ThyroidVol. 31, No. S1 AbstractsFree AccessLate Breaking AbstractsPublished Online:30 Sep 2021https://doi.org/10.1089/thy.2021.29118.lb.abstractsAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail LATE BREAKING HIGHLIGHTED ORAL 1Thyroid Cancer Basic Highlighted OralTERTMUTANT PROMOTER MOUSE MODEL INDUCES CANCER PROGRESSION IN BRAFV600E‐DRIVEN THYROID TUMORS: A NOVEL TOOL TO UNDERSTAND THE BIOLOGY OF TELOMERASE‐REACTIVATED THYROID CANCERSIñigo Landa*1,2, Jingzhu Hao1, Jeffrey Knauf3, Bin Xu3, Joseph Giacalone3, Zach Herbert4, Ronald Ghossein3, James Fagin31Brigham and Women's Hospital, USA,2Harvard Medical School, USA, 3Memorial Sloan Kettering Cancer Center, USA, 4Dana Farber Cancer Institute, USAHotspot mutations in the proximal promoter of the telomerase reverse transcriptase (TERT) gene represent the first cross‐cancer alterations lying in a gene regulatory region. TERT promoter mutations (TPMs) are enriched in advanced thyroid tumors and constitute markers of disease severity. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, reactivating this bone fide oncoprotein. To study TERT deregulation and its downstream consequences in a biologically accurate model, we generated the first Tert‐mutant promoter mouse model via CRISPR/Cas9 engineering of the equivalent murine locus and crossed it with thyroid‐specific Braf‐mutant mice (TPO‐Cre/BrafV600E). BrafV600E animals developed highly penetrant papillary thyroid tumors (PTC) by week 5, but hardly ever progressed. In contrast, BrafV600E+TertMUT animals showed an increased incidence of poorly differentiated thyroid cancers (PDTC) by 20 weeks (30% vs. 0% in BrafV600E; chi‐squared P = 0.03), mimicking those exhibited by a transgenic model of Tert overexpression (BrafV600E+K5‐Tert; 36% PDTCs). Mouse Tert promoter mutation increased Tert transcription in vitro and in vivo, as reported in patients' tumors carrying TPMs. Braf+Tert animals responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert‐reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects (some targetable) other than telomere‐related functions operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre‐clinical settings to understand the regulatory mechanisms and biological effects of TPM‐positive thyroid cancers and other aggressive tumors, and to explore novel therapeutic strategies.LATE BREAKING ORAL 2Thyroid Hormone Metabolism & Regulation Basic OralEVIDENCE OF INTERACTIONS BETWEEN THYROID HORMONES/RECEPTORS AND GLUCOSE, FRUCTOSE OR METHYLGLYOXAL: IMPLICATIONS FOR THYROID DYSFUNCTION IN METABOLIC SYNDROMEIris Geldenhuys, Sarah Martin, James Matheson, George Katselis, Kaushik Desai*University of Saskatchewan, CanadaHigh carbohydrate diets (glucose and fructose) are likely responsible for the globally increasing obesity and type 2 diabetes. Thyroid dysfunction is associated with metabolic syndrome (a cluster of abnormalities such as insulin resistance, visceral obesity, raised triglycerides, blood pressure, fasting plasma glucose, reduced HDL) and obesity. However, cause and effect relationship between thyroid dysfunction and high carbohydrate diet‐induced pathology has not been established. The thyroid hormones, thyroxine (T4) and tri‐iodothyronine (T3), play an important role in development and metabolic homeostasis. They are regulated by the thyroid‐stimulating hormone and thyrotropin‐releasing hormone. They act on thyroid hormone receptors viz. TRα1, TRα2, TRβ1 and TRβ2. Methylglyoxal (MG) is a reactive aldehyde metabolite of glucose and fructose that reacts with proteins, lipids, and DNA to cause dysfunction and contributes to the formation of advanced glycation end‐products (AGEs). Normally, MG is processed by the glyoxalase enzymes I and II into inert D‐lactate. MG levels are elevated in diabetic patients. Elevated MG plays a role in the pathogenesis of type 2 diabetes, hypertension, and other diseases. L‐ and D‐arginine can scavenge MG. We hypothesize that MG, glucose, and/or fructose react with thyroid hormones and their receptors causing thyroid dysfunction, which in turn would adversely affect glucose and lipid metabolism. We analyzed plasma and organ samples from 10 week old male Sprague‐Dawley rats treated with either a high glucose, high fructose, or high sucrose diet (60% of total calories) for 12 weeks, and samples of T3 and T4 (50 ng/mL) incubated with glucose or fructose (25 mM), or MG (5 μM) for 24 h at 37⁰ C. Results: Western blot results showed significant alterations of expression of thyroid receptors in the liver, kidney, brain and skeletal muscle. Mass spectrometric analyses of plasma and incubation samples showed significant differences in the levels or T3 and T4 compared to the control, indicating interactions between T3/T4 and glucose/fructose/MG. These interactions have great clinical significance and provide a mechanistic link between high carbohydrate diets/diabetes/obesity and thyroid dysfunction. Strategies to prevent thyroid dysfunction induced by high carbohydrate diets can be developed.LATE BREAKING ORAL 3Thyroid Cancer Clinical OralEFFICACY AND SAFETY OF PRALSETINIB, A SELECTIVE RET INHIBITOR, IN CHINESE PATIENTS WITH ADVANCED RET‐MUTANT MEDULLARY THYROID CANCER (MTC)Ming Gao*1, Xiangqian Zheng1, Yu Wang2, Yun Fan3, Meiyu Fang3, Yuping Sun4, Meili Sun4, Ankui Yang5, Bin Zhang6, Qinjiang Liu7, Hui Liu8, Xiaohong Zhou9, Tao Huang10, Jianwu Qin11, Zhaohui Wang12, Lili Qu13, Zhenwei Shen13, Sheng Yao13, Jason Yang131Tianjin Medical University Cancer Institute & Hospital, China, 2Fudan University Shanghai Cancer Center, China, 3Zhejiang Cancer Hospital, China, 4Jinan Central Hospital, China, 5Sun Yat‐sen University Cancer Center, China, 6Beijing Cancer Hospital, China, 7Gansu Provincial Cancer Hospital, China, 8Fujian Provincial Cancer Hospital, China, 9Chongqing Cancer Hospital, China, 10Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, China, 11Henan Cancer Hospital, China, 12Sichuan Cancer Hospital & Institute, China, 13CStone Pharmaceuticals (Su Zhou) Co., Ltd., ChinaRET mutations are found in about 70% of MTC, yet no targeted therapy was approved or available in China. ARROW is a phase I/II, open‐label, multi‐cohort study to evaluate the efficacy and safety of pralsetinib in a variety of advanced RET altered solid tumors including MTC. Here we present the results from a phase II cohort of Chinese patients with advanced MTC in ARROW study.Patients with advanced or metastatic MTC who were naïve to systemic therapies (except cytotoxic chemotherapies) were enrolled and treated with pralsetinib 400 mg QD. The primary endpoints are the objective response rate (ORR) by blinded independent central review (BICR) per RECIST v1.1 and safety in Chinese patients.As of 12 April 2021 data cut off, 34 Chinese patients were enrolled and 28 of them were tested as RET mutation‐positive by central testing (mutation: 64.3% M918T, 21.4% cysteine‐rich domain mutations, 14.3% others). Nearly all (96.4%, 27/28) patients had stage IVC disease at baseline. All patients except one were systemic treatment‐naïve . In 26 patients with measurable disease at baseline per BICR, the ORR was 73.1% (95% CI: 52.2, 88.4) with 3 (11.5%) patients achieving complete responses. Disease control rate was 84.6% (95% CI: 65.1, 95.6). The median time to response was 5.75 (range: 1.8‐12.8) months. The median duration of response was not reached yet at data cut‐off. The 6‐month and 9‐month DOR rates were both 100%. All RET‐mutant patients who received at least 1 dose of pralsetinib were included in the safety analysis (n = 28). The most common treatment‐emergent adverse events (AEs) were aspartate aminotransferase increased (60.7%), hypocalcaemia (60.7%), hyperphosphataemia (57.1%), white blood cell count decreased (57.1%%), blood lactate dehydrogenase increased (53.6%), and neutrophil count decreased (53.6%). No patients discontinued treatment or died due to treatment‐related AEs.This is the first pivotal study demonstrating the robust, durable antitumor activity and the manageable safety profile of pralsetinib in Chinese patients with RET‐mutant MTC. The data are consistent with those previously reported from the global population in ARROW study. Overall, pralsetinib provides a potent targeted treatment and valuable addition to the armamentarium for Chinese patients with RET‐mutant MTC.Clinical trial identification: NCT03037385LATE BREAKING ORAL 4Thyroid Hormone Metabolism & Regulation Basic OralA NOVEL THYROGLOBULIN MUTANT MOUSE MODEL TO STUDY GOITROGENESIS IN CONGENITAL HYPOTHYROIDISMXiaohan Zhang*, Bhoomanyu Malik, Inis Isak, Hao Zhang, Dennis Larkin, Aaron Kellogg, Peter ArvanDivision of Metabolism, Endocrinology & Diabetes, University of Michigan, USAHuman patients and animals bearing biallelic TG mutations suffer from primary hypothyroidism. However, goiter development varies: cog/cog mice (Tg‐L2263P) grow a large goiter whereas hypothyroid rdw/rdw rats (Tg‐G2298R) develop a hypoplastic gland. The thyroids of both animals exhibit thyrocyte growth, and death — so why does goitrogenesis differ?We used CRISPR/Cas9 to knock‐in the rdw mutation into the mouse TG locus. We compared WT mice, rdw/rdw homozygous mice, and cog/cog mice, including serum T4; thyroid gland histology; Tg glycosylation and immunolocalization; endoplasmic reticulum (ER) stress; cell death by TUNEL staining; cell proliferation by Ki67 immunoperoxidase staining, and thyroid gland size.We find that body weight in rdw/rdw (and cog/cog) mice increases more slowly than in WT animals, consistent with the observation that both rdw/rdw and cog/cog mice have a similarly decreased serum total T4, indicating growth retardation from hypothyroidism. Histological examination and anti‐Tg immunostaining reveals that both rdw‐Tg and cog‐Tg are retained in the ER, and both are sensitive to endoglycosidase‐H digestion, indicating that the mutant Tg proteins do not advance anterograde from the ER. In rdw/rdw and cog/cog thyroid glands, Western blotting of ER stress markers (BiP, p58IPK and phospho‐eIF2α) and cell death marker (cleaved PARP) — comparable between the two mutants — are significantly elevated and TUNEL staining reveals dead thyrocytes. Remarkably, up to 11 months old, both rdw/rdw and cog/cog mice develop a large goiter. Interestingly, Ki67‐immunostaining highlights persistence of vigorous thyrocyte proliferation in older rdw/rdw mice, but not in rdw/rdw rats ≥15 weeks of age.It has been proposed that Tg‐L2263P (of cog/cog mice) is intrinsically more proteotoxic than Tg‐G2298R (found in rdw/rdw rats). In contrast, we find that homozygous rdw/rdw knock‐in mice behave essentially identically to cog/cog mice, with similar goitrogenesis and all measurable biochemical parameters. Our data suggest that thyroid hypoplasia found in the hypothyroid rdw/rdw rats is explained by an inability to sustain thyrocyte proliferation as a function of age in the Wistar‐Imamichi strain background.LATE BREAKING ORAL 5Thyroid Cancer Clinical OralCABOZANTINIB VERSUS PLACEBO IN PATIENTS WITH RADIOIODINE‐REFRACTORY DIFFERENTIATED THYROID CANCER (DTC) WHO HAVE PROGRESSED AFTER PRIOR VEGFR‐TARGETED THERAPY: UPDATED RESULTS FROM THE PHASE 3 COSMIC‐311 TRIAL AND PRESPECIFIED SUBGROUP ANALYSES BASED ON PRIOR VEGFR‐TARGETED THERAPYMarcia Brose*1, Bruce Robinson2, Steven Sherman3, Barbara Jarzab4, Chia‐Chi Lin5, Fernanda Vaisman6, Ana Hoff7, Erika Hitre8, Daniel Bowles9, Suvajit Sen10, Purvi Patel10, Bhumsuk Keam11, Jaume Capdevila121Abramson Cancer Center, University of Pennsylvania, USA, 2Sydney Medical School, The University of Sydney, Australia, 3Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, USA, 4Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch, Poland, 5Department of Oncology, National Taiwan University Hospital, Taiwan, 6Instituto Nacional de Câncer, Brazil, 7Department of Endocrinology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, Brazil, 8Department of Medical Oncology and Clinical Pharmacology “B,” Országos Onkológiai Intézet, Hungary, 9Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, USA, 10Exelixis, Inc.,, USA, 11Department of Internal Medicine, Seoul National University Hospital, Korea, Republic of, 12Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, SpainAt a preplanned interim analysis (median follow‐up 6.2 months) of the double‐blind, phase 3 COSMIC‐311 trial (NCT03690388), cabozantinib significantly improved progression‐free survival (PFS) versus placebo (HR = 0.22, 96% CI 0.13‐0.36; p < 0.0001) in 187 patients with previously treated radioiodine‐refractory DTC (Brose, Lancet Oncol; 2021). Patients must have received lenvatinib or sorafenib and progressed during or after 1‐2 prior VEGFR inhibitors. We present the final analysis with a longer follow‐up of all randomized patients (ITT population) and for prespecified subgroups who received prior lenvatinib, sorafenib, or both.Patients were randomized 2:1 to cabozantinib (60mg QD) or placebo. Placebo patients could cross over to open‐label cabozantinib upon disease progression per blinded independent radiology committee (BIRC). PFS (ITT) and objective response rate (ORR, first 100 randomized patients) per RECIST v1.1 by BIRC were the primary endpoints.At final analysis 258 patients (170 cabozantinib, 88 placebo) were randomized (data cut‐off 8 Feb 2021); 96 had received prior sorafenib/no lenvatinib, 102 prior lenvatinib/no sorafenib, and 60 prior sorafenib and lenvatinib. Median follow‐up was 10.1 months. Forty patients crossed over from placebo to receive cabozantinib. Median PFS (ITT population) was 11 months for cabozantinib vs 1.9 months for placebo (HR = 0.22, 95% CI 0.15‐0.31; p < 0.0001). For subgroups, median PFS was 16.6 vs 3.2 months for prior sorafenib/no lenvatinib (HR = 0.13, 95% CI 0.06‐0.26); 5.8 vs 1.9 months for prior lenvatinib/no sorafenib (HR = 0.28, 95% CI 0.17‐0.48), and 7.6 vs 1.9 months for prior sorafenib and lenvatinib (HR = 0.27, 95% CI 0.13‐0.54). ORR (ITT population) was 11% for cabozantinib vs 0% for placebo; overall survival HR = 0.76 (95% CI 0.45‐1.31). Grade 3/4 treatment‐emergent adverse events (TEAEs) were 62% with cabozantinib vs 28% with placebo arm with no treatment‐related grade 5 events; 67% vs 5% required dose reductions due to TEAEs; 8.8% vs 0% discontinued treatment due to TEAEs not related to disease.At the final analysis of COSMIC‐311 with longer follow‐up, cabozantinib maintained its superior efficacy versus placebo with a manageable safety profile in patients with previously treated radioiodine‐refractory DTC. The PFS benefit was consistent with the interim analysis and irrespective of prior VEGFR‐targeted therapy.LATE BREAKING ORAL 6Disorders of Thyroid Function Basic OralIODOTYROSINES BIOMARK HYPOTHYROIDISM CAUSED BY ENVIRONMENTAL DISRUPTOR TBBPAPouya Alikhani*1, Marco Borso2, Cristian González‐Guerrero1, Leonardo Pardo3, Alessandro Saba2, Riccardo Zucchi2, José Moreno11Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Spain, 2Department of Pathology, University of Pisa, Italy, 3Department of Computational Biology. University of Barcelona, SpainHalogenated phenols are environmental pollutants that can disrupt the thyroid hormone axis at multiple levels. Specific targets of disruption and their relative importance in vivo are poorly understood. Tetrabromobisphenol A (TBBPA) is a brominated flame retardant widely‐used in plastics, that is detectable in humans. In silico docking identified that TBBPA interacts with the substrate‐binding pocket of DEHAL1, the enzyme that recycles iodide from iodotyrosine deiodination. In vitro, TBBPA reduced 37% mono‐iodotyrosine (MIT) deiodination by DEHAL1. Thus, TBBPA qualified for in vivo testing of iodide‐recycling disruption in an animal model.To determine the pathogenic relevance of TBBPA exposure in vivo on the iodide‐recycling system in wild type (WT) and Delah1‐knockout (KO) mice.For 7 days, 500 mg/kg‐bw/day TBBPA was administered subcutaneously to female WT and KO mice; vehicle was injected to unexposed controls. Blood and urine were collected at day0 and day8. TSH was measured by radioimmunoassay. Plasma (pl) T4, T3, MIT and DIT and urinary (u) MIT and DIT were determined by LC/MS‐MS. Urinary iodine concentration (UIC) was determined by Sandell‐Kolthoff.TBBPA administration induced significant TSH increase of 32% (p < 0.05) and 55% (p < 0.05) in WT and KO mice, respectively. Hypothyroxinemia also developed in treated WT (T4: 23.5 vs 14.5 ng/ml; p < 0.05) and KO mice (24.7 vs 11.2 ng/ml; p < 0.01), while T3 remained unchanged. In TBBPA‐exposed WT mice, MIT significantly increased in plasma (0.16 vs 0.21 ng/ml; p < 0.05) and urine (1.45 vs 2.53 ng/ml; p < 0.05) while, as expected in KO mice MIT was increased in plasma (2‐fold; <0.05) and urine (8‐fold; <0.01) irrespective of TBBPA exposure (pl: 0.3 vs 0.325 ng/ml, n.s.; u: 9.93 vs 10.65, n.s.). Interestingly, DIT decreased in response to TBBPA in both WT (pl: 0.16 vs 0.06 ng/ml, p < 0.01; u: 0.42 vs 0.18, p < 0.05) and KO mice (pl: 0.3 vs 0.17, n.s.; u: 5.14 vs 2.73, p < 0.05).Iodotyrosines in urine biomark a rapidly evolving hypothyroidism caused by TBBPA exposure in vivo. Dehal1‐KO mice are more sensitive to TBBPA exposure, however, a major unidentified target for TBBPA disruption must exist involving differential MIT vs DIT synthesis in the thyroid.LATE BREAKING ORAL 7Thyroid Hormone Action Clinical OralACUTE EFFECTS OF LIOTHYRONINE ADMINISTRATION ON CARDIOVASCULAR SYSTEM AND ENERGY METABOLISMShanshan Chen, George Wohlford, Alessandra Vecchie', Salvatore Carbone, Sahzene Yavuz, Benjamin Van Tassell, Antonio Abbate, Francesco Celi*Virginia Commonwealth University, USAThe potential benefits of liothyronine therapy are hampered by the concerns of cardiovascular toxicity due to supraphysiologic serum T3 concentrations. While the effects of sustained increase in serum T3 concentrations on the cardiovascular system and energy metabolism are well described, little is known on the effects of acute changes in T3 concentrations due to rapid action of thyroid hormone. Here we present a study designed to assess the clinical relevance of transient increase of T3 levels on the cardiovascular system and energy metabolism.We conducted a double‐blind, three arms, placebo controlled, cross‐over study (ClinicalTrials.gov Identifier: NCT03098433). Healthy volunteers age 18‐45 years received liquid formulation of liothyronine 0.7 mcg/kg (equivalent to 50 mcg in a 70 Kg person), equimolar dose of levothyroxine (0.86 mcg/kg), or placebo in three identical study visits separated by at least 48 hours. Blood samples for total T3, free T4 were collected at times 0′, 60′ 120′ 180′ 240′; TSH was measured at 0′ and 240′. Continuous recording of heart rate, blood pressure, and hemodynamic data (cardiac output, stroke volume, and systemic vascular resistance) was performed using the volume clamp method. Resting energy expenditure was measured by indirect calorimetry, and an echocardiogram was performed on each study visit at baseline and after the last blood drawing.Twelve volunteers 3 females, 9 males, age 27.7 ± 5.1 years completed the study, and no adverse event was recorded. Following the administration of liothyronine, serum T3 reached a Cmax of 421 ± 57 ng/dL with an estimated Tmax of 120 ± 26 minutes. A decrease in TSH was observed between time 0′ and 240′, with no significant differences between treatments and placebo. No differences between study arms were observed in heart rate, blood pressure, hemodynamics parameters, energy expenditure, and in echocardiogram parameters.The lack of measurable acute effects on the cardiovascular system following a pharmacologic dose of liothyronine supports the rationale to provide liothyronine therapy in a single dose to facilitate adherence. Long‐term studies in patients affected by hypothyroidism should be conducted in to assess the safety and effectiveness of single dose liothyronine/levothyroxine combination therapy.LATE BREAKING HIGHLIGHTED POSTER 1Please see Late Breaking Oral #6LATE BREAKING HIGHLIGHTED POSTER 2Thyroid Nodules & Goiter Clinical Highlighted PosterSIDE EFFECTS RATES COMPARISON IN THYROID RADIOFREQUENCY ABLATION BETWEEN AMBULATORY SETTING AND OPERATING ROOM SETTINGRoberto Valcavi, Roberto Novizio*Endocrine & Thyroid Clinic (E.T.C.), ItalyThyroid minimally‐invasive ultrasound‐assisted radiofrequency ablation (RFA) may be performed under local anesthesia in ambulatory setting or under general sedation in operating room setting. Which is the most convenient approach remains controversial. This study compares two series of patients treated with each method to establish rates of side effects.A group “A” of 40 patients underwent RFA as outpatient procedure with traditional setting, receiving local pericapsular anesthesia with lidocaine plus ropivacaine, and general sedation using intravenous midazolam. A second group “B” of 314 patients underwent RFA in operating room setting, receiving, in addition to local anesthesia and with anesthesiologic assistance, oxygen supplementation through nasal cannula and intravenous fentanyl, midazolam and propofol through a cannulated a vein. Vital parameters were monitored. Intravenous paracetamol and methylprednisolone were administered after both procedures to prevent pain and swelling. Three groups of side effects were compered between groups “A” and “B”: intraoperative (intense pain, intra‐nodular and pericapsular bleeding, vasovagal reaction and cough), immediate postoperative (swelling, cutaneous burn and laryngeal dysfunction) and periprocedural, within 30 days (bruise, fever, pseudo‐cystic transformation, nodule rupture). Data analysis was performed using SPSS v22 (IBM). To compare side effects rates between groups, chi‐squared test was used.There was a statistically significant reduction of side effects in group B (p‐value <0.05) in all analysis. (group A vs group B) Intra‐operative: intense pain 17.5% vs 0%; Intra‐nodular bleeding 7.5 vs 0.64%; peri‐capsular bleeding 2.5 vs 0.33%; vasovagal reaction 2.5% vs 0%; Cough 5% vs 1.59%. Postoperative: swelling 10% vs 0.95%, cutaneous burn 5% vs 0.33%, laryngeal dysfunction 5% vs 0.33%. Peri‐procedural: bruise 5% vs 1.59%; fever 2.5% vs 0%; pseudo‐cystic transformation 2.5% vs 0%; nodule rupture 2.5% vs 0%.Operating room management of thyroid RFA decreased the incidence of intra‐operative and postoperative side effects, due to general sedation that allows physician to operate without movement interferences. The operating room cost is about 1500‐3000 USD more than the cost of ambulatory setting. However, as side effects drop remarkably with the general sedation protocol and the aid of an anesthesiologist, we recommend RFA to be carried out using the operating room setting.LATE BREAKING HIGHLIGHTED POSTER 3Autoimmunity Clinical Highlighted PosterHEARING DYSFUNCTION AFTER TREATMENT WITH TEPROTUMUMAB FOR THYROID EYE DISEASEConnie Sears*1, Amee Azad1, Brandon Pham1, Clara Men1, Linus Amarikwa1, Daniel Kaplan2, Jocelyn Liu1, Andrew Hoffman2, Austin Swanson2, Jennifer Alyono2, Jennifer Lee2, Chrysoula Dosiou2, Andrea Kossler11Byers Eye Institute, Stanford University School of Medicine, USA, 2Stanford University School of Medicine, USATeprotumumab, an insulin‐like growth factor‐1 (IGF‐I) inhibitor, is an effective therapy for thyroid eye disease (TED). Hearing dysfunction is a documented adverse event previously reported in 10% of patients treated with teprotumumab. The purpose of this study is to characterize the frequency, nature and severity of hearing dysfunction in patients treated with IGF‐I receptor inhibition at one academic institution.This is a prospective observational study of otologic symptoms in TED patients treated with teprotumumab. Patients included received at least 4 infusions of teprotumumab. Patients completed an eye exam and adverse event assessment, including otologic symptoms, at 0, 6, 12 and 24 weeks. Thyroid function tests, IGF‐I, growth hormone (GH), and HbA1c labs were collected at baseline and mid‐treatment. Potential hearing loss risk factors including age, gender, hypertension, thyroid treatments, ototoxic medications and previous history of hearing dysfunction were documented. Audiometry and patulous Eustachian tube (PET) testing were obtained at baseline and during therapy, or if patients complained of new onset subjective hearing dysfunction, with evaluation from otolaryngology for objective changes.Twenty‐seven patients were included in the analysis, 24 females and 3 males, with average age 56.3 years. Twenty‐two patients (81.5%) complained of new subjective otologic symptoms after starting teprotumumab infusions. Onset of symptoms occurred after a mean of 3.8 infusions (SD 1.8). At 8.3 month average follow‐up after the first infusion, 45% had complete resolution of symptoms and 55% had persistent symptoms. Among the clinical and demographic characteristics analyzed, none were found to significantly differ between patients with and without otologic symptoms. Twelve ears had pre‐ and post‐treatment audiometry and 10 had PET testing. Seven of twelve ears had sensorineural hearing loss, which met criteria for ototoxicity, though overall audometric changes were modest. One patient developed abnormal PET testing.Hearing loss is a concerning adverse event and its mechanism and reversibility should be further studied. Until risk factors for hearing loss are better understood, we recommend baseline pure tone and speech audiometry with PET testing and repeat testing if new otologic symptoms develop. Screening, monitoring and prevention guidelines are needed.LATE BREAKING HIGHLIGHTED POSTER 4Autoimmunity Clinical Highlighted PosterNEW ONSET OF GRAVES' DISEASE AFTER COVID‐19: CASE SERIESShaveta Gupta*1, Dragana Lovre1,2, Robert Galagan1,21Tulane University Health Sciences Center, USA, 2Southeast Louisiana Veterans Administration Healthcare System, USAWe report the occurrence of new onset Graves' disease in three patients after COVID‐19.Case 1. A 58‐year‐old female presented to the ER with persistent palpitations and dyspnea. Three months ago she had been diagnosed with COVID‐19 by polymerase chain reaction (PCR). She had no previous history of thyroid illness and had normal thyroid labs preceding her COVID‐19 illness. Exam revealed a symmetric goiter. She was found to have atrial fibrillation with rapid ventricular response. Labs were diagnostic of Graves' thyrotoxicosis:TSH 0.01 uIU/mL (0.50‐5.00),Free T4 1.72 ng/dL (0.60‐1.15),TSI 0.72 IU/L high (<0.54),TPO 131.8 IU/mL (<9.0) andnormal ESR and CRP.Case 2. A 32‐year‐old female presented to the ER with fever and cough and was diagnosed with COVID‐19 by PCR. She had no previous history of thyroid illness and had normal thyroid labs 8 months earlier. CT chest revealed a symmetric goiter and labs confirmed Graves' thyrotoxicosis:TSH <0.010 uIU/mL,Free T4 1.41 ng/dL,TSI 0.72 IU/L,TPO 131.8 IU/mL, andnormal ESR and CRP.Case 3. A 54‐year‐old female was referred to the endocrinology clinic with complaints of palpitations and dyspnea. Her symptoms began 9 months ago when she was diagnosed with COVID‐19 by PCR. She had no prior history of thyroid disease and had normal thyroid labs in 2019. Labs were diagnostic of Graves' thyrotoxicosis:TSH <0.0008 uIU/mL,Free T4 2.35 ng/dL,TSI 1.74 IU/L,TPO 7.0 IU/mLAll three of our patients developed Graves' thyrotoxicosis after diagnosis of COVID‐19 and were controlled with methimazole. COVID‐19 is associated with cytokine storm and immune system dysregulation. The key cytokines IL‐6, IL‐1β, TNF‐α and IFN‐y stimulate the pathogenic CD4+ T lymphocytes ‐ Th17 cells which activate TSHR (TSH receptor)‐specific B cells to produce autoantibodies to the TSH receptor inciting Graves' thyrotoxicosis. Clinicians should be aware of the association of Graves' disease with COVID‐19 and consider proactively screening their COVID‐19 patients for Graves' disease when symptoms persist.LATE BREAKING HIGHLIGHTED POSTER 5Disorders of Thyroid Function Clinical Highlighted PosterA STUDY OF NEUROSTRUCTURAL CORRELATES IN YOUNG PATIENTS WITH SUBCLINICAL HYPOTHYROIDISMPramila Kalra*1, Jitender Saini2, Apurva Shah2, D Kumaraswamy3, Mala Dharmalingam1, Ravi Yadav21M S Ramaiah Medical College and Hospitals, India, 2Nimhans, India, 3Msrins, IndiaHypothyroidism is frequently associated with multiple neurocognitive disorders. In this case control, study involving two tertiary care centers we investigated the utility of diffusion tensor imaging for the evaluation of subtle white matter (WM) abnormalities in the patients with subclinical hypothyroidism. We aimed to establish whether any WM structural changes are present in patients with untreated adult‐onset subclinical hypothyroidism compared to age, gender, educational level and BMI matched healthy controls.Patients were recruited prospectively and underwent 3T MRI. Data Processing and Diffusion data analysis was performed using FMRIB Software Library tools (www.fmrib.ox.ac.uk/fsl), Version 5.0.11. Raw diffusion tensor images were preprocessed using eddy current correction for distortions. Group comparisons of DTI data were performed using Tract‐Based Spatial Statistics (TBSS; http://fsl. fm