bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT019 Ligand-independent Signaling And Migration Of Breast Cancer Cells Overexpressing Membrane Androgen Receptor, ZIP9
Authors: Thomas Peter
Published: October 2023

Disclosure: P. Thomas: None.

The zinc transporter ZIP9 also functions as a membrane androgen receptor (mAR) that mediates androgen-dependent rapid signaling and pro- or anti-apoptotic, proliferative, and migratory responses in fish, rodent, and human cells. Testosterone activation of ZIP9 in two triple-negative breast cancer cell lines, MDA-MB-468 cells and MDA-MB-231 cells transfected with ZIP9 (231-ZIP9), induces G-protein-dependent second messenger signaling and increases in intracellular free zinc. However, the relative importance of these two signaling pathways in the regulation of pro- and anti-tumorigenic responses in these cell lines is unclear because both androgen signaling and zinc status influence tumorigenesis in breast tissues. The effects of overexpression of ZIP9 on free zinc status, G protein- and zinc-dependent regulation of migration, and migration marker expression in 231-ZIP9 cells in the absence of testosterone were compared to those observed in MDA-MB-231 cells transfected with vector alone (231-vect). Migration and invasion of 231-ZIP9 cells were significantly increased after 24-48 hr culture in serum-free media compared to 231-vect cells which was accompanied by a significant increase in free zinc levels. Treatment of 231-vect cells with a zinc ionophore also increased migration, whereas migration of 231-ZIP9 cells was attenuated by treatment with an intracellular zinc chelator, TPEN. Expression of the migration markers, MYL9 and CYR61, was increased in 231-ZIP9 after 24-48 hr culture, whereas expression of apoptotic markers was decreased compared to 231-vect controls. Proximity Ligation Analysis revealed that ZIP9 is closely associated with a stimulatory G protein (Gs) in 231-ZIP9 cells which is consistent with the finding that treatment with the adenylyl cyclase (AC) stimulator forskolin, further increased migration marker expression and migration compared to vehicle controls, whereas the PKA inhibitor, H-89, attenuated these responses as well as the increase in free zinc concentrations. Knockdown of ZIP9 expression in MDA-MB-468 cells which express relatively high levels of ZIP9 with siRNA decreased cell migration and invasion as well as free zinc levels, confirming a role of unliganded ZIP9 in migration in another breast cancer cell line. Treatment of 231-ZIP9 cells with 100 nM testosterone further stimulated CYR61 and MYL9 expression and cell migration which were blocked by co-treatment with a Gs inhibitor and TPEN. The results indicate that high ZIP9 expression in breast cancer cells causes androgen-independent increased cell migration and invasion which in 231-ZIP9 cells is through Gs/mAC/PKA-mediated increases in intracellular zinc concentrations and upregulation of MYL9 and CYR-61 expression. Furthermore, the results suggest that testosterone-dependent signaling through ZIP9 acts through the same pathways to further enhance signaling and migration.

Presentation: Saturday, June 17, 2023
OR22-06 Functional Characterization Of X-linked Genes In Regulating Epigenetic Landscape In Endocrine-resistant Breast Cancer
Authors: Ivan Ramos Enrique , Yang Barbara , Sedano Melina , Reid Victoria , Diwa Kimberly , Hidalgo Axel , Beard Alexandra , Patel Jai , Gadad Shrikanth S
Published: October 2023

Disclosure: E.I. Ramos: None. B. Yang: None. M. Sedano: None. V. Reid: None. K. Diwa: None. A. Hidalgo: None. A. Beard: None. J. Patel: None. S.S. Gadad: None.

Studies show that genes transcribed from chromosome X play critical roles in several biological processes. X-linked genes are tightly regulated and expressed in tissues protected from immune surveillance. However, several of them get dysregulated in diseases such as cancer. Intriguingly, genome-wide analyses showed their presence in the previously considered gene deserts in the human genome. Their direct role in estrogen transcription in tamoxifen-resistant breast cancer and biological outcomes are still unknown. To this end, we leveraged the power of functional genomics, including RNA with 4-thiouridine (4sU) coupled with RNA-sequencing and CRISPR-based genetic screening, to identify X-linked genes with a potential role in tamoxifen-directed estrogen-regulated transcription. Through a series of phenotypic assays, we selected a poorly studied transcript, “H19X,” with limited protein-coding potential; RNA-In-Situ-Hybridization revealed its localization to the nucleus. In the current study, we have identified the H19X-controlled estrogen-dependent gene regulatory mechanisms in tamoxifen-resistant estrogen receptor-positive (ER+) breast cancer cells. We manipulated the levels of H19X in tamoxifen-resistant ER+ breast cancer cells to generate a comprehensive list of direct transcripts using 4sU-RNA-seq. Interestingly, H19X regulates the expression of estrogen-driven intergenic, divergent, and antisense transcripts whose promoters are bound by ER-alpha (ERα) binding sites. Mechanistically, ‘Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq)’ revealed that H19X modulates chromatin structure at target regions to control gene expression. In addition, ‘chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing ChIP-seq’ (H3K27ac, H3K27me3) identified a critical role for H19X in controlling the epigenetic landscape in tamoxifen-resistant ER+ breast cancer cells. Collectively, our study sheds light on the molecular functions of X-linked genes and allows us to identify new diagnostic and therapeutic targets in tamoxifen-resistant ER+ breast cancer.S.S.G. is supported by grants from a) The Cancer Prevention and Research Institute of Texas (CPRIT; RR170020); b) Lizanell and Colbert Coldwell foundation; c) The Edward N. and Margaret G. Marsh Foundation; d) The American Cancer Society

Presentation: Saturday, June 17, 2023
THU672 Fungating And Inflammatory Anaplastic Thyroid Carcinoma In A 64-Year Old Filipino
Authors: Tarrazona - Dominisac Rochelle Anne M , Capuli Isidro Maria Jocelyn
Published: October 2023

Disclosure: R.M. Tarrazona - Dominisac: None. M.C. Isidro: None.

Background: Anaplastic Thyroid Carcinoma is a rare and lethal undifferentiated thyroid cancer that occurs in less than 2% of all thyroid malignancies. In the Philippines, this rare entity has an estimated incidence of 0.7%. Its aggressive nature is strikingly significant because it carries a poor prognosis with a median survival of 5-6 months. An exceptionally rare presentation of an Anaplastic Thyroid Carcinoma is a fungating, exophytic and inflammatory type. Case Summary: This is a case of a 64-year old female with a 2 x 2 cm erythematous patch at her anterior neck. There is progressive enlargement of the reddish neck lesion associated by burning sensation with subsequent development whitish nodules with purulent exudate. The nodules were fragile with noted bleeding on minimal manipulation. Initial impression was anterior neck cellulitis and she was given 7 days of IV antibiotics with no resolution of the lesion. Neck CT scan showed a multinodular heterogeneously enhancing mass in the left neck region measuring 6.3 x 5.2 x 5.5 cm. A core needle biopsy of the mass revealed malignant cells present: anaplastic carcinoma vs squamous cell carcinoma, with immunohistochemical stains: PAX 8 positive, p63 negative, CK 5/6 negative, BRAF negative, TTF-1 focally positive. The patient underwent tumor debulking surgery with tracheostomy. The gross specimen was sent for histopathologic examination and finally revealed Anaplastic Thyroid Carcinoma. Conclusion: The case reported was a diagnostic dilemma early during the clinical presentation due to presence of rapidly enlarging, inflammatory and fungating anterior neck mass with presence of whitish nodules with purulent exudates, bleeding and pain. She was initially treated as an abscess only to discover presence of malignancy upon further work-up. Anaplastic thyroid cancer is the most advanced and aggressive thyroid malignancy. It is very rare and the atypical fungating presentation of this ATC makes it an exceptionally rare entity. Fungating wounds are the result of cancer cells infiltrating and invading the cutaneous structure. This case report highlights the importance of harnessing a high level of clinical suspicion for anaplastic thyroid cancer even in atypical looking anterior neck mass to ensure prompt definitive diagnosis and improve overall prognosis.

Presentation: Thursday, June 15, 2023
THU678 Real-world Performance Of Afirma Genomic Sequencing Classifier (GSC) In A Community Healthcare Setting
Authors: Master Vidisha , Nasir Syeda Javeria , Charatz Seth , Reidy Dawn , Clary Karen
Published: October 2023

Disclosure: V. Master: None. J. Syeda: None. S. Charatz: None. D. Reidy: None. K. Clary: None.

Introduction: Indeterminate thyroid nodules pose a significant clinical challenge due to their potential risk of malignancy. The Afirma GSC has emerged as a valuable tool for the non-invasive management of these nodules. However, its real-world performance in community healthcare settings remains poorly understood.

Aim: Comparison of GSC performance in a community healthcare setting to the validation study (VS) metrics.

Method: A retrospective study was conducted in a community endocrine practice, where 91 Afirma GSC samples were obtained from patients who had either suspicious cytology or atypia of undermined significance (AUS) between 1/1/2021 and 12/31/2022. Ten samples were excluded due to insufficient material. Surgical pathology was used as the gold standard for diagnosis. Molecular benign results without surgical pathology were considered true negatives, and 2 unoperated patients with suspicious results were excluded from analysis. We calculated observed positive predictive value (oPPV) and observed specificity (oSP) to account for these exclusions. Non-invasive follicular neoplasm with papillary-like features is considered malignant. The prevalence of thyroid cancer in the study population was 19%. Results are compared to previously published VS of 191 samples. Result: Our study showed a higher accuracy of 89% of the Afirma GSC in our community healthcare setting, with a sensitivity (SN) of 93%, oSP of 88%, oPPV of 63%, and negative predictive value (NPV) of 98%. In comparison, the VS had a SN of 91%, SP of 68%, PPV of 47%, NPV of 96%, and accuracy of 74%. Additionally, our study showed a higher benign call rate (BCR) of 70% compared to 54% in the VS. Conclusion: Our study provides evidence of the real-world performance of the Afirma GSC and supports its use as a non-invasive tool for the management of indeterminate thyroid nodules. Better oSP and oPPV are suggestive of higher yield of cancers for resected nodules based on suspicious GSC. References: Nasr CE, Andrioli M, Endo M, Harrell RM, Livhits MJ, Osakwe I, Polavarapu P, Siperstein A, Wei S, Zheng X, Jiang R, Hao Y, Huang J, Klopper JP, Kloos RT, Kennedy G, Angell TE. Real World Performance of The Afirma Genomic Sequencing Classifier (GSC) - A Meta-analysis. J Clin Endocrinol Metab. 2022 Dec 6:dgac688. doi: 10.1210/clinem/dgac688. Epub ahead of print. PMID: 36470585. Patel KN, Angell TE, Babiarz J, Barth NM, Blevins T, Duh QY, Ghossein RA, Harrell RM, Huang J, Kennedy GC, Kim SY, Kloos RT, LiVolsi VA, Randolph GW, Sadow PM, Shanik MH, Sosa JA, Traweek ST, Walsh PS, Whitney D, Yeh MW, Ladenson PW. Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules. JAMA Surg. 2018 Sep 1;153(9):817-824. doi: 10.1001/jamasurg.2018.1153. PMID: 29799911; PMCID: PMC6583881.

Presentation: Thursday, June 15, 2023
FRI471 Regulation Of Adult Thyroid Hormone Homeostasis By Early Postnatal Hyperthyroidism In Male Mice
Authors: Kovári Dóra , Szilvásy-Szabó Anett , Penksza Veronika , Gereben Balazs , Fekete Csaba
Published: October 2023

Disclosure: D. Kovári: None. A. Szilvásy-Szabó: None. V. Penksza: None. B. Gereben: None. C. Fekete: None.

The thyroid hormone (TH) negative feedback regulation enables the hypothalamic-pituitary-thyroid (HPT) axis to maintain the relatively steady circulating TH levels. Internal and external factors influence the development of this feedback regulation and consequently evoke life-long changes of the HPT axis activity. The aim of our study was to reveal how perinatal alteration of TH status influences TH homeostasis of adult mice. Mice were treated with 1µg/bwg thyroxine (T4) or vehicle subcutaneously every day between postnatal day (P) 2-6 and sacrificed at adulthood. Early postnatal hyperthyroidism resulted in central hypothyroidism in adults, characterized by decreased thyrotropin releasing hormone (TRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) and lower serum free T4 level, accompanied by unchanged thyrotropin stimulating hormone β (TSHβ) mRNA expression in the pituitary and serum free triiodothyronine level. The two main regulators of the HPT axis are the hypophysiotropic TRH neurons and tanycytes. Tanycytes affect the feedback regulation of TRH neurons by type 2 deiodinase (D2) mediated TH activation. To understand how postnatal T4 treatment results in central hypothyroidism in adult mice, tanycytes and TRH neurons of the PVN were isolated by laser capture microdissection from control and postnatally T4 treated adult mice. Postnatal T4 treatment did not change D2 expression in the tanycytes. Furthermore, using Thyroid Hormone Action Indicator (THAI) mice, we showed that the treatment did not influence TH action in the mediobasal hypothalamus of adult mice. These data together indicate that tanycytes are not involved in mediation of the postnatal T4 treatment induced effects. In contrast, the early postnatal T4 treatment markedly changed the transcriptome of TRH neurons in the PVN of adult mice. The expression of TH receptors, most TH receptor-related coregulators, TH transporters and genes involved in the synthesis of TRH were decreased. Despite of the central hypothyroidism, the energy expenditure of these mice were not decreased and TH action also remained unchanged in most tissues indicating that the peripheral tissues are able to compensate the effect of the generated mild hypothyroidism. These results indicate that alteration of TH levels during the early postnatal period can cause life-long effects on the activity of the HPT-axis likely via epigenetic regulation of TRH neurons.

Presentation: Friday, June 16, 2023
FRI472 Thyroid Hormone Resistance β (RTH- β) Syndrome In Patient With Multiple-system Atrophy Parkinsonian Type (MSA-P)
Authors: Lio Serafino , Albin Monica , Campi Irene , Persani Luca
Published: October 2023

Disclosure: S. Lio: None. M. Albin: None. I. Campi: None. L. Persani: None.

Background: Resistance to thyroid hormone β (RTHβ) is a rare dominantly inherited condition of impaired tissue responsiveness to thyroid hormones (TH) due to variants in the THRB gene encoding the TH receptor β (TRβ). RTHβ patients display a distinctive biochemical feature of central hyperthyroidism with elevated serum levels of FT3 and FT4 and unsuppressed TSH. Unfortunately, this syndrome is sometimes misdiagnosed as primary hyperthyroidism, with a delayed diagnosis or inappropriate treatments. Clinical Case: A 72-year-old lady was diagnosed elsewhere in 2010 with atrial fibrillation (AF) and parkinsonian multisystem atrophy (MSA-P), an orphan disease causing progressive autonomic and motor impairment. The patient reported an unspecified dysthyroidism discovered during the diagnostic work-up of AF, but no further investigations were performed. Bisoprolol, Edoxaban and Levodopa/Benserazide were started. In 2020 she had multiple hospitalization due to fall-related injuries, and multiple rib fractures. A neurological and cardiological reassessment did not highlight new problems, nor MSA-P progression, while discrepant thyroid function tests (TFTs) were found (TSH 2.4 mU/L, fT4 3.5 ng/dl, fT3 7.9 pg/ml; normal ranges: 0.4-4.5; 0.8-1.7 and 2.-5, respectively). Anterior pituitary function and a gadolinium-enhanced pituitary MRI were normal. Thyroid ultrasound revealed a modest goiter, with a normal vascularization and multiple hypo-anechoic and spongiform nodules ≤1 cm. Propylthiouracil has been started At referral in our Center, discrepant TFTs were confirmed (TSH 6.6 mU/L, fT4 2.5 ng/dL, fT3 5.1 pg/ml). TPOAb, TgAb and TRAb were absent. We also excluded assay interferences due to heterophiles antibodies. Being T3 administration contraindicated due to AF, a TRH-test, after suspension of PTU, was performed showing an intense and prolonged response of the TSH (36.7 and 19.2 mU/L at 30 and 120 minutes, respectively), consistent with RTHβ. Consistently, molecular analysis by a targeted NGS panel revealed a heterozygous known pathogenic variant in the exon 9 of the TRHB gene (c.1033G>A, p.Gly345Ser). Conclusion: In the differential diagnosis of central hyperthyroidism RTHβ should be considered even in older patients, as late diagnosis may occur. The association of RTHβ with MSA-P has never been reported before, although a causal relationship is improbable. Nevertheless, central hyperthyroidism could worsen underlying neurological diseases, given the critical role of TH in CNS and muscle. A greater awareness of both neurologists and endocrinologists on rare thyroid diseases is warranted, to improve the care of patients with neurological orphan diseases.

Presentation: Friday, June 16, 2023
FRI478 Pharmacometrics-based Computer Model Utilizing Heart Rate To Monitor Thyroid Function In Children With Graves' Disease
Authors: Steffens Britta , Koch Gilbert , Claude Fabien , Bachmann Freya , Schropp Johannes , Janner Marco , l'Allemand Dagmar , Konrad Daniel , Pfister Marc , Szinnai Gabor
Published: October 2023

Disclosure: B. Steffens: None. G. Koch: None. F. Claude: None. F. Bachmann: None. J. Schropp: None. M. Janner: None. D. l'Allemand: None. D. Konrad: None. M. Pfister: None. G. Szinnai: None.

Graves’ disease (GD) with onset in childhood or adolescence is a pediatric rare disease (ORPHA:525731) with a ten times lower incidence than in adults. Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. First-line treatment are anti-thyroid drugs in order to normalize thyroid function. However, dose finding in pediatric GD is complex due to a broad spectrum of disease severity at diagnosis, and highly variable disease activity during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) turns out to be a useful clinical marker to monitor thyroid activity under treatment. Our overall aim was to provide a practical pharmacometrics-based (PMX-based) computer model characterizing both, individual FT4 dynamics and the relation between FT4 and tachycardia in children with various disease severity of GD during the first 120 days of treatment. Development of the PMX computer model was based on the non-linear mixed effects approach (i) linking FT4 kinetics with HR dynamics, (ii) accounting for inter-individual variability, and (iii) incorporating individual patient characteristics. Retrospectively collected clinical (resting heart rate during consultation) and laboratory data (FT4) from 41 children and adolescents with GD at four pediatric hospitals in Switzerland (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements and 132 HR measurements, and 124 paired measurements, were available and used for model development. Pediatric patients showed median FT4 of 59.6 [IQR 44.5, 73.0] pmol/l and median HR of 112 [IQR 100, 128] bpm at diagnosis. GD severity groups were defined based on FT4 measurement at diagnosis, resulting in equal numbers of mild (13), moderate (14) and severe (14) GD. We observed a significant difference in HR at diagnosis (p < 0.01) between the three GD severity groups based on FT4 at diagnosis. The final PMX computer model accounted for inter-individual variability and clinically relevant covariate effects such as age, gender, and GD severity, and was able to accurately predict FT4 and HR dynamics for each individual patient during the first 120 days of treatment. A PMX-based computer model that leverages individual HR dynamics can be applied to facilitate personalized pharmacotherapy in pediatric GD and mitigate the risk for under- or overdosing of anti-thyroid drugs in these patients. Prospective randomized validation trials are warranted to further validate and fine-tune such computer-supported personalized dosing in children with Graves’ disease.

Presentation: Friday, June 16, 2023
FRI489 The Interplay Between Thyroid Nodular Disease And Insulin Resistance Indices In Pregnant Women
Authors: Jerzy Nowak Andrzej , Trofimiuk-Muldner Malgorzata , Podlewski Jacek , Hubalewska-Dydejczyk Alicja
Published: October 2023

Disclosure: A.J. Nowak: None. M. Trofimiuk-Muldner: None. J. Podlewski: None. A. Hubalewska-Dydejczyk: None.

Thyroid cells proliferation and function is regulated by TSH. Other factor, such as insulin/insulin-like growth factors (IGF), through their mitogenic effects, may affect thyroid growth and nodules formation [1].This study evaluated the interplay between insulin resistance indices and thyroid structure in pregnant women. The study group was recruited from the Polish National Program for Elimination of Iodine Deficiency, conducted between 2007-2017. We assessed the fasting glucose, insulin levels, TSH in 1069 pregnant women (median age 29 years, IQR 6 years). Thyroid ultrasound was performed in each study participant. Based on calculated HOMA-IR, pregnant women were stratified into three subgroups HOMA1 (324 women with HOMA-IR < 1), HOMA 2 (570 women with HOMA-IR ≥1& <2.5) and HOMA3 (175 women with HOMA-IR ≥ 2.5). Results: Median (IQR) TSH concentrations were 1.42 (1.33) mIU/L, 1.65 (1.31) mIU/L, and 1.77 (1.29) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. The mean (±SD) thyroid volume was 12.36 (4.27) mL, 12.71 (5.37) mL, and 13.70 (4.92) mL in HOMA1, HOMA2, HOMA3 subgroups respectively.33 (10.2%) of women in HOMA1, 53 (9.3%) in HOMA2 and 11 (6.3%) in HOMA3 subgroup had at least one thyroid nodule - there was no significant difference between the subgroups (P = 0.4724)Fasting insulin >10 mIU/mL was found in 27.53% of pregnant women (286 out of 1039) with thyroid volume <25 mL, and in 36.67% women (11 out of 30) with thyroid volume ≥25mL (P=0.27).

Conclusions: We have not found any significant relationship between the thyroid volume or structure and insulin or insulin resistance indices in pregnant women.

1. Kimura T., Van Keymeulen A., Golstein J., Fusco A., Dumont J.E., Roger P.P. Regulation of thyroid cell proliferation by TSH and other factors: A critical evaluation of in vitro models. Endocr. Rev. 2001;22:631–656. doi: 10.1210/edrv.22.5.0444.

Presentation: Friday, June 16, 2023
FRI549 The See-Saw Theory - Hypothyroidism Due To Hashimoto's Thyroiditis Followed By Hyperthyroidism Due To Graves' Disease
Authors: Sharma Pranjali
Published: October 2023

Disclosure: P. Sharma: None.

Introduction: Hashimoto's thyroiditis is an autoimmune disorder characterized by chronic inflammation of the thyroid gland that leads to hypothyroidism due to formation of autoantibodies against thyroid antigens such as thyroid peroxidase (TPO Ab). Graves' disease is caused by stimulating TSH-receptor antibodies (TRAb) that cause hypertrophy of the thyroid gland leading to hyperthyroidism. While the transformation of Graves' disease to Hashimoto's thyroiditis has been reported, flipping from Hashimoto's thyroiditis to Graves' disease is uncommon. Case Report: A 62 year old female with 20 year history of hypothyroidism secondary to Hashimoto's thyroiditis presented to establish care. She had run out of levothyroxine refills one year prior during COVID-19 pandemic restrictions. She had tachycardia, diarrhea, fatigue, tremors, hair loss, dysphagia, and weight gain. Thyroid panel testing showed hyperthyroidism with an undetectable TSH (normal range 0.45-4.5uIU/ml) and elevated free T4 (2.84, normal 0.82-1.77ng/ml). Patient denied recent infections, iodine intake or iodine contrast exposure. Repeat labs confirmed hyperthyroidism with undetectable TSH with elevated free T4 (3.17ng/ml). Antibody testing comfirmed hyperthyroidism secondary to Graves disease (TRAb 20.7, normal <1.75IU/L). Patient has been on methimazole with fluctuating response and is reviewing definitive therapy options. Discussion: We demonstrate the rare phenomenon of thyroid function transformation from long-standing inhibition to stimulation after 20 years. Hashimoto's thyroiditis is characterized by chronic inflammation due to autoantibodies against TPO, thyroglobulin and the TSH receptor with gradual gland destruction and hypothyroidism. Stimulating autoantibodies to the TSH receptor (thyroid stimulating immunoglobulin (TSIg), TRAb) in Graves' disease lead to hyperthyroidism from gland hypertrophy. The flip from underactivity to overactivity can be explained by recovery of the gland from Hashimoto's thyroiditis injury which gradually leads to an overt response to TSIg, causing a hyperfunctioning gland. An imbalance between the inhibitory and stimulating antibodies can also lead to this transformation. Age, pregnancy and immunomodulating drugs such as alemtuzumab are also thought to play a role. The recovery theory is unlikely in our patient with a 20 year history of Hashimoto's thyroiditis. We believe that she had a high inhibitory antibody titre initially and now has higher titre of stimulating antibodies later, leading to Graves' disease. Luckily, she ran out of levothyroxine otherwise the additive effect of levothyroxine and intrinsic gland activity could have led to worse symptoms. This case highlights that autoimmune hypothyroidism and hyperthyroidism are conditions in the same spectrum, rather than two distinct entities as previously thought.

Presentation: Friday, June 16, 2023
FRI553 ICI-induced Thyroid Ophthalmopathy With De Novo Graves’ Disease
Authors: Moctezuma Sananda I , Perlman Jordan , Sophie Mammen Jennifer
Published: October 2023

Disclosure: S.I. Moctezuma: None. J. Perlman: None. J.S. Mammen: None.

Background: Immune checkpoint inhibitors frequently target the thyroid gland. However, immune checkpoint inhibitor (ICI)-induced Graves’ disease (GD) is rare. To our knowledge, there are no reported cases of thyroid eye disease after immune checkpoint inhibitor therapy in patients with newly positive anti-thyroid antibodies. Clinical Case: An 81-year-old man developed thyroiditis within three weeks of a single dose of ipilimumab/nivolumab for the treatment of metastatic cholangiocarcinoma. ICI therapy was discontinued for cardiotoxicity. He presented one year later with onset of periorbital edema, pain with downgaze, redness, irritation and progressive proptosis with diplopia. He did not have a prior history of thyroid disease. Thyroid function tests before the start of ICI therapy revealed euthyroidism [TSH 2.982 uIU/mL (0.55 - 4.78)]. Symptoms of palpitations, weight loss, and hyper-defecation that characterized his initial presentation with thyroiditis were absent at the time of onset of eye disease. At presentation of thyrotoxicosis his TSH was <0.01 uIU/mL, free T4 3.6 ng/dL (0.89 - 1.76) total T3 190 ng/dL (60-180) Thyroid-peroxidase autoantibodies (TPOAb) and thyroid-stimulating immunoglobulin (TSI) were negative. When his visual symptoms appeared, TPOAb remained negative while a repeat TSI antibody was positive [0.64 IU/L (0.00 - 0.55)]. Thyroid ultrasound at the time of thyroiditis revealed a heterogeneous gland without discrete nodules and a normal vascular flow. Most cases of ICI-induced GD have been reported at the start of therapy, particularly in the first 6 weeks, although thyrotoxicosis has been described to occur as late as 224 days after starting PD-1 inhibitor. GD is more frequently reported with combination anti-CTLA-4 and anti-PD-1 therapy. Patients with thyroid ICI-induced adverse events experience either isolated hypothyroidism or thyroiditis spontaneously evolving towards hypothyroidism. However, ICI-induced GD is more likely to have a relapsing-remitting disease. In 2021, Peiffert et al. described the antibody profile for 243 patients with ICI-induced thyrotoxicosis. In this case series, 5 patients developed thyrotoxicosis with positive thyrotropin-receptor antibodies (TRAb). Only 2 patients had a typical clinical presentation of GD. TSI antibodies were not reported. Furthermore, none of the patients with positive TRAb had Graves’ ophthalmopathy. Conclusion: Our case demonstrates the acquisition of auto-antibodies capable of mediating Graves’ disease, and raises the possibility that thyroid eye disease-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy. These symptoms developed as late as one year after initiation of therapy. As with sporadic cases, this can occur in the absence of clinically significant hyperthyroidism.

Presentation: Friday, June 16, 2023
OR14-01 Contact Between Thyroglobulin Opposite Domains Assists Its Upstream Regions In Intracellular Trafficking For Thyroid Hormonogenesis
Authors: Citterio Cintia E , Kim Kookjoo , Rajesh Bhavana , Pena Kevin , Clarke Oliver B , Arvan Peter
Published: October 2023

Disclosure: C.E. Citterio: None. K. Kim: None. B. Rajesh: None. K. Pena: None. O.B. Clarke: None. P. Arvan: None.

Thyroglobulin (Tg), must be released into the lumen of thyroid follicles to facilitate thyroid hormone synthesis. The Tg primary sequence (∼2,760 amino acids) includes regions I, II, III, as well as ∼570 residues of cholinesterase-like (ChEL) domain (which bears 47% similarity to acetylcholinesterase), folded as a globular protein with multiple contacts between different Tg regions. The ChEL domain is reported to function as an intramolecular chaperone assisting Tg region I. This function cannot be replaced by acetylcholinesterase or neuroligins, indicating a unique function of Tg ChEL. However, the specific amino acids of ChEL neighboring upstream Tg regions have only recently been identified, and the key functional residues for Tg folding remain unknown. Here, we’ve combined structural analyses with functional characterization of recombinant Tg expressed in cell culture. We’ve identified hTg-ChEL K2223 and W2222 as amino acids that exhibit the closest physical proximity with Tg region I. By cryo-EM of Tg (both human and bovine), Tg-K2223 and Tg-W2222 reside only ∼4.5Å from Tg-W1089 and Tg-P1098, respectively, both of which are located in the Tg 1-9 repeat within region I. We’ve employed site-directed mutagenesis to determine the impact of these contacts by studying both full length Tg as well as Tg expressed in a two-component system in cultured cells. We find that secretory ChEL-K2223E and ChEL-W2222A behave much like WT secretory ChEL; both mutants are reasonably well expressed and secreted efficiently. However, when secretory ChEL was co-expressed with Tg region I-II-III lacking its own ChEL domain, region I-II-III secretion could be rescued in the presence of WT secretory ChEL, but not by co-expression of either ChEL-K2223E or ChEL-W2222A. In context of a single contiguous full length Tg, both expression and secretion of Tg-K2223E and Tg-W2222A were significantly diminished. These results highlight two residues (K2223 and W2222) that are not needed for the independent folding (or endoplasmic reticulum export) of the Tg ChEL domain, but are key residues for contacting Tg region I, thereby offering the overall Tg structure a great increase in conformational stability, which is needed to satisfy endoplasmic reticulum quality control requirements for intracellular protein trafficking. These findings point to the possibility that mutations altering regional contacts within the Tg structure could contribute to the molecular pathogenesis of congenital hypothyroidism.

Presentation: Friday, June 16, 2023
SAT449 Clinical Characteristics Of Patients With Thyrotoxic Periodic Paralysis; An Experience From A Tertiary Care Hospital
Authors: Sun Park Tae , Goak Insun , Jin Heung-Yong , Ae Lee Kyung , Ji Kim Yu
Published: October 2023

Disclosure: T. Park: None. I. Goak: None. H. Jin: None. K. Lee: None. Y. Kim: None.

Backgrounds: Thyrotoxic periodic paralysis (TPP) is a life-threatening complication characterized recurrent episodes of hypokalemia and muscle weakness in the setting of thyrotoxicosis. The present study aimed to describe clinical manifestation and outcome of patients admitted for TPP in emergency department (ED). Methods: This retrospective study analyzed 42 patients with TPP who were admitted ED from January 2000 through December 2020 in a single tertiary referral hospital. Their clinical characteristics were reviewed retrospectively. Results: 42 patients with TPP were identified. The mean age of the patients was 35.0±12.4 years; all were males. The month in which the most patients occurred paralysis symptoms was February (16.7%), followed by October (14.3%). 5 patients had a history of severe exertion, 7 patients had ingested a heavy carbohydrate meal, one patient had an infection, 5 patients had ingested alcohol, but more than half of the patients (57.1%) were without a precipitating cause. TPP was the first presentation of thyrotoxicosis in 85.7% of patients. The most common cause of thyrotoxicosis in TPP patients was Graves' disease (88.1%). At the time of admission, the mean potassium level was 2.77±0.93 mmol/L (reference, 3.5-5.5), mean ionized calcium level was 1.17±0.15 mmol/L (1.13-1.32), mean Free T4 level was 43.36±16.92 pmol/L (11.5-22.7). About half of the patients (47.6%) suffered at least one further attack of TPP. 28 patients (66.7%) diagnosed with Graves’ disease had anti-thyroid drugs alone and 5 patients (11.9%) with thyrotoxic relapses eventually underwent radioactive iodine therapy. None of the patients underwent surgery. Conclusions: TPP can be the presenting feature of previously undiagnosed thyrotoxicosis and should be considered in the differential diagnosis in patients presenting with acute onset of motor paralysis. At the time of the TPP attack, a detailed interview and inquiry with a thorough physical examination usually provide clues to the diagnosis.

Presentation: Saturday, June 17, 2023
SAT454 Repetition Of Fine Needle Aspiration Cytology After An Initial Nondiagnostic Result: Does An Optimal Timing Exist?
Authors: Cosme Inês , Lacerda Nobre Ema , João Bugalho Maria
Published: October 2023

Disclosure: I. Cosme: None. E.L. Nobre: None. M.J. Bugalho: None.

Background: The optimal time to repeat a fine-needle aspiration cytology (FNAC) of a thyroid nodule, after a nondiagnostic (ND) result, is not established. It has been proposed to wait at least 3 months for a 2nd FNAC, in order to mitigate the possible inflammatory cytological changes induced by a previous FNAC. This study aimed to evaluate whether the time between 2 consecutive FNACs, influences the final cytological result. We analysed the occurrence of ND or atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in the 2nd FNAC, in different repetition time intervals. Methods: Retrospective study (2017-2020) including thyroid nodules with a first ND FNAC, submitted to a 2nd FNAC. All FNACs were ultrasound-guided. Demographic data, time interval between FNACs and their results were collected. The 2nd FNAC results were analysed according to FNACs´ repetition interval. We considered 2 intervals: ≤ vs > 3 months and ≤ vs >6 months after the initial FNAC. The 2nd FNAC results were classified as ND, AUS/FLUS or diagnostic (including the other Bethesda FNAC categories). Results: Included 190 nodules (190 patients, 82.1% women, mean age 60±13.7 years) with a 1st ND FNAC submitted to a 2nd FNAC. The 2nd FNAC result remained ND in 63 cases, was AUS/FLUS in 9 and diagnostic in 118 (benign in 116 cases, follicular neoplasm/suspicious follicular neoplasm in 1 and malignant in 1 case). There were no statistical differences in 2nd FNAC result performed ≤3 months (13 ND, 2 AUS/FLUS, 19 diagnostic) vs >3 months (50 ND, 7 AUS/FLUS, 99 diagnostic) - p=0.71. Considering a wider time interval between FNACs, there were also no statistical differences in the 2nd FNAC result: ≤ 6 months (32 ND, 3 AUS/FLUS, 59 diagnostic) vs >6 months (31 ND, 6 AUS/FLUS, 59 diagnostic) - p=0.61. Conclusions: The time interval between FNACs was not relevant to the final cytological result. Early FNAC repetition did not increase the cases of ND or AUS/FLUS.

Presentation: Saturday, June 17, 2023
SAT493 Laser Ablation For Benign Thyroid Nodules: A Way To Treat And Still Preserve The Thyroid
Authors: Kalara Niketa , Maria Bignoli Daniela Laura , Acosta Crystal Maria , Manzano Alex
Published: October 2023

Disclosure: N. Kalara: None. D.L. Bignoli: None. C.M. Acosta: None. A. Manzano: None.

Introduction: Thyroid nodules in adults have a prevalence of 3-7% based on palpation and 20-76% based on ultrasound examination. The majority of which are benign but some increase in size causing compressive symptoms or cosmetic concerns, thus, needing treatment. Laser ablation (LA) is a safe, non-surgical approach for the management of benign thyroid nodules now approved in the US. Nodule reduction is achieved through laser induced cytoreduction and tissue coagulation. Two benign FNA biopsies 3-6 months apart and a nodule size of more than 2.5 cm are some of the inclusion criteria for LA. We present a case of a benign thyroid nodule causing compressive symptoms where LA was done since the patient declined surgery. Case description: 76-year-old female with a history of type 2 diabetes mellitus, hypertension, and multinodular goiter for many years presented with concerns of neck fullness and discomfort for the past 6 months. Thyroid ultrasound confirmed a large dominant right complex nodule of 2.8 x 1.13 x 3 cm with a volume of 5 ml. Thyroid function test showed Thyroid stimulating hormone (TSH) 1.2 mIU/mL (0.40-4.50) and free T4 1.24 ng/dl (0.9-1.7). Two FNA biopsies done 3 months apart in the past were Bethesda II. Given the compressive symptoms due to a multinodular gland thyroidectomy was discussed as a treatment option with the patient which she declined. Hence, LA was discussed as an option for the largest nodule. The procedure was performed without complications. The nodule received 1450 Joules at 6 watts using one Elesta laser fiber. At the end of 2 months post-LA, thyroid ultrasound showed a significant reduction of the nodule with a current size of 1.5 x 1 x 1.6 cm and 1.4ml volume. She continued to be clinically and biochemically euthyroid with a total volume reduction close to 70% and complete resolution in compressive symptoms. Conclusion: Percutaneous laser ablation is a non-surgical, minimally invasive procedure to treat benign thyroid nodules that is now accessible in the US with promising results and a good safety profile. It is covered by insurance in various states. In our case the patient refused surgical intervention, thus, laser ablation was done that resulted in the resolution of her compressive symptoms without any complications. More awareness regarding the laser ablation procedure and its availability for patients is needed, especially in cases where preservation of the thyroid gland is desired. Reference: 1. Gambelunghe G, Stefanetti E, Avenia N, De Feo P. Percutaneous Ultrasound-Guided Laser Ablation of Benign Thyroid Nodules: Results of 10-Year Follow-Up in 171 Patients. J Endocr Soc. 2021 May 5;5(7):bvab081. doi: 10.1210/jendso/bvab081. PMID: 34159286; PMCID: PMC8212682.

Presentation Date: Saturday, June 17, 2023
SAT494 Impending Thyroid Storm during Pregnancy in a Patient with Gestational Trophoblastic Disease
Authors: Kulkarni Rohit , Sibai Zakaria
Published: October 2023

Disclosure: R. Kulkarni: None. Z. Sibai: None.

Background: Gestational trophoblastic disease (GTD) is a rare complication of pregnancy that arises due to abnormal proliferation of trophoblasts of the placenta. The incidence of GTD in the United States of America is about 110 to 120 per 100,000 pregnancies. Abnormal trophoblastic proliferation leads to higher than expected B-HCG levels compared to normal pregnancy. Since the beta subunit of β-hCG has similar structure to TSH, β-hCG stimulates TSH receptor and causes hyperthyroidism during pregnancy which can be asymptomatic, mild or it can lead to severe cases of thyroid storm. Clinical Case: A 19-year-old African American woman with no PMH, 8 weeks primigravida presented with complaints of nausea, abdominal pain and difficulty walking. Associated symptoms included blurry vision, excessive sweating, tremors and palpitations. Physical examination finding included sinus tachycardia and low BMIof 18.6kg/m2, bilateral hand tremors, weakness of bilateral lower extremities. Initial labs showed quantitative β-hCG level of 283,163(H) m(iU)/mL, TSH <0.010 (L) m(iU)/L , FT4 2.54 (H) ng/dL, negativeTSI and TPO Abs. Burch-Wartofsky Point Scale score was 35 suggestive of impending thyroid storm. Pelvic ultrasound showed intrauterine pregnancy with estimated gestation age of 7 weeks 3 days with findings suggestive of fetal demise. Patient underwent Dilatation and Curettage for suspected molarpregnancy. Final histopathological report of aborted specimen verified the diagnosis of partial molar pregnancy. Based on clinical history, physical finding and lab results, patient was diagnosed with gestational trophoblastic disease induced impending thyroid storm. Endocrinology initiated management with Propranolol 40 mg TID and Methimazole 10 mg daily withimprovement in her clinical symptoms in two days. One week follow up as an outpatient showed resolution of symptoms, normalization of free T4 and down trending β-hCG titers to 166 m(iU)/mL. Propranolol and methimazole were stopped. Conclusion:Gestational trophoblastic disease although a rare clinical entity, it is potentially a life-threatening condition. β-hCG is a glycoprotein, and its beta subunit is structurally similar to TSH, allowing it to bind to the TSH receptor and causing hyperstimulation of the thyroid follicular cells leading to various degrees of hyperthyroidism. GTD associated with significant high level of β-HCG, in rare cases can cause severe consequences like thyroid storm. Therefore, GTD should be considered as a differential diagnosis in patient’s presenting with sever thyrotoxicosis during pregnancy. The mainstay of management is evacuation of the molar pregnancy. In severe cases of hyperthyroidism, Beta blocker and thioamides can be considered for symptoms relief and to speed the recovery. Follow-up with serial quantitative β-hCG measurements is crucial to evaluate for persistent molar tissue.

Presentation Date: Saturday, June 17, 2023
SAT517 Papillary Thyroid Cancer in Thyroglossal Duct Cyst.
Authors: Castellanos Paula Lorena , Meek Shon Edward , Chindris Ana Maria , Bernet Victor Joseph
Published: October 2023

Disclosure: P.L. castellanos: None. S.E. Meek: None. A.M. Chindris: None. V.J. Bernet: None.

Approximately 250 cases of papillary thyroid cancer (PTC) within a thyroglossal duct cyst (TGDC) have been reported worldwide. The presence of PTC within a TGDC is rare representing less than 1 % of all TGDC cases. This report describes the case of a young male with PTC in a TGDC suspicious nodules. We present this case along with a review of the literature related to this very uncommon finding. Papillary thyroid carcinoma is a very rare disease but always should be considered when speaking of a mass at the level of the central neck. There is a considerable controversy regarding the role of thyroidectomy to treat thyroglossal duct cyst carcinoma since the treatment of choice is Sistrunk procedure and the only indications to make a thyroidectomy will be aggressive disease and more than 45 years old according to some articles but without any consensus now. With a cure rate of 95 % and recurrence rate of 3 -10 % when this cancer is treated by Sistrunk operation, it doesn’t seem necessary to do an extent surgery if there is not enough thyroid compromised. Long term follow up is necessary to exclude the development of thyroid cancer.

Presentation Date: Saturday, June 17, 2023
SAT527 The Management Of Thyroid Cancer: Where We Started And Where We Are Heading? A Five-decades Text Mining Analysis
Authors: Tessler Idit , Gecel Nir Abraham , Avior Galit , Klang Eyal , Alon Eran , Kolitz Tamara
Published: October 2023

Disclosure: I. Tessler: None. N.A. Gecel: None. G. Avior: None. E. Klang: None. E. Alon: None. T. Kolitz: None.

Aim: Thyroid cancer prevalence rate continues to increase, being the most common endocrine cancer. During the years, significant progress in methods for diagnosis, risk-stratification and management were developed, with the recent advance of molecular testing. Here we explore the evolution of thyroid cancer management over the past five decades through a text-mining analysis. Materials and methods: We have queried PubMed for all available 'thyroid cancer' related entries published during 1970-2022. The following data were extracted for each entry: year of publication, publishing journal, title, keywords, and abstract text. Search terms belonged to demographics, histology, diagnosis methods, treatment, and follow-up. Annual trends of publications were plotted. The slopes of publication trends were calculated by fitting regression lines to the yearly number of publications. We also retrieved the number of citations per publication and analyzed the most impactful papers on each topic.Results: Our search yielded 95,931 papers published during the study period. Publications regarding diagnosis (39,490) outnumbered all other topics, in which molecular testing has significantly sharpest raise (slope p=34.1±3.3). Most publication focused on females (n=56,198) and differentiated thyroid cancer (n=45,953). Surgery remains the most studied treatment method during the whole study period, with recent raise in studies regarding active-surveillance (slope 14.2±1.3). Studies concerning shared decision-making and patient experience emerged in 2000, with a sharp increase in recent years (slope 3.8±0.3, p < .001).Conclusions: Our study provides an overview of the trends in thyroid cancer research over the past five decades. Publications regarding molecular testing outnumbered all other diagnosis methods, identified as the primary trend of the current era. Publications on active surveillance have rapidly risen in recent years, highlighting this method's role in thyroid cancer. Keywords: Machine learning; artificial intelligence; Thyroid cancer; Molecular-tests

Presentation Date: Saturday, June 17, 2023