bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe Thyroid Eye Disease in the US: A National Perspective
Authors: Singh Gurkirpal , Sehgal Maanek , Mithal Alka , Alabiad Chris , Kossler Andrea
Published: May 2021

Background: Thyroid eye disease (TED) is an unpredictable autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring. The majority of patients have mild, self-limited TED, 20-30% of patients experience moderate/severe disease, and 3-5% may develop sight-threatening disease, such as CON or exposure keratopathy. Surgical intervention is commonly necessary for patients with moderate/severe stable disease or sight-threatening disease, however, there is little data on the prevalence of TED requiring surgical interventions. Objective: To document the number of surgical procedures for thyroid eye disease in the US and evaluate the associated costs of these interventions. Methods: National Ambulatory Surgery Sample (NASS) is the largest ambulatory surgery database, representing approximately 14 million ambulatory surgeries performed annually in a hospital setting in the US. Data from 2,699 hospital-owned facilities located in 31 States and the District of Columbia, approximating a 63-percent stratified sample of U.S. hospital-owned facilities performing selected ambulatory surgeries are available for analyses. Data on clinical procedures and diagnoses, disposition of the patient, expected source of payment, and total charges, as well as geographic, hospital-owned facility, and patient characteristics are collected. For the purposes of this study, TED was identified by concomitantly occurring ICD 10 codes of thyroid disease and ICD-10 codes for eye manifestations of thyroid eye disease. CPT codes were used to identify eye surgeries performed in these patients. The coding algorithms were developed by consensus of three ophthalmic surgeons. Results: In 2018, a total of 1,991 patients with TED required eye surgery, with a national prevalence of 0.6 per 100,000 population. Mean age at surgery was 56.2 years (95% Confidence Interval (CI) 55.3-57.2). Women comprised 73% (1455 women and 536 men) of TED patients who underwent surgery. The average charges for each surgical encounter were $21,875 (95% CI $19,066-$24,684). Total charges for TED surgery in the US totaled over 43.5 million annually. While many patients had private insurance (49.7%), Medicare (31%) and Medicaid (13%) were also significant sources of reimbursement. Of all TED-related surgeries, 93% were conducted in teaching hospitals. Only 0.2% of surgeries were conducted in non-urban rural settings. Conclusion: In the US, severe TED requiring surgery, although uncommon, has significant economic impact. Further research is warranted to better understand the natural history of TED that may inform treatment pathways which may prevent complications needing surgery.
The Synergistic Effect of Corticosteroids and Mycophenolic Acid on Chemokines in Orbital Cells From Patients With Graves’ Ophthalmopathy
Authors: Fallahi Poupak , Ferrari Silvia Martina , Ragusa Francesca , Elia Giusy , Ruffilli Ilaria , Paparo Sabrina Rosaria , Patrizio Armando , Benvenga Salvatore , Antonelli Alessandro
Published: May 2021

In recent studies, an improvement of the response rate to therapy has been reported with corticosteroids and mycophenolic acid in patients with Graves’ ophthalmopathy (GO). In GO, retro-orbital cells (fibroblasts, preadipocytes, and extraocular muscle cells) secrete Th1 and Th2 chemokines stimulated by cytokines. Until now, no studies are present in literature regarding the effect of corticosteroids and mycophenolic acid on the secretion of chemokines in GO orbital cells. For this reason, the effect of increasing concentrations of mycophenolic acid or corticosteroids on the secretion of either the Th1 (CXCL10) and Th2 (CCL2) chemokines was tested in primary cultures of myoblasts, preadipocytes and fibroblasts obtained from GO patients. CXCL10 was undetectable in the supernatants of the retro-orbital cells in primary cultures; its release was induced dose-dependently by IFNγ, while TNFα alone had no effect. On the contrary CCL2 release (that was produced in low amounts basally) was dose-dependently induced by TNFα, while IFNγ alone had no effect. In both cases the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion. The release of these chemokines was dose-dependently inhibited by increasing concentrations of mycophenolic acid, or corticosteroids (in a pharmacological range), in presence of IFNγ and TNFα stimulation. Moreover, the association of corticosteroids and mycophenolic acid (in presence of IFNγ and TNFα) had a stronger inhibitory effect on the chemokines release. In conclusion, in GO orbital cells, mycophenolic acid and/or corticosteroids (in a pharmacological range) have an inhibitory role on the secretion of both Th1 (CXCL10) and Th2 (CCL2) chemokines. This suggests a possible therapeutic role of these drugs.
Alert for TSH Measurement in High-Risk Pregnancies in Brazil
Authors: Santos Lívia Marcela , Marietto Déborah Buso Piccinalli , Miura Juliana Miyuki , Megale Luisa Lacaz Martins , Ganadjian Gabriela Terzian , Alvares Leonardo Azevedo , Oyama Priscila Rodrigues Leite , Bueno Thiago Limoli , Boas Roberta Frota Villas
Published: May 2021

Introduction: The hypothyroidism during pregnancy can lead to alterations in fetal neurological formation and has metabolic impact on pregnant women. If not diagnosed and treated it can cause complications during pregnancy and childbirth, besides causing changes in fetal formation. The TSH test is not part of routine examinations of the pregnancy monitoring care in Brazilian public health system (SUS). The test is not requested in low-risk pregnant women like those at high risk. The Overt Hypothyroidism (no subclinical) is prevalent in 0.3% to 0.5% of pregnant women and is asymptomatic in 70% of these patients. Thus, in order to avoid risks to the mother and fetus health due absence of early diagnosis, it would be ideal for pregnancy monitoring care examinations in the public health system to request a TSH test, especially in high-risk pregnancies. Method: A cross-sectional observational study was approved by the Ethics Committee (CAAE 22906619.2.0000.0062) to review 83 medical records of high-risk pregnant women in a Brazilian public hospital, State of São Paulo, Brazil in 2020. Inclusion criteria: All patients who are being followed up in high-risk childbirth or are hospitalized in the high-risk sector on the maternity during the year 2020. Complete medical records containing the data proposed to be researched and results of exams to be analyzed in the research. Results: The study included the review of 83 medical records of high-risk pregnant women with average age of 30 years old, average gestational age of 31 weeks and average weight of 84 kg. From these 11.4% (n = 10) declared that they had hypothyroidism and 2.4% (n = 2) hyperthyroidism in the first consultation. The 47% (n = 39) had their TSH measured during pregnancy, of which TSH had changed 30.8% (n = 12), 5.1% (n = 2) with suppressed TSH and 25.6% (n = 10) with TSH above the limit for pregnancy. Of the pregnant women who had a diagnosis prior to the pregnancy of hypothyroidism, only 1 did not have their TSH collected during pregnancy. Of the pregnant women who had hyperthyroidism, all had TSH collected during pregnancy, but kept TSH suppressed and free T4 at the upper limit throughout the pregnancy. 10% (n = 8) had gestational bleeding, of which only 25% (n = 2) had TSH measured at some point during pregnancy, of these, one had an altered TSH, but no medication was prescribed or the test repeated. Conclusion: Recognizing that the evolution of pregnancy depends on the normal thyroid eixo, we believe that for high-risk pregnant women they should have their thyroid eixo evaluated in the first trimester.
Generation and Transplantation of HiPSC-Derived Thyroid Follicular Cells
Authors: Undeutsch Hendrik Julian , Posabella Alberto , Kurmann Anita A , Kotton Darrell N , Hollenberg Anthony Neil
Published: May 2021

Despite the availability of synthetic thyroid hormone (TH) for therapeutic use, many patients with hypothyroidism do not feel well on replacement doses of TH. Indeed, hypothyroid children may develop various behavioral issues if under- or overtreated for hypothyroidism, suggesting the need of better individualized therapy. The development of stem cell-based models of thyroid replacement would greatly facilitate the treatment of post-surgical and congenital hypothyroidism and our understanding of the causes of congenital hypothyroidism. To generate thyroid follicular cells from human induced pluripotent stem cells (hiPSCs), we utilize a directed differentiation approach by activating endogenous signaling pathways we have previously identified in the mouse. We are employing a hiPSC-line with a GFP reporter targeted to the NKX2-1 locus allowing us to identify and purify cells positive for the transcription factor NKX2-1. Using these cells, we confirmed that BMP4 and FGF2 led to the induction of thyroid progenitors from foregut endoderm, expressing the four transcription factors in thyroid development NKX2-1, PAX8, HHEX and FOXE1. Subsequent differentiation of the purified, NKX2-1-positive progenitors led to follicular cell maturation, expressing genes related to TH synthesis, such as TG, TSHR, NIS (SLC5A5) and TPO. To assess the in vivo function of these hiPSC-derived thyroid follicular cells, we grafted the cells under the kidney capsule of radioablated, immunocompromised mice. First, hypothyroidism was confirmed 4 weeks post-ablation by increased TSH and low T4 levels. Next, mice received matured hiPSC-derived follicular cells, undifferentiated hiPSCs or sham surgery and were monitored for 8 weeks. In this preliminary test, no difference in TH levels was detected between the three groups. However, the grafted follicular cells formed a distinct cell population with thyroid-like histology. In order to optimize our directed differentiation protocol further and obtain a purer thyroid progenitor population, we generated a hiPSC line carrying a tdTomato reporter targeted to the PAX8 locus in addition to the NKX2-1-GFP-reporter. After directed differentiation cells sorted for NKX2-1-GFP and PAX8-tdTomato showed high induction of NKX2-1, PAX8, HHEX and FOXE1 expression, as well as expression of TG and TPO. Utilizing this double-reporter hiPSC line will enhance our ability to generate mature follicular cells for transplantation.
Generation of Adult Stem Cell Derived Organoid Cultures From Thyroid Follicular Cells
Authors: van der Vaart Jelte , Bosmans Lynn , van Santen Hanneke Margo , Vriens Menno R , Clevers Hans
Published: May 2021

The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. Due to the limited number of representative model systems, there is limited understanding of fundamental thyroid biology as well as thyroid carcinogenesis. To fill the caveats in the understanding of thyroid cell biology, we aimed to develop an adult stem cell-derived three-dimensional (3D) organoid culture system using murine and human thyroid follicular cells (TFCs). We have succeeded to grow such an organoid culture system that harbours the complete machinery of hormone production visualised by the presence of colloid in the lumen and essential transporters and enzymes in a polarised cell layer. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1/TTF1. Moreover, the thyroid hormone precursor thyroglobulin is expressed in both cultures to similar levels as in tissue. Extensive characterisation furthermore identifies known and new biological insights in TFC subclassification, subcellular organisation and hormone production using state-of-the art techniques like single cell RNA sequencing, transmission electron microscopy and genome editing. These 3D in vitro cultures allow for a variety of thyroid-related studies including the progression of wild type cells towards cancer. Additionally, due to the success of generating patient-specific tumour organoids of primary differentiated thyroid carcinoma and metastasis, insights in drug resistance and metastases can be identified. In short, this newly developed organoid culture of murine and human wild type TFCs as well as tumour tissue opens up an extensive area of research that will help understand the drivers for growth and development of thyroid (cancer) cells and enable studies upon drug responsiveness.
Thyroid Function in Adults With Prader-Willi Syndrome
Authors: Pellikaan Karlijn , Snijders Fleur , Wilhelmina Rosenberg Anna Gerarda , Van der Lely Aart Jan , de Graaff Laura
Published: May 2021

Introduction: Prader-Willi syndrome (PWS) is a complex genetic syndrome in which hypothalamic dysfunction leads to extreme appetite (hyperphagia) and pituitary hormone deficiencies (PHD), among others. Compared with the ‘general endocrine population’, the population of adults with PWS is characterized by a high prevalence of intellectual disability (ID) and frequent use of psychotropic drugs. Due to hypotonia and the low muscle mass associated with the syndrome, adults with PWS have a low basal metabolic rate (BMR) and a high risk of developing obesity. Therefore, exercising is extremely important. However, PHD like hypothyroidism can cause fatigue and exercise intolerance. If left untreated, hypothyroidism can lead to a further decrease in BMR, an increase in Body Mass Index (BMI) and increased cardiovascular risk. As mortality in PWS is high (3% yearly) and often related to cardiovascular problems and obesity, it is of utmost importance to optimize thyroid function and other factors affecting BMR.

Methods: In 122 adults with PWS (median age 29 y [IQR 21-39], median BMI 29 kg/m2 [IQR 26-36]), we measured TSH, free T4 and T3 (the active form of thyroid hormone) and searched the medical history for use of medication and any pre-existing diagnosis of hypothyroidism. Moreover, we performed an extensive literature search and summarized the current literature on hypothyroidism, T3 and T4 levels in adults with PWS.

Results: Hypothyroidism was present in 17% and more prevalent in females (23%) than in males (10%), even though this was not statistically significant (P=0.06). Although within the reference range, serum T3 levels were relatively high compared to free T4 levels. T3 levels were significantly lower in patients that used psychotropic medication (n=45) than in patients that did not (median 1.7 [IQR 1.5-2.0] vs 2.1 [IQR 1.7-2.3], P=0.013).

Conclusion: We found a prevalence of hypothyroidism of 17% (compared to 3% in the non-PWS population). T3 levels were relatively high, which might be explained by increased peripheral conversion of T4 to T3 by deiodinase type 2. Levels of the active thyroid hormone T3 were significantly lower in patients using psychotropic medication. Based on our findings, we recommend 1) yearly screening of thyroid hormone levels in adults with PWS to avoid negative effects of untreated hypothyroidism on BMR, BMI and cardiovascular risk and 2) extra monitoring of the active thyroid hormone T3 in patients using psychotropic drugs.
TRH Stimulation Testing in Older Individuals with Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration
Authors: Meizlik Paige , Cucchiara Andrew , Kannan Lakshmi , Scattergood Theresa , Cappola Anne Rentoumis
Published: May 2021

Background: Subclinical hypothyroidism is common in older individuals. To better understand the underlying physiology, we examined the pituitary-thyroid axis using thyrotropin releasing hormone (TRH) stimulation testing both at baseline and after levothyroxine (LT4) and liothyronine (LT3) supplementation. Methods: We conducted a randomized, double-blind, cross-over study in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. The primary outcome measures were TSH serum concentration area under the curve (AUC), maximum TSH serum concentration (Cmax), and change in free thyroxine (∆FT4) and total triiodothyronine (∆TT3) levels following TRH stimulation, each measured at three time points: once at baseline and once each after achieving euthyroid TSH levels with the two thyroid preparations. The maximal change in TSH (∆TSH); FT4 and TT3 AUCs; and time to maximal TSH, FT4, and TT3 (Tmax) were also analyzed. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed TRH stimulation testing at baseline and after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day and LT4 dose was 34 (9) µg/day. After TRH stimulation, the mean TSH AUC (0-180) at baseline was 3099.5 (1424.4) µIU*min/mL, and significantly decreased after both LT4 [631.4 (315.2), p<0.001] and LT3 [631.5 (317.3), p<0.001]. There was no difference in TSH AUC (0-180) between LT4 and LT3 treatment arms. Baseline mean TSH Cmax was 27.2 (14.5) µIU/mL and significantly decreased after LT4 [5.5 (3.0), p<0.001] and LT3 [5.4 (2.9), p<0.001], with no difference between the LT4 and LT3 treatment arms. The ∆FT4 was 0.11 (0.07) ng/dL at baseline and decreased significantly on LT3. The ∆TT3 was 0.32 (0.09) ng/mL at baseline and significantly decreased on both LT4 and LT3, with no difference between treatment arms. Conclusions: Older individuals with antibody-negative persistent subclinical hypothyroidism have a heterogeneous TSH response to TRH stimulation. Our data show a significantly diminished response to TRH stimulation after thyroid hormone replacement, and they support the pharmacodynamic equivalence of LT4 and LT3 treatment.
Characteristics and Difficulties in the Management of Thyroid Microcarcinoma in Algeri
Authors: Kaouache Nadjib , Billel Zouraghen
Published: May 2021

Introduction: Thyroid cancer prevalence has increased significantly in recent years, including in Algeria, which primarily concerned microcarcinoma making 30 to 50% of new diagnosed cases. Despite its good prognosis, its management remains highly controversial and debated. We aim to describe characteristics of thyroid microcarcinoma in a series from eastern Algeria monitored in the endocrinology department of Constantine University Hospital and to report the difficulties pertaining to its management. Patients and Methods: A descriptive retrospective study including patients followed and monitored in the thyroid cancer register in the endocrinology department of Constantine University Hospital during the period between January 2015 and December 2018. Results: Of 70 cases of thyroid microcarcinomas, mean age was 44 years [17-84 years] and 94% were women. 94% of the cases were papillary micro carcinomas; the two most frequent variants were the classic papillary and the vesicular variant of papillary carcinoma in 80% of cases. The diagnosis was made following a multi-nodular goiter exploration in 60% and thyroid function was normal in 50%. Moltifocality and bilaterality were reported in 27% and 5.71% of cases respectively. The most common surgical procedure was total thyroidectomy (96%), without lymph node dissection (86%). Classification of the initial risk was impossible due to the insufficient data in 28% of cases. 52% of patients received RAI therapy and 81% were in complete remission. Conclusion: Thyroid micro carcinoma has a good prognosis; however, its management faces several issues, mainly the stratification of risk which would be a source of overtreatment.
Clinical Outcomes of Differentiated Thyroid Cancer With Gross Extrathyroidal Extension Into the Strap Muscles: A Case Control Study
Authors: Chablani Sumedha , Ghaznavi Sana , Tuttle R Michael
Published: May 2021

Background: The 8th edition of the American Joint Committee on Cancer/tumor-node-metastasis (AJCC/TNM) staging system for differentiated thyroid cancer (DTC), implemented in January 2018, classifies patients >/= 55 years of age with gross extrathyroidal extension (ETE) of the primary tumor into the overlying strap muscles as prognostic stage II. However, it remains controversial as to whether or not gross ETE into the strap muscles is an independent predictor of recurrence, response to therapy, need for additional therapies, or overall survival. Using a case control study design, we evaluated the prognostic significance of gross ETE among adults.

Methods: After obtaining IRB approval, we used the tumor registry at our institution to retrospectively identify 51 AJCC stage II patients with DTC aged >/= 55 years with gross ETE into only the strap muscles (51/2,225 patients). For each of the 51 cases, we identified one control who matched on all of the following important prognostic factors: age at diagnosis (± 5 years), sex, histology, size of tumor (± 1 cm), lymph node metastases, distant metastases, completeness of resection, receipt of radioactive iodine (RAI) therapy, and duration of follow-up (± 5 years). The controls (n=51) had no gross ETE.

Results: In the 51 patients with gross ETE into only the strap muscles, the mean age at diagnosis was 64 years, 77% were female, 37% had lymph node metastases, and none had distant metastases. The average tumor size was 2.1 cm with the majority of patients (49/51) demonstrating papillary thyroid carcinoma (1 follicular thyroid carcinoma and 1 Hurthle cell thyroid carcinoma). Only 6% of patients (3/51) had incomplete resections and 92% (47/51) received RAI therapy. The mean duration of follow-up was 8 years.

There were no statistically significant differences between the cases and controls on each of the pre-specified prognostic variables described in the methods. In addition, there were no statistically significant differences between the groups in terms of rates of recurrence: cases 18% (9/51) and controls 29% (15/51) (p=0.24), best response to initial therapy (excellent, biochemical incomplete, structural incomplete, or indeterminate response to therapy), and need for subsequent interventions including surgery, RAI, external beam radiation, or systemic therapy. Furthermore, there were no statistically significant differences between the cases and controls with respect to 10-year disease-free survival (cases 83% and controls 68%, p=0.90) and 10-year overall survival (cases 97% and controls 89%, p=0.10).

Conclusions: In a case control analysis with a mean follow up of 8 years, the presence of ETE into the strap muscles was not an independent predictor of worse clinical outcomes in adults >/= 55 years old with DTC. These findings can be used to inform the future editions of the AJCC/TNM and American Thyroid Association staging systems for DTC.
Effect of Metabolic Health on Severity of Thyroid Cancer: The Scripps Clinic Thyroid Cancer Cohort Analysis
Authors: Sharma Pranjali , Dhar Chirag , Levine Matthew Jason , McCallum James David , Martinez Renil Rodriguez
Published: May 2021

Introduction: The increasing prevalence of obesity has been linked to increased risk of cancers such as prostate, breast and endometrium, but its role in thyroid cancer is not clearly established. Since prevalence of obesity-related metabolic disturbances (dyslipidemia, dysglycemia) varies among individuals, it has been suggested that poor metabolic health, rather than obesity (defined by BMI), plays a role in thyroid cancer. We performed a retrospective review of our thyroid cancer cohort to evaluate the association between metabolic health and severity of thyroid cancer. Objectives: 1. Association between dyslipidemia and stages of thyroid cancer 2. Association between dysglycemia and stages of thyroid cancer. Methodology: The Scripps Clinic Thyroid Cancer Cohort includes 656 patients diagnosed with thyroid cancer from 2017-2020 in the Scripps Health System. IRB approval for our study was obtained in January 2020. Inclusion criteria: 1. Confirmed thyroid cancer on surgical pathology 2. First available lipid profile at least 6 months prior to diagnosis 3. First available HbA1c at least 6 months prior to diagnosis. A total of 214 patients with an available lipid profile were included in the analysis. Of those, 148 had an available HbA1c. Definitions used: 1. Dyslipidemia - total cholesterol >=200 mg/dl or HDL <40 mg/dl in males, <50 mg/dl in females or triglycerides >=150 mg/dl. 2. Dysglycemia - HbA1c >=5.7%. Thyroid cancer stages were compared in patients with and without dyslipidemia and dysglycemia. Subgroup analysis was performed for patients above age of 55 years (n=103) due to difference in AJCC staging. Results: A larger proportion of dyslipidemic patients (28.4% vs 18.1%) had stage 2-4 thyroid cancer, but the difference was not statistically significant (p 0.07). A larger proportion of dysglycemic patients (36.3% vs 15.6%) had stage 2-4 thyroid cancer, a statistically significant difference (p 0.003). Similar findings were noted on subgroup analysis: a larger proportion of dyslipidemic (15.2% vs 8.2%) patients had Stage 3-4 thyroid cancer without statistical significance (p 0.1), while a statistically significant higher percentage of dysglycemic patients (20% vs 2.7%, p 0.01), had stage 3-4 thyroid cancer. A larger proportion of advanced thyroid cancer cases was noted in patients with both dyslipidemia and dysglycemia as compared to patients with only one abnormality or none. Conclusions: 1. Poor metabolic health, particularly dysglycemia, is associated with advanced stages of thyroid cancer, especially in the >=55 years age group. Dysglycemia with dyslipidemia confers highest probability of advanced thyroid cancer. 2. Mechanisms by which dysglycemia affects thyroid cancer severity requires further rigorous study. 3. Based on our study, we recommend a thorough discussion regarding risk of advanced thyroid cancer in patients with poor metabolic health and thyroid nodules.
Effectiveness of Different Thyroid Stimulating Hormone Thresholds for Thyroid Hormone Withdrawal - Aided Radioiodine Ablation in Patients With Differentiated Thyroid Cancer: A Systematic Review and Meta - Analysis
Authors: Rojas Tatiana , Solis-Pazmino Paola , Lincango-Naranjo Eddy , Ledesma Tannya , Alvarado-Mafla Benjamin , Barrera Francisco J , Vega Jorge Luis Salazar , García Cristhian , Ponce Oscar J , Brito Juan Pablo
Published: May 2021

Background: Patients with differentiated thyroid cancer (DTC) may benefit of radioiodine ablation (RAI) to reduce the probability of thyroid cancer recurrence. Guidelines recommend that thyroid stimulating hormone (TSH) of >30mIU/L before RAI to optimize treatment response. However, evidence regarding this recommendation is conflicting. We conducted a systematic review and meta-analysis to compare outcomes (thyroid cancer recurrence and survival at 10 years of follow up) of stimulated TSH threshold before RAI with primary analysis focus on <30 mIU/L versus ≥30 mIU/L, and subgroup analysis on <90 mIU/L versus ≥90 mIU/L in patients with DTC after initial total thyroidectomy.

Methods: The protocol for this study is registered and available online (CRD42020158354). Briefly, we searched several databases from their inception to April 2020. Reviewers, working independently and in duplicate selected studies for inclusion, extracted data, and evaluated each study’s risk of bias. We excluded studies that used recombinant human thyroid stimulating hormone before ablation. Results: We included five retrospective cohort studies, which enrolled a total of 2,514 patients. Risk of bias was low in four studies and high in one study. Mean age was 47 years old (ranged from 40.7 to 47.9) and most of them were female (69%). The most common DTC type was papillary thyroid cancer (78%). From those articles that reported tumor characteristics, 48% had a size ≤2cm (T1b) and 47% >2cm. Moreover, 73% of the patients had no regional lymph metastasis (N0). Two studies reported radioiodine mean dose given of 30 and 100 mci. A total of 301 patients were included in the TSH threshold <30 mIU/L group and 1788 patients in the TSH ≥30 mIU/L group. Comparing stimulated TSH threshold before RAI (<30 mIU/L versus ≥30 mIU/L), there was difference in recurrence at 1 year (RR 2.46 (C.I. 1.09-5.55) and at 20 years (RR 1.71 (C.I. 1.19 – 2.47). However, there was no difference in mortality at 20 years (RR 0.53 (Confidence Interval (C.I.) 0.12-2.23). In addition, 10-years recurrence was not different when we compared <90 mIU/L versus ≥90 mIU/L TSH (RR 1.06; 95%CI: 0.88 – 1.27).

Conclusions: Mortality do not differ between recommended TSH goal (≥30 mIU/L) vs <30 mIU/L in thyroid hormone withdrawal-aided radioiodine ablation in DTC patients. However, the risk of recurrence is reduced when patients achieved a TSH level >30 UI/mL. These results suggest that patients may need to reach a stimulated TSH ≥30 mIU/L stimulated TSH threshold to be treated. Randomized trials are needed to confirm these findings.
Interobserver Variability in Ultrasound Reporting - Tertiary Hospital Radiologists Do Better
Authors: Koch Noam , Applebaum Liat , Mazeh Haggi , Katz Lilach , Pollack Rena
Published: May 2021

Introduction: Thyroid Imaging Reporting and Data System (TI-RADS) was developed to provide a standardized risk-stratification system for patients with thyroid nodules. Single-center studies have demonstrated an acceptable level of interobserver agreement in applying TI-RADS in clinical practice, however data regarding consistency among different centers is limited. In Israel, thyroid nodules are initially evaluated by ultrasound performed by radiologists at the health maintenance organization (HMO) and then patients are referred to tertiary hospitals for ultrasound-guided fine needle aspiration (FNA) biopsy when indicated. Objective: To evaluate the interobserver concordance in TI-RADS classification system reporting between the HMO and a tertiary hospital. Methods: We performed a retrospective analysis of the sonographic features of 370 thyroid nodules TI-RADS category 2 or higher, from 350 patients evaluated by ultrasound at the HMO and at Hadassah Medical Center from January 1, 2018 to December 31, 2019. The primary outcome was concordance between the TI-RADS classification at the HMO compared to the hospital. Additional endpoints included correlation of TI-RADS to the Bethesda category following FNA, and correlation of TI-RADS with malignancy on final pathology. Results: Of 370 nodules, only 73 (19.8%) demonstrated concordance between the HMO and the hospital. The level of agreement was poor, with 277 (74.8%) nodules demonstrating higher TI-RADS at the HMO compared to the hospital, and 20 (5.4%) with lower TI-RADS at the HMO compared to the hospital (p<0.001, weighted Kappa = 0.120). Of the nodules referred to the hospital, 241 (65.1%) were selected for FNA. A strong correlation between the hospital TI-RADS and Bethesda category was demonstrated (p<0.001). Furthermore, 60 (16.2%) nodules were surgically removed. A strong correlation was identified between the hospital TI-RADS and malignancy on final pathology (p<0.001), yet there was no correlation with the TI-RADS of the HMO (p=0.346). Conclusions: There is poor concordance between TI-RADS classification on ultrasound performed in the HMO compared to a tertiary hospital. In patients who underwent FNA and eventually surgery, the hospital TI-RADS strongly correlated with Bethesda category and final risk of malignancy. Standardization of thyroid ultrasound terminology and dedicated training in thyroid imaging are needed to improve the interobserver concordance in clinical practice.
Malignancy Risk in RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Real-World Clinical Experience
Authors: Lu Joseph , Lupo Mark Armin
Published: May 2021

Introduction: Fine needle biopsy (FNB) is the standard procedure for thyroid nodules meeting criteria for biopsy according to current national guidelines (ATA and ACR). However, 15-25% of biopsies are categorized as indeterminate in the Bethesda Categories III (Atypical/FLUS) or IV (Follicular/Hurthle Neoplasm). Molecular testing is a common way to further risk stratify these nodules for surveillance versus surgical resection. BRAF-like mutations have a high probability of malignancy while RAS-like mutations have a variable risk of malignancy. This study examines the performance of RAS mutations in identifying malignancy or NIFTP in a real-world clinical setting.

Methods: 2,372 sequential thyroid FNBs were performed in our center from July 2014 to June 2020. Of these, 367 were subjected to molecular testing with either Thyroseq V2 or V3. 55 RAS-mutated BCIII or IV cases were identified and retrospectively evaluated. NIFTP was considered malignant in the calculations. ATA and ACR ultrasound classification as well as Doppler grade of the study nodule were assessed.

Results: 8 cases were excluded due to lack of follow-up or incomplete data. 40 underwent surgical resection based on the cytology and molecular results. 7 did not undergo surgery based on patient preference or comorbidities and had clinical follow up with stable ultrasound for at least 6 months. Surgical pathology results: 67.5% benign, 7.5% NIFTP and 25% malignant.

All 4 of the Thyroseq “currently negative” RAS nodules were benign. Of the 36 “positive” cases, 6 with additional mutations had a 66.7% ROM and the 30 RAS-only cases had a 30% ROM. Of the 9 RAS-only cases that were not benign, 3 were NIFTP, 5 FVPTC (2 unencapsulated and 3 encapsulated) and 1 was angio-invasive PTC with extensive extrathyroidal extension (this case had high-risk pre-op imaging features). None had lymph node involvement.

Higher allelic frequency, abnormal gene expression (GE) and copy number alterations (CNA) all increased the risk of malignancy/NIFTP; ROM was 50% when both GE and CNA were positive. Nodules that were ATA/ACR moderate and high suspicion had an approximately 40% and 67% ROM respectively with ATA and ACR performing similarly. High intra-nodular vascularity conferred a 46% ROM.

Conclusions: RAS mutations represent the most frequent abnormality found in oncogene testing however isolated RAS mutations have a low risk of malignancy and when malignant are generally non-aggressive. When both GE and CNA are positive, the risk increases. US features, including Doppler also contribute to risk assessment. Combining all these features is recommended when counseling patients on active surveillance versus surgical resection of RAS-mutated thyroid nodules.
Metabolic Factors Can Influence the Risk of Differentiated Thyroid Cancer
Authors: Dumitriu Roxana-Ioana , Burcea Iulia Florentina , Dusceac Roxana , Galoiu Simona , Poiana Catalina
Published: May 2021

Introduction: Worldwide, the increasing incidence of thyroid cancer, along with a parallel increase in obesity and metabolic disorders, suggests that modifications of lifestyle and environmental factors might explain the rise in thyroid cancer incidence (1). Objective: To investigate the association between metabolic syndrome and their elements and their possible association with the risk of thyroid cancer. Materials and Methods: We enrolled 200 patients, who underwent total thyroidectomy for multinodular goiter (Bethesda II-V categories on the basis of fine needle aspiration biopsy cytological examination). We included subjects with differentiated thyroid carcinoma, the ones with poorly differentiated, anaplastic, medullary thyroid carcinomas and secondary tumors were excluded from the analysis. Patients were divided into two groups, according to the post-surgical histological diagnosis: 60 patients diagnosed with papillary or follicular thyroid cancer and 60 diagnosed with benign thyroid disease. The patients had a mean age of 56.9 years old and the majority were females (90%). Relative risk of incident thyroid cancer was assessed by preoperative levels of body mass index (BMI), blood pressure, blood levels of glucose, cholesterol, triglycerides, and the presence of metabolic syndrome (according to the NCEP ATP III definition). The two groups had similar age, gender distribution, smoking habit. Mean BMI was slightly higher in the group with patients with differentiated thyroid cancer and the majority were obese (27.41 ± 5.38 kg/m2versus 26.42 ± 5.18 kg/m2). The patients from the differentiated thyroid cancer group showed a higher percentage of diabetes mellitus and impaired fasting glucose compared to the second group (20% versus 13%), with mean fasting blood sugar levels of 97 ± 2.69 mg/dl in the first group versus 73 ± 3.06 mg/dl in the second group. 30% of the patients from the differentiated thyroid cancer group presented criteria for metabolic syndrome. There was a positive correlation between the presence of hypertension and the diagnosis of differentiated thyroid cancer (p<0.05). Conclusion: Our study showed a potential association between metabolic risk factors and the diagnosis of differentiated thyroid cancer. Besides the improvement of diagnosis, thyroid cancer increasing incidence is probably due to environmental factors and lifestyle modifications. As a future perspective of this study and based on the hypothesis of glucose dependency of many tumor types, another therapeutic strategy can involve diet (low-carbohydrate, high-fat) in order to target metabolism in tumors and alter the Walburg phenothype. Reference: (1). Mele, C., Samà, M. et al. (2019). Circulating adipokines and metabolic setting in differentiated thyroid cancer, Endocrine Connections, 8(7), 997-1006.
Pregnancy During Active Surveillance of Papillary Thyroid Microcarcinoma
Authors: Rosario Pedro Weslley , Mourão Gabriela Franco
Published: May 2021

Introduction: Most patients diagnosed with papillary thyroid microcarcinoma (microPTC) classified as low risk and therefore eligible for active surveillance (AS) are women. Although age is a predictor of tumor progression (more frequent among young people), young adults are “appropriate” candidates for AS. Consequently, a proportion of patients with low-risk microPTC eligible for AS are women of childbearing age and knowledge of the effect of pregnancy on tumor progression is therefore important. In the Japanese population, Ito et al. observed this progression in only 8% of pregnancies. None of the series on the outcomes of AS in western populations has so far reported the behavior of microPTC in women who became pregnant during AS. Methods: We have submitted patients with low-risk microPTC to AS. Our management has been not to interrupt AS, i.e., not to indicate surgery when the patient wishes to become pregnant. We report here the results of five patients who became pregnant during AS and their follow-up up to 6 months after delivery. Results: The patients were 26 to 36 years old (median 29 years) when they became pregnant. None of them had a history of radiation exposure, one had a family history of PTC, one had associated Hashimoto’s thyroiditis, and all of them had only one tumor focus and were considered “appropriate” (but not “ideal”) candidates for AS. In fact, when pregnancy was diagnosed, the patients continued to exhibit the criterion for AS according to our initial protocol (tumor ≤ 1.2 cm, no apparent lymph node metastases [LNM] or extrathyroidal extension [ETE] on ultrasonography [US]). All women were monitored by monthly measurement of TSH and levothyroxine (L-T4) was administered during pregnancy to maintain TSH between 0.1 and 1 mIU/L. US was performed when pregnancy was diagnosed (between 6 and 9 weeks of gestation), around 22 weeks, at the end of pregnancy, and 6 months after delivery. During the evaluations, none of the patients had apparent LNM or ETE on US. None of the patients exhibited tumor growth, defined as an increase in diameter ≥ 3 mm. Tumor growth ≥ 50% was observed in only one patient, with a small reduction after delivery. Conclusions: Our preliminary results suggest that pregnancy is not associated with a high risk of progression of low-risk microPTC and that the desire to get pregnant or pregnancy should not be an exclusion factor for AS. References: Effects of Pregnancy on Papillary Microcarcinomas of the Thyroid Re-Evaluated in the Entire Patient Series at Kuma Hospital. Ito Y, Miyauchi A, Kudo T et al. Thyroid 2016; 26:156-60 AND Active Surveillance in Adults with Low-Risk Papillary Thyroid Microcarcinomas: A Prospective Study. Rosario PW, Mourão GF, Calsolari MR. Horm Metab Res. 2019; 51:703-8.
The Genomic Landscape of Radioactive Iodine Refractory and Avid Papillary Thyroid Carcinomas
Authors: Al-Kuraya Khawla Sami , Siraj Sarah , Masoodi Tariq , Siraj Abdul Khalid , Azam Saud , Qadri Zeeshan , Al-Dayel Fouad
Published: May 2021

Background: Although, standard treatment of Papillary Thyroid Carcinoma (PTC), involving surgery followed by radioactive iodine (RAI) therapy, is curative for most patients, 5-20% of patients develop RAI refractory disease. The repertoire of genomic events enabling RAI refractory disease in PTC needs elucidating. Methods: Whole-exome sequencing was performed on 100 primary PTC tumours, consisting of 47 RAI refractory and 53 RAI avid tumours, with matched germline. The resulting somatic variants were analysed to compare the genomic landscape, driver events and clinically actionable events between RAI refractory and avid PTC. Results: RAI refractory primary tumours were significantly associated with later stage, positive involvement of surgical margins, presence of extrathyroidal extension, lymph node metastases and poorer 5-year disease-free survival. Mutational burden was significantly higher, with additional subclonal mutations in RAI refractory compared to avid PTC patients. RAI refractory primary tumours showed significantly stronger PD-L1 expression. Mutations and PD-L1 expression in RAI Refractory PTC tumours significantly correlated with mutational signatures related to defective DNA base and nucleotide excision repair pathways. Driver mutations were acquired earlier in RAI refractory than in avid primary tumours. Conclusions: We conclude that RAI refractoriness is gained early in PTC, and is significantly associated with a higher mutational burden, PD-L1 expression, and mutational signatures, which may serve as important prognostic factors and indicate suitability for treatment with immune checkpoint inhibitors.
Trabecular Bone Score in Women With Differentiated Thyroid Cancer
Authors: Araujo Sousa Barbara Erika Caldeira , Soares Maria Marta Sarquis , Silva Barbara Campolina , Kakehasi Adriana Maria , Pires Magda Carvalho
Published: May 2021

Introduction: Thyrotropin stimulating hormone (TSH) suppression in patients with differentiated thyroid cancer (DTC) aims to decrease the growth and proliferation of thyroid cancer cells. However, the effect of TSH suppressive therapy on bone microarchitecture remains undefined. Methods: Cross-sectional study including 43 women with DTC undergoing TSH suppressive therapy (sTSH) compared to 20 women also on levothyroxine therapy but with TSH in the low-normal range (nTSH) since the thyroid surgery. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA), and trabecular bone score (TBS) was evaluated using the TBS iNsigth software. The relationship between suppressive therapy-related parameters and bone parameters was investigated. Results: The TBS mean values were not significantly different in the sTSH and nTSH groups (1.273 ± 0.12 vs 1.307 ± 0.14, p = 0.7197). In both groups, postmenopausal women had degraded microarchitecture (TBS 1.216 ± 0.11 vs 1.213 ± 0.09, p = 0.9333), while premenopausal women had normal microarchitecture (1.328 ± 0.11 vs 1.401 ± 0.12, p = 0.195). The percentage of all postmenopausal women with degraded TBS was 54.7%, while the percentage of osteoporosis diagnoses was 16.1%. Body mass index (BMI) and menopausal status were the only variables associated with TBS and BMD. Conclusion: Long-term TSH suppressive therapy does not seem to be associated with deterioration of the trabecular microarchitecture in premenopausal women. However, lower TBS values were observed in postmenopausal women of both groups, even in those with nonsuppressive therapy. These data show that treatment with thyroid hormone in DTC can be detrimental to bone quality in postmenopausal women, regardless of whether TSH levels are maintained chronically suppressed or in the low-normal range.
Unmet Information Needs Among Hispanic Women With Thyroid Cancer
Authors: Chen Debbie W , Reyes-Gastelum David , Hawley Sarah T , Wallner Lauren P , Hamilton Ann S , Haymart Megan R
Published: May 2021

Background: Despite thyroid cancer being the second most common cancer in Hispanic women, little is known about access to and utilization of medical information resources by Hispanic women with thyroid cancer. Methods: Hispanic women who had diagnoses of thyroid cancer reported to the Los Angeles Surveillance Epidemiology and End Results (SEER) registry in 2014-2015, and who had previously completed our thyroid cancer survey in 2017-2018, were offered follow-up surveys in both English and Spanish (N=273; 80% response rate). Acculturation, which is the process by which individuals adopt the language, values, attitudes, and behaviors of a different culture, was assessed with the Short Acculturation Scale for Hispanics (SASH). Health literacy was assessed with the validated single-item question of “How confident are you filling out medical forms by yourself?” with response categories based on a five-point Likert scale from “extremely” to “not at all”. Patients were also asked about their internet access, information resources used, and ability to access medical information about thyroid cancer in their preferred language. We generated descriptive statistics for all categorical variables and used Rao-Scott adjusted chi-square tests to test for a relationship between level of acculturation and the following variables: health literacy, internet access, information resources used, and ability to access information. Results: Participants’ median age at diagnosis was 47 years (range 20-79); 49% were low-acculturated, 25% had low health literacy, and 14% reported no internet access at home. Low-acculturated Hispanic women reported using information resources in both English and Spanish whereas high-acculturated women used resources in English only. Hispanic women were more likely to report the ability to access medical information about thyroid cancer all of the time if they preferred information in English compared to if they preferred it in Spanish (89% vs 37%, P<0.001). Low-acculturated (vs high-acculturated) Hispanic women were more likely to have low health literacy (47% vs 5%, P<0.001) and to report use of in-person support groups (42% vs 23%, P=0.006). Depending on their level of acculturation, Hispanic women accessed the internet differently (P<0.001) such that low-acculturated women were more likely to use only a smartphone (34% vs 14%) or have no internet access (26% vs 1%), and less likely to use both a smartphone and home computer/tablet (28% vs 58%) or use only a home computer/tablet (10% vs 21%). Conclusion: Our findings demonstrate that low-acculturated Hispanic women with thyroid cancer have greater unmet information needs and access information differently compared to high-acculturated Hispanic women. This study emphasizes the importance of a patient-focused tailored approach to providing medical information to this understudied population.