Introduction:
Graves’ Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves’ disease, which is caused by thyrotropin (TSH) receptor antibodies. GO autoimmune origin is supported by histopathological changes found such as infiltration of CD4+ T-lymphocytes that secrete cytokines, amplifying immune response and local inflammation, with orbital fibroblasts as main targets1,2. Glucocorticoids (GC) are the mainstay treatment for active disease. Doses higher than usual cumulative dose of 4.5g, are used for severe or sight-threatening disease and urgent orbital decompression surgery when response is absent or poor3,4,5. Polyphenols have potent anti-inflammatory and antioxidative effects on orbital fibroblast, with a potential role in treatment of GO6. This patient has dramatic improvement of sight-threating GO with oral polyphenols after absent response to high cumulative GC dose.
Case:
41 y.o. female patient with overt hyperthyroidism due to Graves’ disease and active moderate-to-severe bilateral GO, which rapidly progresses to very severe sight-threating eye disease a few months after diagnosis despite hormonal control of hyperthyroidism with thionamides. Patient is hospitalized for immediate IV GC treatment, with poor response and is discharged to continue weekly IV GC treatment and close ophthalmological follow-up do to COVID19 pandemic. With a GC cumulative dose of 9.5g, there’s no improvement of GO and she develops exogenous Cushing disease and is taken off GC. She’s hospitalized one month later because of severe eye pain associated with right eye infectious keratitis. She’s started again on high doses of IV GC (1000mg methylprednisolone for 3 consecutive days) and ophthalmological treatment with no improvement almost 2 weeks later. With evidence of optic nerve compression, emergency orbital decompression surgery is then suggested. PO polyphenols are started TID with dramatic improvement of eye pain and exophthalmos 3 days later, so surgery is postponed. One week later, eye lid retraction improves. Patient has been on oral polyphenols for 3 months since discharge, with no GC, and inactive moderate GO.
Discussion:
GC unresponsive sight-threating GO requires emergency decompression surgery in order to preserve eye-sight, but does not treat underlying cause. Polyphenols control oxidative stress, exert anti-inflammatory actions and restrain autoimmunity and are an option for GO.
Introduction: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder of the orbit that occurs predominantly in Grave's hyperthyroidism. It is an uncommon clinical finding in patients with Hashimoto's thyroiditis and hypothyroidism, presenting with often asymmetric and less severe clinical phenotype. Description of the case: A 62-year-old female patient presented with left eye proptosis, diplopia, and lateral paralysis of the left eye. She had no past medical history of thyroid disease. A year prior, the patient was diagnosed with breast cancer, underwent neoadjuvant chemotherapy and left mastectomy, followed by adjuvant chemotherapy, radiotherapy and hormonotherapy. During routine check-up, 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT) scan revealed pathological 18-FDG uptake of expansive mass within rectus medialis muscle of the left eye (SUVmax=11.0), and similar findings in the right eye (SUVmax=7.1). Magnetic resonance imaging of the orbits depicted retrobulbar mass in the left orbit, with hyperintense signals on FLAIR and STIR sequences, situated within left medial rectus muscle, indented into the adipose tissue of the orbit, offsetting but not infiltrating the optic nerve. In the right orbit, less significant findings were seen as discrete right lateral rectus muscle enlargement. Laboratory findings showed increased thyroid-stimulating hormone level, as well as high anti-thyroid-peroxidase and anti-thyroglobulin antibodies levels, while thyroid stimulating hormone receptor antbodies were negative. Thyroid ultrasound demonstrated diffuse pattern specific to chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis). The patient was diagnosed with subclinical hypothyroidism and TAO and levothyroxine therapy was introduced. Spontaneous improvement of TAO symptoms was attained a year later. Diplopia subsided, and the patient regained full eye movements. Discussion: Correction of hypothyroidism by thyroid hormone replacement therapy can significantly improve symptoms of TAO and render surgical interventions as well as glucocorticoid therapy unnecessary, as it was reported in this patient. Additional value of this case report lies in 18-FDG PET/CT images displaying increased metabolic activity within orbital muscles, which can advance clinical and diagnostic evaluation of TAO. However, lack of correlation between 18-FDG extraocular muscle uptake and inflammation score or muscle diameter has been observed in recent studies, therefore further research is needed in defining its role in detecting and measuring severity of TAO.
Background
The activity of NAD(P)-dependent dehydrogenases is the main indicators of intracellular lymphocyte metabolism due to the fact that this class of enzymes distributes substrate flows along the main metabolic pathways of cells and may be related to the active inflammatory phase in Graves' hyperthyroidism. This study sought to characterize the NAD(P)-dependent dehydrogenases activity of blood lymphocytes in manifesting and relapsing patients with Graves' disease (GD).
Methods
The study includes 151 women with GD and in 75 healthy individuals. Patients were divided into two groups: 64 (42.38%) with newly diagnosed GD and 87 (57.61%), who during the first year after starting thiamazole treatment have relapse of thyrotoxicosis. Serum measurement of TSH, fT4, fT3 and TRAb were performed by ELISA and enzyme immunoassay. The activity of NAD(P)-dependent dehydrogenases were measured using biochemiluminescence method.
Results
It was found that patients with Graves' hyperthyroidism of both groups have comparable level of TRAb: manifesting and relapsing, respectively, 9,51 IU/L (5,07−29,11) and 10,31 IU/L (7,51−16,81). In patients with newly diagnosed of GD, relative to the control values and levels detected in relapse group we observe the increase of glucose-6-phosphate dehydrogenase activity and decrease of NADH-lactate dehydrogenase activity. In GD relapse group compare to the control range in blood lymphocytes decreases the activity of lactate dehydrogenase (LDH) and NADP-isocitrate dehydrogenases (NADP-ICDH). Also, in GD relapse group compare to the values in patients with GD manifestation, the activities of glycerol-3-phosphate dehydrogenase and NADH-glutamate dehydrogenase were reduced.
Conclusion
Intracellular metabolism in newly diagnosed GD patients is characterized by an increase of the synthetic metabolism intensity and due to the activation of G6PDH. In patients with GD relapse, lymphocyte metabolism is characterized by maintaining the intensity of plastic processes and anaerobic glycolysis at the level of the control range. Study results strongly support the hypothesis of a direct immunomodulation effect of thiamazole in patients with GD rather than the theory favoring concomitant immunosuppressive due to thyroid hormone decrease, but point to specific immunological mechanisms influencing the susceptibility and triggers for GD persists.
Objective: Graves’ Orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retroorbital inflammation and tissue expansion, proptosis and diplopia and may ultimately threaten sight. Thyroid stimulating hormone receptor (S-TSHR-Abs) antibodies that induce hyperthyroidism, have been blamed in the pathogenesis of GO via TSHR. Since the effects of IGF-1 and TSH are additive, recent clinical trials in GO with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab) have demonstrated its ability to reduce symptoms significantly including clinical activity scores. However, the molecular mechanisms by which such an antibody achieves this result is unclear.
Results: We now show that stimulating TSHR antibodies are able to induce phosphorylation of the IGF-1R and initiate both TSHR and IGF-1R signaling in mouse and human fibroblasts. IGF-1R-Blocking-mAb (1H7) inhibited all major IGF-1R signaling cascades and also reduced TSHR signaling. This resulted in the antibody-induced suppression of autophagy and the induction of cell-extrinsic apoptosis.
Conclusion: Our observations clearly indicated that stimulating TSHR-Abs were able to enhance IGF-1R signaling and contribute to retroorbital cellular proliferation and inflammation. In contrast, the IGF-1R-Blocking-mAb was capable of suppressing IGF-1R signaling leading to retro-orbital cell death via apoptosis. This is likely the major mechanism involved in proptosis reduction in patients with GO treated by IGF-1R inhibition.
Objectives: We previously examined genetic abnormalities in TSH-secreting pituitary adenomas (TSHomas) using a next-generation sequencer (J Clin Endocrinol Metab. 102(2):566-75, 2017). We identified six somatic DNA variants as candidate driver mutations, and none were recurrent. A single nucleotide polymorphism (SNP) array analysis revealed multiple somatic focal and chromosomal arm-length copy-number abnormalities in eight TSHoma cases. The objective of the present study was to investigate the involvement of these copy-number abnormalities in genetic changes in TSHomas.
Methods: We performed a SNP array analysis of tumor DNA extracted from 12 TSHomas and 12 non-functional pituitary adenomas (NFPAs) and DNA extracted from the peripheral blood leukocytes of eight TSHomas. We also conducted a gene expression microarray analysis using RNA isolated from four TSHomas and four NFPAs.
Results: A total of 75.0% (9/12) of TSHoma samples had at least one gain, copy neutral loss of heterozygosity, and loss event. Among these copy-number abnormalities, copy number gains were more common than copy number losses, while chromosomal arm-length gains were the most frequent on chromosomes 4, 5, 7, 9, and 19. All copy-number changes examined were somatic changes because they were not found in blood samples. In contrast, only focal copy number abnormalities were detected in NFPAs, although one case had a chromosomal arm-length loss. In TSHomas with copy number gains, the expression levels of all genes included in the copy number gain region were not significantly different from those of the same genes in TSHomas without copy number gains. The microarray analysis revealed that the expression levels of genes involved in chromosome segregation in TSHomas did not significantly differ from those in NFPAs. Among the genes for which DNA variants were found in the whole exon analysis, copy numbers increased in the region containing the ASTN2 gene in TSHomas, and ASTN2 mRNA expression levels were lower in TSHomas than in NFPAs.
Conclusion: Comprehensive genetic abnormalities were detected in TSHomas. Further studies are needed to clarify their involvement in tumorigenesis.
Thyroiditis is an inflammatory process that can be triggered by infection, autoimmune diseases, medications, post-partum, and in very rare instances, vaccine adjuvants. In this case report, we focus on the latter cause of thyroiditis as we discuss a 35-year-old male who developed palpitations, heat intolerance, and night sweats after receiving the first dose of the COVID-19 Pfizer-BioNTech vaccine. Our patient presented with clinical symptoms of hyperthyroidism ten days after receiving the vaccine and he did not have a painful thyroid. Initial laboratory studies showed a suppressed TSH, elevated free triiodothyronine (FT3) and free thyroxine (FT4), elevated erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) and negative thyroid autoantibodies. Ultrasound showed a heterogenous thyroid with decreased vascularity and Radioactive Iodine Uptake and Scan had less than 5% uptake. Within two months, laboratory tests progressed into the thyroiditis pattern of transient hyperthyroidism followed by hypothyroidism. Based on imaging and laboratory results in conjunction with the clinical progression of our patient, we hypothesize that he developed vaccine-induced thyroiditis. Given the novelty of the COVID-19 vaccine, this hypothesis has yet to be validated by more reports of similar reactions in other patients. Before arriving to this diagnosis, we carefully evaluated for and excluded more common causes of painless thyroiditis including Hashimoto’s, Graves’ disease, and medication-induced thyroiditis. Interestingly, in recent months there have been reports of two females who developed Graves’ disease three days after receiving the Pfizer vaccine (3) and one female who developed Subacute Thyroiditis five days after the same vaccine (16). A possible explanation for this autoimmune reaction is molecular mimicry due to the vaccine’s spike glycoprotein having genetic similarities with a human heptapeptide (15). Additionally, this innovative vaccine contains a nanoparticle with polyethylene glycol lipid conjugates that has been reported to cause anaphylaxis and to induce autoimmune responses in susceptible patients (10-14). Although the numbers of CoVID-19 infections, and thus morbidity and mortality from this pandemic, have significantly decreased with vaccination, like with any other vaccine, adverse reactions will occur (17). We believe that as more patients get vaccinated, the data regarding vaccine-induced thyroid disease will increase.
Background: Thyroid diseases and diabetes mellitus are common endocrine disorders and Euthyroid Sick Syndrome is common in type2 Diabetes.
Objective: Evaluate the thyroid hormones in absence of thyroid diseases among type2 diabetics .
Method: This case control study was done in Sylhet MAG Osmani Medical College (SOMC) and Hospital and in BIRDEM), Dhaka, Bangladesh during the period of 01/012016 to 31/12/2017. 100 type 2 diabetic irrespective of glycemic status, duration of diabetes, BMI and sex were recruited. Age mathed Control (n=100) were also selected without diabetes or IFG and IGT determined according to ADA criteria and having no clinical thyroid diseases or other systemic diseases determined on clinical ground.
Results: Mean±SD of TT3; (ng/dl) in control (88.91±15.88) and in diabetic subject (84.27±22.29) was not significant to each other (p=0.209). Mean±SD of TT4 (µgm/ dl) in control subjects was 8.32±1.64 and in the diabetic subjects was 9.26±1.44, which is similar in both the groups (p= 0.589). FT4: (pgm/ml) in control subjects was 2.60±0.54 and in diabetics was 2.53±1.72. (p= 0.830). FT4. (µgm/ dl) in control subjects was 1.43±0.22 and in diabetics subjects 1.36±0.25. (p 0.179). TSH (µlu/ml) in control subjects was 1.34±1.00 and in diabetic subjects 1.54±1.21. (p: 0.411). FT3; FT4 and TSH showed no significant difference between control and diabetic subjects. Thyroid hormones (TT3, TT4, FT3, FT4) and TSH were reanalyzed according to HbA1c and BMI and showed no significant difference. But when the FPG and HbA1c goes beyond 12 mmol/l and 10% respectively there was more worsening thyroid hormone pictures in comparison to groups whose FPG and HbA1c were below 12mmol/l and 10%. It was also noticed there was more lower thyroid hormone pictures and more worsen glycemic status in patients with low and normal BMI groups in comparison to higher BMI groups.
Conclusion: Uncontrolled type2 diabetes mellitus is related to ESS or NTIS affecting TT3, FT3 and TSH. This feature is more evident if the BMI is low or within the normal range. The more worsen the glycemic status, there was more worsen ESS.
Hypothyroidism has been recognized as an important cause of hyponatremia in only a few case reports and studies. Although thyroid function may be associated with hyponatremia, there is limited evidence on whether primary hypothyroidism itself can produce hyponatremia in patients with uncomplicated hypothyroidism. We report a case of severe hyponatremia that improved after starting intravenous (IV) thyroid hormone therapy for uncomplicated hypothyroidism. A 76-year-old Hispanic woman with a history of hypertension, type 2 diabetes, hypothyroidism, anxiety, and gastroesophageal reflux disease presented to the emergency room (ER) due to persistently elevated blood pressure measurements on home monitoring device. She reported having systolic pressure readings above 200. She also reported anxiety, depressed mood, decreased appetite, and weight loss. Her home medications consisted of hydrochlorothiazide, levothyroxine, and alprazolam. However, she was discovered to have recently stopped taking levothyroxine. On presentation, she was euvolemic. Her blood pressure was 198/96 mmHg, heart rate 102 beat/min, temperature 97.9 °F, respiratory rate 19 breaths/minute, and O2 saturation 98% on room air. She was alert and oriented and did not have any neurological impairments. Initial labs revealed severe hyponatremia with a serum sodium of 117 mmol/L. She was also found to have uncontrolled hypothyroidism with elevated TSH (33.11uU/mL) and decreased free T4 (0.7 ng/dL). Other significant studies to exclude SIADH and adrenal insufficiency as causes of hyponatremia included serum osmolality (249 mOsmol/kg), urine osmolality (535 mOsmol/kg), and am cortisol (31 ug/dL). Patient’s blood pressure was controlled in the ER with IV antihypertensive medication and she was admitted to the ICU for management of hyponatremia. Hydrochlorothiazide was discontinued immediately. Treatment was initiated with salt tablets, fluid restriction, and oral levothyroxine. However, sodium levels and thyroid function did not improve significantly. Once levothyroxine was changed to IV form to adjust for decreased intestinal absorption, sodium increased to 134 mmol/L and TSH decreased to 5.17 uU/mL. She was discharged home on oral levothyroxine. Improvement of hyponatremia with treatment of hypothyroidism highlights the importance of including TSH levels in the diagnostic workup for hyponatremia and initiating the appropriate IV form of levothyroxine.
Introduction:
Corona virus is known to affect various endocrine glands in the body, causing manifestations such as diabetes, pituitary dysfunction and sick euthyroid syndrome. We report a case series of 5 patients, who presented with post COVID-19 Subacute thyroiditis at our center.
Description:
We included 5 patients who presented to Deshmukh Clinic and Research Centre, Pune, India, between January 2021 to June 2021. All these subjects were males with average age of 38.6 years (32 to 53 years) and presented with neck pain (5/5), low grade fever (4/5) of an average duration of 4 weeks. Goiter was present in 2/5. Diabetes and hypertension were present in 1/5. Thyroid tenderness was present in all, even in absence of goiter. Fatigue and weakness were present in 4/5 and 2 of them had weight loss of 8 kg and 15 kg, respectively. One patient had heat intolerance. All had history of COVID -19 prior to the above symptoms and had raised S. T3 and S. T4 with low S.TSH (average :0.029 mIU/ml), raised ESR (average:26.4mm/hour) and CRP (average: 49.8 mg/lit). None of them had TPO positivity. Average duration between detection of COVID-19 infection and presentation with above symptoms was 12.8 weeks. COVID -19 was mild in one case (required home-care), and moderate (hospitalized without oxygen or ventilatory support) in remaining 4/5. All patients responded well to oral prednisolone and thyrotoxicosis management. Average duration of prednisolone therapy was 2 months and average dose of prednisolone required was 6.8 mg per day. All recovered to euthyroid state with normalization of ESR and CRP in 2 months time without any long term thyroid sequelae.
Discussion:
Atypical thyroiditis has been reported during COVID-19 infection by Muller et al, however, our patients presented with subacute thyroiditis nearly 12 weeks after COVID-19 which is known to cause systemic immune activation and thyroid inflammation and hence, may result in thyrotoxicosis or thyroiditis. We therefore suggest that, it is imperative to monitor thyroid function in COVID-19 affected patients, especially those presenting with throat pain or unexplained fever, long after occurrence of COVID-19.
Objective: Between 1988-1994, prevalence of hypothyroidism was estimated to be 4.6% of the US population.1 This data has not been updated, thus currently cited prevalence rates may be inaccurate. The aim of this study was to identify the annual prevalence of hypothyroidism in a US commercially insured population.
Methods: This study was a descriptive, retrospective, claims-based epidemiologic analysis to determine the prevalence of hypothyroidism in the US. Longitudinal, patient-level data on medical and pharmacy claims were collected from the Optum administrative claims database between 01/01/2012 and 12/31/2018. Diagnosis codes, medication use, and laboratory results were analyzed to determine prevalence, which was calculated for each year from 2012-2018. Treatment was determined through pharmacy claims. Eligible patients were ≥18 years and had available claims data for the entirety of the calendar year. Patients were defined as having hypothyroidism if, in a given year, they had >1 prescription for hypothyroidism treatment or >1 claim indicating hypothyroidism using an ICD-9-CM/ICD-10-CM. Any evidence of synthetic or natural triiodothyronine (T3) or thyroxine (T4) treatment, as identified by pharmacy claims, was defined as treatment. Data are presented as percentage of patients in the database diagnosed with hypothyroidism within each calendar year.
Results: Between 2012 and 2018, data from over 67 million people were available in the Optum database, ranging from 8.3 to 11.3 million per year. Of those, approximately 7 million (10.5%) had claims indicative of hypothyroidism. When assessed yearly, prevalence grew steadily from 9.5% in 2012 to 11.5% in 2018. For every year of the study period, >81% of patients received T4 treatment for hypothyroidism, with >78% receiving T4 monotherapy. On average, 2.2% of patients received T3 monotherapy and 2.8-3.8% received dual T3/T4 medications. During this time, patients diagnosed with hypothyroidism but untreated ranged from 12.7% to 15.4%.
Discussion/Conclusion: This study demonstrated that prevalence of hypothyroidism in a commercially insured US population steadily increased, as did the percentage of hypothyroid-diagnosed patients not receiving treatment, between 2012 and 2018 and that T4 monotherapy dominated hypothyroidism treatment.
References: Hollowell JG et al, J Clin Endocrinol Metab, 2002;87(2):489–499
Objective: As a result of the COVID-19 pandemic, consumer-initiated, mail-in testing has entered the mainstream for both routine and screening tests. The aims of this pilot study were to characterize mail-in test usage and telemedicine service utilization among a consumer-initiated test population with regard to the use of thyroid function testing. Methods: A retrospective analysis of mail-in thyroid test and telemedicine utilization was assessed from a pilot program between March 2021﹣May 2021. Mail-in thyroid test biomarkers included thyroid-stimulating hormone (TSH), free T3, free T4, and thyroid peroxidase antibodies (TPOab). Informational consults with an independent physician were offered to all test-takers over the period, including individuals with a TSH indicative of hyperthyroidism. Individuals aged 18 – 70 years with no known contraindications, as determined by the physician network, and a TSH > 4 mIU/mL or who were currently taking medication to treat hypothyroidism were eligible for a thyroid management physician consult, and subsequent prescription when clinically appropriate. Service utilization was assessed by opt-in rate. Results: Mail-in test usage (N=5,266) and opt-in telemedicine services utilization (N=994) were greater among females, 87.3% and 86.8% versus 12.7% and 13.2% for males. Utilization of mail-in tests and telemedicine services was highest among individuals aged 18-44, 74.2% and 75.8% versus 17.1% and 16.4% for individuals aged 45-55, 7.5% and 6.5% for individuals aged 56-69, and 1.1% and 1.3% for individuals aged 70 and older, respectively. Among individuals who opted-in to telemedicine services, 9.5% (N=94) had a thyroid management physician consultation and 4.2% (N=42) received a prescription. The majority of opt-in telemedicine users (90.5%, N=900) received a non-treatment, informational consultation and were offered to schedule follow-up communication. Conclusion: The COVID-19 pandemic accelerated interest and utilization of mail-in testing and telemedicine services. In combination these services can provide an effective strategy for increasing access to early detection and management of thyroid dysfunction as well as monitoring individuals with subclinical disease. The observed female and age bias among our sample supports targeted outreach efforts to further understand these and additional factors that influence utilization of mail-in thyroid test and telemedicine services among older populations who have an increased prevalence of thyroid disease.
Background
Thyroid function tests (TFTs) are routinely checked in hospitalized patients with or without pre-existing thyroid disease, sometimes even without suspicion of thyroid derangement. Although alternative diagnoses may explain presentations, cultural norms often encourage routine assessment. The objective of this study was to evaluate whether routine measurement of TFTs is beneficial, unnecessary, or even harmful in cost-effective care for hospitalized patients.
Methods
This is a retrospective observational study of 2278 patients admitted to an academic hospital over a 5.5-month period who had their TFTs checked. Chart notes were reviewed to evaluate for pre-admission diagnosis of thyroid disease and clinical indications for ordering TFTs. Results of thyroid function testing were reviewed. Medical records of those with abnormal TFTs were reviewed to assess whether thyroid medication was initiated or adjusted.
Results
Of the thyroid function tests ordered, 20.1% were ordered due to suspicion of thyroid dysfunction, 20.8% due to history of thyroid disease, and 59.0% for reasons not directly related to thyroid dysfunction. 27.3% of those tested had abnormal results. The percentage of abnormal TFTs that led to medication initiation or adjustment was 15.1%, 12.1%, and 5.7%, for those tested on the basis of history of thyroid disease, suspicion of thyroid dysfunction, and reasons not directly related to thyroid dysfunction, respectively. Overall, 65 patients were started on thyroid medication or had the dosage of their thyroid medication adjusted, which represents 10.4% of those with abnormal TFTs and only 2.9% of those tested.
Conclusion
Abnormal thyroid function test results are common, but a disproportionate amount of tests are needed to find a small percentage of clinically significant thyroid dysfunction, of which only a low percentage lead to changes in management. TFTs checked for reasons not directly related to thyroid dysfunction had the lowest percentage of results that led to medication initiation or adjustment, while those checked on the basis of history of thyroid disease had the highest. Education on this topic should be provided to inpatient providers to limit thyroid function testing to instances in which they are clinically indicated and abnormal results would lead to changes in management.
Objective: Historically, amiodarone-induced thyrotoxicosis (AIT) has been classified into three clinical types (type 1, type 2, and mixed), which guides initial treatment strategy. However, the correlation between histopathology and clinical type has not been clearly defined. This study aimed to describe histopathologic findings in a cohort of AIT cases in the effort to better understand the particularities associated with each AIT subtype.
Methods: We retrospectively identified all patients diagnosed with AIT that underwent thyroidectomy at Mayo Clinic, Rochester over a 17-year-period (2002-2019). The pathology material was retrieved and evaluated by an experienced thyroid pathologist, blinded to clinical information. Clinical data were abstracted separately and used to define AIT subtypes.
Results: 19 AIT cases, four of whom were women, were included in the analysis. The mean age was 63 years (SD 12) at the time of thyroidectomy. All had undergone total or near-total thyroidectomy with mean gland weight of 28 grams (SD 37). Average length on amiodarone therapy was 4.2 years. Upon pathology review, all cases had some degree of background hyperplasia. In cases defined clinically as type 1 (n=5), 1 had nodularity although all five had some degree of inflammation (one had evidence of chronic thyroiditis while three had evidence of vacuolated follicular cells in areas of inflammation). Of those identified clinically as type 2 (n=3), all had minimal or absent inflammation and two had normal follicular cells. All three had been treated with glucocorticoids prior to thyroidectomy, and one had persistently high thyroid levels prior to surgery. 11 cases could not be classified as type 1 or 2 with available data due to mixed features of type 1 and type 2. Of these, 10 had evidence of inflammation, eight had evidence of follicular disruption, and four were found to have chronic lymphocytic thyroiditis. One case had normal pathologic findings aside from gland size with marked hyperplasia (60.3 grams).
Discussion/Conclusion: Although case numbers were small, these data suggest that both inflammation and follicular hyperplasia are present in most, if not all AIT cases and likely contribute to the clinical picture of AIT in varying degrees.
Objective: Resmetirom (MGL-3196) is a liver-directed, orally active selective thyroid hormone receptor-𝛽 agonist in Phase 3 development for the treatment of NASH with significant liver fibrosis. In Phase 2 resmetirom reduced MRI-PDFF (magnetic resonance proton-density fat fraction) and NASH on liver biopsy. MAESTRO-NAFLD-1 is a ~1200 patient double-blind 52-week NASH trial that includes open label active resmetirom treatment non-cirrhotic and cirrhotic arms (n~250).
Methods: 105 NASH patients with well-compensated cirrhosis (Child-Pugh A) enrolled in MAESTRO-NAFLD-1(NCT04197479) receiving open-label resmetirom (80-100 mg); 31.4% were receiving thyroxine treatment for hypothyroidism. Baseline characteristics and resmetirom treatment effects at weeks 12-24 were evaluated according to thyroxine treatment.
Results: Baseline, thyroxine treatment (TT) group (n=33) compared to (v) control (CTRL) group (n=72): Mean age, 65 v 61.5; female, 79% v 57%; BMI, 33.9 v 36.1; diabetes, 64% v 74%; hypertension, 82% v 74%; ASCVD score, 17.1% v 15.7%; MRI-PDFF, 7.1% v 8.8%; fibroscan CAP, 328 v 297, p=0.017; fibroscan VCTE, 25.2 v 22.2 kPa; MRE (MR elastography) 6.0 v 5.5 kPa; ALP, 119 v 91 IU, p=0.01; GGT, 125 v 97 IU, p=0.024. Other indices were not different.
TH (TT v CTRL): TPO, 38.8 v 24.8, NS; FT4, 1.26 v 1.05 ng/dL (p<0.0001); TSH, 2.4 v 1.9 IU, NS; FT3, 2. 6 v 2.9 pg/ml, p=0.001; RT3, 26.0 v 19.7 pg/ml, p=0.0001. Non-cirrhotic NASH (n=176),TPO: TT 106 v CTRL 25.1, p=0.0001. Low FT3, high RT3 and high FT4 had also been observed in TT groups in non-cirrhotic NASH (AACE 2021).
In TT, CTRL, at Week 16, MRI-PDFF was -36%, -33% (p<0.0001); In both groups, GGT, ALP, fibrosis biomarkers, and RT3 were reduced. Both groups: LDL-C -23%; apoB -21%; TGs -37 mg/dL (p<0.0001). No thyroid axis or VS changes noted; AE (>5%): ~10% loose stools, only at the beginning of therapy (not different between groups).
Conclusion: Thyroxine treatment is common in NASH cirrhosis and does not correct underlying hepatic hypothyroidism. Resmetirom appears to be safe and effective in lowering lipids, and reducing biomarkers of NASH and fibrosis independent of thyroxine treatment.
Objective
Subclinical hypothyroidism (SCH) is a common biochemical diagnosis with controversial management strategies. We aimed to describe the clinical presentation of patients with SCH and compare clinical features among those who started thyroid hormone replacement and those who were observed.
Methods
Retrospective observational study (University of Arkansas for Medical Sciences, University of Florida, Mayo Clinic and University of Nuevo Leon, Mexico) of patients with SCH (defined as elevated TSH and normal FT4/TT4 levels). Patients who were pregnant, postpartum, severely ill or using thyroid-affecting medications were excluded. Variables of interest were extracted from medical records using piloted forms. Summary statistics (mean, standard deviation) and group comparisons (treated/not treated) are presented.
Results
We included 796 patients with SCH. The mean age was 54 years (18), 34% were ≥65 years, 65% were women, with mean TSH 6.3 mIU/L (2.8). Overall, 21% of patients were started on thyroid hormone treatment. Forty one percent of patients had no symptoms of hypothyroidism, with a higher proportion of asymptomatic patients in the untreated group (43% vs 32%, p=0.0058). The most common symptoms were fatigue (29%) and weight gain (13%), and both were more common among treated patients (41% vs 26%, p=0.0002 and 21% vs 11% p=0.0027). No statistical difference was found between groups for other hypothyroidism-related symptoms. Twenty percent of patients had no significant comorbidities (19% treated vs 20% untreated, p=0.8261). History of cardiac arrythmia was more common in the untreated group (9.7% vs 4.2% p=0.0277) and history of goiter was more common in the treated group (3.6% vs 0.2% p=0.004). Abnormal thyroid physical exam was more common in treated patients (17% vs 9%, p=0.0063).
Discussion/conclusions
In this large, multicenter study of patients with SCH, most were symptomatic and had associated comorbidities. Fatigue and weight gain were the most common complaints and along with abnormal thyroid physical exam and history of goiter were associated with thyroid hormone treatment initiation. History of arrythmia was less common in those treated. These findings suggest that symptoms/comorbidities are common in patients with SCH and in addition to age and degree of TSH elevation can guide management strategies.
Objective: Radioactive iodine (RAI) is considered a safe, efficient and low-cost treatment of hyperthyroidism, which can obviate complications associated with thyroid surgery. The use of RAI therapy in hyperthyroid patients only became available in 2017 at our institution. This work aim to evaluate the outcome of the first years of RAI treatment in these patients, and to determine the influence of biochemical control and iodine activity in this outcome. Methods: In this retrospective study, we included all hyperthyroid patients from our institution submitted to radioiodine treatment during the last three years. Graves Disease (GD) was diagnosed when thyroid autoantibodies were documented in the presence of hyperthyroidism. Together with ultrasonography, thyroid scintigraphy was used to define Toxic Adenoma (TA) or Toxic Multinodular Goiter (TMG). Statistical analysis was performed using SPSS in version 23. Results: We evaluated 73 patients with a mean age at the time of treatment of 51.9±15.1 years (mean±SD), 76.7% were female patients. The majority of patients (n= 35; 47.9%) had GD, 26% (n=19) TMG and 26% (n=19) TA. The majority of patients (n=48; 66%) were treated before RAI with antithyroid drugs, methimazole (95.8%) or propylthiouracil (4.2%). The mean duration of treatment with antithyroid drugs was 38±70.8months.The median dose of RAI was 12.5mCi (min-max:10-20) in GD, 14.13mCi (min-max:10-20) in TMG and 36mCi (min-max:1-48) in TA. Hypothyroidism was achieved in 48.6% percentage of patients with GD after the first RAI treatment. Regarding TMG and TA, 63.2% and 68.4% of patients, respectivly, achived normal thyroid function. The patients with GD that achieved hypothyroidism with the first RAI treatment had lower mean T4L (0.87±0.26 ng/dl), lower mean titers of TRABs (5.70±4.9U/L) but were submitted to lower mean doses of RAI therapy (10.39±1.04mCi), when compare with patients that do not achieved hypothyroidism (T4L 1.56±0.84 ng/dl; TRABs 13.13±16.8U/L; RAI 12.86±3.93mCi). No other clinical or demographic variables have shown influence the outcome. Conclusion: High doses of RAI seems to be responsible for the onset of hypothyroidism, but particularly in patients with GD another factors (T4L; TRABs) may be more relevant.
Objective
Graves Orbitopathy is disabling and disfiguring and has a substantial negative impact on quality of life. Medical therapies to reduce inflammation are widely used, but there is limited data from clinical trials beyond 6 months of follow-up.
Methods
3 year follow up of a subset of the CIRTED trial (N=68) which randomized patients to receive high dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. We assessed 3 year outcomes including CAS, Ophthalmopathy Index, Total Eye Score, GOQOL visual function and visual appearance and the need for surgical intervention.
Results
CAS, Ophthalmopathy Index and Total Eye Score improved over 3 years (p<0.001). CAS fell from baseline (Median 5 IQR 4-5) to a Median of 1 (IQR 0-1) by 3 years. Ophthalmopathy Index fell from 9.45 (SD 3.95) to 6.02 (SD 2.09), Total Eye Score fell from 14.9 (SD 6.27) to 6.33 (SD 4.65). Quality of life at 3 years remained poor, 25% of patients had a GOQOL-Visual Function of 75 or lower and 54.2% had a GOQOL-Visual Acuity of 75 or lower. 24/64 individuals (37.5%) with surgical outcome data required surgical intervention.
Disease duration of greater than 6 months before treatment was associated with increased need for surgery OR=16.8 (95%CI 2.95, 95.0) p=0.001. Higher baseline levels of CAS, Ophthalmopathy Index and Total Eye Score were associated with requiring surgery, although early improvement in CAS was not associated with a reduced need for surgery.
Conclusion
In this first long-term follow-up from a clinical trial of thyroid eye disease, 3 year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS to low levels in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes. Further studies are required to determine if early intervention results in improved outcomes.
Objective: A patient’s trust in their physician is an essential feature of the patient-physician relationship with important implications for treatment outcomes and a patient’s wellbeing. Thyroid cancer is the second most common cancer in Hispanic women in the United States. However, physician trust has not been assessed in this underrepresented patient population.
Methods: Between May and December 2019, we surveyed Hispanic women with diagnoses of thyroid cancer reported to the Los Angeles Surveillance Epidemiology and End Results registry in 2014-2015, and who had previously completed our patient survey on thyroid cancer in 2017-2018. We assessed acculturation with the Short Acculturation Scale for Hispanics (SASH) and health literacy with a validated single-item question of “How confident are you filling out medical forms by yourself?” with response categories based on a five-point Likert scale from “extremely” to “not at all.” Main outcome was patients’ trust in their thyroid cancer physician measured with the 10-item Wake Forest Trust in Physician Scale. We generated descriptive statistics for all variables and used a Wilcoxon rank sum test to assess the relationship between physician trust and acculturation and between physician trust and health literacy.
Results: Of the 273 participants (80% response rate), median age at diagnosis was 47 years (range 20-79); 49% were low-acculturated, and 25% had low health literacy. Median physician trust score was 42 (range 10-50, higher scores indicate more trust). Lower physician trust scores were observed among Hispanic women with low vs high health literacy (median score 39 vs 42, P=0.04). No significant difference in physician trust scores were observed among Hispanic women with low vs high acculturation (P=0.56).
Discussion/Conclusion: Our findings demonstrate that Hispanic women have relatively high trust in their thyroid cancer physicians, similar to that reported by Hall et al in their validation of the Wake Forest Scale in a national patient sample. However, Hispanic women with thyroid cancer and low health literacy reported less trust in their thyroid cancer physician compared to those with high health literacy. This study highlights the need for improving physician trust in this vulnerable population in order to improve care for thyroid cancer patients.
Objective. To assess the role of thyroglobulin determination in the population of pregnant women as a marker of iodine deficiency.
Material and methods. A prospective study was performed, the sample was continuous. 264 pregnant women were included in the 1st trimester, when registering with the antenatal clinic No. 2 in Tyumen from July to December 2019. Pregnant women were questioned, examined by an endocrinologist, the morning portion of urine was taken to determine the excretion of iodine in the urine, and blood was taken for research thyroglobulin and antibodies to thyroglobulin.
Results. The average age of pregnant women was 29 ± 5.2 years. The average gestational age on examination is 9.9 weeks.
The median concentration of ioduria in pregnant women in the 1st trimester was 154.4 μg / l. Ioduria less than 20 mcg / l was not detected, 4.5% of women had less than 50 mcg / l.
The median thyroglobulin was 17.7 ng / ml, the interquartile range (Q1 - Q3) was 9.27 - 25.35 ng / ml. Belgian colleagues proposed a median TG of less than 20 ng / ml as a criterion for iodine deficiency, while other authors suggested indicators of 13 and 10 ng / ml. In our study, there was no correlation with the level of iodine excretion in urine (r = 0.032; p = 0.72), which does not allow us to unambiguously interpret this indicator.
Conclusions. In terms of the median ioduria, against the background of group prophylaxis in the population of pregnant women, the optimal iodine supply was achieved. Further large observational studies in the population of pregnant women are needed to evaluate thyroglobulin as a criterion for iodine deficiency.
Introduction:
Ectopic thyroid and ectopic parathyroid are usually due to defect in their migration journey from their embryological origin (either failure, incomplete or progression). It raises a diagnostic challenge for the clinician. To our knowledge this is the first reported case of Ectopic thyroid and Ectopic parathyroid gland together in the same patient.
Description of the case:
74 Year old female known case of DM, HTN and BA presented to primary health care physician complaining of neck swelling for one year. Her investigation showed normal thyroid and calcium level and low Vitamin D. Ultrasound neck showed multinodular goiter with the the largest nodule at the right lobe measuring 2.8cm. And the largest at the left lobe measuring 3.4cm, FNA of both nodules came back as Benign.
during folow up laboratory investigation revealed elevated calcium and PTH. Sestamibi scan showed two inferior parathyroid gland adenomas with probably another small right upper parathyroid adenoma suggestive of multigland disease. While CT neck showing bilateral Thyroid nodules, evidence of retrosternal mass measuring 4.0 cm exhibiting similar density and enhancement pattern of the known multinodular goiter and no definite communication between these retrosternal mass lesion and both thyroid lobes.
Patient underwent total thyroidectomy (Histology: incidental finding of unilateral micro PTC 7mm ), resection of retrosternal mass (Thyroid Nodular Hyperplasia ) and neck exploration. with Left and Right lower parathyrodectomy: (Cellular parathyroid tissue consistent with parathyroid adenoma/hyperplasia) and Left upper parathyroidectomy : (Benign normocellular parathyroid gland ). Post-operative PTH remained high. Sestamibi/ SPECT parathyroid scan done and showed large ectopic functionally active upper mediastinal parathyroid gland adenoma. Mediastinoscopy was performed and ectopic parathyroid adenoma was resected ( upper mediastinal adenoma at the left tracheoesophageal groove). A reimplantation of small part of the gland in the left sternocleidomastoid muscle was done .
Post operative PTH was normal and remaind so in subsequent follow up visits.
Discussion:
Ectopic thyroid tissue and ectopic parathyroid gland though uncommon they may coexist. The presence of ectopic retrosternal thyroid tissue could mask mediastinal parathyroid adenoma in the context of multigland disease. Studies including ultrasound, sistamibi syntighraphy with SPECT, MRI and CT are required for full preoperative assessment.
Background:
Epigenetic dysfunction contributes to development of thyroid cancer. Aberrant histone lysine methylation that is controlled by the histone lysine (K)-specific demethylase family of genes (KDMs) has been demonstrated in breast, prostate, and ovarian cancers. The role of KDMs in development of thyroid cancer is unknown.
Objective:
In this study we examined expression of histone lysine-specific demethylases (KDM5C, KDM5D and KDM6A) in benign and malignant thyroid tumors.
Material and Methods:
Thyroid tissue samples from 46 patients (34 female and 12 male) presenting with benign (16) or malignant (30) thyroid lesions were used for analysis. Lymph node metastases were detected in 12/30 cancer patients. The nucleic acids were extracted from tumors and the corresponding normal tissue using the AllPrep DNA/RNA Micro Kit (Qiagen) on the QIAcube Connect. RNA concentrations and qualities were assessed by NanoDrop 2000. Three different sets of primers-probes were used for amplification of KDM5C, KDM5D and KDM6A by real-time PCR.
Results:
In benign thyroid lesions the mRNA levels of KDM5C, KDM5D and KDM6A were upregulated as compared to the corresponding normal thyroid in 3/16 (18.7%), 2/16 (12.5%), and 4/16 (25%) cases respectively. In thyroid cancers, the mRNA levels of KDM5C, KDM5D and KDM6A were upregulated in 13/30 (43.3%), 2/30 (6%), and 7/30 (23.3%) cases respectively. In thyroid cancer tissue, KDM5C and KDM6A were detected in samples from male and female patients, whereas KDM5D was detected only in thyroid samples from male patients. The levels of KDM5C, KDM5D and KDM6A expression were not significantly associated with patient’s age. There were no significant differences between the mRNA levels of KDM5C, KDM5D and KDM6A in cancers presenting with or without metastases. Overexpression of KDM5C, KDM5D or KDM6A was found in 2/4 tumors with BRAFV600 mutations, and in 2/5 tumors harboring RAS mutations.
Conclusions:
The development of both benign and malignant thyroid tumors appears associated with aberrant expression of histone demethylases. The sex-specific patterns of KDMs expression in thyroid tissue suggest that epigenetic mechanisms controlling thyroid carcinogenesis may differ in male and female patients.
Introduction: RET fusions have been reported in 22% to 45% of children and young adults with papillary thyroid carcinoma (PTC). Selpercatinib, a highly selective RET inhibitor, was recently approved in children 12 years and older with radioactive iodine (RAI) refractory advanced or metastatic RET altered PTC.
Description of the Case: A 13-year-old female presented with multiple large neck masses. Biopsy of a cervical lymph node demonstrated PTC harboring a RET-NCOA4 fusion. CT scan revealed bilateral level II, III, IV, V, and VI lymphadenopathy and pulmonary metastases. Total thyroidectomy and bilateral central and lateral lymph node dissection revealed follicular variant PTC with TNM staging T4aN1bM1. Patient received 40 mCi I-131. Post-RAI WBS revealed lung metastases and bone metastases involving the spine and pelvis. TSH stimulated Tg was greater than 5000 ng/mL. Patient received two additional RAI treatments with a cumulative dose of 285 mCi. She transferred care to our institution 17 months after her last RAI treatment for persistent RAI refractory disease and increasing dyspnea. She had tachypnea with bilateral rales at rest and worsening dyspnea with exertion. Tg on levothyroxine was 232.9 ng/mL with a TgAb of 2 IU/mL. FDG-PET CT revealed extensive lung metastases, sclerotic lesions throughout the spine and left humeral head, and multiple hyperdense lesions in the brain. MRI brain showed numerous enhancing metastatic parenchymal lesions with largest lesion measuring 1.7 cm. I-123 WBS showed avid intracranial and pulmonary lesions with no uptake in bone lesions. Oral selpercatinib was initiated at 120 mg twice per day. After 4 weeks, patient reported mild improvement in breathing, and Tg improved to 21.2 ng/mL. After 8 weeks, MRI brain showed interval decrease in size of the metastatic lesions and resolution of some lesions. CT chest revealed stable pulmonary lesions. The patient remains on selpercatinib for 3 months with no adverse events and continues to have clinical improvement.
Discussion: Selpercatinib is effective in children with metastatic RET fusion-positive PTC that is refractory or not amenable to RAI treatment and shows activity against intracranial lesions. Further investigations are necessary to determine length of treatment and durability of response.
Introduction
The treatment options are still very limited for patients who developed progressive radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC), especially for those resistant to the first-line TKIs like sorafenib or lenvatinib. Anlotinib, as an antiangiogenic TKI targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit, has shown a promising disease control rate in advanced RAIR-DTC and medullary thyroid cancer. In this case, we applied a multi-dimensional strategy to evaluate the efficacy of anlotinib in a RAIR-DTC patient who has failed in the treatment of sorafenib, in terms of glucose metabolism by 18F-fluorodeoxyglucose (18F-FDG) PET/CT, angiogenesis by 68Ga arginine–glycine–aspartic acid (RGD) PET/CT targeting avβ3, and traditional methods including structural imaging and serum thyroglobulin (Tg).
Description of the Case
A 64-year-old woman with recurrent and metastatic RAIR-DTC has been evaluated as progression after an 8-months sorafenib treatment upon a suspicious mediastinal lymph node metastasis being observed. The patient was then enrolled in an exploratory clinical trial of anlotinib for further help. After 2 circles of a 12mg p.o. daily with a 2-week on/1-week off regimen, an inspiring efficacy of anlotinib was observed on functional imaging, structural imaging, and biochemical dimensions. The SUVmax of her target lesion in the left lung significantly decreased by 40.1% and 55.3% on FDG (from 9.94 to 5.95) and RGD (from 4.50 to 2.01) PET/CT scans, respectively. Along with the rapid changes in molecular images, a 22.2% shrinkage of the lesion in the longest diameter (from 27mm to 21mm) was observed, and the serum thyroglobulin decreased from 131.00ng/mL to 37.00ng/mL (thyroglobulin antibody level remains stable about 1000IU/mL).
Discussion
Significant effects of anlotinib have been observed by this multi-dimensional evaluation as a second-line treatment in a RAIR-DTC patient, and the anti-angiogenesis effect of anlotinib has been revealed in vivo by 68Ga-NOTA-PRGD2 PET/CT at the first time. These encouraging responses verify the value of PET imaging in early response assessments of anlotinib in RAIR-DTC, while the correlation between PET parameters and further response needed to be explored in the future.
Introduction:
Among differentiated thyroid cancer cases, papillary thyroid carcinoma accounts for the majority of cases followed by follicular thyroid carcinoma. Poorly differentiated and anaplastic thyroid carcinomas are rare entities but are often associated with aggressive disease. Though distant metastasis from thyroid cancer is rare, the most common sites of involvement are the lung and the bone. Adrenal metastasis is uncommon and is often associated with lung and bone involvement.
Description of the Case:
A 68-year-old Caucasian man presented with abdominal pain and a subsequent CT scan demonstrated a heterogeneously enhancing 4.7 cm x 4.6 cm x 3.8 cm right adrenal mass concerning for a malignant lesion. He underwent right laparoscopic adrenalectomy with pathology revealing a 4.3 cm metastatic carcinoma. Immunohistochemistry staining was positive for thyroglobulin, TTF-1, and PAX8 suggestive of thyroid, lung or kidney origin. Subsequent evaluation to identify a primary malignancy revealed a 1.2 cm irregularly shaped nodule in the isthmus of the thyroid gland. We performed a fine needle aspiration biopsy of the thyroid nodule with cytopathology suspicious for follicular neoplasm. Molecular analysis showed a positive HRAS mutation. He subsequently underwent total thyroidectomy with pathology noting a 1.2 cm solid variant papillary thyroid carcinoma with focal angioinvasion and no lymphatic invasion. He received adjuvant radioactive iodine ablation with 184 millicuries of I-131 with subsequent whole-body scan negative for distant metastatic disease. One year following initial treatment, serum thyroglobulin is undetectable and neck ultrasound is without evidence of disease persistence.
Discussion:
We present a case of solid-variant papillary thyroid carcinoma and adrenal metastatic disease with excellent response to initial therapy. Adrenal metastasis from thyroid cancer is a rare occurrence and is generally associated with a poor prognosis. There is currently limited data on solid-variant papillary thyroid carcinomas associated with adrenal metastatic lesions.
Introduction
Studies have suggested that multikinase inhibitors (MKIs) are associated with prolonged progression-free survival in patients with radioiodine refractory differentiated thyroid cancer (RAIR-DTC). Currently, disease progression is primarily factored into the initiation of MKI, while the optimal timing of MKI therapy remains controversial. Here we report a case of metastatic RAIR-DTC patient who showed long-term clinical benefit from apatinib treatment.
Description of the Case
A 64-year-old woman underwent 3 times thyroidectomy and was confirmed to papillary thyroid cancer (PTC) by pathology. She presented as progressive pulmonary metastases and rising serum thyroglobulin (Tg) after 7 times radioiodine therapy of which accumulative 131I activity was up to 1100 mCi, with no radioiodine uptake over the metastases, and was identified as RAIR-DTC. Then she was eligible for a phase Ⅱ trial of Apatinib and started by 500 mg once daily for only one measurable 10.5mm lesion in pulmonary metastatic diseases in 2016 and a suppressive Tg level of 15.2 ng/ml. There was a quick shrinkage of the target lesion (6.4 mm) and a Tg decline to 1.72 ng/ml upon assessment after 1st cycle (28 days). Then it cavitated thereafter, and there had been a durable response biochemically and structurally from cycle 2 to cycle 26. It slowly progressed and assessed as stable disease (RECIST criteria v1.1) till cycle 55, when progressive disease was observed for the targeted lesion increased to 11.3 mm by cycle 56 (April 2021). Throughout the whole therapy, no severe adverse effect was observed, thereby no dose reduction was requested.
Discussion
We describe an elderly woman with progressive oligo metastatic RAIR-DTC who demonstrated a 53-month-progression-free survival (PFS) long-term benefit from 500 mg qd apatinib treatment with manageable adverse effects. The encouraging outcome in this case demonstrates that apatinib is highly effective in RAIR-DTC patients, and early MKI therapy can be considered for low-considerable tumor load. The promising outcome together with the relatively low progressive tumor burden upon initiation of apatinib urge a reconsideration of the optimal timing for MKI therapy.
Introduction
Metastatic follicular thyroid carcinoma (FTC) is rare in pediatrics. Osseous and lung metastases are the most common FTC metastases sites. Rare metastatic sites reported in adults include lumbosacral spine, bladder, brain, liver, and kidney. FTC may be associated with germline mutations or as part of tumor predisposition syndromes in children. We present the first known pediatric case of FTC with ocular metastasis associated with a pathogenic germ-line variant in CHEK-2.
Description of the Case
A healthy 2-year-old female presented to pediatric endocrinology with enlarging right neck mass. Ultrasonography confirmed multiple right lobe nodules (largest 1.7x.1.3x1.3 cm) and perithyroidal lymph nodes; thyroid function tests and thyroid antibodies were normal. Fine needle aspiration was inconclusive, and she ultimately underwent hemithyroidectomy at another institution. Pathology results were reported as chronic lymphocytic thyroiditis. Three years later, routine vision screening identified complete loss of vision in her left eye resulting from choroidal mass and retinal detachment, which became acutely painful. Left eye enucleation was performed at a different institution with pathology reported as ectopic normal thyroid tissue. Upon returning to pediatric endocrinology, an I-123 scan showed uptake consistent with osseous and cervical spinal metastases. Review of the pathology from initial hemithyroidectomy and ocular enucleation confirmed FTC with ocular metastasis. Completion thyroidectomy was performed, and pathology identified normal thyroid tissue with a 0.25 cm minimally invasive FTC. Post-operatively, spinal MRI demonstrated substantial cord edema surrounding the cervical lesion. Her neurologic exam was normal. She was treated with dexamethasone and external beam radiation followed by treatment with 150 mCi I131. Next generation sequencing performed on completion thyroidectomy specimen revealed CHEK-2 germline pathogenic variant. Molecular studies of the primary FTC are pending.
Discussion
This challenging case highlights the need for high index of suspicion for malignancy in a thyroid mass presenting at an unusually young age. The finding of an unusual site for thyroid ectopy increased the suspicion of malignancy. Further testing (including iodine uptake scans) should be considered when a pathological diagnosis does not align with clinical suspicion for metastatic disease. The case emphasizes the need for expert pathologist consultation for timely identification of rare conditions.
Introduction
BRAF and RAS point mutations, and gene fusions involving RET, NTRK, or PAX8-PPARG are well described in thyroid carcinomas. PAX8-PPARG [t(2;3)(q13;p25)] gene fusion is found in approximately 30% of follicular thyroid carcinomas and 1-5% of follicular variant of papillary thyroid carcinoma. PAX8-PPARG oncoprotein is a fusion of two transcription factors and contains both DNA binding domains of parent proteins. The PPARG portion is particularly important in directing PAX8-PPARG to its target genes. Chromosomal location 3p25 is a breakpoint hotspot region. Another transcription factor, CREB3L2 has been reported to partner with PPARG (CREB3L2-PPARG, t(3;7)(p25;q34) in thyroid follicular carcinoma. Here, we report another transcription factor, PHF3, as a novel fusion partner of PPARG in an encapsulated papillary thyroid carcinoma.
Description of the Case
A 70-year-old female presented with multiple thyroid nodules, ranging in size from 1-2 cm. Initial biopsies were benign. Serial ultrasounds revealed considerable growth of one nodule in the left lobe, from 1.3 cm to 2.2 cm, over the course of one year. Subsequent ultrasound guided fine needle aspiration of this lesion revealed a cytopathology diagnosis of “Suspicious for Follicular Neoplasm” (Bethesda category IV). Nuclear enlargement, crowding, and abundant nuclear grooves were identified. Reflex Next generation sequencing (NGS) analysis for detection of gene mutations (in 30 genes) and gene fusions (involving 18 oncogenic genes) was positive for a PHF3-PPARG fusion. While a fusion between PHF3 and PPARG genes has not been previously reported, the PPARG breakpoint observed in this fusion was identical to that observed in the PAX8-PPARG fusion. Left thyroid lobectomy performed two months later revealed an encapsulated papillary carcinoma and an incidental classic papillary thyroid carcinoma. Repeat NGS analysis confirmed the PHF3-PPARG gene fusion, in the encapsulated papillary carcinoma.
Discussion
Gene fusions are important driver events in different types of cancers. They also act as diagnostic markers or as therapeutic targets. To our best knowledge, PHF3 is the third transcription factor and gene fusion partner of PPARG driving thyroid carcinoma. It provides further evidence of chromosomal location 3p25 being a breakpoint hotspot region and can provide potential therapeutic considerations.
Primary Squamous Cell Carcinoma of the Thyroid (SCC-T) is a very rare, aggressive malignancy accounting for <1% of primary thyroid cancers with grave prognosis. We report a rapidly progressive SCC-T with lung and bone metastases.
A 65-yr-old Nepalese female with history of Type 2 diabetes, hypertension, and longstanding goiter presented with odynophagia, dysphagia, and dysphonia for few weeks. Thyroid ultrasound showed ~ 4 cm right thyroid mass. FNA-thyroid showed keratinized squamous cells with atypia. She underwent total thyroidectomy, bilateral central neck and right posterolateral level II-V neck dissections. Postoperative FDG PET-CT showed no evidence of residual disease. The 4.1x3.9x3.2 cm thyroid tumor was staged as pT3a,pN0,M0 with microvascular and lymphatic invasions. Tumor cells were positive for PAX8, Ki-67, P40, and TTF-1 (in entrapped residual follicular elements), but negative for HBME-1. Second pathologist commented on unusual pathology as “invasive, moderately-differentiated squamous cell carcinoma (SCC) arising in a preexistent follicular thyroid nodule”. She completed radiation therapy (XRT) 16/30 fractions. 4 months after thyroidectomy, she was found to have metastasis in spine and received palliative XRT. Multiple new small lung nodules with a 16 mm discrete one in right upper lobe were subsequently found on PET-CT. CT-guided lung nodule biopsy showed invasive moderately-differentiated keratinizing SCC. Distinguishing primary lung cancer with thyroid metastasis or vice versa or two metachronous primaries is often difficult. We believe this is SCC-T with metastasis. Molecular Lung Panel revealed no abnormalities. Based on high PDL-1 (70%), undetectable rearrangements of ALK and ROS1, she was started on carboplatin, nab paclitaxel, and pembrolizumab. She is tolerating the regimen and is euthyroid on levothyroxine 125 mcg daily.
WHO (2017) classification defines SCC-T as exclusive squamous carcinoma with no other cancer cells component. Positive PAX-8 with comprehensive immunohistochemistry (IHC) panel will help differentiate primary from metastasis. There is still no standardized treatment guideline due to its rarity. Radical tumor resection is ideal with better survival. SCC-T is not amenable to thyroid suppression or radioiodine therapy. Chemotherapy or radiotherapy has not been effective. Targeted therapies has been promising with extended survival rate. Exploring more about genomic analysis will guide us new targeted and immunotherapies.
Introduction:
Thyroid cancer has rarely been associated with elevated thyroid function. Thyroid storm typically develop as an exaggeration of the underlying hyperthyroidism, caused by Graves' disease, toxic solitary thyroid nodule, multinodular goiter or thyroiditis. The precipitating events may include infection, trauma, or acute iodine load. The initial response to exogenous iodine is a transient reduction in thyroid hormone known has Wolff-Chaikoff effect, later it may be followed by thyrotoxicosis due to Jod-Basedow phenomenon when the thyroid gland escapes the physiologic negative feedback.
Description of the Case:
This is a 60-year-old female with known history of goiter and heroin abuse who presented with altered mentation and generalized tonic-clonic seizure. Patient was intubated and admitted to MICU for hypoxic respiratory failure with acute encephalopathy. CT angiograph of the brain revealed massive thyroid enlargement with a 9 cm dominant right thyroid mass, leftward tracheal deviation and multiple upper chest mediastinal lymph nodes. EKG recorded sinus tachycardia with left bundle branch block. Troponin was elevated at 5.28 ng/mL. Echocardiogram showed bi-ventricular heart failure. Patient was treated for NSTEMI, with plan for cardiac catheterization. However, patient developed tachycardia, hyperthermia 39.2oC and elevated liver function tests (ALT 249, AST 592). Thyroid function changed from normal TSH 0.97 and low free T4 0.46 on admission to TSH <0.015 and high free T4 4.07 after CT with contrast. TSI was negative. In addition to treatment with PTU and beta-blocker, patient underwent three sessions of plasmapheresis successfully trending down free T4. Total thyroidectomy and isthmectomy were performed later when free T4 normalized. Pathology revealed an encapsulated papillary thyroid carcinoma with predominantly follicular growth pattern. Patient developed bradycardia after the surgery and cardiac catheterization was negative.
Discussion:
We report case of a patient with papillary thyroid cancer who developed life-threatening thyrotoxicosis after receiving iodine load from contrast due to Jod-Basedow phenomenon. Although it is very rare for thyroid cancer to be functional and secrete thyroxine, physicians should be cautious about IV contrast use in patients with a large thyroid mass. Plasmapheresis is very effective in removing the offending agents, cytokines, thyroid hormones and control iodine induced thyroid storm.
Objectives: To study clinicopathological characteristics, predictors of metastatic spread to the neck for pediatric papillary thyroid cancer (PTC) and outcomes of management.
Methods: Pediatric thyroid carcinoma patients (<18 years) who treated from 2016 to 2020 at our institution were included and their presentation, neck metastasis feature, outcomes were reviewed.
Results: There were 48 pediatric patients with PTC that were managed during the study period. The rate of female was 66,7%. Thirdty patients were older than 15 years of age. 79,2% of the patients was larger than 10 mm. The number of patients with unifocal lesion was 29 (60,4%). Fourteen (27,1%) tumours were characterized by extrathyroidal extensions. There were 3 patients with distant mestastasis (lung metastasis). The proportion of central lymph node metastasis and lateral neck metastasis were 83,3% and 62,5%, respectively. Univariate logistic regression demonstrated that central neck lymph node metastasis and lateral neck lymph node metastasis were associated with age (≤15 years), tumour size > 10 mm, multifocality and external extension. The two most common complications were temporary recurrent laryngeal nerve injury (27,1%) and temporary hypoparathyroidism (20,8%). After an overall median follow-up of 33 months, four patients had recurred neck compartments. The 1-year, 3-year recurrence-free survival rates were 100% and 92.6%, respectively. Overall survival was 100%.
Conclusions: PTC spread to the neck is common in children. Age (≤15 years), tumour size > 10 mm, multifocality and external extension were risk factors of neck metastasis. However, outcomes of management were excellent for pediatric PTC.
Objective: To validate the ATA risk stratification for differentiated thyroid cancer (DTC) in children.
Methods: The clinical information from patients less than 21 years of age diagnosed with DTC between 2000 and 2015 at Texas Children’s Hospital, Seattle Children’s Hospital, Children’s Healthcare of Atlanta, Children’s Hospital Colorado and Nationwide Children’s Hospital were retrospectively analyzed.
Results: Two hundred and sixteen patients were eligible. Median follow-up was 4.4 years (range 0.2 - 16.5 years). Diagnoses included papillary thyroid carcinoma (PTC) (123), PTC-follicular variant (60), PTC-diffuse sclerosing variant (7), PTC with oncocytic variant (1), PTC with mixed variants (5), papillary microcarcinoma (2), follicular thyroid carcinoma (16), and Hurthle cell (2). Twenty-eight patients had a prior history of cancer; of these, 15 had history of radiation to the neck. The median age at diagnosis was 14.8 years (range 5 - 20.9 years). One hundred and sixty-five (73.4%) patients were female. Patients identified as White (68.5%), Black (8.3%), Asian (4.2%), other (11.6%), and unknown (7.4%). Initial surgery was total thyroidectomy in 170 patients (78.7%), lobectomy in 43 (19.9%) and other in 3 (1.4%). Lymph nodes were surgically evaluated in 163 patients; 82 had a comprehensive central lymph node dissection (LND); 54 had a lateral LND. Ninety (41.7%) had regional lymph node involvement; 33 (15.2%) had lung metastases. There were 111 ATA low-risk, 29 intermediate-risk, and 76 high-risk patients. Seventy-five (67.6%) of the low-risk, 28 (96.6%) of the intermediate-risk, and 74 (97.3%) of the high-risk patients received radioactive iodine (RAI). Median cumulative RAI dose was 107.1 mCi. None received chemotherapy/targeted therapy as part of the initial treatment. The 4-year progression free survival for low-risk was 83%, intermediate-risk was 64%, and high-risk was 43%. The disease related overall survival was 100%.
Conclusion: ATA risk stratification classifies patients into distinct risk groups for disease progression. Prior to the introduction of the ATA guidelines, a majority of patients underwent a total thyroidectomy followed by RAI. Widespread implementation of current ATA guidelines may lead to reduction in the number of DTC patients receiving RAI.
Introduction: One of the major complications following total thyroidectomy is hypocalcemia. Early prediction of hypocalcemia may be necessary to timely prevent it. The reliability of early (< 3 hours) postoperative parathyroid hormone (PTH) levels for predicting postoperative symptomatic hypocalcemia has been confirmed. However, only few studies have evaluated the effectiveness of delaying postoperative PTH levels measurement for predicting the development of symptomatic hypocalcemia. The aim of this study is to evaluate the usefulness of measuring serum PTH as a predictor of symptomatic hypocalcemia at 7 hours after thyroidectomy.
Methods: A cross-sectional study including all patients who underwent thyroidectomy at Hospital Metropolitano, Quito - Ecuador over the period from January 1, 2017 to December 31, 2019 was conducted. PTH of ≤10 ng/l was defined as high risk of symptomatic hypocalcemia. Prevalence ratio (PR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio (LR) were used to assess the association of postoperative PTH values and symptomatic hypocalcemia. JASP 0.11.1.0 was used.
Results: A total of 212 patients that underwent total thyroidectomy were included. Their mean age was 52.1 years and 179 (84.4%) were female. The indications for surgery were papillary carcinoma 123 (58.0%), suspicious nodule 52 (24.5%), multinodular goiter 26 (12.3%), and others 9 (4.3%). Out of 212 patients, only 48 (22.6%) patients had PTH measured at mean 7 hours (range 4 to 10 hours) after surgery and 31 (14.6%) patients had symptomatic hypocalcemia. Of them, 11 (35.4%) patients had high risk of symptomatic hypocalcemia. Four (36.0%) of the 11 symptomatic patients underwent central compartment lymph node dissection and 2 (18.2%) underwent central + lateral compartment lymph node dissection. In bivariate analysis, PTH levels ≤10 ng/l have a sensitivity of 0.55, specificity 0.78, PPV: 43%, NPV: 85%, and PR: 2.91 (95% CI 1.06 - 8.01) for predicting symptomatic hypocalcemia.
Conclusions: Measuring PTH level of ≤10 ng/l at 7 hours after surgery is useful for predicting symptomatic hypocalcemia in patients undergoing total thyroidectomy.
Objective. The majority of malignancies identified in indeterminate thyroid nodules (ITN) are low risk. Therefore, the need for total thyroidectomy or adjuvant treatment such as completion thyroidectomy or radioactive iodine (RAI) therapy in the treatment of ITNs is uncertain. This study aimed to analyze the likelihood of a need for total thyroidectomy and RAI therapy in the management of ITNs.
Methods. All ITNs diagnosed on FNA cytology from 2014-2018 at NYU Langone Health were reviewed. ITNs managed with surgery were selected. Demographics, nodule characteristics, final pathology, treatment detail, and clinical outcomes were recorded.
Results. During the study period, 218 patients with surgically excised ITNs were identified. One hundred forty-two (65.1%) patients underwent thyroid lobectomy (TL), and 76 (34.9%) had total thyroidectomy (TT) upfront. In the lobectomy group, 26 (18.3%) had a malignant nodule on final surgical pathology, 8 (5.6%) underwent completion thyroidectomy, and 5 (3.5%) received RAI. In the total thyroidectomy group, 26 (34.2%) were diagnosed as malignant, and 14 (18.4%) received RAI. Follicular variant of papillary thyroid carcinoma (FVPTC) was the most common malignant diagnosis in both groups (TL: 20, 76.9%; TT: 12, 46.2%). Adenomatous nodule was the most common benign diagnosis (TL: 55, 72.5%; TT: 15, 51.2%). NIFTP accounted for 28.2% (40) of nodules treated with lobectomy and 27.6% (21) of nodules treated with upfront total thyroidectomy. In the entire cohort, only two (1%) patients had significant pathology in the contralateral lobe (1 [0.5%] with papillary thyroid carcinoma [PTC] and 1 [0.5%] with multifocal micro-PTC). Of all 218 ITNs, only 19 patients (8.7%) received RAI. With a median follow-up of 31.5 months (interquartile range = 21-39.5), no recurrences or progression was seen.
Conclusion. The need for completion thyroidectomy or adjuvant RAI therapy in the treatment of ITN was low in our series. These data suggest that initial management of ITNs with lobectomy might be sufficient in the majority of cases.
Objective: Thyroid ultrasound use increases the incidence of thyroid cancer and fuels thyroid cancer overdiagnoses. A recent systematic review showed that between 15-80% of thyroid ultrasounds are ordered inappropriately (iUS). This pervasive issue demands a clearer definition of iUS and a more efficient audit mechanism that could be applied across institutions through passively collected data available in electronic medical records (EMR). The goal of this study is to develop an automated algorithm for identification of iUS by leveraging natural language processing (NLP).
Methods: The study cohort consisted of 4944 adults (≥18 years) identified from the radiology registry at Mayo Clinic Rochester, Minnesota who received a thyroid ultrasonography between March 2015 and November 2017. A working definition of iUS, was developed based on guideline recommendations and refined with the engagement of 17 clinicians (endocrinologists and primary care ) , resulting in the addition of supplementing criteria: no evidence of previous thyroid surgery, thyroid nodule, thyroid cancer, neck pain, dysphonia, or dysphagia. This refined definition was then implemented into NLP lexical patterns and rules for identifying iUS cases in the cohort. The development leveraged an established NLP framework at Mayo Clinic, which can handle nuanced contexts such as negation and host section. Specifically, the NLP algorithm was used to screen clinical notes within 3 months prior to the ordering date of each thyroid ultrasonography.
Results: The composition of the cohort was 85.6% white, 69.9% female, and with a mean age of 55.9 (standard deviation 16.2). Among the 4944 patients, the NLP algorithm determined 64.7% (n=3199) were iUS, i.e., no justifiable evidence documented in the notes within past 3 months. Among those considered appropriate orders, the most common justifications were presence of thyroid nodule, dysphagia, and neck pain.
Discussion: The preliminary results suggested that more than half of the thyroid ultrasounds ordered in a tertiary medical center may be inappropriate. Our next step is further refinement and validation of the accuracy of the NLP algorithm. If successful, this approach has great potential to assist in identifying the drivers of iUS, to develop interventions, and to reduce overdiagnoses of thyroid cancer.
Objective - Thyroid surgery has greatly evolved since Kocher perfected the technique of the conventional thyroidectomy in the late 1800s. A procedure once considered a ‘foolhardy’ practice some 150 years ago, performed only emergently for thyroid enlargement-related respiratory obstruction is now at the summit of minimally invasive removal of the gland. Although traditional cervical thyroidectomy remains the gold standard of thyroidectomy, the last 30 years have ushered in a new era of minimally invasive techniques like endoscopic and robotic thyroidectomy. We provide a literature review herewith.
Discussion - The benefit in minimally invasive techniques lies in decreased morbidity, improved cosmetic outcomes, and improved patient satisfaction. The introduction of new technology like intraoperative nerve monitoring and improved hemostasis using the harmonic scalpel and LigaSure systems have provided further impetus to these methods of thyroidectomy. Although these procedures have generated significant interest in some countries like South Korea, the acceptance in the United States has been slower based on regional practice patterns, reimbursement, and patient preference.
Minimally invasive approaches include axillary, breast, bilateral axillo-breast, and facelift techniques. Axillary and facelift approaches are more commonly used in the United States. Multiple analyses reported in the literature suggest increased operative time, cost, and a steep learning curve when compared to conventional thyroidectomy. Some reports demonstrate improved short-term (<1 year) patient satisfaction results, which remain to be studied long-term (>1 year). There have been reports of perioperative complications related to hemorrhage, nerve injury, and inferior oncologic resection. Conventional thyroidectomy is still considered standard of care in the United States as there is no definite data showing oncologic equivalency of minimally invasive techniques. The ideal candidate is a patient presenting with a thyroid nodule <3 centimeters with interest in avoiding a cervical scar. Minimally invasive techniques can perhaps be used with benefit in patients predisposed to keloid formation to improve cosmesis.
Conclusion - The American Thyroid Association guidelines do accommodate for minimally invasive techniques to be practiced under the blanket of strict selection criteria and in high-volume thyroid centers. Further comparative trials within the United States between traditional and modern techniques are required to arrive at a definite consensus.
Objective: Genetic changes are known to impact the outcome of papillary thyroid cancer (PTC) patients. While loss of heterozygosity (LOH) in PTC has not been well-explored, it has been associated with aggressive disease and poor prognosis in other malignancies such as gliomas and gastric, pancreatic, and breast cancers. On the other hand, aggressive lymph node (ALN) status has been clearly defined as a prognosticator in the American Thyroid Association (ATA) risk of recurrence (ROR) stratification. We demonstrate that LOH within primary PTC is associated with ALN status, and therefore bears prognostic weight.
Methods: Seventy-three patients with PTC who underwent surgery with curative intent were queried for LOH. Analysis was carried out with the PancraGen test utilizing polymorphic microsatellite situated in close proximity to common tumor suppressor genes situated at 10 genomic loci.
Results: Loss of single and multiple alleles were found in 26.0% and 19.2% of cases. Loss of 3p was the most common event, followed by loss of 1p, and 22q. No LOH was found in 54.8% of cases evaluated. LOH was associated with ALN (p = 0.0003) and extranodal extension (p = 0.0001).
Conclusion: Prior PTC LOH studies support the idea that loss of tumor suppressor genes are late events correlating with increased biological aggressiveness. Here, we demonstrate for the first time an association between LOH and ALN status (p = 0.0003), which in turn, is associated with time to progression on Kaplan Meier analysis (p < 0.0001). Ultimately, we demonstrated that LOH and ALN status are interrelated poor prognosticators, but further LOH analysis on more patients from this cohort is needed.
Objective:
To report the result of a patient who underwent a repeat reactivation of NaI-symporters for radioiodine refractory BRAFV600E mutated, progressive metastatic papillary thyroid cancer (PTC).
Methods:
We use the following protocol for patients with radioiodine negative, FDG-PET positive BRAFV600E mutated thyroid cancer metastases for reactivation of NaI-symporters: After 3-4 weeks on the BRAF-inhibitor dabrafenib (Tafnilar®, Novartis) 150mg x2, a diagnostic I-131 scan is performed with 2 mCi (77 MBq) for confirming reactivation, measurement of maximum tolerable activity (MTA) and tumor dosimetry (TD). After further 2-3 weeks pretreatment, I-131 is administrated with a dosage based on MTA and TD. Diagnostic scans and radioiodine treatment are performed under stimulation with rhTSH.
Results:
A 76 year old woman with BRAFV600E-mutated radioiodine refractory metastatic PTC was treated with 300 mCi (11.1 GBq) I-131 after pretreatment with dabrafenib in 2018. The dosage was decided based on MTA and TD. It resulted in 100 Gy to target lesions (TL). TL volumes were reduced by 27%. Before treatment Tg-doubling time was 6 months and increased to 56 months after treatment. The patient achieved relief of symptoms and had good quality of life for more than a year before the disease again progressed with negative diagnostic radioiodine scan and positive FDG PET/CT. Based on the successful result from the previous treatment (presented at ATA 2019), we decided to try another radioiodine treatment after pretreatment with dabrafenib. Diagnostic I-131 scan after 4 weeks on dabrafenib showed high uptake in the metastases. After 6 weeks pretreatment with dabrafenib 357 mCi (13.2 GBq) I-131 was administrated. Post-therapy scan showed high radioiodine uptake in the numerous metastatic lesions with high uptake on FDG-PET/CT. Post-therapy dosimetry showed consistent with the pretreatment measurements 80 Gy tumor dose in target lesions. Before treatment Tg=3527 µg/L, dropped to 1975 µg/L after 4 months. Unfortunately, the patient deteriorated and died before we were able to further monitor treatment effect.
Conclusion:
With this case report we have demonstrated that it is possible to reactivate NaI-symporters for the second time, in radioiodine refractory BRAFV600E-mutated metastatic PTC, allowing for up to 100 Gy tumor dose.
Objective: Advanced loco-regional medullary thyroid cancer (MTC) has historically been treated with both surgery and adjuvant/post-operative radiation therapy (PORT). Our objective was to study the evolution of the use of PORT over time, evaluating indications for PORT, the overall and survival of patients treated with PORT, and compare this cohort to a non-PORT cohort.
Methods: Clinicopathologic factors and survival outcomes were collected for all patients with MTC surgically managed at a single tertiary care institution August 1993 -January 2019. Patients were separated into two cohorts, PORT and non-PORT. Patients were further separated into subgroups according to date of presentation (pre vs. post 2013) to assess changes in medical practices following the FDA approval of systemic targeted agents.
Results: 346 patients were included, of which 49 (14%) received PORT. 19% (n=38) of patients pre-2013 received PORT, compared to 8% (n=11) post-2013 (p=0.003). PORT was primarily given in patients with T4 disease or extrathyroidal extension (ETE) in the pre-2013 era (n=40), while ETE with adjacent mucosal involvement was the principal reason in the post-2013 era (n=11) (p=0.032). The use of PORT was associated with worse OS after accounting for cancer stage, with an adjusted hazard ratio (HR)=2.37 (95CI 1.38-4.07) (p=0.002). The use of PORT and targeted therapy did not improve OS, adjusted HR=0.70 (95CI 0.30-1.65) (p=0.416)
Conclusion: PORT has not demonstrated improvement in OS in patients with MTC, regardless of disease stage. Over the past 3 decades the use of PORT in MTC has significantly decreased, coinciding with the advent of more effective systemic targeted therapy. Additionally, indications for use of PORT in MTC have become more selective.
Objective:
Despite a favorable prognosis, cervical lymph nodes (LN) metastases of differentiated thyroid carcinoma (DTC) origin are not uncommon. Fine needle aspiration biopsy (FNA) for cytology (FNAC) and for thyroglobulin (Tg) measurement (FNA-Tg) are recommended for suspicious LN evaluation. We aim to assess, in a clinical setting, the diagnostic accuracy of a novel point-of- care assay for Tg (POC-Tg), able to detect within 10 minutes Tg in the needle washout of a suspicious LN.
Methods
The POC-Tg is a lateral flow chromatographic immunogold assay for qualitative detection of Tg in FNA. In the pre-clinical phase, the limit of detection for Tg was set at a concentration of 5 ng/mL following needle content dilution with 1 mL of 0.9% saline. The POC-Tg was assessed in the FNA clinic when a suspicious LN was biopsied in a patient with known or suspected DTC; and in the operating room (OR) when suspicious LN was found during thyroid surgery. Each LN was evaluated using both the formal accepted method (in the FNA clinic, the combination of FNAC and FNA-Tg; and frozen section in the OR), and the novel POC-Tg. Clinical decisions were made according to the formal evaluation only. The POC-Tg performance was analyzed retrospectively.
Results:
FNA clinic: 15 LN were tested. Eight were found to be positive in both our POC-Tg and the standard Tg immunoassay. Final histology reported metastatic DTC in all the patients. Six LN were negative in both our POC-Tg and the standard Tg immunoassay, all with benign cytology. One LN was negative in our POC-Tg but showed low detectable Tg in the standard immunoassay. Neck ultrasound, performed by a dedicated radiologist, described this LN as benign, and it was not dissected. OR: We tested 11 LNs from four patients and compared our POC-Tg against the frozen section results: four LNs were positive and seven negative; concordance was perfect between our POC-Tg and the frozen section results.
Conclusion
The POC-Tg demonstrated a diagnostic accuracy for LN metastases of DTC origin approaching 100%. A larger validation study is needed to establish the potential of the POC-Tg to be incorporated into diagnostic and treatment algorithms.
Background Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancer with limited therapy available. Monotherapy in ATC and other aggressive cancers is not effective or results in treatment resistance and disease progression. To identify novel synergistic therapeutic strategies, we used quantitative high throughput screening (qHTS) and drug matrix screening of active compounds in ATC cells. The aim of this study was to determine the anticancer activity and mechanism(s) of action of the two most active and synergistic compounds (nitazoxanide, auranofin) in ATC we found from our qHTS and drug matrix screening studies.
Method We evaluated the effect of vehicle, nitazoxanide, auranofin and combination nitazoxanide and auranofin treatment in ATC cell lines (8505C, C643). To determine the mechanism(s) of action, we evaluated the effect of treatment on canonical activated tyrosine kinase (TK) signaling pathways, programmed cell death pathways, and RNAseq for a global analysis.
Results Combination nitazoxanide and auranofin synergistically inhibiting cellular proliferation in ATC cell lines compared to single agents and vehicle control that resulted in cell death within 24 hours of treatment (p<0.001). Combination nitazoxanide and auranofin treatment significantly inhibited colony formation and migration compared to control (p<0.001). While investigating the effect of combination nitazoxanide and auranofin treatment on the canonical activated TK signaling pathways, we found increased pERK levels and cellular morphologic changes suggestive of cellular oxidative stress. Indeed, combination nitazoxanide and auranofin treatment increased ROS levels compared to control (p<0.001). We found no evidence of apoptosis but observed increased LC3B-II (autophagy) levels with combination treatment. RNAseq analysis identified HMOX-1 expression was significantly increased at multiple time points and in both cell lines with combination nitazoxanide and auranofin treatment, which was validated by Western blot analysis. Given the cellular morphologic changes, induction of autophagy, and increased HMOX-1 levels suggesting a ferroptosis mechanism of cell death, we evaluated the expression of GPX4 (a gatekeeper of ferroptosis). We found reduced expression of GPX4 with combination nitazoxanide and auranofin treatment compared to vehicle by Western blot analysis.
Conclusions Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in ATC cells and this effect is mediated through induction of ferroptosis-mediated autophagy.
Introduction
Re-induction of radioiodine uptake with Selumetinib, Vemurafenib, Trametinib and/or Dabrafenib for RAIRMDT was reported for 30 of 64 patients in five case series based on BRAF and RAS mutation stratification. Partial structural response after 6 – 12 months follow up was reported for 15 of 64 patients.
Methods
We explored the impact of TruSight Oncology 500 panel on mutation and rearrangement detection for 11 primary tumours (4 patients underwent resensitisation, 7 are scheduled for resensitisation) and one additional lung metastasis of RAIRMDT. Four of the 11 tumours and the additional lung metastasis were previously analysed by WES. RNA and DNA were extracted with Invitrogen All prep kit and Qiagen FFPE DNA isolation kit respectively from macrodisected FFPE tumour material. TSO500 library preparation and sequencing was done according to the manufacturer’s protocol.
Results
In the 11 primary tumours we detected 6 BRAF, 2 NRAS, 7 TERT promoter, 1 EIF1AX mutation and 2 RET and 2 NTRK rearrangements as known drivers. Concurrent mutations included 5 BRAF mutations with TERT, 1 NCOA-RET rearrangement + NRAS, 1 ETV6-NTRK rearrangement + TERT, and 1 sample with NRAS + EIF1AX + TERT. Further mutations that could be targeted with currently available drugs were AKT2 E17K, AKT1 E17K, PIK3CA E542K, and CDK6 T320S. 5/11 patients had at least one mutation in a BRCAness associated gene. One patient with an additional lung metastasis analysed had 2 BRCAness mutations in the primary and 3 different BRCAness mutations in the metastasis. Mean TMB for all 11 primary tumour samples was 1.8, highest 4.7.
In addition to the actionable mutations detected by WES, TSO500 also detected the targetable rearrangements, the targetable PIK3CA, and the BRCAness mutations. The only potentially targetable mutation detected by WES and not TSO500 was a serotonin receptor mutation.
Conclusion
NGS of RAIRMDT leads to identification of important therapeutic targets in addition to only BRAF and RAS thus far used for resensitisation stratification. TSO500 should be preferred over WES because of the detection of additional targetable mutations (due to a higher sequencing depth), especially rearrangements and TERT mutations which have been reported to be associated with radioiodine resistance.
Objectives:
RET mutations and fusions are frequently found in medullary thyroid cancer and other thyroid cancers (TC). TC treatment algorithms are evolving due to recent developments in clinical genomic testing and targeted therapies. This study, conducted prior to approval of selective RET inhibitors, aimed to explore perceived challenges and educational needs related to the treatment of RET-altered TC.
Methods:
A mixed-methodology was used sequentially combining semi-structured qualitative interviews (January – March 2020) and online surveys (March – April 2020), conducted among endocrinologists (ENDOs), oncologists (ONCs), and pathologists (PTHs) from Germany (GE), Japan (JP), the United Kingdom (UK), and the United States (US). Inclusion criteria were: actively practicing for at least 3 years, minimum yearly TC patient caseload (ONCs: 20, ENDOs: 10), or a minimum of 10 TC samples for PTHs. Awareness of the data for selective RET inhibitors was not an inclusion criterion. Interviews were coded through thematic analysis, and survey data was analyzed with Chi-square and Kruskal-Wallis tests.
Results:
A total of 422 physicians participated (interviews n=44; survey n=378), 66% of which report never or rarely testing for RET alterations. A majority of physicians reported suboptimal knowledge of the mechanism of actions of selective RET inhibitors (67%) and multi-kinase inhibitors (61%). Fifty-five percent (55%) of ONCs across all surveyed countries perceived that selective RET-inhibitors could make treatment monitoring more challenging when compared to multi-kinase inhibitors. ENDOs reported skill gaps managing the side effects of selective RET inhibitors (84%) and multi-kinase inhibitors (83%). Interviewed ENDOs disclosed uncertainty weighing the risk-reward of RET inhibitors, as they reported perceiving selective RET inhibitors to be associated with higher levels of toxicities and more frequent dose reduction or treatment discontinuation than other agents. Access to selective RET inhibitors (through clinical trials) was reported to vary by country.
Conclusion:
This study, conducted before approvals of RET-specific agents, identified knowledge gaps, misperceptions and skill gaps among physicians from four countries that could impact optimal integration of RET inhibitors in practice and hinder their ability to treat patients with RET-altered TC. Specific educational interventions, for example case-based online modules, could help bridge some of the identified learning gaps.
Introduction:
Seizures are a manifestation of abnormal electrical brain activity that is often precipitated by varying factors such as alcohol use, tumors, and medications. In the event of a suspected seizure, there has been some utility in testing creatine kinase, prolactin, and lactate to help determine if the patient had an actual seizure. The finding of an elevated TSH in the presence of a seizure has not been fully explored. Herein we present a case of a patient with elevated TSH following a seizure.
Case:
A 39-year-old Asian female, with a history of transaminitis of unclear etiology, presented to the Emergency department with an episode of a witnessed tonic-clonic seizure. On examination, the patient's vitals were unremarkable. Physical examination was unrevealing for pitting edema, tremors. No precipitating factors were revealed. Basic metabolic panel was unremarkable, and the hepatic function panel was at her baseline. CT Head and MRI brain showed no remarkable findings, and routine EEG revealed no abnormal electrical brain activity. Incidentally, on admission, blood work revealed a TSH level of 13.4 and free T4 1.1. One day later, the TSH was 5.55. She was later discharged home two days later without any anti-epileptic medications.
Discussion:
There is a paucity of literature regarding subclinical hypothyroidism post-seizure activity, mainly in the adult population. The postulated physiology is that there is an effect on the hypothalamus-pituitary axis during seizure activity given that there is an increase in prolactin, cortisol, growth hormone, and thyrotropin (1) as seen in our patient, which subsequently trended down 24 hours post-seizure activity.
The potential elevation of thyrotropin is vital to note as clinicians should not hasten to treat elevated TSH even though a patient is symptomatic by seizure activity. Thyroid function levels should be re-tested 24-48 hours after a seizure to aid in the confirmatory diagnosis of hypothyroidism vs. hyperthyroidism.
As of now, thyrotropin levels may help assess possible seizure-like activity similar to prolactin, lactate levels.
Introduction
Thyrotropin resistance is not an extremely rare disease and is usually caused by mutations in genetic loci such as PAX8. In this case, the mutated locus was in the DUOX2 gene, and the congenital abnormality of thyrotropic hormone resistance was masked by Graves' disease (GD) in the early stage of the disease.
Description of the case
A 27-year-old female with history of GD for 11 years, she received three times of radio iodine therapy 6 years ago, and currently be pregnant for 55 days. In May 2009, the patient presented with goiter, fear of heat and sweating, polyphagia, trembling, and was diagnosed with "hyperthyroidism (GD)" at the local hospital. She was treated with methimazole, propylthiouracil and other drugs, however, her thyroid function was not well controlled, so she was treated with 131I (dose unknown) in Jan, Jun 2013 and Oct 2014 at the local hospital. After definitive therapy, she was given replacement "levothyroxine". Abnormal thyroid function (multiple elevated FT3, FT4 while elevated TSH) was monitored at the time of pregnancy in Apr 2017, and the fetus was induced in July because of neural tube defects. Her father was manifested similar thyroid function (elevated FT3 while elevated TSH). In August of the same year, the pituitary MRI showed no significant abnormality. Genetic testing suggested that the patient had a heterozygous mutation in DUOX2 gene: a heterozygous mutation considering a change in the base at site 127 of the coding region from adenine A to thymine T (c.127A>T), resulting in a pathogenic change in the amino acid at site 43 of the protein sequence from asparagine to tyrosine (p.N43Y).
Discusssion
1. When patients present with unexplained thyroid function abnormalities, careful analysis of past history, changes in disease dynamics, and family members' thyroid function is required to interpretation of abnormal thyroid function. 2. Mutations in the DUOX2 gene that cause thyrotropin resistance are rare, especially coexist with GD. Clinicians should be familiar with the disease to accurate diagnosis and treatment.
Objective:
After total thyroidectomy, some patients still report symptoms of hypothyroidism and poor psychological well-being despite normalized thyroid stimulating hormone (TSH) on levothyroxine (LT4) monotherapy. Several single‐nucleotide polymorphisms in deiodinase genes (DIO2) expressed in the brain could limit the conversion of inactive to active thyroid hormone, contributing to decreased psychological well-being. However, polymorphisms in the DIO2 gene, i.e. D2‐Thr92Ala, was identified in only 16% of the population of larger study by Panicker et al 2009, and therefore likely underpowered in previous studies to see the effect. In this pilot study, we hypothesize that at least 10-15% of euthyroid patients will report a poorer quality of life after total thyroidectomy despite adequate LT4 monotherapy.
Methods:
This cross- sectional study included 61 biochemically euthyroid patients (TSH<2.0) after total thyroidectomy from the Endocrine Faculty Practice at Northwell Health in Great Neck, NY. Two self- reported questionnaires were used. The Profile of Mood States (POMS-40) assessed mood disturbance with 5 negative subscales and 2 positive subscales. The Billewicz Diagnostic Index (BDI) screened for hypothyroidism related symptoms.
Results:
Based on the BDI, 1 patient (2%) had hypothyroid symptoms, 31 patients (58%) had unclear hypothyroid symptoms and 21 patients (40%) had no hypothyroid symptoms. Of the negative mood disturbance subscales: confusion (p= 0.122), depression (p=0.289) and tension (p=0.266) were significantly higher in patients with unclear hypothyroid status compared to patients without hypothyroidism, however there was no statistical significance in anger (p=0.1279) or fatigue (0.0573) between groups. There were no clinically significant findings in the positive subscales between the unclear and no hypothyroidism groups.
Conclusion/Discussion
Our results show 58% of participants were in the unclear hypothyroid category suggesting hypothyroid symptoms were not completely resolved despite being biochemically euthyroid on adequate LT4 replacement. In the unclear hypothyroid group, about 68% of participants experienced significantly higher scores on negative scales (namely confusion, depression, and tension) suggesting a poorer psychological well-being compared to the group without hypothyroid symptoms. Our pilot study results helped to identify a subset of euthyroid patients that may benefit from genotyping for polymorphisms of DIO2 genes, which can lead to earlier initiation of combination therapy (LT4 and triiodothyronine) and improved psychological well-being.
Objective:
The purpose of this study was to evaluate time course of FDG-PET/CT findings in patients with extranodal mucosa-associated lymphoid tissue (MALT) lymphoma in the thyroid who underwent external radiation therapy (RT).
Methods:
We included 35 patients with pathologically confirmed primary MALT lymphoma of the thyroid with clinical stage of IE(n=25) or IIE(n=10), who were treated by RT. Either TgAb or TPOAb or both were positive in all patients. The dose of RT was 40Gy/20f.
The follow up duration ranged from 27 to 109 months.
PET/CT scans were imaged using a dedicated scanner, and were repeatedly performed as follows:
before RT (PET/CTpre, n=35), 3-7mos. after RT (PET/CT1,n=35), 15-28mos. after RT (PET/CT2,n=35), 33-48mos. after RT (PET/CT3,n=33), and 58-96 mos. after RT (PET/CT4,n=28).
Both visual interpretation and semi-quantitative analysis with SUVmax were performed . Visual assessment was done according to the Deauville five-point scale (5PS) from the Lugano Classification. Negative FDG uptake was defined as thyroidal FDG uptake less intensive than that of the liver (score < 3). Therapeutic outcome was confirmed by biopsy in 19 pts. or by clinical examination and other imaging modalities in the remaining 16 pts.
Results:
On PET/CT pre, 5-PS was 4 or 5 in all patients but one. Thyroidal FDG uptake was focal in 12 (34%) and was diffuse in 23 (67%). After RT, CR was achieved in 33 out of 35 pts (94%). On PET/CT1, the 5-PS score was decreased to 3 in all 12 patients with focal FDG uptake. In patients with diffuse FDG uptake, 5-PS score remained 4 or 5 in 78% (18/23) on PET/CT1, 70%(16/23) on PET/CT2, 60%(12/20) on PET/CT3, and 53%(9/17) on PET/CT4, respectively. More than 25% increase in SUVmax on PET/CT1 compared with PET/CTpre was observed in 9 of 23 pts(39%) with diffuse thyroidal FDG uptake.
Conclusions:
Persistent high FDG in the thyroid gland on FDG-PET/CT1 was observed in about 40% of patients with diffuse FDG uptake on pretreatment. This finfing may be due to Hashimoto’s thyroiditis, which is almost always associated with primary thyroid lymphoma and accumulates FDG.
Introduction
Acromegaly is a hormonal disorder as a side effect of growth hormone hypersecretion. Increased incidence of toxic multinodular goiter and thyroid carcinoma have been reported. We present a patient with acromegaly complicated by toxic multinodular goiter and hyperthyroidism.
Case
A 56-year-old female with past medical history of rheumatoid arthritis and hyperthyroidism on methimazole presented with complaint of blurry vision. On physical exam, she was found to have large goiter and physical features consistent with acromegaly. IGF-1 and growth hormone were found to be elevated (IGF-1:764 ng/ml; GH: 40.6). Thyroid hormone and TSH levels were well-controlled on methimazole (TSH: 0.618 mU/ml, T4: 1.20 ng/dl T3: 3.14 pg/ml, TSI negative). Gonadotropins, prolactin were normal with cortisol and ACTH appropriately suppressed on steroids (Prolactin: 8.6 ng/dl, LH: 24.4, FSH: 46.8, Testosterone total: 11.5 ng/dl, Cortisol: 3.3 mcg/dl, ACTH: 9.7 pg/ml). Pituitary MRI showed a 2.2 cm x 1.6 cm x 1.9 cm intrasellar mass likely reflecting a macroadenoma which was resected endoscopically. Post-operatively, thyroid ultrasound was consistent with a multinodular goiter with at least 4 discrete, calcified solid nodules. Patient underwent total thyroidectomy with benign surgical pathology.
DISCUSSION
Retrospective studies have analyzed the thyroids of patients after diagnosis of acromegaly found the duration of illness of acromegaly is significantly longer in patients with moderately to markedly enlarged diffuse goiter1. This contributes to the theory that long-term stimulation by GH and IGF-1 of thyroid follicular cells are responsible for the formation of multinodular goiter. Moreover, thyroid volume has been correlated with the estimated duration of untreated acromegaly2. While it is reported that up to 92% of acromegalic patients have goiter, most (67%) are euthyroid and about 25% are hypothyroid3, meaning the vast majority are non-toxic nodular goiters. Acromegaly and hyperthyroidism is not as well described in the literature and is reported to be seen in anywhere from 3.5-26% of acromegalic patients4. While data regarding the association between acromegaly and thyroid cancer remains controversial, it is important to screen acromegalic patients with US for thyroid cancer as it occurs significantly more often in acromegalic patients than in the general population5.
Objective
Thyroid nodule risk stratification based on ultrasound features allows clinicians to personalize the care of patients with thyroid nodules. However, how much clinicians agree on the classification of thyroid nodules features and thyroid cancer risk categories remains unclear. We aim to evaluate inter-rater agreement in the interpretation of thyroid nodules ultrasound features in a large and diverse sample of clinicians.
Methods
Endocrine Society and Latin American Thyroid Society members were invited to participate in a voluntary web-based survey study that included demographic questions and ten thyroid nodule cases (three images per case) to be evaluated for: composition, echogenicity, shape, margins, and presence of echogenic foci. The risk category for thyroid cancer was calculated following the ACR-TIRADS framework from individual responses. Descriptive statistics were calculated and Gwet’s agreement coefficient (AC1) was used to assess the primary outcome of inter-rater agreement for ACR-TIRADS risk category and individual features; subgroup analysis of inter-rater agreement for ACR-TIRADS category was performed according to preferred reporting system, type of practice, and number of monthly thyroid nodule appraisals.
Results
A total of 144 participants were included, mostly endocrinologists (82%). Individual feature evaluation showed the level of inter-rater agreement for absence of echogenic foci [AC1 0.53, 95% confidence interval (CI) 0.24-0.81] and composition (AC1 0.54, 95% CI 0.36-0.71) was reasonable. Low agreement on margins (AC1 0.24, 95% CI 0.15-0.33), echogenicity (AC1 0.34, 95% CI 0.22-0.46), and shape assessment (AC1 0.42, 95% CI 0.13-0.70) partially drove low inter-rater agreement of ACR-TIRADS risk category (AC1 0.29, 95% CI 0.13-0.46). In only 3 cases, ≥60% of participants agreed on ACR-TIRADS risk category. The AC1 of ACR-TIRADS between overall and subgroup analysis were similar.
Discussion/conclusions
A primary goal of thyroid nodule ultrasound risk stratification is to standardize reporting and provide consistent management recommendations across practices. Our study shows that differences in inter-rater agreement pose a challenge for consistent management recommendations based on thyroid cancer risk. Particularly, the variability in the classification of thyroid nodule margins, echogenicity, and shape should be addressed in future educational programs. Practices implementing thyroid nodule risk stratification should focus on strategies that improve inter-rater agreement.
Objective:
Approximately 75% of thyroid nodules with indeterminate cytology (Bethesda III/IV) are benign. Avoiding futile diagnostic hemithyroidectomies for these nodules is crucial. FDG-PET/CT has shown promise as an additional diagnostic to improve preoperative differentiation.
Methods:
In this triple-blinded, nationwide, randomized-controlled trial in the Netherlands (NCT02208544), 132 patients with an indeterminate thyroid nodule underwent one FDG-PET/CT of the neck and were randomized to the FDG-PET/CT-driven or standard management group in a 2:1 ratio. In the FDG-PET/CT-driven group, patient management was based on the undisclosed FDG-PET/CT result: when the nodule was visually FDG-positive, diagnostic surgery was advised; when FDG-negative, watchful waiting was recommended. The nodule was presumed benign when it remained unchanged on a confirmatory ultrasound after one year. In the standard management group, diagnostic hemithyroidectomy was advised to all patients according to current guidelines. The primary outcome was the accurate reduction in unbeneficial management, i.e., diagnostic surgery for benign nodules or watchful waiting for malignant and borderline nodules.
Results:
In the FDG-PET/CT-driven group, 42% (38/91) of management was unbeneficial as compared to 83% (34/41) in the standard management group (p<0.001). FDG-PET/CT-driven management avoided 40% (25/63) of futile diagnostic surgeries for benign nodules. In the standard management group, 2.9% (1/35) of benign nodules did not undergo surgery (p<0.001). No malignant or borderline tumors were observed in patients who underwent watchful waiting. Sensitivity, specificity, NPV, PPV (95% confidence interval), and benign call rate of FDG-PET/CT were 94.1% (80.3%-99.3%), 39.8% (30.0%-50.2%), 95.1% (83.5%-99.4%), 35.2% (25.4%-45.9%), and 31.1% respectively. In the 101 non-oncocytic nodules, the benign call rate was 39.6%; 48% (23/48) futile diagnostic surgeries were avoided in the FDG-PET/CT-driven group. The benign call rate in oncocytic nodules was only 3% (1/31) and no reduction in unbeneficial management was seen.
Conclusion:
FDG-PET/CT-driven management in the preoperative workup of indeterminate thyroid nodules is practice changing due to a strong, accurate, and oncologically safe reduction in futile surgeries. As nearly all HCN/SHCN nodules are FDG-positive, application of FDG-PET/CT should be limited to non-oncocytic nodules to optimize diagnostic yield and use of resources.
Objective:
Thyroid nodule radiofrequency ablation (RFA) is a non-surgical procedure that is gaining popularity in the United States for treatment of symptomatic benign thyroid nodules. Our institution created a multidisciplinary thyroid RFA tumor board comprised of surgeons, interventional radiologists, and endocrinologists to ensure appropriate patient selection and the best outcomes for this burgeoning technology. The objective of this study was to determine the efficacy of the multidisciplinary thyroid RFA tumor board in altering diagnosis and treatment plans in patients initially referred for thyroid RFA.
Methods:
An IRB approved retrospective chart review was performed of patients presented to the multidisciplinary thyroid RFA tumor board since its inception in 7/2020 until 6/2021. Treatment plans were reviewed and were recorded for whether the patient was appropriate for RFA, not appropriate for RFA, or if the patient needed additional studies prior to RFA consideration. Outcomes are reviewed and compared for those that underwent RFA, those that underwent further studies, and those that ultimately underwent surgery.
Results:
65 patients were newly referred for RFA for biopsy proven benign nodules. 58 patients were referred for mass effect symptoms and 7 for autonomous function. After multidisciplinary review, 37 (56.9%) were approved for RFA, 22 (33.8%) needed additional studies, 2 (3.0%) were recommended for surgery, and 4 (6.2%) were recommended against intervention. Of those patients that had additional studies requested, 15 were recommended for RFA and 4 patients had surgery recommended due to a suspicious clinical picture. Of those that underwent surgery, 2 returned with thyroid cancer on final pathology. 7 patients were unable to proceed with RFA due to insurance denial. The average nodule volume recommended for RFA was 15.1mL, whereas for surgery it was 40.9mL (p= 0.08). There were no significant complications in patients that underwent RFA or those that underwent surgery.
Discussion/Conclusion
Thyroid nodule RFA can be an effective treatment option for symptomatic benign thyroid nodules. Comprehensive neck ultrasounds and cytopathology should be reviewed by dedicated thyroid specialists to prevent inappropriate treatment with this new technology. A multidisciplinary approach provides optimal patient selection for thyroid RFA.
Objective. Association of thyroid disorders with T2DM is cross-linked to a lower level of metabolic control, worsening of the prognosis and leading to early manifestations of cardiovascular catastrophes. The objective was the selection of the optimal genetic marker, which would increase the awareness of the possible association risks of thyroid nodular disease and T2DM.
Methods. We have recruited a group of early detected T2DM (56 patients, 47 females, 9 males) with an average age of 51,8±7,3 years having associated thyroid nodular disease. As a control group – 259 healthy individuals were recruited (156 females, 103 males, average age 34,3±8,9), who have not had any thyroid or metabolic disorders. We have tested HbA1c, thyroid status and lipid profile. Patients and volunteers were genotyped for a series of SNP-s in genes responsible for the fat mass-metabolism and cell energy expenditure.
Results. There was no significant difference in Thyroid function in between the groups, both patients and controls were euthyroid. Of the selected number of 30 SNP’s, 7 were the most markedly different. They were rs11075990, rs1121980, rs1421085, rs17817449, rs3751812, rs9939609, rs9940128. All this polymorphisms were belonging to the FTO gene. The “negatively associated” alleles as well as heterozygotic combinations were more frequent in patients having both thyroid nodular disease and T2DM. The odds ratio for them was varying from at least 2,43 (1,02-5,80) for the C/T heterozygotic carriers of rs1421085 polymorphism (p=0,012), up to 4,64 (1,79-12,02)for the homozygotic G/G carriers of rs17817449 (p=0,0022).
Discussion. Taking in to consideration a possible linkage of the SNP’s in to a single inheritance disequilibrium block, we can predispose a specific “Genetically Burdened T2DM Haplotype” that will require more efforts at the initial stage of diagnosis, still decreasing the number of severe complications due to proper medical attention.
Conclusion. The examined cohort still continues a prolonged clinical observation. Further studies are required to determine a proper initial marker for an increased need in early diagnostic and medical intervention.
Objective
To compare patient-reported outcome measures (PROM) surveys in patients with benign versus malignant thyroid nodules pre- and post-surgery. We hypothesize that i) patients may exhibit improved PROM responses following surgery and ii) patients with malignant neoplasms may report less improvement compared to those with benign disease.
Methods
A prospective observational study was conducted at a single institution. Patients completed various PROM surveys during pre- and postoperative visits. Those with benign nodules completed Thyroid-Specific Worry Survey (TSWS), Voice Handicap Index-10 (VHI-10), and Patient-Reported Outcomes Measurement Information System short-form global health instrument (PROMIS). Those with malignancy completed TSWS, VHI-10, and MD Anderson Symptom Inventory Thyroid Cancer module (MDASI).
Results
We included 131 patients in our analysis, 71 with benign thyroid nodules and 60 with malignancy. When comparing pre- and postoperative visits, both benign and malignant patients had a significant improvement in levels of worry about (possibly) having thyroid cancer (p<0.001, p<0.001) and undergoing thyroid surgery (p<0.001, p<0.001). Benign patients had a significant improvement in thyroid-related problems, swelling, and scar. Benign patients had significant worsening of total VHI-10 scores following surgery (p<0.028). A significant improvement was reported in the PROMIS’ mental health domain (p<0.040) and global health item (p<0.003) in benign patients. There was no significant difference in any of the MDASI symptom subscale scores but there was a significant worsening of walk-activity-work interference subscale score (p<0.032). Preoperatively, benign patients had a significant lower degree of worry about (possibly) having thyroid cancer compared to malignant patients (p<0.001). Postoperatively, benign patients expressed a lower degree of worry about (possibly) having thyroid cancer (p<0.016) and undergoing thyroid surgery (p<0.001). There was no significant difference in VHI-10 total scores between benign and malignant patients pre- versus postoperatively.
Discussion/Conclusion
Across various PROM, we observed significant differences in line with expectations. However, even in the setting of a high-volume experienced thyroid surgeon, patients’ responses suggest that there remains a significant level of worry experienced between surgery and the 1st postoperative visit. Our study details patient concerns that may need to be addressed via a tailored patient education in the 1st postoperative visit by the treating surgeon.
Objective. Eponyms contextualize medical discourse, paying homage to the people who helped pave the way to our modern understanding of anatomy, physiology, and disease processes. The aim of this historical review is to learn not only about the surgical significance of eponyms commonly encountered during thyroid operations, but also about the people behind them: the individuals who have lent their names to anatomical structures and surgical landmarks important for completing a safe and effective thyroidectomy.
Methods. The surgical significance of eponyms commonly encountered during thyroid operations, and the individuals who have lent their names to anatomical structures and surgical landmarks important for completing a safe and effective thyroidectomy were retrospectively evaluated. Not included are eponyms relating to thyroid disease processes or procedures, nor anatomical structures or landmarks in the neck that would not be commonly encountered during a thyroid operation.
Results. Kocher describes anomalous venous anatomy and the proper patient positioning, incision placement, and technique for meticulous hemostasis. Reeve and Joll define anatomical spaces relevant to dissection of the upper pole of the thyroid that assist with identification and preservation of the external branch of the superior laryngeal nerve (EBSLN), or the nerve of Galli-Curci, named after a famous opera singer whose career was ended after she underwent goiter surgery. The Glands of Owen, or parathyroid glands, must be carefully identified and preserved during thyroidectomy. Further dissection of the thyroid gland, with identification and protection of the recurrent laryngeal nerve (RLN), is guided by anatomical landmarks described by Berry and Zuckerkandl, as well as triangles named after Lore, Beahrs, and Simon.
Conclusion. There has been a call for eliminating eponyms and replacing them with descriptive names; however, their elegant simplicity and efficiency in describing complex surgical anatomy and surgical concepts continue to make their utilization useful during thyroid operations.
Objectives
There is increasing population-based evidence that hypothyroidism is associated with excess mortality mitigated in some by “optimal” thyroxine therapy. We aimed to confirm such data locally and compared age and gender specific mortality rates in patients with and without hypothyroidism in Wales between 2015-2019.
Methods
Age and gender specific mortality data for patients with and without a recorded diagnosis of hypothyroidism in Wales was obtained from the Office of National Statistics, 2015-2019. The prevalence of hypothyroidism (defined as those on thyroxine treatment currently) was obtained from Welsh general practice records. Age and gender distributions for hypothyroidism from the UK Clinical Practice Research Datalink was extrapolated to the Welsh cohort and validated by Welsh primary care databases. Age and gender specific standardised mortality rates and individual cause of death related life expectancy years lost were derived for the population with hypothyroidism.
Results
Discussion
We have shown that between 2015-2019 the prevalence of Hypothyroidism in Wales was 3.8%, with a high female preponderance. Hypothyroidism was associated with an increased mortality risk which was higher in younger age groups compared to older age groups, with 8.6 life expectancy years lost per death. Further studies will be needed to confirm these modelled population-based estimates using individual person level data.
Objective: To assess the quality of sleep, daytime sleepiness, depression severity in subjects with overt and subclinical primary hypothyroidism using Pittsburgh sleep quality index (PSQI), Epworth sleepiness score (ESS), Patient Health Questionnaire-9 (PHQ-9) respectively.
Methods: This was a questionnaire-based cross-sectional study done on patients attending the Endocrinology clinic. A personal interview was conducted on 39 subjects. Study subjects included treatment naïve individuals with hypothyroidism, individuals on levothyroxine treatment with elevated TSH, and individuals with subclinical hypothyroidism. PSQI was used to assess the quality of sleep, ESS for daytime sleepiness, and PHQ-9 for the presence of depression.
Results: Total number of subjects included was 39. Majority of the subjects were females (n=32/39) and the rest were males. The Mean age was 37±13.2 years. Twenty-eight had overt hypothyroidism (TSH>10mIU/L) and 11 were subclinical. Median TSH was 13.8mIU/L (IQR 8.32-27). Mean neck circumference was 33.5±5.9cm and collar circumference was 39±4.1cm. Mean PSQI was 8.25 (SD=4.21). Twenty-eight subjects had a Global PSQI score of 6 or above indicating poor sleep quality. Median for ESS and PHQ-9 were 3 (IQR 1-8) and 6 (IQR 1-10) respectively. Two subjects had severe excessive daytime somnolence (ESS>16), 4 had mild excessive somnolence (ESS 11-12). One subject had a PHQ-9 score of 15 indicating moderately severe depression, while 9 had moderate depression (PHQ-9 score=10-14).
Discussion:
Hypothyroidism is one of the most common endocrine disorders. It is associated with obstructive sleep apnea, poor architecture of sleep, and abnormal ventilatory drive. Neuropsychiatric manifestations include anxiety and depression which are reversible with treatment. Our study demonstrated the presence of poor sleep quality in the majority of the patients. Hypothyroidism may be associated with both obstructive and central sleep apnea. A high ESS in six subjects supports this association. Depressive symptoms are often ignored by most treating clinicians when treating hypothyroidism. This study showed that depression can co-exist even in young individuals with hypothyroidism and it is important to recognize it. The study population had one patient with moderately severe depression and 9 with moderate depression which highlights the significance of screening for depression among untreated patients with hypothyroidism.
Background: The novel severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) virus has led to the pandemic of Coronavirus disease 2019 ( COVID-19). COVID-19 has wide range of complications; cases of subacute thyroiditis have been reported post COVID-19.
Aim: To highlight the severity of subacute thyroiditis post COVID-19 infection in comparison to other etiologies and timely intervention with high dose steroids and anti-inflammatory drugs.
Case Description: A 33-year-old woman was referred to endocrinology clinic with swelling and pain of her anterior neck for four weeks duration. She developed her symptoms two weeks after contracting COVID-19 viral infection. Initially, she noticed swelling and pain in her neck, which was radiating toward the right ear. She also had a fever with malaise and myalgia. Her primary care physician prescribed medrol dose pack twice but her symptoms resumed as soon as she stopped it.
On physical examination, her temperature, blood pressure and heart rate were normal. She is obese with a BMI of 32. Neck exam exam revealed thyromegaly and anterior neck tenderness. Laboratory investigation revealed low thyroid-stimulating hormone (TSH) of 0.04mU/L. Free thyroxine (T4) was normal. Thyroid peroxidase antibody and thyroid-stimulating immunoglobulin were negative. Thyroid ultrasound revealed a heterogeneously enlarged thyroid gland with two small 4 mm solid hypoechoic nodules in the isthmus. She was treated with the third round of medrol dose pack but her condition relapsed after completing it. Our patient was started on oral prednisone 40 mg per day with Ibuprofen 800 mg once daily. Her symptoms improved within two weeks and steroids were tapered off gradually.
Conclusion: Subacute thyroiditis is a self-limiting complication of various viral infections that generally responds well to short course of steroids. Our case highlights the unusual severity of subacute thyroiditis after COVID-19 infection and the role of early aggressive therapy with high dose steroids to limit morbidity.
<Introduction>
A unique clinical course was observed in a 55-year male patient with resistance to thyroid hormone β (RTHβ) by a variant of the THRB gene leading to replacement of glycine with arginine in codon 347 (p.G347R). At X months, he was hospitalized due to heart failure and presented with the syndrome of inappropriate secretion of TSH (SITSH; TSH 2.02 µIU/mL and fT4 2.60 ng/dL). At X+10 months, 200mg/day of Bezafibrate (BZ) treatment was initiated. He slowly developed progressive hypothyroidism (TSH 100.90 µIU/mL and fT4 0.65 ng/dL at X+97 months), while his thyroid gland further enlarged and serum Tg levels increased. After suspending BZ treatment at X+109 months (TSH 69.80 µIU/mL and fT4 1.70 ng/dL), his thyroid function showed a rapid change by as soon as 3 weeks after (TSH 13.10 µIU/mL and fT4 2.45 ng/dL). To elucidate this unusual event, we conducted clinical studies and performed experiments.
<Methods>
A retrospective cohort analysis of non-RTHβ patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1, DIO2, DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor β with p.G347R (G347R TRβ). Mice with G347R TRβ were generated by hydrodynamic gene delivery and compared to mice overexpressing wild-type TRβ (WT TRβ).
<Results>
In the non-RTHβ patients, BZ treatment did not change serum free T3 and TSH but even increased free T4. DIO3 reporter activity was paradoxically increased by BZ administration in the context of G347R TRβ, which was inconsistent with DIO1 and DIO2 reporter assays. In the livers of mice overexpressing G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 mRNA.
<Discussion>
While hypothyroidism associated with BZ treatment did not occur in non-RTHβ patients, it was observed in a patient with RTHβ due to the p.G347R variant. Analyses using reporter assays and mice overexpressing G347R TRβ identified the possible mechanism whereby upregulation of type 3 iodothyronine deiodinase caused consumptive hypothyroidism.
Objective: Reaching up to 37%, for patients with thyroid cancer in whom central neck dissection is associated to total thyroidectomy, hypocalcemia represents one of the most common postoperative complications. Parathyroid gland detection through autofluorescence has determined a significant decrease in the number of intraoperative parathyroid lesions and hypoparathyroidism rate, implicitly.
Methods: Over a period of 8 months 23 patients diagnosed with papillary thyroid carcinoma that underwent total thyroidectomy and central neck dissection have been selected (AF group). Intraoperative parathyroid identification was performed by means of the near-infrared (820 nm) autofluorescence system FLUOBEAM® LX (Fluoptics, Grenoble, France). A group of 23 patients with similar clinical characteristics that underwent the same surgical procedure prior to the use of autofluorescence was used as control.
Results: A significant increase in number of excised lymph nodes was recorded in the AF group (p<0.01), with a mean of 18.6±9.4 compared to controls, where a mean of 11.1±5.8 lymph nodes were observed. Carcinomatous infiltration was present in 82 and 29 lymph nodes for the AF and control group, respectively, with a significant increase in positive lymph node rate (p=0.02). The autofluorescence system allowed the identification of all parathyroid glands in 69.5% of patients, 3 parathyroid glands were observed in 13% of cases, with 2 parathyroid glands in just 8.7% of cases and 5 parathyroid glands in 8.7% of patients, respectively. Three patients in the AF group presented clinical signs of transient hypocalcemia, requiring specific treatment for no more than two months. A total of 94 parathyroid glands were identified, with 87 in situ and 7 glands on excision specimens, amongst which 2 excised deliberately (one with carcinomatous infiltration and one with an oncocytic parathyroid adenoma) and 5 accidentally, two of these being located in the pretracheal fat. Accidental parathyroid gland excision rate was 5.3%. At 6 months postoperatively all patients presented with normal calcemia and PTH levels.
Conclusions: The intraoperative identification of parathyroid glands through the autofluorescence system allows for a more extensive cervical lymphadenectomy to be performed, increasing the total number of excised lymph nodes and the number of metastatic lymph nodes.
Objective:
The absorption of levothyroxine (LT4) may be influenced by gastric pH, as reported for LT4 tablets whose absorption appears to be affected by concomitant use of proton pump inhibitors (PPIs). This study aimed to characterize the effect of PPIs administration on the single dose pharmacokinetics (PK) of LT4 given as a new formulation of oral solution (Tirosint-SOL®) to 36 healthy adults.
Methods:
This was a randomized, 3-way crossover, comparative bioavailability study in healthy adults (F/M) under fasting conditions. A steady state of stomach pH was achieved with oral administration of omeprazole 40 mg delayed-release capsule once daily from Day 1 to 6 (on the morning for Treatment-A, each evening for Treatment-B). Tirosint-SOL® 150 mcg/mL was administered as a single dose of 600 mcg on Day 5 in the morning. In Treatment-C only LT4 was administered. Blood samples were collected at three timepoints prior to dosing (for baseline levels) and up to 48 hours post-dose. The washout period was at least 35 days. Total serum LT4 concentrations were measured using a validated LC-MS/MS method. Non-compartmental PK parameters were calculated using both uncorrected and baseline-corrected data. The maximum concentration (Cmax) and the area under the concentration-time curve (AUC0-48) were calculated and included in an analysis of variance to obtain ratios and corresponding 90% confidence intervals.
Results:
The PK population included 30, 28 and 31 subjects in Treatments A, B and C, respectively. For both comparisons (Treatment-A vs. Treatment-C and Treatment-B vs. Treatment-C), geometric mean ratios and confidence intervals for uncorrected and baseline-corrected PK parameters were within the pre-defined equivalence boundaries of 80% to 125%.
Discussion/Conclusion:
This comparative bioavailability study demonstrated that the absorption of Tirosint-SOL® is not affected by co-administration of a representative PPI given simultaneously or staggered by about 12 hours compared to administration of LT4 alone.
Introduction
With the advancement of technology to prevent the devastating complications following Recurrent laryngeal nerve (RLN) during anterior neck surgeries. Laryngeal adductor reflex-continuous intraoperative nerve monitoring (LAR-CIONM) decreased RLN injury as it provides real-time updates about the functional integrity of the RLN intraoperatively. However, intraoperative LOS does not necessarily imply nerve injury. We thought to investigate the false-positive rates of loss of LAR signal intraoperatively and investigate the predictors of false-positive LOS.
Methodology
In this prospective cohort study, we investigated statistical measures of LAR-CIONM during thyroidectomy, parathyroidectomy, and central neck dissection. We calculated the rates of false-positive LOS of RLN. We also looked for predictors of false-positive LOS during neck surgeries.
Results
A total of 101 patients with a mean age of 56.59±12.83 years were enrolled in the study. Females represented 71.29% of the study population. The mean BMI was 32.0232.02±7.92 kg/m2, and the mean height was 167.67±9.38 cm. The endotracheal tubes (ET) size was determined according to gender, BMI, and height. A total of 23 patients (22.7%) exhibited false LOS. False LOS occurred more frequently in patients who had a small ET size to their BMI (N= 12, 63.16%) compared to patients who received appropriate ET size for their BMI (N=11, 13.41%). Furthermore, a false LOS significantly occurred in patients who received an ET tube that was small for gender than appropriate for their gender (N=12, 66.67%) compared to patients who had an appropriate ET tube for their gender (N= 11, 13.25%). Finally, a false drop LOS significantly occurred in patients with small-sized ET tube for height (N= 12, 66.67%) compared to patients who received an appropriate ET tube for gender (N= 11, 13.25%), patients with small-sized ET for height had higher odds of exhibiting false LOS (OR=1.93, 95%CI:1.25-2.97,p< 0.001).
Conclusion
Ultimately, LAR-CIONM is a burgeoning tool in the field of head and neck surgery. Smaller ETT is significantly associated with increased rates of false LOS. As such, surgeons should fully know the effect of ETT size on false LOS better to interpret intraoperative signaling and, subsequently, surgical decisions.
Objective: While the need for thyroidectomy in symptomatic retrosternal goiters (RSG) is indisputable, the management of apparently “asymptomatic” imaging-detected RSG remains controversial. We reviewed our experience in these cases and compared outcomes and complications of performing thyroidectomy for patients with symptomatic and asymptomatic RSG to create a management algorithm.
Methods: Information from our prospective electronic thyroid surgery database was obtained from 2011 to 2019 to identify all patients operated for RSG. Patient data with comorbidities and risk stratification, symptoms and signs, modality of diagnosis, type of procedure, pathological findings and complications and outcomes were compared between the symptomatic and asymptomatic groups.
Results: A total of 42 out of 477 thyroidectomies (8.8%) had RSG based on our definition. The mean age was 53 years with a higher proportion of females (73.8%). 29 patients (69%) were asymptomatic from their goitre. The majority (78.6%) of the patients were ASA II and below. 19 and 23 patients underwent hemi- and total thyroidectomy respectively with no statistical difference between the symptomatic and asymptomatic groups. There were no significant statistical differences in the symptomatic and asymptomatic group in terms of operative time, nerve injury, hypocalcemia or blood loss. Although biochemical hypocalcemia (serum ionized calcium < 1mmol/L) was common in the immediate post-operative period, only two patients in the symptomatic group developed symptomatic hypocalcemia that resolved completely in 3 weeks. All patients in the asymptomatic group underwent a cervical thyroidectomy whereas two patients in the symptomatic arm needed an additional extracervical approach.
Conclusion: A proportion of “asymptomatic” imaging-detected retrosternal goiters do have subtle symptoms on thorough history. Early thyroidectomy can be safely performed in surgically fit asymptomatic patients with minimal complications and excellent outcomes.