Abstract
LATE BREAKING HIGHLIGHTED ORAL 1
Thyroid Cancer Basic Highlighted Oral
TERT
MUTANT PROMOTER MOUSE MODEL INDUCES CANCER PROGRESSION IN BRAFV600E‐DRIVEN THYROID TUMORS: A NOVEL TOOL TO UNDERSTAND THE BIOLOGY OF TELOMERASE‐REACTIVATED THYROID CANCERS
Iñigo Landa*1,2, Jingzhu Hao1, Jeffrey Knauf3, Bin Xu3, Joseph Giacalone3, Zach Herbert4, Ronald Ghossein3, James Fagin3
1Brigham and Women's Hospital, USA,2Harvard Medical School, USA, 3Memorial Sloan Kettering Cancer Center, USA, 4Dana Farber Cancer Institute, USA
Hotspot 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 2
Thyroid Hormone Metabolism & Regulation Basic Oral
EVIDENCE OF INTERACTIONS BETWEEN THYROID HORMONES/RECEPTORS AND GLUCOSE, FRUCTOSE OR METHYLGLYOXAL: IMPLICATIONS FOR THYROID DYSFUNCTION IN METABOLIC SYNDROME
Iris Geldenhuys, Sarah Martin, James Matheson, George Katselis, Kaushik Desai*
University of Saskatchewan, Canada
High 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 3
Thyroid Cancer Clinical Oral
EFFICACY 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 Yang13
1Tianjin 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., China
RET 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: NCT03037385
LATE BREAKING ORAL 4
Thyroid Hormone Metabolism & Regulation Basic Oral
A NOVEL THYROGLOBULIN MUTANT MOUSE MODEL TO STUDY GOITROGENESIS IN CONGENITAL HYPOTHYROIDISM
Xiaohan Zhang*, Bhoomanyu Malik, Inis Isak, Hao Zhang, Dennis Larkin, Aaron Kellogg, Peter Arvan
Division of Metabolism, Endocrinology & Diabetes, University of Michigan, USA
Human 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 5
Thyroid Cancer Clinical Oral
CABOZANTINIB 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 THERAPY
Marcia 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 Capdevila12
1Abramson 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, Spain
At 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 6
Disorders of Thyroid Function Basic Oral
IODOTYROSINES BIOMARK HYPOTHYROIDISM CAUSED BY ENVIRONMENTAL DISRUPTOR TBBPA
Pouya Alikhani*1, Marco Borso2, Cristian González‐Guerrero1, Leonardo Pardo3, Alessandro Saba2, Riccardo Zucchi2, José Moreno1
1Thyroid 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, Spain
Halogenated 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 7
Thyroid Hormone Action Clinical Oral
ACUTE EFFECTS OF LIOTHYRONINE ADMINISTRATION ON CARDIOVASCULAR SYSTEM AND ENERGY METABOLISM
Shanshan Chen, George Wohlford, Alessandra Vecchie', Salvatore Carbone, Sahzene Yavuz, Benjamin Van Tassell, Antonio Abbate, Francesco Celi*
Virginia Commonwealth University, USA
The 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 1
Please see Late Breaking Oral #6
LATE BREAKING HIGHLIGHTED POSTER 2
Thyroid Nodules & Goiter Clinical Highlighted Poster
SIDE EFFECTS RATES COMPARISON IN THYROID RADIOFREQUENCY ABLATION BETWEEN AMBULATORY SETTING AND OPERATING ROOM SETTING
Roberto Valcavi, Roberto Novizio*
Endocrine & Thyroid Clinic (E.T.C.), Italy
Thyroid 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 3
Autoimmunity Clinical Highlighted Poster
HEARING DYSFUNCTION AFTER TREATMENT WITH TEPROTUMUMAB FOR THYROID EYE DISEASE
Connie 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 Kossler1
1Byers Eye Institute, Stanford University School of Medicine, USA, 2Stanford University School of Medicine, USA
Teprotumumab, 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 4
Autoimmunity Clinical Highlighted Poster
NEW ONSET OF GRAVES' DISEASE AFTER COVID‐19: CASE SERIES
Shaveta Gupta*1, Dragana Lovre1,2, Robert Galagan1,2
1Tulane University Health Sciences Center, USA, 2Southeast Louisiana Veterans Administration Healthcare System, USA
We 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) and
normal 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, and
normal 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/mL
All 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 5
Disorders of Thyroid Function Clinical Highlighted Poster
A STUDY OF NEUROSTRUCTURAL CORRELATES IN YOUNG PATIENTS WITH SUBCLINICAL HYPOTHYROIDISM
Pramila Kalra*1, Jitender Saini2, Apurva Shah2, D Kumaraswamy3, Mala Dharmalingam1, Ravi Yadav2
1M S Ramaiah Medical College and Hospitals, India, 2Nimhans, India, 3Msrins, India
Hypothyroidism 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 (
A total of 33 cases and 18 controls were recruited. The mean age was 29.78 ± 8.34 years in cases and 29.67 ± 7.2 years in controls (p = NS). The females were 81.8% (N = 27) in cases and 77.8%(N = 14) in controls. The mean TSH was 3.23 ± 1.36 in controls and 6.60 ± 1.23 mIU/L in cases (P = 0.01). We found widespread WM changes in patients with subclinical hypothyroidism in form of increased diffusivity measurements involving corpus callosum, internal capsule, superior longitudinal fasciculus, inferior fronto‐occipital fasciculus, external capsule, temporal lobe WM and brainstem areas. Also left hemisphere showed more changes as compared to the right cerebral hemisphere (FDR corr p < 0.05). FA comparison showed more localized clusters of decreased FA involving the genu of corpus callosum and frontal WM.
Subclinical hypothyroidism is associated with significant WM alteration in the brain WM which can potentially explain the array of neurological dysfunction seen in these subjects. Presence of significant changes in diffusivity metrics especially AD and MD suggests axonopathy and Wallerian degeneration. Less changes noted on FA might be because of proportional increase in both MD and RD values which can potentially keep FA values unchanged.
LATE BREAKING HIGHLIGHTED POSTER 6
Autoimmunity Basic Highlighted Poster
ROLE OF CD11C+B CELLS IN THE PATHOGENESIS OF GRAVES' DISEASE
Yedi Cao*1, Xue Zhao1, Ran You2, Youyuan Huang1, Yan Gong2, Linzi Miao2, Chenxue Qu2, Ying Gao1, Junqing Zhang1
1Department of Endocrinology, Peking University First Hospital, Beijing, China, 2Department of Clinical Laboratory, Peking University First Hospital, China
Thyroid‐stimulating hormone receptor antibody (TRAb) is a pathogenic antibody for Graves' disease (GD), which is secreted by plasmablasts and plasma cells. In recent years, it has been reported that a new subset of B cells, CD11c+B cells, is significantly increased in infectious diseases and chronic inflammatory diseases, which is closely related to the occurrence of diseases. Therefore, this study aims to explore the role of CD11c+ B cells in the pathogenesis of GD.
A total of 67 GD patients and 42 gender and age‐matched healthy controls were enrolled in the current study. Flow cytometry was used to detect the frequency and the average fluorescence intensity (MFI) of the CD38, CD27, CD138, IgD, T‐bet, CXCR3, CXCR5 in CD11c+CD19+B cells. Immunohistochemistry and immunofluorescence staining were used to determine the location of CD11c+CD19+B cells in the thyroid from 5 GD patients.
The frequency of CD11c+CD19+B cells was significantly increased in GD group compared to control group (p < 0.0001), which were correlated with TRAb levels (p < 0.0001, r = 0.6526). The frequency of CD11c+CD19+B cells showed no correlation with the levels of TgAb, TPOAb and TSH, T4, fT4, T3, fT3. CD11c+CD19+B cells expressed higher frequency of CD38, CD27, and CD138 as compared to CD11c‐CD19+B cells, but the frequency of IgD showed no difference, suggesting that CD11c+CD19+B cell was characterized with the phenotype of memory B cells and plasma cells. In addition, CD11c+CD19+B cells expressed higher frequency and MFI of T‐bet (p < 0.001), and showed a distinct expression pattern of chemokine receptor with increased expression of CXCR3 and reduced expression of CXCR5 compared with CD11c‐CD19+B cells (p < 0.001). Immunohistochemistry and immunofluorescence staining revealed that CD11c+CD19+B cells aggregated in the lymphocyte infiltration area and germinal center in thyroid tissue from GD patients.
The frequency of CD11c+B cells is correlated with the titers of TRAb, accompanied with a distinct pattern of chemokine receptor and higher density of T‐bet. It is indicated that CD11c+CD19+B cells which were poised to become plasma cells could be recruited and resided in thyroid tissue with chronic inflammation, then participate in the occurrence and development of GD.
LATE BREAKING HIGHLIGHTED POSTER 7
Thyroid Hormone Metabolism & Regulation Basic Highlighted Poster
HYDROGEN SULFIDE PROMOTES THYROID HORMONE SYNTHESIS AND SECRETION BY UPREGULATING SIRTUIN‐1
Xue Zhao*, Yedi Cao, Lanbo Zhang, Hongfang Jin, Yang Yu, Youyuan Huang, Ying Gao, Junqing Zhang
Peking University First Hospital, China
Hydrogen sulfide (H2S), as a gas signal molecule, participates in many physiological and pathological processes by upregulating sirtuin‐1 (SIRT1). The aim of the current study is to explore whether H2S promote the synthesis and secretion of thyroid hormones by upregulating SIRT1.
Serum from patients with hypothyroidism (n = 10), hyperthyroidism (n = 24) and healthy donors (n = 42) were collected. Thyroid function was assayed by chemiluminescence in all the subjects and serum H2S concentration was observed by an H2S‐Selective Sensor. Real‐time PCR and immunohistochemistry were used to detect the mRNA and protein levels of H2S‐generating enzymes [cystathionine β‐synthase (CBS), cystathionine γ‐lyase (CSE) and 3‐mercaptopyruvate transferase (3‐MPST)] in normal thyroid tissues. In vitro, primary thyrocytes were incubated with H2S donor sodium hydrosulfide (NaHS) and SIRT1 inhibitor (EX527), respectively. Thyroid hormones synthesis and secretion related proteins [thyroid peroxidase (TPO), sodium iodide transporter (NIS), Pendrin protein, monocarboxylic acid transporter 8 (MCT8)] were analyzed by Real‐time PCR and western blotting.
The levels of H2S in serum from hyperthyroid patient were higher than that in hypothyroid patients and healthy donors [0.23 (0.18, 0.35) vs. 0.18 (0.10, 0.25) vs. 0.16 (0.10,0.26), (P < 0.01)]. H2S level was positively correlated with FT3 (r = 0.3141, P < 0.01), FT4 (r = 0.2628, P < 0.05), T3 (r = 0.2721, P < 0.05), and T4 (r = 0.2941, P < 0.05), respectively. CBS was the major H2S‐generating enzymes localized in thyroid follicular cells. In vitro, protein levels of TPO, NIS, Pendrin and MCT8 were upregulated in a concentration‐dependent manner of NaHS in primary thyrocytes, and l FT4 level in the cell supernatant incubated with 100μM NaHS was also increased (P < 0.01). After blocking SIRT1 with EX527, we found that the protein levels of TPO, NIS, Pendrin, MCT8 in thyrocytes incubated with the same concentration of NaHS were downregulated (P < 0.05), and the FT4 level in the cell supernatant was also decreased significantly (P < 0.01). These results indicated that H2S promoted synthesis and secretion of FT4 by upregulating SIRT1.
Serum thyroid hormones levels are positively correlated with H2S levels. H2S promotes the synthesis and secretion of thyroid hormones and the expression levels of related proteins by upregulating SIRT1.
LATE BREAKING HIGHLIGHTED POSTER 8
Thyroid Cancer Clinical Highlighted Poster
ROLE OF LONG‐NONCODING RNA (PVT1) IN DETERMINING MALIGNANCY IN INDETERMINATE CATEGORY OF THYROID NODULES
Susmita Dutta*, Soham Tarafdar, Nitai Bhattacharyya, Pradip Mukhopadhyay, Sujoy Ghosh
IPGME&R, SSKM Hospital, India
Molecular testing is being increasingly used to detect malignancy in indeterminate category thyroid nodules. We aimed to determine expression of long non‐coding RNA (lncRNA) in plasma of patients with thyroid nodule and assess its feasibility as a non‐invasive marker to differentiate malignant from benign nodule.
Patients underwent ultrasonography (USG) and USG guided FNAC and surgery, where indicated. Total RNA was extracted from plasma samples, FNAC materials and tissue samples and quantification, purity of isolated RNA was determined by using a Biospectrophotometer. Expression of PVT1 lncRNA was determined by Quantitative Real time PCR with respect to internal control (18s and GAPDH). The expression levels of lncRNAs were calculated using ΔCt and relative expression (fold change) was calculated as 2^‐ΔΔCt. In initial analysis (determination of cut‐off), PVT1 expression levels were compared between healthy control, Bethesda 2 and Bethesda 5 &6 to establish a cut‐off value that could differentiate malignant from benign nodules. In the subsequent analysis, the aforementioned cut‐off was applied (validation of cut‐off) to those with indeterminate nodules to check ability to predict malignancy. Mann‐Whitney U tests, Kruskal‐Wallis tests and Receiver operating characteristic (ROC) curves were performed.
FNA (n = 182) yielded patients with Bethesda 2 (n = 97), Bethesda 5 & 6 (n = 31) who underwent histopathological confirmation. PVT1 lncRNA ΔCt levels in these 2 groups were 5.74 ± 2.35 and 0.68 ± 0.59 respectively. PVT1 lncRNA was up regulated in differentiated thyroid cancer compared to healthy and benign group (P < 0.001). A PVT1 (ΔCt) cut‐off of 2.29, with AUC of 0.995 (95% CI, 0.98‐1.0) with 100% sensitivity and 94.8% specificity was established to identify malignant lesions. Indeterminate group (Bethesda 3 & 4) patients underwent surgery (malignant n = 31), (benign n = 23). Using the previously identified cut‐off for PVT1 expression, we were able to identify malignant lesions with a sensitivity of 93.5% and specificity of 95.6%.
PVT1 expression from plasma could help in differentiating malignant from benign thyroid nodules.
LATE BREAKING HIGHLIGHTED POSTER 9
Thyroid Cancer Clinical Highlighted Poster
EFFECT OF AGE ON EFFICACY AND SAFETY OF CABOZANTINIB VERSUS PLACEBO IN PATIENTS WITH RADIOIODINE (RAI)‐REFRACTORY DIFFERENTIATED THYROID CANCER (DTC) WITH PROGRESSION AFTER VEGFR‐TARGETED THERAPY: SUBGROUP ANALYSIS FROM THE PHASE 3 COSMIC 311 STUDY
Bruce Robinson*1, Steven Sherman2, Jolanta Krajewska3, Chia‐Chi Lin4, Fernanda Vaisman5, Ana Hoff6, Erika Hitre7, Daniel Bowles8, Jorge Hernando9, Kamalika Banerjee10, Roman Levytskyy10, Jennifer Oliver10, Bhumsuk Keam11, Jaume Capdevila9, Marcia Brose12
1Sydney Medical School, The University of Sydney, Australia, 2Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, USA, 3Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch, Poland, 4Department of Oncology, National Taiwan University Hospital, Taiwan, 5Instituto Nacional de Câncer, Brazil, 6Department of Endocrinology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, Brazil, 7Department of Medical Oncology and Clinical Pharmacology “B,” Országos Onkológiai Intézet, Hungary, 8Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, USA, 9Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Spain, 10Exelixis, Inc, USA,11Department of Internal Medicine, Seoul National University Hospital, Korea, Republic of,12Abramson Cancer Center, University of Pennsylvania, USA
In the phase 3 COSMIC‐311 trial (NCT03690388), the multikinase inhibitor cabozantinib, significantly improved progression‐free survival (PFS) compared to placebo in previously treated patients with RAI—refractory DTC (HR 0.22, 96% CI 0.13‐0.36; p < 0.0001). The impact of age on efficacy and safety is presented here in the prespecified subgroup analysis.
In the data analysis with February 8, 2020, cutoff date, 258 patients were randomized 2:1 to receive cabozantinib (60 mg QD) or placebo. Patients were stratified by prior lenvatinib treatment and age (younger subgroup: ≤65 years; older subgroup: >65 years). Patients with RAI‐Refractory DTC must have progressed on or after VEGFR‐targeted therapy. The primary endpoint of PFS and other outcomes were analyzed by subgroups based on age with February 8, 2020, data cut.
Prior sorafenib/lenvatinib was received by 69%/60% in the younger subgroup (130 patients), and 51%/65% in older subgroup (128 patients), respectively. Median PFS with cabozantinib arm was 11.0 months (95% CI 7.20─NE) versus placebo 1.9 months (95% CI 1.81─3.61) for the younger subgroup (HR 0.19, 95% CI 0.12─0.32; p < 0.0001) and 11.1 months (95% CI 5.88─13.83) versus placebo 3.6 months (95% CI 1.87─5.36) for the older subgroup (HR 0.27, 95% CI 0.17─0.45; p < 0.0001). The discontinuation rate of cabozantinib due to treatment‐emergent adverse events related to study treatment was 5.8% in the younger subgroup and 5.7% in the older subgroup versus 0% with placebo; the percentage of patients with any cabozantinib dose reduction was 65% for the younger subgroup and 69% for the older subgroup. The safety profile of cabozantinib was similar between age groups. No treatment‐related grade 5 adverse events were reported.
This subgroup analysis demonstrates the clinical benefit of cabozantinib in patients with previously treated RAI‐refractory DTC is maintained irrespective of age.
LATE BREAKING HIGHLIGHTED POSTER 10
Thyroid Cancer Translational Highlighted Poster
MIRNA DYSREGULATION IN PEDIATRIC THYROID CANCER
Julio Ricarte Filho*1, Amber Isaza1, Tasleema Patel1, Lindsay Sisko1, Jonathan Wasserman2, Andrew Bauer1, Aime Franco1
1Children's Hospital of Philadelphia, USA, 2The Hospital for Sick Children, Canada
miRNAs are promising diagnostic and prognostic markers for cancer and play a role in thyroid tumor progression. Most miRNA studies in thyroid cancer have focused on adult cases. In this study, we evaluated the miRNA transcriptome in pediatric thyroid tumors.
We performed the simultaneous screening of more than 2,000 miRNAs using a next generation sequencing (NGS) probe‐based assay in 60 pediatric lesions, including 13 benign, 40 papillary thyroid cancers (PTC) and 7 follicular thyroid cancers (FTC). miRNA expression data was compared with available mutational data and clinicopathological parameters.
miRNAs were differentially expressed in benign versus malignant tumors (n = 823), PTC vs FTC (n = 309) and follicular vs classic variants of PTC (n = 139). Differentially expressed miRNAs in malignant tumors included those previously reported in adult cancers (miR‐34a‐5p, miR‐146b‐5p, miR‐222‐3p) as well as miRNAs specifically altered in pediatric tumors (miR‐4458 and mir‐885‐3p). One miRNA, mir‐503‐3p, was significantly upregulated in tumors harboring fusions of RET and NTRK1/3 fusions when compared to BRAF‐mut tumors. Four cases (3 fvPTC and 1 FTC) showed hotspot mutations in the RNase IIIb domain of DICER1, supposedly leading to defects in processing miRNA‐5p strands. Accordingly, these particular tumors show overall increase in several miRNA‐3p strands, including the overexpression of miR‐135b‐3p, miR‐450a‐1‐3p and miR‐181a‐2‐3p.
To our knowledge, this is the largest study of miRNAs in pediatric thyroid cancer. Additional experiments are ongoing to perform an integrated molecular analysis of pediatric thyroid cancer by including mutational analysis and gene expression. These studies will help dissecting the molecular mechanisms underlying the worse outcome (increased invasive behavior and decreased response to RAI therapy) of those cases harboring oncogenic fusions of RET, NTRK and ALK.
LATE BREAKING HIGHLIGHTED POSTER 11
Thyroid Cancer Clinical Highlighted Poster
CONTRIBUTION OF CYTO‐HISTOLOGIC GENETIC PROFILE TO THE DECISION CRITERIA OF TREATMENT WITH RADIOIODINE IN DIFFERENTIATED THYROID CARCINOMA
Maria de Lurdes de Matos*1, Paula Soares2, Maria João Bugalho3, Ana Luísa Papoila4, Mafalda Pinto2, Marta Alves4
1Hospital Curry Cabral, Portugal, 2IPATIMUP, Portugal, 3Hospital Santa Maria, Portugal, 4Centro de Investigação do Centro Hospitalar Universitário de Lisboa Central, Portugal
The development of differentiated thyroid carcinoma (DTC) has been associated with the activation of oncogenes that are implicated in the cell signaling pathway, interfering in cancer promotion and outcome. Radioiodine is the treatment of choice, after surgery, for aggressive DTC with vascular, lymphatic invasion or long distant metastases, accordingly to the risk stratification and international guidelines. Genetic profile may contribute to a better understanding of tumors aggressiveness and the decision for radioiodine treatment.
The aim of this study is to evaluate the genetic profile (TERTp, BRAF and RAS (NRAS, HRAS and KRAS)), by using a paired series of ultrasound‐guided fine‐needle aspiration cytology (US‐FNAC) and histologic samples of DTC, in order to establish the contribution of molecular profiling to the decision‐making process for adjuvant radioiodine therapy.
Samples, from 78 consecutive patients with DTC, derived either from FNAC and/or from the corresponding formalin‐fixed paraffin‐embedded (FFPE) tissue of the corresponding surgical specimen, were analyzed for genetic alterations by polymerase chain reaction followed by DNA sequencing. The associations of the genetic alterations with clinicopathological features and with the radioiodine treatment decided upon classical criteria were evaluated.
The frequency of mutations in this series of 78 patients with DTC of whom 40 cases (51,3%) were not treated with radioiodine and 38 cases (48,7%) underwent adjuvant radioiodine therapy was as follows, TERTp: 7,5% v 15,8%; BRAF: 32,5% v 39,5%; NRAS: 7,5% v 10,5%; HRAS: 7,5% v 2,6%; and KRAS: 2,5% v 2.6%, respectively. Regarding these mutations, no statistically significant differences between patients treated and not treated with radioiodine were found. However, although not directly associated with the treatment, our data presented several statistically significant associations between the molecular and clinicopathological features of the tumors. TERTp and BRAF mutations were associated with aggressiveness and extrathyroidal invasion, in particular in the presence of concomitant TERTp+BRAF mutations. On the contrary, RAS mutations were associated with less aggressive clinicopathological features.
Results of our exploratory study may suggest the inclusion of genetic profile to further refine the criteria to select patients for radioiodine treatment, however further studies with larger samples are needed.
LATE BREAKING HIGHLIGHTED POSTER 12
Thyroid Cancer Clinical Highlighted Poster
MOLECULAR CLASSIFICATION OF FOLLICULAR THYROID CARCINOMA BASED ON
TERT
PROMOTER MUTATIONS
Hyunju Park*1, Hyeong Chan Shin2, Heera Yang1, Jung Heo1, Chang‐Seok Ki3, Hye Seung Kim4, Jung‐Han Kim5, Soo Yeon Hahn6, Yun Jae Chung7, Sun Wook Kim1, Jae Hoon Chung1, Young Lyun Oh8, Tae Hyuk Kim1
1Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of, 2Department of Pathology, Keimyung University School of Medicine, Korea, Republic of, 3Green Cross Genome, Korea, Republic of, 4Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of, 5Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of, 6Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of, 7Department of Internal Medicine, Chung‐Ang University Hospital, Chung‐Ang University College of Medicine, Korea, Republic of, 8Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of
Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer‐specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification.
We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease‐free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C‐index.
CSS was significantly different in encapsulated angioinvasive (EA)‐FTC patients stratified by TERT promoter mutations [wild‐type (WT‐TERT) vs. mutant (M‐TERT); P < 0.001] but not in minimally invasive (MI)‐FTC and widely invasive (WI)‐FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI‐FTC with WT‐TERT and M‐TERT; EA‐FTC with WT‐TERT), Group 2 (WI‐FTC with WT‐TERT), and Group 3 (EA‐FTC with M‐TERT; WI‐FTC with M‐TERT). Both PVE (22.44 vs. 9.63, respectively) and C‐index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C‐index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups.
Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.
LATE BREAKING HIGHLIGHTED POSTER 13
Thyroid Cancer Clinical Highlighted Poster
ROLE OF LONG‐NONCODING RNA (PVT1) IN DETERMINING MALIGNANCY IN INDETERMINATE CATEGORY OF THYROID NODULES
Susmita Dutta*, Soham Tarafdar, Nitai Bhattacharyya, Pradip Mukhopadhyay, Sujoy Ghosh
IPGME&R, SSKM Hospital, India
Molecular testing is being increasingly used to detect malignancy in indeterminate category thyroid nodules. We aimed to determine expression of long non‐coding RNA (lncRNA) in plasma of patients with thyroid nodule and assess its feasibility as a non‐invasive marker to differentiate malignant from benign nodule.
Patients underwent ultrasonography (USG) and USG guided FNAC and surgery, where indicated. Total RNA was extracted from plasma samples, FNAC materials and tissue samples and quantification, purity of isolated RNA was determined by using a Biospectrophotometer. Expression of PVT1 lncRNA was determined by Quantitative Real time PCR with respect to internal control (18s and GAPDH). The expression levels of lncRNAs were calculated using ΔCt and relative expression (fold change) was calculated as 2^‐ΔΔCt. In initial analysis (determination of cut‐off), PVT1 expression levels were compared between healthy control, Bethesda 2 and Bethesda 5 &6 to establish a cut‐off value that could differentiate malignant from benign nodules. In the subsequent analysis, the aforementioned cut‐off was applied (validation of cut‐off) to those with indeterminate nodules to check ability to predict malignancy. Mann‐Whitney U tests, Kruskal‐Wallis tests and Receiver operating characteristic (ROC) curves were performed.
FNA (n = 182) yielded patients with Bethesda 2 (n = 97), Bethesda 5 & 6 (n = 31) who underwent histopathological confirmation. PVT1 lncRNA ΔCt levels in these 2 groups were 5.74 ± 2.35 and 0.68 ± 0.59 respectively. PVT1 lncRNA was up regulated in differentiated thyroid cancer compared to healthy and benign group (P < 0.001). A PVT1 (ΔCt) cut‐off of 2.29, with AUC of 0.995 (95% CI, 0.98‐1.0) with 100% sensitivity and 94.8% specificity was established to identify malignant lesions. Indeterminate group (Bethesda 3 & 4) patients underwent surgery (malignant n = 31), (benign n = 23). Using the previously identified cut‐off for PVT1 expression, we were able to identify malignant lesions with a sensitivity of 93.5% and specificity of 95.6%.
PVT1 expression from plasma could help in differentiating malignant from benign thyroid nodules.
LATE BREAKING POSTER 14
Autoimmunity Clinical Poster
RISK FACTORS FOR THYROID DERMOPATHY (PRETIBIAL MYXEDEMA): A CASE‐CONTROL STUDY
Ekaterina Sabanova*1, Valentin Fadeyev1, Andrey Lvov2
1Sechenov University, Russian Federation, 2Moscow State University, Russian Federation
Thyroid dermopathy (TD) or pretibial myxedema is a rare autoimmune manifestation of Graves' disease with postulated multifactorial etiology. Due to the rarity of the condition, data on risk factors for TD are scarce.
We performed a case‐control study of 124 patients with Graves' disease to determine the risk factors and predict the odds for developing TD. 31 patients diagnosed with pretibial myxedema and 93 control patients without TD entered the study. Multivariate logistic regression models were used for case‐control comparisons.
We identified two independent risk factors for TD out of 10 considered variables. A late‐onset of Graves' disease was associated with TD, the odds were 1.11 times larger for every one‐year increase in age (odds ratio, 1.11; 95% confidential interval [CI], 1.05 to 1.18). Thyrotropin receptor antibodies were another significant risk factor for TD occurrence (odds ratio, 1.07; 95% CI, 1.02 to 1.12). Serum levels of thyroid hormones, thyrotropin, I‐131 treatment, body mass index, smoking, Graves' orbitopathy, and its treatment modalities were unrelated to TD.
Our study identified older age at diagnosis of Graves' disease and thyrotropin receptor autoimmunity as independent risk factors for TD occurrence.
LATE BREAKING POSTER 15
Disorders of Thyroid Function Clinical Poster
TAKING THE HEART BY STORM: THYROID STORM WITH ST ELEVATIONS
Mariya Khan*, Franklin Thelmo, Zain Ali
Abington Memorial Hospital, USA
Thyroid storm is a life‐threatening exacerbation of the hyperthyroid state. Association with cardiovascular complications including arrhythmias and cardiomyopathies have been well described. Reports of thyroid storm manifesting with ST‐elevation are rare. We describe a case of a premenopausal female presenting with thyroid storm complicated by Supraventricular tachycardia, ST‐elevations, and thyrotoxicosis‐induced cardiomyopathy.
A 48‐year‐old female with recently diagnosed hyperthyroidism presented to the emergency room for evaluation of back pain and spasms. Initial vital signs were temperature 100.4 C, blood pressure 98/55, and heart rates in the 120s saturating 100% on room air. In the emergency room, she was found to have supraventricular tachycardia with a heart rate in the 190s. She became hemodynamically unstable, for which she underwent cardioversion. Subsequent electrocardiograms revealed ST elevations in the inferior and lateral leads. Troponins peaked at 2568 ng/L. She underwent cardiac catheterization which was revealed normal coronary arteries. An echocardiogram showed her LVEF to be 20‐25% with global hypokinesis. The presentation was consistent with thyroid storm, confusion, pyrexia, and cardiovascular dysfunction. She was treated with intravenous propranolol, hydrocortisone, propylthiouracil, and potassium iodide. She reported that she had not been adherent to medications and had been taking cyclobenzaprine for back spasms. Her TSH was found to be <0.01ulU/ml, with T4, was 1.6 ng/dl and T3 was 128 ng/dl. After being stabilized she was later discharged on methimazole with a planned outpatient thyroid uptake scan.
Thyrotoxicosis with ST‐elevation has scarcely been described in literature. The etiology of the ST‐elevations as seen in our case, have been thought to be related to coronary vasospasm, autoimmune myocarditis, and acute stress cardiomyopathy. The use of cyclobenzaprine may have further potentiated arrhythmias, as cyclobenzaprine has the potential for sodium channel blockade and ventricular dysrhythmias although cardiac toxicity. Our case exhibits the multitude of cardiac complications that may be seen with thyroid dysfunction. It emphasizes the importance of adherence to treatment and vigilance when prescribing drugs with the potential for adverse reactions in diagnosed cases.
LATE BREAKING POSTER 16
Health Disparities Clinical Poster
IMPACT OF SOCIAL DETERMINANTS OF HEALTH ON OUTCOMES IN PEDIATRIC MEDULLARY THYROID CANCER
Arifeen Rahman*, Christopher Low, Alice Huang, Karthik Balakrishnan
Stanford University Medical Center, USA
Medullary thyroid cancer (MTC) is a rare disease process in pediatric patients. We examine the relationship between major social determinants of health and MTC outcomes.
Retrospective data from the Surveillance, Epidemiology and End Results (SEER) database from 1975‐2016 was gathered for patients aged 0‐19. County characteristics including language isolation, percent of population below the poverty line, and percent of the population with less than high school education were also attained. Univariate and multivariable Cox proportional hazard analysis were conducted.
174 pediatric medullary thyroid cancer patients with primary tumors were identified. 56% of patients were female and 47% were male. Disease Specific Survival was 98.3% and Overall Survival was 97.7% at five years. All patients underwent surgery, with 2.3% receiving beam radiation and 0.5% receiving chemotherapy. 68% had localized disease, 21% regional, and 4% had distant disease. Male sex increased the odds of death with a hazard ratio of 3.9 (95% CI 1.07‐14.70, p = 0.038). No difference was found between the survival curves of Caucasian and non‐Caucasian patients. County characteristics reflecting social determinants of health were not shown to be associated with poorer survival in univariate and multivariable Cox regression. Sex, race, and county characteristics were not shown to be associated with more distant disease at presentation with logistic regression.
Male sex is associated with poorer overall survival in pediatric medullary thyroid cancer.
LATE BREAKING POSTER 17
Thyroid Cancer Clinical Poster
NOVEL RECOMBINANT HUMAN THYROID‐STIMULATING HORMONE FOR POST‐OPERATIVE ASSESSMENT IN CHINESE PATIENTS WITH DIFFERENTIATED THYROID CANCER
Yan‐Song Lin*1,2, Hui Yang3, Xiao‐Yi Li4, Ai‐Min Yang5, Zai‐Rong Gao6, Yong Ding7, Shao‐Qiang Zhang8, Ying‐Qiang Zhang1,9, Zhuan‐Zhuan Mu1,2, Li‐Qing Wu10
1Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & PUMC, China, 2Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, China, 3Department of Nuclear Medicine, Affiliated Tumor Hospital of Zhengzhou University, China, 4Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, China, 5Department of Nuclear Medicine, First Affiliated Hospital of Xi'an Jiaotong University, China, 6Department of Nuclear Medicine, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, China, 7Department of Nuclear Medicine, The Fifth Medical Center of the General Hospital of the Chinese People's Liberation Army, China, 8Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Xi'an Jiaotong University, China, 9Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicin, China, 10Department of Clinical Research, Suzhou Zelgen Biopharmaceuticals Co., Ltd., China
Patients with differentiated thyroid cancer (DTC) after total thyroidectomy usually indicated for disease assessing and radioactive iodine (RAI) therapy indication selection, during which thyroid hormone withdrawal (THW) is usually required to conduct stimulated thyroglobulin (Tg) measurement and RAI whole‐body scanning (WBS). To avoid the undesirable hypothyroidism induced by THW, this phase I study was aimed to evaluate the efficacy and safety of a domestic novel recombinant human thyroid‐stimulating hormone (rhTSH) in Chinese DTC patients.
A total of 64 DTC patients were enrolled. 24 patients in the dose‐escalation cohort were divided into 4 dose groups: 0.9 mg × 1d, 0.9 mg × 2d, 1.8 mg × 1d, 1.8 mg × 2d sequentially, 6 patients in each group. The 0.9 mg × 2 d dose group was expanded to 40 patients in the dose‐expansion cohort. All patients underwent both the rhTSH and THW phase to compare the TSH levels, RAI uptake, stimulated Tg, as well as the quality of life (QoL).
Serum TSH levels were increased from 0.11 ± 0.12 mIU/L at baseline to a peak of 122.11 ± 42.44 mIU/L, 24h after the last dose of rhTSH injection. In the THW phase, patients underwent a median of 23 days to achieve TSH ≥30 mIU/L, with mean TSH levels of 82.20 ± 31.37 mIU/L. The QoL in rhTSH phase was significantly better than those in THW phase, presented as the lower Billewicz score (‐51.30 ± 4.70 vs ‐39.10 ± 16.61, P < 0.001) and POMS score (91.70 ± 16.70 vs 100.40 ± 22.11, P = 0.011). RAI uptake reflected by WBS were concordant between the rhTSH and THW phases in 57 of 64 (89.1%) patients. Among the 59 patients with negative thyroglobulin antibody, taking 1 ng/ml as the cut‐off values of Tg, the consistent diagnosis rate was 84.7% (50/ 59) between two phases. There were no serious adverse events (AEs) observed, the most common rhTSH related AEs were headache (6.3%), lethargy (4.7%), fatigue (3.1%), all were mild and transient.
rhTSH is a safe and effective method to stimulate serum Tg and RAI uptake in DTC patients undergoing post‐operation assessment, using rhTSH could also maintain a higher QoL to THW.
LATE BREAKING POSTER 18
Thyroid Hormone Action Clinical Poster
ROLE OF THYROTROPIN‐RELEASING HORMONE TEST IN THE EVALUATION OF SUBCLINICAL HYPOTHYROIDISM
Myung Hi Yoo*1, Hye Jeong Kim2, Suyeon Park1, Hyeong Kyu Park1, Dong Won Byun1, Kyoil Suh1
1Soonchunhyang Univ. Hosp., Korea, Republic of, 2Soonchunhyang Uni. Hosp., Korea, Republic of
Subclinical hypothyroidism is defined as elevated TSH level with normal T4 level, and common endocrine disorder but the decision of treatment in patients with serum TSH level 4‐10 uU/ml is controversial. Consensus statements suggested clinical practice combining physician's clinical judgement and patient's preference, but both looked subjective rather than objective guidelines.
We tried to evaluate the incidence of exaggerated TSH response on TRH test in subclinical hypothyroidism which would mean the need of treatment.
We evaluated 8944 subjects who performed routine health examination from April 2019 to Aug 2020. at Soonchunhyang University Hospital and Hanshin Medipia in Seoul, Korea. Among 1458 subjects with TSH levels higher than 4.0 uU/ml, TRH test was performed in 206 subjects. 1. Among 8944 subjects, TSH level higher than 4.0uU/ml was found in 1458 subjects(16.3%) with female preponderance (men 13.5% v.s. women 22.6%, p < 0.01) and increased incidence in older age group ( 15.6% in age younger than 50yrs, v.s. 17.7%, in age older than 50yrs, p < 0.01) 2. Distribution of the subjects according to basal TSH level showed subjects with TSH 4‐5 uU/ml, 5‐6 uU/ml and 6‐10 uU/ml composed 36,4%, 27.2 % and 36.4 % of subclinical hypothyroidism respectively 1. TRH stimulation test result according to the basal TSH level showed exaggerated TSH stimulation in 48% of the subjects with basal TSH level 4‐5 uU/ml (n = 75), 60.7% with TSH 5‐6 uU/ml (n = 56), 75.0% with TSH 6‐7 uU/ml (n = 40), 87.5% with TSH 7‐8 uU/ml (n = 24), 100% with TSH 8‐9uU/ml (n = 4) and TSH 9‐10uU/ml (n = 7)
Incidence of exaggerated TSH stimulation in subclinical hypothyroidism increased dependently with basal TSH. Our results showed about two thirds of subclinical hypothyroidism resided TSH level 4‐6 uU/ml and TRH test could identify about half of the patients who would need the treatment. More than 75 % of subjects with TSH 6‐10 uU/ml showed exaggerated TSH stimulation, Our data suggested TRH test was a useful guide to decide the treatment of subclinical hypothyroidism.
LATE BREAKING POSTER 19
Thyroid Cancer Clinical Poster
NEGATIVE THYROGLOBULIN AS A (SOLITARY/INDEPENDENT) METHOD OF FOLLOW‐UP FOR LOW‐RISK DIFFERENTIATED THYROID CANCER AFTER TOTAL THYROIDECTOMY
Abdallah Attia*, Mahmoud Omar, Mohamed Abouiesha, Ruhul Munshi, Mohamed Shama, Emad Kandil
Tulane University, School of Medicine, USA
Despite the high survival rate associated with thyroid cancer, it is associated with high care expenses due to monitoring imaging, biopsy, surgery, and long‐term medical therapy; cervical ultrasound (CUS) is currently seen as the chief element of follow‐up, and it is usually done regardless of non‐stimulated thyroglobulin (Tg) levels. We sought to emphasizes whether there is a clinical benefit from the routine US in Differentiated thyroid carcinoma (DTC).
A retrospective database study was conducted on cervical ultrasound exams performed in thyroglobulin negative antibody patients post thyroidectomy. The accuracy of ultrasound results was assessed based on fine‐needle aspiration as a gold standard, with sub‐group analysis comparing low‐risk and high‐risk recurrence patients.
A total of 223 patients underwent a total of 767 CUS, with a mean age of 55.08 ± 11.95 years; of them, 181 were females (70.4%), TG was negative in 626 of which CUS was true negative in 478 (76.35%), true positive 9 (1.43%) false‐negative, and false‐positive was 139 (22.22%) with a positive predictive value of 6.08% (CI = 5.30% to 6.97%) and accuracy of 77.80% (CI = 74.33% to 80.99%). On subgroup analysis, the Positive predictive value was significantly lower in low‐risk recurrence patients 2.60% (CI = 2.14% to 3.14%) compared to intermediate‐risk patients 10.00%(CI = 7.66%to12.95%). p < 0.001.
US showed no additional benefit to the TG in the follow‐up of a low‐risk differentiated thyroid cancer patient after total thyroidectomy, with a high false‐positive rate leading to unnecessary expensive, invasive procedures.
LATE BREAKING POSTER 20
Disorders of Thyroid Function Clinical Poster
A DECADE OF HOSPITALIZATIONS FOR HYPERTHYROIDISM IN THE US
Hafeez Shaka*1, Oluwatomi Adeoti2, Michael Salim3, Asim Kichloo4
1John H. Stroger, Jr. Hospital of Cook County, USA, 2Boston Medical Center, USA, 3Mount Sinai Hospital, USA, 4Central Michigan University, USA
The prevalence of hyperthyroidism in the United States is estimated to be around 1.2% to 1.3%. There is limited literature on patients who are hospitalized due to hyperthyroidism. This study analyzed the prevalence and outcomes of hospitalizations due to hyperthyroidism over the last decade to provide epidemiologic information regarding the impact of various changes in healthcare policies and provisions on this group.
This was a retrospective interrupted trends study involving hospitalizations principally for hyperthyroidism in the US from 2008 to 2018. These databases were searched for hospitalizations with a principal discharge diagnosis of hyperthyroidism using ICD codes. The biodemographic trends over time of the studied populations were highlighted. We trended crude hospitalization rate, estimated incidence of hospitalizations, trends in inpatient mortality rate, mean length of hospital stay (LOS), and mean total hospital cost (THC) of patients with hyperthyroidism.
Overall, between 2008 – 2018, the number of hyperthyroid hospitalizations decreased from 12,689 in 2008 to 9,110 in 2018 (28.2%) (p trend <0.001). The crude hospitalization rate decreased from 33 – 25 per 100,000 adult hospitalizations over the study period. There was also a significant decrease in the estimated incidence of hyperthyroidism hospitalization from 441 – 288 per 100,000 adults with hyperthyroidism. The mean age over the period ranged from 47.1 – 49.7 years. Most of the hospitalizations involved females and Whites.
Although there has been a significant reduction of hospitalizations due to hyperthyroidism in the US, there has been no significant change in mortality during hospitalizations. This may represent improving outpatient management of hyperthyroidism. However, this has not translated to improved outcomes in the hospital setting.
LATE BREAKING POSTER 20
Thyroid Imaging Clinical Poster
LARYNGEAL ADDUCTOR REFLEX; A BETTER MODALITY OF NERVE MONITORING DURING ENDOCRINE NECK SURGERY
Mahmoud Omar, Abdallah Attia*, Mohamed Abouiesha, Mohamed Shama, Emad Kandil
Tulane University, School of Medicine, USA
Recurrent Laryngeal Nerve (RLN) is considered as the most important structure at risk during neck Surgeries, despite the various modalities that were introduced for intraoperatively monitoring the nerve, the incidence of developing nerve palsy still varies between 1.5‐14%. We sought to investigate the efficacy of intermittent Intraoperative nerve monitoring (Intermittent IONM), and continuous intraoperative nerve monitoring using laryngeal adductor reflex (LAR) in preventing the injury to the RLN.
This is an observational study from a high‐volume single surgeon at a North American institute. We included data from consecutive intermittently monitored nerves‐at‐risk from July 2017 to March 2019 and prospectively recorded data from consecutive nerves‐at‐risk monitored with continuous LAR during 2020. We estimated the incidence of nerve injuries in both groups, test benefit ratio, and relative risk reduction for continuous LAR over intermittent IONM.
A total of 437 patients, of them, 101 patients we monitored with the LAR. There was a significant difference in the mean age of the LAR group (53.43 ± 15.06 years), compared to the Intermittent group (56.24 ± 12.51 years), p = 0.08. The rate of loss of a drop of signal among the LAR group was 6.7% compared to 4.5% in the intermittent IONM group, p = 0.223. Among those who had a drop of signal, the rate of RLN injury among the LAR group was significantly lower than the intermittent IONM group, 11.1% vs 62.5%, p = 0.017.
The rate of developing temporary vocal cord weakness based on post‐operative laryngoscopy in the LAR group was 0.7% (N = 1) compared to 2.8% (N = 10) with intermittent IONM, p = 0.148. No cases had developed permanent vocal cord paralysis with the LAR group. However, one case developed a permanent vocal cord paralysis (0.2%), p = 0.725. The LAR group showed a significant relative risk reduction of 89.9% over the intermittent group.
Our study demonstrated that continuous intraoperative nerve monitoring using LAR is an efficient modality to prevent the development of RLN injury. It provides the surgeon with a prompt response to do corrective actions compared to the intermittent modality.
LATE BREAKING POSTER 21
Disorders of Thyroid Function Clinical Poster
SEVERE GESTATIONAL TRANSIENT THYROTOXICOSIS
Bishow Shrestha*1, Rebecca Deboer1, Chheki Sherpa1, Anita Gabriely2, Ilan Gabriely1
1Reading hospital, USA, 2Thomas Jefferson University, USA
20‐year‐old female G2P1001 at 10w1d gestation presented with palpitations, dizziness, dyspnea on exertion, visual disturbances, progressively worsening nausea and vomiting. On initial presentation, she was diagnosed with SVT treated in the Emergency department with IV adenosine with return to sinus rhythm. Initial lab findings (TFT) TSH <0.020 uIU/L (reference 04‐4.5 uIU/L), FT4 4.22 ng/dL (reference range 0.58‐1.64 ng/dL), FT3 5.28 pg/mL (reference range 2.20‐4.10 pg/mL) hCG 212,563.8 mIU/L. She was started on metoprolol succinate 25 mg once daily, IV fluids and ondansetron 4 mg every 8 hours as needed with improvement in nausea and vomiting. Two days later, repeat TSH 0.006 uIU/L, FT4 3.48 ng/dL. With improving thyroid function tests and with clinical improvement, anti‐thyroid medications were not started. Instead, the patient was discharged with recommendations to closely monitor her thyroid function tests.
Our case presented with severe gestational thyrotoxicosis and hyperemesis gravidarum. She was treated with B‐ blocker, IV fluids, Ondansetron. Her thyroid function test improves after 2 days. She was discharged with recommendations to closely monitor her thyroid function tests.
GTT can present with exceptionally high free T4. The thyroid function test progressively normalized as the pregnancy progressed. In this instance, less is more. Symptom management was enough.
LATE BREAKING POSTER 22
Thyroid & Development Clinical Poster
A DELAYED DROP OF INTRAOPERATIVE PARATHYROID HORMONE OVER TIME IN ELDERLY POPULATION WITH PRIMARY HYPERPARATHYROIDISM
Mahmoud Omar*, Abdallah Attia, Mohamed Abouiesha, Eman Toraih, Mohamed Shama, Emad Kandil
Tulane University, School of Medicine, USA
Metabolism and excretion of Parathyroid hormone (PTH) are mainly managed by the kidneys. Rapid intraoperative parathyroid hormone (IOPTH) is a vital prerequisite for successful parathyroid surgeries in patients with primary hyperparathyroidism (PHPT). The impact of variations in the estimated glomerular filtration rate (eGFR) and the pattern of IOPTH drop among different age groups was never studied before. The aim of our study is to examine the time variations to achieve surgical success among different age groups with different glomerular filtration rates.
We performed a retrospective study including patients with PHPT who underwent parathyroidectomy with IOPTH monitoring at a tertiary North American institution. Statistical analysis was performed to estimate the time to achieve curative surgeries.
A total of 290 patients were included, with a mean age of 61.4 ± 14.0 years; Elderly (> 65 years) showed longer time to achieve IOPTH drop >50% with a mean of 31.7 ± 26.2 minutes compared to 11 ± 9.7 minutes in the younger population, p < 0.001, furthermore, elderly patients showed a longer duration (>50 minutes) to achieve a value below normal level compared (31‐35 minutes) in the younger population, p = 0.007. Elderly patients had a lower eGFR 75.236 ± 27.51 mL/min/1.73 m2 compared to 89.569 ± 22.52 mL/min/1.73 m2 in the younger group, p < 0.001. Both age and eGFR are independent predictors for a longer time to achieve curative surgeries.
For the first time, we are showing that age and GFR are directly affecting the time needed to achieve an appropriate drop‐in IOPTH. Preoperative evaluation of eGRF could be helpful in predicting IOPTH pharmacokinetics. These findings could help to avoid postoperative hypoparathyroidism in elderly populations.
LATE BREAKING POSTER 23
Thyroid Cancer Clinical Poster
A NOVEL METHOD FOR DOSIMETRIC PLANNING AND TREATMENT OF METASTATIC WELL‐DIFFERENTIATED THYROID CANCER WITH COMBINED 131‐IODINE AND STEREOTACTIC RADIOTHERAPY
Harry Quon Quon, Paul Ladenson, Prasanna Santhanam*, Robert Hobbs, Hao Wang, Katie Lowe, Dana Kaplin, Shirley Dipasquale, George Sgouros
Johns Hopkins University School of Medicine, USA
Metastases from well‐differentiated epithelial thyroid cancers are sometimes treatable with radioiodine (RAI), but these lesions not infrequently partially lose their RAI avidity, resulting in sub‐therapeutic RAI uptake with a lesion absorbed dose <80 Gy. These patients—as well as those whose RAI uptake becomes sub‐therapeutic after previous RAI treatments or who progress despite theoretically therapeutic RAI exposure–might benefit from the combination of RAI with external beam radiotherapy (EBRT). Until now, accurate prediction of the absorbed dose from such combined radiotherapy has not been available. We have developed software with the ability to generate absorbed dose maps from such combined sub‐therapeutic RAI and EBRT. This method has the promise of safely and effectively delivering combined RAI and EBRT fusion treatment that meets a target tumor absorbed dose while respecting normal organ dose limits, especially for stereotactic EBRT. We illustrate this approach using a hypothetical case below:
This novel dosimetric radiotherapy strategy based on combined sub‐therapeutic RAI and stereotactic EBRT introduces a fundamentally new treatment paradigm that leverages well‐established RAI therapy, which is often sub‐therapeutic alone, with widely available EBRT for treatment of nonresectable metastatic lesions in advanced thyroid cancer patients. The trial is currently open to patient accrual (NCT04892303).
LATE BREAKING POSTER 24
Thyroid Cancer Clinical Poster
FACTORS ASSOCIATED WITH NODE METASTASIS IN CENTRAL LEVEL IN THYROID CANCER
Francisco Gallegos*1, Karen Radilla2, José Abrego1
1Hospital de Oncología, Mexico, 2Hospitla de Oncología, Mexico
Prophylactic dissection of the central level of the neck (CLD) is controversial, is associated with surgical complications, and is not always helpful. The selection of candidate patients for CLD is necessary; the factors that predict the presence of metastases must be identified to decide to perform CLD.
To know which factors are associated with central lymph node metastases in patients with DTC undergoing CLD.
Retrospective, cross‐sectional, observational, analytical study; patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy and CLD were included; variables evaluated: tumor size, glandular capsular rupture and invasion of peri‐thyroid tissues, the cervical status of the lateral necks, gender, age, number of dissected nodes; and they were compared with the presence of lymph node metastases.
There were 85 patients, with a mean age of 49 years. The factors associated with the presence of metastases at the central level were: tumor size and the presence of capsular rupture with infiltration of peri‐thyroid tissues (pT3).
Extrathyroid tumor extension and tumor size of 4cm or greater in CLT are the two factors that are most significantly associated with metastases at the central level; elective dissection is indicated in these patients.
LATE BREAKING POSTER 25
Thyroid Hormone Metabolism & Regulation Basic Poster
THE ROLE OF CYSTEINE IN THYROGLOBULIN BIOSYNTHESIS
Cintia Citterio*1,2, Cinthia Fijalkowky1, Peter Arvan2
1Instituto de Inmunología, Genética y Metabolismo (INIGEM), Universidad de Buenos Aires (UBA) – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina, 2Division of Metabolism, Endocrinology & Diabetes. Department of Internal Medicine, University of Michigan, USA
Thyroglobulin (Tg), the thyroid hormone precursor protein (MW ∼330kDa), is synthesized under the influence of TSH in thyrocytes, where it represents ∼50% of total protein synthesis. Tg structure has been shown to be stabilized by a multitude of disulfide bonds formed within the endoplasmic reticulum (ER). It has been suggested that oxidation of Tg cysteines to cystine may be critical for Tg structural maturation and secretion, although little is known about cytosolic cysteine availability for thyroidal protein synthesis. What is known is that in cystinosis, deficiency of a functional lysosomal cystine transporter (which provides, under physiological conditions, a cytosolic supply of cysteines) is genetically linked to hypothyroidism. To better understand the importance of cysteine availability, we examined PCCL3 thyrocytes exposed to Cys‐limited medium. We noted that upon Cys‐deprivation, there was a progressive and significant decrease of Tg mRNA, suggesting either diminished TG gene expression or enhanced TG mRNA turnover. By 24h of Cys‐deprivation, Tg protein synthesis (and secretion) was dramatically decreased. The formation of disulfide pairs in the ER is thought to be catalyzed by a large group of resident oxidoreductases of the ER lumen. We found that in PCCL3 cells, ER oxidoreductin‐ɑ (Ero1ɑ) is positively regulated by TSH. To test the importance of Ero1ɑ for Tg folding and export, we co‐expressed recombinant Tg with or without recombinant Ero1ɑ (in 293T cells) and observed that increased Ero1ɑ expression resulted in significantly increased Tg secretion. By contrast in PCCL3 cells, siRNA knockdown of Ero1ɑ resulted in decreased Tg expression and secretion.
Taken together, these results suggest that both cysteine availability, and the capacity to catalyze disulfide bond formation in the ER, impact on Tg expression and its subsequent secretion leading to thyroid hormonogenesis. These findings are likely to contribute to an understanding of the pathogenesis of hypothyroidism in cystinosis; moreover, this work serves as the launch point for further studies of Tg biosynthesis in relation to intracellular glutathione and sulfur amino‐acid metabolism.
LATE BREAKING POSTER 26
Thyroid Nodules & Goiter Clinical Poster
AUDIT OF EXTENDING RAPID ON‐SITE EVALUATION TO ALL THYROID FINE NEEDLE ASPIRATIONS
Raphaela Muri1, Urs Borner2, Sabine Weidner3, Mafalda Trippel4, Roman Trepp*1
1Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland, 2Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital and University of Bern, Switzerland, 3Department of Nuclear Medicine, Inselspital, Bern University Hospital and University of Bern, Switzerland, 4Institute of Pathology, University of Bern, Switzerland
Rapid on‐site evaluation (ROSE) of thyroid fine needle aspirations (FNAs) can significantly reduce the rate of nondiagnostic Bethesda category I results. We aimed to assess if ROSE is also able to reduce the rate of Bethesda categories III and V and whether ROSE is able to improve the quality of the smears.
We conducted a retrospective study including 5,030 thyroid FNAs. We separately analyzed if nondiagnostic Bethesda I results were attributable to insufficient cellularity or due to artifacts. Furthermore, we differentiated Bethesda III and Bethesda V results into cellular without artifacts, sparsely cellular or artifacts. We hypothesized that ROSE reduces the rate of Bethesda categories I, III, and V and, in turn, increases benign and malignant cytological diagnoses (Bethesda category II and VI, respectively). We assume that this is due higher rates of satisfactory cellularity on the one hand, and due to a decrease in artifacts on the other.
3,726 aspirates were taken without ROSE and 1,304 were taken with ROSE. FNAs with ROSE not only showed a significantly lower nondiagnostic Bethesda I rate, but also a significant reduction of Bethesda III category. Combined, they decreased the need for a repeated FNA by a factor of 9.3 (non‐ROSE 39.9 % vs. ROSE 4.3 %). With ROSE, Bethesda III and V results were less likely to be sparsely cellular compared to without ROSE. Moreover, ROSE was also associated with a significantly 8.3 times lower rate of artifacts obstructing Bethesda I, III, and V cytologies (non‐ROSE 2.5 % vs. ROSE 0.3 %). The better diagnostic conclusiveness with ROSE not only resulted in an increase in benign Bethesda II results (non‐ROSE 51.1 % vs. ROSE 86.5 %), but also doubled the rate of malignant Bethesda VI cytologies (non‐ROSE 2.6 % vs. ROSE 5.1 %).
ROSE was able to generate more diagnostically conclusive FNAs and can be seen as a valuable addition to FNAs of thyroid nodules. We therefore recommend the implementation of ROSE as standard of care, especially in institutions where less than 90 % of specimens are categorized as either benign (Bethesda II) or malignant (Bethesda VI).
LATE BREAKING POSTER 27
Disorders of Thyroid Function Clinical Poster
PERSISTENT PAIN: RECURRENT SEVERE SUBACUTE THYROIDITIS FROM COVID 19 INFECTION
Franklin Thelmo*, Francine Ryan, Stephanie Tzarnas, Nathaniel Rosal, Kimberly Lessard
Jefferson‐Abington Hospital, USA
Subacute thyroiditis is an acute inflammatory response in the thyroid which usually follows a viral infection. This report highlights a case of subacute thyroiditis in a patient with a history of benign COVID 19 infection without indication for supplemental oxygen or hospitalization. This case is unique in the fact that the patient required multiple doses of steroids for symptom control.
A 36‐year‐old female with a past medical history of hyperlipidemia, essential hypertension, obesity, type two diabetes, and recent COVID‐19 infection six months prior presented to the hospital for evaluation of persistent anterior neck pain, fevers up to 100.9° F, ten pound weight loss, and palpitations. Two months before presentation she developed anterior neck pain that radiated into the left side of her neck and jaw. This was evaluated by an outpatient otolaryngologist who performed a nasopharyngeal laryngoscopy with unremarkable findings. She was placed on a muscle relaxant, ibuprofen, and a course of steroids. She saw another physician who trialed an additional course of steroids shortly after. Unfortunately she continued to experience excruciating discomfort prompting this hospitalization. Admission labs revealed that the patient's TSH was less than 0.01 uIU/mL. Her free T4 was 1.9 ng/dL and her free T3 was 3.6 pg/mL. A CT scan of the neck showed a 1.9 x 1.0 cm hypodense lesion. Further imaging with a thyroid ultrasound showed a heterogenous thyroid with generalized hypo echogenicity, decreased blood flow, without discrete nodules, cysts, or calcifications concerning for acute thyroiditis. The patient was started on intravenous methylprednisolone with improvement in symptoms. She was subsequently transitioned to oral prednisone on discharge.
Subacute thyroiditis most commonly follows a viral infection. With our patient, symptoms developed shortly after her COVID19 infection. Once a diagnosis of subacute thyroiditis is made, patients are treated with a short course of Non‐Steroidal Anti‐Inflammatory Drugs (NSAIDs) and occasionally oral steroids which resolves most symptoms. This case was unique in that our patient required three regimens of steroids before her symptoms improved. Given these findings, a prolonged course of steroids may be indicated for covid‐19 induced subacute thyroiditis.
LATE BREAKING POSTER 28
Disorders of Thyroid Function Translational Poster
OUTCOMES AND PREDICTORS OF 30‐DAY READMISSION FOR HYPERTHYROIDISM: A NATIONWIDE STUDY
Oluwatomi Adeoti*1, Michael Salim2, Asim Kichloo3, Hafeez Shaka4
1Boston University School of Medicine/Boston Medical Center, USA, 2Mount Sinai Hospital, USA, 3Central Michigan University, USA, 4John H Stroger Hospital of Cook County, USA
Hyperthyroidism is associated with an elevated risk of cardiovascular events and worse hospital outcomes. Hyperthyroidism is one of the most common endocrine conditions globally. Although there is literature discussing its epidemiology, there is a lack of information on readmissions related to hyperthyroidism in the United States. This study aims to analyze the impacts of hyperthyroidism on readmissions rate, the clinical outcomes, and the predictors for readmissions.
The Nationwide Readmissions Database (NRD) for 2018 was used for this retrospective cohort study. The primary outcome was the rate and reasons for 30‐day readmission in patients with hyperthyroidism. Secondary outcomes included the comparison of mortality, length of hospital stay (LOS), total hospital charges (THC), cost of hospitalization (COH), and predictors of 30‐day all‐cause readmissions of hyperthyroidism.
6,979 hospitalizations were identified in the current study. The 30‐day all‐cause readmission rate for hyperthyroidism was 10.3%. The highest proportion for readmissions was hyperthyroidism (21.7%). The readmissions were associated with a significantly increased odds of inpatient mortality (OR: 7.04, 95% CI: 3.97 – 12.49), increased LOS (5.2 vs 4.0 days, 95% CI: 0.7 – 1.8 days), and higher THC and COH when compared to the index admission. Independent predictors of 30‐day all‐cause readmissions included Charlson index ≥3 (aHR: 1.76, 95% CI: 1.15 – 2.71), discharged against medical advice (aHR: 2.30, 95% CI: 1.50 – 3.53), protein‐energy malnutrition (aHR: 1.54, 95% CI: 1.15 – 2.07), and atrial fibrillation (aHR: 1.41, 95% CI: 1.11 – 1.79). The patients in the readmission cohort were associated with significantly increased odds of inpatient mortality. Independent predictors of 30‐day all‐cause readmissions included index hospitalizations with Charlson index ≥3, discharged against medical advice, protein‐energy malnutrition, and atrial fibrillation.
Readmission for hyperthyroidism within 30 days was associated with significantly increased odds of inpatient mortality, increased mean LOS, and higher THC and COH. Independent predictors of 30‐day all‐cause readmissions included index hospitalizations with Charlson index ≥3, being discharged against medical advice, protein‐energy malnutrition, and atrial fibrillation. Thus, aggressive but appropriate monitoring may be warranted in patients with these conditions and hyperthyroidism.
LATE BREAKING POSTER 29
Thyroid Cancer Basic Poster
THYROID NODULES IN FUKUSHIMA: AN ANALYSIS OF RESULTS OF 2ND ROUND THYROID EXAMINATION
Yutaka Hamaoka*
Keio University, Japan
After the Fukushima nuclear accident, thyroid ultrasound examinations have been conducted in Fukushima Prefecture. In the three round tests completed, 115, 71, and 31 thyroid cancers (include suspicious cases) were detected in some 300,000 participants. Although previous studies have focused on thyroid cancer, the low detection rates of 0.039%, 0.028%, 0.026%, and 0.014% make it difficult to detect the effects of radiation exposure. On the other hand, the detection rates of thyroid nodules (≧5.1 mm in diameter) are 0.76%, 0.82%, and 0.687%, respectively, which are 20 times higher than those of thyroid cancer, suggesting that the effects of radiation exposure can be easily detected from the viewpoint of statistical power. The purpose of this study was to examine the relationship between radiation exposure and thyroid anomalies in Fukushima.
This study utilized publicly available municipality level data (N = 59). Considering the nature of thyroid cancer: progress might be slow, thus 1st round is too early, and limitation of data: municipality level data is not disclosed for the third or later examination, results of 2ndround examination was analyzed. Through Poisson regression model, the number of participants with thyroid anomalies: thyroid nodule or malignancy were explained by UNSCEAR's revised thyroid absorbed dose estimates for 1 years old (UNSCEAR 2021), age at disaster, and age at examination.
Although UNSCEAR estimated thyroid absorbed dose was marginally significant for thyroid malignancy, beta = 0.051 (95% CI = ‐0.007, 0.110), it was positive and significant for the number of participants with nodule (diameter≧5.1mm) who received fine needle aspiration test, beta = 0.063 (95% CI = 0.026, 0.099).
Results implicate, nodules were due to radiation exposure, As Imaizumi et al. (2005) found risk of thyroid cancer development is higher for with nodule groups, long term health follow‐up for children in Fukushima is necessary. In addition, for the third and later round, municipality level data is undisclosed, to confirm this results, data should be disclosed.
LATE BREAKING POSTER 30
Thyroid Cancer Clinical Poster
A SYSTEMATIC REVIEW OF FACTORS ASSOCIATED WITH DISCOMFORT FROM THYROID NODULE FINE NEEDLE ASPIRATION BIOPSY
Tao Liu*, Manisha Tilak, Joshua Lakoff
Queen's University, Canada
Thyroid nodules are an extremely common clinical presentation, requiring thorough investigation to rule out malignancy. Fine‐needle aspiration biopsy (FNAB) is recommended for suspicious thyroid nodules; however, the procedure can be uncomfortable for subsets of patients. It remains unclear which patients are more likely to experience pain or discomfort during thyroid nodule FNAB. This systematic review aimed to investigate the patient‐, procedure‐ and analgesia‐related factors that affect pain levels during thyroid nodule FNAB.
Pre‐defined inclusion and exclusion criteria were set to identify relevant studies. EMBASE, MEDLINE, CINAHL, Cochrane electronic databases were searched, with relevant reference lists being screened as well. Two independent reviewers screened citations and assessed full‐length studies to determine the final set for inclusion. Conflicts were resolved by consensus. Quality of each study was performed.
2244 citations were identified and 21 studies were included in this review. The studies varied in patient populations, study methodologies and results, however some trends were identified. Non‐modifiable factors potentially increasing discomfort include age <25, female sex, high baseline anxiety levels, increasing number of needle passes, increasing nodule depth location, and presence of calcification within the nodule. Modifiable factors potentially increasing pain include aspiration technique (as opposed to capillary‐action), perpendicular needle placement (as opposed to parallel) during biopsy, second aspiration. Whereas larger needle size did not appear to correlate with pain. Needle free lidocaine injection appears to provide the best pain relief whereas lidocaine injections may increase discomfort and results were mixed for Emla cream.
This is the first study to systematically review factors affecting pain levels during thyroid nodule FNAB. While there was limited data, modifiable and non‐modifiable factors were identified to predict pain with fine‐needle aspiration biopsy of thyroid nodules. For patients at a higher risk for pain undergoing multiple biopsies, prophylactic analgesia is likely to provide a benefit.
LATE BREAKING POSTER 31
Thyroid Cancer Clinical Poster
THYROID STORM AFTER THYROIDECTOMY? THINK “FUNCTIONAL METASTATIC THYROID CANCER”
Mohammed Hamdi*, Aysha Chaudhri, Neel Shah, Philip Orlander, Absalon Gutierrez, Marc Cillo, Reem Al‐Dallal
The University of Texas Health Science Center | McGovern Medical School, USA
Poorly differentiated thyroid cancer (PDTC) falls in the spectrum of severity between differentiated and anaplastic thyroid cancers. It accounts for 2% to 15% of all thyroid cancers. The majority of patients with PDTC die of metastatic disease.
This case presentation is of a patient with PDTC complicated by functional thyroid metastases resulting in thyroid storm, which is an exceedingly rare occurrence.
A 74‐year‐old female with a history of left hemithyroidectomy over 50 years ago for thyroid nodules that were reportedly benign presented to the hospital with right lower extremity pain. Xray and CT femur showed a pathological fracture of the right distal femur. Bone scan showed focal uptake in the right distal femur and left iliac bone suggestive of lytic lesions. Right femur biopsy was pursued, and it was consistent with metastatic carcinoma with primary thyroid features. CT chest/abdomen/pelvis showed an 11 cm right thyroid mass extending into the mediastinum with extensive disease and MRI brain showed metastases. She later received external beam radiation therapy for brain metastases.
Patient subsequently underwent completion thyroidectomy and pathology showed poorly differentiated carcinoma arising from follicular variant of papillary thyroid cancer. Patient was to follow up outpatient for initiation of systemic treatment. However, she was readmitted to the hospital with encephalopathy, tachycardia, and hypoxia. Labs showed TSH <0.005 uIU/mL, free T4 > 8.0 ng/dL, total T3 > 8.0 ng/mL, as well as positive TPO antibodies and thyroid stimulating immunoglobulins. Patient was treated for thyroid storm with propylthiouracil, hydrocortisone, potassium iodide and propranolol. She has yet to follow up with her outpatient endocrinologist.
Fewer than 100 cases of hyperthyroidism due to functional thyroid metastases can be found in the literature and fewer than 20 of these cases are due to papillary carcinoma. Bone and lung metastases are the most common sites for functional lesions. Thyrotoxicosis shouldn't be eliminated from the differential when a patient has had thyroidectomy especially when they have metastatic disease. Symptoms include weight loss, palpitations, and weakness but patients don't have ophthalmopathy. Radioactive iodine may be used to ablate metastatic deposits and treat thyrotoxicosis.
LATE BREAKING POSTER 32
Thyroid Imaging Clinical Poster
CHANGE OF REAL‐TIME ULTRASOUND STRAIN ELASTOGRAPHY IN GRAVES' DISEASE
Kun‐Yo Lai*, Sih‐Da Chen
Chang Gung medical hospital, Taiwan
The purpose of this study is to detect stiffness change of thyroid with Graves' disease (GD) by real‐time ultrasound strain elastography (SE).
A total of 70 subjects (57 women and 13 men) aged from 16 to 68 (43.5, IQR,34.75 to 51) years‐old with GD were enrolled from January 2019 through December 2020. They were divided into hyperthyroid (N = 41) and euthyroid (N = 29) groups. Two measurements of elastic modulus values, i.e. liver fibrosis index (LFI) and strain index were performed (Hitachi Avius with a 7.5 MHz linear probe; Hitachi, Japan). Thyroid function tests and thyroid autoantibodies including anti‐thyroperoxidase, anti‐thyroglobulin and anti‐TSHR (TRAB) were detected in all patients. Fisher's exact test, Mann‐Whitney U test, Spearman's correlation, multiple variable analysis and ROC curve were applied for statistical analysis.
The elastic modulus value of LFI in hyperthyroid and euthyroid groups were ‐2.1 to 3.23 (0.91, IQR, ‐0.03 to 1.94) and ‐0.10 to 2.09 (0.40, QR, 0.03 to 1.02) without significant difference (p = 0.152). The strain index in hyperthyroid and euthyroid groups were also similar and ranged from 0.01 to 3.15 (0.67, IQR, 0.03 to 1.33) and 0.01 to 2.78 (0.81, IQR, 0.28 to 1.51, p = 0.162), respectively. We then divided patients into strain index >1 (N = 27) and ≤1 (N = 43) to represent relative stiffness individually to correlate multiple factors such as age, gender, thyroid function and autoantibodies.
In subgroup of strain index >1, LFI ranged from ‐0.40 to 2.89 (1.74, IQR, 0.23 to 2.21) and ‐0.10 to 2.09 (0.30, IQR, ‐0.09 to 0.91) in the euthyroid (N = 13) and the hyperthyroid group (N = 14); respectively, p < 0.05. Significant difference of T4, TSH (p < 0.001), gender, age and TRAB (p < 0.05), were also found between these subgroups. ROC‐AUC statistics for predicting hyperthyroidism assessed by LFI was 0.76, with a sensitivity of 92.9%, and a specificity of 61.5%, with a cutoff value of 1.59.
LFI of SE correlates with thyroid function status in GD patients in patient with strain index >1. In addition, TRAB and age could influence thyroid stiffness of GD.
LATE BREAKING POSTER 33
Thyroid Nodules & Goiter Clinical Poster
EARLY DISCHARGE AFTER TOTAL THYROIDECTOMY IN ASIAN PATIENTS USING IONISED CALCIUM TREND
Geraldine Lei*, Reyaz Singaporewalla
Khoo Teck Puat Hospital, Singapore
In Asia, demand for acute hospital beds is increasing. Total thyroidectomy patients are often monitored for 48‐72 hours in many hospitals. We prospectively evaluated the safety and predictive value of post‐operative ionized calcium (iCa) trend for early discharge after total thyroidectomy in Asian patients.
All patients undergoing Total thyroidectomy for benign or malignant pathology underwent pre‐operative optimisation of Vitamin D. Trend of iCa levels immediate post‐surgery and post‐operative day 1 (POD1) were evaluated along with symptoms of hypocalcemia. Asymptomatic cases with iCa levels ≥ 0.9 mmol /L (normal 1.13‐1.32 mmol/l) were discharged next morning.
Among the 95 consecutive patients (mean age 41.7 ± 11.6 years, F:M ratio = 77:13) undergoing total thyroidectomy, the indications were multinodular goiter (63.3%), malignancy (13.3%), Graves' (16.7%) and Hashimoto's (6.7%). Mean Vitamin D levels before and after optimisation were 19.1 (IQR 16.2 ‐ 29.3) and 27.4 (IQR 25.02 ‐ 34.6) ng/L respectively. Mean immediate post‐operative and POD1 iCa levels were 1.10 [IQR 0.7 ‐ 1.12] and 1.01 [IQR 0.76 ‐ 1.18] mmol/L respectively showing a significant downward trend (beta = ‐0.76, p value <0.001). Symptomatic hypocalcemia was absent at iCa level ≥ 0.9 mmol/L. 91% patients were successfully discharged with an average hospitalisation of 1.3 days and no unscheduled readmissions. All patients were weaned off post‐operative calcium and Vitamin D supplements within 2 weeks.
After optimisation of vitamin D deficiency, iCa trend after total thyroidectomy is a simple and accurate marker to safely discharge patients early.
LATE BREAKING POSTER 34
Disorders of Thyroid Function Clinical Poster
EXCESS MORTALITY ASSOCIATED WITH HYPOTHYROIDISM IN WALES – A POPULATION BASED ESTIMATE FROM 2015‐2019
Lakdasa Premawardhana*1, Michael Stedman2, Onyebuchi Okosieme3, Peter Taylor1, Adrian Heald4, Colin Dayan1
1Cardiff University School of Medicine, United Kingdom, 2Res Consortium, United Kingdom, 3Cwm Taf University Health Board, United Kingdom, 4Salford Royal Foundation Trust, United Kingdom
There is increasing population‐based evidence that hypothyroidism is associated with excess mortality mitigated in some by “optimal” thyroxine therapy. We aimed to confirm such data locally and compared age and gender specific mortality rates in patients with and without hypothyroidism in Wales between 2015‐2019.
Age and gender specific mortality data for patients with and without a recorded diagnosis of hypothyroidism in Wales was obtained from the Office of National Statistics, 2015‐2019. The prevalence of hypothyroidism (defined as those on thyroxine treatment currently) was obtained from Welsh general practice records. Age and gender distributions for hypothyroidism from the UK Clinical Practice Research Datalink was extrapolated to the Welsh cohort and validated by Welsh primary care databases. Age and gender specific standardised mortality rates and individual cause of death related life expectancy years lost were derived for the population with hypothyroidism. The total prevalence of hypothyroidism was 3.8% (n = 121,219, total population 3.126 million, average age 65.7 years, male:female ratio 1:4.2). During the period 2015‐2019, there were 20,824 deaths associated with hypothyroidism and 145,788 deaths in the non‐hypothyroid population [3.44% (hypothyroidism) vs 0.97% (non‐hypothyroid) respectively for each year of study] (p = 0.001). In this same period (2015‐2019), in the Hypothyroidism group (a) there were 2630 excess deaths; (b) and the all‐cause standardised mortality ratio (SMR) (95% Confidence Interval) was 1.16 (1.13‐1.20), (p < 0.001) compared to the Non Hypothyroid population; (c) SMR (95% CI) in 25–49‐year‐old subjects was 2.08 (1.53‐2.64)(p < 0.001), [1.85 (1.25‐2.69) females, 2.82 (1.49‐3.41) males, p < 0.001], and was higher in this age group compared to older age groups. Hypothyroidism was associated with 8.6 life expectancy years lost per death, with no gender preponderance.
We have shown that between 2015‐2019 the prevalence of Hypothyroidism in Wales was 3.8%, with a high female preponderance. Hypothyroidism was associated with an increased mortality risk which was higher in younger age groups compared to older age groups, with 8.6 life expectancy years lost per death. Further studies will be needed to confirm these modelled population‐based estimates using individual person level data.
LATE BREAKING POSTER 35
Disorders of Thyroid Function Clinical Poster
SPECTRUM OF SLEEP ABNORMALITIES IN PRIMARY HYPOTHYROIDISM
Himamshu Acharya*, Pramila Kalra, Mala Dharmalingam
Ramaiah Medical College, India
To assess the quality of sleep, daytime sleepiness, depression severity in subjects with overt and subclinical primary hypothyroidism using Pittsburgh sleep quality index (PSQI), Epworth sleepiness score (ESS), Patient Health Questionnaire‐9 (PHQ‐9) respectively.
This was a questionnaire‐based cross‐sectional study done on patients attending the Endocrinology clinic. A personal interview was conducted on 39 subjects. Study subjects included treatment naïve individuals with hypothyroidism, individuals on levothyroxine treatment with elevated TSH, and individuals with subclinical hypothyroidism. PSQI was used to assess the quality of sleep, ESS for daytime sleepiness, and PHQ‐9 for the presence of depression.
Total number of subjects included was 39. Majority of the subjects were females (n = 32/39) and the rest were males. The Mean age was 37 ± 13.2 years. Twenty‐eight had overt hypothyroidism (TSH >10mIU/L) and 11 were subclinical. Median TSH was 13.8mIU/L (IQR 8.32‐27). Mean neck circumference was 33.5 ± 5.9cm and collar circumference was 39 ± 4.1cm. Mean PSQI was 8.25 (SD = 4.21). Twenty‐eight subjects had a Global PSQI score of 6 or above indicating poor sleep quality. Median for ESS and PHQ‐9 were 3 (IQR 1‐8) and 6 (IQR 1‐10) respectively. Two subjects had severe excessive daytime somnolence (ESS >16), 4 had mild excessive somnolence (ESS 11‐12). One subject had a PHQ‐9 score of 15 indicating moderately severe depression, while 9 had moderate depression (PHQ‐9 score = 10‐14).
Hypothyroidism is one of the most common endocrine disorders. It is associated with obstructive sleep apnea, poor architecture of sleep, and abnormal ventilatory drive. Neuropsychiatric manifestations include anxiety and depression which are reversible with treatment. Our study demonstrated the presence of poor sleep quality in the majority of the patients. Hypothyroidism may be associated with both obstructive and central sleep apnea. A high ESS in six subjects supports this association. Depressive symptoms are often ignored by most treating clinicians when treating hypothyroidism. This study showed that depression can co‐exist even in young individuals with hypothyroidism and it is important to recognize it. The study population had one patient with moderately severe depression and 9 with moderate depression which highlights the significance of screening for depression among untreated patients with hypothyroidism.
LATE BREAKING POSTER 36
Disorders of Thyroid Function Clinical Poster
A 33‐YEAR‐OLD WOMAN WITH SEVERE SUBACUTE THYROIDITIS POST COVID‐19
Sravani Konatham1, Lubna Mirza*2, Rohit Reddy Mekala3
1Kamineni Institute of Medical Sciences, India, 2Norman Regional Health System, USA, 3Armed Forces Medical Sciences, India
The novel severe‐acute‐respiratory‐syndrome‐coronavirus‐2 (SARS‐CoV‐2) virus has led to the pandemic of Coronavirus disease 2019 ( COVID‐19). COVID‐19 has wide range of complications; cases of subacute thyroiditis have been reported post COVID‐19.
To highlight the severity of subacute thyroiditis post COVID‐19 infection in comparison to other etiologies and timely intervention with high dose steroids and anti‐inflammatory drugs.
A 33‐year‐old woman was referred to endocrinology clinic with swelling and pain of her anterior neck for four weeks duration. She developed her symptoms two weeks after contracting COVID‐19 viral infection. Initially, she noticed swelling and pain in her neck, which was radiating toward the right ear. She also had a fever with malaise and myalgia. Her primary care physician prescribed medrol dose pack twice but her symptoms resumed as soon as she stopped it.
On physical examination, her temperature, blood pressure and heart rate were normal. She is obese with a BMI of 32. Neck exam exam revealed thyromegaly and anterior neck tenderness. Laboratory investigation revealed low thyroid‐stimulating hormone (TSH) of 0.04mU/L. Free thyroxine (T4) was normal. Thyroid peroxidase antibody and thyroid‐stimulating immunoglobulin were negative. Thyroid ultrasound revealed a heterogeneously enlarged thyroid gland with two small 4 mm solid hypoechoic nodules in the isthmus. She was treated with the third round of medrol dose pack but her condition relapsed after completing it. Our patient was started on oral prednisone 40 mg per day with Ibuprofen 800 mg once daily. Her symptoms improved within two weeks and steroids were tapered off gradually.
Subacute thyroiditis is a self‐limiting complication of various viral infections that generally responds well to short course of steroids. Our case highlights the unusual severity of subacute thyroiditis after COVID‐19 infection and the role of early aggressive therapy with high dose steroids to limit morbidity.
LATE BREAKING POSTER 37
Disorders of Thyroid Function Translational Poster
BEZAFIBRATE‐INDUCED HYPOTHYROIDISM IN A PATIENT WITH RESISTANCE TO THYROID HORMONE β: CONSUMPTIVE HYPOTHYROIDISM?
Ichiro Yamauchi*1, Takafumi Yamashita2, Taku Sugawa1, Takuro Hakata1, Yohei Ueda1, Toshihito Fujii1, Yoriko Sakane3, Akihiro Yasoda4, Nobuya Inagaki1
1Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Japan, 2Metabolism and Endocrinology Division of Internal Medicine, Kishiwada City Hospital, Japan, 3Sugawa Clinic, Japan, 4Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan
A unique clinical course was observed in a 55‐year male patient with resistance to thyroid hormone β (RTHβ) by a variant of the THRB gene leading to replacement of glycine with arginine in codon 347 (p.G347R). At X months, he was hospitalized due to heart failure and presented with the syndrome of inappropriate secretion of TSH (SITSH; TSH 2.02 μIU/mL and fT4 2.60 ng/dL). At X + 10 months, 200mg/day of Bezafibrate (BZ) treatment was initiated. He slowly developed progressive hypothyroidism (TSH 100.90 μIU/mL and fT4 0.65 ng/dL at X + 97 months), while his thyroid gland further enlarged and serum Tg levels increased. After suspending BZ treatment at X + 109 months (TSH 69.80 μIU/mL and fT4 1.70 ng/dL), his thyroid function showed a rapid change by as soon as 3 weeks after (TSH 13.10 μIU/mL and fT4 2.45 ng/dL). To elucidate this unusual event, we conducted clinical studies and performed experiments.
A retrospective cohort analysis of non‐RTHβ patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1, DIO2, DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor β with p.G347R (G347R TRβ). Mice with G347R TRβ were generated by hydrodynamic gene delivery and compared to mice overexpressing wild‐type TRβ (WT TRβ).
In the non‐RTHβ patients, BZ treatment did not change serum free T3 and TSH but even increased free T4. DIO3 reporter activity was paradoxically increased by BZ administration in the context of G347R TRβ, which was inconsistent with DIO1 and DIO2 reporter assays. In the livers of mice overexpressing G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 mRNA.
While hypothyroidism associated with BZ treatment did not occur in non‐RTHβ patients, it was observed in a patient with RTHβ due to the p.G347R variant. Analyses using reporter assays and mice overexpressing G347R TRβ identified the possible mechanism whereby upregulation of type 3 iodothyronine deiodinase caused consumptive hypothyroidism.
LATE BREAKING POSTER 39
Thyroid Cancer Clinical Poster
IMPROVEMENT OF CENTRAL NECK DISSECTION BY MEANS OF PARATHYROID DETECTION THROUGH AUTOFLUORESCENCE
Octavian Neagoe*1,2, Mihaela Ionica2, Octavian Mazilu1,2
1Second Discipline of Surgical Semiology, First Department of Surgery, ”Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, 2Second Clinic of General Surgery and Surgical Oncology, Emergency Clinical Municipal Hospital Timisoara, Romania
Reaching up to 37%, for patients with thyroid cancer in whom central neck dissection is associated to total thyroidectomy, hypocalcemia represents one of the most common postoperative complications. Parathyroid gland detection through autofluorescence has determined a significant decrease in the number of intraoperative parathyroid lesions and hypoparathyroidism rate, implicitly.
Over a period of 8 months 23 patients diagnosed with papillary thyroid carcinoma that underwent total thyroidectomy and central neck dissection have been selected (AF group). Intraoperative parathyroid identification was performed by means of the near‐infrared (820 nm) autofluorescence system FLUOBEAM® LX (Fluoptics, Grenoble, France). A group of 23 patients with similar clinical characteristics that underwent the same surgical procedure prior to the use of autofluorescence was used as control.
A significant increase in number of excised lymph nodes was recorded in the AF group (p < 0.01), with a mean of 18.6 ± 9.4 compared to controls, where a mean of 11.1 ± 5.8 lymph nodes were observed. Carcinomatous infiltration was present in 82 and 29 lymph nodes for the AF and control group, respectively, with a significant increase in positive lymph node rate (p = 0.02). The autofluorescence system allowed the identification of all parathyroid glands in 69.5% of patients, 3 parathyroid glands were observed in 13% of cases, with 2 parathyroid glands in just 8.7% of cases and 5 parathyroid glands in 8.7% of patients, respectively. Three patients in the AF group presented clinical signs of transient hypocalcemia, requiring specific treatment for no more than two months. A total of 94 parathyroid glands were identified, with 87 in situ and 7 glands on excision specimens, amongst which 2 excised deliberately (one with carcinomatous infiltration and one with an oncocytic parathyroid adenoma) and 5 accidentally, two of these being located in the pretracheal fat. Accidental parathyroid gland excision rate was 5.3%. At 6 months postoperatively all patients presented with normal calcemia and PTH levels.
The intraoperative identification of parathyroid glands through the autofluorescence system allows for a more extensive cervical lymphadenectomy to be performed, increasing the total number of excised lymph nodes and the number of metastatic lymph nodes.
LATE BREAKING POSTER 40
Thyroid Hormone Action Clinical Poster
THE PHARMACOKINETICS OF A NOVEL SOLUTION OF LEVOTHYROXINE IS NOT INFLUENCED BY PROTON‐PUMP INHIBITORS
Murray Ducharme*1,2, Corinne Seng Yue1, Claudia Scarsi3, Elisa Bettazzi3, Giuseppe Mautone3, Francesco Celi4
1Learn and Confirm Inc., Canada, 2Faculté de pharmacie, University of Montréal, Canada, 3IBSA Institut Biochimique SA, Switzerland, 4Department of Internal Medicine, Virginia Commonwealth University, USA
The absorption of levothyroxine (LT4) may be influenced by gastric pH, as reported for LT4 tablets whose absorption appears to be affected by concomitant use of proton pump inhibitors (PPIs). This study aimed to characterize the effect of PPIs administration on the single dose pharmacokinetics (PK) of LT4 given as a new formulation of oral solution (Tirosint‐SOL®) to 36 healthy adults.
This was a randomized, 3‐way crossover, comparative bioavailability study in healthy adults (F/M) under fasting conditions. A steady state of stomach pH was achieved with oral administration of omeprazole 40 mg delayed‐release capsule once daily from Day 1 to 6 (on the morning for Treatment‐A, each evening for Treatment‐B). Tirosint‐SOL® 150 mcg/mL was administered as a single dose of 600 mcg on Day 5 in the morning. In Treatment‐C only LT4 was administered. Blood samples were collected at three timepoints prior to dosing (for baseline levels) and up to 48 hours post‐dose. The washout period was at least 35 days. Total serum LT4 concentrations were measured using a validated LC‐MS/MS method. Non‐compartmental PK parameters were calculated using both uncorrected and baseline‐corrected data. The maximum concentration (Cmax) and the area under the concentration‐time curve (AUC0‐48) were calculated and included in an analysis of variance to obtain ratios and corresponding 90% confidence intervals.
The PK population included 30, 28 and 31 subjects in Treatments A, B and C, respectively. For both comparisons (Treatment‐A vs. Treatment‐C and Treatment‐B vs. Treatment‐C), geometric mean ratios and confidence intervals for uncorrected and baseline‐corrected PK parameters were within the pre‐defined equivalence boundaries of 80% to 125%.
This comparative bioavailability study demonstrated that the absorption of Tirosint‐SOL® is not affected by co‐administration of a representative PPI given simultaneously or staggered by about 12 hours compared to administration of LT4 alone.
LATE BREAKING POSTER 41
Thyroid Imaging Clinical Poster
ENDOTRACHEAL TUBE SIZE AS A PREDICTOR OF FALSE POSITIVE LOSS OF SIGNAL DURING CONTINUOUS LARYNGEAL ADDUCTOR REFLEX MONITORING
Mahmoud Omar*, Abdallah Attia, Mohamed Abouiesha, Mohamed Shama, Emad Kandil
Tulane University, School of Medicine, USA
With the advancement of technology to prevent the devastating complications following Recurrent laryngeal nerve (RLN) during anterior neck surgeries. Laryngeal adductor reflex‐continuous intraoperative nerve monitoring (LAR‐CIONM) decreased RLN injury as it provides real‐time updates about the functional integrity of the RLN intraoperatively. However, intraoperative LOS does not necessarily imply nerve injury. We thought to investigate the false‐positive rates of loss of LAR signal intraoperatively and investigate the predictors of false‐positive LOS.
In this prospective cohort study, we investigated statistical measures of LAR‐CIONM during thyroidectomy, parathyroidectomy, and central neck dissection. We calculated the rates of false‐positive LOS of RLN. We also looked for predictors of false‐positive LOS during neck surgeries.
A total of 101 patients with a mean age of 56.59 ± 12.83 years were enrolled in the study. Females represented 71.29% of the study population. The mean BMI was 32.0232.02 ± 7.92 kg/m2, and the mean height was 167.67 ± 9.38 cm. The endotracheal tubes (ET) size was determined according to gender, BMI, and height. A total of 23 patients (22.7%) exhibited false LOS. False LOS occurred more frequently in patients who had a small ET size to their BMI (N = 12, 63.16%) compared to patients who received appropriate ET size for their BMI (N = 11, 13.41%). Furthermore, a false LOS significantly occurred in patients who received an ET tube that was small for gender than appropriate for their gender (N = 12, 66.67%) compared to patients who had an appropriate ET tube for their gender (N = 11, 13.25%). Finally, a false drop LOS significantly occurred in patients with small‐sized ET tube for height (N = 12, 66.67%) compared to patients who received an appropriate ET tube for gender (N = 11, 13.25%), patients with small‐sized ET for height had higher odds of exhibiting false LOS (OR = 1.93, 95%CI:1.25‐2.97, p < 0.001).
Ultimately, LAR‐CIONM is a burgeoning tool in the field of head and neck surgery. Smaller ETT is significantly associated with increased rates of false LOS. As such, surgeons should fully know the effect of ETT size on false LOS better to interpret intraoperative signaling and, subsequently, surgical decisions.
LATE BREAKING POSTER 42
Thyroid Nodules & Goiter Clinical Poster
ASYMPTOMATIC RETROSTERNAL GOITERS: SHOULD WE INTERVENE?
Geraldine Lei*, Tang Hon, Anil Rao, Reyaz Singaporewalla
Khoo Teck Puat Hospital, Singapore
While the need for thyroidectomy in symptomatic retrosternal goiters (RSG) is indisputable, the management of apparently “asymptomatic” imaging‐detected RSG remains controversial. We reviewed our experience in these cases and compared outcomes and complications of performing thyroidectomy for patients with symptomatic and asymptomatic RSG to create a management algorithm.
Information from our prospective electronic thyroid surgery database was obtained from 2011 to 2019 to identify all patients operated for RSG. Patient data with comorbidities and risk stratification, symptoms and signs, modality of diagnosis, type of procedure, pathological findings and complications and outcomes were compared between the symptomatic and asymptomatic groups.
A total of 42 out of 477 thyroidectomies (8.8%) had RSG based on our definition. The mean age was 53 years with a higher proportion of females (73.8%). 29 patients (69%) were asymptomatic from their goitre. The majority (78.6%) of the patients were ASA II and below. 19 and 23 patients underwent hemi‐ and total thyroidectomy respectively with no statistical difference between the symptomatic and asymptomatic groups. There were no significant statistical differences in the symptomatic and asymptomatic group in terms of operative time, nerve injury, hypocalcemia or blood loss. Although biochemical hypocalcemia (serum ionized calcium <1mmol/L) was common in the immediate post‐operative period, only two patients in the symptomatic group developed symptomatic hypocalcemia that resolved completely in 3 weeks. All patients in the asymptomatic group underwent a cervical thyroidectomy whereas two patients in the symptomatic arm needed an additional extracervical approach.
A proportion of “asymptomatic” imaging‐detected retrosternal goiters do have subtle symptoms on thorough history. Early thyroidectomy can be safely performed in surgically fit asymptomatic patients with minimal complications and excellent outcomes.