Objective: Synthetic analog SG-2 was found to produce a time-dependent recovery of autophagic activity in U87MG cells, due to the downregulation of mTOR. A protective effect of SG-2 against neuronal plasticity impairment has been further confirmed in a transgenic Alzheimer’s disease (AD) mouse model, suggesting that SG-2 may have therapeutic potential in the treatment of AD.

Our study aimed to determine whether SG-2 can protect U87MG cells from the toxic effects induced by Aβ_25-35, a neurotoxic peptide commonly used in cellular models of AD.

Methods: In our experimental setting, exposure to 25 microM Aβ_25-35 for 72h was found to produce a significant (***p<0.005) reduction of U87MG cells viability (35.24% ± 2.29), as detected by MTT assays.

To examine whether pretreatment with SG-2 can prevent Aβ_25-35 neurotoxicity_, U87MG cells were exposed to 10 microM SG-2 for 24h, followed by treatment with 25 microM Aβ_25-35 for 72h. In another set of experiments, the effect of SG-2 post-treatment in rescuing U87MG cells’ viability after exposure to Aβ_25-35 was evaluated. Next, to ascertain whether the exposure of U87MG cells to Aβ_25-35 may further reduce their autophagic activity, gene expression analysis of autophagy-related genes was undertaken through qPCR.

Results: Pretreatment with SG-2 efficiently prevented Aβ_25-35 cytotoxicity in U87MG cells (*p<0.05), while post-treatment with SG-2 restored cell viability to a lesser extent (*p<0.05). Treatment with 25 microM Aβ_25-35 for 72h caused a significant overexpression of potent autophagy inhibitors mTOR (**p< 0.01) and sirtuin 5 (Sirt5) (**p<0.01), as well as a reduced expression of pro-autophagic genes, including sigma-1 receptors (Sig-1R) (***p<0.001) and nuclear sirtuins Sirt1 (*p<0.05) and Sirt6 (**p<0.01). Notably, pretreatment with 10 microM SG-2 significantly counteracted the effects of Aβ_25-35 on the expression of all the autophagy-related genes examined (*p<0.05). Moreover, in U87MG cells exposed to SG-2, the expression of pro-autophagic genes (Sig-1R, Sirt1 and Sirt6) was particularly pronounced as compared to U87MG control cells (***p<0.001). Consistently, in SG-2 treated cells an increased expression of the specific marker of autophagy LC3 was also observed (**p<0.01).

Conclusions: Taken together our results provide strong evidence that SG-2’s pro-autophagic activity can prevent Aβ_25-35 toxicity in U87MG cells.

Objective: The thyroid autoantibodies are mainly of IgG class and are produced by antibody-secreting cells (ASCs) infiltrating the thyroid in Hashimoto’s thyroiditis (HT). IgG is a glycoprotein with two N-linked glycans attached to its crystallizable fragment. The changes in glycosylation on thyroid autoantibodies are a novel pathological feature and are involved in HT development. Disturbances in various cytokines are found in the thyroid microenvironment of HT. Thus, we investigated the regulatory effects of elevated cytokines in HT on glycosylation enzymes and IgG glycan patterns.

Methods: In our two-step B cell differentiation culture system, primary B cells were co-cultured with IFN-γ, TNF-α, IL-21, IL-17A, IL-6, BAFF, or APRIL respectively during the differentiation period to ASCs. The IgG concentration in the supernatants was measured by ELISA. The glycosylation levels of IgG under different stimuli were measured by a lectin microarray. Then, the expression of glycosyltransferases and glycosidases in B cells was detected by real-time PCR and Western blotting under the stimulation by several cytokines.

Results: We found that cytokines significantly promoted IgG production in vitro and changed the expression of glycosylation enzymes, then resulting in considerably different IgG lectin patterns. Specifically, we found that the expression of β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) was upregulated by IL-21 and IL-17A (All p<0.05), but no significant expression changes of sialidase-1 (NEU1) was detected, which led to the increased sialylation of IgG. And the expression of β-1,4-galactosyltransferase 1 (B4GALT1) was upregulated by IFN-γ (p<0.05), then resulting in the increased galactosylation of IgG. We found that IL-6 decreased the sialylation of IgG, but the expression of ST6GAL1 and NEU1 showed no significant changes in B cells. In addition, the expression of mannosyltransferases were upregulated by IL-21, IL-17A, and IFN-γ, which increased the mannosylation of IgG. But IL-6 significantly downregulated the expression of α-1,2-mannosyltransferase 11 and upregulated the α-mannosidase 2, then led to the decrease of mannosylation of IgG (all p<0.05).

Conclusion: Elevated cytokines in the thyroid microenvironment prompted the IgG secretion and altered the glycan patterns of IgG by regulating the expression of glycosylation enzymes to disrupt immune homeostasis of IgG, then involving in the pathogenesis of HT.

Thyroid Eye Disease (TED) is an autoimmune disorder that attacks the muscle and fat tissue behind the eye, causing inflammation and scar tissue to develop, which can lead to proptosis, strabismus, and diplopia. In March 2020, the Food and Drug Administration approved Teprotumumab-trbw for TED, a monoclonal antibody that blocks the IGF-1R autoantibody, decreases proptosis, and administered over 8 infusion cycles every 3 weeks. We present 3 TED patients administered Teprotumumab-trbw by a Home Infusion Specialty Pharmacy.
 

66 y/o Indian male diagnosed 4/2020 with Graves’ Disease. Failed oral medications, symptoms worsened. TED diagnosed 6/2020. Exophthalmos, tearing, headaches, orbital pain, 2+ brow ptosis, BUL retraction; EOM/Diplopia significant restriction, CAS 4. Teprotumumab-trbw started 4/2021. Eye photos taken at Baseline visit. Headaches, tearing, pain and vision improved. Second infusion resolution of headaches and tearing.   

67 y/o Caucasian male diagnosed 6/2020 with TED after losing vision for a few hours. Failed oral medications, symptoms worsened. Exophthalmos; diplopia, 1+ ptosis, ophthalmoplegia OD, pain, swelling, redness, tearing. CAS 5. Teprotumumab-trbw started 4/2021.  Eye photos taken at Baseline visit.  Decreased swelling, tearing, pain, and redness after second infusion. Three infusions completed.

54 y/o Caucasian male, 20+ year battle with thyroid disease. TED diagnosed 2020. Failed oral medications, symptoms progressed. Exophthalmos, edema, redness, dryness, tearing, proptosis, diplopia, Cas>3. Decreased edema, redness, tearing, dryness, proptosis, diplopia, and exophthalmos after third infusion. Teprotumumab-trbw started 12/2020.   Four infusions completed. Treatment held during medication shortage- restarted 5/2020.  Eye photos were not taken due to patient decision.  

Soleo Health, a national Home Infusion Specialty Pharmacy, has treated over 280 TED patients with Teprotumumab-trbw. Unique providers/dispenses are over 150/1580.  Mean demographics: 52 YOA/77% female/65.52 inches/76.51 kg/27.6 BMI.  Over 1200 Graves' Orbitopathy Quality of Life (GO-QOL) collected through a proprietary clinical outcomes program, SoleMetrics^®.  Mean GO-QOL scores, Type of Payor, and Referral Source will be presented.  Using the SoleMetrics^® platform allows clinicians to collect photos of patients (front, right, left) by written consent, along with other infusion-related data during their course of treatment related to ADRs, efficacy, and symptoms, which are shared with the treating physician to manage clinical status.

Introduction:

Several case reports and retrospective studies have described the association of COVID-19 and thyroiditis. However, the spectrum of thyroid dysfunction in patients with COVID-19 remains uncertain. Currently, there are only two case reports describing the association of COVID-19 with Graves’ disease (GD). Here, we report another case of new onset GD following recovery from mild COVID-19 infection. 

Case: 

A 22-year-old Hispanic male with no pre-existing conditions presented to our clinic with a 10-pound progressive, unintentional weight loss over one month associated with palpitations, heat intolerance, and worsening anxiety. He noticed these symptoms around 2 weeks after his COVID-19 diagnosis. His COVID-19 symptoms were mild (diarrhea, fever, and myalgia), resolved after 2 weeks, and did not require hospitalization. Exam was notable for mild tremor on upper extremities with no thyromegaly or thyroid tenderness. Thyroid function tests revealed a low thyroid-stimulating hormone (TSH) of <0.02 uIU/mL (0.34 - 5.60 uIU/mL) with an elevated free T4 of 5.63 ng/dL (0.58 - 1.64 ng/dL) suggestive of thyrotoxicosis. Thyroid-stimulating immunoglobulin, TSH-receptor antibody, and thyroid peroxidase antibody tests were positive. Thyroid ultrasound revealed a diffusely enlarged, heterogenous, and hyperemic thyroid, consistent with thyroiditis. There was no use of amiodarone, intravenous contrast, lithium, or family history of thyroid disorders. He was started on methimazole 15 mg twice a day and atenolol 50 mg daily with marked improvement in symptoms on follow up at 1, 2, and 3 months and normalization of free T4 and TSH.  

Discussion:

This case reports the occurrence of Graves' thyrotoxicosis following mild symptomatic COVID-19. Research suggests that autoimmunity in GD is associated with several factors including genetic susceptibility and environmental factors such as stress, smoking, iodine exposure, drugs, and viral infections. Proposed mechanisms of GD development following viral infection include antigen exposure, molecular mimicry, cytokine release, and inflammatory response. Although there is no established causal relationship between COVID-19 infection and GD, our case adds to the limited existing literature to suggest SARS-CoV-2 as a potential trigger for GD. More definitive studies are required. 

Objective: To search for the degree of lymphocyte infiltrations, fibrosis, and antibody titers and evaluate Hashimoto’s thyroiditis progression; additionally, to propose a new classification of Hashimoto's thyroiditis (autoimmune disease).

Methods: Among 9008 thyroid cases operated on at our hospital from 2008 to 2016, 257 cases (2.9%) were operated on for Hashimoto's disease or malignant lymphoma, and eighty-nine cases (0.99%) diagnosed with Hashimoto's thyroiditis by final histology were analyzed retrospectively. We subjectively divided them into 3 groups:  (I) slight: lymphocyte infiltration less than 10 % with little fibrosis, (II) moderate: lymphocyte infiltration between 10-20 % with fibrosis less than 10 %, and (III) severe: lymphocyte infiltration exceeding 20 % with fibrosis more than 10 %. Evaluation of the lymphocyte infiltration and fibrosis area were performed by using WinROOF ver. 7.0 Image analysis software. 

Serum levels of anti-thyroglobulin autoantibodies (TgAb) and anti-thyroperoxidase autoantibodies (TPOAb) were measured by chemiluminescent enzyme immunoassay.

Results: Among 89 cases of Hashimoto’s thyroiditis, slight, moderate, and severe cases were 17, 55, and 17 cases, respectively. The degree of lymphocyte infiltrations revealed (mean (SD) %), 5.1 (3.9) in slight, 18.9 (10.3) in moderate, and 21.2 (8.6) in severe, respectively (P <.0001). The degree of fibrosis revealed (mean (SD) %), 2.9 (3.7) in slight, 6.3 (6.8) in moderate, and 11.7 (10.1) in severe, respectively (P =.002). There was a positive correlation between the ratios of lymphocyte infiltration and TgAb (r =.32 P =.01), but no significant different correlation with TPOAb (r =.16 P =.19). However, there was a positive correlation between the ratios of fibrosis and TgAb（r=.31 P =.01）, TPOAb（r =.25 P =.04）. According to the cut-off point by the area under the curve (AUC), we suggest the Activity level as A1, A2, A3 (cut-off point; 13.0, 16.08, respectively) according to lymphocyte infiltration, and the Stage level as F1, F2, F3 (cut-off point; 3.39, 16.6, respectively) according to fibrosis.

Conclusions/Discussion: 

Lymphocyte infiltration, fibrosis and antibody titers suggested association with Hashimoto's thyroiditis progression. We suggest progression of Hashimoto's thyroiditis classification according to the cut-off point of lymphocyte infiltration and fibrosis.

Objective: Thyroid eye disease (TED) results in varying degrees of proptosis and diplopia.  Although these sequelae result in significant disfigurement, visual changes and disability, no formal health state utility (HSU) research has been completed. HSU values range from 0 (death) to 1 (perfect health).  We developed HS for active, moderate-severe TED and elicited utility values to determine the impact of varying severities on patients’ quality of life (QOL).  

Methods: Six TED HS descriptions were developed from 2 placebo-controlled clinical trials (171 TED patients, clinical activity score ≥4, ±diplopia/proptosis). The descriptions were refined/validated by interviews with US TED patients (n=9) including 3 patient advocates and physician experts (n=3). Using time-trade-off methods, the HS descriptions and questionnaire were piloted with 10 US general population participants, and then administered to another 101 participants of the general population to elicit utility values for each HS. Visual Analog Scales (VAS) were administered to confirm/discern differences in the findings. Statistical tests evaluated differences in utility scores by severity and as sensitivity testing.

Results: The lowest utility values (representing greatest impact on QOL) were observed for the most severe disease state (constant diplopia/large proptosis) with mean value 0.30 (CI 0.24-0.36), followed by constant diplopia/small proptosis with 0.34 (0.29-0.40), intermittent or inconstant diplopia/large proptosis with 0.43 (0.36-0.49), no diplopia/large proptosis with 0.46 (0.40-0.52), and intermittent or inconstant diplopia/small proptosis with 0.52 (0.45-0.58). The highest value, 0.60 (0.54-0.67), was observed for the least severe disease state, no diplopia/small proptosis. The population mean was 0.44.  

There was a significant difference between 9 of 15 HS comparisons including the most severe HS (constant diplopia/large proptosis) versus the least severe HS (no diplopia/small proptosis) (p<0.001), but not between some pairs of neighboring HS (n=6) comparisons. VAS scores were confirmatory.

Discussion/Conclusion: These data indicate that active, moderate-severe TED patients have significant disutility, with increasing severities having a greater QOL detriment. To our knowledge, this is the first study to fully assess utility values for TED. These data provide a baseline for future assessment of improvement (utility gains) from new TED therapies. 

The occurrence of Graves’ disease (GD) after subacute thyroiditis (SAT) is rare, with only 34 cases, mostly middle-aged women, being described in the literature. Our patient is a 32-year-old Chinese man with no previous history of thyroid disease who developed typical SAT with anterior neck swelling and pain, sore throat, 14-pound weight loss, fever and mild hyperthyroidism (TSH 0.03 mIU/mL, FT4 2.40 ng/dl, and normal T3). Antibiotics were prescribed without improvement and testing for SARS CoV-2 RNA was negative. CRP and ESR were elevated (4.3 mg/dl and 21 mm/hr respectively) and thyroid autoantibodies were negative at initial presentation. Glucocorticoid treatment for 6 weeks led to resolution of hyperthyroidism and symptoms. Three weeks after discontinuation of steroids, hyperthyroidism recurred (TSH <0.01 mIU/mL, T3 257 ng/dl and FT4 3.03 ng/dl) without neck tenderness and with normal repeat CRP and ESR (0.1 mg/dl and 4 mm/hr, respectively). Repeat thyroid autoantibodies were elevated (TSI 3.42 IU/L, TPO Ab 805 IU/mL, TRAB 8.72 IU/L), thyroid radioactive iodine uptake (RAIU) was elevated (66.2%), and thyroid scan showed diffuse homogeneous radiotracer uptake consistent with Graves’ disease (GD). The patient had complete resolution of symptoms of hyperthyroidism and normalization of thyroid function (FT4 at 1.32 ng/dl and TT3 at 110 ng/dl) one month after starting methimazole. HLA testing revealed presence of HLA- B*35 and -DRB1*15:01 alleles which are associated with SAT and GD respectively; the latter allele has been found specifically in Chinese patients with GD. GD after SAT is rare in a young healthy man; this phenomenon has not been reported in a Chinese patient. This unusual change in diagnosis should be considered when symptoms and signs of hyperthyroidism do not resolve as expected or return after a period of improvement since management is dependent upon accurate diagnosis. Change from SAT to GD can be determined by new elevation of thyroid autoantibodies, change from elevated to normal ESR and CRP, and elevated RAIU. Testing for presence of HLA alleles revealed an underlying genetic predisposition to SAT and GD in our case.   

Introduction:

Resistance to thyroid hormone (RTH) is a genetic condition characterized by decreased response of target tissues to thyroid hormone (TH), secondary to germline mutations in the TH receptor (THR).

Case:

A 65-year-old female was diagnosed with Hashimoto’s thyroiditis and hypothyroidism after presenting with fatigue. Thyroid exam and US were unremarkable. She was referred to endocrinology due to fluctuating control.

On presentation her TSH was 0.6 mIU/L (normal 0.5-5.0) on levothyroxine (LT4) 300 mcg. Subsequent decrease in dosage resulted in fluctuating TSH levels with the highest TSH of 121 on LT4 150 mcg. FT4 level ranged between 1.5-2.7 ng/dl (normal 0.8-2.0) and FT4 by equilibrium dialysis ranged between 1.9-2.8 ng/dl (normal 1.1-2.4). 

Genetic testing revealed heterozygous positivity for the c.997G>A (p.GLU333LYS) variant in THRβ gene which hasn’t been previously reported  in the online database. 

Discussion:

THR which mainly refers to T3 receptor is a nuclear receptor that possesses 4 functional domains. It contains two genes: THRα and THRβ. THRβ gene mutation is responsible for 80-90% of RTH (1,2). It is located on chromosome 3 and contains 10 exons, encoding a total of 461 amino acids (2) Up until now, all THRβ mutations have been reportedly located in 3 hotspots between Exon 7 and 10 which correspond to the ligand-binding pocket in the 3D structure, Mutations in this area can lead to  reduced or  loss of binding between THR and TH(1) In our patient, the mutation found was not reported in the  literature but is situated within a hotspot and corresponds to a position associated with other known pathogenic missense variants.

Previous studies have confirmed that there is no clear correspondence between RTH genotypes and phenotypes. (2) The clinical manifestations of RTH are highly heterogeneous. Genetic diagnosis is the most reliable method for diagnosing RTH. However, the gene defect in 15% of subjects remains unknown (2,3)  Treatment depends on clinical symptoms instead of aiming to normalize TH.  In most subjects, the partial tissue resistance to TH is adequately compensated for by an increase in the endogenous supply of TH and thus treatment is not required (2). 

Introduction

Moyamoya disease（MMD）is a rare cerebrovascular disorder characterized by bilateral stenosis or occlusion of the terminal portions of the internal carotid arteries accompanied by typical net-like collateral vessels in the basal ganglia. Clinically, a very small number of patients with severe hyperthyroidism are prone to complications of MMD.

Description of the case

A 20-year-old female with a history of refractory Graves’ Disease (GD) for 2 years and high dose of methimazole, propylthiouracil，lithium carbonate, methylprednisolone all failed to improve her hyperthyroidism. She presented with severe goiter and tracheal compression. On 25^th Feb 2019, the patient had a sudden onset of weakness in the left limb with only grade 1 muscle strength. Cranial MRA showed that hypoperfusion in the right frontal and basal ganglia regions, occlusion of the right internal carotid artery and middle cerebral artery, and slender visualization of the right anterior cerebral artery. The hyperthyroidism was not well controlled during recovery from cerebral infarction. Considering recovering from a acute cerebral infarction and high TRAb levels, she was not appropriate to receive surgery or ¹³¹I therapy. Thus, conservative treatment including hemodialysis, rituximab in combination with ATD and glucocorticosteroids had been taken. After the above treatment, the patient's hyperthyroidism improved significantly and the TRAb level gradually decreased. Therefore, twice low dose ¹³¹I therapy were administered on 7^th Jan and 15^th Mar 2020, followed by moderate dose of ATD and glucocorticoids combined to control hyperthyroidism. Currently, the patient's hyperthyroidism-related indicators and symptoms are gradually improving.

Discusssion

When hyperthyroidism is complicated by cerebral infarction, patients should be alerted to the possibility of MMD. For the two combined diseases, control of hyperthyroidism is the basis. Besides, surgery/¹³¹I therapy is not recommended during the recovery period of MMD and conservative medical treatment is the main choice, in which hemodialysis and RTX should be considered if necessary. Lastly, the optimal timing of surgery/¹³¹I for hyperthyroidism after acute cerebral infarction needs to be confirmed.

Hyperthyroidism in pregnancy has a prevalence of 1-2%. Fetal hyperthyroidism carries significant morbidity, thus early identification and differentiation from physiological changes in thyroid hormone economy in pregnancy is essential. 

A 33-year-old pregnant woman with history of infertility, menorrhagia, chronic pancreatitis, asthma, MTHFR Gene Mutation, and homocystinuria was evaluated by endocrinology for abnormal thyroid function tests. She conceived a dichorionic, diamniotic pregnancy assisted by intrauterine insemination and clomiphene. At gestational week 11 she developed worsening insomnia along with tachycardia, nausea, and soft/frequent stools. TFT’s showed thyrotoxicosis (TSH <0.01 IU/ml, FT4 2.06ng/dl), and negative thyrotropin receptor (TSI and TBII) and anti-TPO antibodies. She was started on propylthiouracil. An ultrasound at 13 weeks was concerning for vanishing twin. Follow-up ultrasound at 16 weeks showed a viable pregnancy and a uterine cystic structure consistent with a molar pregnancy. Shortly thereafter she developed chest pain and shortness of breath. CT angiography showed bilateral reticular infiltrates and multiple pulmonary nodules concerning for metastasis, with high suspicion for Gestational Trophoblastic Disease (GTD). After extensive counseling, she opted for termination of the viable pregnancy and removal of the molar pregnancy. After termination, she developed acute cardiopulmonary decompensation with hypoxia, hypotension and tachycardia requiring oxygen. TFT’s at this time showed a TSH <0.01 IU/ml, FT4 2.6 ng/dl, FT3 5.8 ng/dl, hCG 109,722 mlU/mL. Respiratory status improved with supportive care. Later she underwent therapy with methotrexate for her lung metastasis which resulted in normalization of her hCG, TSH & FT4. Pathology confirmed full molar pregnancy/Gestational Trophoblastic Neoplasm. 

Hyperthyroidism due to GTD is a rare cause of hCG-mediated hyperthyroidism. hCG is structurally similar to TSH and, in the setting of trophoblastic disease, has enhanced thyrotropic activity compared to normal hCG. Severe rare complications have been reported, including thyroid storm, multi-organ failure including acute respiratory distress syndrome, and pulmonary hypertension. Treatment includes surgical removal, when possible, followed by chemotherapy: Methotrexate single agent therapy is used for low-risk disease, whereas high-risk tumors are treated with EMA-CO (etoposide, methotrexate/leucovorin, and actinomycin-D, followed by cyclophosphamide and vincristine).

Objective:-Subacute thyroiditis(SAT) is a spontaneously remitting disorder of the thyroid gland, thought to be caused by a viral infection or a post viral inflammatory process with a minimal role of autoimmunity. There is limited data about  anti-thyroid antibodies in SAT  and few previous studies have described absent or low titres of  circulating thyroid antibodies in SAT.This study was done to  determine the frequency of antithyroid antibodies at the time of diagnosis of SAT in Indian subjects.

Material and Methods:- Participants were 80  subjects (70% females)  diagnosed with   SAT and a control group of  80 age and sex matched healthy euthyroid subjects. SAT was diagnosed based on clinical findings of a painful swelling and tenderness in the thyroid gland and lab findings of  elevated FT3, FT4 with low TSH and 99mTc uptake of <1.0%. Quantitative measurements of antithyroid peroxidase antibody (Anti-TPO ) and anti-Thyroglobulin (Anti-Tg) antibody were done.

Results:-Mean age of the patients was 44.9 ± 9.7 years and BMI 27± 5.2 and controls had mean age 45.5 ± 10.1 years; and BMI 28.4± 4.9.The mean ESR was   49 mm/hour in patients and  14 mm/hour in controls (p-0.001). Anti-TPO  antibody levels were detected to be above the assay-specific cut off in 13.7% subjects and 6.2% controls (p 0.027). Anti Tg antibody was elevated in 8.7% subjects and 3.7% of controls (p-0.032). 

Discussion/Conclusion:-Subacute thyroiditis (SAT) is an inflammatory condition of the thyroid with characteristic presentations and clinical course following  a viral infection. It is generally believed not to be associated with significant autoimmunity and  the transient presence of autoantibodies  noted in the acute phase of the disease has been attributed to a virally induced autoimmune response. In this study we have found increased antithyroid antibodies levels among the subjects with SAT as compared to controls. According to some authors an autoimmune reaction is possible as the  patients with SAT often manifest HLA-Bw35. Also some recent studies  have   reported significantly  high prevalence of antithyroid antibodies in SAT patients. We suggest larger studies to confirm our findings and  consider SAT while assessing the differential diagnosis of Graves and Hashimoto disease.

Objective:

Thyroid hormones are known to have a significant effect on the cardiovascular system through cellular effects on cardiac myocytes and myocardial and vascular smooth muscle cells. It has also been stated cardiovascular complications, such as arrythmias, ischemia, and cardiomyopathy, are due to hyperdynamic status and decreased systemic vascular resistance. Incidence of cardiac complications varied between studies. We aimed to conduct a large-scale retrospective study to explore the incidence and effects of cardiovascular complications in the setting of thyroid storm.

Methods:

We utilized the National Inpatient Sample database provided by the Healthcare Cost and Utilization Project (HCUP-NIS) 2018. Variables included in this database were demographic variables (age, race, sex), admission diagnoses, procedures, and outcomes, such as inpatient mortality, length of stay, and disposition, among others. We identified patients with thyroid storm and subdivided them into patients with and without cardiac complications. Descriptive and comparative statistics were reported. Alpha value of 0.05 was used to ascertain statistical significance.

Results: 

A total of 3,475 admissions for thyroid storm were identified in 2018 in the United States. median age was 43 years with interquartile range of 31-57 years. Majority of patients were female (73.2%, n=2,545). About 52.1% of patients developed cardiac complications (n=1,810), and these patients were older (median age 48 vs 38 years, p<0.001) and more likely to be males (29.3% vs 24%, p<0.001). Cardiac arrhythmias were the most common cardiac complications (39%, n=1,355), followed by acute heart failure (16.4%, n=570), acute coronary syndrome (6.3%, n=220), and hypertensive crisis (4.9%, n=170). Inpatient mortality was higher in patients with cardiac complications (8.4%, n=140) as compared to patients without cardiac complications (1.2%, n=1660) (p<0.001). Duration of the hospitalization was longer in patients with cardiac complications (5 days, IQR 2-9) than in patients without them (3, IQR 2-6)(p<0.001).

Conclusion:

In patients who are hospitalized with thyroid storm, cardiac arrythmias were found to be the most common complication. It was also noted, patients with cardiac complications in the setting of thyroid storm had a higher mortality and hospital length of stay.

OBJECTIVE

Effects of Covid19 vaccine (authorized by the Food and Drug Administration and manufactured by Pfizer-BioNTech , Moderna) on thyroid are still not reported. We present two cases of healthy middle aged south Asian patients who developed hyperthyroidism symptoms and confirmed as subacute thyroiditis (SAR) following the administration of COVID 19  (mRNA) vaccines within 2-6 weeks. Interestingly, both of them received PfizerBioNTech vaccine

CASE 1

 A 35 year-old male with Past Medical History (PMH) of seasonal allergies with palpitations and neck pain 10 days after receiving first dose of Pfizer-BioNTech vaccine. Initial labs after 2 weeks of vaccination showed biochemical hyperthyroidism .Repeat labs trended down.

DOSE -1 : 03/26/21 , DOSE -2  : 04/18/21

TEST DATE

04/13/21 : TSH ( 0.450- 4.50uIU/mL) - 0.07uIU/mL  , Free T 4 (0.82-1.77ng/dL4) - 3.04ng/dl , TotalT3 (71 - 180ng/dl) - 200ng/dl , TPO(Thyroid Peroxidase ) - negative , TSI(Thyroid Stimulating immunog lobulin)  - negative , Thyroid Ultrasound – No nodules

04/22/21 : TSH - 0.012uIU/mL , Free T 4 - 2.11ng/dl , TotalT3- 198ng/dl

CASE 2

 A 41 year old female with unremarkable PMH was referred by Primary care physician(PCP)  for evaluation of secondary amenorrhea and infertility .She did receive her second dose of PfizerBioNTech vaccine 4 weeks prior. Initial work up confirmed biochemical hyperthyroidism. Repeat tests 4 weeks later trended down with clinial improvement of symptoms.

DOSE -1  :  12/2020  , DOSE -2  : 01 /2021

TEST DATE

02/21 : TSH-0.019uIU/mL, Free T4 - 2.52ng/dl, TotalT3- 233ng/dl

03/21 : TSH- 0.006uIU/mL, Free T4 -3.06ng/dl  TotalT3- 257ng/dl . TPO -negative , TSI - negative , Thyroid Ultrasou nd – No nodules, Technetium-99m pertechnetate uptake scan – decreased radio tracer uptake in both the lobes of the thyroid gland.

04/21  : TSH - 0.020uIU/mL, Free T 4 - 1.51ng/dl , TotalT3- 102ng/dl

DISCUSSION.

The mechanism of SAR induced by mRNA covid19 vaccine still  remains unclear

Some unique characteristics seen in this case study

-Incidence – in young and middle age group,both male and female got affected

-Ethniciity – both are of  South Asian  ethnicity

-Never had COVID infection in the past

-Seen  with both  the first dose and second dose of vaccination 

The cross recognition between the coronavirus spike protein targeted with the mRNA vaccine and healthy thyroid cell antigen exists as evidenced by this case.Hence  association of COVID vaccination with SAT should be considered as a significant addition to literature 

Accurate diagnosis and treatment of thyroidal illness depends on quality thyroid function testing. Concerns about the accuracy and reliability of current FT4 assays have been raised by the clinical laboratory community. Traceability of laboratory measurements to an accuracy basis is crucial to maintain high measurement quality.  CDC Clinical Standardization Programs (CDC CSP) address these concerns by creating a FT4 standardization program to standardize FT4 measurements. As one key component of this program, a highly accurate and precise candidate Reference Measurement Procedure (cRMP) for FT4 was developed for assigning values to serum-based materials to assist with assay calibration and verification and implement metrological traceability. 

The CDC FT4 cRMP is based on equilibrium dialysis and ID-LC-MS/MS analysis. FT4 fraction is isolated from protein-bound T4 in serum samples at 37 oC by equilibrium dialysis according to the CLSI C45-A guideline.   Collected dialysate samples with FT4 are spiked with internal standard (13C6-T4) and undergo further cleanup by solid and liquid extractions. IRMM-468 certified primary reference material (JRC, Belgium) is used for calibration. Gravimetric measurements of specimens and calibrator solutions, calibrator bracketing, isotope dilution, enhanced chromatographic resolution, and T4-specific mass transitions were used to ensure the accuracy, precision, and specificity of the cRMP. Excellent specificity is ensured by baseline chromatographic separation of T4 from potential interferents on a C18 reverse-phase column eluted with gradient mobile phase. Tandem MS analysis is performed using positive electrospray ionization and selective ion reaction.  

The CDC FT4 RMP is in excellent agreement (mean bias < 2.5%) with the only currently recognized by the Joint Committee for Traceability in Laboratory Medicine (JCTLM) RMP established by Ghent University. The CDC RMP is very precise with the intra-day, inter-day, and total imprecision within 3.3%.  The limit of detection (LOD) was 0.90 pmol/L. The measurement range is 3.02–258 pmol/L, is sufficient for analysis of hypo- as well as hyperthyroid samples.  

The proposed CDC-RMP for FT4 has been developed for optimal sensitivity, precision, and accuracy. The high accuracy and precision of the CDC-RMP enables it to serve as an accuracy basis for assays undergoing standardization. 

Objective: After the diagnosis of hypothyroidism the usual therapy is tablet levothyroxine (L-T4); once the thyroid-stimulating hormone (TSH) levels are stabilized in the normal range, it is recommended to conduct an annual testing in treated 
subjects to warrant suitable replacement.

Until now, little is known about the stability of TSH levels in hypothyroid patients (with no malabsorption issues) treated with liquid L-T4, in comparison to those treated with tablet L-T4, and with this study we intend to delve into this topic.

Methods: We enrolled patients with normal serum TSH levels at the basal evaluation, with no malabsorption or drug interference issues, who were in treatment with liquid or tablet L-T4.

Six hundred and forty eight hypothyroid patients in treatment with liquid L-T4 were compared to 324 hypothyroid subjects in treatment with tablet L-T4; both groups were matched by gender and age. The enrolled patients were followed for two years, and serum TSH, FT3, FT4 levels were measured after one and two years.

Results: The considered parameters at the first abnormal TSH value were: gender, age, body mass index, history of chronic autoimmune thyroiditis, initial TSH level, and L-T4 dose. These parameters, at the time of initial normal TSH, were not associated significantly with time to abnormal TSH values. Normal TSH values were recorded: 1) after 1 year, in 87% of the patients who received L-T4 liquid formulation, while only in 81% of patients who received tablet L-T4; 2) after 2 years, in 85% of patients administered with L-T4 liquid formulation, whereas only in 73% of patients with tablet L-T4 (p<0.05).

Conclusion: The reported findings suggest that liquid L-T4 can permit to maintain more efficiently normal TSH levels in hypothyroid patients in the long term follow-up, than tablet L-T4.

Introduction.Residual hypothyroid symptoms (RHS) in patients on levothyroxine (LT4) adjusted to normal thyroid stimulating hormone (TSH) concentrations are common. Their free T3 (FT3) concentrations are lower and the free T4 (FT4) to FT3 ratios higher than in reference populations. Adding plain liothyronine has been shown repeatedly to confer no significant benefit. A 20-year old promising slow-release liothyronine (SR-T3) preparation by Hennemann, Visser and colleagues has not been assessed for efficacy yet is readily available from compounding pharmacies for use in clinical practice.

Description of Cases. At their request34 women and 6 men with RHS on LT4 at normal TSH levels were prescribed 5 mcg SR-T3 to be taken at the same time as LT4. The dose was increased monthly by 5 mcg until FT3 modal reference range concentrations were reached. RHS, body weight and thyroid indices were measured monthly. No patients experienced adverse effects.

In 9 patients lipid profiles became serendipitously available through orders by their referring physicians.  

The mean RHS fell 83% (p<0.025, range 50-93%), the weight by 2.3 kg. The FT3 increased 22% from 4.1 to 5.0 pmol/L (p<0.001) on an average of 19.5 (range 5 –50) micrograms per day of SR-T3. There were no significant changes in FT4 or TSH. The mean FT4/FT3 ratio decreased from 4.0 to 3.3 (p<0.001). 

In the lipid subgroup of 9 patients the mean (95% Confidence Interval) total cholesterol decreased 12.6% (-36–-11) from 5.6 to 4.9 and the LDL-cholesterol fell 19.2% (-56 –-17) from 3.5 to 2.6 mmol/L, with no significantchanges in HDL-cholesterol and triglycerides. In this subgroup FT3 concentrations increased 33% (11 –50), FT4 levels fell 8.4% (-29 –7.7) from 19.2 to 16.7 pmol/L. The TSH fell 77% (-93 –-43).

Discussion.These cases show that adding SR-T3 to LT4 in hypothyroid patients with RHS caused a marked clinical improvement, normalized their thyroid hormone profiles and significantly decreased total and LDL cholesterols, with no negative effects. It demonstrates the feasibility of mimicking the normal thyroid hormone milieu and emphasizes the urgency for efficacy studies to create a new paradigm for treating hypothyroidism.

Introduction/Objectives:

Hypothyroidism has been associated with adverse surgical outcomes, including excess intra-operative bleeding and post-operative atrial fibrillation. However, it remains uncertain whether the diagnosis of hypothyroidism is associated with worse hospital outcomes following surgery. Therefore, we compared hospital outcomes (in-hospital mortality, length of stay (LOS)) between those with and without hypothyroidism following two distinct types of surgery: hip replacement and organ transplant. 

Methods:

This was a cross-sectional study of a large US hospital claims database of adult patient admissions for either organ transplant (heart, lung, liver, kidney) or hip replacement from January 1, 2008 to December 31, 2015 (n = 197,468). Hypothyroidism was determined based on diagnosis code and/or the prescription of thyroid hormone replacement. Propensity score matching was utilized to create a hypothyroid and matched control group within the two surgical populations. Hypothyroid patients were matched on gender, age, region of US, year of admission, Charlson comorbidity index, transplanted organ, and type of hip replacement.

Results:

Hypothyroidism was identified as a diagnosis in 22979 admissions (11.6%). In total, patients with hypothyroidism accounted for an excess of 4505.3 hospital days over the study period. In the unmatched analysis, patients with hypothyroidism had excess in-hospital mortality (0.085% versus 0.044%, p = 0.02) and longer LOS (2.87 versus 2.73 days, p <0.001) following hip replacement. Patients with hypothyroidism had longer LOS following organ transplant surgery (12.7 versus 11.8 days, p = 0.042). In the propensity score-matched analysis, average LOS remained higher (2.87 versus 2.77 days, p <0.001) and mortality was greater (0.085% versus 0.040%, p = 0.040) in patients with hypothyroidism receiving hip replacement surgery. After matching, differences in LOS were similar in patients with and without hypothyroidism following organ transplantation. No differences in in-hospital mortality were present following organ transplant in unmatched or matched analyses.

Discussion/Conclusion:

Hypothyroidism was associated with excess in-hospital mortality and increased length of stay following hip replacement surgery. Hypothyroid patients should be informed of the incrementally increased mortality risk prior to hip replacement surgery, although the overall risk remains small.  

Background and Objective: The clinical feasibility of heart rate (HR) monitoring using wearable devices in subjects with thyrotoxicosis has been demonstrated, but the association of HR monitored by wearables with hypothyroidism has not been examined.

We assessed the association between serum thyroid hormone concentration and three HR parameters measured by a wearable device (WD-HR parameters) in hypothyroid subjects.

Methods: Forty-four subjects scheduled for radioactive iodine therapy (RAI Tx) after thyroid cancer surgery were included in this single-center, prospective observational study. Thirty subjects were prepared for RAI Tx by thyroid hormone withdrawal (hypothyroidism group) and 14 subjects by recombinant human thyrotropin (control group). Participants used the wearable activity/HR tracker during the study period. Three WD-HR parameters were calculated from the HR data collected during rest, during sleep, and from 2 a.m. to 6 a.m., respectively. We analyzed the changes in conventionally measured resting HR at a clinic visit (On-site rHR) and WD-HR parameters relative to thyroid hormone levels.

Results: Serum free T4 levels, On-site rHR, and WD-HR parameters were lower in the hypothyroid group than in the control group at the time of RAI Tx. A decrease in On-site rHR and WD-HR parameters by one standard deviation (On-site rHR, ~12 bpm; WD-HR parameters, ~8 bpm) was associated with a 0.2 ng/dL decrease in free T4 levels (p < 0.01) and a 2-fold increase of the odds ratio of hypothyroidism (p < 0.01). WD-HR parameters displayed a better goodness-of-fit measure (lower quasi-information criterion value) than On-site rHR in predicting the hypothyroidism.

Conclusion: This study identified WD-HR parameters as informative and easy-to-measure biomarkers to predict hypothyroidism.

Thyroid storm is an acute life-threatening condition caused by severe thyrotoxicosis, with an incidence of 0.57 to 0.76 per 100,000 persons per year in the US. Standard treatment includes thionamides, iodine solution, bile acid sequestrants, hydrocortisone, and beta-adrenergic receptor blockers. However, plasmapheresis can be used as an alternative treatment when standard treatment cannot be used due to side effects or inefficiencies.  

A 31 year-old African American female with history of Graves’ disease and medication non-compliance was admitted with two-week history of chest pain and palpitation. Initially found to have SVT with pulse 180 bpm in ER. She was given Adenosine without improvement, followed by propranolol, which subsequently resulted in hypotension requiring pressure support. She was found to have elevated free T4 of 3.02 pg/ml, free T3 of 4.03 pg/ml with suppressed TSH of < 0.01 uIU/ml. Treated with Decadron, Methimazole, Lugol and Propranolol. Following her morning dose of Propranolol, she developed asystole. The code lasted 7 minutes and patient required intubation. She was then switched to IV Hydrocortisone 100 mg q 8 h, PO PTU 200 mg q 4 h, and Lugol 10 drops q 8 h. Later found to have marked transaminitis after cardiopulmonary arrest. Given severe acute liver injury, PTU was discontinued, leaving treatment options limited. Decided to start plasmapheresis once a day for total of 3 days; which resulted in normalization of Free T4 and Free T3.Thyroidectomy was then safely performed without incident. Subsequently, she required levothyroxine for post-surgical hypothyroidism and was discharged in stable condition. 

 Although rare, thyroid storm has a high rate of in-ICU mortality; with multiple organ failure and cardiogenic shock greatly impacting prognosis. Current guidelines recommend individual decision making when using plasmapheresis. Given the need for prompt and aggressive management, and the dramatic improvement with plasmapheresis, this treatment method should be considered earlier in the course of thyroid storm.

Objective. Hypothyroidism is one of the most common endocrine disorders in the United States. It constitutes a significant clinical burden, as it affects the management and progression of other medical conditions. Therefore, we examined the prevalence, national trends of hospitalization, and mortality in patients with hypothyroidism.

Methods. We utilized the Nationwide Inpatient Sample (NIS) database from 2016 to 2018 of patients aged 18 and older. Primary and secondary diagnoses of hypothyroidism were identified with ICD 10 codes. In addition, population estimates obtained from the United States Census data were used to study trends in adult hypothyroidism, reasons for hospitalizations, and in-hospital mortality.

Results. There were 10,561,234 hospitalizations for patients with hypothyroidism from 2016 to 2018, out of which 16,665 (0.15%) were primary diagnosis and 10,544,569 (99.85%) were secondary diagnosis. The annual hospitalization rates for the primary diagnosis of hypothyroidism increased from 21.7 admissions per million in 2016 to 22.9 per million in 2018. The increase in the annual rates of primary diagnosis of hypothyroidism was more prevalent among the 55-74 age groups and predominantly females. The hospital mortality rate increased from 1.6% in 2016 to 2.2% in 2018 with the primary diagnosis of hypothyroidism. Among hospitalized patients with any primary diagnosis and secondary diagnoses of hypothyroidism, the mortality rate declined slightly from 2.5% to 2.4%. We identified primary reasons for hospitalizations in patients with the secondary diagnosis of hypothyroidism as sepsis, congestive heart failure, osteoarthritis, myocardial infarction, and pneumonia.

Conclusion. Our results highlighted changes in the hospitalization rates in patients with hypothyroidism over the past few years. The increased mortality rate in hypothyroidism patients suggested that proper management of thyroid function is crucial to improve survival. It emphasizes the importance of medical attention to thyroid function correction in hospitalized hypothyroidism patients. 

Objective: The objective of the meta-analysis was to evaluate the performance of Gene Sequence Classifier (GSC) and ThyroSeq V3 (ThyroSeq) in the diagnosis of thyroid nodules with indeterminate fine-needle aspiration biopsy results.

Methods: This systemic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. We searched PubMed, Google Scholar, Scopus, and Cochrane Library for studies published between January 2017 and March 2021. Keywords included a combination of “Thyroid nodule” AND “gene sequencing classifier” OR “ThyroSeq v3.” Inclusion criteria were indeterminate thyroid results via FNA that included Bethesda categories III and IV, use of Afirma GSC and Thyroseq V3 as an index test, and conclusive histopathological results. Studies with no postsurgical diagnoses were excluded. For each included study, sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) with 95% confidence intervals based on the exact binomial Clopper-Pearson method were calculated. Sensitivity and specificity were pooled jointly using a bivariate binomial random-effects model. A p-value less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed by using R, version 4.0.2.

Results: Our search yielded 431 non-duplicate articles, of which 13 were included in the study (7 GSC, 6 Thyroseq V3). Pooled data for GSC studies on 472 thyroid nodules showed a sensitivity of 96.6 (95 confidence interval= 89.7-98.9%), specificity of 52.9% (23.4-80.5%), PPV of 63% (51-74%), and NPV of 96% (94-98%). Pooled data for ThyroSeq studies on 530 thyroid nodules showed a sensitivity of 95.1% (91.1-97.4%), specificity of 49.6% (29.3-70.1%), PPV of 70% (55-83%), and NPV of 92% (86-97%). There was no statistically significant difference in diagnostic performances of the two tests (p-values for sensitivity=0.89, specificity=0.82, PPV=0.43, NPV=0.17).

Discussion/Conclusion:  High sensitivity and NPV in both GSC and Thyroseq V3 may help rule out malignancy among thyroid nodules with indeterminate cytology results. In addition, no difference in diagnostic performances between the two molecular tests indicates that either test is appropriate to determine the malignancy of thyroid nodules. However, further long-term outcome data are warranted to make a clear recommendation.

Introduction

Anaplastic carcinoma is the most aggressive form of thyroid malignancy. The common presenting features includes a patient who had a long standing thyroid mass with abrupt increment of size and palpation revealed a a firm and  stony hard mass. The treatment for anaplastic carcinoma has been a controversy as this type of cancer are refractory to surgery, chemoradiation, or radio iodine ablation. In elderly patient, the treatment is mostly conservative. The surgery is only indicated for airway establishment in the form of tracheostomy.

Description of the Case

We highlight two cases of anaplastic carcinoma. Both cases were female patients who presented with thyroid mass associated with difficulty in breathing and dysphagia. The first case had thyroidectomy with partial sternotomy and tracheostomy, as the initial FNAC points toward papillary thyroid carcinoma. Post operatively, patient was complicated with poor wound healing and her post operative tissue HPE came back as anaplastic carcinoma. She was on regular follow up for neck wound dressing and finally succumbed to the disease at 8 months post surgery. The second case, was a lady presented with sudden increase of the thyroid mass associated with hoarseness. She had worsening breathing difficulty that necessitate tracheostomy despite her inconclusive FNAC. Post tracheostomy, her FNAC result came back as papillary carcinoma with anaplastic transformation. Due to her medical comorbidities, the treatment was conservative.

Discussion.

Anaplastic carcinoma commonly affecting elderly patients with longstanding of thyroid swelling in our local patient population in Malaysia. The prognosis is poor with survival is 6 -12 months post diagnosis. The issue of surgery is critical as need to be meticulously considered by the treating clinician. Airway obstruction necessitate early tracheostomy. If patient had significant dysphagia and stridor, the thyroidectomy relieved these compressive symptoms but with the risk of poor wound healing, especially if patient having medical comorbidities. Selected group of patient who is not a surgical candidate may be offered palliative radiation but at the expense of radiation-related complications. This can be offered to patient with the agreement of immediate family members, if they were hesitant for the 'do nothing' or TLC approach

Introduction: Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare malignant tumor of the thyroid gland. It is believed to arise from thymic tissue or branchial pouch remnants showing thymic or branchial pouch differentiation. Besides its reported slow growing rate, its diagnostic importance lies in its representative metastatic potential. Fewer than 50 cases have been reported around the globe. Herein, we report one case of SETTLE. 

Description of Case: A 24-year-old male with no significant medical history and no risk factors for thyroid cancer, was admitted to the head and neck department complaining of a rapidly growing neck mass. Physical examination revealed a 4.2 x 5.4 cm, hard, painless, and immobile mass in the anterior neck. A complementary ultrasonography showed a 4.1 × 3.2 cm left lobe mass with solid and cystic components. Fine-needle aspiration biopsy of the nodule was compatible with undifferentiated carcinoma with spindle cells Bethesda VI. Therefore, before operating on the patient, a whole-body CT was ordered. It confirmed a thyroid mass raising from the left lobe of 5.3 x 4.3 x 4.3 cm comprising the trachea with some cervical lymph nodes up to 1 cm. There was no evidence of distant metastasis. In light of rapidly progressive obstructive symptoms the patient underwent total thyroidectomy with central (2/6 positive) and left lateral (14/14 negative) lymph node dissection. The patient was uneventfully discharged on postoperative day 1. No radiotherapy was planned. To confirm the suspected SETTLE, histopathology and immunohistochemistry were performed (positive for cytokeratin, CD99, TTF-1, and smooth muscle actin). The analysis confirmed the diagnosis of SETTLE in the left lobe of this patient’s thyroid. 

Discussion: To the best of our knowledge, this is the first Ecuadorian patient being diagnosed with SETTLE. Although SETTLE is a very rare neoplasm of the thyroid, physicians should include this entity as a differential diagnosis. Our patient’s tumor was detected and treated timely. However, we set up a strict follow-up as there is not enough evidence about SETTLE and its natural history.

MEN1 usually presents with parathyroid, pituitary, and/or pancreatic islet cell tumor/hyperplasia. Papillary Thyroid Cancer (PTC) is not classically associated with MEN1 as it is more associated with BRAF, RAS (NRAS being the most common of the RAS mutations), and receptor tyrosine kinase (RET) mutations. Previous studies of the two describe no correlation in their occurrence. Of the case reports written, all patients phenotypically expressed the MEN1 mutation while only incidentally having PTC. We present a case of NRAS positive PTC with distant metastasis to brain, pelvis and lung who was incidentally found to have a MEN1 mutation. 

A 43-year-old female Iranian immigrant presented with a history of thyroid cancer for which she underwent total thyroidectomy five years prior while living in Iran. Family history was limited. Upon initial presentation, her chief complaint was pain in her back, hips, and hands that made it increasingly difficult for her to walk/stand/sit. Labs were obtained revealing a TSH of 0.011, free T4 1.76, thyroglobulin markedly elevated at 1934, and a thyroglobulin antibody<1.8.  PET CT revealed at least six right lung nodules and four left lung nodules. A CT guided lung biopsy was performed and findings were in keeping with metastatic papillary thyroid carcinoma. A whole body I-131 scan revealed avid radioiodine uptake in multiple brain metastasis, both lungs, as well as destructive sacral osseous metastasis. Genetic testing of biopsy was performed and revealed mutations in MEN1 and NRAS, though she had no other features of MEN1. 

Given the diffuse metastatic nature of her cancer she was treated palliatively with radiation for her bone metastasis, and dexamethasone for metastatic brain lesions. To this date this is the first case report of MEN1 with no parathyroid abnormalities and diffusely metastatic papillary thyroid cancer.

Introduction

  The treatment benefits of antiangiogenic multi-kinase inhibitors (MKIs) are mainly confined to limited progression-free survival for differentiated thyroid cancer (DTC) patients who are refractory to radioiodine (RAIR) with progressive status, and disease will finally progress someday. With an aim to look for an effective option for RAIR-DTC, we innovatively commenced an exploratory phase II clinical trial combining antiangiogenic MKI, apatinib, and anti-PD-1 antibody, camrelizumab, in progressive RAIR-DTC patients (ClinicalTrials.gov Identifier: NCT04560127), and reported the response of a patients during the treatment.

Description of the Case

  A 43-year-old man diagnosed as follicular thyroid cancer (FTC) with metastases in lungs, the 7th cervical vertebra and malignant lymph nodes mainly in the mediastinum, was identified as RAIR due to the non-RAI-avidity over pulmonary metastases. After disease progression in an antiangiogenic phase III clinical trial of donafenib (2.0 months with placebo and 8.5 months crossed to the experimental group), followed by a 4-week donafenib discontinuation, he was enrolled into the trial with 250 mg apatinib orally once daily and 200 mg camrelizumab intravenously once every 2 weeks in a 4-week cycle. The patient was evaluated every cycle in the first 2 cycles and every 2 cycles thereafter. A new lesion was identified in the apical segment of the right lung by CT imaging after one cycle’s treatment with other lesions kept stable. Considering the possibly delayed action of anti-PD-1 therapy and no adverse events observed, the regimen was continued without other intervention. Upon the 6 cycles’ assessment, the new lesion significantly shrank and cavitated, and the other metastases kept stable.

Discussion

  Apatinib in combined with camrelizumab might be a salvage therapy for RAIR-DTC patients, especially for those who failed to antiangiogenic intervention, and its efficacy is worth time to wait.

Introduction:

Several molecular tests for thyroid nodules with indeterminate cytology are available commercially, but the extent of their validation differs. Diagnosis of Hurthle cell carcinoma (HCC) requires testing for copy number alterations (CNA) and TERT and TP53 mutations, which is not present in all panels.  We report a case of HCC assessed by two molecular techniques.

Description of the case:

A 78 year old female was found incidentally to have a 2.8 cm left thyroid nodule. Ultrasound-guided cytology was classified as Bethesda III and ThyGeNEXT/ThyraMIR molecular results detected no mutations but showed a positive microRNA classifier with a cancer risk estimated at 15-20%.  Six months later the nodule was enlarging, and the patient was referred to a multidisciplinary center where on ultrasound it was 4.2 cm, TI-RADS 4, where the initial cytology was recharacterized as Bethesda IV with atypia bordering on Bethesda V.  The patient agreed to left lobectomy revealing a bulging lobar mass adherent to the esophagus, jugular vein and thymus, that was resected en bloc.  On pathologic examination, 4.8 cm tumor showed ETE and consisted predominantly of poorly differentiated carcinoma (PDTC), with ~10% anaplastic (ATC) and ~10% well-differentiated HCC.  PET/CT showed nonspecific FDG-avidity in the thyroid bed without distant uptake, and the patient is proceeding with chemoradiation and RAI.

Thyroseq v3 molecular studies on the resection specimen showed multiple CNA and a TP53 mutation in the HCC component, and multiple CNA, TP53 and VHL mutation in the PDTC and ATC component. Performed by scraping lesional cells from the glass slide, Thyroseq v 3 analysis on the original cytology smear demonstrated the same high-risk signature:  TP53 RI58H mutation at 86% AF, high level genome haploidization type CNA, and chromosome 7 MET amplification.  Clonal evolution analysis of sequencing data from different tumor areas confirmed TP53-p.RI58H as an early and VHL-c.463+2T>A as late events in HCC-to-ATC progression.

Discussion:

In this interesting case, ThyGeNEXT/ThyraMIR testing failed to identify an aggressive thyroid cancer.   Tumoral phylogenetic analysis suggests that early identification and resection of HCC carrying aggressive genetic markers like TP53 may prevent progression to anaplastic thyroid cancer.

Introduction

Pre-operative diagnosis of follicular thyroid carcinoma (FTC) is extremely difficult because the diagnosis of FTC depends on histopathological vascular or capsule invasion which cannot be observed in fine-needle aspiration cytology. Through a visualized and quantitative QCIGISH method, epigenetic imprinted genes biomarkers have shown their ability to distinguish benign and malignant tissues in ten tumor types including thyroid tumor. However, whether the imprinted gene biomarkers can be used for the presurgical diagnosis of FTC has not been tested yet.

Description of the case

We report a case of a 45-year-old male patient with enlargement of right neck and physical examination revealed thyroid nodule for one week. The ultrasound revealed a TR5 nodule according to American College of Radiology (ACR) thyroid imaging reporting and data system (TI-RADS) and recommended fine-needle aspiration for further examination. The fine needle aspiration cytology (FNAC) revealed indeterminate result, while epigenetic imprinted genes showed high level of aberrant expression which predicted a malignant result. A subtotal thyroidectomy of the thyroid tumor was undertaken. Intraoperative frozen section diagnosis was follicular neoplasm, and the paraffin section pathology indicated follicular thyroid cancer and follicular variant of papillary thyroid microcarcinoma of the right lobe. 

Discussion

Hence, epigenetic imprinted genes biomarkers might be helpful for the detection of malignant tumors of thyroid, and helpful to distinguish FTC from follicular thyroid adenoma. Further study has been carried out to develop an imprinted gene model for follicular thyroid tumors diagnosis, which could help the clinicians make proper treatment decisions.

Introduction

The principle treatment for thyroid malignancy is surgery. In selected cases however, oncology treatment is a viable option as the tumor is inoperable. The indication of oncology versus surgery as a treatment choice should be considered based on patient's factors, tumor's factors, expertise and logistic factors.

Case Description.

Two cases of extensive thyroid malignancy are highlighted. First case is a middle age Malay male who presented with a gross thyroid mass with multiple skin nodules. CT scan of the neck showed heterogenous thyroid mass which abutting the carotid sheath. The FNAC of skin nodules confirmed metastatic carcinoma. Patient was deemed inoperable and he was referred to oncology team for chemoradiation. Patient received 3 cycles of chemotherapy and the skin nodules were regressing. Second case, is a middle age patient presented with thyroid mass associated with sternal mass and periorbital mass. After CT scan assessment, he also deemed inoperable and was referred for oncology treatment. Patient defaulted oncology follow up and re presented to medical unit with massive pleural effusion and necessitate chest tube insertion and drainage. He again was reviewed by oncology team and was planned for re stage CT scan and kiv chemotherapy.

Discussion.

In selected cases of thyroid malignancy, clinicians need to meticulously considered the risk and benefit of the surgery versus the oncology treatment. A detailed characteristic of tumor and its extension, patient's general condition and comorbidities and the availability of expertise and facilities should be taken into consideration when deciding the best optimal treatment for the patients. Some patient might be benefited from the chemoradiation, even though it still can be operated in a highly trained hand. Patient's factor like financial status, family support and other logistic issues also contribute significantly to the overall comprehensive thyroid patient's management.

Background

Existing studies have indicated that the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) has prognostic as well as diagnostic values for differentiated thyroid cancer (DTC). We have found that race may exert significant influence on the frequency of aggressive histologic features (extra-thyroidal extension, lymphovascular invasion, and margin involvement) and lymph node metastasis in DTC. In this study we examined the influence of race on the prognostic values of the BSRTC. 

Method

We conducted a retrospective chart review of endocrine surgery patients seen between 2013 and 2020 who 1) underwent pre-operative fine-needle aspiration (FNA) of thyroid nodules; 2) subsequently underwent thyroid surgery and 3) had malignancy found on surgical pathology.

Results

Of the final analysis of 1,057 patients, the mean age was 49.5±14.8 years, 75.4% were women, and 21.2% were Black. Approximately half (47.6%) of the patients had Bethesda VI on pre-operative FNA. Black patients had more Bethesda II nodules (Blacks 29.9% vs non-Blacks 11.2%) and fewer Bethesda VI nodules (Blacks 25.9% vs non-Blacks 53.7%) compared to non-Black patients (overall p<0.001). Classic variant of papillary thyroid cancer was more common among Bethesda V and VI nodules (p<0.001). The frequency of aggressive histologic features, overall lymph node metastasis, and lateral neck involvement were positively associated with the increasing severity of the BSRTC (p<0.05). No significant difference was found in the frequency of aggressive histologic features between Blacks and Non-Blacks across BSRTC.  However, Blacks had lower rates of lymph node metastasis in the indeterminate (Bethesda III and IV combined, 1.4% Blacks vs 9.3% non-Blacks, p=0.02) and malignant (Bethesda V and VI combined, 31.3% Blacks vs 47.3% non-Blacks, p=0.005) nodules. A similar pattern observed in Bethesda II nodules did not reach statistical significance (1.5% Blacks vs 5.3% non-Blacks, p=0.32).

Conclusions

In our patient population, thyroid nodules within indeterminate and malignant BSRTC categories in Blacks had lower rates of lymph node metastasis compared to non-Blacks, but exhibited no differences in the benign category or in the frequency of aggressive histologic features. These observations suggest that race as well as BSRTC may provide guidance for the extent of surgery for thyroid nodules. 

OBJECTIVE: The ATA Pediatric Guidelines recommend children with Papillary Thyroid Cancer (PTC) undergo staging 12 weeks after initial surgery. The staging algorithm advises measurement of a TSH-suppressed serum thyroglobulin (suppTg) in ATA Pediatric Low-Risk patients and a TSH-stimulated thyroglobulin (stimTg) coupled with a diagnostic whole-body scan in Intermediate- and High-Risk patients to assess for residual disease. It would be helpful to garner staging information sooner than 12 weeks postoperatively, to aid in determining whether radioactive iodine is warranted. With a half-life of 3 days, Tg should, theoretically, decline rapidly in the absence of residual PTC, to a low or even undetectable level within several weeks of surgery. In our practice, children with PTC are seen ~2 weeks after surgery and have a TSH and thyroglobulin panel drawn. This study investigates whether an early postoperative Tg level correlates with ATA Pediatric Risk category and/or recurrence.

METHODS:  Retrospective analysis on patients <21 years of age who underwent surgery for PTC from 2011-2020 and had a thyroglobulin measured within 35 days of the operation. Patients with a positive Tg antibody titer were excluded.  Postoperative Tg levels were analyzed based on ATA Pediatric Risk category and recurrence over time.

RESULTS: 27 patients met inclusion criteria (13 Low, 8 Intermediate, and 6 High-Risk). High-Risk patients had a significantly higher median postoperative Tg (33.25 ng/mL, range 0.45-414.0). compared to Low Risk (3.35 ng/mL, 0-15.05 ng/mL) (p=0.05). Serum Tg significantly correlated with ATA Risk category (p=0.049).  Tg in all Low-Risk patients declined to <1 ng/mL by 160 days postoperatively. There were 5 recurrences over a median follow up of 55.9 months (range 11.1-94.9). All who recurred had an initial postoperative suppTg >5 ng/mL. The area under the curve for the ROC for the suppTg and recurrence was 0.833.

CONCLUSIONS: Our data suggest that an early postoperative serum Tg correlates with extent of disease. A lower postoperative Tg (<5 ng/mL in our series) may correlate with a lower risk for recurrence. Analysis of a larger sample is needed to determine the specific Tg level to use for decision-making regarding RAI treatment.

Objective:

To analyze the rates of biochemical remission and locoregional recurrence and morbidity after revision surgery for papillary and medullary thyroid carcinoma.

Methods:

This is a single institution retrospective chart review study of patients undergoing revision surgery for locally recurrent papillary (PTC) or medullary thyroid carcinoma (MTC) from 2004 to 2020 with intraoperative neural monitoring (IONM). Primary outcomes are incidence of surgical complications, biochemical remission (BCR) rates and disease-free survival.  

Results:

Among 239 cases meeting inclusion criteria for this study, 33.9% of patients presented for their second or more revision surgery. The majority of patients (95%, n=227) presented with recurrent PTC and 12 patients (5%) presented with recurrent MTC. Preoperative vocal cord paralysis (VCP) was present in 26 patients (10.9%) while 29 patients (12.1%) had permanent preoperative hypocalcemia. Following surgery, 3 new patients (1.2%) developed permanent VCP due to recurrent laryngeal nerve (RLN) invasion by the tumor; 10 patients (4.2%) and 13 (5.4%) developed temporary and permanent hypocalcemia, respectively. In 37.2% of patients with PTC, a BCR was achieved after the final revision surgery with undetectable postoperative Tg levels. The mean Tg level was 50.5 ng/ml preoperatively and 20.9 ng/ml postoperatively (P = 0.003, paired t test), representing a mean decline of 78.4%%. There was no statistically significant difference in the calcitonin level preoperatively compared to the level after revision surgery, but the sample size (n=12) in this subset is perhaps too small to detect such a difference. The rate of cervical nodal recurrence and distant metastasis was 6.7% (n=16) and 7.1% (n=17) at a median follow-up of 3.2 years. There were no thyroid cancer-related deaths during the study period.  

Discussion/Conclusion:

In experienced hands, revision surgery with IONM for recurrent PTC or MTC can result in high biochemical remission rates and prolonged disease-free survival with limited morbidity even among patients with advanced age who have undergone multiple prior reoperations.

Objective: Molecular testing (MT) of thyroid nodules with indeterminate cytology on FNA can help guide management decisions such as surgery or surveillance. The presence of certain BRAF-like and RAS-like mutations confers high risk of malignancy and usually results in a recommendation to undergo surgery. However, low-risk (LR) or low-level mutations alone may not be sufficient for full cancer development and can be expected to carry a much lower risk of NIFTP or typically indolent cancer. The aim of this study was to analyze the clinicopathologic features and surveillance outcomes of nodules with LR mutations.

Methods: Between 11/2017 and 12/2020, 216 consecutive cases of thyroid nodules from one institution that yielded a “currently negative” result on ThyroSeq v3 testing due to LR mutations were identified. Retrospective review was performed to collect data on surveillance and surgical outcomes.

Results: In total, 216 nodules were identified in 215 patients. 234 molecular alterations were identified, most commonly EIF1AX (25%), PTEN (20%), TSHR (13%) or low-level RAS (10%) mutations, and copy number alterations (19%). 93 (43.3%) patients had ultrasound surveillance, and at 5-42 months follow-up (mean 24) only 7 (7.5%) patients had a clinically significant increase in size of whom none underwent surgery. 16 patients (7.4%) had repeat FNA, none with malignant cytology. 39 patients (18.1%) underwent surgical removal of nodules, of which 10(25.6%) were malignant or NIFTP, representing 4.6% of LR mutation nodules.  Although these included 4 papillary carcinomas, 4 Hurthle cell carcinomas and 2 NIFTP, 9/10 (90%) were histologically ATA Low Risk cancers, and 6 had low-level RAS mutations. Malignant nodules were more likely than benign nodules to have Bethesda IV cytology (50% vs 17.2%, p=0.087) and an ultrasound TIRADS 4/5 score (70% vs 41.4%, p=0.155).

Conclusions: Most nodules with a ThyroSeq v3 MT result reported as “currently negative” did not grow in short-term follow-up, and if resected yielded a cancer/NIFTP rate of 4.7% which was usually an ATA Low Risk cancer. The findings suggest that surveillance is an acceptable approach for indeterminate thyroid nodules with LR mutations, among which nodules that carry low-level RAS mutations may need closer surveillance.

Objective: Papillary thyroid microcarcinomas (PTMC) are frequently incidental, remain mostly indolent and have an increasing incidence worldwide. The aim of this study was to identify predictive factors for the incidental occurrence of PTMCs in patients undergoing total thyroidectomy for presumed benign pathologies.

Methods: We retrospectively reviewed the 2395 records of patients who underwent total thyroidectomy at Cliniques Universitaires de Bruxelles –Hôpital Erasme between 2001 and 2019. A total of 1591 patients were enrolled and divided in two groups: incidental PTMC group (N=127) and benign (control) group (N=1464). Clinical, biological, histological and molecular biology data were analyzed for all patients.

Results:  Univariate analysis revealed that the median thyroid volume measured by ultrasound was significantly lower in the PTMC group in comparison with the control group (33.35cm3 vs. 40cm3, p<0.02), while the median preoperative serum Thyroid-stimulating hormone (TSH) was significantly higher in the PTMC group (0.89mU/L vs. 0.71mU/L, p<0.001). The detection of circulating anti thyroid antibodies (anti TPO-Abs and/or anti Tg-Abs) and the presence of histological lymphocytic thyroiditis were both significantly more frequent in the PTMC group than in the control group (25.4% vs. 17.3%, p=0.036 and 46.4% vs. 31.8% p<0.001 respectively). In multivariate analysis, histological thyroiditis (OR=1.693, 95% CI: 1.170 - 2.450, p=0.005) and preoperative serum TSH (OR=1.206, 95% CI: 1.034 - 1.406, p=0.017) were identified as independent risk factors for the incidental finding of PTMC. Molecular biology data were available for a total of 56 PTMC patients of our cohort. In presence of anti TPO-Abs/anti Tg-Abs and/or histological thyroiditis we observed a decreased rate of BRAF^V600E positive mutation finding, without however reaching a statistical significance.

Conclusion: Higher serum TSH and presence of histological lymphocytic thyroiditis were associated with an increased risk of finding an incidental PTMC during total thyroidectomy. Prospective studies are also required to validate these findings and to determine whether they are associated with differences in PTMC's clinical progression.

Objective

This study describes health related quality of life (HRQOL) outcomes in adolescents and young adults (AYAs) treated for differentiated thyroid carcinoma (DTC) and identifies risk factors affecting HRQOL.

Methods

AYAs (n=46) aged 11 to 21 years with DTC at least 6 months status post total thyroidectomy enrolled in this IRB approved prospective, cross-sectional study at a free-standing children's hospital. All AYAs/caregivers provided informed consent/assent according to age and institutional guidelines. The PedsQL 4.0^TM, a validated, age-appropriate HRQOL questionnaire, was completed by AYAs and caregivers (for youth <18 years of age).  Demographic data, tumor characteristics, treatment history and complications were obtained via systematic chart review. We aimed to 1) compare AYA HRQOL to historical controls, 2) compare AYA and caregiver HRQOL reports, and 3) evaluate potential predictors of HRQOL outcomes (sex, age at diagnosis, ATA class, cancer stage, I131 treatment, TSH level, and hypoparathyroidism). 

Results

There were 14 males/32 females with median age at diagnosis of 14.5 years and median duration follow up of 3.3 years. Diagnoses included papillary carcinoma (n=40, 87.0%), follicular carcinoma (n= 5, 10.9%), and Hurthle cell carcinoma (n=1, 2.2%). 34 were stage 1 and 12 were stage 2. Most had a single thyroid cancer surgery; 15 AYAs (32.6%) required multiple surgeries. Radioactive iodine was previously administered to 37 (80.4%). Hypoparathyroidism was present in 9 (19.6%). 

AYAs and their caregivers reported significantly lower HRQOL than healthy historical controls [PedsQL Self-Report Total Score M=77.8 (p=0.03); PedsQL Proxy Total Score M=72.2 (p=0.04)]. Caregivers reported significantly lower HRQOL by proxy than AYAs by self-report (p<0.01). There was a trend toward lower HRQOL in AYAs with prior radioactive iodine and those with hypoparathyroidism in univariate analysis (p<0.10).

Discussion/Conclusion:

While several studies have described HRQOL and evaluated risk factors for decreased HRQOL in adult DTC patients, pediatric outcomes are not well described. Pediatric DTC patients experience lower HRQOL compared to healthy peers. As with many pediatric cancers, caregivers report lower HRQOL by proxy-report than do patients themselves. Additional research is needed to determine why pediatric DTC survivors experience adverse HRQOL and to develop interventions aimed at improving outcomes.

Introduction

Thyroid cancer occupies the 9^th position of global cancer incidence and in Panama is the 8^th most frequent malignancy. It is usually diagnosed in females between 35 to 65 years old, presenting papillary carcinoma as its most common histopathology. Unlike other cancers, it has shown an increase in incidence through the last decades and there is no published data of thyroid cancer(TC) in Panamanian population to this date.

Methods

A descriptive study was performed, acquiring data from medical records of the National Cancer Institute (NCI) of Panama. Sociodemographic, diagnosis, staging and treatment of TC aspects were evaluated. All patients with diagnosis of TC treated in the institution from January 2013 to December 2018 were included, this represented 794 records of which 707 were eligible. Data tabulation and statistical analysis were carried out using Microsoft Excel 2019 © and SPSS©. 

Results 

Eighty six percent were female and the mean age was 47  15 years. The most frequent histopathology was papillary (94%) followed by follicular (3%), medullar (2%) and anaplastic (1%). At the time of diagnosis, 47% presented localized disease to the thyroid, 45% regional lymph nodes involvement and 8% with distant metastasis. The treatment provided most frequently was total thyroidectomy (83%), followed by radioiodine ablation (64%), unilateral thyroidectomy (11%), neck dissection (16%), and other therapies such as chemotherapy and radiotherapy represented 8%. The majority of the patients (75%) were initially treated surgically in another institution and referred to the NCI. The median overall survival was 631 days (CI 95% = 164 – 1097)

Conclusions 

Approximately 120 subjects are treated each year for thyroids cancer at our institution. Predominantly female, between 32 and 62 years old with papillary histology. Distant metastasis was diagnosed in 8% of the cases, with a 93% 5-year Overall Survival (OS).  

Objective: Uptake of the I-131 in differentiated thyroid cancer (DTC) patients undergoing radioactive iodine ablation (RAIA) can be augmented by TSH stimulation using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH). A low iodine diet (LID) is advised prior to ablation to further increase the RAIA efficacy. The impact of LID on disease outcomes remains controversial, with the rhTSH group being underrepresented in most. We evaluated if pre-ablation urinary iodine levels can be used to predict disease recurrence/persistence in patients receiving either THW or rhTSH preparation. 

Methods: We retrospectively reviewed 304 patients (THW: n = 189; rhTSH: n = 115) with DTC who underwent thyroidectomy and initial RAIA between 2007-2020. All patients were advised to adhere to a 2-week LID. Urinary Iodine/Creatinine Ratio (UICR) was used as a reflection of total body iodine level.  The primary endpoint was disease recurrence/persistence at 12 months post-ablation, defined as the presence of any one of the following: basal serum thyroglobulin ≥1 ng/mL or stimulated thyroglobulin ≥2 ng/mL, a positive neck ultrasound, or a positive whole-body scintigraphy. Multiple logistic regression was used to evaluate the factors associated with disease outcomes.

Results: There was no statistical difference in disease recurrence/persistence between the two groups (14% in THW vs 10.4% in rhTSH group, p = 0.33). Average UICR was higher in the rhTSH vs THW group (p < 0.0001). In multivariate analysis of the entire cohort, adjusting for age, sex, tumor size, and preparation, higher UICR was associated with an increased likelihood for disease recurrence/persistence [OR 1.004, 95% CI (1.001-1.007), p = 0.03]; female sex [OR 3.24, 95% CI (1.34-7.88), p=0.009] and older age [OR 1.06, 95% CI (1.02-1.09), p=0.0005] were independently associated with disease-free status at 12 months post-ablation. When patients were stratified by the RAIA preparation method, a similar trend was seen only in the THW group (p = 0.04).

Conclusions: Pre-ablation UICR may be a useful marker for predicting outcomes of DTC in patients prepared for RAIA using THW. UICR was less sensitive in predicting outcomes in the rhTSH group.

Purpose: Though hypoxia is well-studied as a molecular mechanism and potential therapeutic target for thyroid carcinoma, few have explored how hypoxic diseases may potentially influence the natural course of thyroid carcinoma. In particular, biological models suggest that obstructive sleep apnea (OSA), characterized by intermittent nocturnal hypoxemia and sleep fragmentation, is potentially carcinogenic. We aim to clarify the epidemiological associations of OSA with thyroid carcinoma incidence and mortality.

Methods: We systematically searched PubMed, Embase, Scopus and Cochrane Library from inception till 15 November 2020 for observational or randomized studies of associations of OSA, measured by diagnostic codes or any index, each with thyroid carcinoma incidence or mortality in adults, compared to participants with no/mild OSA. Two reviewers independently selected studies, extracted data, evaluated study bias using the Newcastle-Ottawa scale and quality of evidence using GRADE. We performed inverse variance-weighted, random-effects meta-analyses and computed the population attributable fraction (PAF) using published estimates of worldwide OSA prevalence.

Results: We included 3 observational studies (1,647,881 participants), all with moderate/low risk of bias, from 1,725 records. Moderate quality evidence suggests that a diagnosis of OSA tripled the incidence of thyroid carcinoma (pooled HR 3.27, 95%CI 2.80-3.82, I²=0%), after multi-adjustment for demographics, body mass index, smoking, alcohol use, and various comorbidities. The association remained significant and large upon leave-out-one influence analyses, though publication bias could not be assessed due to insufficient studies. Globally, up to 22.5% (95%CI 21.9-23.2%) of incident thyroid carcinomas may be associated with OSA, based on the calculated PAF which assumes perfect adjustment for confounders. This may vary across countries, from >61.4% in territories with >70% OSA prevalence (e.g. France, Haiti, Malaysia, Singapore, Switzerland) to <18.5% in territories with <10% OSA prevalence (e.g. Bangladesh, Cambodia, Ethiopia, Hong Kong, India). No information was available on thyroid carcinoma mortality in relation to OSA.

Discussion/Conclusion: Meta-analysis of 3 observational studies suggests that OSA may carry substantial risk and burden of thyroid carcinoma. Intermittent hypoxia and sleep fragmentation should be investigated in biological models of thyroid carcinoma. Clinical studies should investigate OSA severity in relation to thyroid carcinoma aggressiveness, recurrence, metastasis and mortality, stratified by tumor histology.

Backgrounds 

Either total thyroidectomy or lobectomy is recommended for patients with differentiated thyroid cancer >1cm and <4cm without extrathyroidal extension (ETE), and without clinical evidence of any lymph node (LN) metastasis. The aim of this study is to evaluate the prognosis and risk factors for structural recurrence after thyroid lobectomy in patients with 1-4cm papillary thyroid cancer (PTC).

Methods

This retrospective cohort study initially included patients with 1-4cm PTC who underwent thyroid lobectomy at Asan Medical Center, Seoul, Korea from January 2005 to December 2012. A total of 596 patients were enrolled after excluding patients with aggressive variants of PTC, gross ETE into major neck structure, lateral cervical LN metastasis, or short follow-up periods. We evaluated independent risk factors for structural recurrence after lobectomy in 1–4cm PTC.

Results

During the median 7.7 years of follow-up, the structural recurrent disease was confirmed in 31 patients (5.2%). Fifteen patients (48.4%) had a recurrent disease in the contralateral remaining thyroid lobe and the other recurrence was in cervical LN or operation bed. In multivariate analysis, gross ETE [HR, 2.56; CI, 1.57 – 5.60; p=0.018] and cervical LN metastasis [HR, 3.38; CI, 1.45 – 7.88; p=0.004] were independent risk factors for recurrent disease. Compared to patients without both gross ETE and cervical LN metastasis, patients with both gross ETE and cervical LN metastasis have a greater risk of recurrence [HR, 8.49; CI, 2.94 – 24.51; p<0.001].

Conclusion 

Gross ETE and cervical LN metastasis are associated with an increased risk of recurrence after lobectomy in patients with 1–4 cm PTC. Completion thyroidectomy would be considered in patients with both gross ETE and cervical LN metastasis. 

Objective: Until 2015, standard of care for low risk papillary thyroid cancer (PTC) >1 cm was a total or near total thyroidectomy. Despite changes in guidelines and surgical management of low risk PTC since 2015, little data are available regarding the effect on the need for additional surgery or risk for development of lymph node metastases. Our aim was to determine outcomes in patients who underwent initial thyroid lobectomy for low risk PTC at a high volume tertiary care institution.

Methods: Retrospective review of patients ≥18 years old with biopsy proven low risk PTC 1-4 cm who underwent partial thyroidectomy (e.g. lobectomy/isthmusectomy) at Mayo Clinic, Rochester, MN between March 2016 and June 30, 2019.  

Results: From 1,481 thyroidectomies performed during study period, 940 contained PTC on final pathology.  Of these, 87 (of 123) patients who had an initial thyroid lobectomy met inclusion criteria.  Five (6%) of these patients proceeded to completion thyroidectomy, with 3 requiring completion thyroidectomy and radioactive iodine in first postoperative year and 2 undergoing only completion thyroidectomy in second postoperative year. No post-operative complications reported. No patient in cohort required additional surgery or treatment for newly discovered lymph node metastases during follow-up period.  Forty-three (of 72, 60%) patients not on thyroxine therapy preoperatively were started on thyroxine therapy postoperatively.
Conclusions: Early outcomes for those undergoing thyroid lobectomy for low risk PTC at our institution have been favorable.  These results support the 2015 ATA guidelines to offer lobectomy for those with low risk PTC 1-4cm.

Introduction - Thyroid cancer (TC) is the most common endocrine malignancy worldwide. TC comprises a large range of benign and malignant lesions, leading to prognostic differences. Before surgery, the existing diagnostic tools for thyroid cancer are ultrasonography, followed by a fine-needle aspiration biopsy (US-FNAB). US-FNAB is the most accurate, cost-effective and minimal invasive preoperative test to distinguish benign from malignant thyroid nodules, aiming to resolve patient management. However, up to 30% of FNABs are classified as indeterminate nodules, making the decision on patient management crucial to avoid unnecessary surgeries. Several studies recommend the use of molecular tests for a complete diagnosis of malignancy. The development of TC has been associated with the activation of oncogenes (TERTp, BRAF and RAS (NRAS, HRAS and KRAS)), that are implicated in the cell signaling pathway, interfering in cancer promotion and outcome. 

Aims - This  study aim to compare the cyto-histologic genetic profile (TERTp, BRAF and RAS (NRAS, HRAS and KRAS)), by using a paired series of US-FNAB and histologic samples, in order to establish whether the molecular profile defined by US-FNAB is reliable to further characterize indeterminate nodules. 

Material and methods - The series in this study was composed by one FNAB and corresponding formalin-fixed paraffin-embedded (FFPE) tissue from 90 consecutive patients. The genetic alterations were examined by polymerase chain reaction (PCR), followed by DNA sequencing. The association of the genetic alterations with clinicopathologic features was evaluated.

              Results and Discussion - We found mutation frequencies in cytology and histology specimens, as follow, TERTp: 6.7% and 9.1%; BRAF: 24.7% and 24.4%; NRAS: 5.6% and 5.6%; HRAS: 3.3% and 4.4%; and KRAS: 0% and 2.2%, respectively. A good cyto-histologic correlation was obtained (76.7%) suggesting that US-FNAB can be used to anticipate the molecular profile of a tumor. Moreover, our data present several statistically significant associations between the clinicopathological and molecular features of the tumors. BRAF mutations were associated with local aggressiveness and the same was observed for the presence of concomitant TERTp+BRAF mutations. On contrary, RAS mutations were associated with a better patient outcome.

Background and Objective: Active surveillance (AS) can be considered as a treatment option in low-risk papillary thyroid microcarcinoma (PTMC), and currently, the initial treatment choice in AS candidates is depends on the patients’ wishes. Therefore, it is necessary to identify the factors that influence the patient's decision-making.

Methods: We analyzed surveys about treatment choice from 857 subjects enrolled in ongoing multicenter prospective cohort study on active surveillance of low-risk PTMC (MAeSTro) and surveys regarding AS from 19 physicians participated in the study.

Results: Five hundred fifty-four subjects (male = 128; mean age = 49.4 ± 11.6 years) with low-risk PTMC chose AS while 303 subjects (male = 55; mean age = 46.6 ± 10.7 years) chose immediate surgery. Subjects who chose AS were older (p < 0.001) and had smaller tumors (6.2 ± 1.6 vs. 6.8 ± 1.9 mm, p < 0.001). The proportion of AS was different according to the centers where the study conducted. Subjects who chose AS were more likely to already know AS of low-risk PTMC when they discussed about treatment options, and subjects who chose surgery were more likely to answer they know very little about thyroid cancer treatment. Although patient him-/herself and medical staff mainly influenced their treatment decision in both AS and surgery groups, subjects in AS group were more influenced by media and those in surgery group were by their family members. Subjects who consulted AS-friendly physicians were more likely to choose AS and the same trend was observed for surgery.

Conclusions: This study suggests that physicians should update their own knowledge about the treatment of low-risk PTMC as well as provide sufficient, accurate information to their patients in the process of initial treatment choice for low-risk PTMC.

Objectives

Patients undergoing prophylactic central compartment dissection (CLND) for papillary thyroid cancer (PTC) are often overtreated. Molecular fluorescence-guided imaging (MFGI) and spectroscopy may be useful for the detection of PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. This study aims to identify a PTC-specific antigen targeted by a clinical available near infrared fluorescent (NIRF)-tracer; associate protein overexpression of the selected antigen with locoregional recurrence rates; assess selective binding of the selected NIRF-tracer in vitro and evaluate safety and efficacy of the selected NIRF-tracer for the detection of PTC NM using MFGI and quantitative spectroscopy in humans.

Methods

A data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) was used to identify tumor-specific antigens. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n=741) and NTT (n=108) and correlated with ten-year locoregional recurrence-free survival (LRFS). In vitro selective binding of EMI-137 to MET was assessed using MET positive (TPC1) and negative (T-47D) cell lines. A multicenter, phase-1 dose-escalation study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET.

Results

MET was selected as antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p=0.02). In vitro selective binding of EMI-137 was confirmed. In 19 patients, no adverse events directly related to EMI-137 injection occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (8.17x10⁷ p/sec/cm²/sr [IQR 1.19x10⁸] versus 1.62x10⁷ p/sec/cm²/sr [IQR 3.63x10⁷]; p<0.0001) and spectroscopy (3.2x10^-3 Q.µ_a^f_axmm^-1 [IQR 1.3x10^-3] versus 1.7x10^-3 Q.µ_a^f_axmm^-1[IQR 7.5x10^-4]; p<0.0001). MFGI identified 5/19 levels (26.3%) without pathology confirmed NM. In vivo EMI-137 selective binding was confirmed. 

Conclusion

MET is overexpressed in PTC and associated with worse LRFS. Perioperative intravenous administration of EMI-137 is safe and facilitates detection of MET positive PTC NM using MFGI and spectroscopy, potentially reducing the number of negative prophylactic CLNDs with more than 25%.

Objectives: Cytology-based diagnosis has limitation in accurate delineation of thyroid malignancies. Hence, the study aims to develop an affordable molecular- cytology tool to improve the diagnoses. The objectives of the study i) Identification and validation of aberrant glycosylation pattern of benign and malignant thyroid nodules in histologically annotated tissues by lectin histochemistry. ii) Validate lectin markers in cytology and evaluate the efficacy of lectins in delineating thyroid malignancy as compared to histopathology diagnosis.

Methodology: Towards achieving the first objective, three lectins Wheat germ agglutinin (WGA), Sambucus Nigra Aggluttinin-1(SNA-1) and Maackia amurensis Aggluttinin (MAA) were selected for lectin immunohistochemistry based on existing evidence in oral, prostrate and gastric malignancies. Lectin histochemistry was performed on retrospectively collected tissue specimens (Formalin Fixed Paraffin Embedded surgical samples) of the subjects, who were histopathologically diagnosed as benign and malignant thyroid nodules. The marker expression was compared with histology diagnosis and best marker selected for prospective cytology validation in FNAC samples. The molecular cytology scores were compared to cytology Bethesda scoring and histology diagnosis. The efficacy of the combination of markers to delineate benign and malignant thyroid nodules through cytology diagnosis was evaluated. Statistical significance was assessed using ANNOVA/ t test (P value < 0.05) and Receiver Operating Characteristic (ROC) curve analysis.

 Results: WGA and MAA expression were validated in the first set of histologically annotated benign (n=26) and malignant (n=38) FFPE tissue sections.  The WGA expression was significantly (p<0.05) higher in malignant (149.37±8.9) thyroid samples as compared to benign (36.25 ± 9.13). MAA also showed a significantly increased expression (p<0.05) in malignant thyroid tissue (69.57±6.81) as compared to benign (9.95±2.78). ROC curve analysis of WGA and MAA significantly delineated benign and malignant samples with a sensitivity of 89.5% and 84.2% respectively and specificity of 92.3% and 88.5% respectively. Both the markers showed an Area under the curve (AUC) of 0.89. 

Conclusion: WGA and MAA lectins to significantly distinguish benign and malignant thyroid nodules. This preliminary data will help us build a lectin panel to distinguish benign and malignant thyroid nodules, and subsequently use this in thyroid cytology.

Objective:

Given higher morbidity with pediatric thyroidectomy, the need for accurate pre-operative malignancy detection is critical. Fine needle aspiration (FNA) remains the gold diagnostic standard, but it is often indeterminate. Indeterminate FNAs typically prompt thyroidectomy in children, potentially leading to overtreatment and increased morbidity in this population. ThyroSeq is a molecular test used to improve diagnosis in such indeterminate thyroid nodules. The test has been extensively validated in adult thyroid nodules, but never in pediatric thyroid nodules. The goal of this study is to explore the molecular landscape of pediatric thyroid nodules and assess the performance of ThyroSeq in this unique population.

Methods:

In this IRB-approved study, formalin-fixed paraffin embedded (FFPE) surgical tissues from pediatric patients (< 21 years old) who underwent thyroid surgery between 2003–19 were submitted for testing using the ThyroSeq v3 multigene genomic classifier. Matching FNA smears (Diff-Quik, H&E, and Pap stains) were also tested when available. Clinical information was gathered via retrospective chart review. Multivariable regression analyses were performed to identify clinical factors associated with malignancy, including FNA Bethesda categories and post-surgical outcomes.

Results:

A total of 114 nodules (59 benign; 55 malignant) were successfully evaluated, including 26 with matching FNAs (7 benign, 7 indeterminate, and 12 malignant). Testing confirmed the unique molecular landscape of malignant pediatric thyroid nodules (as compared to adults), which is composed of frequent gene fusions (most commonly NTRK and RET), few BRAF/RAS alterations, and no TERT promoter mutations. Several poorly differentiated thyroid cancers harbored somatic DICER1 mutations. Benign nodules appeared to be almost exclusively driven by TSHR alterations. Despite a distinct molecular landscape compared to adult nodules, ThyroSeq v3 had a sensitivity of 0.94, specificity of 0.78, positive predictive value of 0.82, and negative predictive value of 0.92 with regards to malignancy detection in children. Companion FNAs demonstrated 100% diagnostic concordance with FFPE tissues.

Conclusions:

Pediatric thyroid nodules have a unique molecular landscape yet remain amenable to diagnosis by the ThyroSeq v3 multigene genomic classifier. This molecular test may help with the management of indeterminate thyroid nodules in children and reduce unnecessary morbidity.

Introduction: Ectopic thyroid tissue (ETT) is characterized by the presence of thyroid tissue in any location other than its normal anatomic position. Mediastinal ectopic thyroid gland is a rare entity, accounting for 1% of all ETT cases. In this abstract, we present six cases with mediastinal ETT over the last 25 years admitted to Stanford hospital.

Description of the cases: The mean age of our six cases was 54 years and 50% were female. Symptoms included chest pressure (2), cough (2), voice hoarseness (1), chronic dysphagia (1), and neck pain (2). Two of the patients had no significant presenting symptoms and the thoracic mass was an incidental finding. Thyroid function test was checked in 50% of the cases with two of the patients having a thyroid stimulating hormone (TSH) checked before surgery and one patient having TSH after surgery.  All TSH values were within normal limits. Before surgery, the diagnosis of ectopic thyroid tissue was probable in all patients, but no one had a biopsy proven diagnosis. Based on the medical history of malignancy including melanoma and lung neuroendocrine tumor in two of the cases, there was concern for metastatic disease. All patients in our study had CT imaging of the chest detecting the mass of which three were in the anterior, two in the posterior, and one in middle mediastinal region. The mean lesion diameter was 3.7 cm (range, 2‐6 cm). Histopathology of the mass revealed ectopic thyroid tissue negative for malignancy in all cases.

Discussion: Ectopic mediastinal thyroid tissue is a rare clinical entity that should be considered in the differential diagnosis of all mediastinal masses as it requires different management and treatment.

OBJECTIVE: Hypothyroidism and atrial fibrillation (AF) are both common conditions in elderly patients.  Levothyroxine has a narrow therapeutic window and requires monitoring to ensure that thyroid-stimulating hormone (TSH) remains within the reference range; thyroxine (fT4) is not routinely monitored.  Subclinical hyperthyroidism is associated with higher rates of AF.  However, studies have not shown a clear association between TSH and AF in patients treated with levothyroxine.  Several cohorts have shown an association between higher fT4 levels and risk of AF in euthyroid patients.  No studies have been performed in patients on levothyroxine, who tend to have higher fT4 levels.

METHODS: This was a retrospective cohort study of patients aged 18 and older who were treated with levothyroxine. Exclusion criteria were pre-existing diagnosis of AF and use of amiodarone in the prior year. Patients were followed 2012 through 2019 and stratified into four groups based on mean TSH value or mean fT4 value in 2012. Primary outcome was incidence of AF. Rates of AF between groups were assessed via Poisson regression with control of underlying confounders.  

RESULTS: Of 21035 patients, 1091 (5.2%) developed AF during follow up.  TSH at baseline was not significantly associated with incident AF.  Higher fT4 levels at baseline were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio 1.32; 95% CI 1.11-1.58, for the highest quartile versus the lowest quartile of fT4).

CONCLUSION: In hypothyroid patients treated with levothyroxine, higher circulating fT4 levels are associated with increased risk of incident AF.  There is no association of serum TSH with risk of AF.   In patients are risk of AF, consideration should be given to avoiding fT4 levels in the highest quartile.

DISCLAIMER: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense or the U.S. Government

Introduction

               In patient with hyperparathyroidism due to hyperplasia or parathyroid adenoma, parathyroidectomy is sometimes indicated to correct the abnormality. This could lead to thyrotoxicosis  due to palpation thyroiditis. This is a case of thyrotoxicosis post parathyroidectomy.

Case Description

                68-year-old female with past medical history of hyperparathyroidism, goiter with normal thyroid function, chronic kidney disease (CKD) stage 4, osteopenia,  was referred for parathyroidectomy due to chronic elevation of parathyroid hormone (PTH). Patient had right superior adenoma on sestamibi scan 4 years prior to surgery. Due to her worsening CKD, she also developed secondary hyperparathyroidism. Her average PTH level was 500 pg/ml with highest level of 724 pg/ml. Other findings include calcium of 9 mg/dL and albumin of 3.5 g/dL. Prior to been referred to surgery, patient was started on cinacalcet, however had to be stopped due to her insurance not covering the medication. She was also on both calcitriol and vitamin D supplement.  This level of PTH elevation could not be managed by medication alone so she underwent partial parathyroidectomy and parathyroid adenoma removal. The surgery was uneventful, however, patient developed hyperthyroidism 7 days post parathyroidectomy. Prior to surgery Thyroid stimulating hormone (TSH) level 1.810 IU/mL. However on post-op day 7, TSH  0.02 IU/mL, Triiodothyronine (T3) was 452ng/dL, thyroxine (total T4) was 18.8 mcg/dL and free T4  3.91 ng/dl. There was no recent use of biotin, iodine contrast dye, or amiodarone.  Patient was asymptomatic when found to be biochemically hyperthyroid. Thyroid antibodies including Thyroid stimulating immunoglobulin (TSI) and thyroid peroxidase antibody (anti-TPO) and thyroglobulin antibody (ATA) were negative ruling out new onset Grave disease or Hashimoto thyroiditis. Thyroid lab values were rechecked 1 month later and patient was found to have normal thyroid function with TSH 1.85 IU/mL, T3  101 ng/dL, T4 of 7.7 mcg/dL and free t4  1.15 ng/dL. Patient has been following with endocrinology and her thyroid function has remain stable.

Discussion

                Palpation thyroiditis has clinical significance as this could lead to medical complications. Complications reported include diagnoses such as  new onset atrial fibrillation and pulmonary edema.

Objective

The prohormone T4 is converted into the active hormone T3. Thyroid hormone (TH) metabolites include rT3, 3,5 T2 (T2), and 3-T1AM (T1AM). T3 is believed to be the precursor for T2; the endogenous pathway for T1AM production is being currently investigated. We examined data regarding T2 and T1AM levels after T3 administration to gain insight into relationships between thyroid hormone metabolites.

Methods

We measured T2 and T1AM concentrations in two series of experiments. In Series A, THs and metabolites were documented for 72 hours after a single dose of 50 mcg T3 in healthy volunteers (n=12). In series B, a daily dose of 30-45 mcg T3 replaced T4 therapy in individuals with hypothyroidism (n=18). Trough levels of THs and metabolites were measured weekly for 6 weeks and then hourly for 8 hours after the last T3 dose of the study. Repeated measures analysis was performed using SAS 9.4 software.

Results

In series A, female patients (n=4) had significantly higher T1AM levels by 3.91-fold than male patients (n=8) (p-value= 0.034). In the weekly samples from series B, T4 and FT4 were significantly associated with T2. T2 was higher by 0.033 with each unit increase in T4 and 0.24 higher with each unit increase in FT4 (p-values were 0.007, 0.0365 respectively). In the hourly samples from series B, T3 and T2 were both significantly correlated with T1AM. Patients with T3 values higher by one unit had T1AM values that were smaller by 0.004 (p-value=0.0473); patients with T2 higher by one unit had T1AM values higher by 2.45 units (p-value= 0.0044).

Conclusions

Sex differences in T1AM levels in healthy volunteers following T3 administration remain to be confirmed. The positive correlations between both T4 and FT4 with T2 during the series B weekly sampling and their significance with respect to T2 production is unclear. This occurred during a time that T4 therapy had been switched to T3 therapy. The negative correlation between T3 levels and T1AM, but positive correlation between T2 and T1AM could support that T1AM production is via T2. The changes were noted in hourly sampling after T3 administration.

This is a case of 44-year-old female who comes to the clinic referred by her ophthalmologist after been diagnosed with severe thyroid-associated orbitopathy currently on steroid therapy. Thyroid ultrasound has done previously showed enlarged homogenous thyroid gland with a single isoechoic nodule of 2.2x1.6x1.9cm with faint peripheral calcifications and vascularity. The patient was presenting with palpitations, heat intolerance, sweating, and discriminatory features such as double vision and left eye exophthalmos. On physical examination, there was no goiter or palpable thyroid nodules, but it was remarkable for left eyelid lag retraction and mild proptosis. Evaluation showed clinical and biochemical hyperthyroidism with TSH: 0.068 mU/ml (n:0.5-5.0mU/ml), FT4: 1.39ng/dl (n:0.87-1.85ng/dl), TSH receptor antibody: <1.10IU/L and thyroid-stimulating immunoglobulin: 0.54IU/L (borderline high). The patient was placed in antithyroid drugs and B-blockers for disease control. Afterward, the patient underwent a thyroid uptake scan reporting toxic adenoma on the left lobe, however even when the biochemical workup of GD is inconclusive, patient clinical findings are highly suggestive of it.  Due to the risk of worsening orbitopathy with radioactive iodine therapy, patient was referred for surgical excision of toxic adenoma and total thyroidectomy was decided since residual thyroid tissue may expose the patient to circulating thyroid-stimulating immunoglobulin leading to hyperthyroidism recurrence and put her at risk of associated thyroid excess detrimental complications such decreased bone mineral density and high-output cardiac failure. Surgical specimen gross pathology biopsy reported the thyroid gland with hyperplastic changes of Grave’s Disease. Severe thyroid-associated orbitopathy was managed with decompression surgery but did not improve, for which an alternative therapeutic approach is decided with novel immunomodulatory agent Teprotumumab. This recently approved therapy is a monoclonal antibody and targeted inhibitor of insulin growth factor-1 receptor involved in Thyroid Eye Disease.

 Is unusual to see two different superimposing thyroid pathologies, but disease presentations can be atypical and can be present concomitantly. In this scenario, several factors must be taken into consideration when choosing an adequate therapy approach. Our case is an example that we need to individualize management options based on guidelines recommendations, patient's clinical settings, benefits in therapy, and decreased risks of future complications.

Introduction 

Lymphoma involves the thyroid rarely, but may present as a thyroid mass, goiter or thyroid fibrosis. Most are B-cell non-Hodgkin lymphomas. We present an unusual case of classic Hodgkin lymphoma presenting as goiter in an adolescent female.

Description of the Case 

A 15 year old female presented with a painless, firm goiter associated with vocal hoarseness. Fever, fatigue, weight loss, and night sweats were absent. Examination demonstrated diffuse thyroid enlargement and tissue firmness, especially in the right lobe. Multiple enlarged lymph nodes, including supraclavicular, were palpated. The patient was clinically and biochemically euthyroid at presentation. 

Ultrasound demonstrated a 6.8 by 2.5 cm mass predominantly in the right lobe with extension into the isthmus and left lobe. The mass was mostly solid and hypoechoic with some cystic areas and calcifications. Multiple enlarged lymph nodes with cortical hypertrophy and calcifications were identified raising suspicion for metastatic papillary thyroid carcinoma (PTC). 

Fine needle aspiration (FNA) of a suspected metastatic lymph node demonstrated atypical B-cell proliferation which stained diffusely positive for CD20, and negative for antigens associated with PTC (BRAF, PAX8, TTF, and cytokeratin AE1,3). Excision of an axillary lymph node was required for definitive diagnosis. Histology showed predominantly small lymphocytes with few interspersed large atypical cells with prominent nucleoli (Reed-Sternberg cells), traversed by paucicellular fibrosclerotic septae imparting a nodular pattern. Final diagnosis was classic Hodgkin lymphoma, nodular sclerosing subtype, stage IIA. 

She initiated therapy with ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) and had excellent response. She was changed to doxorubicin, vinblastine, and dacarbazine to reduce toxicities, omitting bleomycin to reduce pulmonary risks in the setting of the COVID-19 pandemic. Eleven months after therapy completion, she has no evidence of disease. She did not require thyroid surgery or radiotherapy.

Discussion

While PTC is strongly suspected with this presentation, lymphoma should be a diagnostic consideration in patients with a thyroid mass. In this case, FNA was valuable in raising the possibility of a lymphoproliferative disorder, which led to excisional lymph node biopsy to confirm the diagnosis. Initiation of chemotherapy in this chemo-sensitive tumor averted unnecessary thyroid surgery and extensive lymph node dissection. 

Objective: To evaluate a multi-cycle quality improvement [QI] project aimed at reducing rates of transient and permanent hypoparathyroidism/hypocalcemia and improving perioperative care of pediatric total thyroidectomy [TT] patients.

Methods: A retrospective review of perioperative management and outcomes of 122 pediatric TTs as baseline from January 1, 2010 to Aug 31, 2015, was compared to 121 subsequent TTs managed by protocol in a large, free-standing children’s healthcare system. Process measures included serum calcium measurement 6-12 hours post-operatively, PTH measurement 6 hours post-operatively, administration of pre-operative iodine for Graves disease, and administration of post-operative prophylactic calcium carbonate. Primary outcomes included hypocalcemia during the surgical admission and permanent hypoparathyroidism.

In 2015, an EMR (Electronic Medical Record) protocol was initiated with standardization of laboratory monitoring and medication administration to reduce variation in care in the subsequent 121 TT’s. Five PDSA cycles were completed annually focusing on order set implementation, refinement, usage and education, along with the addition of post-operative calcitriol administration. Throughout the project, a multidisciplinary team including endocrinologists, ENT and general surgeons met regularly, face-to-face, to review outcomes and modify care coordination.

Results: All perioperative process measures improved throughout the PDSA cycles compared to baseline. Measurement of post-operative serum calcium increased from 42% at baseline to 100%. Measurement of post-operative PTH increased from 11% to 97%. Pre-operative iodine administration for Graves TTs increased from 72% to 94%. Post-operative calcium carbonate administration increased from 36% to 100%. There was a trend toward lower rates of severe hypocalcemia (serum calcium <7 mg/dl, <1.75 mmol/L) during admission over the subsequent PDSA cycles, starting at 11.6% at baseline and improving to 3.4% by PDSA5

With regular multidisciplinary review of outcomes, surgical volume consolidated among high-volume providers, which was associated with a decrease in permanent hypoparathyroid rate of 20.5% at baseline to 10% by PDSA5.

Discussion/Conclusion: In standardizing pediatric TT care, implementation of a QI project improved perioperative management and multidisciplinary team involvement resulted in immediate and long-term benefits in TT patient outcomes.

Objective:  Radiofrequency or ethanol ablation of cytologically benign thyroid nodules has gained clinical favor.  However, reliably excluding malignancy remains a diagnostic challenge. The study aim was to evaluate the clinical course of a patient with aggressive thyroid cancer with repeatedly benign cytology prior to ethanol ablation and assess the frequency and type of molecular abnormalities in cytologically benign nodules.

Methods:  We evaluated the index case and an IRB-approved multicenter series of cytologically benign fine needle aspiration (FNA) samples using 112 gene targeted next-generation sequencing-based molecular testing (MT). 

Results: A healthy and euthyroid 42-year-old woman presented with a partially cystic thyroid nodule which had no high-suspicion ultrasound features and 2 cytologically benign FNA results and was treated with percutaneous ethanol ablation.  When nodule growth was observed 3 years later, repeat FNA was suspicious (Bethesda Category V), and after resection, a poorly differentiated thyroid cancer was diagnosed.  MT of the FNA sample was positive for a late hit alteration (TERT) typically seen in aggressive thyroid malignancies, which was found to be present prior to ablation.  In evaluation of 825 consecutive cytologically benign nodules submitted for clinical MT, positive results were present in 121 (15%) cases.  Alterations detected included mutations in RAS, DICER1, and BRAF V600E, gene fusions (most common, THADA-IGF2BP3), and copy number alterations. Nineteen samples had BRAF V600E-like alterations associated with an intermediate risk for recurrence and 5 had high risk alterations in TERT (n=3) or TP53, or alterations associated with medullary thyroid cancer (MTC). Overall, 25 had intermediate- or high-risk molecular alterations, which represented 20.7% of the 121 MT-positive cytologically benign nodules and 3% of the 825 nodules with benign cytology. On surgical follow-up available for 36 patients with MT-positive nodules, 16 (44%) were malignant, 3 (8%) were NIFTP, and 16 (44%) were benign.  Among 3 nodules with high-risk mutations and surgical follow-up, pathology included a tall cell variant PTC, an invasive encapsulated follicular-variant PTC with lymph node metastasis, and a 4.5 cm MTC.   

Conclusion:  The safety of thyroid nodule ablation relies on accurate exclusion of malignancy

and may be enhanced with pre-ablation molecular testing in select cases. 

Objective. Caring for patients with thyroid nodules requires an understanding of their risk for thyroid cancer and their personal situation. To achieve patient centered care, physicians need to integrate the clinical evidence guiding thyroid cancer risk assessment and collaborate with their patients when deciding the next step in management. To facilitate this process, we developed and pilot tested a conversation aid to support shared decision making.

Methods. We developed a web-based Thyroid NOdule Conversation aid (TNOC) following a human-centered design approach through active collaboration with clinicians, patients, and designers using observations of clinical encounters and literature review. An observational, pre–post study was conducted [TNOC vs. usual care (UC)] to assess the impact of TNOC on the quality of conversations. Data sources included recordings of clinical visits, post encounter surveys, and review of electronic health records. Summary statistics and group comparisons are reported and adjusted when an intraclass correlation (by clinician) was detected.

Results. Sixty five patients were analyzed (32 in the UC and 33 in the TNOC cohort). Most patients were women (89%) with a median age of 57 years (Interquartile range, 38 – 69). Most thyroid nodules were incidentally found (62%) and were at low risk for thyroid cancer (71%). The median size was 1.4 cm (Interquartile range, 1.1-1.9). At baseline, the groups were similar except for higher health numeracy in the TNOC cohort. The use of TNOC was associated with increased involvement of patients in the decision making process (observing patient involvement in decision making - OPTION score,  33.3 TNOC vs 20.8 UC, p<0.001), clinician satisfaction, and discussion of relevant topics for decision making. In addition, decreased decisional conflict (2.3 TNOC  vs 17.8 UC, p=0.007) and fewer thyroid biopsies as next management step were noted in the TNOC cohort. No differences in terms of knowledge transfer, length of consultation, thyroid cancer risk perception, or concern for thyroid cancer diagnosis were found.

Discussion/conclusion. In this small observational study, using TNOC in clinical practice was feasible and seemed to help patients and their clinicians collaborate when deciding on the next diagnostic step in the management of thyroid nodules.

When may be healing the hypocalcemia after thyroidectomy?

Objective:Hypocalcemia after thyroidectomy may be seen transient or permanent.Recovery of the hypocalcemia lasts various time that may be short time or years.If a little amount of parathyroid gland tissue is stayed in place,hypocalcemia may return.Postoperative hypocalcemic patients were followed up and it is found that postoperative Ca levels can be an indicator for recovery time.

Methods:Patients with postoperative hypocalcemia after thyroidectomy operation were followed up and explored retrospectively.Recovery times,initial values of calcium,last calcium values were examined.

Results:There are 13 patients in our patients group.Mean follow up is 23(2-84) months.Mean postop first Ca level and mean last Ca level are 7,05(4,3-8,3)mg/dl and 8,7(7,45-9,6)mg/dl respectively.All of the patients have normal values of albumin.The replacement therapy were given.When the replacement therapy were not enough,doses of the medicaments were increased.Ca normal range is 8.5 to 10.5mg/dl.When the Ca levels were in normal range,replacement therapy was stopped gradually,after than,if the Ca levels were normal in the cases,the therapy was stopped.They all responded to the treatment.All of the 10 patients have healed totally(Table 1).Three patients have healed partially that, all of the three patient's last Ca levels were higher than 7,45mg/dl.These patients' first postoperative Ca levels were 7,6mg/dl,6mg/dl, 4,3mg/dl respectively.

Table 1:

Postoperative first Ca(mg/dl)     Number of patients        Treatment period(months)

8-8,5                                                               2                                            2

7,5–7,9                                                           3                                           13,5

7–7,4                                                               1                                             10

6,5–6,9                                                            2                                              24

6–6,4                                                               2                                              66

Discussion/Conclusion:In the postoperative period,first Ca level may give us an impression about parathyroid glands damage,if the Ca results do not depend on hunger bone cases.If the Ca level is very low,recovery period may take longer.Our series showed that;If first Ca level was under 7mg/dl,recovery time can be longer than the patients with upper level of 7mg/dl.Briefly we can say that when the first Ca level is near the normal level,recovery time will decrease.As a result that postoperative Ca levels can be an indicator for recovery time.

Background 

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. 

Methods 

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.

Results 

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.

Conclusion

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. 

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.

Discussion

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.

Conclusion

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

Background:

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.

Methods:

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.

Results:

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.

Conclusion:

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.

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: 

INSERT FIGURE 1 (submitted to ATA separately)

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). 

Introduction. 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.

Objective: To know which factors are associated with central lymph node metastases in patients with DTC undergoing CLD.

Material and methods. Retrospective, cross-sectional, observational, analytical study; patients with diferentiated thyrod cacner (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.

Results. 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).

Conclusions. 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.

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. 

Objective

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.

Methods

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.

Results

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 %).

Conclusion

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).