Radioactive Iodine Uptake Research Articles

[18F]TFB PET/CT misses intense [124I]iodine-avid metastases after redifferentiation therapy in metastatic thyroid cancer

BackgroundFluorine 18-labelled tetrafluoroborate ([18F]TFB) is a substrate for the sodium/iodide symporter. In thyroid cancer, [18F]TFB-PET/CT may be an alternative to iodine imaging to evaluate the extent of disease, eligibility for radioiodine treatment, and success of redifferentiation therapies. We report the results of a pilot study to determine tumor uptake of [18F]TFB and compare its properties to [124I]IodinePET/CT in patients with metastatic thyroid cancer.MethodsFive patients were included in a prospective study. All patients received PET/CT 1 h after injection of 356 ± 12 MBq [18F]TFB and were given 230 ± 9 MBq [124I]Iodine orally on the same day, followed by PET/CT after 48 h. Before redifferentiation therapy, patients underwent an additional baseline [124I]Iodine PET/CT. Cases were analyzed by two board-certified specialists. Detection rates and Spearman correlation for [18F]TFB and [124I]Iodine were calculated.ResultsThree patients had poorly differentiated thyroid cancer and received trametinib in a redifferentiation trial. Two patients had papillary thyroid cancer and did not receive redifferentiation therapy. Of the 33 lesions seen before/without redifferentiation therapy, 19 (58%) were visible on [18F]TFB and 30 (91%) on [124I]Iodine imaging. In the patients who underwent redifferentiation therapy, 48 lesions were newly seen on [124I]Iodine PET/CT with a median SUVmax of 3.3 (range, 0.4–285.0). All of these lesions were [18F]TFB-negative.Conclusion[18F]TFB failed to predict radioactive iodine uptake in patients with poorly differentiated thyroid cancer who underwent redifferentiation therapy with trametinib. It is unclear whether such discrepancies may also occur in other redifferentiation therapies or may even be encountered in redifferentiation-naïve thyroid cancer.Trial registration numberNCT03196518, registered on June 22, 2017.

9188 Hashitoxicosis To Graves': A Case Of Fluctuating Thyroid Autoimmunity Induced By The Covid Vaccine

Abstract Disclosure: K. Lamar: None. N. Meda: None. J. Straughan: None. D. John: None. S.K. Suryanarayanan: None. Introduction: Thyroid antibodies are essential for identifying autoimmune thyroid disease. In Graves' disease thyroid stimulating immunoglobulin (TSI) is crucial to diagnosing, guiding treatment, and determining prognosis for ophthalmopathy; thyroid peroxidase (TPO) antibody is likewise crucial in the diagnosis of Hashimoto’s Thyroiditis. Conversion between these two diseases is extremely rare. Case: The patient is a 60-year-old female with a medical history of hypertension, asthma, T2NxM0 low grade gastrointestinal stromal tumor (GIST), and hyperaldosteronism who was referred to the endocrine clinic for “thyroid disorders'' with symptoms including weight gain and palpitations. Her labs showed thyroid stimulating hormone (TSH) <0.01mIU/L, free Triiodothyronine (fT3) 6.5ng/mL, free Thyroxine (fT4) 1.6ng/dL, TPO antibodies 46IU/mL, negative TSI antibodies 102%, and a negative Thyroglobulin antibody (Tg Ab) <1IU/mL. A slightly enlarged thyroid was noted on ultrasound. Radioactive iodine uptake (RAI) was normal with 15% uptake at 6 hours and 25% at 24 hours. These findings led to the diagnosis of Hashimoto thyrotoxicosis. She started methimazole 10mg and atenolol 50mg. One year later, she received the Pfizer mRNA COVID-19 vaccine and had her GIST tumor resected. She then began switching between hyper-, hypo-, and euthyroid states with multiple titrations of her Methimazole dose. Repeat testing demonstrated a positive TPO 41 IU/mL, negative Tg Ab <1, positive TSI 294%, and positive RAI with 47% uptake at 6 hours and 61% at 24 hours, consistent with Graves’ disease. It was found that even minor titration by 2.5mg in her Methimazole led to profound changes in her thyroid laboratory values and symptoms. She underwent total thyroidectomy and was started on levothyroxine with significant improvement. Discussion: This patient initially presented with antibodies as well as low uptake on the radio-iodine scan indicating her state of hyperthyroidism was due to Hashitoxicosis, but then later these tests were repeated and were more indicative of Grave’s disease. This was possibly due to immune challenges in the patient, assay inter-variability of thyroid autoantibodies, or an effect of the patient receiving the COVID vaccine. The phenomenon of TSI antibodies converting from negative to positive has not been well documented previously. The goal of this case was to report an interesting conversion of Grave’s disease identifying antibodies and the importance of evaluating underlying immune challenges which could play a role in altering clinical disease. Presentation: 6/1/2024

7314 The Thyroid Tetralogy: Hypothyroidism, Graves' Disease, AFTN, and Thyroid Cancer in a Single Patient

Abstract Disclosure: F. Sajid: None. F. Mohammadrezaei: None. K. Tiwari: None. J. Shapiro: None. F. Mohsin: None. T. Lin: None. Introduction: In this case, we explore a rare and complex situation involving a patient's shift from hypothyroidism to hyperthyroidism. This transition led to the diagnosis of Marine Lenhart Syndrome (MLS), an uncommon condition characterized by the coexistence of Graves' disease and autonomously functioning thyroid nodules (AFTNs). Adding to the complexity of the case, the patient was also diagnosed with papillary thyroid carcinoma (PTC). Case Presentation: A 47-year-old woman with a history of hypothyroidism, treated with levothyroxine for 14 years, presented with palpitations, weight loss, and insomnia for a few months. Her levothyroxine dose was gradually reduced and eventually discontinued by her primary care physician due to low TSH and high free T4 levels. Post-discontinuation, her symptoms were improving. Laboratory tests showed TSH 0.01 mIU/mL (0.39-4.08), Thyroglobulin (TG) 72 ng/mL (3-40), Free T4 2.5 ng/dL (0.8-1.8), Free T3 11.5 ng/dL (0.2-0.5ng/dL). Furthermore, Thyrotropin Receptor Antibody (TRAb), and Thyroid Peroxidase Antibody (TPO Ab) were positive leading to a diagnosis of Graves' Disease and initiation of Methimazole. After three months on Methimazole, her TSH remained suppressed with normalized free T4 and T3 levels. A thyroid ultrasound revealed bilateral nodules, with a calcified well-circumscribed nodule in the right mid-pole. A Radioactive iodine uptake (RAIU) scan showed a hyperfunctioning right mid-pole thyroid nodule. Fine-needle aspiration biopsy was consistent with Bethesda V, suggestive of possible malignancy. Consequently, she underwent a total thyroidectomy, with pathology confirming multifocal classic PTC, stage pT1bN0. Post-surgery, she developed hypothyroidism and was started on levothyroxine. Four weeks later, her TSH remain suppressed, other thyroid function tests and calcium levels were within normal range: TSH 0.01 mIU/mL, Free T4 1.0 ng/dL, TG 4.6 ng/mL, Thyroglobulin antibodies 1 IU/mL (less than or equal to 1), PTH intact 43 pg/mL (16-77), and Calcium 8.9 mg/dL (8.6-10.2). Conclusion: This case represents a complex and unusual medical scenario where a patient transitioned from hypothyroidism to hyperthyroidism, ultimately leading to the diagnosis of MLS in conjunction with PTC. The exact mechanism behind this transition is not fully understood. In the management of hypothyroidism, adjustments in thyroxine dosage are common, but significant tapering of the dose should prompt further investigation. The presence of PTC in AFTNs is considered rare, as AFTNs are typically characterized as hot nodules, implying they are hyperfunctioning and generally considered to be less likely malignant compared to cold nodules. This case underscores the need for comprehensive evaluation and follow-up in patients with thyroid disorders, especially when there is a change in thyroid function or the presence of nodules. Presentation: 6/3/2024

8105 Radiation-Induced Hyperthyroidism in the Context of Palliative Radiation Therapy

Abstract Disclosure: A. Randhawa: None. G. Palaguachi: None. J.G. Karam: None. Introduction: Palliative radiotherapy, designed to alleviate focal symptoms in advanced, incurable cancer, aims to enhance quality of life with minimal treatment burden. The thyroid gland's susceptibility to neck radiation is known, primarily leading to hypothyroidism. However, hyperthyroidism is a much less frequently reported adverse effect that is poorly understood. This case report highlights an unusual instance of radiation-induced hyperthyroidism. Case Presentation:The patient is a 53 years-old woman with history of Ewing’s sarcoma of the sacrum diagnosed in August 2022, treated initially with chemotherapy (cyclophosphamide, vincristine, etoposide and ifosfamide), but diagnosed with leptomeningeal metastasis and T12/L1 mass in October 2023 when she presented with lower extremities weakness and urinary incontinence. She underwent T12-L1 laminectomy, resection of tumor and fusion, and was started on palliative intent radiation therapy for the brain and C-spine. A month later, she was admitted for altered mental status and was found to be persistently tachycardic at 140 bpm. Thyroid function testing was sent and revealed hyperthyroidism with TSH of 0.07 mIU/L (0.39-4.08), Free T4 of 1.74 ng/dl (0.58-1.64), T4 of 10.7ug/ml (4.4-9.5), T3 of 0.54 ng/ml (0.72-1.35), with undetectable Thyroid Peroxidase Antibodies and Thyroid Stimulating Immunoglobulin level. Thyroid Ultrasound showed a small and homogenous thyroid gland with no discrete nodules. Radioactive Iodine uptake and scan was not obtained because of exposure to iodized contrast during hospital stay. The patient had no available baseline thyroid function tests. She had no recent fever or viral illness. Unfortunately, her clinical condition deteriorated rapidly, and she passed away on the seventh day of admission. Conclusion: While hypothyroidism is a well-established consequence of high-dose irradiation, the mechanisms behind the rarer radiation-induced hyperthyroidism remain unclear. Speculation includes the release of autoantigens from damaged thyroid glands, triggering an immune response and potentially leading to Graves' hyperthyroidism. However, our case more likely represents a hyperthyroid phase in the triphasic sequence of destructive subacute thyroiditis, given the absence of elevated thyroid antibodies, thyroid nodules, and other causes of thyroiditis. Increasing awareness of radiation-induced hyperthyroidism, unraveling its mechanisms, and refining diagnostic strategies such as obtaining baseline and monitoring thyroid function testing are crucial, particularly in the context of palliative therapy, where striking the delicate balance between efficacy and minimizing toxicity is paramount. Presentation: 6/3/2024

8288 Navigating Diagnostic Challenges of Amiodarone Induced Thyrotoxicosis in a Psychiatrically Complex Patient within a Community Hospital Setting

Abstract Disclosure: M.S. Shah: None. K.P. Sanu: None. S. Humayon: None. R. Chawla: None. N.K. Bains: None. This case delves into the intricate diagnostic and therapeutic journey of a 64-year-old male who presented to a community hospital with psychosis. Medical history was pertinent for ventricular arrhythmias treated with amiodarone 400 mg once daily, bipolar disorder with medication non-compliance and heart failure with reduced ejection fraction status post automatic implantable cardioverter-defibrillator placement. Collaboration with the patient's family revealed a history of repeated hospitalizations for similar presentations as well as recent weight loss. The challenge lay in distinguishing between manic episodes and other potential underlying medical causes. The patient's recent weight loss and amiodarone use prompted a thyroid panel, revealing a TSH of 0.01 mlU/L (n = 0.27 to 4.20 mIU/L), free T4 of >7.77ng/dL (n = 0.93 to 1.70 ng/dL), and free T3 of >7.51ng/dL (n = 2.00 to 4.40 pg/mL). Inadequate facilities for a radioactive iodine uptake (RAIU) scan and thyroid doppler ultrasound heightened the diagnostic challenge, making the history and physical exam pivotal in steering the course of this patient's care. The Burch-Wartofsky score was found to be elevated at 30 due to delirium and abdominal pain reported in the emergency department. Amiodarone use for over two years with no prior history of thyroid dysfunction, along with the absence of a goiter or thyroid antibodies suggestive of Graves disease heightened the suspicion for amiodarone-induced thyrotoxicosis type 2 (AIT type 2). Due to the lack of RAIU scan and thyroid ultrasound to better differentiate between AIT type 1 and type 2, the patient was treated with methimazole and prednisone along with an antipsychotic medication regimen. The discontinuation of antipsychotic medications became necessary due to QTc prolongation and subsequent defibrillator discharge. The patient's further improvement without psychiatric medications highlighted the success of the tailored treatment strategy, emphasizing the importance of accurate diagnosis in patients with psychiatric comorbidities. The patient’s relatively rapid clinical response also aids in differentiating AIT type 1 from type 2. This case brings awareness to the importance of a comprehensive history and physical exam, particularly in the setting of a community hospital with limited diagnostic resources. Despite the inability to obtain history directly from the patient and having diagnostic constraints, the judicious use of available resources and clinical acumen led to the diagnosis of Amiodarone-induced thyrotoxicosis type 2. Clinicians should keep a broad differential to avoid confirmation bias in treating psychiatric patients with a complex medical history. This case serves as a testament to the importance of a holistic approach to patient care and the need for ongoing advancements in diagnostic capabilities within community healthcare settings. Presentation: 6/2/2024

6601 A Case of Recurrent Painless Thyroiditis and Discussion of Management

Abstract Disclosure: M.C. Slack: None. S. Grock: None. Introduction: Painless (silent) thyroiditis is characterized as a subacute and generally self-limited disease process in which patients develop transient thyrotoxicosis, which is often followed by a hypothyroid phase before entering the recovery euthyroid phase. Given high frequency of positive thyroid antibodies, it may be autoimmune-mediated; recurrence is rare. Here we present a case of recurrent painless thyroiditis and discuss management options. Clinical Case: A Korean woman was followed by endocrinology from age 38 to 60 and experienced at least seven episodes of painless thyroiditis over this time. The episodes occurred without an identifiable trigger and were not preceded by viral illness. During episodes she developed palpitations, hair loss, and dyspnea on exertion and biochemical evidence of thyrotoxicosis with TSH suppressed to <0.2 mIU/mL (normal 0.3-4.7) and elevated free T4 levels as high as 5.4 ng/dL (normal 0.8-1.7). TSI, TPO, and TSH receptor antibodies were checked during multiple episodes and resulted negative, though thyroglobulin antibody was significantly elevated. A radioactive iodine uptake scan was obtained during an active episode of thyroiditis and revealed diffusely low uptake. The patient’s episodes lasted approximately two to three months before normalization of her TSH and FT4. She had at least one instance of transient hypothyroidism after thyrotoxicosis with a TSH of 13.2 and FT4 of 0.6 which subsequently normalized 6 weeks later. The patient did not have known cardiovascular disease and DXA scans revealed mild osteopenia with the lowest T-score -1.3. RAI was considered for the patient based on the total number and increasing frequency of her episodes. She ultimately declined treatment with RAI and continues to follow with endocrinology. Clinical Lessons: While the deleterious effects of prolonged hyperthyroidism (e.g. osteoporosis, arrhythmia, cardiovascular disease) are well known, it is unclear what risk recurrent painless thyroiditis episodes pose. As there are no guidelines regarding treatment, clinical gestalt incorporating frequency and duration of episodes, as well as symptoms, is often used to determine if definitive management is indicated. There are case reports in the literature of treatment of recurrent thyroiditis with RAI ablation performed during a euthyroid state, which eliminated recurrence of episodes but did lead to permanent hypothyroidism necessitating hormone replacement. Surgical thyroidectomy may also be considered in select patients. This case highlights the challenges in treating rare cases of recurrent painless thyroiditis given the lack of research or established guidelines. It is reasonable to consider the frequency, severity, and total number of episodes, as well as patient risk factors, symptoms, and preferences when making recommendations regarding management. Presentation: 6/1/2024

6770 Graves’ disease induced by COVID-19 infection in a 49 year old male

Abstract Disclosure: N. Al-hosainat: None. A. Al Najada: None. T. Salar: None. S. Iqbal: None. K. Abdel Gadir: None. Introduction: Graves’ disease is an autoimmune disease causing hyperthyroidism, characterized by elevated thyrotropin-receptor antibodies. COVID-19 infection has been increasingly reported as a trigger of thyroid illness including Graves’ disease. We present a unique case of 49-year-old patient who was diagnosed with Graves’ disease after COVID-19 infection. Case description: A 49-year-old male patient with history of prediabetes presented with complaints of tremor, fatigue, generalized itching, and unintentional weight loss (30 Ibs in 6 months). He had COVID-19 infection 3 months prior. The remainder of review of systems was negative. No family history of thyroid disease. On exam, the patient had sinus tachycardia with otherwise normal vital signs. Diffuse thyromegaly was noted along with an intermittent fine tremor of the extremities. Blood work was notable for low TSH <0.01 uIU/mL, elevated free T4 (3.4 ng/dL), free T3 (17.6ng/dL), and TSH receptor antibody (12 IU/L). Thyroid ultrasound showed mild goiter with 2 nodules, one of which was TIRADS 4 and 1.5cm. This nodule was biopsied and found to be benign. Radioactive iodine uptake scan revealed homogeneous diffuse increased thyroid uptake. The diagnosis of Graves’ disease was made, and the patient was started on propranolol and methimazole with significant improvement of his symptoms and his laboratory tests normalizing. Discussion: Graves' disease is an autoimmune disease, characterized by hyperthyroidism, goiter, occasional orbitopathy and dermopathy. Caused by antibodies against thyroid-stimulating hormone receptors which stimulate thyroid hormone secretion and thyroid growth. Treatment is aimed to decrease thyroid hormone synthesis by either a Thionamide, radioiodine ablation, or surgery. Remission rates with antithyroid drugs average under 40 percent after one to two years of treatment and could exceed 80 percent after 5 to 10 years of treatment. COVID-19 is a multi-system disease, caused by SARS-CoV-2 virus, transmitted by large droplets and small particle aerosols, was declared a pandemic in 2020 and affected millions of people worldwide. There is emerging data showing the association of COVID-19 with various thyroid diseases including thyroiditis and relapse of known Graves' disease after the infection. We present a case of newly diagnosed Graves’ disease after COVID-19 infection in a patient with no personal or family history of such disease which raises the concern of autoimmune pathway activation induced by the infection. The onset of Graves’ disease after COVID-19 infection does not depend on the presence of pre-existing thyroid pathology and in this case responded well to antithyroid medication. Conclusion: COVID-19 can lead to the development of a range of medical illnesses. In patients who develop symptoms of thyrotoxicosis, Graves’ disease should be suspected, investigated, and treated appropriately Presentation: 6/3/2024

8791 A Case of Hyperfunctioning Thyroid Nodules Evaluated for Thyroid Metastasis in the Setting of Oropharyngeal Squamous Cell Carcinoma

Abstract Disclosure: M. Alashoor: None. J. Gogineni: None. A. Bakar: None. Introduction: Identifying and evaluating hyperfunctioning thyroid nodules in the setting of metastatic head and neck cancers represents a diagnostic challenge that may result in inaccurate identification of perithyroidal lymph node metastasis as malignant or metastatic thyroid nodules with standard workup. Case presentation: A 72-year-old male with a history of stage IV metastatic oropharyngeal squamous cell carcinoma, metastasized to the lymph nodes, lungs, mediastinum, and bilateral iliac bones. He was diagnosed two years ago and received chemotherapy, maintenance immunotherapy with pembrolizumab, and targeted palliative radiation therapy, with good clinical response. Restaging PET-CT two years later revealed local progression. During his workup, he was noted to have persistently abnormal thyroid function test with low TSH (0.03​​µIU/mL, n 0.3-5.33), normal free T4 (0.97ng/dL, n 0.60 - 1.40), mildly elevated free T3 (3.91pg/mL, n 2.5-3.9), negative thyrotropin receptor antibodies levels, negative TSI, negative TPO antibody, noted evidence of subclinical hyperthyroidism consistent over the past year. Radioactive iodine uptake demonstrated multinodular gland, mildly elevated 24-hour uptake of 28% consistent with hyperthyroidism, with decreased activity in the left lobe. Thyroid ultrasound revealed multiple probable malignant thyroid nodules, a 1.8 cm TI-RADS 5 lesion of the deep margin of the lower pole of the right lobe, and a 1.6 cm TI-RADS 5 lesion of the upper pole on the right lobe. He was treated with methimazole 5 mg. Further workup with fine needle aspiration demonstrated the right upper lobe nodule sample was positive for squamous cell carcinoma, findings suspicious for metastasis. He subsequently proceeded with radical tonsillectomy, right neck dissection, and right hemithyroidectomy. Surgical pathology results noted, right neck metastatic HPV-associated squamous cell carcinoma involving the lymph nodes with extranodal extension, right oropharyngeal HPV-mediated squamous cell carcinoma. The thyroid gland biopsy was significant for incidental papillary microcarcinoma 2mm, thyroid follicular nodular disease, without evidence of squamous cell carcinoma or metastatic infiltration. Post-hemithyroidectomy, his thyroid function normalized, and methimazole was discontinued. Conclusion: Thyroid metastasis from head and neck cancers represent a rare entity. In patients with a history of malignancy, evaluation of new thyroid masses remains crucial. While FNA is a sensitive method for detecting thyroid metastases, inaccuracies may occur, impacting the identification of thyroid nodules in the presence of local metastatic lymphadenopathy. Identifying squamous cell carcinoma in the thyroid can significantly influence the treatment plan of patients with metastatic carcinomas, therefore careful consideration must be undertaken on evaluation. Presentation: 6/1/2024

8135 A Rare Case of Late Recurrence of Graves’ Disease Decades After Radioactive Iodine Therapy: Is it Really a Definitive Treatment?

Abstract Disclosure: K.S. Hill: None. R. Osman: None. Graves’ disease (GD) is the most common cause of hyperthyroidism in the US and worldwide. Radioactive iodine (RAI) therapy has excellent success rates in treatment of GD. Studies have demonstrated that RAI successfully treats GD with a single session in the majority of cases. Recurrence after RAI, if it occurs, is most commonly seen in the first year after RAI. However, this is rare particularly in patients who have developed evidence of successful treatment in the form of post-ablative hypothyroidism. Only a few case reports have demonstrated recurrence of GD more than 10 years after treatment of GD with RAI and development of post-ablative hypothyroidism. We report a case of GD recurrence approximately 30 years after ablation. A 69 y/o woman presented for evaluation of hyperthyroidism and newly discovered thyroid nodule. Her history was significant for GD with orbitopathy diagnosed in the early 1990s and treated with RAI. Following the ablation, she developed hypothyroidism and was managed for over 20 years on levothyroxine therapy. In recent years she began to develop symptoms of palpitations and heat intolerance with biochemical evidence of thyrotoxicosis despite reductions in her levothyroxine dose. She also developed recurrence of her orbitopathy, confirmed by ophthalmology. During this time, a neck CT incidentally described an atrophic thyroid gland with a 9 mm soft tissue nodule in the left thyroid bed. Follow up ultrasound showed a 1.1 cm nodule with increased vascularity in the left thyroid bed with an otherwise atrophic gland and no lymphadenopathy. Her levothyroxine was stopped for one month in preparation for a thyroid uptake scan, during which TSH increased to 15 mcU/mL. Scan showed overall severely decreased radioactive iodine uptake of the gland consistent with prior ablation although there was a faint uptake most focally conspicuous on the left side inferiorly. Thyroid stimulating immunoglobulin (TSI) was elevated at 1.35 IU/L (Ref 0.00-0.55). After discussion with the patient, the decision was made for surgical treatment with thyroidectomy. Pathology was benign. She was continued on her prior dose of levothyroxine 75 mcg daily however now with clinical and biochemical evidence of hypothyroidism requiring continued increase in levothyroxine dose to normalize TSH levels. GD is the most common cause of hyperthyroidism and RAI therapy is the most common definitive treatment for GD in the US. Recurrence of GD after ablative hypothyroidism is rare, particularly in the case of late recurrence decades after ablation. Only a few cases are reported in the literature, ours with the longest interval-to-relapse. Recurrence of orbitopathy may be the first clue. Our case highlights the need to continue to monitor clinically for recurrence of Graves’ disease long after RAI use. Presentation: 6/3/2024

Association of COVID-19 with thyroid dysfunction and autoimmune thyroid disease: A retrospective cohort study

BackgroundSince the end of the COVID-19 pandemic, the potential roles of thyroid-inflammatory derangements in driving or being associated with the prognosis of COVID-19 remain controversial. We aimed to clarify the association between COVID-19 infection and thyroid dysfunction, and highlight the impacts of subsequent autoimmune thyroid disease (AITD) on the prognosis of COVID-19. MethodsThe retrospective, multicenter, cohort study enrolled 2,339 participants with COVID-19 from three hospitals located in the north, middle, and south regions of Shaan Xi Province, China, between December 2022 and July 2023. 464 non-COVID-19 patients within the same period were supplemented, divided into groups with and without AITD. At hospital admission (baseline), 3- and 6-month follow-ups, we presented a dynamic description and correlation analysis of thyroid-inflammatory-autoimmune derangements in patients with AITD. ResultsA total of 2,082 COVID-19 patients diagnosed with AITD and 257 cases without AITD were included in the study, and 464 non-COVID-19 patients were supplemented, dividing into 14 AITD and 450 non-AITD cases. We found that COVID-19 infection was closely associated with thyroid dysfunction (χ2 = 1518.129, p = 0.000). AITD patients with COVID-19 showed a higher prevalence of symptoms and comorbidities and longer hospital stays at baseline than non-AITD patients with COVID-19 (p = 0.000, p = 0.000, and p = 0.000). The baseline free triiodothyronine (FT3), free thyroxine, and radioactive iodine uptake at 24 h in AITD cases significantly decreased (p = 0.000, p = 0.000, and p = 0.000), while thyroid stimulating hormone, thyroglobulin, reverse triiodothyronine (rT3), and thyroid antibodies varying elevated from the baseline to the follow-up (baseline: p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.000, and p = 0.000; 3-month follow-up: p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.030, and p = 0.000). C-reactive protein, calcitonin, interleukin-6, -8, -10, and tumor necrosis factor-α rose significantly at baseline (p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.000, and p = 0.000) in AITD. Interferon-α and interferon-γ at baseline showed a significant decrease (p = 0.000 and p = 0.000), and remained at low levels after 6 months (p = 0.000 and p = 0.000). FT3 and rT3 were positively and negatively correlated with hospitalization, respectively (r = -0.208 and 0.231; p = 0.000 and p = 0.000). ROC curves showed that FT3 and rT3 had better robustness in predicting severe COVID-19 prognosis (AUC = 0.801 and 0.705). Ordered logistic regression revealed that ORs were 0.370, 0.048, and 0.021 for AITD [(subacute thyroiditis, Grave's disease, and Hashimoto's thyroiditis compared to non-thyroidal illness syndrome (NTIS)] with COVID-19 risk, indicating that NTIS was the predominant risk factor for the severity of COVID-19. ConclusionsA robust association has been identified, wherein COVID-19 infection is closely associated with thyroid dysfunction, and the subsequent AITD may aggravate the poor prognosis of COVID-19.

Médecine nucléaire et cancers de la thyroïde en 2024 : iode 131, TEP et nouvelles approches théranostiques

NUCLEAR MEDICINE AND THYROID CANCERS IN 2024: IODINE 131, PET AND NEW THERANOSTIC APPROACHES: Nuclear medicine has long been a mainstay in the management of thyroid cancers. In patients with differentiated thyroid cancer (DTC), the most common histotype, radioiodine (RAI, 131I) has been for years a cornerstone for the treatment of RAI-avid metastases. Post-therapeutic 131I scintigraphy helps guide these treatments and contributes to the definition of refractory cancers. In these refractory patients, who represent fewer than 5% of CTDs, 18FDG PET plays a central diagnostic and prognostic role. From a therapeutic perspective, RAI uptake can be re-induced in some of these patients with the BRAF mutation by using redifferentiation protocols. In anaplastic thyroid cancer (A TC) that is rare, aggressive and undifferentiated, 18FDG PET remains the metabolic imaging of choice. In medullary thyroid cancer (MTC), PET imaging is mainly based on the use of 18F-DOPA, even if 18FDG also provides prognostic data and 68Ga-DOTATOC could allow a theranostic approach. Other radiopharmaceuticals offering new theranostic avenues in thyroid cancers are also discussed, such as prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP). After decades of a "one-size fits all" approach in thyroid cancer management, molecular imaging is paving the way towards personalized medicine.

Le cancer thyroïdien différencié réfractaire à l’iode : quelle prise en charge en 2024 ?

TREATING RADIO-IODINE REFRACTORY DIFFERENTIATED THYROID CANCER IN 2024: About 5 to 10% of patients with differentiated thyroid cancer (DTC) have advanced tumors at presentation or recurrence, with invasive cervical disease and/or distant metastases that cannot be effectively treated by conventional treatment, i.e. thyroid surgery and radioactive iodine. These DTC cases are defined as refractory to radioiodine (RAIR) and require expert multidisciplinary management. In France, patients are referred to centers of the ENDOCAN-TUTHYREF Network. This review summarizes current management of RAIR DTC patients and therapeutic options available in 2024. We discuss following topics : epidemiological data, modalities of local ablative treatment for selected metastatic lesions, molecular tests to be performed, optimum timing for initiating systemic therapy, choice of first-line treatment among validated tyrosine kinase inhibitors (TKIs), alternative targeted treatments (including selective TKIs adapted to the molecular profile, some of which can redifferentiate and restore radioactive iodine uptake), proactive management of TKI side effects, and finally give an overview of systemic strategies. Management of RAIR DTC is still challenging but substantial progress has been made over the last decade that has significantly improved outcome for these more aggressive thyroid cancer.

Lipoma: An Unusual Iodine-131 Uptake on Whole-Body Scanning: A Case Report

Whole-body radioiodine scintigraphy plays a major role in detecting metastases or recurrence of differentiated thyroid cancers. However, radioactive iodine uptake is not specific to thyroid tissue, and many physiological and pathological variants can bind radioactive iodine, resulting in false positives that can compromise the correct interpretation of results. We report the case of a 73-year-old patient with papillary thyroid carcinoma who underwent surgery 2 years ago, and whose whole-body scan, performed in the face of rising thyroglobulin levels, revealed abnormal fixation on the thigh, and further investigations suggested a lipoma. Our aim in reporting this case is to contribute to the knowledge of new false positives linked to iodine-131 fixation, in order to avoid unusual diagnostic errors that can lead to the unnecessary administration of therapeutic doses of iodine-131 or to aberrant surgical interventions.

Recent insights into trends of thyroid cancer incidence in Lithuanian population exposed to Chernobyl fallout early in life

In the last three decades, an increase in thyroid cancer incidence has been observed worldwide, as well as in Lithuania. Although the rise was linked to overdiagnosis, the role of lifestyle and environmental factors, including exposure to ionizing radiation, cannot be excluded. In our retrospective study, we aimed to assess the association between the average age-specific thyroid dose due to the radioactive iodine uptake during childhood and adolescence from the Chernobyl fallout in Lithuania, and the trends of incidence of thyroid cancer from 1991 to 2015 in different regions. Averaged age-dependent thyroid doses were estimated for every municipality based on radioiodine activity in milk, reconstructed from available 131I activity measurements in the grass. Thyroid cancer incidence rates were calculated for the entire population and for two age at the time of exposure groups: 0–19 years and 0–9 years. Thyroid cancer relative risk (RR) was estimated for three municipality-specific thyroid dose (for 0-year-old babies) categories: less than 100 mGy (reference group), 100–199 mGy, and ≥200 mGy. Over the study period (1991–2015), a total of 5664 cases of thyroid cancer were registered in the entire Lithuanian population; 817 cases in the age group from 0 to 19 years at the time of the Chernobyl accident, and 266 cases in the age group from 0 to 9 years. Age-standardized thyroid cancer incidence rates have notably increased since 2000, peaked in 2009 (especially in females), and then slightly decreased and stabilized. The estimated average municipality-specific age-dependent thyroid doses ranged from 270 mGy in western Lithuania to 1.5 mGy in central and northern Lithuania. For the age group of 0–19 years at the time of the accident, in the period 1991–1995, the thyroid cancer relative risk was significantly increased (RR 3.91; 95 % CI: 1.27–10.29, p=0.01) in the highest dose category, compared to the lowest (although based on a small number of cases). For the age group 0–9 years at the time of the accident, a tendency of increased RR in the highest dose category appeared in the most recent period, 2011–2015. Our observations need to be confirmed by further following trends of thyroid cancer incidence in the cohort of 0–19-year-old Lithuanians at the time of the Chernobyl accident.

Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers.

Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used and has demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

SETMAR Facilitates the Differentiation of Thyroid Cancer by Regulating SMARCA2-Mediated Chromatin Remodeling.

Thyroid cancer is the most common type of endocrine cancer, and most patients have a good prognosis. However, the thyroid cancer differentiation status strongly affects patient response to conventional treatment and prognosis. Therefore, exploring the molecular mechanisms that influence the differentiation of thyroid cancer is very important for understanding the progression of this disease and improving therapeutic options. In this study, SETMAR as a key gene that affects thyroid cancer differentiation is identified. SETMAR significantly regulates the proliferation, epithelial-mesenchymal transformation (EMT), thyroid differentiation-related gene expression, radioactive iodine uptake, and sensitivity to MAPK inhibitor-based redifferentiation therapies of thyroid cancer cells. Mechanistically, SETMAR methylates dimethylated H3K36 in the SMARCA2 promoter region to promote SMARCA2 transcription. SMARCA2 can bind to enhancers of the thyroid differentiation transcription factors (TTFs) PAX8, and FOXE1 to promote their expression by enhancing chromatin accessibility. Moreover, METTL3-mediated m6A methylation of SETAMR mRNA is observed and showed that this medication can affect SETMAR expression in an IGF2BP3-dependent manner. Finally, the METTL3-14-WTAP activator effectively facilitates the redifferentiation of thyroid cancer cells via the SETMAR-SMARCA2-TTF axis utilized. The research provides novel insights into the molecular mechanisms underlying thyroid cancer dedifferentiation and provides a new approach for therapeutically promoting redifferentiation.

Impact of molecular therapy on radioactive iodine uptake in patients with oncogene-driven metastatic differentiated thyroid cancer.

TPS10078 Background: Targetable kinase fusions and mutations are common in pediatric and young adult patients with papillary thyroid cancer (TC) and are associated with metastatic disease and lack of response to radioactive iodine therapy (RAI). While survival outcomes are excellent, less than 20% of children with metastatic TC achieve a complete response to standard treatment with surgery and radioactive iodine (RAI). Thus, repeated RAI therapy is common, increasing the risk of pulmonary fibrosis and secondary malignancies. Targeted kinase inhibitors are highly effective at shrinking oncogene-driven TC. Preliminary data suggest that these targeted therapies can improve tumor differentiation and RAI sensitivity. However, optimal integration of targeted therapy with standard of care RAI for TC remains uncertain. The objective of this study is to evaluate if targeted inhibitors in patients with metastatic, oncogene-driven differentiated TC will improve or restore tumor RAI uptake and ultimately induce durable clinical responses in patients with metastatic differentiated TC. Methods: Patients with TC lung metastases, both RAI naïve and refractory, with an identified targetable molecular driver (Table) and intent to start oncogene-specific targeted therapy are eligible for this study. Patients who received a prior oncogene-specific targeted therapy are excluded. A RAI-whole body scan (WBS) is performed at baseline and after 4 weeks of targeted therapy. Patients will be followed for up to 5 years to monitor clinical response. Response parameters include structural (CT, WBS, and/or neck US) and biochemical (thyroglobulin, thyroglobulin antibodies) evaluation. The primary endpoint is the change in RAI avidity between baseline and 4 weeks of treatment. This will be calculated as the ratio of RAI uptake in the lungs/disease sites versus the whole body for each subject at each time point. Secondary endpoints include progression free survival and the proportion of patients who achieve a complete response to the combination of targeted therapy and RAI. Five of 32 patients have been enrolled. Clinical trial information: NCT05024929 . [Table: see text]

Deciphering Molecular Signatures Behind Different Radioactive Iodine Uptake Patterns in Differentiated Thyroid Cancer with Distant Metastases

Deciphering Molecular Signatures Behind Different Radioactive Iodine Uptake Patterns in Differentiated Thyroid Cancer with Distant Metastases