiogenic signalling in MSCs in an integrin-dependent fashion, providing further evidence of the critical role of TH in the regulation of angiogenesis and the anti-angiogenic activity of tetrac in the context of tumour stroma formation.

Circulating RNA (circRNA), like exosomal circRNA, regulates various bioactivities in cells. Better understanding of the exosomal circRNA may provide novel insights into pathogenesis of Graves' disease (GD) and clinical management of patients. This study profiled exosomal circRNAs in GD vs. healthy control sera using human circRNA microarrays and then functionally analyzed these differentially expressed circRNAs (DEcR) bioinformatically. Serum samples were obtained from five primary GD patients and five healthy controls to isolate the exosome using the ultracentrifugation. After confirmed with Transmission electron microscopy, these samples were subjected to the microarray profiling of the DEcR using human circRNA microarrays. Two each of the most upregulated and downregulated circRNAs were selected for validation in 20 GD and healthy controls using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The circRNA/microRNA/mRNA interaction network was then assembled and assessed bioinformatically and the Gene Ontology and four other annotation tools for pathway analyses (KEGG, Biocarta, PANTHER, and Reactome) were utilized to predict the potential functions of these DEcR in GD. There were 15 DEcR revealed in primary GD cases, e.g., hsa_circRNA_102059 and hsa_circRNA_000102 were upregulated and confirmed, whereas hsa_circRNA_004939 and hsa_circRNA_072697 were downregulated and confirmed in primary GD vs. healthy controls. The bioinformatical analysis identified the most potential targeting miRNAs of these four DEcR. The functional analyses predicted involvement of these DEcR in pathways of immune system activation. Microarray profiling identified 15 DEcR in primary GD vs. healthy controls and four of them were verified by qRT-PCR, suggesting their involvement in pathways of immune system activation. The targets of these DEcR were also predicted and may involve in GD development and progression. Future study will discover DEcR expression as biomarkers for GD diagnosis and treatment.

There are two highly conserved Thyroid hormone (T3) receptors (TRs) genes, TRα and TRβ, in all vertebrates, and the expression of TRα but not TRβ is activated earlier than T3 synthesis during development. In human, high levels of T3 are present during the several months around birth and T3 deficiency during this period causes severe developmental problems including the improper maturation of intestine. It is, however, difficult to study this period in mammals as the embryos and neonates depend on maternal supply for survival. On the other hand, Xenopus tropicalis undergoes a T3-dependent metamorphosis which drastically changes essentially every organ in the tadpole. Of interest is intestinal remodeling, which involves de novo formation of the adult intestinal stem cells, resembling intestinal maturation around birth in mammals. We have previously demonstrated that TRs are essential for formation of the intestinal stem cells during metamorphosis. To investigate the role of TRα in this process and the underlying mechanisms, we generated TRα deficient Xenopus by using TALEN method. We then observed that TRα knockout causes defects in intestinal remodeling, including reduced stem cell proliferation. In addition, apoptotic activity during intestinal remodeling was also decreased in TRα deficient tadpoles. By RNA-sequencing analysis (RNAseq) on intestinal RNA from wild type and TRα-deficient tadpoles treated with or without T3 for 1 day, we identified 1191 genes which were up-regulated by T3 treatment in the wild type animals. Among them, 1069 genes appeared to be specifically regulated by TRα. Gene ontology and pathway analysis revealed that the TRα-regulated genes were enriched with cell cycle-related genes. Our findings indicate that TRα is the predominant TR mediating the effects of T3 on intestinal remodeling and that TRα controls intestinal stem cell formation and/or proliferation at least in part by regulating cell cycle genes. Our findings indicate that TRα is the predominant TR mediating the effects of T3 on intestinal remodeling and that TRα controls intestinal stem cell formation and/or proliferation at least in part by regulating cell cycle genes.

I^– transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroid follicular cell to mediate active I^– accumulation. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism due to loss-of-function mutations in the Na⁺/I^– Symporter (NIS)-coding slc5a5 gene. Here, we aimed to determine whether a pediatric patient with a clinical phenotype of ITD harbors an inactivating mutation in the slc5a5 gene, and if so, to ascertain the molecular mechanisms of the effect of the mutation on NIS function.

The whole coding region of the slc5a5 gene was PCR-amplified and subjected to Sanger sequencing, and in silico computational and in vitro functional studies of a newly identified NIS mutation were performed. We report a novel homozygous missense and loss-of-function mutation in the slc5a5 gene as a cause of dyshormonogenic congenital hypothyroidism. The proband carries a G > A transition at position +1.682 in exon 14 resulting in a Gly to Glu substitution at residue 561 (G561E) located in the intracellularly facing NIS carboxy-terminus. We show that G561E markedly reduces I^– uptake when the protein is heterologously expressed in MDCK-II cells, because the transport of G561E NIS to the plasma membrane is severely impaired. Significantly, G561Q NIS, like G561E, is severely retained in the endoplasmic reticulum. Bioinformatics reveal fully conserved tryptophan-acidic (WD) motif whose disruption (W565A/D566A NIS) leads to NIS retention in the endoplasmic reticulum. Computational and biochemical analysis indicates that G561E impair the recognition of the adjacent WD motif by the kinesin light chain (KLC) 2, thus impairing mutant NIS exit from the endoplasmic reticulum. Moreover, short-hairpin RNA-mediated KLC2 knock-down in FRTL-5 cells reduces NIS expression at the plasma membrane, and consequently minimal NIS-mediated I^– accumulation.

Altogether, our data indicate that G561E shifts the equilibrium of the unstructured WD motif towards a more structured and rigid conformation unable to interact with KLC2, thus severely affecting NIS maturation beyond the endoplasmic reticulum and reducing I^– accumulation in the thyroid follicular cell.

Anuran amphibians such as Xenopus tropicalis offer a unique opportunity to study how the adult organs and their organ-specific stem cells are formed in vertebrates during the so-called postembryonic development. The postembryonic events such as the maturation/remodeling of many organs are totally regulated by thyroid hormone (TH). Of particularly interest among TH target gene is PRMT1, which methylates histone H4R3 and functions as a TH receptor co-activator. We have shown previously that PRMT1 mRNA and protein expression peaks at the climax of metamorphosis in the intestine when adult stem cells are forming de novo and rapidly proliferating, and that transgenic PRMT1 overexpression increases the number of adult intestinal stem cells during metamorphosis. To determine the function of the endogenous PRMT1 gene, we adapted the gene editing technology, transcriptional activator–like effector nuclease (TALEN), to knock out PRMT1 gene in X. tropicalis. After generating PRMT1 heterozygous frogs (F1) with out of frame mutations, we produced PRMT1^−/−animals by intercrossing the F1 frogs. We then measured the survival rate, animal size, the developmental stage and histone H4R3 di-methylation level by western blot of the F2 resulting tadpoles. Additionally, to analyze the effect on the TH-induced metamorphic changes, we treated tadpoles with 10nM TH in rearing water, and then analyzed TH-inducible gene expression by quantitative RT-PCR. These studies revealed that all PRMT1^−/− tadpoles died within 14 days after fertilization although they completed embryogenesis to form apparently normal feeding stage tadpoles. In addition, morphological analysis showed that PRMT1^−/−tadpoles had delayed development and growth. Finally, histone H4R3 di-methylation level and TH-inducible genes expression were significantly reduced in PRMT1^−/−siblings. Our findings indicate that PRMT1 is not required for embryogenesis but is important for tadpole growth and survival prior to natural metamorphosis. We are now taking advantage of the ability to precociously induce metamorphosis by treating with physiological levels of TH to investigate how PRMT1 knockout affect TH-induced metamorphosis and adult intestinal stem cell development.

Anaplastic thyroid cancer (ATC) is the most lethal human malignancy in endocrine system, but its molecular characteristics are not fully unveiled. Twenty-seven ATCs from Korean patients and the additional 86 advanced thyroid cancer (TC) including 15 poorly-differentiated thyroid cancers (PDTCs), 28 focal ATC/PDTCs, 12 widely invasive follicular thyroid cancers (wiFTCs), and 31 metastatic papillary thyroid cancers (PTCs) were sequenced by whole-genome, whole-exome, or targeted sequencing to reveal the key genomic events which prompt the progression of TC. Also, RNA sequencing data from 13 ATCs and 162 differentiated thyroid cancers (DTCs) were analyzed to elucidate the transcriptomic changes during TC progression. In ATC, BRAF (40.74%) and RAS (44.44%) were the most recurrently mutated driver genes, but no fusion gene was found. Also, AKT1/PIK3CA and EIF1AX were frequently co-mutated with BRAF and RAS, respectively and those mutations were mutually exclusive with each other. Tumor suppressors such as TP53 (44%) and CDKN2A (22%) were altered in 70% of ATC, and this incidence was greatly higher than advanced TCs. In particular, ATC and advanced TC patients with CDKN2A loss represented shorter disease-specific survival (p = 0.03 and p < 0.001, respectively). TERT alteration was the second most prevalent mutation in ATC (56%), but, interestingly, it was more frequently found in wiFTC (92%). We identified PDE8B-TERT and TERT upstream translocation which triggers enhancer hijacking in wiFTC. We found the new molecular subtype of TC, ATC-like, in addition to BRAF-like, RAS-like, and NBNR. Moreover, the up-regulation of two immunotherapeutic target genes, CD274 and PDCD1LG2 which encode PD-L1 and PD-L2, respectively in ATC, compared with DTC. With differentially expressed gene and pathway analyses, the activation of JAK-STAT signaling pathway in FTC origin ATC and notch signaling pathway in PTC origin ATC which commonly stimulate the overexpression of MYC were found. In this study, we revealed the genomic and transcriptomic characteristics which induce the progression and aggressiveness of TC. We expect that our result would allow us to find tailored diagnostic and therapeutic strategies for this fatal disease.

Tropomyosin receptor kinases (TRKs) are encoded by neurotrophic tyrosine receptor kinase genes (NTRK). Fusion proteins involving NTRK genes are oncogenic and have been reported in a wide variety of malignancies, including non-medullary thyroid cancer (TC). Larotrectinib is a potent and highly selective oral TRK inhibitor. In a recent pooled analysis from three studies involving 55 patients with TRK fusion cancer, the ORR was 75% according to independent review (IRC) (Drilon et al., NEJM 2018). Here, we summarize the activity and safety of larotrectinib in advanced TRK fusion TC. Patients with previously treated TRK fusion TC were treated under clinical trial (NCT02122913, NCT02637687, NCT02576431) and enrolled based on NTRK gene fusions identified by local testing. Most patients received the dose equivalent of 100mg BID on a continuous 28-day schedule. Efficacy was assessed by IRC using RECIST v1.1. As of July 17, 2017, seven patients with TRK fusion TC were enrolled; histologies included 5 papillary and one each with follicular and anaplastic TC. Median age was 57 (range 15-75). Four patients harbored an ETV6-NTRK3 fusion, and one each with TPM3-NTRK1, PPL-NTRK1 and IRF2BP2-NTRK1 fusions. All patients had undergone thyroidectomy, 5 had received prior systemic treatment (median of 3 prior lines), and 3 had received iodine-131. All 5 patients with measurable disease responded with a median time of first response of 1.8 months; per IRC, there was 1 complete response and 4 partial responses. The duration of response ranged from 1.9 to 18.8 months, with 4 ongoing in response. The patient with anaplastic TRK fusion TC progressed after 3.7 months in response but remained on treatment post-progression. Larotrectinib was very well tolerated, with treatment-related adverse events being predominantly grade 1. All patients continued to receive larotrectinib treatment at time of data cutoff. Larotrectinib is highly active and very well tolerated in patients with TC harboring NTRK gene fusions across all histologies reported here. These results strongly support the inclusion of NTRK gene fusions as part of routine molecular testing for patients with advanced TC.

Thyroid hormone is essential for fetal neurodevelopment. The relationship between maternal thyroid dysfunction in pregnancy and pregnancy outcomes as well as offspring brain development have been well evaluated. However, limited evidence was provided regarding the relationship between preconception thyroid stimulating hormone (TSH) level of women planning for pregnancy and preterm birth (PTB). This study aimed to examine the association between preconception TSH level and risk of PTB. We conducted a historical cohort study which recruited 4320584 rural reproductive age women participated National Free Pre-pregnancy Checkups (NFPC) in 2013-2016 in China. Data on preconception TSH, history of pregnancy and diseases, and other variables were obtained from the physical examination record in NFPC. Follow-up evaluation was conducted from June 2013 to Dec 2017. Successful conception and pregnancy outcomes were documented during the follow-up period. In the present study, PTB which is defined as any birth within 28 to 37 weeks of gestational age were the end point event of the cohort. Participants who are failure to get pregnant within 6 months, suffered from fetal death, still birth abortion, and multiple gestation were excluded from the analysis. Logistic models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for confounding variables. Restricted cubic spline models were applied to evaluate the dose-response relationships. Until Dec 2017, 283854 (6.57%) PTB events were documented. The PTB incidence was lowest in women with TSH of 1.00-1.49 mIU/l (6.23%), while the PTB incidence was highest in women with TSH of ≥10.00 mIU/l (7.46%). Compared to women with TSH of 1.00-1.49 mIU/l, the multivariable-adjusted OR (95% CI) for PTB was 1.20 (1.18-1.22) for women with TSH <0.44 mIU/l, 1.09 (1.08-1.11) for 0.44-1.00 mIU/l, 1.02 (1.01-1.03) for 1.5-2.49 mIU/l, 1.15 (1.13-1.18) for 4.00-9.99 mIU/l, and 1.19 (1.12-1.27) for ≥10 mIU/l, respectively. Our study identified a V-shaped relationship between maternal preconception TSH level and PTB risk. Decreasing or increasing preconception TSH levels can significantly increase the risk of PTB.

Programmed cell death protein ligand-1 (PDL-1) inhibitors are novel anti-cancer therapies but are associated with potentially therapy limiting immune-related adverse effects (IRAEs). We aimed to characterize thyroid-related IRAEs in order to improve case detection and overall patient management. We conducted a retrospective cohort study of cancer patients receiving PDL-1 inhibitors between 6/1/2016 – 1/30/2018 at the Mayo Clinic. Clinico-pathologic and laboratory data, including overall survival (OS) was collected. Of 91 patients treated with PDL-1 inhibitors (median age 68 years, 52% male) with a median follow up of 5 (IQR 2 – 9) mo, 42 (46%) developed an IRAE, including 23 (25%) thyroid IRAEs (22 from atezolizumab, 1 from avelumab). The median time to thyroid IRAEs was 1.4 mo or after 2 doses of PDL-1 inhibitor. Acute thyroiditis occurred in 5 (22%), of which 3 progressed to hypothyroidism. New onset hypothyroidism occurred in 14 (61%) patients, 4 overt and 10 subclinical, of which 2 resolved. Worsening hypothyroidism occurred in 4 (17%). Management included observation in 52% and levothyroxine in 48%. Thyroperoxidase (TPO) antibodies were elevated in 4/13 (31%) at baseline, of which 2 developed thyroid IRAE. TPO antibodies were elevated in 4/18 (22%) at the time of thyroiditis/hypothyroidism (median titer 220 IU/mL). Diffusely elevated fluorodeoxyglucose (FDG) thyroid uptake on positron emission tomography (PET) scan was present in 6/24 of which 5 developed thyroid IRAE (p = 0.001). The mean OS since start of PDL-1 inhibitor therapy was 9.2 mo, and on subgroup analysis, was 12 mo in patients with thyroid IRAE versus 9.9 mo without (p = 0.03). Thyroiditis, presenting as acute thyrotoxicosis progressing to hypothyroidism or as new onset hypothyroidism, is the most common endocrine IRAE following PDL-1 inhibitor therapy and has comparable and/or higher incidence than with other immune checkpoint inhibitors. Diffuse thyroid uptake on FDG-PET scan but not elevated TPO antibodies appears to identify patients at risk for thyroiditis/hypothyroidism. Whether patients developing thyroiditis, or other IRAEs, may be a biomarker of anti-tumor immune response and improved overall survival requires additional study.

To show how fetal dysthyroidism (FD) and neonatal dysthyroidism (ND) can be predicted from perinatal variables. We performed a retrospective multicenter study using data from the medical records of all patients monitored for pregnancy from 2007 to 2014 in 10 obstetric centers of the Assistance Publique des Hôpitaux de Paris Women with Graves' disease who were positive for TRAb at least once during pregnancy were included. Among 280,000 births, 2,288 medical records of women with thyroid dysfunction were selected and screened and 417 women with Graves' disease and positive for TRAb during pregnancy (estimated prevalence of Graves' disease 0.15%) were finally included. Multivariate regression analysis revealed that the TRAb level in the mother and child was the strongest independent predictor of FD and ND. The expected frequencies were not significantly different from the observed frequencies using the Hosmer-Lemeshow test (P = 0.84 for TRAb level at days 0 to 5; P = 0.76 for maternal TRAb level). Using the maternal TRAb levels, the cutoff value of 2.5 IU/L best predicted for FD, with a sensitivity of 100% and specificity of 64% positive predictive value (PPV) of 26%, negative predictive value (NPV) of 100% and the optimal cutoff value for predicting ND was 5.9IU/L (sensitivity of 100%, specificity of 82%, PPV of 26%, NPV of 100%) Using the newborn TRAb levels, the cutoff value of 6.8 IU/L best predicted for ND, with a sensitivity of 100% and a specificity of 94%, PPV of 50%, NPV of 100%.the risk of FD and ND increases with maternal hormonal imbalance and is also greater in the patients receiving antithyroid drugs (ATDs) during pregnancy. In our study, 65.0% of women with a history of Graves' disease did not receive ATDs during pregnancy but were still at risk of ND. We have clearly shown in a large number of cases that precise TRAb cutoffs can be used to establish the best perinatal follow-up and that fine tuning of the mother's thyroid status. In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction and treated, if necessary.

In Graves' disease (GD), brain-derived symptoms are prevalent. During the hyperthyroid state, the volumes of medial temporal lobe (MTL) structures, e.g. the hippocampi, are reduced. This has been attributed to the high thyroid hormone levels, but we hypothesize that the structural changes and mental symptoms may be due to autoimmunity per se. Here, autoimmunity directly related to the thyroid as well as other autoimmunity may be important. The aim of the present paper was to determine the relations between non-thyroid autoimmunity and MTL volumes during hyperthyroidism in GD. The CogThy project is a longitudinal observational prospective case-control study where 65 premenopausal women were evaluated within 2 weeks after the diagnosis of GD with FT4 > 50 pmol/L (reference 12-22) and after 15 months of anti-thyroid treatment. Thyroid-stimulating hormone receptor antibodies (TRAb), thyroid stimulating immunoglobulins (TSI), angiotensin II type 1- (anti-AT1), beta 1 adrenergic- (anti-B1) and M2 muscarinic- (anti-M2) receptor antibodies were measured in the hyperthyroid state. MTL structures were assessed with a 3-Tesla MR scanner to determine hippocampal and amygdala volumes using automatic segmentation with MAPER and normalisation to intracranial volume. We here report preliminary data on the non-thyroid antibodies at baseline in patients. Data on the thyroid antibodies are reported separately. There was a negative correlation between the volume of the left amygdala and the levels of anti-B1 (r = -0.28, p = 0.030) and anti-M2 (r = -0.40, p = 0.002).

Anti-AT1 correlated negatively with the volume of the right hippocampus (r = -0.27, p = 0.043).

There were no correlations between TRAb or TSI vs anti-AT1, anti-B1 or anti-M2.

These data support our hypothesis that autoimmunity that is not directly connected to the thyroid may be involved in the impairment of brain function in GD, and introduce a new concept that needs further evaluation. Longitudinal measurements and control data are awaited from the CogThy study.

Endogenously expressed TSH receptors (TSHR) in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) utilize crosstalk with insulin-like growth factor 1 receptors (IGF1R) to induce hyaluronan secretion, a major component of GO. We previously showed that this phenomenon occurred upstream of mitogen-activated protein kinase (ERK) phosphorylation and proximal to both receptors. Since G protein-coupled receptor/β-Arrestin/ERK complexes have been reported in several cell types, we sought to test whether β-Arrestin 1 or 2 was a necessary component of TSH/IGF1 receptor crosstalk. Protein knockdowns of IGF1R, β-Arrestin 1 and β-Arrestin 2 were performed in orbital fibroblasts obtained from GO patients. Secreted hyaluronan was measured following treatment with TSHR-stimulating antibodies M22 or KSAb1. Associations between TSHR and IGF1R were confirmed microscopically using the Duolink Proximity Ligation Assay. As previously shown, treatment with M22 resulted in biphasic dose-response stimulation of hyaluronan secretion, where the high-potency phase was IGF1R-dependent and the low potency phase was independent of IGF1R. KSAb1 produced a monophasic dose-response, whose potency was lowered, i.e. its EC₅₀ was right-shifted at least 10-fold, following IGF1R knockdown. β-Arrestin 1 knockdown similarly inhibited M22's high-potency phase and lowered KSAb1's potency. β-Arrestin 1 was also necessary for TSHR/IGF1R proximity as shown by the proximity ligation assay. In contrast, β-Arrestin 2 knockdowns did not show these effects. TSH and IGF1 receptors must be in close vicinity for crosstalk to occur, and this depends on β-Arrestin 1. These findings further support a model of crosstalk where signaling pathways converge proximal to the receptors.

Serum levels of TSH receptor (TSH-R) stimulating antibodies (TSAb) correlate with clinical activity/severity of Graves' thyroidal disease (GD) and associated orbitopathy (GO). We hypothesized a highly significant differentiation between patients with GD versus GD+GO by analyzing TSAb levels in serially diluted serum samples. Twenty GD and 20 GD+GO patients were investigated. Serial 1:3 dilutions were performed on each patient sample (200μl) into TSAb-negative control serum (400μl) up to a final dilution of 1:6561. Results from the TSAb bioassay (Thyretain, Quidel, cut-off SRR% 140) were compared with five TSH-R-Ab binding immunoassays: Kronus ELISA (cut-off 1IU/L), Dynex ELISA (2U/L), Cobas (Roche, 1.75IU/L), Immulite (Siemens, 0.55IU/L), and Kryptor (Thermofisher, 1.8IU/L). All undiluted samples of hyperthyroid GD patients were positive in the TSAb bioassay (median SRR% 237, range 217-336) and became negative at dilution 1:27. In contrast, all undiluted samples of hyperthyroid GD+GO patients were positive in the bioassay (median SRR% 627, 576-752) and all remained positive at dilutions 1:3, 1:9, 1:27, and 1:81, all p < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of TSAb-positivity for GD+GO patients was 75%, 35%, 5%, and 0% respectively (all p < 0.001). Even after methimazole treatment, all euthyroid GD+GO samples were still positive at the high dilution of 1:729. TSH-R-Ab positivity with the Cobas binding assay was 85% in undiluted GD-only samples and 50% at dilution 1:3 whereas TSH-R-Ab positivity of undiluted GD+GO samples and at dilutions 1:3-1:243 was 100%, 85%, 85%, 75%, 15%, and 5%, respectively. The five binding ELISA and/or automated immunoassays confirmed this marked difference of anti-TSH-R-Ab detection between GD versus GD+GO observed with the TSAb bioassay; however the Kronus, Dynex, Cobas, Immulite, and Kryptor binding assays were all negative in GD-only samples at low dilutions of 1:27, 1:9, 1:9, 1:9, and 1:9, respectively. This novel TSAb dilution analysis significantly differentiates between GD and GD+GO. It also emphasizes the higher sensitivity of anti-TSH-R-Ab detection in the TSAb bioassay versus all ELISA and automated binding assays.

Diagnosis of autoimmune poly glandular syndrome type 2 (APS 2) is often difficult due to the non-specific and insidious nature of symptoms and signs. Usually stressful insults such as infection, surgery or trauma may precipitate adrenal crisis (AC).

45 year old Caucasian women with known Hashimoto's Thyroiditis for 2 years, on levothyroxine 50 mcg daily, came to our ER with nausea, vomiting and diarrhea for two days. She reported 20 lb weight loss, lethargy, skin darkening, muscle aches, insomnia and anxiety over 6 months. Family history was significant for Grave's Disease and Hashimoto's Thyroiditis.

Patient appeared sick and confused. BP 88/50. HR 100. Exam showed signs of dehydration and tanned skin tone.

Labs: Sodium 116mmol/L, Potassium 5.1mmol/L, Bicarbonate 17 mmol/L, TSH 0.073uIU/ml, T3 234ng/dl, T4 14.8ug/dl, serum cortisol on admission 2 ng/dl. Adrenal antibody titer 1: 40 (normal <1:10) antiTG 4, antiTPO 131, TSI 564. Initial work up for infectious causes was negative. Upon follow up 4 weeks after hospital discharge, patient was doing well on hydrocortisone and fludrocortisone and was clinically and biochemically euthyroid.

She was negative for TSI when she was initially diagnosed with Hashimoto's Thyroiditis.

APS2 is characterized by autoimmune adrenal insufficiency (AI) associated with autoimmune thyroid disease and/or Type 1 Diabetes mellitus. When thyroid disease is associated with APS2, 50% is Graves' disease and 50% is either Hashimoto's or atrophic thyroiditis. Our patient did not have any identifiable stressor for AC. Development of TSI and subsequent hyperthyroidism while on levothyroxine therapy was deemed to be the precipitating factor.

In undiagnosed AI, initiation of thyroxine replacement may induce AC due to increased cortisol metabolism, but our patient was on a stable dose of levothyroxine for over 1 year prior to development of symptoms of AI. Clinicians should have a high index of suspicion for AI in those with a family history of autoimmune disease and in patients with one autoimmune disorder who develop nonspecific or serious illness.

In Graves' disease (GD), hyperthyroidism per se may entail tachyarrhythmia, atrial fibrillation and heart failure. Known GD complications are, however, of autoimmune origin.

In GD patients with heart complications, stimulatory autoantibodies targeting the cardiovascular system (CardAbs) are frequent. Although previous studies were relatively small and used non-standardized methods, we hypothesize that CardAbs are frequent in GD in general and affect heart function. We used standardized ELISA assays to determine if CardAbs 1) were more frequent in hyperthyroid GD patients than controls, 2) were influenced by antithyroid drugs (ATD), 3) correlate with heart related symptoms or biomarkers. Our preliminary data with higher beta1 adrenergic receptor antibody (anti-B1) levels in GD that decreased after ATD strengthen our hypotheses. Premenopausal women (n = 60) with FT4 > 50 pmol/L (ref 12-22) were evaluated at diagnosis and after 7.5 months for CardAbs (anti-B1, muscarinic type 2 receptor (anti-M2) and angiotensin II type 1 receptor (anti-AT1) antibodies), symptom score, NTproBNP (marker of heart failure) and Troponine-I (TNI, marker of cardiac myocyte damage). In matched controls, CardAbs and heart biomarkers were assessed once. Anti-B1 and anti-M2 were higher (p < 0.0001) in patients at baseline compared to controls (anti-B1: median 1.9 (IQR 2.7-1.3) vs 1.1 (1.7-0.8) μg/ml, anti-M2: median 20.5 (38.3-14.0) vs 6.0 (9.9-3.2) U/ml), but anti-AT1 did not differ. Anti-B1 and anti-M2 decreased at 7.5 months (both p < 0.001), but were still higher than in controls. NTproBNP was higher in patients than in controls (median 240 (372-134) vs <35 (67 to <35) ng/L, p < 0.0001). TNI was below the detection limit in most subjects, but still higher in GD than controls (p = 0.02). NTproBNP and TNI normalised by ATD. CardAbs did not correlate with heart symptoms or biomarkers. Our first hypothesis was confirmed, and interestingly various CardAbs behaved differently. Although no correlation between CardAbs and heart function was observed, an autoimmune effect on the heart cannot be excluded in subpopulations, as the functional properties of antibodies remain to be determined.

Autoantibodies are useful biomarkers for the prediction of autoimmune diseases. Thyroid autoantibodies are associated with an increased risk of clinical hypo or hyperthyroidism. Therefore, the aim is to determine the prevalence of thyroid autoantibodies and their associated factors in euthyroid individuals. In this study, 200 euthyroid subjects chosen by stratified sampling from an inception cohort of 1403 individuals were included. None of the subjects was under treatment. Thyroid function was evaluated by measuring serum levels of TSH (0.3-4.5 μIU / ml) and T4L (5.2-12.7μg/dl). In addition, anti-peroxidase (TPOAb), anti-thyroglobulin (TgAb), and anti-TSH receptor (TrAb) antibodies were evaluated together with 14 additional autoantibodies. The analysis included sociodemographic, clinical, and environmental characteristics. Data were analyzed by using chi-square (χ2), Kruskal-Wallis, Mann-Whitney and logistical regression tests. Thyroid autoimmunity was observed in 16.5% of the cases (TPOAb in 13% and TgAb in 2%). In three individuals, both autoantibodies were seen. No TrAb was detected. Subjects with African-ancestry had a higher risk of positivity for TgAb (OR: 7.2 95% CI: 1.4-46.8) while individuals with Amerindian-ancestry appeared to be protected (OR: 0.2, CI 95%: 0.03-0.9). The multivariate analysis confirmed a greater presence of TgAb in individuals of African descendant compared to other ethnic groups (p = 0.023, β = 7.82, 95% CI: 1.3-46). Additionally, TgAb levels were associated with years of smoking exposure (Rs = -0.17, p = 0.015), anti-CCP3 levels (Rs = 0.31 (p < 0.001), and years of exposure to wood smoke (Rs = 0.24, p = 0.001). In relation to TPOAb, its positivity was determined by the familial autoimmunity (OR: 2.5, 95% CI: 1.1-5.9), a result also confirmed by multivariate analysis (p = 0.03, β = 2.5 CI: 1.1-5.9). Subclinical thyroid autoimmunity is not rare. Environment and immunological factors as well as ancestry are associated risk factors. These results will facilitate the implementation of screening strategies in order to provide timely diagnosis and treatment.

While Hashimoto's thyroiditis and Graves' disease are common causes of hypothyroidism and hyperthyroidism in adults, respectively, the development of Graves' hyperthyroidism in a hypothyroid patient with Hashimoto's disease is very rare. A 68-year-old woman with 28-year history of hypothyroidism treated with Levothyroxine (LT4) 88mcg daily and bilateral thyroid nodules presented for a regular 6-month follow up. The patient reported 3-month history of weight loss >20 pounds associated with hyperadrenergic symptoms. On examination, global increase in thyroid gland size was noted compared with prior evaluation. During the clinic visit, TSH was found to be <0.01mIU/mL (0.4-4.0) with elevated fT4 1.73ng/dL (0.7-1.5) and fT3 5.0pg/mL (2.18-3.98). In spite of gradual LT4 dose decrease and then discontinuation over next 5 months, she remained biochemically hyperthyroid. At this point, serum autoimmunity markers were measured and showed elevation of titers of thyroid stimulating immunoglobulin of 682% (<140) and thyroid peroxidase antibody of 920IU/mL (0-8) suggesting presence of Graves' disease; therefore, methimazole therapy was initiated. Biopsy of two enlarging dominant nodules showed abundant Hurthle cells and scant colloid. Hurthle cell carcinoma was suspected and total thyroidectomy was performed. Final surgical pathological report demonstrated Hashimoto's thyroiditis with extensive Hurthle cell change and no evidence of malignancy. The patient was post-operatively started on LT4 therapy and remains euthyroid. The conversion of hypothyroidism to Graves' hyperthyroidism is quite rare. Patients with Hashimoto's disease develop hypothyroidism due to antibody mediated destruction of the thyroid gland. Graves' disease is caused by production of antibodies that target the TSH receptor within the thyroid gland, resulting in stimulation of thyroid hormone production. Initial hypothyroidism in patients who later develop Graves' disease may be the result of TSH receptor blocking antibodies which then convert to stimulating antibodies. Euthyroid patients with Hashimoto's thyroiditis on chronic LT4 therapy who experience new onset hyperthyroidism should undergo biochemical evaluation for Graves' disease.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism, but the number of reported cases have been increased in the last decade. Although a few cases are associated with mutation of the multiple endocrine neoplasia type1 (Men1) gene or thyroid hormone receptor beta gene, the cause of TSHomas remain largely unknown. We have recently reported an analysis of genetic abnormalities in TSHomas using next-generation sequencer. We found six somatic DNA variants as candidate driver mutations, but no variants were so far recurrent. However, SNP array analysis revealed multiple somatic focal and chromosomal arm-length copy-number abnormalities in 8 cases of TSHomas. Therefore, the objective of this study is to investigate the specificity of this copy-number abnormalities in TSHomas. We performed a Single Nucleotide Ploymorphism (SNP) array analysis of tumor DNA extracted from twelve TSHomas and twelve non-functional pituitary adenomas (NFPAs). SNP array analysis were also performed for DNA extracted from peripheral blood leukocytes of eight TSHomas. These analyses revealed multiple focal and chromosomal arm-length copy-number abnormalities in tumor DNA form TSHomas. We observed that 75.0 % (9/12) of TSHoma samples were involved in at least one gain, copy neutral LOH (cnLOH) and loss event respectively. In these copy-number abnormalities, copy number gain were fairly common compared to copy number loss and chromosomal arm-length gain was most frequent on 4p, 5p, 5q and 7p. In addition, we found several broad regions of cnLOH were found in 5 cases of TSHomas. All copy-number changes examined were somatic changes, because these changes were not found in blood samples. In contrast, only focal copy number abnormalities were found in NFPAs, although only one case had a chromosomal arm-length loss. Furthermore, the number of chromosomal arm-length copy-number gain was significantly higher than that of non-functional pituitary tumors. The somatic copy-number abnormalities, which are specifically found in TSHomas, may be involved in the tumorigenesis of TSHomas.

Gestational hypothyroidism has detrimental effects on the fetus leading to cognitive deficiency like impaired learning and memory. The molecular mechanisms that underlie these effects are unknown. Cytokines and their receptors are able to modulate synaptic plasticity, learning and memory. Interleukin-4 (IL-4), a pro-inflammatory cytokine, seems to play a role regulating memory and learning processes. IL-4 knockout mice presented impaired spatial memory and adoptive transfer of IL-4 secreting lymphocytes recovers their learning and memory ability. In this work the following hypothesis was evaluated: “The offspring gestated in hypothyroidism has low plasmatic levels of IL-4 and its exogenous administration improves their learning capacity”. Gestational hypothyroidism was induced in mice C57BL6 and the offspring were used at the age of P55 days old. IL-4 serum levels were analyzed in the offspring gestated in hypothyroidism and the cognitive capacity was evaluated using Barnes Maze and the Novel object recognition test. Before test mice were i.p. injected with IL-4 and the cognitive capacity and IL-4 serum and brain levels were evaluated. IL-4 serum levels were analyzed in the offspring gestated in hypothyroidism and significantly low levels were detected in the brain compared to control offspring. The offspring gestated in hypothyroidism showed low performance in cognitive tests like Barnes Maze and Novel object recognition. Interestingly, the offspring gestated in hypothyroidism improved their cognitive capacity after they were i.p. injected with IL-4 before the test. The level of IL-4 in the brain increased after exogenous injection of IL-4. The significant increase of IL-4 observed in the brain of injected Control and Hypo mice correlate with an improvement in learning and memory. These findings contribute with new knowledge regarding the mechanisms that underlie the cognitive deficiency in the offspring gestated in hypothyroidism. The administration of IL-4 can be used as a therapy for the cognitive impairment in the progeny gestated in hypothyroidism.

Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. In neonates, a complete diagnosis of CH should include clinical examination, biochemical thyroid tests, ultrasound, and radioiodine or technetium scintigraphy, however, the molecular diagnosis underlying the pathogenesis of CH remains to be elucidated. One-hundred and ninety-two patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the intertance pattern of causative genes was analysised by the study of family pedigrees. Our results showed that 93 patients (48.44%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in seven genes (DUOX2, DUOXA2, DUOXA1, TG, TPO, SLC5A5 and Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 familiy pedigrees. Additionally, fifteeen mutations in five transcription factors (FOXE1, NKX2-1, PAX8, NKX2-5 and HHEX) that lead to thyroid dysgenesis were identified in fourteen probands, of which, only one patient carried biallelic mutations in FOXE1 and the other 13 cases had heterozygous mutation in those transcription factors. Family study indicated hypothyroidism was not observed in parents of these 14 probands. The genetic pathophysiology of the CH for 94/192 Chinese patients were definite by comprehensive screening of 21 candidate genes while a second mutation could be existed due to technical limitations of the direct sequencing analysis of 21 genes for the remaining patients that the phenotype caused by a monoallelic defect.

To discuss the clinical characteristics of hyperthyroid heart disease (HHD) and explore the strategy to guarantee radioiodine-131 therapy (RAI) safety. Analyze the clinical data and treatment regimens of 40 HHD patients who were admitted into our department from 2012-2016. The incidence of atrial fibrillation (AF) was 45.0%. Heart failure (HF) is always left ventricular ejection fraction (LVEF) reserved (80.0%); the severity of HF was accompanied with serum brain natriuretic peptide (BNP) increase and LVEF decrease. Liver function was moderate-medium impaired (61.5%), direct bilirubin positively correlative with the degree of HF (R = 0.390, P = 0.012). The RAI one-dose cure rate for hyperthyroidism was 77.5%. ATD use before RAI has no effect on the cure rate. Four patients who can't be treated with ATD deteriorated after RAI, two of them died because of seriously infection and HF, the other two recovered with saturated solution of potassium iodide or lithium. Familiar with medical therapy of comorbid conditions and using ATD before RAI is very important for HHD, if ATD is contraindicated, glucocorticoids, saturated solution of potassium iodide or lithium are the choices according to the patients' conditions.

PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. However, the correlation between PD-L1 expression and the specific clinicopathological features in papillary thyroid carcinoma (PTC) of Chinese patients has not been investigated. We evaluated the PD-L1 expression in Chinese PTC patients. A total of 226 patients were included (female = 172, male = 54, low risk = 91, intermediate risk = 111, high risk = 24 and 142 patients' tumor size ≤1cm). We evaluated the frequency of PD-L1 expression by immunochemical staining with a rabbit monoclonal antibody (clone SP142). The correlation between the PD-L1 expression with the clinicopathological features, TERT promoter and BRAF V600E mutation was evaluated.PD-L1 was positively expressed in 39.4% PTCs, and its expression was positively correlated with female gender (P = 0.025), tumor size (P = 0.011) and tumor number (P = 0.012). There was no significant association between PD-L1 expression and other clinicalpathological factors, including age, tumor extension or invasion, lymphnode metastases, distant metastases, recurrence risk, and background chronic lymphocytic thyroiditis (CLT). In addition, PD-L1 expression showed no significant correlation with BRAF V600E and TERT promoter mutation. Our results have not found that the PD-L1 expression is related the important clinicalpathological factors which may have effects on patients' overall survival and recurrence. We need enlarge our study to verify this primary result.

Cytological diagnosis of “suspicious for malignancy (SFM)” under Bethesda system is reserved for aspirates with cytological features that raise a strong suspicion for malignancy but are not sufficient for conclusive diagnosis. Reported prevalence of SFM is 1-6% of thyroid fine needle aspiration (FNA) biopsies with estimated cancer risk of 60-75%. As per ATA 2015 thyroid nodules guideline, additional mutational testing may be considered in nodules with SFM cytology. Diagnostic surgical excision is the long established standard of care for management of SFM cytology nodules. No recent isolated study has evaluated incidence of thyroid cancer in patients especially with this category. We performed retrospective chart review of patients with cytological diagnosis of SFM on FNA of thyroid nodule specimens received at Upstate University Hospital between 1/2007 to 1/2018. We obtained demographic, clinical, laboratory, cytological and histological data. Incidence of malignancy in patients with cytological diagnosis of SFM was similar to that reported in 2015 ATA thyroid nodule guidelines. About 17% of patients who had benign disease might have benefited from molecular studies which could have avoided thyroidectomies and related complications and lifelong hormone replacement therapy. Our study suggests consideration of a more conservative approach for patients with thyroid nodules that belong to cytologically indeterminate “SFM” category. Incidence of malignancy in patients with cytological diagnosis of SFM was similar to that reported in 2015 ATA thyroid nodule guidelines. About 17% of patients who had benign disease might have benefited from molecular studies which could have avoided thyroidectomies and related complications and lifelong hormone replacement therapy. Our study suggests consideration of a more conservative approach for patients with thyroid nodules that belong to cytologically indeterminate “SFM” category.

Thyroid hormones impact many organ systems including cardiovascular system. Cardiac manifestations of hypothyroidism include reduction in cardiac output, stroke volume, heart rate, systolic blood pressure, and pulse pressure. Pericardial effusions are present in approximately 25% of hypothyroid patients. We present a case of waxing and waning pericardial effusion correlating with serum levels of free thyroxine (FT4) in patient with central hypothyroidism. 38 y female with history of Sheehan's syndrome complicated by central hypothyroidism, central adrenal insufficiency and growth hormone deficiency presented with worsening chest pain for 3 weeks. Vitals were stable. Physical exam revealed loud P2, holosystolic murmur and pedal edema. Echocardiogram showed massive pericardial effusion with impending cardiac tamponade and newly reduced ejection fraction of 30-35%. Patient admitted non adherence with Levothyroxine (LT4) with FT4 of 0.16 ng/dL (0.93 - 1.70 ng/dL). She was continued on oral LT4 125 mcg daily. Repeat echocardiogram 3 days later showed significant improvement in mitral flow velocity but unchanged pericardial effusion. She was treated conservatively. Echocardiogram 2 months later showed complete resolution of pericardial effusion and normalization of FT4. From chart review, it was noted that patient has multiple hospital admissions with similar presentation and noted to have waxing and waning pericardial effusion correlating with levels of serum FT4. Hypothyroidism causes decreased synthesis of albumin and increased capillary permeability leading to loss of albumin from intravascular to extravascular compartment resulting in increased interstitial fluid volume and impaired lymphatic drainage. This mechanism is thought to cause pericardial effusion in hypothyroidism. This process occurs slowly over a period of time, and therefore rarely causes hemodynamic compromise. It responds rapidly to treatment with LT4. Our patient showed resolution of pericardial effusion following normalization of FT4, and reaccumulation once levels of FT4 became sub therapeutic. Uncontrolled hypothyroidism remains one of the important differential diagnosis of pericardial effusion.

This study investigated the association between lifestyle factors and thyroid dysfunction in the She ethnic minority in South China.

We performed a cross-sectional study to determine the prevalence of thyroid dysfunction and its epidemiological characteristics, as well as its association with lifestyle factors. A total of 5154 permanent residents of She ethnic residents aged 20-80 years were enrolled in our study. life style information was collected using a standard questionnaire. Body mass index (BMI), Blood pressure and serum TSH, TPOAb, triglycerides (TG), total cholesterol (TC) and high–density lipoprotein cholesterol (HDL) were collected. The study showed that people who drank, had higher education or suffered from insomnia have lower incidence of hyperthyroidism (P < 0.05). On the other hand, smoking, alcohol consumption, exercise, undergoing weight watch and chronic headache were associated with decreased incidence of hypothyroidism (P < 0.05). Using multivariable logistic regression analysis, we found that alcohol consumption was associated with decreased probability of hyperthyroidism, hypothyroidism, as well as positive TPOAb. The amount of cigarettes smoked daily displayed a positive correlation with hyperthyroidism among smokers. Accordingly, smoking seemed to be associated with decreased risk for hypothyroidism and positive TPOAb. Exercise and maintaining a healthy weight might have a beneficial effect on thyroid health. Interestingly, daily staple amount showed an inverse correlation with incidence of positive TPOAb. Within the Chinese She ethnic minority, we found associations between different lifestyle factors and the incidence of different thyroid diseases. Understanding the nature of these associations requires further investigations.

TSH levels are unreliable for assessing thyroid status in patients with pituitary diseases. Endocrine Society recommended low or low normal free thyroxine (fT4) levels as a diagnostic test for central hypothyroidism. We wanted to know the diagnostic performance of TRH stimulation test and basal free T4 levels for predicting central hypothyroidism in pituitary surgery patients. Among 164 patients who underwent pituitary surgery at Chonnam National University Hwasun Hospital from 2006 to 2012, 119 patients had postoperative combined pituitary stimulation test (insulin hypoglycemia, LHRH and TRH stimulations). Postoperative basal fT4 levels and TSH responses to TRH stimulation were analyzed according to the need for levothyroxine replacement during the follow-up period (at least over 12 months). 28 patients (23.5%) needed T4 replacement and most patients were accompanied with panhypopituitarism. T4 replacement group showed lower basal fT4 (1.12 ± 0.41 vs. 1.34 ± 0.3 ng/dL, p = 0.003) lower TSH (1.04 ± 0.99 vs 2.5 ± 2.03 mU/L, p < 0.001), and lower peak TSH levels after TRH stimulation (3.18 ± 3.58 vs.10.67 ± 9.15 mU/L, p < 0.001). While TRH stimulation test was more sensitive (85.7%, specificity 54.9%), basal fT4 levels were more specific (94.5%, sensitivity 21.4%) and accurate (77% vs. 62.2% in TRH stimulation test). Both basal fT4 and TRH stimulation tests showed suboptimal performance in receiver operating characteristics curve analyses. Postoperative basal fT4 levels are more accurate in predicting central hypothyroidism in pituitary surgery patients, but the diagnostic performance is suboptimal. The decision for thyroid hormone replacement in pituitary surgery patients is not easy immediately after the surgery, it should be determined in clinical context during follow-up period.

Thyroid disease can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. In the vast majority of cases, it is caused by thyroid itself. Much less often it is caused by pituitary gland. Thyroid function tests are useful for evaluating the causes of thyroid disease. However, sometimes it is difficult to distinguish the two causes especially when they are accompanied. This study is to see how many cases would accompany thyroid disease in patients who undergoing transsphenoidal adenomectomy (TSA) for pituitary disease. We reviewed the medical records of patients who underwent TSA for pituitary disease during the 10 years from 2008 to 2017 at Severance Hospital. Among the 2202 patients, 297(13.5%) patients had thyroid disease before TSA. Hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodule and s/p thyroidectomy were accompanied by 45(2.0%), 107(4.9%), 5(0.2%), 72(3.3%) and 73(3.3%) patients, respectively. There were 17(0.8%) patients of primary hyperthyroidism, but 6(0.3%) patients of them were suspicious. One patient who had undergone total thyroidectomy due to Graves' disease 18 years ago was finally diagnosed with TSH-secreting pituitary adenoma. Secondary hyperthyroidism was accompanied by 28(1.3%) patients, and 25(1.1%) patients of them were confirmed by pathology. Primary hypothyroidism was accompanied by 44(2.0%) patients, but 11(0.5%) patients of them were of dubious causes. Secondary hypothyroidism was accompanied by 63(2.9%) patients. Out of the total patients, 133(6%) patients had samples that stained positively for TSH. We should be careful because thyroid disease sometimes accompany with pituitary disease and it may be due to a different cause than originally thought.

ATA guidelines emphasize shared decision making when selecting between medication, radioactive iodine, and surgery for Graves' Disease treatment. There is limited literature on the effect of TPOAb on success with anti-thyroid medication. TPOAb has been associated with lower relapse rates after remission. This is a retrospective analysis of patients with Graves' disease (defined by clinical presentation, imaging features, or TSI+) who presented to Scottsdale Endocrinology Institute between 1/2011-04/2017 and received pharmacological treatment. Exclusion: <1 year of follow-up, thyroid cancer, pregnancy. Wilcoxon Rank Sum test and two-sided Wald test were used in analysis. Of the 107 patients with a new hyperthyroidism diagnosis, 40 patients (age: 46.90 ± 16.53; BMI: 23.68 ± 3.52 kg/m²; 62.5% female; 55% white, 7.5% Hispanic, 15% Asian, 10% African American) met inclusion criteria. 67.5% had TPOAb. The mean number of presenting symptoms was 4.35 ± 2.30 with a mean of 1.93 more symptoms in TPOAb+ patients. Lower TPOAb levels were associated with more symptoms. TPOAb+ patients had more sleep disturbances, anxiety/depression, and dry skin. Although symptoms significantly decreased with treatment, TPOAb positivity was associated with an average of 1.50 more persistent symptoms. Average post-treatment BMI was 1.62 kg/m² higher for TPOAb+ patients, although non-significant. Mean time to euthyroid was 68.7 days for TPOAb+ patients and 62.5 days for TPOAb- patients (nonsignificant difference). 19.05% of patients seen in clinic for >2 years achieved full remission and an additional 29.41% required only minimal maintenance dose therapy. TPOAb was not associated with remission. Presence of goiter, fatigue, palpitations, Vitamin D deficiency, and progression to hypothyroidism were also not associated with TPOAb. Initial TPOAb level impacted initial symptoms but no other outcomes. Although time to euthyroidism and remission rates were similar, patients with TPOAb positivity, especially low level positivity, exhibited more symptoms of thyroid dysfunction and had persistent symptoms despite normalization of thyroid function. Larger multi-center studies could further inform the use of anti-thyroid therapy for TPOAb+ patients.

It was difficult to deal with the Graves' Disease (GD) which has a huge-size, whatever the function controlling or the operation. To this kind of GD, antithyroid drugs (ATDs) and radioiodine (RAI) sometimes show little effect while operation may bring serious bleeding and hazard of thyroid storm. The team tried to settle the problem by multi-disciplinary treatment and strict peri-operative period management. There were 8 GD cases with huge-sized thyroid treated in PUMCH during Jan. 2006 to Dec. 2016. All the cases proved to be ATDs and RAI non-sensative/non-effective/contraindicational (allergy/liver damage/granulopenia). We sitll use ATDs to controll the thyroid function to the best and then strictlly iodine drink. In 24 hours pre-operation, interventional radiologist carry on main arterial embolization of thyroid. The changes of thyroid size/blood supply pre-operation/bleeding and other things in-operation/function and relapses post-operation after ATDs/iodine preparation/arterial embolization before operation were observed and analysed. The patients got little bleeding in or after operation, no thyroid storm cases. Long-term follow up showed satisfactory thyroid function. After standard ATDs/iodine preparation and main arterial embolization of thyroid, patients got little bleeding in operation/smooth recovery/perfect long-term effects. Multi-disciplinary treatment and peri-operative period management are very important to those huge-sized GD, main arterial embolization of thyroid can decrease the in-operation- bleeding effectively.

Serum thyroid-stimulating hormone (TSH) level and cerebro-cardiovascular events (CVE) increase with age, but their relationship remains unclear. Our objective was to examine the association between serum TSH levels and the history of CVE (hCVE) in middle-aged/elderly subjects. This was a retrospective cross-sectional study of cases collected from Takasaki Hidaka Hospital between 2003 and 2007. Overall, 11,197 participants of health checkups were analyzed. The mean age was 48 ± 9 years (age range: 22–88 years). Rates of subclinical hypothyroidism (SCH) defined by normal thyroid hormone level but elevated TSH level were 6.1% in women and 3.3% in men. However, the serum TSH level increased with age, with the 97.5^th percentile being 8.6 mU/liter at 70∼ years old in men and 10.0 mU/liter in women. In 2,752 men over 50 years old, multivariate logistic-regression analyses revealed that the serum TSH levels in subjects with hCVE were significantly higher than in those without hCVE (1.8 ± 1.1 mU/liter vs. 2.2 ± 2.8 mU/liter: p = 0.0179), but SCH had no effect. In fact, sixteen out of 135 (12%) subjects diagnosed with SCH had a history of CVE, but patients with SCH and serum TSH level above the 97.5^th percentile in each decade of life had a higher percentage (11 out of 66 subjects, 17%). The adjusted odds ratio (OR) of hCVE in patients with SCH and serum TSH level above the 97.5^th percentile was 2.7 (95% CI, 1.1-5.1; p = 0.005). However, other metabolic factors had no effects. In women, diastolic blood pressure and serum triglyceride were higher in SCH compared with those in euthyroid subjects. Higher age-adjusted serum TSH level appeared to be related to hCVE in middle-aged/elderly men.

The most frequent cause of central hypothyroidism (CH) is pituitary adenomas, however, its details remains unclear. Objective of this study was to investigate thyroid status and the involvement of Growth Hormone (GH)/IGF-1 to CH in large scale of untreated patients with pituitary adenomas, particularly nonfunctioning and GH-secreting adenomas. This is a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2010. One hundred-thirty nine cases of non-functioning pituitary adenoma (NFA) and 150 cases of GH-secreting pituitary adenoma (GHoma) were analyzed. The correlation between the thyroid status and several clinicopathological parameters and its involvement to GH/IGF-1 system were examined. Twenty-four percent of the NFA showed CH, and the severity did not correlate with the tumor size, age, gender, or other hormonal deficiency, and it is of interest to note that all cases showed a normal TSH level. In contrast, only 8.7% of GHomas showed CH, and about half exhibited a normal TSH level and the rest showed a low. The mean serum TSH levels in GHoma were significantly lower, and the free T4 and free T3 levels were higher than those in NFA. Furthermore, about one fourth of GHoma showed a normal free T4 and a low TSH level. In addition, the serum free T4 level positively and the serum TSH levels negatively correlated with the serum IGF-1 levels. T4/T3 ratio is not significantly different between the two groups.1) High prevalence of CH with a normal TSH level in NFA pituitary adenomas, 2) Low frequency of CH in GHoma, which may be due to the stimulation by high level of IGF-1.

Subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) increase with age; however, their relationship remains unclear. To investigate the relationship between SCH and indices of metabolic syndrome. Overall, 11 498 participants of health checkups were analyzed in the cross-sectional and longitudinal follow-up studies. Serum free T4 levels were lower in women than men in most of the age groups. The prevalence of SCH was 6.3% in women vs 3.4% in men, and prevalence increased with age, reaching 14.6% in 70+ year age group of women. Multivariate logistic-regression analyses revealed that waist circumference and the serum triglyceride and low-density lipoprotein-cholesterol levels among women were significantly higher in subjects with SCH compared to those without SCH. Reflecting these findings, the adjusted odds ratio of MetS in patients with SCH was higher than in the euthyroid women participants with an odds ratio of 2.7 (95% confidence interval 1.1–5.6; P .017) but not in male participants. Furthermore, progression from euthyroid into SCH resulted in a significant increase in the serum triglyceride levels but not low-density lipoprotein-cholesterol in women. Japanese women exhibited a high prevalence of SCH associated with low free T4 levels. There was a strong association between SCH and several indices of metabolic syndrome in women. SCH may affect serum triglyceride levels and be a risk factor for metabolic syndrome.

In addition to heredity and living habits, the risk of environmental pollutants affecting the thyroid hormone levels and interfering with thyroid function cannot be ignored. A high concentration of pentachlorophenol can be detected in drinking water in Shanghai continuously. Pentachlorophenol has been confirmed as an environmental pollutant that can interfere with thyroid hormones. This study in one community in Fengxian District, Shanghai which has a high incidence of thyroid disease to find out the association between the level of pentachlorophenol exposure and thyroid hormones;the thyroid disrupting effect of pentachlorophenol at population level. A method was established to detect the concentration of pentachlorophenol in human serum. A total of 100 cluster random samples in this community were taken from the population to collect blood and urine. Thyroid function indicators (FT3, FT4, TSH, TgAb and TPO) were measured. Also the concentration of pentachlorophenol in serum and urinary iodine (as indicators of iodine levels in the body) was measured. Considering age, gender, iodine (urine iodine) and other factors on the impact of thyroid function in the population, the association between the exposure of pentachlorophenol and the interference of thyroid hormone was analyzed. The results indicate that the pentachlorophenol exposure in serum in the investigation population is at the nanogram level (ND-5.30 ng/mL) and the detection rate is 98%. The results of correlation analysis (controlling urinary iodine) indicate that there is a negative correlation between the exposure level of pentachlorophenol and FT4 levels (r = 0.682, P < 0.05), but no significant correlation with other thyroid hormone markers. People in the community generally contain pentachlorophenol. Although the concentration of pentachlorophenol in the body is at trace level, the exposure of pentachlorophenol at the nanogram level can interfere with thyroid hormone in the body and disturb thyroid function. In the future, a large-scale population epidemiological investigation is needed to further clarify and confirm whether pentachlorophenol is a potential risk factor accounting for high incidence of thyroid disease.

We report a classic case of myxedema coma, presenting with altered mental status, hypothermia, hypoglycemia, hypotension, hyponatremia, and bradycardia, in a patient with amiodarone-induced hypothyroidism.73 year-old female with history of iatrogenic hypothyroidism due to amiodarone presented with lethargy. Vitals revealed hypotension (90/40 mmHg), bradycardia (40 beats/minute), and hypothermia (35.2° C). She was minimally responsive with tremors, dry skin, periorbital and pretibial edema. Labs showed glucose 50, TSH 99.589 uIU/mL, and sodium 134 meq/L. Urinalysis with >900 WBCs, prompting cefepime. IV Levothyroxine 75mcg was started, as well as stress dose IV hydrocortisone, which resulted in rapid improvement. Hypoglycemia was corrected with 1 amp D50. AM cortisol was 5.7 mcg/dL, which ruled out concurrent adrenal insufficiency. The patient was given Levothyroxine 50 mcg IV daily with repeat TSH 40.293 uIU/mL, free T4 0.48 ng/dL, total T3 0.2 ng/mL. Upon discharge, vitals, mental status, and edema had normalized. The presumed etiology was medication non-compliance, as well as a precipitating UTI. Myxedema coma is rare due to wide availability of thyroid replacement therapy. The condition could be precipitated by many events, including infection. Despite the name, patients more often present with lethargy and confusion rather than coma. Stress dose steroids should be administered until concurrent adrenal insufficiency is excluded¹. Amiodarone's thyrotoxic profile has been well established but amiodarone associated myxedema coma has only been outlined in a handful of reports. Given its high mortality, it is crucial to recognize myxedema coma, so prompt treatment can be initiated for this life-threatening disorder. Our case also argues for the importance of routine thyroid function tests for patients on amiodarone, as myxedema coma occur.

We present a rare case of a patient with pre-existing hyperthyroidism who developed non-Hodgkin's lymphoma of the thyroid.61-year-old male with a 10 year history of hyperthyroidism presented with 2 months of right-sided neck swelling. The palpable mass was further evaluated with CT neck that revealed an enlarged homogenously enhancing nodule under the right sternocleidomastoid concerning for a pathologic lymph node, and a smaller satellite node. The dominant lymph node was excised, and pathology showed low grade B cell lymphoma consistent with marginal zone lymphoma. No bone marrow involvement was noted on biopsy. PET scan showed diffuse asymmetric thyroid activity prominent in the right isthmic region, possibly due to thyroiditis. At that time, the patient was taking Methimazole 10 mg daily. He was biochemically euthyroid with negative thyroid stimulating immunoglobulin. Thyroid ultrasound showed a heterogeneously enlarged thyroid with a 4cm hypoechoic nodule within the right lower pole, and an 11mm hyperechoic nodule in the left lower pole. Right thyroid nodule cytology and flow cytometry revealed non-Hodgkin's lymphoma. The patient was diagnosed with marginal zone lymphoma of thyroid and right cervical nodes, stage IIE and is being managed with radiation therapy. Primary thyroid lymphoma is an incredibly uncommon condition with an annual incidence of approximately 0.000002. When it does occur, it is mostly in the setting of Hashimoto's thyroid disease. There are very few cases reporting thyroid lymphoma in patients with pre-existing hyperthyroidism. Since there are few cases demonstrating an association between hyperthyroidism and thyroid lymphoma reported, clinicians may not easily recognize the importance of certain diagnostic tests. In regards to our case, we would like to highlight the importance of obtaining flow cytometry based upon clinical context, especially since diagnosis may alter treatment.

A thyroid storm is a life-threatening presentation, with congestive heart failure and tachyarrhythmias being common manifestations. We describe a patient who was admitted for a thyroid storm precipitated by pneumonia, who later developed an acute flail mitral valve from chordae tendineae rupture. A 55 year-old lady with no past medical history was admitted with fever, dyspnea, lower limb swelling and hemoptysis. She was febrile, tachycardic and in fluid overload. Her heart sounds were dual and no murmurs were heard. Initial investigations indicated primary hyperthyroidism and pneumonia. She was diagnosed with a thyroid storm precipitated by a pneumonia, complicated by heart failure. Her Burch-Wartofsky score was 70. She was started on IV hydrocortisone, PO propylthiouracil, PO lugols's iodine and PO cholestyramine, together with IV amoxicillin-clavulanate and IV furosemide. She continued to deteriorate in the Medical Intensive Care Unit with worsening hypoxia and hypotension. Echocardiography showed an acute flail posterior mitral valve leaflet with torrential mitral regurgitation due to rupture of the chordae tendineae. She subsequently underwent a bioprosthetic mitral valve replacement. An acute flail mitral valve precipitated by thyroid storm leading to refractory cardiogenic shock is rare. Factors contributing to the rupture of valve chordae tendineae include the effect of hyperthyroidism on papillary muscle function, a hyperdynamic circulation leading to vulvular stress, as well as pre-existing mitral valve pathology. A flail mitral valve from chordae tendineae rupture can also be a cause of worsening heart failure and cardiogenic shock in a thyroid storm, albeit a rare complication.

This case describes a patient who was admitted for a thyroid storm 1 month after radio-iodine treatment. A 71 year-old Chinese lady was admitted to the emergency department for a 3 day history of fever and confusion. She had a history of toxic multinodular goitre diagnosed 2 years ago and had been on carbimazole 5mg OM until 4 months ago when she was found to be neutropenic on routine testing. Carbimazole was stopped and she was started on choleystramine 4g OM and sent for radio-iodine treatment. A bone marrow aspirate done later showed good marrow production, although she was persistently leukopenic despite stopping carbimazole for more than 4 months. 20 mCI of Iodine-131 had been administered to her 1 month before her admission.

Her Burch-Wartovsky score on admission was 80. She did not complain of any neck pain or swelling. She was started on IV hydrocortisone 100mg 8H, PO propranolol 10mg 8H, PO cholestyramine 4g 8H. Propylthiouracil was also started at 100mg 8H cautiously. There was no evidence of any stroke or myocardial infection, and her procalcitonin level was low. Antibiotics were started for a presumptive urinary tract infection. She improved clinically and was continued on a tailing dose of steroids on discharge. Post-radioiodine thyroiditis is usually asymptomatic and typically manifests a few days to 2 weeks therapy after administration, with a temporary exacerbation of thyrotoxicosis in previously hyperthyroid patients. Contributing factors include ineffective anti-thyroid pharmacotherapy due to ongoing evaluation for possible carbimazole-induced agranulocystosis, large radio-iodine dose relative to goitre size, as well as precipitating infections.

Thyroid storm is a rare complication of post-radioiodine thyroiditis.

Thyrotroph hyperplasia is a rare heterogeneous entity, often seen in severe hypothyroidism. It is postulated that this pituitary enlargement occurs due to persistent stimulation from the lack of thyroxine. Barring any emergent indications such as visual impairment- treatment is levothyroxine replacement. Reports have described that resolution of the hyperplasia with levothyroxine occurs between months to years. Herein, we describe a patient who had thyrotroph hyperplasia which has improved significantly with complete resolution of visual field defect, galactorrhea, hyperprolactinemia.

Case:

25-year-old woman presented with galactorrhea was found to have a 2 cm pituitary mass impinging on optic chiasm. Visual field testing revealed mild field cut bilaterally although she denied visual deficit. Her pituitary hormonal evaluation revealed elevated prolactin and TSH. Mild hyperprolactinemia was likely due to stalk effect. A hook effect was ruled out by prolactin dilution assay. Interestingly, she was found to have elevated TSH (150 mIU/L) with low free T4 (0.3 ng/dl) with positive anti-TPO antibody. She was started on levothyroxine resulting in resolution of galactorrhea, hyperprolactinemia, more importantly, a significant reduction of the size of the pituitary mass and resolution of the visual field defect.

Discussion: This case describes the importance of thorough clinical history and hormonal workup that may result in avoidance of unnecessary pituitary surgery in a patient with pituitary mass. Primary hypothyroidism should always be considered in the differential diagnosis of hyperprolactinemia associated with pituitary enlargement and thyroid hormone replacement should be started. Regression of pituitary enlargement on MRI follow-up can confirm the diagnosis. Although complete resolution of pituitary hyperplasia may take several months, the clinical improvement including features of hypothyroidism, hyperprolactinemia, and the visual field deficit is completely reversible and happens early in the course of therapy.

Not every patient with galactorrhea, hyperprolactinemia and a pituitary mass has a prolactinoma. Thyroid hormone replacement can reverse pituitary enlargement due to thyrotroph hyperplasia.

Radioiodine-avid thyroid cancer lesions usually are 18F-FDG -nonavid, and vice versa. There are very few reports showing thyroid cancer with both uptakes of 18F-FDG and 131-I. Herein, we report a case of follicular and poorly differentiated thyroid cancer (PDTC) with both 18F-FDG and RAI uptake at the metastatic site.

Case:

A 47-year-old female with follicular thyroid cancer with a large right hip bone metastasis. Her pathology of thyroidectomy specimen showed follicular thyroid cancer with a poorly differentiated component. FNA of her hip lesion showed follicular thyroid cancer. Seeing a component of PDTC, a18F-FDG PET/CT scan was done to evaluate iodine avidity of her bone metastases. This revealed 18F-FDG uptake in the metastatic site. Given her high risk for recurrence, she was treated with 200 mCi RAI. A post-therapy scan showed marked uptake in the metastatic right hip which did light up on PET/CT scan. The true effectiveness of RAI therapy for her hip metastasis is unknown because she was only recently treated. Interestingly, RAI treatment resulted in marked reduction of thyroglobulin level and the size of the hip mass.

Discussion: 18F-FDG PET/CT is sensitive and effective in detecting metastatic and recurrent differentiated thyroid cancer (DTC), especially in patients with iodine-negative tumors and elevated serum thyroglobulin level. PDTCs tend to be FDG-PET positive, and non-RAI-avid. Although the method of choice to image iodine negative metastases is 18F-FDG PET/CT, metastatic differentiated thyroid cancer lesions with both uptake of 18F-FDG and 131-I have also been reported in previous studies. At some hospitals, 18F-FDG PET/CT is done as an initial staging modality in high-risk patients with differentiated thyroid carcinoma. It is to keep in mind that positive 18F -FDG uptake does not always necessarily confirms a non-iodine avid disease. Clinicians should be aware of the fact that ¹⁸F-FDG-avid tumor might also be radioiodine-avid, although rare. Decision to give radioiodine therapy in a patient with metastatic thyroid cancer to be taken based on initial risk categorization.

Seaweed is known to affect thyroid function because of its iodine content. Here we discuss a case of hyperthyroidism that was further exacerbated by seaweed consumption during inpatient admission despite use of antithyroid drugs.

A 54 year old female with a history of untreated Graves' disease presented with progressive dyspnea for two months. She had heat intolerance, diaphoresis, weight loss, increased appetite, hair loss, dry skin, dyspnea, palpitations, and fatigue. On physical exam, she was anxious, tachycardic, had lid lag but no other ophthalmic findings, and fine tremors in hands and feet. Chest radiograph revealed pulmonary edema. EKG showed sinus tachycardia. Troponin increased from 0.16 to 3.48. Coronary angiogram showed nonobstructive coronary artery disease in the right coronary artery. Thyroid stimulating hormone (TSH) was <0.01, free T4 (FT4) was 7.18, and free T3 (FT3) was 12.7. Methimazole 30mg daily and metoprolol XL 50mg daily was initiated with improvement in labs and symptoms. Patient was discharged, but returned four days later with increased anxiety and dyspnea. TSH was <0.01, FT4 2.93, FT3 12.2. Methimazole was increased to 20mg BID. After four days of treatment, FT4 increased from 2.93 to >8.00. Although patient initially denied consumption of iodine containing foods, she was found consuming seaweed snacks and seaweed juice while in the hospital. She stopped all seaweed containing products and thyroid function tests normalized. Thyroid hormone synthesis requires iodine 150 μg daily, while kelp and seaweed are very iodine rich and contain between 16 μg/g and >8000 μg/g. The thyroid gland has intrinsic regulatory mechanisms that maintain normal thyroid function even in the presence of iodine excess, however patients with Graves' disease are prone to develop iodine-induced hyperthyroidism. Excess iodine in hyperthyroid Graves' disease may also reduce the effectiveness of antithyroid drugs. Both of these phenomena were observed with our patient. Patients with thyrotoxicosis, especially from Graves' disease, should be counseled about iodine containing products as these can exacerbate their thyrotoxicosis and make antithyroid drugs less effective.

Older individuals often present with a subdued presentation of hyperthyroidism, termed apathetic. While systemic manifestations such as tremor and diarrhea are absent, cardiac manifestations such as tachyarrhythmias will prevail. The presence of cardiomyopathy (CMO) in the setting of overt thyrotoxicosis or thyroid storm, has been attributed to several etiologies including tachycardia-induced and takotsubo's (stress induced) CMO. A 77-year-old woman with no medical follow up presented to the emergency department complaining of shortness of breath, malaise, poor oral intake, palpitations and orthopnea for the past week. Patient also endorsed 40-pound weight loss over the past year. On physical exam it was noted to have a BMI of 17 and was in atrial fibrillarion (AF) at a rate of 160's. The exam showed evidence of proptosis and jugular venous distension. Laboratory data was pertinent for an elevated troponin (0.113 ng/mL) and BNP (3294 pg/mL). Hemoglobin A1C was 10.8%. Thyroid studies revealed TSH <0.01 mIU/L, free T4 1.48ng/dL (0.7-1.48ng/dL), total T3 0.66 ng/mL (0.58-1.59ng/mL). Thyroid ultrasound showed multinodular goiter. Thyroid Stimulating Immunoglobulin 488 (<140 % baseline) and thyroid microsomal antibody 263.65 IU/mL (<5.61). Iodine uptake scan was deferred to the outpatient basis. Transesophageal echocardiography demonstrated severely reduced ejection fraction of 10-15%. All four chambers of the heart demonstrated extensive clot burden with chamber dilations. Hypercoagulable workup was pertinent for Protein C antigen 45% (70-140 %). She was started on apixaban, methimazole and metoprolol succinate with improvement in hemodynamics. While, conditions such as AF and CMO alone may predispose to cardiac thrombi, overt hyperthyroidism has been suggested to independently be associated with a hypercoagulable state through unclear mechanisms. Previous reports have suggested that elevated free T4 levels, increased TBG, and rare reports of protein C deficiency, have been reported in associated with hyperthyroidism and the hypercoagulable state. Further investigation is needed to identify the duration of the hypercoagulability once patient is euthyroid in order to manage duration of anticoagulation.

Thyroid dysfunction is a known cause of menstrual irregularities, including oligomenorrhea, amenorrhea and menorrhagia. We present a patient with life-threatening anemia due to menorrhagia in the setting of newly-diagnosed hypothyroidism. A 43-year-old female with no significant history presented with worsening fatigue, lightheadedness and menorrhagia for the past 6 months. Her menstrual cycle had become heavier, irregular and of longer duration. On presentation, she was found in hemorrhagic shock with a systolic blood pressure of 76 and heart rate of 138. Physical exam was remarkable for skin and conjunctival pallor, proximal muscle weakness and dark blood with clots in the vaginal vault. Laboratory tests revealed a hemoglobin of 5.6 g/dL. She received 3 L of IV fluids and 2 units of packed red blood cells with subsequent improvement of hypotension. A transabdominal and transvaginal ultrasound were unremarkable, ruling out organic disease of the genital tract. Upon further workup, the patient was found to have a TSH level of 188 mIU/L, FT3 of 0.4 pg/mL and FT4 < 0.10 ng/dL indicative of hypothyroidism. She was started on levothyroxine 125 mcg daily and iron supplements and was discharged to follow-up with Endocrinology after stabilization of her hemoglobin levels. Thyroid disorders are associated with a wide spectrum of reproductive disorders ranging from abnormal fetal development, menstrual irregularities and infertility. Menorrhagia and metrorrhagia can be complicated presenting symptoms of profound hypothyroidism, a consequence of anovulatory dysfunctional uterine bleeding and hemostasis disturbance. It is known that with thyroid hormone replacement therapy, TSH levels normalize and abnormal uterine bleeding usually resolves within 3 to 6 months. The American Thyroid Association estimates that 1 in 8 women develop a thyroid disorder at some point in their lives. Thyroid dysfunction should be strongly considered and screened in patients presenting with menstrual abnormalities. Correction of thyroid abnormalities can significantly improve abnormal uterine bleeding, avoid life threatening complications and invasive surgical interventions.

The incidence of pericardial effusion in hypothyroidism is 3% in the early mild stage and up to 80% in patients with myxedema. We present three cases of severe hypothyroidism causing cardiac tamponade.

CASE 1. 61-year-old woman with Hashimoto's thyroiditis who initially presented with generalized muscle weakness, found to have a large pericardial effusion with tamponade physiology. Initial labs revealed TSH 198.74 and FT4 < 0.10. Pericardiocentesis was done draining 1.5 L of fluid.

CASE 2. 63 year-old woman with no past medical history presented after a mechanical fall, found to have an acute basal ganglion ischemia. TTE was obtained to complete CVA work-up revealing a large pericardial effusion with with tamponade physiology. labs were notable for a TSH 47.

CASE 3. 66 year-old woman with hypothyroidism presented with lethargy and dyspnea. TTE revealed large pericardial effusion with tamponade physiology. CT chest revealed a large pericardial effusion that was narrowing the distal left mainstem and left lower lobe bronchi. Pericardiocentesis was done draining 1.1 L of fluid. Pericardial effusion in hypothyroidism is due to increased capillary permeability and impaired lymphatic drainage with subsequent leakage of fluid rich proteins and glycosaminoglycans into the interstitial space. Factors affecting capillary permeability include absence of FGF signaling and decrease in adrenomedullin, resulting in destabilization of the VE-cadherin/β-catenin complex at the cell–cell junctions. There has been no correlation with TSH levels and the existence of effusion.

Clinical symptoms of tamponade are uncommon due to slow accumulation of fluid and pericardial distensibility. It is hypothesized that heart rate is within normal range or bradycardic due to decrease sympathetic activity.

The color of the fluid is most commonly straw-colored or gold. And the cells are predominantly lymphocytes.

The treatment should be individualized. The effusion can be reversed only with levothyroxine because the slow rate of accumulation. Pericardiocentesis is only done when there is hemodynamically instability. Cardiac tamponade presenting with normal or low heart rate with high TSH is highly suggestive of hypothyroidism as the culprit.

Amiodarone-induced thyrotoxicosis (AIT) develops in 3% of amiodarone-treated patients in North America. Its long half-life allows its effects to persist for months. In a patient with unstable cardiac function, uncontrolled AIT can be life-threatening. We present a case of severe cardiac disease and a prolonged course of AIT treated with a total thyroidectomy. A 61-year-old man with congestive heart failure (CHF) is admitted with worsening heart failure and recurrent ventricular arrhythmia.

Six months prior, the patient received one dose of amiodarone at an outside hospital and subsequently, was found to have new hyperthyroidism with a TSH 0.00 uIU/mL (0.5-4.8), free T4 2.8 ng/dL (0.9-1.8), and total T3 220 ng/dL (87-178). Thyroid antibodies were normal. A thyroid ultrasound showed a homogeneous gland with no nodules. An I-131 thyroid scan showed uptake of 1.7% (10-30%). He was treated with prednisone for presumed thyroiditis.

One month ago, he was admitted with worsening CHF and ventricular tachycardia (VT). He reported noncompliance with prednisone and was found to have a TSH <0.008 uIU/mL, free T4 3.1 ng/dL, and total T3 0.87 ng/mL. Echocardiogram showed ejection fraction (EF) of 30%. He was treated with a beta blocker, prednisone 40mg daily and methimazole 30mg daily.

He is now readmitted with recurrent VT. TSH is <0.008, free T4 5.1 and EF has decreased to 12%. Due to the worsening cardiac status and persistent hyperthyroidism, a total thyroidectomy is recommended after symptomatic control with prednisone and beta blocker. The pathology shows thyroid parenchyma with changes consistent with type 2 AIT. Amiodarone-induced thyrotoxicosis (AIT) can develop in patients with underlying thyroid abnormalities (type 1) or in patients with normal thyroid glands (type 2). Differentiating type 1 from type 2 AIT is crucial as it has therapeutic implications. Type 1 is treated with anti-thyroid drugs while type 2 is treated with steroids. Uncontrolled and persistent hyperthyroidism is associated with an increased incidence of ventricular arrhythmias and a rapid decline in cardiac function. A total thyroidectomy needs to be considered in unstable patients when AIT is persistent and difficult to control.

The mainstay of treatment for amiodarone induced thyrotoxicosis (AIT) type 2—a form of destructive thyroiditis—is the use of oral glucocorticoids. However, the literature offers limited insight into the impact of the type and route of glucocorticoid on treatment response. We present a case of AIT type 2 which required the administration of intravenous (IV) glucocorticoids in order to achieve euthyroidism. A 64 year-old male presented to our hospital in thyrotoxicosis (initial labs showed TSH 0.03 mIu/L and free T4 3.66 ng/dL) complicated by atrial fibrillation with rapid ventricular rate and exacerbation of congestive heart failure. He had been maintained on amiodarone for a history of persistent atrial fibrillation despite prior ablation. We initiated methimazole 40mg daily and prednisone 30mg BID after stopping amiodarone given concern for AIT. Type 2 AIT was ultimately suspected based on low thyroid uptake and scan, negative thyroid antibodies, elevated interleukin-6 level, and unremarkable neck ultrasound; methimazole was therefore discontinued. After 17 days, the patient's poor clinical status and free T4 level were unchanged. His persistent volume overload raised the suspicion of enteral malabsorption, and we therefore transitioned from oral prednisone to IV hydrocortisone 50mg every six hours. Within four days, his free T4 decreased by half with resolution of atrial fibrillation, and the patient was rendered euthyroid within two weeks. Prednisone 0.5-0.7mg/kg per day is recommended for mixed AIT or AIT type 2, though rates of free T4 normalization are often slow. Compared to prednisone, parenteral hydrocortisone has the advantages of higher bioavailability and immediate activity without first requiring hepatic conversion to an active steroid metabolite. Equipotent IV glucocorticoid therapy has shown greater efficacy compared to oral administration in the treatment of other conditions, such as Graves' ophthalmopathy. This case demonstrates that parenteral glucocorticoids should be considered for recalcitrant disease in select AIT type 2 patients, particularly those with critical illness or refractory hyperthyroidism. Larger, placebo-controlled studies are needed to support this approach.

Sialadenitis is among the most common complications of thyroid carcinoma treated with radioactive iodine (RAI). Symptoms include pain, xerostomia, and swelling. To date there are a paucity of studies that characterize ultrasound findings in patients with RAI sialadenitis. The objective of this study is to demonstrate ultrasound findings in patients with a history of radioactive iodine exposure (RAI) and suspected RAI associated sialadenitis.22 patients with a history of thyroid carcinoma treated with RAI who presented for evaluation of sialadenitis were identified. Ultrasound (US) examination was performed in each patient. Ultrasound findings studied included intraglandular and/or main ductal dilation, presence of echogenic foci with or without posterior acoustic shadowing, echotexture, and vascularity of the gland. Representative images were captured, and relevant measurements were taken. The mean age of patients was 47 years. The majority (20/22) of the patients were female (91%). The parotid gland was most affected (90%) followed by the submandibular gland (10%) The average cumulative dose of RAI was 165 mCi with a SD of 108 mCi with a 95% CI (115,215).

US examination demonstrated obstruction in 19 patients (86%), ductal dilation was present in 14 patients (63%) and intraglandular dilation was noted in 17 (77%). Gland parenchyma appeared homogeneous in 9 (41%) and heterogeneous in 11 (50%). 18/22 (81%) glands were considered to be normovascular. No calculi were identified in this cohort.

US examination demonstrated obstruction in 19 patients (86%), ductal dilation was present in 14 patients (63%) and intraglandular dilation was noted in 17 (77%). Gland parenchyma appeared homogeneous in 9 (41%) and heterogeneous in 11 (50%). 18/22 (81%) glands were considered to be normovascular. No calculi were identified in this cohort. The ultrasound findings of RAI sialadenitis can vary. The most common finding noted is ductal dilation, which suggests obstruction. The majority of the glands are of normal vascularity. Heterogeneity of the gland is a less consistent finding.

Sialadenitis is among the most common complications of thyroid carcinoma treated with radioactive iodine (RAI). Symptoms include pain, xerostomia, and swelling. Treatment focuses on prevention of the symptoms by promoting the excretion of the isotope by gland massage, use of sialogogues, radioprotective antioxidants, and muscarinic receptor agonists. However, once sialadenitis symptoms become present, treatment options for patients nonresponsive to conservative management have been previously limited to sialadenectomy. Recently sialendoscopy was introduced as an alternative. This study examines sialendoscopy as treatment option for RAI induced sialadenitis. This study is retrospective review of 22 patients with persistent sialadenitis symptoms related to RAI treated with sialendoscopy. All patients sought evaluation of sialadenitis after failure of conservative measures. The parotid gland was affected in 90% and submandibular gland in 10%. Symptoms were periprandial in 75% of patients and included pain (65%), xerostomia (50%), discharge (40%) and swelling (100%) with unilateral presentation in 80% of patients. Average time between symptom onset and evaluation was 11 months. Symptoms manifested an average of 10 months after RAI treatment was completed. The average dose of one time RAI was 168 mCi. Sialendoscopy revealed strictures in 17 patients (75%), inflammatory sialadenitis changes in 3 patients (15%) and normal ducts in 2 patients (10%). All patients demonstrated mucosal discoloration, mucous plugs, and debris.

Symptom improvement was achieved in 20/22 patients (91%) after intervention. Three patients had symptom recurrence. Repeat sialendoscopy on two of these patients led to permanent resolution of symptoms. One patient did not follow up. Sialendoscopy is a functional, minimally invasive option for treating sialadenitis and strictures induced by RAI treatment for thyroid carcinoma refractory to conservative management.

Bariatric surgery is highly effective for the treatment of obesity. Nutrient deficiencies are common post-bariatric surgery, especially after Roux-En-Y gastric bypass. Iodine absorption occurs primarily in the proximal small intestine. To date, there have been few studies assessing iodine status following gastric bypass. We aimed to assess urinary iodine concentrations (UICs) pre- and post-bariatric surgery and to determine predictors of postoperative UICs.

This was a prospective observational cohort study. Patients undergoing bariatric surgery at Boston Medical Center from January 2014 - July 2016 were enrolled. Individuals using thyroid medications, amiodarone, lithium or with recent exposure to iodinated contrast media were excluded. Spot UICs, serum TSH, vitamin B12, iron, ferritin, folate, thiamine and 25-OH-vitamin D levels were collected prior to and 3-6 months post-bariatric surgery. A questionnaire including 24-hour dietary recalls and multivitamin use was administered at the pre- and post-operative visits.

85 patients (86% female) were included. Mean age was 36.0 ± 11.1 years. Roux-En-Y gastric bypass surgery and sleeve gastrectomy were performed in 60 and 25 patients, respectively. Dehydration, numbness, ataxia, anemia, and/or severe electrolyte abnormality occurred in 8 subjects. Median UIC was higher after surgery than at baseline (331 [range 72-1500] vs. 201 [range 16-2176] μg/L, p < 0.001). Post-operative UICs were positively correlated with ingestion of eggs (r = 0.53, p 0.01) and the number of daily servings of high-iodine foods (bread, seafood, dairy, eggs) (r = 0.28, p 0.04). Serum TSH after surgery was lower than at baseline (1.53 ± 0.50 vs. 1.12 ± 0.54 U/mL, p < 0.001). Although serum TSH levels decreased after surgery, they remained within normal range. The TSH change was not associated with weight change, UICs, vitamin supplement or high-iodine foods.

Median UIC was higher after bariatric surgery than before, due to changes in diet. Iodine deficiency did not occur preoperatively or postoperatively in this sample.

Thyroid nodules (TN) are common with aging. Fine needle biopsy (FNB) with molecular testing of indeterminate TN (ITN) biopsies is a cost-effective method to detect malignancy. Surgery is the preferred treatment for suspicious/malignant TN. The aim was to understand TN features in older patients (≥70 yrs). This is a retrospective case series study. Between 2/2015 – 6/2016, 453 sequential FNBs were performed on TN >1 cm. TN size by ultrasound evaluation, cytology including molecular studies and surgical pathology were collected. Results were compared between TN from the older (O: ≥70 yrs) and younger (Y: <70 yrs) patients. Of the total thyroid FNBs, 17.7% (80/453) were in the O patients (76.1 ± 5.0 yrs) and the rest were in the Y patients (49.5 ± 12.6 yrs). Compared with the Y group, in the O patients, male to female ratio was higher (23.8% vs 13.4%, P = 0.02), multiple TN was more common (97.5% vs 85.5%, P < 0.01), while the mean TN size was similar (2.6 ± 1.1cm vs 2.6 ± 1.4cm, P = 0.54). Cytology results in the O patients were 13.7% unsatisfactory, 57.5% benign, 23.8% indeterminate (Bethesda III/IV/V) and 5% malignant. Unsatisfactory cytology (13.7 vs 9.9%, P = 0.05) and benign cytology (57.5% vs 49.3%, P = 0.03) were more frequent while indeterminate results were less frequent (23.8% vs 36.2%, P < 0.01) in the O vs Y patients. ThyroSeq V.2 molecular testing of ITN, had a similar positive rate in the O vs Y patients (36.8% vs 35.8%, P = 0.74). Rates of surgery were significantly lower in the O vs Y patients in the entire series (18.8% vs 29.0%, P = 0.01), in the subgroup of benign (6.5% vs 15.7%, P < 0.01) and ThyroSeq-positive ITN (28.6% vs 53.5%, P < 0.01). Surgically confirmed malignancy occurred similarly in 9/80 (11.3%) and 36/373 (9.7%) of the O and Y patients, respectively (P = 0.66). TN of the older patients (≥70 yrs) was more likely to occur in men with a multinodular gland while insufficient and benign cytology was more common and indeterminate was less likely to occur. Aging may not affect the risk of a positive ThyroSeq V.2 test in ITN. Older patients were less likely to have surgery for both benign and molecular positive ITN.

The Swedish iodine fortification program with 50 μg iodine/g table salt has been considered sufficient for an adequate iodine nutrition in the population. Therefore, there have been no systematic monitoring. We recently reported from a national study that mild iodine deficiency (ID) was present among pregnant women. We have formulated the hypothesis that mild ID has not emerged now, but been persistent for a long time. The aim of this study was to explore iodine intake and iodine excretion in early pregnant women in samples from 2006. Pregnant women (n = 65) were included during the first trimester at the maternal health care centre in Kungälv in 2006. This cross-sectional study included registration of a food frequency questionnaire for calculation of iodine intake, blood samples for thyroid hormones, thyroglobuline (Tg) and urine samples both collected as spot urinary iodine concentration (UIC) and as 24 hours urinary iodine excretion (24-UIE). Urinary iodine was analysed with the Sandell-Kolthoff reaction. Six pregnant women were excluded from this preliminary analysis because of miscarriage, one because of mola hydaditosa and three did not complete the study. In those remaining 56 women, supplements that included iodine were used by 13 women (22.8%). The iodine intake was 220 μg for the whole group including supplements. For the women not taking supplements, the intake of iodine was 148 μg. Thyroid hormones and Tg did not differ between groups. Median spot UIC and 24UIE among all were 80.0 (IQR 62.5-137.5) μg/L and 158.3 (130.1-233.2) μg/day, respectively. In the supplement users median spot UIC was 89.0 (IQR 65.5-173.0) μg/L and in non-supplement users 78.0 (60.0-131.0) μg/L, p = ns. The corresponding values for 24UIE were median 312.6 (266.6-418.9) μg/day and 149.3 (122.5-173.0) μg/day for supplement and non-supplement users, respectively, p < 0.01. Low UIC and 24UIE in non-supplement users imply ID already 12 years ago that can be attributed to insufficient intake of fish, milk and dairy products. The most important is, however, to increase the use of fortified salt in ready-made products and half made productions instead of using non-iodinated salt.

Although adequate folic acid or multivitamin intake can prevent up to 70% of neural tube defects (NTDs), the cause of NTDs in some cases remains unknown. Other risk factors are thought to be involved, such as a high level of total homocysteine (tHCY). In this study, we examined the serum levels of thyroid hormone and tHCY among pregnant women with NTDs fetuses. A case control study was performed in a rural mountain area of China, where a high prevalence of NTDs was reported between 2007 and 2009. A marked increase in fT4 levels above the normal range before 20 gestational weeks was observed in the control group, but not in the pregnant women with NTDs fetuses. No significant difference in serum tHCY levels was seen between the controls and the cases at ≤20 gestational weeks. Among the women with fT4 levels ≤15.2 pmol/L, the tHCY levels were significantly higher in the NTDs group than in the control group (P = 0.003). According to a logistic regression model adjusted for gestational week, maternal age and urine iodine, the odds ratio of the serum levels of coexisting fT4 levels ≤15.2 pmol/L and tHCY >13μmol/L was 5.3 (95% confidence interval: 1.6-17.8), but no increased NTDs risk was observed for the other conditions. Thyroid hormone was an effect-measure modifier of tHCY using a logistic regression model analysis. Thyroid hormones reportedly increase the activities of enzymes involved in riboflavin metabolism, thereby augmenting the synthesis of flavin adenine dinucleotide, a cofactor of methylenetetrahydrofolate reductase that maintains methylenetetrahydrofolate reductase activity, and decreasing the serum levels of HCY. Therefore, a biologic interaction between relatively a low level of thyroid hormone and a high level of tHCY cannot be ruled out.

TAZ is a transcriptional co-activator (transcriptional co-activator with PDZ-binding motif) known to regulate the activity of thyroid transcription factors PAX8 and NKX2-1 by direct interaction and is, therefore, a central player in thyroid-specific transcription This interaction leads to significant enhancement of the transcriptional activity of PAX8 and NKX2-1 including their binding to the thyroglobulin (TG) gene promoter, one of the specific genes involved in thyroid differentiation. We previously reported that a small molecule called ethacridine, identified as a TAZ activator, was able to induce thyroid specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells. In order to understand the mechanism of ethacridine transcriptional regulation we studied the epigenetic changes in methylation and acetylation in the promoter region of selected genes in human embryonic stem cells (hES) undergoing thyroid cell differentiation. On examining the predicted CpG islands for methylation using methylation- specific primers we observed only very low amounts (<10%) of methylation in the NKX2-1 promoter and no signbificant methylation in the PAX8 and TAZ promoters which are key drivers for human thyroid cell differentiation. In contrast, the promoter activity of NKX2-1, PAX8 and TG was highly induced in ethacridine and Activin A treated hES cells as measured by acetly-histone H4 immunoprecipitation (ChIP) assay (64 fold, 4 fold, and 6 fold respectively) suggesting active chromatin states of these promoters. These results indicated that the small molecule ethacridine is able to induce an acetylation mediated open chromatin state in human ES cells leading to a path for thyroid speciation. Thus epigenetic changes are likely to be a hallmark of thyroid cell speciation.

Cone photoreceptors mediate high acuity vision in daylight. Cones also mediate color vision, which requires cone sub-populations that respond to different regions of the light spectrum. In most mammals, these cone sub-types express M and S opsin photopigments for response to medium-longer (M “green”) and short (S “blue”) wavelengths of light, respectively. The generation of cone diversity is fundamental to visual function but the underlying mechanisms are poorly understood. We previously found that thyroid hormone receptor b2 (TRb2) encoded by Thrb is essential for M opsin expression in mice. Mutations in the human THRB gene have been associated with photoreceptor abnormalities. We generated a knockin mouse that expresses fluorescent GFP protein in cones to allow isolation of cones from control or TRb2KO mice for single cell RNA-sequencing. Cones were collected from dorsal and ventral retinal regions that are enriched for M and S cone types, respectively. More than 150 single-cell RNA-seq libraries were analyzed. Results were corroborated by analysis of pools of cone cells. Selected genes were further validated by quantitative PCR (qPCR), in situ hybridization or immunohistochemical analyses. A modest number of genes including those encoding M and S opsins showed significantly different expression between dorsal and ventral retina in control samples, suggesting that in mice, cone types are defined by gradients of expression of opsins and limited groups of other genes. In TRb2KO mice, only a small group of cone genes displayed disrupted expression but this group included a high proportion of gradient genes. Investigation of TRb2 genomic binding sites using chromatin-affinity purification identified binding sites in a substantial proportion of genes that show disrupted expression in TRb2KO mice, suggesting a direct mechanism of regulation. Our single cell analysis reveals that TRb2 regulates genes that define cone diversity. in TRb2KO mice, cones display a relatively undifferentiated transcriptome indicating a key role for TRb2 in the generation of cone diversity.

Congenital Hypothyroidism occurs in 1:2000 to 1:4000 live births¹. Thyroid function is critical to neurologic development and growth. Newborn screening, while standard in many countries, is not universal. Here we present a case of delayed diagnosis of congenital hypothyroidism, presenting with severe menorrhagia, short stature, and incomplete fusion of multiple growth plates. The patient is a 33 years old nulliparous female with no past medical history, born at term in Mexico, who completed secondary school. All family members are of normal height. She had repeated menorrhagia and critical anemia Hgb of 2.1g/dL (1.3 mmol/L). She was treated with dilatation and curettage twice (hyperplasia without atypia, features suggest endometrial polyps), iron and Norethindrone followed by IUD placement. Yet the vaginal bleeding persisted. On transvaginal US: an enlarged uterus without fibroids. Physical exam significant for: short stature (4 feet 2 inches; 127cm), brachydactyly, short neck, absence of palpable thyroid tissue, normal nasal bridge, normal shape and position of ears, no café-au-lait spots, waddling gait and mild bowing of legs. She had a TSH of 78.15 uIU/mL, free T4 by Equilibrium dialysis <0.20 ng/dL. TPO Ab 9 IU/mL (range 0 – 34 IU/mL). No normal thyroid tissue identified on ultrasound. Cortisol rose from 16.5 to 28.8ug/dL (455 to 795 nmol/L) after cosyntropin. Bone survey revealed irregular fusion of inferior pubic rami and incomplete fusion across the lesser trochanter apophyses bilaterally. Mild coxa valga deformity of femurs. Mild widening of sacroiliac joints. Chromosomal analysis with 46XX karyotype ruled out Turner's syndrome. Levothyroxine was initiated and titrated to 112mcg daily. She ultimately required transabdominal hysterectomy, bilateral salpingectomy and left oophorectomy. Late diagnosis of congenital hypothyroidism is potentially quite morbid. Severe, persistent menorrhagia warrants further evaluation for secondary causes. Given the growing diversity of our global population it is imperative to consider alternative culprit etiologies, congenital defects, and latent childhood illnesses.

Intratracheal thyroid (ITT) is rare. Because of the hidden site, slow growth and insufficient knowledge, ITT can always be misdiagnosed and the patients will suffer from inappropriate treatments. It is also a challenge for the surgeon to remove the ITT without tracheal stenosis. Our study is a systemic review of ITT with 38 cases, which includes 4 new cases (the largest cases in one report in the past 60 years) of our hospital and 34 cases electronically searched in the PubMed since 1958. We analyzed the details of these 38 cases and summarized the epidemiological data, clinical features and therapeutic regimens, and we also put our new interpretations on the mechanism of ITT.ITT was less common in men than women (male/female ratio of 1:3). We found that the symptoms of ITT could emerge from neonates to 85-year-old, which was different from the data (30-50 years old) provided in the old literatures. 50% of our ITT cases have goiters in normal neck thyroid. Our data also showed the malignant change accounts for 5% (2 cases), and it was much lower than the widely-cited 11% reported in 1962. Imaging examinations showed that the center of ITT lies at the post-lateral tracheal wall of the 1st ∼3rd ring, which is the common site of the ligament of berry (LOB). In most cases, more than 70% of the tracheal lumen is occluded when ITT is diagnosed. Stalks between the ITT and normal thyroid lobe were clearly seen in 10 cases during surgeries. 32 cases underwent surgical treatments (27 cases through tracheal fissure, 5 cases through endoscopic resection), one neonate received thyroid suppression therapy, one ITT case with PTC accepted radiotherapy and died of recurrence, and the left 4 cases died before treatments. We firstly hypothesize that the over attachment of LOB during embryonic development maybe play an important role in the occurrence of ITT. Surgical resection is an effective treatment for ITT. We also provide some clinical experiences for the protection of tracheal function.

The thyroid locates at the root of the neck, and locally advanced thyroid cancer is likely to invade the mediastinum. The sternal splitting approach is the conventional surgical approach for mediastinal tumor as the mediastinum is surrounded by the bony thorax. In order to avoid the injuries of the major arteries, lungs and other important organs, the surgical field should be exposed adequately. Our study summarized and evaluated the surgical treatments for differentiated thyroid cancer with mediastinal invasion (MIDTC). A total of 21 MIDTC patients who had been admitted between January 2008 and May 2018 were retrospectively analyzed, and the mediastinal invasions were caused by the primary/metastatic tumor. They included 5 men and 16 women, median age 53 years (range 21–73 years), whose pathology included PTC (n = 20) and thymic-like thyroid cancer (n = 1). In 20 cases, the tumors were limited to the supra-aortic region, while in one case the infra-aortic region was invaded. All the patients underwent surgical treatments through transsternal approach (3 cases through sternal splitting approach, 5 cases through manubrium splitting approach, 8 cases through partial resection of sternoclavicular joint and manubrium approach, and 5 cases through partial resection of clavicle and manubrium approach). They all received a dose of 200-300mCi for RAI therapy after the operations. The mean follow-up was 60 months (range 1 to 120 months). All the tumors were removed completely with a safety margin macroscopically. All patients discharged on Postoperative Day 5-21 except one patient died of bleeding on Postoperative Day 5. The complications caused by surgeries included unilateral vocal cord paralysis (n = 1), permanent hypoparathyroidism (n = 1) and bleeding of the invaded internal carotid (n = 1). Overall 3- and 5-year survival rates were 65% and 48%, respectively. Most MIDTC with an invasion of the supra-aortic region can be removed completely through partial resection of sternoclavicular joint, clavicle and manubrium (PSSI), which can effectively expose the surgical field and avoid the severe complications caused by the sternal splitting incision. PSSI is one of the optimal approaches for the surgical treatment of MIDTC.

Aldo-keto reductase family 1, member C2 (AKR1C2) gene encodes for a member of the AKR superfamily and participates in the metabolism of various drugs. Moreover, thyroid tumor and adjacent normal tissues show an evident difference in the expression level of this gene. We downloaded and analyzed the data consisting the clinicopathological features of 490 papillary thyroid carcinoma (PTC) tumor tissues and 59 normal thyroid tissues from The Cancer Genome Atlas (TCGA) cohort. Diverse statistical methods, such univariate and multivariate Cox regression analyses, and Kaplan–Meier survival curves were used. PTC cell lines with transfection of plasmid were utilized to investigate the functions of AKR1C2 gene, including migration assays and invasion assays. We divided all patients into AKR1C2 under-expressed (n = 245) and over-expressed groups (n = 245) from TCGA cohort. We subsequently analyzed the data and obtained the following findings: (a) AKR1C2 was significantly down-regulated in PTC (p < 0.001), (b) Kaplan-Meier revealed that high expression levels of AKR1C2 were correlated with favorable survival in PTC (p = 0.043), and (c) AKR1C2 expression was a biomarker independently associated with recurrence-free survival (hazard ratio [HR], 0.819; p = 0.041). The cell experiment revealed that the overexpression of AKR1C2 significantly weakened the abilities of migration and invasion in PTC cell lines. Our results indicate that AKR1C2 exerts inhibitory effects on PTC oncogenesis, elevated AKR1C2 expression is associated with the favorable prognostic biomarker in recurrence free survival and AKR1C2 may act as a druggable target in PTC.

Few studies on prognostic indicators for primary thyroid lymphoma (PTL) have been presented due to the uncommon nature of the tumor. This is the first study to explore the independent prognostic factors in the two PTL subtypes. We retrospectively reviewed 1,653 cases of PTL. The cases comprised 28 Chinese patients and 1,625 patients from the SEER database from 1973 to 2013. Statistical analysis was performed to determine the demographics and prognostic factors of PTL patients. The disease-specific survival (DSS) and prognostic indicators were significantly different between patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and patients with diffuse large B-cell lymphoma (DLBCL). Patients with MALT lymphoma were younger (P = 0.011) and had lower clinical stage (P = 0.014) compared with patients with DLBCL. Cox regression analysis revealed that age, treatment modalities employed, clinical stage, and number of other types of cancer were independent prognostic factors for DLBCL patients. PTL demonstrates specific clinical features and is associated with a relatively good prognosis. Older age is associated with poor DSS in both MALT patients and DLBCL patients. Additionally, combination of different treatment modalities is associated with improved DSS in DLBCL patients.

Substernal goiter occurs in 2-48% of thyroidectomies. Reports on substernal goiters typically come from goiter endemic regions, with a paucity of literature from the United States. We report outcomes of thyroidectomy for substernal goiter at a tertiary-referral center. Retrospective review of 111 patients having thyroidectomy for substernal goiter from November 2003 - June 2017. The incidence of substernal goiter was 8.7%. Total thyroidectomy was done in 49% with a transcervial approach in 138 and sternotomy in 8 patients. Operating times were 210 ± 80 and 138 ± 56 minutes in patients having sternotomy and transcervical approach respectively. Estimated blood loss was 213 ± 125 mL with sternotomy and 83 ± 58 mL without. Length of stay was 3.8 ± 4.3 days following sternotomy and 1.0 ± 1.4 days after transcervical approach. The rate of transient hypocalcemia was 25% after sternotomy and 7.2% after transcervical approach. IV calcium was needed by 2.9% of patients after transcervical approach. Temporary voice changes occurred in 37.5% of patients with sternotomy and 19.6% without. Permanent RLN injury occurred in 2.9% of patients with transcervical operation while one patient with sternotomy had RLN sacrifice. There were no neck hematomas in either group. Thyroidectomy morbidity is increased by substernal extension of a goiter. Most studies note higher rates of hypocalcemia and RLN injury associated with substernal goiter, but some high-volume centers have reported complication rates similar to those for cervical goiter. Outcomes in the United States are less well established, likely due to a lower incidence of substernal goiters than endemic goiter regions. Complication rates at our center were similar to many reports by surgeons in goiter endemic regions; however, temporary hypocalcemia and transient voice changes were seen at higher rates than reported by some other high-volume centers. Sternotomy was associated with higher rates of transient hypocalcemia and transient voice changes compared to a transcervical approach. These findings support the referral of substernal goiters to high volume centers to maximize patient outcomes.

SRC-kinases are a group of genes encoding for cytoplasmic nonreceptor protein kinases. Multiple signaling pathways important in oncogenesis and cancer progression mediate through SRC. SRC plays critical roles in cell proliferation, survival, motility, migration, cell-matrix adhesion dynamics, and cytoskeleton regulation, via multiple downstream signaling pathways. SRC-kinases are over-expressed in human neoplasms including thyroid carcinoma. Aggressive thyroid carcinoma has been linked with aberrant activation of SRC [1-2]. However, inhibiting SRC alone is not very effective. Multiple signaling cascades mediate C-SRC activation via interaction with alpha-6 integrin (α6β4), an epithelial-specific integrin that functions as a receptor for members of the laminin family of extracellular matrix proteins [3]. The signaling function of α6β4 contributes to a motile and invasive cancer phenotype [4]. Study showed that α6β4 signals through SRC and Akt to increase S100 expression [2]. Pharmacologic inhibition of SRC activity by small molecule inhibitor (PP2) in breast cancer cells effectively blocks α6β4-dependent invasion in a concentration-dependent manner, suggesting that SRC is indeed an important mediator of α6β4 signaling. In this study, we characterized expression of c-SRC/α6β4 by immunohistochemistry in matched samples of benign and malignant thyroid tissues (WDTC, PDTC, and ATC). The expressions of c-SRC/α6β4 were analyzed in 36 benign and 43 WDTC, PDTC, and ATC. c-SRC/α6β4 were expressed in most benign thyroid epithelium but were up-regulated at moderate or strong levels in 14 of 18 node-positive thyroid carcinomas. In seven samples of PTC, c-SRC/α6β4 was overexpressed. Weak expression of c-SRC/α6β4 were detected in the benign thyroid epithelium. In PDTC/ATC thyroid cancers, c-SRC/α6β4 were overexpressed at moderate or strong levels in 13 of 15 tumors. These results provide the first evidence that c-SRC/α6β4 expression is variably upregulated in thyroid cancer and suggest that up-regulation occurs at an early stage of tumorigenesis.

Although many studies have reported that estradiol (E₂) has tumorigenic effects on thyroid carcinomas, the role of BRAF^V600E mutation in estrogen responsiveness of thyroid cells is still unknown. We aimed to elucidate the effect of BRAF^V600E on increased metastatic potential induced by E₂in a normal human thyroid cell line Nthy-ori 3-1 (Nthy). In this study, we used the two newly-established cell lines Nthy/BRAF^WT (Nthy/WT), Nthy/BRAF^V600E (Nthy/V600E) and another BRAF-positive thyroid cancer cell line B-CPAP. Expression of estrogen receptors (ER) was evaluated by RT-qPCR and Western blot analysis. Metastatic phenotypes induced by E₂ were investigated by migration, invasion and Soft-agar assays. To exclude the influence of E₂ and other steroid molecules present in fetal bovine serum (FBS), the cell were starved for 48h using phenol red-free RPMI1640 supplemented with 2% dextran-coated charcoal-treated FBS (DCC-FBS) prior to migration and invasion assays. All cell lines were expressing ER alpha and beta, and Nthy/V600E showed higher ESR1/2 ratio than that of Nthy/WT. Similarly, ESR1/2 ratio in BCPAP was decreased by knock-down of BRAF^V600E. The BRAF^V600E mutant cells showed increased migration, invasion, and anchorage-independent growth induced by E2 compared to their counter parts. Our data show that BRAF^V600E mutation plays a crucial role in estrogen responsiveness of thyrocytes. These findings suggest the clinical importance of E₂ might be variable depending on BRAF^V600E-mutational status in thyroid cancer patients, and would help further studies for hormone therapies based on estrogen signaling pathways.

BRAF^V600E is the most common mutation found in thyroid carcinomas. However, direct relationship between BRAF^V600E and initiation of human thyroid carcinoma has not been proven. To investigate the role of BRAF^V600E in thyroid carcinogenesis, we utilized a mouse xenograft model for different tumor formation capacity of a normal human thyroid cell line Nthy-ori 3-1 (Nthy) depending on BRAF mutation status. We previously established the two cell lines Nthy/BRAF^WT (Nthy/WT) and Nthy/BRAF^V600E (Nthy/V600E), where two cell lines having the same genetic background differ only by the mutation status of BRAF. Each cell line was subcutaneously injected into the right flank of the NSG mice and the dimension of grown tumors was measured with a caliper. Four weeks after injection of each cell line, the xenografted mice were sacrificed to collect tumors at the initial injection site as well as tumors formed at different organs. The acquired tumors from primary sites and metastatic sites were formalin-fixed and paraffin-embedded, and Hematoxylin and Eosin (H&E) stain was performed for histological analysis of the tumors. While Nthy/WT did not form a tumor, Nthy/V600E formed tumors in all the injected mice. In Nthy/V600E-injected mice, tumors were observable a week after injection and showed a rapid growth after two weeks of injection. The mean volume of the tumors was 2420 mm³ (SEM = 331.53, n = 11) and the mean tumor weight was 1.94 g (SEM = 0.172, n = 11) in a month after injection. A significant weight loss occurred only in Nthy/V600E-injected group at the end-point of experiments (Mean with SD; 29.49 ± 2.8 vs 27.79 ± 3.2, n = 11, p = 0.0038). As a result of an end-point autopsy, metastasis to the right axillary lymph node was found in about 63.6% of Nthy/V600E-injected mice (n = 11). Our data show that expression of BRAF^V600E enable a normal human thyroid cell line to form a tumor and spread to a lymph node in a mouse xenograft model. It suggests that BRAF^V600E plays a crucial role in a tumor initiation and explains a poor prognosis of BRAF^V600E-positive human thyroid carcinomas. This mouse xenograft model using Nthy/V600E would be able to contribute to further studies on BRAF^V600E-initiated thyroid cancers.

Mutations are fundamental to thyroid tumorigenesis, the biological consequences of each specific mutation varies across a spectrum from strong, highly predictive of cancer (BRAF V600E), to low drivers being present in both benign and malignant states (RAS, PAX8/PPAR). Thyroid cancer itself is biologically heterogeneous making a mutational only approach less efficient in risk stratifying indeterminate nodules. Here we report on an expansion panel of mutations and RNA fusions designed to work in concert with a complementary microRNA (miRNA) profiling assay, which together enable a greater understanding of the role of low driver mutational states without diminishing rule in and rule out diagnostic and predictive testing properties. Mutational analysis was carried out using our expanded oncogene panel. In combinations with our miRNA classifier to further characterize the malignancy risk for individual thyroid nodules. Clinical validation was performed by blinded review of molecular results of 73 needle aspirates from nodules with known surgical pathology outcome. From the combination of both test results, risk of malignancy to individual specimens, for the combined test were determined. At 24% thyroid cancer prevalence, combination testing showed 92% negative predictive value and 100% positive predictive value for subset of thyroid nodules with no detectable mutational change, low mutational drivers and strong drivers. miRNA profiling effectively detected malignancy is a subset of nodules lacking detectable mutational change and low driver states thus both ruling in and ruling out cancer where currently such binary prediction is not possible. Clinical performance of combined testing was superior to mutational analysis or RNA classifier determination performed alone. Furthermore, the % malignancy risk was accurately predicted for all individual indeterminate thyroid nodules. The combination testing approach, employing miRNA to independently predict risk of malignancy, maintained highest performance in ruling out cancer in low risk nodules and ruling in cancer in high risk thyroid nodules including those with no detectable or low driver mutations, thereby optimizing clinical decision making.

Mutational analysis is an important component source of diagnostic and predictive information for resolving cytologic indeterminate thyroid nodules accomplished most comprehensively by next generation sequencing (NGS). Technical hurdles can arise requiring novel solutions when expanding the existing scope and number of mutations and fusions detected, especially when starting material is limited in both quality and quantity. We recently expanded the mutation detection and RNA fusions tested as of our combination testing approach and here we describe critical issues that had to be addressed to maintain highest accuracy and analytic sensitivity of the sequencing results.

An existing platform of DNA mutations and RNA fusions (ThyGenX) was expanded to include additional DNA oncogene point mutations (RET, ALK, PTEN, PNAS, GNAS), TERT promoter mutations (GC rich segment) and 32 RNA oncogenic fusions (BRAF, NTRK, THADA, ALK, TERT and other fusion families) reported in thyroid cancer. High GC molecular targets were separately amplified and merged into overall library prep thereby removing potential amplification bias. Validation of the NGS results of the expanded panel, ThyGeNEXT, using 162 patient samples showed 100% concordance with ThyGenX test results. In addition, in 17 of these samples (∼10%), we were able to detect alterations specific to ThyGenNEXT: TERT and RET DNA mutations, and THADA fusions. Precision and reproducibility of detection (CV) for the DNA markers was found to be within 1-12%, and 100% for RNA fusions on yes/no basis. Lower limit of detection (LLD) for the DNA markers was 2% VAF, and about 300 copies of RNA fusions (∼2% TBP) for most of the fusion transcripts.

Critical modifications to library prep proved sufficient to expand DNA and RNA based mutational analysis without compromising molecular testing performance, analytic sensitivity for mutation detection (2%) or depth of sequencing. Separate handling of G/C rich sequence targets was crucial in achieving these goals, which maintained diagnostic and prognostic characteristics of this test.

Tall cell variant papillary thyroid carcinoma (TCPTC) is reportedly associated with aggressive clinicopathological parameters and poor outcomes; however, the molecular mechanisms underlying TCPTC remain poorly understood. We aimed to clarify the molecular alterations and identify novel diagnostic biomarkers for TCPTC. The gene mutation types and mRNA expression profiles of patients with TCPTC were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified. Pathways in the interaction network and the diagnostic approaches of candidate markers for TCPTC were investigated.BRAF mutation was particularly prevalent in TCPTC with a mutation frequency of 78%. TCPTC was associated with a patient age >45 years, tumor multifocality, extrathyroidal extension, a higher T stage, advanced AJCC TNM stages, BRAF V600E mutation, and poor disease-free survival. We identified 4138 TCPTC-related DEGs and 301 TCPTC-specific DEGs. Intriguingly, the gene expression pattern revealed that the dysregulated levels of both putative oncogenes and tumor suppressors in TCPTC were higher than those in classical/conventional variant PTC (cPTC). Functional enrichment analyses revealed that these DEGs were involved in several cancer-related pathways, including the PI3K-Akt and MAPK signaling pathways. A protein-protein interaction (PPI) network was constructed from the 301 TCPTC-specific DEGs, and 3 subnetworks, and 8 hub genes were verified. Receiver operating characteristic (ROC) analyses revealed that 6 hub genes, including COL5A1, COL1A1, COL10A1, COL11A1, CCL20 and CXCL5, could be used not only for the differential diagnosis of PTC from normal samples, but also for the differential diagnosis of TCPTC from cPTC samples. Our study might provide further insights into the investigations of the tumorigenesis mechanism of TCPTC and assists in the discovery of novel candidate diagnostic markers for TCPTC.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and its incidence has increased over the last few decades. The molecular mechanisms underlying PTC tumorigenesis and progression are still unclear.miRNAs expression patterns of PTC were revealed by miRNA mircroarray analysis and validated with the TCGA data. Promoter DNA methylation rates of miR-204 were analyzed by Sequenom Methylation MassArray analysis and validated with TCGA data. The underlying molecular mechanisms of miR-204 involved in PTC were studied by bioinformatics analyses. A total of 181 differentially expressed miRNAs (89 downregulated and 92 upregulated miRNAs) between PTC and normal tissues were detected in this study. We identified miR-204 as one of the most significantly downregulated microRNAs in PTC. Downregulation of miR-204 was related to PTC extrathyroidal extension, higher T stage, lymph metastasis, BRAF V600E mutation and more aggressive tall cell variant. Sequenom MassArray results indicate that most of the CpG sites located at the promoter of miR-204 were hypermethylated in PTC tissues compared with normal tissues. The promoter methylation rates of miR-204 in PTC were negatively correlated with the expression levels of miR-204 and its host gene Transient Receptor Potential Cation Channel Subfamily M Member 3 (TRPM3). Downregulated miR-204 expression was related with a series of significant pathways and mechanisms involved in tumorigenesis and progression. Promoter DNA methylation-silenced miR-204 could be served as a potential biomarker in PTC diagnosis. Downregulation of miR-204 may play an important role in PTC via the involvement in many tumor-related pathways. Novel target genes and putative mechanism of miR-204 in PTC need to be further validated.

The incidence of papillary thyroid carcinoma (PTC) is increasing globally. While the majority of patients with PTCs have an excellent prognosis, select patients present with more aggressive disease. These cases of PTC are associated with genomic alterations. However, little is known about the role of DNA methylation abnormalities in these PTCs.

In order to address this, we profiled the DNA methylome of 20 formalin-fixed paraffin-embedded PTCs comprised of high (HR) (stage IV) (n = 14) and low risk (stages I/II) (LR) (n = 6) disease. Supervised analysis was performed between the groups, followed by gene ontology (GO) and motif analyses of probe-related genes/regions.

In relation to the LR group, the HR PTCs presented 246 differentially methylated CpG probes (DMPs) (118 hypermethylated and 128 hypomethylated), distributed across CpG islands (CGI) (n = 21, 9%), shores (Sh) (n = 52, 21%) and intergenic/open sea regions (OpS) (n = 173, 70%). The nearest genes associated with the hypermethylated CGI/Sh DMPs were enriched for pathways related to response to stress, brain development and Rap-1 signaling, involved in metastasis of several cancers, while hypomethylated Sh/OpS genes were enriched for amine response and IL-12 signaling pathways. DMP located in the OpS regions overlapped with 151 predicted enhancers, known to be active. Hypomethylated enhancers were enriched for bZIP motifs, binding sites for AP-1 complex - Fra1, Fra2, Fosl2, JunB (p < 0.0001), which have been shown to be involved in tumorigenesis/progression in cancer. Our results suggest that distinct DNA methylation patterns in promoter and non-promoter regions are associated with genes/pathways involved in cell migration and invasion and cancer growth (e.g. Rap-1, AP-1) and novel pathways.

These results bolster the hypothesis that DNA methylation participate in the regulatory control of PTC aggressiveness. Further validation of these findings may also offer opportunities to develop drugs targeting PTC growth and recurrence.

The better biological behavior of papillary thyroid cancer (PTC) may relate to its immunogenicity. Here we explore the expression of potential tumor antigen in papillary thyroid carcinoma by both transcriptome sequencing and mass spectrometry.

The tumor tissues and corresponding thyroid tissues from 10 patients with pathologically confirmed PTC were obtained for transcriptome sequencing on Illumina Hiseq platform. Data Independent Acquisition method of mass spectrometry was performed of tumor tissues and adjacent tissues from 17 patients with PTC. Differentially expressed proteins and their genes that were consistently differentially expressed were analyzed. Neoantigens were analyzed by combining the somatic mutations and gene fusions of tumor tissue with the corresponding HLA allele results from transcriptome sequencing by netMHCpan method.

When the criterion of differential expression was |log₂FoldChange|≥1 and Padj ≤0.05, there were 26 high-expressed molecules and 8 low-expressed molecules in tumor tissues by combining transcriptome sequencing and mass spectrometry. When the criterion of differential expression was |log₂FoldChange| ≥ 2 and Padj ≤ 0.05, the expression of FN1, THBS1, POSTN, ANXA1, PDLIM4, PROS1, MFGE8 and VCAN were higher in tumor tissue than in adjacent tissue by both transcriptome sequencing and mass spectrometry. Two nonamer epitopes, KSAELSPFL (KSR1-LGALS9) and RASCQLTVL (FARSA-SYCE2), were predicted and filtered out by genetic fusion data. Three nonamer epitopes were filtered out by genetic variation data: LAHPGFFYF (P4HA1), KTYERLFYM (PHLDB3), LLYSNGYNY (IGKV2(D)-28).

The expression of FN1, THBS1, POSTN, ANXA1, PDLIM4, PROS1, MFGE8 and VCAN were higher in tumor tissues by combining transcriptome sequencing and mass spectrometry, they may contribute to the development of PTC. KSAELSPFL (KSR1-LGALS9), RASCQLTVL (FARSA-SYCE2), LAHPGFFYF (P4HA1), KTYERLFYM (PHLDB3) and LLYSNGYNY (IGKV2(D)-28) have their own HLA class I restrictions, and they may be immunogenic enough for further study.

There is an urgent need for the development of effective targeted therapies for advanced thyroid cancer. While our lab has shown Src is a key mediator of growth, invasion and metastasis in thyroid cancer, single-agent inhibitors targeting Src have had limited efficacy in solid tumors. We recently reported that combined Src and MAPK inhibition results in synergistic inhibition of growth and increased apoptosis in BRAF- and RAS-mutant cells, while PIK3CA-mutant cells are resistant (Beadnell et al 2016; 2018). Using an unbiased proteomics approach, we identified a previously unrecognized regulation of the PI3K/AKT pathway by Src in thyroid cancer, and that combined inhibition of Src and MEK1/2 promotes growth arrest and apoptosis through the inhibition of Src, MAPK, and PI3K/AKT. Here, we have further delineated the mechanism(s) of synergy, and the molecular mechanisms of apoptosis in this response. Western blotting was performed on BRAF- (BCPAP, SW1736), RAS- (Cal62, C643), or PIK3CA-mutant (T238, TCO1) thyroid cancer cell lines treated with the Src inhibitor, dasatinib, combined with the MEK1/2 inhibitor, trametinib. Growth and apoptosis assays were performed on cells ectopically expressing a constitutively active AKT (myr-AKT) or empty vector. We show BRAF- and RAS-mutant cell lines exhibit a 4- to 6-fold induction of apoptosis in response to Src/MEK inhibition, which correlates with a 6- to 12-fold induction of the pro-apoptotic protein, BIM. As expected induction of BIM was not observed in PIK3CA-mutant cell lines. Ectopic expression of myr-AKT nearly abrogated the apoptotic response driven by Src/MEK inhibition in BCPAP cells compared to empty vector expressing cells (p < 0.02), and blocked inhibition of pAKT and induction of BIM. Finally, myr-AKT promoted resistance to growth arrest in response to combined Src/MEK inhibition by >300-fold in the BCPAP cells (EV IC50 0.05nM; myr-AKT IC50 18 nM). Combined inhibition of Src and MEK1/2 promotes growth arrest and apoptosis through the inhibition of three key signaling nodes: Src/FAK, MAPK, and PI3K/AKT, and induction of BIM is important for the apoptotic response of combined Src and MEK inhibition.

In recent years, it was shown that high nitrates concentration in drinking water (NCDW) increased carcinogenic effect of thyroid irradiation in children of Belarus after Chornobyl. We compared the incidence rate (IR) of pediatric thyroid cancer (PedTC) and NCDW among irradiated (born before Chornobyl) and unirradiated (born after Chornobyl) persons aged up to 18 years at surgery in different regions of Ukraine. Patients with PedTC from the Clinical-morphological register of post-Chornobyl thyroid cancer (395 potentially radiogenic and 188 sporadic) were selected from three northern Ukrainian regions (NUR) and three southern ones (SUR). The IR of PedTC in irradiated groups was significantly higher in NUR than in SUR (p < 0.001), which was associated with higher ¹³¹I thyroid doses in NUR (from 58 mGy in Chernihiv to 87 mGy in Zhytomyr region) than in SUR (<15 mGy in every region). Certain influence of NCDW on the IR of PedTC was observed in both NRU and SRU. In Chernihiv region (NUR) with lower ¹³¹I thyroid dose, but with high NCDW (174 mg/l), the IR (3.64) was higher than in Zhytomyr region (2.74) with higher ¹³¹I thyroid dose, but lower NCDW (39 mg/l). In Kherson region (SUR), with low ¹³¹I thyroid dose (14 mGy), but with a high NCDW (163 mg/l), the IR (0.96) was higher than in Zaporizhzhya region (0.35) with the same ¹³¹I thyroid dose (11 mGy), but lower NCDW (75 mg/l). In persons born after Chornobyl, there were no significant differences in the IR of PedTC, both in NRU and SRU.

The high NCDW could increase the carcinogenic effect of ¹³¹I due to Chornobyl, both in most and least contaminated regions, which indicates the need to continue studies of combined effect of radiation and nitrates on thyroid carcinogenesis.

Yearly incidence of thyroid cancer has nearly tripled in the past four decades, due to improvement and better use of diagnostic proceedings, which allows to detect tumors of smaller size, such as papillary microcarcinoma (MPC), defined as equal or less than 10 mm.

The aim of our study was to validate the increasing incidence rate, to describe the characteristics and the circumstances of discovery of MPC, based on the Marne-Ardennes thyroid cancer register, from 1975 to 2014. Our observational, descriptive, historical cohort study is based on data from the specialized thyroid cancer register, which includes all subjects living in the Marne or Ardennes French departments, who were diagnosed with thyroid cancer between 1975 and 2014. 2671 patients with thyroid cancer between 1975 and 2014 were included, whose 966 (36.2%) were MPC. This percentage increases from 18.9% to 45.1% between the 1975-1984 period and the 2005-2014 period.

Standardized incidence rates per 100,000 PY increased from 0.86 to 6.20 between the 1975-1984 period and the 2005-2014 period. Incidence was higher in women (1.15 in 1975-1984; 8.91 in 2005-2014) then in men (0.20 in 1975-1984; 2.54 in 2005-2014).

Incidence rates increased more in ≥50 year-old people (from 0.41 in 1975-1984; to 4.21 in 2005-2014) then in <50 (0.45 in 1975-1984; to 1.99 in 2005-2014). Most of MPC (80.4%) were incidentally discovered on histological examination. They were mainly unifocal (79.4%).

There tumors were associated with excellent morbidity and survival rate: there were few evolutive events (1.9%); no patient died from MPC (91 deaths due to other cause). Our retrospective study demonstrates a large rise in the incidence of MPC. Most of MPC were incidentally discovered on histological examination in the context of surgery for benign pathology. Changes in access to health care, and physician's and pathologists' practices are likely explanations of our results.

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C cells, which may occur in the hereditary form (20-30%), as part of multiple endocrine neoplasia type 2 (MEN 2) syndrome, or as sporadic form (70-80%). The development of both sporadic and hereditary MTC cases have been associated with mutations in the RET gene. Clinical heterogeneity observed within and among families with same RET point mutation, or even absence of RET mutation in some sporadic cases, suggests that additional genetic event might be involved in the tumorigenesis of MTC. Somatic copy-number alterations (SCNAs) are an important type of structural variation that might be associated with tumor pathogenesis. In this study, we sought to investigate whether CNA might be related with the pathogenesis of MTCThree frozen MTC samples (cases) were compared to their respective paired blood sample (control) using SNP Array and analyzed by PennCNV and Genotyping Console software. To evaluate whether the selected CAN were functional, their expression was assessed in a series of paraffin embedded MTC. mRNA expression was evaluated by qPCR in 10 MTC sample and protein expression was evaluated by immunohistochemistry in 27 MTC samplesGenome wide analysis identified over 80 CNAs. To identify CNAs that are more likely associated with a tumor phenotype, we selected those CNAs that were found in at least 2 cases (out of 3 total cases) but absent in controls. We identified seven focal regions that met these criteria. Validation analysis confirmed that two genes located at 14q32.2 and 22q11.21 chromosome regions, which were mapped within CNAs, presented copy number gain (p < 0.0001). Moreover, qPCR analysis showed that both genes were overexpressed in MTC samples when compared to blood samples (p < 0.0001). Immunohistochemistry analysis confirmed their overexpression in most MTC samples, while its expression was not detected in normal thyroid tissueThis study identified two copy number gains involving genes that are likely functional might be involved in the pathogenesis of MTC

Hereditary medullary thyroid carcinoma (MTC) represents 25% of all MTC and is associated with an autosomal dominant mutation of RET gene. Other endocrine neoplasia are usually associated with MTC giving origin to different phenotypes: Multiple Endocrine Neoplasia type 2A (MEN2A) with pheocromocytoma (PHEO) and parathyroid adenomas, MEN2B with PHEO and marfanoid habitus and an isolated familial form of MTC (FMTC). So far the MEN2A has been considered the most prevalent form.

Aim of this study was to evaluate the prevalence of the 3 phenotypes of MEN2 syndromes after the introduction of the RET genetic screening; we also evaluated the correlation between phenotype, genotype and onset modality of MTC. Clinical, biochemical and genetic data of MTC patients belonging to 165 RET positive families were analysed.

We distinguished 112 FMTC families (68%), 40 MEN2A (24%) and 13 MEN2B (8%): this prevalence was significantly different from that reported in the literature. Eighty-six/165 (52%) families were diagnosed as hereditary with the RET genetic screening since their index cases, although “apparently sporadic”, carried a RET germline mutation. The mean age at diagnosis of the “apparently sporadic” index cases (IC), of their affected family members (AFM) and their gene carriers (GC) was 48.3 + 12.4yrs, 46.3 + 17.9yrs and 35 + 16yrs respectively. At variance, the mean age of the familial IC, of their AFM and their GC was 31 + 14yrs, 31 + 17yrs and 18 + 9yrs, respectively. We confirmed that MEN2B patients have a worse prognosis than those with MEN2A or FMTC. A worse prognosis was also found to be associated with RET highest/high risk mutations, that are associated with MEN2A phenotype. At variance, no difference of the outcome was observed in IC and their AFM diagnosed as hereditary with the RET genetic screening respect to those presenting as familial.

In conclusion, the introduction of the RET genetic screening in the diagnostic workflow of MTC cases allowed to identify hereditary syndromes apparently sporadic at diagnosis determining a significant increase of the prevalence of FMTC phenotype compared to the others (MEN2A and 2B), however the late diagnosis did not affect the outcome of this subgroup of MTC patients.

Thyroid cancer incidence, especially papillary carcinoma (PTC), has increased worldwide during the last decade. Ecuador presents the highest incidence among Latin American countries and the world. Molecular studies report that BRAF oncogene mutations are involved in the carcinogenesis and prognosis of PTC. The aim of this study was to determine the prevalence of the BRAF^V600E mutation in PTC patients from the northern Ecuadorian Andes.169 tumors were classified according to the TNM system (AJCC 7th edition) and the patients were managed based on the 2015 ATA guidelines from June 2014 to December 2017 in Hospital Eugenio Espejo in Quito-Ecuador. PTC genomic DNA from FFPE tissue were analyzed for exon 15 of the BRAF oncogene by Sanger Sequencing.BRAF^V600E mutation was found in 128/169 (75.6%). The BRAF codon 600 status was related to clinical-pathological characteristics as sex, age, family history, BMI, geographical area of residence, tumor size, PTC variant, extrathyroidal extension, focality, capsular and vascular invasion, lymphatic and distant metastases. BRAF^V600E showed a significant correlation with BMI >30 (32.1%, p = 0.03), tumor size >10mm (66.3%, p = 0.037) and Hashimoto's thyroiditis (10%, p = 0.03).

Although the increase in TC is currently attributed to the overdiagnosis (lesions <10mm), in the present investigation, tumors larger than 10mm were significantly correlated with the BRAF^V600E mutation. The high prevalence (75.6%) of the mutation in this particular Ecuadorian studied population versus other published worldwide series draws attention. The majority of patients (58.6%) comes from the northern region of Ecuadorian Andes where certain environmental characteristics (average altitude >2000 masl and constant exposure to volcanic ash) could impact in the higher incidence of PTC with BRAF mutation. Environmental factors as altitude and volcanic ash content may be related with higher mutation prevalence of BRAF oncogene in PTC patients from northern Ecuadorian Andes.

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, making up about 85% of the cases. Although in recent years several genes (e.g. BRAF, RAS, RET/PTC, TERT) have been demonstrated to play crucial roles in PTC, the molecular basis of carcinogenesis is not well understood. Using a bioinformatics tool, we investigated, through a network unbiased approach, the genes and pathways involved in this complex landscape. We exploited SWItchMiner (SWIM) software to analyze gene expression profiles available on The Cancer Genome Atlas. SWIM is able to identify a small pool of regulatory genes (switch genes), which are likely to be critically associated with drastic changes in cell phenotypes. We built networks based on switch genes (nodes) and their correlation value > |0.7| (connection). Finally, we selected those genes that were present only in the tumor or in the normal network. Comparing RNA-sequencing data between thyroid cancers and thyroid normal tissue samples, we identified 131 switch genes out of 1718 differentially expressed genes. We selected forty of them: four were present only in normal network while the others 36 in cancer network. Most of the selected genes are involved in cAMP-dependent pathway and phospholipase C signaling, and suggest a potential inhibition of the former and activation of the latter, with a release of Ca(2+) from the endoplasmic reticulum into the cytoplasm. Moreover, there was an over-expression of genes promoting cellular cycle, NFkB and Wnt/bcatenin pathways and a down-regulation of genes involved in apoptosis and in the non-homologous end joining. Genes involved in metabolism suggest an increase in glycine and lipid synthesis, with an increase in the storage of the latter in lipid drops. Network analysis may provide an additional approach to explore the molecular basis of cancer and to select the main mechanisms involved in carcinogenesis. Although the data obtained need to be validated by vitro experiments, they may result in significant progress in diagnosis, prognosis and therapy of PTC.

Anaplastic thyroid carcinoma is a rare but aggressive cancer. Recurrently, there was lack of effective treatment options. Immune checkpoint inhibitors, like Anti-programmed cell death ligand 1 (PD-L1) have recently proved to be effective in some cancer, like lung, melanoma, and lymphoma. The role of Anti-PD-L1 on ATC is still understudied. In this study, we examined the prevalence of PD-L1 expression in the tumor cell in patients with ATC. We also correlated with pathological status, prognosis and outcome with PD-L1 expression. Slides from 17 patients who diagnosed with ATC by biopsy or surgical resection were retrieved. By using immuo-histo-chemical stain and Tumor Proportion Score, the PD-L1 expression on tumor cell was assessed. Positive on PD-L1 expression was defined as TPS >1% and high PD-L1 expression defined as TPS >50%. Findings of PD-L1 expression were correlated with clinicopathological profile and overall survival. Slides from 17 patients with median age of 80 at diagnosis were included. Median overall survival was 11 weeks. Median TPS was 60% (0-100%). and PD-L1 was positive in 15 patients (88.2%). Patients with positive PD-L1 had a poor overall survival (7 vs 178 weeks, p = 0.014) and tended to present with extra-thyroidal invasion, lymph node, and distant metastasis. Overall survival was also correlated to the degree of PD-L1 expression. (Negative vs. PD-L1 expression vs. high PDL1 expression: 178 vs. 15 vs. 7 weeks, p = 0.033)

The PD-L1 expression is prevalent in ATC tumor cell. The degree of expression correlated with aggressiveness of tumor in patients with ATC. Patients with PD-L1 positive ATC should be treated aggressively and clinical role of anti-PD-L1 should be further evaluated.

In recent years, there has been an increase in the development of assisted reproductive technologies and other reatments to overcome infertility, so there are now more women who use fertility drugs than in the past. Te use of fertility drugs that may cause alterations in endogenous hormones and multiple ovulations has raised concerns about the long-term safety of such medications. A lot of attention has focused on whether the use of fertility enhancing drugs can have an effect on malignancies associated with breast cancer, endometrial carcinoma, ovarian cancer, and cervical cancer. Several studies have investigated the relationship between the use of fertility drugs and thyroid cancer; however, their results have been contradictory. Terefore, we conducted a meta-analysis based on the current literature, and the results are reported in this study. To investigate the clinical signifcance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecifed fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a signifcant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35;95% confdence interval [CI] 1.12–1.64;P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12–1.88;P = 0.005). Afer pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61–1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. PTC is prone to metastasize to the cervical lymph nodes (LNs), especially to the central LNs; the incidence of cervical lymph node metastasis is 20–90%. Cervical lymph node metastasis, a common cause of relapse following surgical treatment, is associated with suboptimal surgical removal of these lymph nodes at the time of initial surgery. Although it is important to standardize the surgical removal of cervical lymph nodes, there is no clear consensus on this topic or regarding the indications for surgery. Clinicopathologic data from 829 patients (104 men and 725 women) with PTC, operated on by the same thyroid surgery team at the First Afliated Hospital of Harbin Medical University from January 2013 to May 2017, were analyzed.

Overall, 309 patients underwent total thyroidectomy with bilateral lymph node dissection, 488 underwent right thyroid lobe and isthmic resection with right central compartment lymph node dissection, and 32 underwent near-total thyroidectomy (ipsilateral thyroid lobectomy with contralateral near-total lobectomy) with bilateral lymph node dissection. The overall rate of central compartment lymph node metastasis was 43.5% (361/829), with right central compartment lymph node and RPELN metastasis rates of 35.5% (294/829) and 19.1% (158/829), respectively. Tumor size, number, invasion, and location, lymph node metastasis, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis were associated with RPELN in the univariate analysis, whereas age and sex were not. Multivariate analysis identifed tumors with a diameter ≥1 cm, multiple tumors, tumors located in the right lobe, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis as independent risk factors for RPELN metastasis. Lymph node dissection, including RPELN dissection, should be performed for patients with PTC with a tumor diameter ≥1 cm, multiple tumors, right-lobe tumors, right central compartment lymph node metastasis, or suspected lateral compartment lymph node metastasis.

Bone metastases (BM) are diagnosed clinically in 5-25% of patients with differentiated thyroid cancer (DTC). The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) attending a single medical center and to investigate variables predictive of better long-term outcomes. The Rabin Medical Center Thyroid Cancer Registry was searched for patients with BM from DTC. The cohort included 64 patients (48.4% female) diagnosed at mean age 62.1 ± 14.3 years. Mean primary tumor size was 41 ± 30 mm. Most patients (63%) were stage T3/T4; 45.5% had extrathyroidal extension; 38% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 40.6% and 32.8%, respectively, and intermediate/poorly differentiated carcinoma in 26.5%. Radioactive iodine was administered to 62 (96.9%) after thyroidectomy. BM were synchronous in 67.2%. Mean follow-up was 11 ± 9.6 (median 8) years from detection of DTC. The common sites of BM were spine (46.9% of patients), pelvis (37.5%), ribs (21.9%) and limbs (12.5%). After initial treatment 62/64 of patients (96.7%) had structural persistent DTC. At the last follow-up, structurally-progressive disease was documented in 57.8% of patients. Overall, 55.6% of patients had died, 71.43% of DTC. Improved outcomes in terms of survival and disease progression were associated with younger age, lower tumor stage, non-extra-thyroid extension, bone-only distant metastases, and non-spinal BM. Selected patients with DTC and BM may achieve fair long-term outcomes. Novel therapies might be necessary in a significant proportion of these patients, and the reported prognostic factors can aid in their identification.

The response to therapy assessment tool is well validated for patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioiodine, but limited data is available for patients treated with lobectomy. The main limiting factor is thyroglobulin (Tg) produced by the remaining lobe, and the lack of data on normal ranges of thyroglobulin in this scenario. Our objective was to define normal range of Tg after lobectomy, with subgroup analysis for Hashimoto's thyroiditis (HT), autoantibodies (TgAb), and contralateral nodules. We included patients from the Rabin Medical Center Thyroid Cancer Registry who had lobectomy for DTC, followed for >1 year without completion thyroidectomy, and who had sufficient data on Tg and TgAb levels. One-hundred seventeen patients met inclusion criteria. Age at diagnosis was 49.6 ± 15 year, and 86% were women. Lobectomy was performed for classic papillary thyroid cancer (PTC) in 68% and for follicular variant PTC in 32%, with tumor size of 9.1 ± 5mm. Following thyroidectomy, Tg levels were 10.8 ± 13ng/ml (median 8.6ng/ml), excluding one patient with Tg of 1,041ng/ml (found benign after completion). Of 36 patients with HT, 50% had positive TgAb with titers of 285 ± 410IU/mL, and 50% had no TgAb, with Tg levels of 9.9 ± 5 ng/ml. In 19 patients with contralateral nodule ≥1cm, Tg was 17.7 ± 23 ng/ml. During the first two years of follow up, Tg declined ≥1 ng/ml in 40% of patients (by 7 ± 6.7 ng/ml), remained stable in 20%, and increased in 40% (by 8 ± 8.9 ng/ml). During 71 ± 41.1 months of follow-up, 10 patients had completion thyroidectomy and five were diagnosed with contralateral cancer (n = 3) or lymph node metastases (n = 2). All recurrent disease was diagnosed using ultrasound. Of these five cases, there was a steady rise in Tg in two cases, Tg was stable in two cases, and in one case TgAb decreased from 1534 to 276 in the presence of a new LN metastasis. Analyzing the whole cohort, basal Tg and Tg change did not predict disease recurrence. Thyroglobulin used independently is of limited value to predict or detect locoregional recurrence following lobectomy. Other potential roles of Tg, such as exclusion of distant metastases following lobectomy should be further studied.

Cervical lymph node (CLN) metastases (mets) from differentiated thyroid cancer (DTC) do not always correlate with specific clinical or pathological features of the primary tumor. In a retrospective study, we examined clinical and pathological features of patients (pts) with DTC diagnosed at Houston Methodist Hospital between 2006 and 2018. Based on existing literature, we hypothesized that the presence of CLN mets would correlate with tumor size and multicentricity. We compared three groups: patients with pathologically confirmed CLN mets (N1); patients with no mets in CLN (N0); and patients in whom no lymph nodes were resected (Nx). There were 72 pts in N1; 85 pts in N0; and 74 pts in Nx. Mean age (yr +/-SD) for pts in N1 (44.0 + 16.7) was significantly lower than that in N0 (47.9 + 14.6) or Nx (50.6 + 13.9). 92% were papillary thyroid carcinoma; 8% were follicular thyroid carcinoma.N1 pts were significantly younger than Nx pts but N0 was not different than N1 or Nx. ANOVA analysis did not find any differences among the groups in gender or tumor type. Significant differences among groups were present for tumor size (p < 0.001), multicentricity (p < 0.004), AJCC Stage (p < 0.001), and the presence of thyroglobulin autoantibodies (TgAb) (p < 0.003). N1 pts had a higher incidence of TgAb compared to N0 and Nx, but there was no difference between N0 and Nx. N1 pts had significantly larger tumors compared to N0 and Nx, but there was no difference between N0 and Nx. Finally, N1 pts had a significantly higher incidence of multicentricity than N0 or Nx with no difference between N0 and Nx. There is a high correlation of clinical features between the N0 and Nx groups. We conclude that larger or multiple primary tumors increase the likelihood of CLN mets. We suggest that increased vigilance for CLN mets is appropriate in larger tumors, in multicentric tumors, and in patients with elevated TgAb. Furthermore, Nx pts are very similar to N0 pts and could be managed as if they were N0.

Thyrotoxic Periodic Paralysis (TPP) is an alarming complication of hyperthyroidism characterized by muscle paralysis and hypokalemia due to intracellular shift of potassium. TPP mainly affects male patients of Asian descent. Some TPP patients do not have obvious symptoms or signs of hyperthyroidism. We describe here a case of TPP in the setting of Graves' disease.

This is a 39-year-old Vietnamese male who presented with palpitations and weight loss despite good appetite in the setting of tachycardia, lid lag and tremors. His brother had Graves' and his mother had hyperthyroidism. He had a suppressed TSH <0.01 uIU/ml, elevated fT4 and fT3 at 3.5 ng/dL and 4.4 ng/dL respectively as well as an elevated TSI at 168%, normal <140%, confirming Graves' disease. He was started on propranolol. He refused methimazole and RAI ablation. Five months after his diagnosis, the patient reported an episode, upon awakening, of total body paralysis more severe in the lower extremities and lasted three hours in the setting of persistent hyperthyroidism. Serum potassium was 3.7 mEq/L down from 4.7 about one month ago. He was diagnosed with TPP and advised to increase potassium in his diet and avoid carbohydrate rich food. No further episodes were reported.

Patients with TPP often experience the paralytic attack a few hours after a carbohydrate rich meal or in the early morning upon waking up. Paralysis after strenuous exercise is also a common presentation. TPP occurs only in the presence of hyperthyroidism and is abolished when thyroid hormone levels are normalized. TPP is characterized by hypokalemia which occurs due to a massive shift of potassium into muscle cells. Moreover, thyroid hormones can increase Na/K-ATPase activity in skeletal muscle, liver, and kidney to induce an influx of potassium into the intracellular space. Catecholamines and insulin can also increase Na/K-ATPase activity playing a role in the potassium shift. The mainstay of treatment includes replacing potassium carefully, beta blockade and, ultimately, definitive treatment of the hyperthyroidism.

In short, increased awareness among Physicians about TPP will result in early diagnosis, appropriate treatment, and the prevention of sequelae of this disorder.

Intra-operative frozen sections (FS) are often utilized on indeterminate thyroid nodules to determine if a lobectomy should be converted to a total thyroidectomy. We seek to examine how intra-operative FS affects surgical decision making, and its correlation to ultra sound guided fine needle aspiration (USFNA) results in the age of molecular testing and the updated 2015 ATA Guidelines on Differentiated Thyroid Cancer. This was a retrospective review of all thyroid FS from 2012 - 2017 at a single tertiary care center. Patient demographics, complications, USFNA results, molecular testing results, FS diagnosis, and final diagnosis were recorded. Fisher's Exact tests were used for analysis.738 total patients had an intra-operative FS performed. Intra-operative management was affected by the FS 53 times (7.2%). An USFNA diagnosis of “suspicious for malignancy” significantly correlated with FS altering the operation (n = 17 out of 55, p = 0.0001). Molecular testing was sent on 92 USFNA specimens, 80 of which were deemed “suspicious.” Of those 80 patients FS affected the type of surgery performed 6 times (7.5%, p = 0.82). Of the 53 patients whose management was altered intra-operatively based on FS, 27 (51%) would not necessitate a completion thyroidectomy under the 2015 ATA guidelines based on final pathology. Intra-operative frozen sections rarely alter the pre-surgical plan. Molecular testing of indeterminate USFNA results does not appear to predict meaningful intra-operative FS results. Consistent with prior studies, an USFNA result of “suspicious for malignancy” did correlate with altered management and represents cases where FS can still be useful. Furthermore, the most recent 2015 ATA guidelines on differentiated thyroid cancer a reflect of a shift towards less aggressive surgical interventions to reduce morbidity. In approximately half of our historical cases where a lobectomy was converted to a total thyroidectomy based on the intra-op FS, the need for the completion thyroidectomy would now not necessarily be recommended.

The ultimate goal of thyroid nodule evaluation is to detect thyroid cancer. Clinical risk assessment, ultrasound (US) and US-guided fine needle aspiration biopsy (US-FNA) represent the primary tools for evaluation. Using the largest of its kind prospective cohort analysis of consecutive nodules, we sought to analyze the clinical landscape of nodule assessment and determine the relative impact of variables upon malignancy. From 1995-2017, demographic, sonographic, cytologic and histopathologic data were prospectively collected for all patients evaluated with US-FNA for a thyroid nodule ≥1cm. Descriptive statistics and malignancy risks were calculated. Mixed effect logistic regression was performed for all nodules, and also for those with atypical (AUS) or follicular neoplasm (SFN) cytology. We analyzed 20,001 nodules from 9,967 patients. Median age was 53 yrs (18-95 yrs), 8,372 (84%) patients were female, and median nodule size was 17mm (10-128 mm). Thyroid cancer was confirmed in 1,974 nodules (9.9%) from 1624 subjects (16.3%), of whom 87.4% had papillary thyroid carcinoma. For all nodules, multivariate regression analysis showed odds of cancer were increase for male sex (OR: 1.71 [1.48-1.98], p < 0.0001) and larger nodule size (OR: 1.30 [1.14-1.49] for 20-29mm, OR: 1.59 [1.34-1.88] for 30-39mm, OR: 1.72 [1.43-2.06] for ≥40mm, p < 0.0001 for all). In contrast, the risk of cancer was lower with increasing age (OR: 0.98 [0.97-0.98], p < 0.0001), >75% cystic component (OR: 0.20 [0.15-0.28], p < 0.0001), and when there were ≥4 nodules ≥10mm (OR: 0.19 [0.16-0.23], p < 0.0001). Thus, for example, cancer risk in a solitary solid ≥40mm nodule in a male <50 years old was 14/31 (45%) compared to 1/218 (0.46%) for a 10-19mm >75% cystic nodule in a multinodular gland (≥4 nodules) from a woman >50 years old (p < 0.0001). For nodules with AUS or SFN cytology that underwent resection, only younger age (OR: 0.99 [0.98-0.99], p = 0.03) and multinodularity (≥4 nodules; OR: 0.64 [0.43-0.95], p = 0.03) were significant predictors of malignancy. In this extensive analysis, we convey the landscape of thyroid nodular disease, and demonstrate the precise impact of clinical and US risk factors for predicting thyroid cancer.

Thyroidectomy is an accepted same day procedure. While risks of airway hematoma, hypocalcemia, and recurrent nerve injury cannot be eliminated, advances in monitoring and technique provide for an increasingly safe patient experience. The ATA Statement on Outpatient Thyroidectomy suggests guidelines for same day surgery which take into account eligibility criteria, patient risk factors, and discharge criteria; these can be adapted to create institution-specific guidelines. We retrospectively reviewed thyroidectomies performed by a single surgeon to determine eligible thyroidectomy patients for same day discharge. Currently, all patients at our institution stay overnight. Eighty-nine sequential adult patients undergoing hemi-thyroidectomy, total thyroidectomy, or completion thyroidectomy were reviewed from September 2017-February 2018, after a two-hour post-operative PTH lab draw was implemented for total and completion thyroidectomy patients. Charts were reviewed for demographic characteristics, comorbidities, as well as surgical sequelae of hematoma, hypocalcemia, and RLN injury. ATA pre-operative, peri-operative, and post-operative discharge criteria were used to determine patients fit for same day discharge, with a PTH value set at 15. Of the 89 patients reviewed in this time period, 76 (85%) met criteria for same day discharge. This included 48 total thyroidectomies and six completion thyroidectomies. No patients experienced hematoma, post-operative stridor, or need for return to the OR. Two RLNs were purposefully sacrificed for tumor invasion. Two patients (2%) had post-operative PTH values <15. Medical comorbidities determined ineligibility for same day discharge for nine additional patients: one had known RLN injury from prior anterior cervical discectomy and fusion, six patients had sleep apnea; one had liver failure and was on the liver transplant list; one was on Plavix. Thyroidectomy is a safe outpatient procedure. Risks of hematoma, hypocalcemia, and RLN injury are not higher with same day surgery. Approximately 85% of our patients who currently stay overnight are eligible for same day discharge. Now we aim to prospectively discharge patients according to our outlined criteria.

Bilateral axillo-breast approach (BABA) robotic thyroidectomy is a novel “scar-less” techniques in the US. Its efficacy for large goiter as well as advanced or metastatic thyroid cancers has been demonstrated in the literature. This study evaluates the initial experience of BABA technique for benign and malignant thyroid disease in the US. From June 2015 to October of 2017, BABA technique was performed in selected patients who were either prone to forming an undesirable scar or with a personal preference for avoiding a neck scar. Four 8mm remote incisions were utilized (periareolar and axillary skin fold). Endoscopic subplatysmal flap dissections were performed. Thyroidectomy and lymph node dissections were performed using the robotic platform. Intraoperative nerve monitoring was performed throughout the surgery. Patients were followed in 1 week and 4-6 months after the surgery. A series of 50 cases (26 hemithyroidectomies, 21 total thyroidectomies with central neck dissections when indicated, 1 lateral neck dissection, and 2 completion thyroidectomies) were performed. All patients were female with an average age of 37.8 (range 17-68) and median BMI of 25 (range 19-49). Indications for surgery were cancer (N = 11; 22%), Graves' disease (N = 9, 18%), toxic goiter (N = 5, 10%), symptomatic goiter or indeterminate nodule (N = 21, 42%). On pathology, average tumor size was 3.4cm (range 0.7-6.5), and chronic lymphocytic thyroiditis was present in 15 cases (30%). Average specimen weight for Graves' disease was 54.6gm (range 25-101). The median operative time was 250 minutes (range 192-420), and the median estimated blood loss was 20 ml (range 10-300). Mean length of stay was 0.5 days (Median 0; Range 0-3). Complications included transient vocal cord paresis with spontaneous recovery in <2 months (N = 2, 4%), transient hypoparathyroidism (N = 2, 1%), and neck seroma requiring needle aspiration (N = 2, 4%). There were no mortalities, postop hematomas, open conversions, infections, permanent hypoparathyroidism, or permanent recurrent nerve injury. BABA robotic thyroidectomy can be safely implemented in the US with excellent surgical and cosmetic outcomes in a selective group of patients with benign and malignant thyroid diseases.

Radioiodine refractory (RAI-R) thyroid cancer is uncommon, with an estimated incidence of 5% of patients with differentiated thyroid cancer (DTC). Outcomes vary among patients with RAI-R disease. In clinical trials of kinase inhibitors, more than half of refractory patients in the placebo arm showed disease progression, however, there were still 30-50% showed control disease, which means, without progression. The aim of this study is to evaluate the prognostic value of ¹⁸F-FDG PET/CT in the disease progression of patients with RAI-R thyroid cancer. We retrospectively reviewed 2329 DTC patients treated at our hospital from 1986 to 2014. About 10% (235 patients) of them had distant metastases in the initial diagnosis or during follow-up. Patients with distant metastases who had PET scan and confirmed having RAI-R disease were included into this study. Finally, 49 patients were included. Prognostic factor analysis included age, sex, histology, disease stage, initial ATA risk, lesion ¹⁸F-FDG avidity, lesion size, etc. The primary end-point was progression free survival less than 2 years after the ¹⁸F-FDG PET scan according to RECIST criteria. The average age at refractory disease confirmed was about 56 of age. The average interval from diagnosis of cancer to refractory disease were 7.2 years. Mean follow-up after ¹⁸F-FDG PET were 5.2 years. About 60 percents (22/49) of patients experienced disease progression less than 2 years after ¹⁸F-FDG PET.

Univariate analysis showed that initial advanced stage (stage III-IV), serum Tg level higher than 13.5ng/ml, lesion ¹⁸F-FDG uptake higher than SUVmax 4.5, age at refractory older than 55 of years were predictive factors of progression free survival less than 2 years. In multivariate analysis, only the lesion ¹⁸F-FDG uptake was independent factor to predict progression free survival less than 2 years. The ¹⁸F-FDG uptake of structural lesion is an independent prognostic factor to predict short-term disease progression. The results of this study may improve the selection of candidates for kinase inhibitors in patients with refractory thyroid cacner.

Laryngeal recurrent nerve and parathyroid gland injury are major complications following thyroidectomy. The bifurcation of laryngeal recurrent nerve and location of parathyroid gland may variate between individual patients. We seek to investigate the relationship of these anatomical variations and post-operative complications. A cohort of 50 consecutive patients planned for thyroidectomy were enrolled in this study. All surgeries were operated by an experienced endocrine surgeons. Recurrent laryngeal nerves were carefully dissected and exposed for the entire length. Parathyroid glands were carefully identified and preserved in situ if possible (otherwise we would perform auto-transplantation). Short term and long term post-operative complications such as harsh voice, muscle cramps and paresthesia were observed. Follow-up time was 6 months after surgery. A total of 84 recurrent laryngeal nerves were dissected (36 left and 48 right). 42 (50%) nerves bifurcated into at least 2 branches. No patients experienced post-operative complications related to recurrent laryngeal nerve injury. 168 parathyroid gland sites were explored and 152 glands (80 superior and 72 inferior) were successfully identified. Among them, superior parathyroid glands has a significantly higher rate of identification during surgery (95.2% vs 85.7%, p = 0.035), and a significantly lower rate of auto-transplantation (2.5% vs 20.8%, p < 0.01). However, short term post-operative complication rate was not different between the in situ preservation group and auto-tranplantation group (20.0% vs 22.2%, p = 0.84) and no patients suffered from long-term complications due to parathyroid gland injury at follow-up. Anatomical variations of recurrent laryngeal nerves and parathyroid glands are common and special attentions should be paid during thyroidectomy. However, post-operative complications were not increased due to nerve bifurcation or parathyroid gland auto-transplantation acording to our results. Novel techniques that help localizing and preserving the inferior parathyroid glands should be investigated.

ATC has poor prognosis with median OS of approximately 6 months. We previously reported high PD-1/PDL-1 staining in anaplastic thyroid cancer (ATC), raising the possibility of the productive application of the immunotherapeutic pembrolizumab in ATC. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg IV every 3 weeks, combined with chemoradiotherapy [docetaxel/doxorubicin, 15 mg/m² each IV weekly plus (neck/tumor bed) intensity modulated radiation therapy (IMRT)] was initiated as front-line therapy in ATC to assess efficacy and toxicities. Six-month overall survival (OS) was selected as the primary endpoint using a Simon's optimal design with interim analysis (target accrual 25 patients; Cohort A: prior resection Cohort B: no resection). Based upon historical patient cohort treated similarly, but without pembrolizumab, the design was such that, if 6 month true survival is 75%, the probability of declaring the trial worthy of further pursuit would be 91%. Three patients were enrolled; two with rapidly enlarging neck masses. Initial tumor response was favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation - one from tumor progression, and two experiencing infectious complications leading to their death. An unscheduled meeting with the involved Data Safety and Monitoring Board was undertaken, and study closure was recommended and implemented. Although initially well tolerated and effective in terms of locoregional control, disappointing survival outcomes compared to historical control and the unexpected occurrence of two deaths from complications other than tumor progression, limit our enthusiasm for study reactivation.

Differentiated thyroid cancer (DTC) has the fastest rising cancer incidence in the U.S., yet remains vastly underexplored in terms of quality of life and survivorship experiences. Favorable outcomes after diagnosis of high-risk DTC may be partly due to use of radioactive iodine (RAI) therapy. The range and impact of post-RAI side effects are not well documented. The purpose of this study was to identify the range of symptoms experienced by patients after RAI and use this information to develop a survey targeting this patient population. We used a mixed methods approach. First we conducted focus groups with patients diagnosed with DTC treated with RAI within the past 10 years. Trained facilitators guided participants' discussion. We audiotaped and transcribed discussions. Trained raters coded transcripts and identified themes for survey development. Then we conducted a pilot of the survey with patients diagnosed with DTC following RAI therapy. From the focus groups, we identified several themes that most impacted quality of life following RAI. These included salivary symptoms such as dry mouth, nasal symptoms such as burning, and eye symptoms such as tearing. Psychosocial factors such as uncertainty regarding the thyroid cancer diagnosis and unpreparedness for treatment were also prevalent. The pilot survey (n = 59) revealed that in this mostly female population (83.1%), the most frequently experienced symptoms were dental cavities (81.4%), dysgeusia (42.4%), dry eyes (35.6%), and salivary gland obstruction (30.5%). Other identified factors affecting quality of life included decreased sex drive (45.8%) and feeling uninformed regarding the side effects of RAI (61%). Patients with DTC treated with RAI reported a wide range of symptoms after treatment. Symptoms ranged from mild to burdensome. As most participants reported that they were unprepared for the range, type, or severity of symptoms, study findings have implications for patient-physician communication and treatment decision-making. Our targeted survey can be used to guide physicians and patients through the treatment process and will be prospectively observed and validated through objective measures in phase II of our study.

Thyroid nodules and thyroid cancer are among the extraintestinal manifestations of familial adenomatous polyposis (FAP), with prevalence of 35-80% and 3-12% respectively. Predominantly seen in females before age 28. The incidence of thyroid cancer, mainly the cribriform-morular variant of papillary carcinoma is higher in FAP patients than in the general population, however, routine thyroid cancer screening is not consistently performed by most providers for them.

Objective: To assess the frequency of thyroid cancer screening among patients with FAP and the prevalence of thyroid cancer among these patients.

Method: We performed a retrospective chart review of all adult patients with an ICD-9 and ICD-10 diagnostic code for FAP, between January 2000 and December 2016 at our center. Of the 5568 charts reviewed, 49 patients were identified with confirmed diagnosis of FAP based on colonoscopy and pathology report. Medical charts were reviewed and their demographics, clinical, histopathology, laboratory and imaging data were collected.

Of the 49 patients with FAP syndrome, 24 (49%) were female with mean age of 38 ± 16years. Only 12 patients (24.5%) had thyroid ultrasound performed, 8 of whom had thyroid nodules, size ranging from 0.3-2.0 cm, and all were female. 6 patients had fine needle aspiration and 1 patient had thyroid cancer. With limited data, our study showed decreased prevalence of thyroid cancer of 8%, when compared to some prior studies. Most adult FAP patients do not receive thyroid cancer screening. This may be due to lack of awareness of their medical providers on the increased incidence of thyroid cancer in FAP. Another reason may be lack of patient education on the importance of screening, as several patients had the study ordered but not completed. Every clinician managing FAP patients should be educated on the increased risk of thyroid cancer in FAP and the role of thyroid ultrasound screening for early detection of thyroid cancer.

Thyroid cancer screening is not recommended for asymptomatic adults by the US Preventive Task Force. However, the role of screening in selected populations, such as individuals with family history of thyroid cancer, remains to be elucidated. Starting from 2009, neck sonography screening was offered to the first-grade relatives of all patients with differentiated thyroid cancer (DTC) followed at the Thyroid Cancer Unit of Sapienza University of Rome. Cytology was performed in suspicious nodules according to the available guidelines. The rate of newly-diagnosed thyroid cancers (primary endpoint) and thyroid nodules (secondary endpoint) were stratified according to the number of DTC affected members in the kindred. Among 2287 individuals eligible for the screening, 1176 from 473 kindreds accepted the examination (age 41.7 [26.0-55.6] years, 652 females, 55.4%). Patients refusing the screening were older (54.2 [38.6-70.0], p < 0.0001) and more frequently males (54.7%, p < 0.0001).

Overall, 500 individuals with nodules were detected (42.5%) and 95 (19%) underwent fine-needle aspiration cytology. Twelve (1%) new cases of DTC were diagnosed: 7 in 346 kindreds with 1 known DTC case (2%), 2 in 103 kindreds with 2 DTC cases (1.9%), and 3 in 24 kindreds with ≥3 cases (12.5%). The OR for detection of DTC in kindreds with ≥3 cases was 6.98 (95%CI 1.76 – 27.71, p < 0.001). Younger age (<45 years) and/or multifocality in the index case did not increase the likelihood of new thyroid cancer detection. Thyroid nodule detection rate in the families with 1, 2, and ≥3 cases, was 62%, 75%, and 66.7%, respectively. In conclusion, the thyroid cancer detection rate is significantly higher in kindreds with at least 3 DTC cases, making this specific subgroup potentially eligible for a screening program. Whether such an approach improves health outcomes remains to be evaluated. Moreover, screening is likely to detect a large number of benign thyroid nodules, requiring long-term follow-up and additional diagnostic procedures.

Large population-based analyses of squamous-cell thyroid cancer (SCTC) are few. In this study, we investigated the prognosis of this rare neoplasm as compared to the common subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Information regarding patients with a diagnosis of PTC, FTC, or SCTC, between 2004 and 2013, was acquired from the Surveillance, Epidemiology, and End Results (SEER) database. Patient survival curves were assessed by Cox proportional hazards regression analyses, Kaplan-Meier analyses, and log-rank tests. On Kaplan-Meier analysis of the entire cohort of thyroid cancer patients, cancer-specific survival declined modestly in patients with PTC and FTC, but declined sharply in patients with SCTC. Unadjusted Cox regression analysis and Kaplan Meier curve analysis showed that SCTC had a poorer prognosis compared to PTC and FTC. Similar results were obtained after adjustments for different confounding factors. Our study, comprising a large cohort, assessed the prognosis of SCTC as compared to that of PTC and FTC, and found relatively accurate hazard ratios for the death rate due to SCTC as compared to PTC and FTC. This could aid in the development of evidence-based recommendations for informed clinical decision-making in the management of SCTC. Based on these findings, an aggressive treatment modality may be recommended for this rare subtype of thyroid cancer.

Insular thyroid cancer (ITC) is a relatively rare thyroid malignancy that has an unclear prognosis. Recent studies have indicated that watchful waiting is sufficient for younger patients with more differentiated thyroid lesions such as papillary thyroid microcarcinoma (PTMC). In this study, we investigated the prognosis of younger patients (<45 and <55 years old) with ITC and compared their outcomes to patients with PTMC and follicular thyroid microcarcinoma (FTMC). We hypothesized that ITC, like PTMC and FTMC, can be managed with active surveillance in younger patients with this disease. We investigated a large cohort of younger patients with ITC, PTMC, or FTMC who were listed in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for younger ITC patients (<45 and <55 years) was lower than that for PTMC and FTMC. Kaplan-Meier analyses revealed that the cancer-specific and all-cause mortality rates in younger ITC patients were similar to those of PTMC and FTMC. Similar results were obtained when cases with tumor extension were excluded from the analysis. The unanticipated excellent prognosis of younger patients with ITC challenges the current clinical practice of automatically treating this disease, and offers new implications for management such as pursuing active surveillance instead.

According to the surveillance, new cases of thyroid cancers in the young population have increased. The thyroid ultrasound screening for children aged 0-18 was performed in Fukushima after the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases in the young population have been found. To explore the carcinogenic mechanisms of the cancers, we analyzed their clinicopathological and genetic features. We analyzed 145 patients (53 males and 92 females) operated between 2013 and 2016 at Fukushima Medical University. The mean age at operation was 17.8 years old. The mean size of the tumors was 14.9mm. The majority of the patients (90%) were diagnosed as papillary thyroid cancer (classical type). We analyzed BRAF(V600E) mutation by direct DNA sequencing in 123 cases. The BRAF(V600E) mutation was observed in 71.5% of the thyroid cancers. On the contrary, the RET/PTC3 rearrangement was observed in 0.8%. The RET/PTC3 rearrangement has been found in pediatric post-Chernobyl thyroid cancer. However, the RET/PTC3 rearrangement with PTC was detected only 0.8% in our cases. The prevalence of the BRAF(V600E) mutation was comparable to Japanese adult sporadic cases, implying that the carcinogenesis mechanism may be similar between young population and adult papillary thyroid cancers.

Recently, the concept of natural orifice transluminal endoscopic surgery (NOTES) has been introduced to thyroid surgery. With this approach, an endoscope is passed through a natural orifice (e.g., the mouth) into an internal organ (e.g., the thyroid).We reviewed the medical records of 63 consecutive cases who underwent transoral endoscopic thyroidectomy via a trivestibular approach between July 2016 and May 2018 in our hospital. We performed 63 transoral endoscopic thyroid surgeries in 62 patients. The average tumor diameter was 1.23 cm (range: 0.3–7.5 cm). Postoperative pathology revealed PTC in 52 cases (82.5%), nodular hyperplasia in seven (11.1%), follicular carcinomas in two (3.2%), a follicular adenoma in one (1.6%) and a hyalinizing trabeculae tumor in one (1.6%). All surgical margins were negative. Two patients exhibited transient vocal cord palsy and recovered within 2 months. One patient who developed vocal cord palsy has not yet recovered for more than 3months. Five patients who underwent total thyroidectomy developed transient hypocalcemia, but recovered within 3 months. Four patients without drain developed seroma, but resolved after aspiration. No sensory change or facial weakness around the lower lip was reported by any patient. No patient developed a wound infection or fistula between the oral incision and anterior neck. The transoral endoscopic approach provides a short, direct route to the thyroid gland and seems to be safe and feasible. It is important to further develop and refine the surgical techniques. The approach is optimal, and will become widely used for thyroid surgery in the near future.

TORT through oral vestibule draws attention recently because it requires minimal flap dissection and postoperative scar disappears in several weeks. In this study, we evaluated surgical outcomes of TORT and compared them with those of bilateral axillo-breast approach robotic thyroidectomy (BABA RT) after propensity score matching. The medical reports were retrospectively reviewed. A propensity score matching analysis was done with seven covariates including age, gender, tumor size, extrathyroidal invasion, pathologic diagnosis, multiplicity and thyroiditis. Propensity score matching identified 92 pairs of patients. There were 87 and 85 females in BABA RT and TORT group, respectively. The mean tumor size was 1.1 and 1.0 cm for BABA RT and TORT group, respectively. Operation time for total thyroidectomy was shorter in TORT than BABA RT group (220.3 vs. 301.9 min, p = 0.023). Mean postoperative pain scores at operation day 0 and 1, and analgesic requirement were lower in TORT group. Hospital stay was shorter in TORT than BABA RT group. There were no significant differences between TORT and BABA RT group in transient vocal cord palsy rate (0% vs. 4.0%) and transient hypoparathyroidism rate (0% vs. 18.1%). TORT could be performed safely and showed comparable outcomes with BABA RT in selected patients. TORT might be an alternative approach for the patients who want scarless thyroidectomy.

Right paraesophageal lymph nodes are rare metastatic foci and are likely to be overlooked during first operation. This study aimed to determine the incidence, to identify the predictable factor of right paraesophageal lymph nodes metastasis. We conducted a retrospective review of 415 patients with papillary thyroid cancer who were dissected right paraesophageal lymph nodes in primary thyroidectomy from March 2007 to December 2017. The clinicopathologic results were analyzed for comparison between paraesophageal lymph nodes positive and negative groups. The incidence of right paraesophageal lymph nodes metastasis was 21.2%. Patients with right paraesophageal lymph nodes positive groups were associated with male, large tumor size, extrathyroid extension, lymphovascular invasion, perineural invasion, more than T3 stage and presence of metastatic lymph nodes in the right paratracheal lymph nodes in univariate analysis. A multivariate analysis revealed that the presence of metastatic lymph nodes in the right paratracheal lymph nodes was the only predictive factor for the presence of right paraesophageal lymph nodes metastasis. In more than three lymph node metastases in right paratracheal lymph nodes, the presence of metastasis in right paraesophageal lymph nodes metastasis was 46.2%. The metastases in right paraesophageal lymph nodes were not so rare for papillary thyroid cancer patient and skip metastasis can be occurred. Careful right paraesophageal lymph node dissection should be considered for patients who have presence of more than three metastatic nodes in right paratracheal lymph node.

In an ongoing multicenter prospective cohort study of active surveillance on low risk papillary thyroid microcarcinoma (PTMC), we aimed to compare the quality of life (QOL) of participants according to the choice of treatments; active surveillance (AS) and immediate surgery (OP).QOL was evaluated using validated Korean version of thyroid-specific QOL questionnaire at initial diagnosis and during follow-up in 203 participants with AS and 192 with OP. Score was 10-point scale, with 0 representing the worst possible and 10 representing the best possible QOL. Mean age was 47.3 ± 11.7 and 45.6 ± 10.5 years, and a mean tumor size was 5.7 ± 1.6 and 6.5 ± 2.1 mm in AS and OP group, respectively. Baseline psychological health was significantly better in AS than in OP group (7.1 ± 1.3 vs., 6.8 ± 1.7, respectively, p = 0.022), while physical and spiritual health scores were similar. During a mean follow-up period of 8.2 ± 4.6 months, change of average physical, psychological, and spiritual health was similar between AS and OP group. However, OP group experienced more fatigue, had more changed voice and appearance, felt less satisfied, while less fearful of recurrence than AS group. Self-assessed financial burden was similar at baseline and follow-up in both groups. In correlation analysis, the choice of treatment (AS or OP), age, sex, tumor size, and thyroid function was not related to the average scores of QOL. In OP group, there was positive correlation between psychological health and follow-up duration (r = 0.158, p = <0.001). In patients with low risk PTMC, baseline psychological health was better in AS than in OP group. However, overall changes of QOL was similar, except for QOL related to postoperative changes. Therefore, it is important to give patients detailed and precise information about their treatment options, because psychological health status at their diagnosis could affect decision making.

The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1-4 cm may be treated with lobectomy alone, a departure from the previous recommendation for total thyroidectomy. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy for low-risk DTC identified on initial lobectomy, and factors influencing surgical decision-making.

All patients from 2014-2017 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included in the study. Microcarcinomas <1 cm were excluded as updated guideline recommendations did not change for this group. Patients were divided into pre- and post-guideline cohorts (2014-2015 and 2016-2017, respectively). The rate of completion thyroidectomy was compared between the two cohorts. Patient demographics and tumor characteristics in each time period were examined for association with completion thyroidectomy.

A total of 226 underwent thyroid lobectomy for malignancy during the time period, and 130 patients met study criteria: 63 patients in the 2014-2015 (“pre”) and 67 in the 2016-2017 (“post”) group. In the “pre” period, 41 (65.1%) patients received completion thyroidectomy, compared to 35 (52.2%) in the “post” period (p = 0.157). In the “post” period, aggressive histology, lymphovascular invasion, extrathyroidal extension, and multifocality were associated with completion thyroidectomy (p < 0.05 for all). Gender, race, age, and tumor size did not affect decision to undergo completion thyroidectomy. Of low-risk patients with DTC between 1-4 cm in size, 17/35 (48.6%) received completion thyroidectomy in the “pre” period, compared to 12/41 (29.3%) in the post period, resulting in a 40% drop in the rate of completion surgery for this group (p = 0.10). The rate of completion thyroidectomy decreased by 40% for low-risk patients with DTC between 1-4 cm, demonstrating gradual adherence to the 2015 ATA guidelines. However, nearly one-third of these patients underwent completion thyroidectomy, suggesting additional factors influencing the decision for further treatment.

The prognostic effect of central compartment neck dissection (CCND) is still controversial in papillary thyroid carcinoma patients. In this study, we evaluated the prognostic value of central lymph node yield (LNY) and metastatic lymph node ratio (LNR) during CCND on the recurrence rate in papillary thyroid carcinoma patients. We retrospectively reviewed 1820 papillary thyroid carcinoma patients who underwent thyroidectomy with CCND between 2009 and 2012 at Seoul St. Mary's Hospital. The central LNY was separated into three groups (low: 1–5 nodes; medium: 6–15 nodes; high: 16+ nodes). The metastatic LNR was divided three groups (low: <0.3, medium: 0.3≤ <0.6, high: ≥0.6). We analyzed the correlation of central LNY, LNR and the recurrence rate. Of 1820 patients, 1498 patients were female and median age was 46 years. The median follow up period was 77 months [0-110]. The mean central LNY were 8.6 ± 6.2 per patient and mean LNR was 0.15 ± 0.24. The recurrent diseases were observed in 35(1.92%) cases. In multivariable analysis, patient's age, central LNY and LNR were associated with recurrence. In patients with high central LNY, the risk of recurrence was 1.21 times higher than that of patients with low central LNY (P = 0.009). Patients with high LNR showed 2.01 fold higher risk of recurrence than those with low LNR (P < 0.0001). The high central LNY and LNR is an independent predictive factor on the recurrence following thyroidectomy and CCND for papillary thyroid carcinoma.

Background: Our objective was to create a comprehensive THYROid Cancer REgistry (ThyroCARE) in an urban tertiary care hospital that serves a diverse, urban population of patients, many of whom are from minority and international backgrounds and low socioeconomic groups. ThyroCARE incorporates a comprehensive panel of recently recognized risk factors for tumor persistence and recurrence.

Methods: ThyroCARE was designed with the intent to capture both retrospective and prospective individual patient data at the Boston Medical Center (BMC). The registry resides in an easily accessible browser-based Research Electronic Data Capture (REDCAP) program. ThyroCARE contains up to 1100 discrete data points related to initial and ongoing patient management. This complex data are captured via individual record review rather than automatic electronic medical record extraction.

Results: In an IRB approved protocol, we enrolled 1,158 patients (78% female; 22% male) with thyroid cancer seen at BMC between January 2000 - May 2018 into ThyroCARE. Our diverse population is reflected by the demographics of ThyroCARE (62% Caucasian, 10% black, 13% Hispanic, 5% Asian, and 10% other), of which, 27% are foreign born. A difference in education was seen in the Caucasian (27% high school or less; 32.1% 2 or 4 year college degree; 20.4% graduate or profession degree) compared to the non-Caucasian group (60% high school or less; 14.0% 2 or 4 years college degree; 10.5% graduate or profession degree). Prior or current smoking was more often found in the Caucasian (45%) than in the non-Caucasian group (21.4%). The distribution of pathology within ThyroCARE is: papillary thyroid carcinoma (PTC) 92%, follicular variant of PTC 2.6%, follicular carcinoma 2.6%, Hurthle cell carcinoma 2.3%, and poorly differentiated carcinoma 0.7%.

Conclusions: We created a large comprehensive longitudinal thyroid cancer registry (ThyroCARE) based in an urban, academic center whose patients are racially, ethnically, and socioeconomically diverse. This registry should allow us to understand the importance of the many reported risk factors predicting tumor persistence and recurrence in this particularly underserved population.

Thyroid cancer is the most common type of endocrine malignancy adn papillary thyroid carcinoma comprises eighty percent of all thyroid cancer. Recent researches have explored controversial functions of PRDM16 gene in solid cancers. The study was performed retrospectively to investigate the role of positive regulatory domain containing 16 (PRDM16) in papillary thyroid cancer (PTC). Patients (n = 11 0) who underwent surgery and was pathologically confirmed as PTC at Fudan University Shanghai Cancer Center (FUSCC) were enrolled, and data from The Cancer Genome Atlas (TCGA) was identified as a validation cohort. We investigated PRDM16 mRNA expression in PTC tumor tissues and the adjacent normal tissues using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). We compared PRDM16 expression level of tumor tissue and paired normal tissue and analyzed the correlation of PRDM16 with clinicopathological features and BRAF^V600E mutation status. Human-derived normal thyroid epithelial cell line Nthy-ori 3-1 and human papillary thyroid cancer cell lines K1 and BCPAP were used to verify our findings. PRDM16 was significantly downregulated in PTC tumor tissues compared with the adjacent normal tissues (P < 0.001), as well as in K1 and BCPAP compared to Nthy-ori 3-1. Low PRDM16 expression level had a significant correlation with lymph node metastasis (LNM) and extrathyroidal extension (ETE) in both the FUSCC and TCGA cohorts. PRDM16 low expression was an independent risk factor for ETE in multivariate analysis. Besides, PRDM16 low expression was also associated with BRAF^V600E mutation status in the TCGA cohort. In conclusion, PRDM16 low expression was identified as a potential biomarker for aggressive behavior, especially for ETE in PTC and poor prognosis of PTC.

Implementation of survivorship care plans (SCPs) is in direct response to the Institute of Medicine's (2006) report From Cancer Patient to Cancer Survivor: Lost in Transition and accreditation requirements by the Commission on Cancer (CoC, 2016) for cancer centers to provide SCPs to 75% of eligible patients by 2018, with accreditation criteria revised December 2017 down to 50%. The primary objective of this study was to identify a systematic process for distributing SCPs to well-differentiated thyroid cancer patients through a nurse practitioner (NP) led survivorship clinic. The study setting was an ambulatory endocrinology practice at a tertiary care center in the Midwest. A quantitative convenience sample took place over six months (April 1-October 1, 2017). Eligibility criteria included patients ≥18 years with well-differentiated thyroid cancer and had completed curative intent therapy. Patients <18 years, non-English speaking, medullary/anaplastic thyroid cancer, or active/persistent disease were excluded. Of eligible patients (N = 174), 84% received a SCP at six months compared to 0% at baseline. As time has been noted to be a barrier in completing SCPs, time data was analyzed. Time to complete SCPs by a registered nurse/licensed practical nurse (n = 125) ranged from 7-45 minutes (M = 17.50, SD = 7.93, 95% CI [16.10, 18.91]), and by the NP (n = 48) ranged from 2-35 minutes (M = 12.16, SD = 8.41, 95% CI [9.72, 14.61]). Survivorship visits (n = 146) ranged from 25-90 minutes (M = 48.84, SD = 11.50, 95% CI [46.96, 50.72]). Patients further from diagnosis/last intervention spent shorter time in visits whereas patients closer to diagnosis/last intervention had longer visits (p = 0.0025). This study reinforces the need to deliver SCPs early on following a cancer diagnosis and suggests an NP-led survivorship clinic is one model able to deliver SCPs and meet CoC accreditation standards.

Classic and Follicular Variant are the most common types of papillary thyroid cancer (PTC). Recent evidence has emerged suggesting to rename a subset of non-invasive encapsulated FVPTC (EFVPTC) as Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features (NIFTP) given low reported risk of adverse outcomes. This shift in nomenclature and re-classification of this entity as “non-cancer” is thought to reduce the clinical consequences and psychological burden of a cancer diagnosis on people afflicted by it. Our study aimed to evaluate clinicopathological characteristics in patients with EFVPTC, assess sonographic features of these tumors, and quantify the morbidity associated with previously established treatment modalities. A retrospective chart review was performed on all patients with FVPTC from 01/2010 to 03/2014 at the Cleveland Clinic with approval by the Institutional Review Board. Data were collected to look for specific variables pertaining to clinical outcomes and morbidity with a minimum follow up of 3 years. Of 201 patients, 27 (13.4%) had non-invasive EFVPTC, 27 (13.4%) had EFVPTC with invasion of the capsule (IEFVPTC) and 148 (73.2%) had infiltrative FVPTC. Among patients with EFVPTC, malignant nodules could be assessed by US in 77% of cases. Compared to IEFVPTC, EFVPTC were less likely to have nodules with microcalcifications (7.4% vs 33%; p = 0.018), irregular contour (14.3% vs 47%; p = 0.019) and nodules taller than wide (16.75% vs 42.8%; p = 0.024). After excluding patients with concomitant thyroid cancers, 20 EFVPTC and 15 IEFVPTC cases remained. One patient with IEFVPTC (6%) had lymph node involvement compared to none in the other group. All cases of EFVPTC were stage I vs 80% in IEFVPTC. None of EFVPTC cases had disease recurrence vs 20% for IEFVPTC. 15% had surgical complications vs 13% for IEFVPTC (p = 0.89). 60% of EFVPTC received radioactive iodine therapy vs 73% for IEFVPTC (p = 0.37). EVPTC is less likely to have suspicious features on US compared to IEVPTC. Based on the clinicopathological characteristics, it is not associated with high risk disease characteristics. The risk of recurrence seems to be lower than in other subsets, with a higher rate of surgical complications.

The detection of incidental or small thyroid nodules has increased. Although the 2015 ATA guidelines for adults stated that fine needle aspiration (FNA) was not recommended for nodules <1cm, establishment of an appropriate size cutoff has been problematic in children. We reviewed surgically resected pediatric thyroid specimens with microcarcinomas to investigate associated clinicopathological features. All surgically resected thyroid carcinomas in patients age ≤18 years old from 2000-2017 were retrospectively reviewed. All microcarcinomas (size <1 cm) were examined for clinical and pathological findings. Of 94 thyroid carcinomas, 15 (16%) were microcarcinomas (mean 0.6, range 0.1-0.9 cm). The average patient age was 14.7 years (range 0.9-18.4 years) and most were female (73%). The final histological diagnoses were papillary (13, 87%) and medullary (2, 13%). There was a pre-operative FNA in 12 (80%) targeting the small nodule in 11 (73%), with a diagnosis of papillary thyroid carcinoma (PTC) (2, 17%), suspicious for PTC (1, 8%), suspicious for follicular or oncocytic neoplasm (6, 50%), and atypia of undetermined significance (2, 17%). One negative FNA (1, 8%) occurred in a case of a 0.1cm papillary thyroid carcinoma that was not targeted by the FNA. Three (20%) were in patients' with a history of genetic syndromes (NF1, MEN2, and Gardner). Nine had molecular testing (60%) with 6 (67%) testing positive for a mutation (3 NRAS, 2 RET/PTC1, 1 RET) using a 7-gene panel or ThyroSeq 1 or 2. All are alive with no evidence of disease with a mean follow-up of 3.8 years. Thyroid microcarcinomas are diagnosed in approximately 15% of pediatric thyroid cancer patients, which is lower than that reported in adults. Although small nodules can be challenging to target, size alone should not guide clinical management without consideration of sonographic and clinical findings. When appropriately sampled with FNA, the findings can be helpful in triaging small thyroid carcinomas for early treatment.

The prevalence of thyroid cancer is rapidly increasing worldwide. Though emphasis has been placed on recurrence in risk stratification, the concept of persistent disease as a separate entity is rarely addressed. This study explores the relationship between lymph node yield and ratio in neck dissections for well-differentiated thyroid cancer as they pertain to risk for persistence following surgery. A retrospective review was conducted of patients undergoing central or lateral neck dissection for well-differentiated thyroid cancer at the authors' institution from 1994 to 2016. Based on inclusion criteria, patients were divided into a persistent disease group, or a control group with no disease at 2 years post-treatment. Demographic characteristics, adjuvant therapy, and tumor and lymph node features were extracted. Total lymph nodes removed as well as the ratio of positive nodes to total yield were compared based on Wilcoxon rank sum analysis. Location of disease persistence and need for additional therapy were also reported.175 patients were included in the control group while 49 were determined to have disease persistence. The nodal yield of patients with central neck persistence was significantly less than those who had no recurrence/persistence (4.8 vs. 11.9 p < .0001). The yield in lateral neck persistence was also lower than those in the control group (14.8 vs. 31.0; p < .0001). Positive node ratio was higher in patients with persistence in both the central and lateral neck (29.4% vs. 74.2%, p < .0001 and 19.8% vs. 54.2%, p < .0001, respectively). Disease persisted in the lateral neck in 40.6% of patients, in the central neck in 36.7%, and both locations in 22.4%. Lower lymph node yield and higher node ratio from neck dissection are associated with greater risk of persistent disease in thyroid cancer. Suboptimal initial surgery results in additional intervention and carries significant implications for risk stratification, adjuvant therapy, and follow up.

Ewing sarcomas represent only 1 percent of all the thyroid malignancies. We describe the case of a 31 y female with a primary Ewing sarcoma of the thyroid. This 31 y female presented with an asymptomatic enlarging neck mass 11 months prior to evaluation. On physical exam she had a mobile, painless nodule in the right thyroid lobe measuring 5 cm with no palpable lympadenopathy. Ultrasound revealed a right thyroid hypoechoic nodule with microcalcifications, irregular borders and a vascular flow grade 2. FNA biopsy demonstrated a markedly cellular specimen with single and clusters of round to oval cells with salt and pepper chromatin and occasional nuclear inclusions. Fixed smear showed focal positive staining for chromogranin. These findings were consistent with medullary thyroid carcinoma. CT scan of the neck did not showed lymphadenopathy. The patient underwent total thyroidectomy. Pathology described sheets of small round blue cells with scant cytoplasm and high N/C ratio. Immunohistochemical stains were positive for CD99, AE1-3, PanCK, GATA3, chromogranin and InI-1. FISH and EWSR1 translocation were positive. These findings were consistent with Ewing sarcoma. PET/CT was negative for any evidence of distant metastases. Post-operative, she began adjuvant chemotherapy with alternative cycles of vincristin, doxorubicin, cyclophosphamide, alternating with ifosfamide and etoposide with mesna given days 1-5. Plan is for a minimum of 8 cycles, followed by radiation therapy to the primary tumor siteEwing sarcoma of the thyroid is extremely rare. Kabata et al described eight cases in ten years. Most patients are male ranging from 9 to 67 years. Most present as a fast-growing mass in the neck with normal thyroid function test. Usual diagnostic methods like FNA failed to give the correct diagnosis and only after surgery was the diagnosis made by the presence of EWSR1 mutation. Given the high rate or recurrent disease, treatment of Ewings sarcoma involves a systemic combination chemotherapy in the neoadjuvant and adjuvant setting.

Primary Ewing sarcoma of the thyroid is a very rare thyroid malignancy and diagnostic challenge. It should be suspected in any patient with a rapidly growing thyroid mass.

Despite an increasing number of thyroid cancer survivors, worry about recurrence and death in these patients remains understudied.

Patients diagnosed with differentiated thyroid cancer in 2014-2015 from the Surveillance, Epidemiology and End Results Program (SEER) registries of Georgia and Los Angeles County were surveyed two to three years after diagnosis. After excluding 188 (9%) patients with persistent or recurrent thyroid cancer and 111 (5%) patients with missing data, multivariable logistic regression was used to identify correlates of worry about recurrence and death in the 1,798 patients who reported that their cancer was gone after initial treatment. Of the 1,798 patients in the sample, 1,398 (78%) were female, 1,077 (60%) were white and 836 (46%) had a college degree or higher. At diagnosis, 1,555 (86%) patients reported that worrying about their thyroid cancer made them feel upset, 1,086 (60%) that it made it difficult to carry out their daily activities, and 764 (42%) that it made them feel distant from family and friends. After two to three years, 676 (38%), 428 (24%) and 345 (19%) patients reported these concerns respectively. However, 1,088 (61%) patients reported worry about recurrence and 714 (40%) reported worry about death two to three years after diagnosis. In multivariable analyses with separate models for recurrence and death, worry about both outcomes was significantly higher in younger patients (≤40 years: p < 0.001, p = 0.002; 41-55 years: p < 0.001, p = 0.004, respectively; reference 56-70 years), patients with lower education (some college: p = 0.003, p = 0.003; high school and below: p < 0.001, p < 0.001, respectively), and patients with higher stage (T2: p = 0.003, p < 0.001; T3/T4: p = 0.005, p = 0.042; N1: p = 0.002, p = 0.008, respectively). Worry about death was also significantly associated with being Asian (p = 0.025), Hispanic (p = 0.030) or Black (p = 0.047).

Although thyroid cancer-related worry affecting day-to-day life decreased two to three years after diagnosis, worry about recurrence and death remained common in this group of patients. Younger age, lower education and higher stage were associated with worry about recurrence and death. Physicians may use these findings to identify patients at risk.

According to increasing the concern about cosmesis, patients are distressful to the neck scar after thyroidectomy. Various attempts have been adopted to reduce those scars. Recently, it has been reported that botulinum toxin type A (Botox), which has been used for a long time due to cosmetic effects such as wrinkle improvement, suppress scar enlargement at the incision site. The aim of this study was to evaluate the effect of Botox administration on postoperative neck scar during thyroid surgery. A prospective randomized double-blind clinical trial was performed for the patients undergoing conventional thyroidectomy at Haeundae Paik Hospital from January to July 2016. The patients with previous neck operation, neck irradiation, or planning radical neck dissection or operation avoiding neck scar were excluded. Conventional thyroidectomy was performed after 5 cm low collar incision. The wound was closed with absorbable synthetic material after injecting 50 U Botox mixed with 1 mL normal saline or 1 mL of saline into subplatysmal muscle at 1 cm interval. Skin scars were assessed using SBSES (Modified Stony Brook Scale Evaluation Scale) and MSS (Manchester Scar Scale) at 1 week, 3 months, and 6 months postoperatively in all patients. Demographic data and operative results will be analyzed statistically using student t-test, chi-square test and repeated ANOVA. Forty patients who underwent conventional thyroidectomy were enrolled and 20 patients in the experimental group and 20 patients in the control group were randomly assigned. At now, skin scarring was assessed up to 3 months and statistical analysis will be performed if follow-up results are added for the next 6 months. The purpose of this study is to investigate the effect of Botox on cervical incision scar after conventional thyroidectomy. Based on the results of this study evaluating the usefulness of Botox, it is expected that the new modality of cervical scar management will be presented.

Recommendation 59 in the 2015 American Thyroid Association (ATA) states that “[f]or low-risk patients who have undergone lobectomy, TSH may be maintained in the mid to lower reference range (0.5–2mU/L) while surveillance for recurrence is continued. Thyroid hormone therapy may not be needed if patients can maintain their serum TSH in this target range.” Studies published prior to 2015 addressed this question and estimated that anywhere from 5-49%^3-12 of patients need thyroid hormone supplementation after thyroid lobectomy, with the majority of these studies ranging between 15-30%. However, this data was not based on the new ATA TSH suppression guidelines. Therefore, we sought to evaluate the percentage of patients that need to be on thyroid hormone therapy after thyroid lobectomy to stay in accord with the new guidelines. Retrospective chart review of patients that underwent a thyroid lobectomy from 1/1/2010 to 12/31/2017 for any cause. Head and Neck cancer patients and patients that underwent completion thyroidectomies were excluded. We collected pre/post-operative TSH numbers and the number of patients prescribed Synthroid pre and post-operatively. We performed 339 thyroid lobectomies; 59 head and neck cancer and 100 completion thyroidectomy patients were excluded. Final patient cohort was 180 patients; 20 had WDTC. Mean/median pre-operative TSH for the entire cohort was 1.49/1.26. 6 week, 6 month, and one year mean/median TSH was 6.0/2.79, 2.75/2.56, and 3.19/2.23 respectively. 14% and 42% were on Synthroid pre-operatively/post-operatively. WDTC patients had pre-operative mean/median TSH was 1.265/1.22. 6 week, 6 month, and one year mean/median TSH was 7.345/3.045, 2.254/2.0, and 1.93/1.82 respectively. 20% of these patients were on synthroid pre-operatively, 60% were on synthroid post-operatively, and 75% of people met 2015 ATA guidelines for post-operative thyroid hormone supplementation. Quoting historical data citing rate of Synthroid supplementation rates of 15-30% is likely not accurate for WDTC to stay in congruence with 2015 ATA guidlines. Our study indicates need for thyroid hormone supplementation in WDTC patients to be 75%.

The optimal management for papillary thyroid microcarcinoma (PTMC) remains controversial. Therefore, the purpose of this study is to explore clinicopathologic factors predictive of regional lymph node metastasis in conventional PTMC and to improve perioperative decision making for those harboring regional lymph node metastasis. We retrospectively reviewed 2,404 PTMC patients who underwent lobectomy or total thyroidectomy with central neck dissection and/or lateral neck dissection between January 2010 to December 2017 in a university hospital in China. In overall conventional PTMC patients, 915(38.1%) and 184(7.7%) cases were found to have central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM), respectively. Multivariate regression analysis found male (adjusted odds ratio [OR] = 1.977, p < 0.001), age less than 45 (adjusted OR = 1.579, p < 0.001), tumor size greater than 5mm (adjusted OR = 1.963, p < 0.001), extrathyroidal extension (ETE) (adjusted OR = 1.679, p < 0.001), multifocality (adjusted OR = 1.420, p < 0.001), and intrathyroid spreading (adjusted OR = 3.355, p < 0.001) were independent predictors for CLNM. Chronic lymphocytic thyroiditis (CLT) was significantly associated with decreased risk of CLNM (adjusted OR = 0.726, p < 0.01). In a smaller cohort of PTMC patients with BRAF V600E tested (n = 644), 548 (85.1%) harbored BRAF V600E mutation, 43.6% (239/548) and 39.6% (38/96) had CLNM in cases detected with and without BRAF V600E mutation, respectively (p = 0.462). In the subgroup analysis focusing only on PTMC patients, undergoing lateral neck dissection (n = 248), multifocality (adjusted OR = 1.75, p = 0.083) and intrathyroid spreading (adjusted OR = 6.75, p < 0.066) had a statistical trend towards significance, while other clinicopathologic features (sex, age, tumor size, ETE, lymphovascular invasion, CLT, and BRAF V600E mutation) were not significantly associated with LLNM. In the patients undergoing prophylactic central neck dissection, male, age, tumor size, ETE, multifocality, and intrathyroid spreading were found to be predictive of CLNM. No association was observed between BRAF V600E mutation and regional lymph node metastasis in Chinese PTMC patients.

After the Fukushima Daiichi Nuclear Power Plant accident that followed the Great East Japan Earthquake and tsunami on March 11, 2011, a large-scale thyroid ultrasound examination (TUE) survey began for people aged 18 years or younger at the time of the disaster. We would like to report the thyroid cancers screenedd from this survey.

In the first round survey, 300,476 subjects were screened by March 31, 2016. Among them, 116 subjects were diagnosed with malignancy or suspected malignancy by fine needle aspiration cytology (FNAC) A second and third round survey were completed with 270,511 and 120,596 subjects, among whom 71 and 4 were also diagnosed with malignancy by FNAC.

Among the 191 subjects diagnosed with malignancy or suspected malignancy by FNAC, 153 underwent surgery, and one benign nodule and 152 thyroid cancers were confirmed. Of the 152 operated thyroid cancer cases, 145 underwent surgery at our department. We analyzed clinicopathological findings of our operated 145 thyroid cancer.

Among these 145 subjects, 143 papillary thyroid carcinomas, one poorly differentiated thyroid carcinomas, and one other thyroid carcinoma were postoperatively confirmed. Mean age at diagnosis was 17.8 years, and mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were positive in 79%, 45%, and 2.1% of all cases, respectively. Total thyroidectomy was performed in only 12 cases (8.3%) and hemi-thyroidectomy was performed in the remaining cases.

We are aware of the high prevalence of thyroid cancer detected by sophisticated and large-scale ultrasound screenings following the accident. However, there are no choice which don't carry out TUE in the current Fukushima residents who were exposed radiation after the accident.

Analysis of the integrity of plasma circulating cell-free DNA (ccfDNA) has emerged as a promising tool in diagnosis of malignant vs benign breast and prostate tumors. The goal of this study was to analyze if ccfDNA could serve as a biomarker of malignancy in patients with thyroid nodules with indeterminate cytology. Sixty-eight patients with indeterminate thyroid nodules (Bethesda III), who underwent hemi- or total-thyroidectomy were enrolled in this study. All patients underwent plasma collection within 24-72h before the surgery. Additionally, nine patients had samples collected from the vein draining the nodule and peripheral vein during the surgery. The ccfDNA was extracted from plasma using Thermo Fisher Scientific King Fisher Duo Prime Purification System. The isolated ccfDNA was subjected to quantitative real time PCR, which utilized two different primer sets to amplify both shorter (ALU115) and longer fragments (ALU247) of consensus ALU sequences. Human genomic DNA was used as a standard to determine ccfDNA concentration in the samples. ccfDNA integrity index (cDI) was calculated as the ratio of ALU247 to ALU115. The average age of thyroid nodule diagnosis was 46 ± 15 years, tumor size 1.9 ± 1.8 cm, and 80.9% (55/68) of the patients were women. Women were characterized by lower cDI than men (0.42 ± 0.14 vs.0.51 ± 0.17, p = 0.049). There was no difference in cDI between patients with benign (n = 29) and malignant (n = 39) lesions (0.46 ± 0.16 vs 0.42 ± 0.14, p = 0.31, respectively). There were no differences in cDI in samples derived from vein draining the nodules and peripheral vein (0.35 ± 0.19 vs. 0.39 ± 0.18, p = 0.43). Patients with T1 tumors (<2 cm) were characterized by lower cDI than patients with tumors exceeding 2 cm (0.42 ± 0.13 vs 0.50 ± 0.14, p = 0.02, respectively). There was a weak inverse correlation between cDI and age (r = -0.3). Patients older than 45 years were characterized by lower cDI than younger patients (0.39 ± 0.15 vs 0.47 ± 0.14, p = 0.03). Integrity of plasma circulating cell-free DNA is associated with patient's age, gender and tumor size, but has limited utility as a biomarker differentiating between benign and malignant thyroid nodules with indeterminate cytology.

A low iodine diet (LID) limiting iodine content to <50 ug daily has been recommended as a method of preparation for radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer (DTC). The 24h urinary iodine excretion (UIE) is routinely utilized to confirm an iodine-deplete status. There are no data on the optimal UIE cutoff associated with beneficial progression free survival (PFS). Seventy-one patients with intermediate- and high-risk DTC, who underwent total-thyroidectomy ± central/lateral lymph node dissection and RAI therapy were enrolled in this study. All patients were recommended to adhere to two weeks of LID and underwent 24h urine collection before RAI therapy. UIE was categorized as <50 ug/24h, 50-99 ug/24h, 100-250 ug/24h and >250 ug/24h. Kaplan-Meier analyses were performed to compare PFS between the groups. A Cox proportional hazards regression model was performed to study the contribution of age, tumor size, presence of metastases on PFS. The study group was characterized by a median age at diagnosis of 42 [IQR 32.5, 54.5] years, tumor size 2.8 [IQR 1.8-4.5] cm, presence of central neck lymph node metastases in 64.8% (46/71), lateral neck in 33.3% (24/71) and distant metastases in 24% (17/71) of patients. Patients were treated with 1 to 5 RAI dosages with median cumulative activity of 150 [IQR 104-325] mCi. During the follow-up of 45 [IQR 17.5-78] months, 22.5% (17/71) of patients had disease progression. While there was no difference in PFS between the patients with UIE <50 ug/24h, 50-99 ug/24h, and 100-250 ug/24h, patients with UIE >250 ug/24 were characterized by higher risk of progression (HR 22.5, CI 3-170.9, p = 0.03) and shorter time to progression (HR 11.7, CI 2.0-67.4, p = 0.01). However, a multivariate model revealed that only tumor size was a significant factor affecting PFS (HR1.9 1.03-3.7, p = 0.03), while UIE was of borderline significance (p = 0.05). A UIE exceeding 250 ug/24h is associated with a higher likelihood of progression in intermediate and high-risk thyroid cancer patients treated with RAI. These data suggest that a simplified, rather than stringent LID might be sufficient for appropriate preparation for RAI.

Papillary Thyroid Cancer (PTC) measuring ≤1 cm is known as Papillary Thyroid Microcarcinoma (PTMC). This definition does not depend on the presence or absence of high risk features such as lymph node metastasis and/or distant metastasis. Although apparently small thyroid carcinomas frequently are present in otherwise healthy adult people, most of them are considered harmless to their hosts. Active surveillance (AS) of low risk PTMC was adopted by the American Thyroid Association guidelines since 2015. However, in our center all diagnosed PTMC underwent surgery. Observational, cross-sectional, retrospective study of 867 patients that underwent total thyroidectomy between 2012 and 2017, in CEDIMAT, Dominican Republic. From those, 205 (23.4%) were diagnosed as Differentiated Thyroid Cancer (DTC), of which 82 (40%) were confirmed as PTMC. For studying purposes this group was subclassified in ≥5 mm and <5 mms. From the 82 PTMC, 68 (83%) presented ≥5 mm and 14 (17%) < 5 mms. Metastasis was reported in 5 patients (6.09%) with >5mm. PTMC diagnosis was incidental in 4 patients operated from Primary Hyperparathyroidism (PHPT), 3 of them (80%) presenting adenomas and 1 (20%) parathyroid carcinoma. Almost half of our DTC cases were PTMC of which only 6% were of high risk. Active surveillance of PTMC is not a common practice in Dominican Republic, sociocultural factors may be related to this behavior. Would active surveillance in our context translate into delayed surgical intervention? Are there genetic factors that increase the incidence of PTMC?

Genetic testing for mutations in the RET gene, which cause the Multiple Endocrine Neoplasia Type 2 (NEM2) syndrome, has become crucial in the management of patients with medullary thyroid carcinoma (MTC). With rare exceptions, mutations in the RET gene occur in heterozygosis in an autosomal dominant inheritance, so that the offspring of a MEN2 patient can present 2 genotypes (with corresponding phenotype): wild/wild (not affected) and wild/mutated (affected). Double germline mutations in different codons of the RET gene in the same patient have been described, but mosaicism has never been reported. We report the case of a patient who died at age 41 years from locally advanced MTC and whose mother had also died from MTC. Due to MEN2A hypothesis, her siblings went through genetic RET investigation. We surprisingly found that they had inherited three different genotypes: homozygous wild type, heterozygous p.C634G mutation or heterozygous p.C634R mutation.Ten out of 11 proband's siblings and her father had the RET gene analyzed in blood samples. Three had wild-type RET gene, 4 had a heterozygous mutation in codon 634 – p.Cys634Gly (c.1900T>G) - and 2 had a different heterozygous RET mutation in the same codon- p.Cy634Arg (c.1900 T>C). Her older brother was deceased from gastric cancer. Their parents were first-grade cousins, but the father was 80-years-old at the time of the evaluation and had no RETmutation. As the patient's mother was deceased many years before, the mutated alleles, which were less frequent, could not be identified in paraffin-embedded thyroid tissue through Sanger sequencing. Exome sequencing succeeded in detecting the three nucleotides in the same position. Therefore, we hypothesized that a germline mutation followed by early somatic mutation during embryogenesis leading to mosaicism in the proband's mother's RET gene might have caused this rare occurrence. We describe for the first time the occurrence of a mosaicism affecting the RET gene in a MEN2A family. This case also reinforces that, when genotype and phenotype do not match, one should consider the possibility of mutations or diverse inheritance patterns that could have been overlooked through direct sequencing.

Lateral lymph node metastasis (LNM) is not uncommon in papillary thyroid microcarcinoma (PTMC). Our present study aimed to determine the incidence and patterns of and to investigate the risk factors associated with lateral LNM in PTMC. From January 2014 to July 2015, a retrospective review was performed of 215 patients with PTMC who underwent total thyroidectomy and central lymph node dissection (CND) with lateral CND. The clinicopathologic results were reviewed, and the incidence and patterns of lateral LNM were analyzed. Among the aforementioned cases, 163 cases(75.814%) were PTMC with the presence of Lateral LNM. The most commonly metastatic site of Lateral LNM was level III (82.219%), followed by level IV (65.644%), level II (38.037%) and level V (10.429%). Then the most commonly model of distribution was two levels (41.104%) and single 1evel (33.742%) followed by three levels (20.245%) and four levels (4.908%). Lateral LNM without central LNM was observed in 14 (8.589%) cases of PTMC. A multivariate analysis revealed that the predictive factors for the presence of lateral LNM were central LNM (OR = 8.280, 95% CI, 3.430–19.988) and upper portion location of primary tumor (OR = 2.856, 95% CI, 1.339–6.089). The lateral LNM of PTMC was often involved in level III and level IV, most found in two levels and single 1evel models. Patients with central LNM or upper pole location should be paid more attention to the status of lateral lymph node.

External beam radiotherapy (EBRT) is an important adjunct to surgery and radioactive iodine (RAI) in the treatment in locally advanced differentiated carcinoma of thyroid (LATC). Second primary tumour (SPT), particularly those developed inside radiation portal, represents an uncommon yet dreaded long-term complication that significantly impacts cancer survivorship. For LATC, epidemiology for in-field SPT after adjuvant EBRT is uncertain. We have conducted a retrospective cohort study, including 60 consecutive patients who received adjvant EBRT for locally advanced, surgically resected thyroid cancer from 2005 to 2007 in a tertiary oncology center in Hong Kong. All patients received total thyroidectomy, central and lateral compartment lymph node dissection as indicated, followed by adjuvant radioactive iodine. Adjuvant EBRT was delivered mostly with intensity-modulated radiotherapy (IMRT) technique at a dose from 60-66Gy to planning target volume covering thyroid bed and bilateral cervical lymph nodes. Median follow up was 10.89 years. We observed no SPT within radiation field and 4 SPTs out of radiation field.

We compared the incidence of SPTs with a cohort of 759 patients who received definitive EBRT with or without chemotherapy for nasopharyngeal carcinoma (NPC). Between two groups, the median age was similar (p = 0.331, mann-whitney U test), smoking was more prevalent for patients with NPC (OR 2.54, Chi-square test, p = 0.004) and median follow up was longer in LATC group (10.89 years vs 6.40 years). We noted a significantly lower risk of in-field SPT for LATC patients (0 in 1000 person-years vs 4.6 in 1000 person-years, p = 0.013, log rank test), while risk of out-field SPT is similar (6.18 in 1000 person-years for LATC vs 6.07 in 1000 person-years in NPC, p = 0.0612, log rank test). There is still a trend for lower risk of SPT (HR 0.34, 95% confidence interval 0.103-1.133) for patients with LATC after adjustment for smoking in multivariate analysis, though the statistical significance was marginal. This study shows that the risk of in-field SPT for patients receiving adjuvant EBRT for LATC is lower than those receiving EBRT for definitive treatment of NPC. Further study with larger cohort is warranted.

Current guidelines suggest that metastatic disease from papillary thyroid microcarcinoma (PTMC) is rare. Active surveillance has been recommended for these patients as an alternative to immediate surgery. Periodic ultrasonography (US) is used to identify unfavorable features such as lymphadenopathy, extrathyroidal invasion and location adjacent to the trachea, at which point surgery is recommended. However, it is well documented that cervical US has variable accuracy depending on the ultrasonographer's experience. Inability to identify unfavorable features on US can impact the management of these patients. This study aims to analyze the reliability of preoperative radiology and surgeon-performed US (SUS) in identifying nodal disease in patients with PTMC who underwent thyroidectomy. Retrospective chart review of 249 consecutive patients with PTMC (≤1cm) who underwent thyroidectomy at a single tertiary referral institution over a period of 10 years was performed. Clinical information and preoperative SUS and radiology performed US were analyzed and compared with operative and pathology findingsOf the 249 patients with PTMC, 38 (15%) had lymph node metastasis on final pathology. Thirty –five (14%) had central and 6 (2%) had lateral node metastasis. Ninety-seven (39%) patients were found to have multifocal PTMC and 7 (3%) had extrathyroidal extension. The classic subtype was predominant in 182 (73%) and the follicular variant in 65 (26%) patients. Of the 38 patients with loco-regional metastasis, preoperative SUS visualized 18 (47%) of the central and 6/6 (100%) of the lateral neck disease, whereas radiology performed US identified none of the central neck lymphadenopathy and only 1/6 (17%) lateral metastasis. This study suggests that nodal metastasis from PTMC is not as rare as previously believed and is often not recognized on preoperative US. Although nodal metastasis may not affect patient survival, active surveillance and determination of patients who can be treated non-operatively may be compromised by unreliable US findings, particularly when performed by non-dedicated radiologists. We suggest caution when recommending observation for patients with PTMC if a specialized ultrasonographer is unavailable.

Primary hyperparathyroidism with concomitant occurrence of nonmedullary thyroid carcinoma is rare, occurring less than 4%. Concurrence of papillary thyroid carcinoma and parathyroid adenoma is extremely rare. To our knowledge, this is the first described case of Hobnail variant papillary thyroid carcinoma (HVPTC) and intrathyroidal parathyroid adenoma (IPTA) within same thyroid lobe. Herein, we report a case of a 61-year-old woman presented to our endocrine clinic with generalized ache, bone pain and polyuria for few months. This was associated with right neck swelling. She underwent fine needle aspiration (FNA) followed by right lobectomy. Further radiological investigation found 4.6 cm complex nodule within right thyroid lobe and Sestamibi scan was suggestive of parathyroid adenoma and cold nodule in the right thyroid lobe. Laboratory findings revealed hypercalcemia and hyperparathyroidism. FNA revealed atypical follicular lesion of undetermined significance (FLUS). Right thyroid lobectomy was performed, which resulted in normalization of intraoperative rapid parathyroid hormone levels. Final pathology demonstrated 2.0 cm HVPTC and 2.0 cm IPTA with supportive immunohistochemical stains in addition, BRAF V600 mutation was positive within the HVPTC. To our knowledge, this is the first reported case of concurrence of HPTC and IPA. This report is a reminder that the presence of parathyroid adenoma should not exclude the diagnosis of thyroid carcinoma; therefore, careful thyroid evaluation should be considered for all patients with primary hyperparathyroidism to prevent missing concurrent thyroid cancers. Furthermore, describing the cytomorphologic features to distinguish thyroid from parathyroid cells on FNA cytology samples and the utilization of ancillary study of immunohistochemical stains will be discussed.

Anaplastic thyroid carcinoma (ATC) arises de novo or through a process of de-differentiation of a pre-existing well-differentiated thyroid carcinoma. Such transformation has been most commonly described to occur within the thyroid gland primary tumor. Here, we describe a case where ATC was found in the lateral neck lymph nodes without evidence of de-differentiation of the primary thyroid cancer.

A 58-year-old female with Hashimoto's thyroiditis presented with a one-year history of worsening subjective central neck fullness in the setting of clinical thyromegaly. Over 4 months, consecutive ultrasounds demonstrated a stable heterogenous gland with no discrete nodules; however, on ultrasound just prior to referral to endocrine surgery, new pathologic right lateral neck lymphadenopathy was noted. Ultrasound guided fine needle aspiration of the right thyroid and a right lateral neck lymph node were consistent with papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy with bilateral central and right modified radical neck dissection. Pathology demonstrated a right lobe 3.1cm T3 PTC, Warthin-like variant with peripheral tall cell features. Margins were uninvolved, and no lymphovascular invasion was present. All level VI lymph nodes were benign; however, 2/35 right lateral neck lymph nodes demonstrated ATC. The patient was further treated with 100mCi radioactive iodine, external beam radiation totaling 66cGy, and 5 weeks of cisplatin therapy. She has been in remission for 30 months.

In this case, the primary cancer was a Warthin-like variant of PTC, which is rare, and typically has an excellent prognosis with metastases uncommon. ATC is a highly aggressive cancer with a median survival of approximately six months and a disease-specific mortality nearing 100%. Here, ATC was found within lateral neck lymph nodes without evidence of de-differentiation or ATC within the primary tumor. This is uncommon with few similar cases reported in the literature.

Having ATC isolated to lymph nodes and not within the thyroid increased the resectability of the anaplastic disease in this patient. This, combined with adjuvant chemoradiation, resulted in prolonged survival.

A nonrecurrent laryngeal nerve (NLN) is a rare entity encountered in less than 1% of the population. Given the unique embryology of NLNs, patterns of lymphatic spread may vary in these patients. Surgeons should be aware of these variations to prevent iatrogenic injury to the nerve as well as for oncologic clearance of disease. A 54-year-old female presented with an incidentally noted right lower cervical cystic lesion, found on a thoracic spine MRI ordered for back pain. A CT and MRI of the neck were performed for further evaluation, revealing a 2cm cystic mass surrounded by clear fat planes lateral to the thyroid and posterior to the carotid artery. Ultrasound-guided biopsy revealed cells of thyroid origin. Formal ultrasound of the thyroid and neck was within the normal limits without any concerning cysts or nodules greater than 4mm or any pathologic lymphadenopathy in the central or lateral necks. The patient was taken to the operating room and found to have a NLN on the right side. There was a cystic mass noted within the right carotid sheath- posterior to the carotid and deep to the vagus nerve. The mass was carefully excised, preserving the vagus and nonrecurrent inferior laryngeal nerve, and sent for frozen pathological analysis. Frozen section pathology returned as papillary thyroid cancer in a cystic node. Total thyroidectomy and central compartment neck dissection were performed. Final pathology revealed 4 micro papillary thyroid carcinomas within the thyroid gland: 1mm and 5mm in the left lobe (classical type), 3mm and 2mm in the right lobe (infiltrative follicular variant). There were 4 metastatic nodes within the right cystic mass located within the carotid sheath but no positive metastatic nodes in the central compartment. We present an extremely unusual case of an isolated papillary thyroid carcinoma metastasis within the carotid sheath in a patient with a NLN. To our knowledge, such a case has not been reported in the literature. We suspect that the unusual lymphatic spread may be associated with the NLN. Surgeons should be aware of the potential for highly unusual metastatic patterns in papillary thyroid cancer, particularly in patients with a NLN.

Mucoepidermoid carcinoma (MEC) of the thyroid gland is a rare entity first described in 1977 by Rhatigan et al. Since then, two distinct subtypes have been identified. The first displays invasive tumor nests with squamous and glandular differentiation, often associated with conventional papillary thyroid carcinoma (PTC). The second, termed sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), occurs in a background of severe lymphocytic thyroiditis and shows tumor cells in a dense fibrocollagenous stroma with abundant eosinophils. We present two cases to show the distinct histologic and molecular features of these lesions. Case 1: 74 y.o. F presented with a lateral neck mass and a thyroid nodule. The surgically resected thyroid revealed areas of papillary thyroid carcinoma, tall cell variant, with adjacent nests of atypical cells with mucin. The neck mass showed metastatic mucoepidermoid carcinoma, similar in appearance to the mucoepidermoid component in the thyroid, along with poorly-differentiated areas. Gene sequencing of the neck mass revealed mutations in BRAF (V600E), PIK3CA, and TP53. The patient died within months with multiple lung and liver metastases. Case 2: 60 y.o. F presented with “goiter.” She underwent thyroidectomy and a diagnosis of Hashimoto thyroiditis was made. 20 years later she developed “recurrent goiter.” Excised tissue showed a tumor diagnosed as SMECE. Review showed that the tumor had been present in the original slides. MEC of the thyroid gland is a rare entity with uncertain origin. Previous authors have suggested SMECE may originate from ultimobranchial rests. The lateral location of SMECE in the thyroid and the association of severe lymphocytic thyroiditis with hyperplasia of the ultimobranchial remnants support this idea. Molecular analysis has shown no signatures of follicular, C cell or salivary type epithelium present in SMECE. The histologic origin of conventional MEC in the thyroid gland is also unclear. However, we suggest the association of MEC with conventional forms of thyroid carcinoma and the lack of background thyroiditis support transdifferentiation from existing PTC. In our case, this is further supported by the BRAF V600E mutation in the metastatic MEC.

NGS increasingly allows tumor profiling for targeted therapies in recurrent or metastatic disease. Here we present a case report of sporadic PDTC arising within a longstanding benign multinodular goiter.71 year old female presented to ED with enlarging thyroid mass, neck pain, weight loss and worsening dysphagia. FNA showed malignant cells strongly positive for PAX-8 and TTF-1. A palpable right neck mass corresponded with CT findings of IJV thrombus. Flexible laryngoscopy confirmed right vocal cord paralysis. MRI confirmed invasion into the internal jugular vein and tracheal narrowing, and PET/CT revealed possible pulmonary metastases as well as a sternal bone metastasis. Therefore she was scheduled for total thyroidectomy and bilateral neck dissection.

Tumor pathology was consistent with poorly differentiated thyroid carcinoma with extensive LVI and intravascular tumor thrombi, however 112 lymph nodes were negative for carcinoma. She subsequently underwent RAI 250 mCi, followed by CyberKnife treatments to the sternum; local recurrence at the cricothyroid joint, with extension into the subglottic airway required tracheostomy and EBRT. Next generation sequencing found TP53, p.R248q, a missense variant, which leads to loss of tumor suppressor activity. TP53 mutations are found in 14% of malignant thyroid tumors, more often in poorly differentiated tumors. This particular variant has been previously reported in other cancer types but not in thyroid cancer. There are currently no FDA approved targeted therapies for patients with this mutation.

TP53 mutations with derangement of a fundamental apoptotic/cell senescence pathways are found in 50% of human cancers, however there are no targeted therapies approved as monotherapy. Strategies to reverse the effects of mutated p53 within the tumor microenvironment include viral transfection to restore wild-type p53, use of mutated p53 as antigen in vaccine trials, and regulation of inhibitor molecules MDM2/MDM4. Even more promising has been combined approaches with immunotherapy, possibly with tumor debulking and/or palliative radiotherapy to stimulate the primed host immune system. NGS in advanced PDTC can help guide treatment strategies.

A 68-year-old man presented with painless swelling and a hematoma on his right ring finger. Symptoms started one month ago and there was no associated trauma. Radiography showed an osteolytic lesion involving the terminal phalanx. A biopsy revealed a malignant tumor with infiltration of the epidermis. The immunohistochemistry revealed a strong expression of thyroglobulin, corresponding to a metastasis of a thyroid carcinoma. Lab tests found a thyroglobulin >2500 μg/l. Sonography of the right lobe (37 ml) showed an inhomogeneous, hypoechoic, borderline calcified nodule of 23 × 32 mm, but no further clear malignancy criteria were noted. The left lobe exhibited only small cystic lesions. A thyroid scan showed a cold nodule, and fine-needle aspiration revealed a follicular lesion. In addition, a chest CT revealed pathological lymph nodes in the mediastinum (dorsal to the superior vena cava) measuring up to 56 mm and small intrapulmonary secondary lesions. Therapeutically, the amputation of the right terminal phalanx of the fourth finger was performed first. 3 weeks later, the patient underwent a combined procedure: thyroidectomy with neck dissection and thoracoscopic metastasis removal via VATS. A rapid section revealed the diagnosis of a multifocal solid papillary thyroid carcinoma with a transition into a poorly differentiated form pT3 (m), N1(12/24), L1, V0, RX, M1. Six weeks postoperatively, the patient underwent radioiodine treatment with 3,7 GBq J131. Under thyrogen stimulation, the whole body scan revealed uptake on the neck, in the mediastinum on both sides and in the left scapula. Further imaging with 18F-FDG-PET/CT showed lytic secondary blastomatous lesions along L2-L3, showing no iodine uptake. Thus a palliative radiotherapy was performed by single shot therapy with a total dose of 8 Gy. The patient was adjusted for thyroid hormone substitution in TSH-suppressive doses and Denosumab. Thyroglobulin decreased to 500 μg/l. A re-evaluation is planned for the coming weeks.

Conclusively, this case shows that patients with thyroid cancer may remain asymptomatic for a long time, underlining the question whether sonographic and laboratory thyroid screenings should be included in screening programs.

Autonomous thyroid nodules in children are generally benign. Fine-needle aspiration is rarely required, and treatment consists of surgical resection or antithyroid drug as a bridge to radioiodine ablation. Hyperfunctioning thyroid carcinoma is a rare cause of thyrotoxicosis. We report the case of a 15-year-old with thyrotoxicosis caused by a hyperfunctioning, metastatic, differentiated thyroid carcinoma harboring a somatic mutation in the TSH receptor. A 15-year-old girl presented with a neck mass and right cervical lymphadenopathy. Laboratories showed thyrotoxicosis with suppressed TSH <0.005 mIU/L (0.7-5.7) and high free T4 2.96 ng/dL (0.8-1.9) and total T3 261 ng/dL (80-260). TPO antibodies were elevated, but Tg Ab, TSI, and TBII were negative. Ultrasound demonstrated bilateral thyroid nodules and two abnormal right sided lymph nodes (2.6 cm, 3.1 cm) that were round and showed loss of the normal hilum, intranodal necrosis and calcifications. FNA cytology yielded atypical cells of uncertain significance in a 1.8 cm right lobe nodule and both lymph nodes. I-123 SPECT-CT revealed autonomy of the right nodules (24hr uptake 26%), negligible uptake in the left lobe, and abnormal uptake in the lymph nodes. Patient underwent right hemithyroidectomy and lateral neck dissection. Histology showed differentiated thyroid carcinoma throughout the right thyroid lobe and in the two lymph nodes with features of papillary, follicular and Hürthle cell carcinoma. Completion thyroidectomy was performed, and histology was benign. Mutational analysis of the tumor revealed an activating mutation of the TSHR gene (c.1358T>C, p.M453T) in 38% of cells. Due to tumor size, metastatic and functional nature, thyroid hormone withdrawal and dosimetry will be pursued to calculate I-131 therapeutic dose. Hyperfunctioning thyroid carcinoma in children is rare. While autonomous nodules are generally benign, careful evaluation with ultrasound and scintigraphy are necessary. Suspicious findings such as sonographically abnormal lymph nodes and radioiodine uptake outside the thyroid bed should prompt further evaluation for possible malignancy. Like many benign autonomous nodules, hyperfunctioning cancers may contain activating mutations in TSHR.

Anaplastic thyroid carcinoma (ATC) is a rare malignancy of the thyroid with a high mortality rate. The most common sites of metastases related to ATC are: lungs, pleura, adrenal glands, liver, brain, heart, and intrathoracic, neck and retroperitoneal lymph nodes. Skin represents only 2.8 – 10.4% of all ATC metastases. A 66-years-old female patient was admitted to outpatient clinic due to skins lesions (figure 1). The symptoms began 6 moths prior to admission with intense pain at the level of the cervical spine associated with the presence of a rapidly growing nodulation at the level of the thyroid gland currently associated with dysphagia to solids. During the physical examination, multiple indurated nodular skin lesions in scalp were found, the biggest of approximately 3 centimeters of diameter, and clinical data of root compression in higher and lower limbs. A fine-needle aspiration biopsy reported anaplastic thyroid carcinoma. A PET-CT (figure 2) showed left thyroid tumor with metastatic disease of bone, lymph nodes, muscle, adrenal, pancreatic, pulmonary, splenic, cutaneous, cerebral, and renal. The vertebral metastases in C3 and L3 present intraspinal extension conditioning the narrow channel, and finally brain metastasis without data of associated hypertensive skull. ATC is still an extremely rare kind of thyroid carcinoma in which high mortality is related to its aggressive behavior. In this case, despite the lack of an early diagnose, the metastases were a poor prognosis predictor. Cutaneous metastases of anaplastic carcinoma of the thyroid are very rare, because this tumor has a rapid growth that leads to death, although it has a relatively high potential to develop metastases in other organs, usually lung and bone.

Differentiated thyroid cancers causing malignant pleural effusions are rare. We present the case of a 57 year-old Caucasian woman with a history of follicular variant papillary thyroid carcinoma who presented with one week of shortness of breath and cough. She was found to have a large left pleural effusion on imaging. Thoracentesis was performed with pleural fluid cytology consistent with malignant papillary thyroid carcinoma. Thyroglobulin level in the pleural fluid 468 ng/ml while the serum thyroglobulin returned at 9.5 ng/ml (TSH 35 mIU/L). A subsequent pleural biopsy confirmed the diagnosis of PTC. Two years prior, patient had been diagnosed with unencapsulated follicular variant papillary thyroid carcinoma. She initially presented with a right neck mass, subsequently underwent fine needle aspiration biopsy with pathology revealing papillary thyroid carcinoma. She then underwent total thyroidectomy, central and right neck dissection. Surgical pathology revealed papillary thyroid carcinoma, follicular variant with lymph node involvement (13/31 involved with extranodal extension). Subsequently the patient received 78.9mCI of radioactive iodine ablation. Her post ablation whole body scan was negative for any distant metastatic disease. Her thyroglobulin level one year after her diagnosis was 0.7 ng/ml. She was then lost to follow up until one year later when she presented to our hospital as above. FDG PET scan demonstrated multiple tiny bilateral pulmonary nodules with FDG avid (SUV 5.7) pleural thickening on the left. A left sided pleural effusion was also noted to be faintly FDG avid. The patient required chest tube drainage and was started on lenvatinib for RAI-refractory PTC.

A review of the literature shows less than twenty cases of papillary thyroid cancer-related pleural effusions. Our case is also unusual in that the stimulated serum thyroglobulin level was not significantly elevated (9.5 ng/ml) and one year prior, a post RAI whole body scan was negative for metastatic disease to the lungs. The speed of recurrence is very unusual for most cases of papillary thyroid carcinoma. Although PTC rarely leads to death, a malignant pleural effusion unfortunately portends a poor prognosis and survival rate.NA

Metastases to the thyroid gland are not commonly encountered in clinical practice. Literature review of postmortem examination studies suggests that as many as 2 - 24% of patients who die of non-thyroid malignancies have metastases to the thyroid gland. In autopsy series, the most common primary site with metastasis to the thyroid is the lung, whereas in clinical series the most common primary tumor with metastasis to the thyroid is renal cell carcinoma (RCC). Only 2% of reported metastatic cancers to the thyroid are sarcomas. We present the case of a 35 year old female with past medical history of right tibia osteosarcoma diagnosed in 2010. She received neoadjuvant chemotherapy with doxorubicin/cisplatin/methotrexate/ifosfamide followed by right extremity above the knee amputation in 2011.

On follow up in 2014, she was found to have an enlarged suspicious left thyroid mass for which she underwent left thyroidectomy. Pathology confirmed the diagnosis of metastatic osteosarcoma to the thyroid with a 6.0 cm lesion removed. Furthermore, in 2014 she was found to have several lung micronodules suspicious for metastases which showed slow progression in size during surveillance. In 2016 she underwent stereotactic body radiotherapy (48Gy in 4 fractions) to 3 lung nodules.

On follow up in January 2018, she was found to have a right thyroid lobe nodule (measuring 3.0 × 1.8 × 2.8 cm), left superior neck lesion (measuring 2.5 cm) and a posterior scalp mass (measuring 2.0 × 3.2 × 3.1 cm). She underwent surgical resection of these lesions, for all of which pathology report was positive for metastatic high-grade osteosarcoma.N/ASarcomas metastatic to the thyroid are very rare as the majority of thyroid metastases, as reported in clinical series, are caused by tumors of the kidneys (25%), lungs (22%), GI tract (13%), mammary glands (13%) and melanomas (4%).

This is the first reported case of osteosarcoma with metastasis recurring to the thyroid gland. Other sites of osteosarcoma metastases in this patient were lungs and scalp.

Myasthenia gravis (MG) is a neuromuscular junction disease characterized by muscular weakness and fatigability caused by antibodies against the acetylcholine receptor (AChR). We present a rare case of paraneoplastic MG in the context of papillary thyroid carcinoma (PTC). A 59-year-old Filipino man presented to his family physician with progressive dysphagia in the spring of 2017. Neck ultrasound and fine needle aspiration biopsy of a right-sided thyroid nodule disclosed an underlying PTC. The patient underwent a two-stage total thyroidectomy in July and October 2017. Pathology reported a dominant right-sided 2.8 cm classical PTC with extrathyroidal extension. The patient's dysphagia worsened after surgery and he was eventually sent to the emergency room by his family physician with a suspicion of impending myasthenic crisis. In retrospect, the patient began experiencing intermittent droopy eyelids, diplopia worse in the evenings and progressive dysphagia since April 2017. The combination of clinical muscular fatigability and impaired neuromuscular transmission on repetitive nerve stimulation led to the diagnosis of MG in November 2017, five months after the onset of symptoms. Anti-AChR antibody levels are pending, and chest imaging showed no thymic enlargement. The patient was promptly treated with prednisone 30 mg daily and pyridostigmine 60 mg QID, with rapid improvement of his symptoms after one week of treatment. MG associated with thyroid carcinoma is rare but can be life-threatening if unrecognized. Undiagnosed MG can also pose a higher surgical risk for thyroid cancer patients. Awareness of this combination may help with early identification, prompt intervention, and timely prevention of myasthenic crisis.

Ectopic bone formation (EBF) can occur in a wide variety of soft tissues. However, EBF developing in a thyroid cancer is quite rare. Over-expression of bone morphogenic proteins and a variety of bone growth factors, such as FGF, have been reported in thyroid cancers. These could foster the development of osseous tissues. We report a case of EBF in a papillary thyroid carcinoma (PTC) that also demonstrated extramedullary hematopoiesis (EMH). A 74 y male underwent resection of a PTC that was discovered incidentally while having a FDG-PET scan to monitor status of recurrent plasmacytomas. Histology revealed classical PTC that was multicentric with 3 of 7 lymph nodes positive for PTC (T2; N1a; M0 – Stage II AJCC 8th edition). In addition, he has metaplastic ossification within the tumor showing mature bone with osteoblasts and osteoclasts. Further, he had normal bone marrow elements adjacent to the bone within the tumor. A whole body scan after 100 mCi of 131-Iodine did not reveal any metastatic uptake. His serum thyroglobulin is currently <0.1 ng/ml. PTC often contains calcifications (up to 53%) and psammoma bodies. In several series from Asia, EBF has been reported in 16-23% of all PTC. EBF can also occur in benign nodular goiters. The impact of EBF on local recurrence and prognosis, however is not well defined. The co-occurrence of EBF and EMH has only been reported rarely in the medical literature. It has been suggested that EBF with EMH is more common in patients with hematologic malignancies, as in our patient. At this time, the most common proposed theory for these rare occurrences involves the role of bone morphogenetic proteins, VEGF, and fibroblast growth factors. This gentleman recently had a recurrences of his plasmacytoma but has no evidence of residual thyroid cancer. In older patients with EBF in a thyroid cancer, clinicians should be aware that occult lymphoid malignancies appear to be more common.

The anterior pituitary regulates the function of several glands including the thyroid gland. Pituitary secretion of thyroid-stimulating hormone (TSH) is subject to feedback inhibition by thyroid hormone (TH), a fundamental mechanism for maintaining thyroid hormone homeostasis. The THRBgene encoding TRb is expressed in the anterior pituitary and is mutated in the syndrome of resistance to thyroid hormone. However, the genome wide regulation of pituitary gene expression by TH and the role of TRb in this regulation is poorly defined. Hypothyroidism was produced in wild type and TRbKO male mice groups by administration of methimazole (MMI) in drinking water for 4 weeks. Hyperthyroid groups were additionally treated with T3 in the drinking water for the 4th week. Pituitaries were isolated for RNA-sequencing (RNA-seq) to identify genome-wide gene expression patterns. Expression changes for selected genes were confirmed by quantitative real time PCR (qRT-PCR). Epigenetic changes were investigated by determining histone modifications (chromatin-immunoprecipitation-sequencing) and open chromatin analysis (ATAC-seq). Transcriptome analysis revealed that known TH responsive genes such as Tshb and Cga were down regulated whereas Hr and Gh were upregulated in hyperthyroid versus hypothyroid groups. Several hundred genes displayed statistically different expression between these two treated groups. However, in TRbKO mice, expression of most of these genes was impaired. Specific histone acetylation marks were dynamically regulated in enhancer regions of many genes. We report a comprehensive analysis of pituitary responses to TH at the level of the transcriptome, histone modification and chromatin accessibility status. A majority of TH response genes depend to some extent upon TRb suggesting a major role for TRb in pituitary regulation. Chromatin modification in enhancer regions of target genes is associated with TH-dependent regulation in the pituitary.

We have recently reported using TRH knockout mice that TRH acts as a strong stimulant of NR4A1 (Nurr 77) in pituitary thyrotrophs, which then stimulates expression of the TSH gene (PLoS One. 2012;7(7):e40437.). Mechanisms underlying negative regulation of the TSHb gene by thyroid hormones remains unclear. We therefore hypothesized that pituitary NR4A1 levels may be regulated by thyroid hormone and affect expression of the TSHβ gene.

It has been postulated that triiodothyronine (T₃), a thyroid hormone, is involved in breast cancer (BC) progression, as T₃ was shown to modulate the expression of various genes, including amphiregulin (AREG). AREG is an oncogene overexpressed in various types of cancers, and it is related to poor prognosis and tumorigenesis. The effect of interplay between T₃ and AREG on BC cells remains largely unclear. The present study aimed to examine the modulatory effects of T₃ on AREG expression, and the involvement of extra nuclear signaling pathways in MCF-7 human BC cell line. Cells were treated with 10 nM T₃ for 1 h, in the presence or absence of the (i) phosphatidylinositol 3-kinase pathway inhibitor, LY294002; (ii) targeting ligand for integrin αvβ3 peptide, RGD; or (iii) MAP/ERK pathway inhibitor, PD98059. AREG mRNA expression and protein synthesis were analyzed by RT-qPCR and western blotting, respectively. T₃ increased the expression of AREG in MCF-7 cells, and this effect was inhibited by all compounds tested. Western blotting analysis confirmed these results, indicating the dependency of AREG expression on the PI3K, MAP/ERK, and integrin pathways. These results demonstrate that activation of the PI3K, MAP/ERK, and integrin signaling pathways is necessary for the T₃-mediated effects on AREG expression in MCF-7 cells, highlighting the non-genomic action of T₃. In this study, we demonstrate that T3 increases AREG expression through extranuclear pathways. The data obtained present a great potential for application, since the identification of new signaling pathways and other mecanisms by which thyroid hormones act can lead to the development of specific drugs, to activate or block such pathways, promoting desirable effects and blocking undesirable ones.

Monocarboxylate transporter 8 (MCT8), is a membrane-spanning protein that specifically transports iodothyronines. MCT8 shares its 3D topology with other major facilitator superfamily members, whith two 6 TMH-bundles, an N-terminal bundle linked by an extended linker peptide to a C-terminal bundle. Each of its 6 TMH-domain surrounds the translocation pore, which could be depicted through the translocation process as extracellular opened, extracellular partly occluded and intracellular opened conformations. Several residues inside the pore have been identified to participate on the translocation process by alanine scanning and molecular docking simulations, nevertheless; this method does not describe the substrate diffusion in proteins, required to define the roles of specific amino acids at atomic level. In this work, we use microsecond molecular dynamics (MD) to describe the T4 and T3 interactions inside MCT8 substrate–translocation pore at different conformations, and to provide insight into MCT8 dynamics beyond the docking models. Extracellular opened, extracellular partly occluded and intracellular opened conformations MCT8 homology models as described by Protze et al. were embedded into an explicit POPC, hydrated and ionized by 0.15 M NaCl. Starting initial conformation of each T4, T3 and MCT8 complex were produced by docking. MD were conducted in AMBER18 package. Each MD included a minimization, heating and equilibration by 50 ns, then, 1 us production NPT MD simulation was conducted with periodic boundary conditions at 310 K and 1Bar. We characterized the interactions between iodothyronines and several residues of TMH 7 and TMH10 as example L492, G495, D498, F50, L512 and His415 and Lys418. As described by docking models, Arg445 and Asp498 interaction with T3 is observed in all MCT8 states. Also, Lys418 participate on T3 binding and attracting other charged sidechains at the pore. Other residues and interaction partners will be further described, as molecular simulations are currently underway. Molecular dynamics Simulations were conducted to describe T4 and T3 diffusion inside MCT8, revealing key interactions of the different conformations that guide these substrate through the pore

Hyperthyroidism remains as one of the endocrinology disorders that have a broad effect on the patient's body system. Recent evidence shows that hyperthyroidism could lead to impairment of insulin activity. This mini systematic review addresses the correlation between overt hyperthyroidism that could lead to insulin resistance state.

Literature searching through four databases, which are PubMed^®, Cochrane Library^®, PROQUEST^®, and SCOPUS^® was performed. Articles were appraised for validity, importance, and applicability. There were five studies met the criteria before the critical appraisal is conducted. Four of five studies showed a significant linear correlation between overt hyperthyroidism and insulin resistance. Two studies also showed that overt hyperthyroidism altered insulin sensitivity in the post-prandial state. Each of studies also studied any components which suggestively contributed to insulin resistance developing, i.e. glucagon and ghrelin hormone, glucose intolerance (as performed by OGTT). Insulin resistance is commonly developed in patients with overt hyperthyroidism, either in fasting or postprandial state. Pathogenesis-related to development of insulin resistance as a consequence of overt hyperthyroidism should be determined briefly as there are many pathways have their role contributed to this condition.

The changes of thyroid hormone levels during pregnancy vary greatly among different racial and geographic groups. It is recommended to establish population-based reference range more representative of the local population being treated. Our aim was to establish the reference values for serum TSH, fT3 and fT4 during the first trimester of pregnancy in a healthy Canadian population. We conducted a cross-sectional study at the CIUSSSE-CHUS academic hospital in Sherbrooke, Quebec. We recruited a convenient sample of healthy pregnant women at their first antenatal visit, before 13 weeks of gestational age (determined by sonography). We excluded women with past/actual history of thyroid disease, past/actual use of interfering drugs (levothyroxine, anti-thyroid drugs, amiodarone), recent exposure to high dose iodine, past head and neck irradiation/surgery, twin pregnancy and features of hyperemesis gravidarum. Women with positive thyroid peroxidase antibody results were subsequently excluded. Reference ranges were established as the 2.5^thand 97.5^thpercentiles. We recruited 121 women aged between 19 and 38 years (mean of 28). Gestational age ranged between 7.4 and 13 weeks (median 12.3). Reference ranges during the first trimester in our population were: 0.17-3.16 mUI/L for TSH, 4.01-6.29 pmol/L for fT3 and 11.40-19.12 pmol/L for fT4. We found no statistical difference in TSH values between age subgroups (<30 y.o vs >30 y.o), even though our study was not powered for this analysis. We observed a trend towards lower TSH values at the end of the first trimester (12-13 vs 7.4-12 weeks subgroups), seemingly reflective of the peaking hCG values; however, the number of patients in those subgroups were too small to draw firm conclusions. We established reference values for TSH, fT3 and fT4 during the first trimester of pregnancy in our center, in a well-characterized population, as recommended by various medical associations. The results of the TSH values are slightly under the normal non-pregnant reference range in our center (0.35-3.50 mUI/L); this is consistent with the latest 2017 ATA guidelines that suggest a reduction in the non-pregnant TSH upper reference limit of ∼0.5 mUI/L.

Many features of thyroid nodules increase the risk of malignancy. Focal FDG-PET uptake in a thyroid nodule confers a risk of cancer of 30% to 50%, depending on the series. The risk is also significantly increased with higher SUV uptake.

We here report two cases of highly suspicious thyroid nodules, with significant FDG-PET focal thyroid uptake with final benign histology.

Case 1: A 71 yo man, without significant medical history and no exposure to radiation, was referred for a left thyroid nodule, measuring 30x30x40 mm, solid and hypoechoic on ultrasound (US). His TSH was normal at 2,41 mUI/L. A FDG-PET done to investigate pulmonary nodules showed a very high focal uptake of the thyroid nodule, with a SUV of 112. The pulmonary nodules were metabolically inactive. The fine needle aspiration (FNA) showed a follicular neoplasm. His McGill thyroid nodule score (MTNS) was 17 pts, confering a risk of malignancy of 93%. On the final pathology report after total thyroidectomy, the left nodule was a benign follicular adenoma, with no capsular or vascular invasion. An inframillimetric papillary carcinoma was found in the right lobe, away from the surgical margins.

Case 2: A 87 yo man treated for renal cancer, was found with a pulmonary nodule on control imaging. On FDG-PET, the pulmonary nodule was mildly active with a SUV of 2,5, and a highly metabolically active right thyroid nodule was found with a SUV of 53. There was no renal uptake. His TSH was normal at 2,08 mUI/L. On US, a multinodular goiter was seen, and the highly active nodule was solid, hypoechoic and measured 21x18x34mm. The FNA showed a follicular neoplasm. The MTNS was 16 pts, with a risk of malignancy of 93%. He had a total thyroidectomy and the final pathology reported a multinodular hyperplasia. There was no sign of vascular or capsular invasion. These two patients had thyroid nodules with many suspicious features: male sex, age, size, hypoechogenicity on US, and very high focal FDG-PET uptake. There was no molecular testing done because of their limited access in our clinical setting. They both underwent surgery, and fortunately, had benign lesions. Even in highly active suspicious thyroid nodules, malignancy is not necessarly the explanation.

Whether recombinant human growth hormone (rhGH) therapy in adults alters thyroid function is controversial because results of previous reports were inconsistent. Here, we show a representative case and results of our retrospective study. A 53 year-old female with primary hypothyroidism was suffered from fatigue. We diagnosed as isolated GH deficiency: serum IGF-1 level was 30 ng/mL and peak serum GH levels were 7.45 ng/mL in GHRP-2 stimulating test and 0.25 ng/mL in arginine test. 0.25 mg/day of rhGH therapy improved her symptoms and increased IGF-1 to 116 ng/mL. Interestingly, her serum fT3 level increased from 2.53 to 3.13 pg/mL, fT4 decreased from 1.940 to 1.880 ng/dL, and TSH decreased 0.823 to 0.280 μIU/mL. In addition, her serum levels of total-cholesterol, LDL-cholesterol, and creatinine were decreased (254 to 219, 161 to 126, and 0.82 to 0.69, respectively). Then, we performed a retrospective study focused on 20 consecutive patients with severe adult GH deficiency who received rhGH therapy in our institution. After 3 months of rhGH therapy, median serum fT3 level increased from 2.38 to 2.78 pg/mL (p < 0.001), fT4 decreased from 1.115 to 1.065 ng/dL (p = 0.081), and TSH decreased from 0.834 to 0.624 μIU/mL (p = 0.029). Considering an increase in serum fT3 level and decreases in serum levels of cholesterols and creatinine, rhGH therapy might augment thyroid hormone action. We hypothesize that rhGH therapy is more effective for patients with adult GH deficiency who present low serum fT3 level. We verified that rhGH therapy increased serum fT3 level and decreased fT4 and TSH in the patients with severe adult GH deficiency. Data on thyroid function might be useful in the management of adult GH deficiency.

Management of hypothyroidism may be challenging due to malabsorption or non-adherence. Replacement of enteral dose is 1.6-1.8mcg/kg with intestinal absorption of 70-80%. Some patients require higher doses of levothyroxine (LT4 > 1.9mcg/kg). Various gastrointestinal disorders that lead to malabsorption or loss of intestinal secretions may result in higher requirement. We present a case of refractory hypothyroidism despite large doses of oral levothyroxine due to malabsorption of oral LT4. A 60-year old, 130 kg female presented with fatigue and intermittent diarrhea, with TSH 206 uIU/ml (0.45-5.33 uIU/ml) and FT4 < 0.25 ng/dl (0.61-1.44 ng/dl). She had had total thyroidectomy and radioiodine treatment at outside institution for papillary thyroid microcarcinoma and had normal thyroid function tests on standard doses of LT4 until she underwent cholecystectomy. She reported intermittent diarrhea and abnormal thyroid function tests (TSH 206 uIU/ml) following cholecystectomy. Her doses were increased gradually and she was taking LT4 1200 mcg and lliothyronine 25mcg orally daily on an empty stomach without missed doses when she presented. Extensive gastrointestinal evaluation failed to reveal any evidence of malabsorption. She was hospitalized multiple times for severe symptomatic hypothyroidism. LT4 absorption tests revealed poor enteral absorption. Subcutaneously administered LT4 did not result in a rise in FT4 or TT4. She responded to twice weekly intravenous 300mcg LT4 and daily 600 mcg LT4 soft gel capsules, with TSH improving to 18uIU/ml and FT4 0.68ng/dl. Hypothyroidism in our patient was refractory to large doses of oral LT4 and responded to intravenous but not subcutaneous LT4. Studies indicate possible hypotheses including intestinal malabsorption of LT4 due reduction in bile salts after cholecystectomy, type 3-deiodinase overexpression and altered intestinal microbiota. About 10-20% of hypothyroid patients require greater than weight based amounts of LT4 for unknown reasons. We recommend early initiation of parenteral LT4 therapy to reduce morbidity. More studies are needed to evaluate mechanism of enteral LT4 malabsorption in such refractory cases.

Our objective was to assess to comparison of clinicopathologic features of thyroid nodules according to the thickness of hypoechoic rim on ultrasonographyFrom January 2016 to December 2016, 235 thyroid nodules were having hypoechoic rim on ultrasonography were included. All patients underwent preoperative thyroid ultrasonography and thyroid surgery. The thickness of hypoehoic rim of each thyroid nodule were retrospectively reviewed according to the clinicopatholgic features. Thick group was defined as a thickness of hypoechoic rim of ≥1mm. Of the 235 thyroid nodules (mean size, 2.01 ± 1.6cm; mean thickness, 0.86mm), 81 were thick group and 154 were thin group. A statistically significant difference was found between thick and thin group regarding the malignant nodules (p = .0.04) and extrathyroidal tumor extension (p = .0.04), while no significant differences were observed in the tumor size, age, sex, op method, status of lymph node metastasis, the number of metastatic lymph node, or lymphovascular tumor extension of the lesion (p > 0.05) The thickness of hypoechoic rim of thyroid nodules on preoperative ultrasonography were helpful for predicting malignancy and extrathyroidal tumor extension.

While hypocalcemia remains the most common complication associated with thyroid surgery, technological developments have focused on lowering morbidity associated with bleeding, vocal cord palsy and scar burden. Optical coherence tomography (OCT) is a portable imaging modality that uses near-infrared light interferometry to reproduce in real-time the microarchitecture of tissues. Given its properties, several groups have proposed that OCT could serve as an adjunct tool to differentiate neck tissues and identify parathyroid glands during thyroid surgery. In fact, preliminary studies have demonstrated that OCT imaging characteristics correlate closely with histopathologic findings for each tissue type. Previously, our group described the feasibility of obtaining high-quality, 3D OCT imaging of tissue in an in vitro and in vivo setting. The objective of this study is to determine the sensitivity, specificity and reliability of OCT in differentiating parathyroid glands, thyroid, lymph nodes and fat during thyroid surgery.

Thirty-two patients undergoing thyroidectomy, parathyroidectomy and/or neck dissection were prospectively recruited. Surgical specimens of parathyroid, thyroid, lymph nodes and fat were imaged with a commercial grade OCT system prior to histopathological evaluation and diagnosis. Two blinded reviewers examined all images and independently classified them by tissue type based on OCT characteristics. The same reviewers were asked to review the same images 4 weeks later to calculate inter-rater and test-retest reliability with Cohen's kappa. Fourteen pathology-proven specimens of parathyroid were imaged, 27 of thyroid, 26 of lymph node, and 19 of fat. The sensitivity and specificity of OCT in identifying each of these tissue types were respectively: 92.9% and 100%, 96.3% and 98.3%, 100% and 98.5%, and 92.9% and 98.3%. Inter-rater and test-retest reliability were 0.952 and 0.968. This proof-of-concept study suggests that OCT is an innovative imaging modality with excellent sentivity, specifity, inter-rater and intra-rater reliability. It has the potential to assist surgeons in parathyroid identification and preservation during thyroid surgery and central neck dissections.

Both radioiodine FDG PET/CT and WBS scans play an important role in the management of higher-risk differentiated thyroid cancer (DTC). For several years our institution has offered a combined protocol in which both of these scans are performed sequentially. Following stimulation with either thyroid hormone withdrawal or the use of recombinant human Thyroid Stimulating Hormone, the patient undergoes a PET/CT followed by a dedicated PET/CT of the neck. Following this scan, the patient is administered radioiodine (RAI), and returns 24-48 hours later to receive a WBS. Baseline and stimulated thyroglobulin (Tg) levels are also obtained. Thirty randomly selected studies were analyzed. Collected data included demographic information, PET/CT and WBS results, Tg levels, additional radiographic data, and clinical information. The patients were predominantly female (22/30), aged from 20 to 78 years (mean 49.4). All had DTC, with 27 diagnosed with papillary thyroid cancer, two with follicular thyroid cancer, and one with components of both. Most were TNM stage 1 (20/30) at initial diagnosis, five stage 2, one stage 3, and four stage 4. The primary indication for the combination of studies was aggressive features; time from diagnosis to scan ranged from 0.3 to 18 years (mean 6.9). All but two had been treated with 131I.

Residual or recurrent disease was diagnosed in 11 patients. PET/CT proved sensitive, detecting all of these cases, but relatively nonspecific. WBS proved less sensitive, detecting only four of those with disease, although only three false positives were noted. WBS demonstrated a benefit accurately showing a good response to therapy and predicting RAI distribution following therapy. Stimulated Tg levels accurately detected six patients with disease; three of the patients not detected in this manner had Tg antibodies, although one patient with PTC demonstrated no Tg stimulation. Combined stimulated PET/CT and WBS provides a valuable tool at our institution for efficiently evaluating higher-risk DTC patients. PET/CT proved sensitive, although unspecific. WBS was relatively insensitive, although did demonstrate other clinical benefits. Tg levels were relatively specific, but complicated by antibodies.

To validate a new risk stratification system for thyroid nodule, K-TIRADS was proposed by Korean Society of Thyroid Radiology. Despite the high diagnostic performance, 30 ∼ 80% of biopsied nodules turned out benign. To reduce unnecessary biopsy, other assessment methods were evaluated, i.e.elastography, which measures the stiffness of nodule. Here, we present the prospective study of US elastography to evaluate the role of elastography in differentiating indeterminate thyroid nodules by ultrasonography in order to decrease the number of tissue biopsies. From May 2015 to Jan. 2017, we recruited subjects who were referred to perform FNA from primary physician. During the period, elastography was performed on 145 nodules from 127 subjects before FNA. Among them, 11 nodules were not biopsied. Among 134 nodules, 4 nodules showed unsatisfactory and 1 nodule came out as a follicular neoplasm but didn't undergo surgery. Finally, 129 nodules from 116 subjects were enrolled in the analysis. The mean maximum diameter of nodule was 13.7 ± 7.3 mm. Incidence of malignant nodule proven by cytology with/without pathologic report was 32.1% of total. The diagnostic performances in category 4 and 5 of K-TIRADS showed 97.6% sensitivity, 39.1% specificity, 43.6% positive predictive value, 97.1% negative predictive value (NPV) and 58.1% accuracy. There's no benefit of additional diagnostic yield of combining ECI value of elastography in whole patients. Among indeterminate nodule by K-TIRADS (category 4), applying cut off value determined by ROC curve (2.255), the overall NPV was slightly better, 100% compared to 97.1% respectively. Elastography should not replace US, but it may be used as a complementary tool for assessing nodules for FNA in indeterminate nodules, especially due to its high NPV.

Bilateral axillobreast approach (BABA) endoscopic thyroidectomy can be a good option for huge benign thyroid goiter larger than 5 cm. This study aimed to describe the effectiveness and technical aspects for Bilateral axillobreast approach (BABA) endoscopic thyroidectomy in detail. Between January 2008 and October 2017, 30 patients with a benign thyroid goiter larger than 5 cm or Graves' disease underwent BABA endoscopic thyroidectomy. Parathyroid hormone was measured at postoperative day 1 in all patients. The bilateral axillo-breast approach endoscopic thyroidectomy was successful in all patients, was performed by a single surgeon, and none required conversion to open surgery. The operation types were lobectomy (n = 20), subtotal thyroidectomy (n = 2), near total thyroidectomy (n = 3), and total thyroidectomy (n = 5). There were no postoperative vocal cord paralysis or postoperative bleeding. Postoperative transient hypocalcemia occurred in 3 patients (10.0%), but permanent hypocalcemia occurred in only 1 patient (3.3%). BABA endoscopic thyroidectomy can be safely performed in patients with a thyroid goiter larger than 5 cm, and it showed excellent clinical and cosmetic outcomes.

Lipodystrophy (LD) and insulin receptor mutation (INSR) syndromes are characterized by severe insulin resistance (IR) and hyperinsulinemia. High-dose insulin and leptin are common treatments and both have the potential to increase cell growth and proliferation via MAPK signaling, which may be enhanced as IRS/PI3K signaling is impaired. There is evidence that milder IR in type 2 diabetes may lead to increased thyroid volume (TV) and thyroid nodules/cancer.

The aim was to analyze thyroid abnormalities in severe IR and to determine if leptin therapy is associated with thyroid structural changes.81 patients with LD and 11 with INSR (mean age 32 ± 18 and 18 ± 12y (p = .0002) with available thyroid ultrasound (US) were analyzed. 60 were on leptin therapy. TV was similar in LD and INSR (10.6 ± 6.5 and 9.3 ± 7ml, p > .05). Echotexture was heterogenous in 61% and 73% with normal vascularity in 96% and 91%, in LD and INSR (p > .05). Thyroid cysts were present in 60% and 73% of LD and INSR patients (p > .05). Thyroid nodules (TN) were present in 36.3% of LD patients (55 TN in 29 patients; mean size 1.1 ± 1.5cm). 40% of TN were solid; 11% hyperechoic and 81.8% hypoechoic with ill-defined or lobulated/irregular margins in 22% and 3.6%. Macro/peripheral calcifications were found in 23.6% of TN (13/55). In patients <18y, there was no difference between LD and INSR groups for gender, TV and prevalence of TN.

In LD, there was no difference in TV, cysts, or TN between patients on leptin vs those never treated with leptin. INSR patients on leptin had greater TV (15.4 ± 8.6) vs those never treated with leptin (6 ± 3ml, p = .04). However, all leptin-treated patients were homozygous while those never treated with leptin were all heterozygous for INSR mutation.

3.2% of patients (2 LD, 1 INSR, mean age 25 ± 12y) were diagnosed with low risk papillary thyroid cancer. 1 LD patient never treated with leptin and other 2 patients were on leptin. Patients with severe IR have a high prevalence of TN and thyroid cancer at young age, which occurred in both leptin-treated and never treated patients. Further studies are needed to determine the etiology of thyroid abnormalities in patients with severe IR, and whether leptin treatment increases risk of PTC.

The purpose of this study was to evaluate the results of radionuclide therapy with iodine-131 (I-131) in patients (pts) with autonomously functioning thyroid nodules (AFTNs) and a normal thyroid stimulating hormone (TSH) blood level. Up to our knowledge, this is the first study which has scintigraphically evaluated the effect of I-131 therapy in patients with AFTNs and normal TSH blood level.

In this study 76 cytological benign AFTNs in 67 pts (58 female and 9 male) with normal TSH level have been treated with a fixed I-131 doses (370 MBq). Clinical exam, ultrasonography with color Doppler (US), fine needle aspiration biopsy (FNAB), TSH, FT4, FT3, anti-TPO, anti-Tg and thyroid scan (scintigraphy) have been performed in all pts before and 6 months after I-131 therapy. The median age of the pts was 57 (range 35 – 83) years. AFTNs were located more frequently in the right thyroid lobe (44 nodules) than in the left lobe (32 nodules). In 11 pts a solitary AFTN has been found on ultrasonography and the other 56 patients had AFTNs in multinodular goiter. Nine pts had two AFTNs. On post I-131 therapy thyroid scan in 52 AFTNs complete therapy effect has been observed, but in 24 AFTNs a scintigraphycally partial effect has been noted. Statistical analysis showed a significant reduction in the thyroid (p = 1.1815E-18) and AFTNs (p = 0.00049) volume after J-131 therapy. TSH value significantly increased (p = 0.00225) and FT4 value significantly decreased (p = 0.00054) after I-131 therapy. FT3 (p = 0.3616), anti-TPO (p = 0.9387) and anti-Tg (p = 0.2713) values did not change significantly.

This study shows that radionuclide therapy with I-131 in pts with AFTN and normal TSH blood level is a simple, cheap and very effective modality. The effect of the I-131 therapy on AFTNs can be evaluated with a thyroid scan 6 months after I-131 therapy.

Following thyroidectomy, transient hypocalcemia is a common and well recognized complication. Whether a low preoperative vitamin D level increases the risk of this complication continues to be a topic of debate. The aim of this study was to determine whether 25-hydroxyvitamin D (25[OH]D) level predicts postoperative hypocalcemia in patients undergoing total or completion thyroidectomy. A single center retrospective study was conducted including all patients receiving total or completion thyroidectomy between January 2007 and March 2017. 25-hydroxyvitamin D (25[OH]D) levels were measured within 42 days of surgery or one day post operatively. Hypocalcemia was defined as an adjusted calcium (based on albumin levels) of <8.0mg/dL or symptomatic hypocalcemia with a positive Chvostek's sign. Univariate analysis was performed using a two-sample t-test and chi-squared test while multivariate analysis was performed using logistic regression analysis to determine whether preoperative 25-hydroxyvitamin D (25[OH]D) level is a predictor of postoperative hypocalcemia. Significance was determined with an alpha level of 0.05. A total of 517 subjects were included in the study. 15.67% (n = 81) of subjects experienced postoperative hypocalcemia with an average serum calcium level of 7.64 ± 0.48mg/dL compared to 8.92 ± 0.51mg/dL in the normocalcemic population (p ≤ 0.0001). The mean 25-hydroxyvitamin D (25[OH]D) level for hypocalcemic patients was 24.43 ± 11.97 ng/mL compared to 27.49 ± 12.21 ng/mL in normocalcemic patients (p = 0.0382). Subjects who were hypocalcemic experienced a significantly longer hospital stay (2.93 ± 2.47 vs. 1.37 ± 1.08; p < 0.0001). After adjusting for preoperative calcium, 25-hydroxyvitamin D (25[OH]D) levels was a significant predictor of postoperative hypocalcemia (OR = 1.023; p = 0.0420; 95% CI (1.001, 1.045). We have demonstrated that 25-hydroxyvitamin D (25[OH]D) level is a significant predictor of postoperative hypocalcemia after thyroidectomy.