Radioiodine Research Articles

Metabolic Reprogramming in Thyroid Cancer: Role of the Epithelial-Mesenchymal Transition

Thyroid cancer (TC) represents the most common endocrine malignancy, with an increasing incidence all over the world. Papillary TC (PTC), a differentiated TC subtype, is the most common and, even though it has an excellent prognosis following radioiodine (RAI) ablation, it shows an aggressive behavior in 20–30% of cases, becoming RAI-resistant and/or metastatic. On the other side, anaplastic thyroid carcinoma (ATC), the most undifferentiated TC, is a rare but devastating disease, indicating that progression of differentiated to undifferentiated forms of TC could be responsible for RAI-resistance and increased mortality. The epithelial-to-mesenchymal transition (EMT) plays a pivotal role in both tumor progression and resistance to therapy. Moreover, during tumor progression, cancer cells modify their metabolism to meet changed requirements for cellular proliferation. Through these metabolic changes, cancer cells may adopt cancer stem cell-like properties and express an EMT phenotype. EMT, in turn, can induce metabolic changes to which cancer cells become addicted. Here we review metabolic reprogramming in TC highlighting the role of EMT with the aim to explore a potential field to find out new therapeutic strategies for advanced-stage PTC. Accordingly, we discuss the identification of the metabolic enzymes and metabolites, critical to TC progression, which can be employed either as predicting biomarkers of tumor response to RAI therapy or possible targets in precision medicine.

Radioiodine treatment: an historical and future perspective.

Radioiodine (RAI) therapy has been used to treat thyroid diseases for around 80 years, and yet it is only relatively recently that we are beginning to manipulate its use, as we understand more of the cellular complexities which govern its success. From the benign nature of hyperthyroidism to malignant thyroid carcinomas and their metastases, RAI has profoundly changed the management of thyroid disorders. However, the complex journey which has elicited this simple therapy is worth exploring.

Cytomorphological features of papillary thyroid carcinomas with the development of radioiodine-resistance

Background. The problem of diagnosis and treatment of papillary thyroid cancer (PTC) are radioiodine resistant metastases (RIRM). An urgent issue is the possibility of their early prediction and diagnosis based on the detection of cytomorphological features of the PTC and its metastases, which correlate with the development of radioiodine (RI) resistance. Purpose – detection of cytomorphological features of primary PTC and its metastases in patients who subsequently showed resistance to 131I therapy, compared with the control group of patients who achieved a positive effect of 131I therapy. Materials and Methods. A comparative analysis of morphological features in histological conclusions and the study of cytological characteristics in the fine-needle aspiration (FNA) smears of primary PTC and their primary metastases, as well RIRM оf experimental and control groups of patients were conducted. The experimental group consisted of 152 patients who showed resistance to RI therapy, the control group – 161 patients who achieved a positive effect of RI therapy. Statistical processing was done in Statistica 12. Results and discussion. It is shown that the frequency of follicular structures in the material of primary PTC of patients with a positive effect of 131I therapy is significantly higher, and the frequency of necrotic changes is significantly lower than in patients with the development of RIRM (p <0.05 by criterion χ2). The frequency of follicular structures in the histological material and FNA smears of primary metastases of patients with a positive effect of 131I therapy is significantly higher, and oxyphilic changes are significantly lower than in patients with the development of RIRM (p <0.05 by criterion χ2). Oxyphilic changes were observed significantly more often in the RIRM compared with primary metastases of the control group (p = 0.03). It was proved that cystic changes are significantly more common in FNA smears and histological material of RIRM in comparison with primary metastases of experimental and control groups of patients (p <0.05). Conclusions. TThe use of the presence of oxyphilic and cystic changes in the FNA smears and histological material of metastases of the PTC as prognostic factors of RI resistance is proposed. The presence of follicular structures in the materials of primary PTC and metastases can be a prognostic factor of effective RI therapy.

Real-World Efficacy and Safety of Multi-Tyrosine Kinase Inhibitors in Radioiodine Refractory Thyroid Cancer.

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (n = 33), lenvatinib (n = 53), and pazopanib (n = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

PSMA Expression in Differentiated Thyroid Cancer: Association With Radioiodine, 18FDG Uptake, and Patient Outcome.

Little is known about prostate-specific membrane antigen (PSMA) expression in patients with cervical involvement of differentiated thyroid cancer (DTC). We investigated PSMA expression in neck persistent/recurrent disease (PRD) using immunohistochemistry and the association with radioiodine (RAI) or 18-fluorodeoxyglucose (18FDG) uptake, and patient outcome. Data from 44 consecutive DTC patients who underwent neck reoperation from 2006 to 2018 in a comprehensive cancer center. Immunostaining was performed with vascular endothelial marker CD31 and PSMA. PSMA expression was quantified using the immunoreactive score (IRS). RAI and 18FDG uptake were assessed before surgery using posttherapeutic RAI scintigraphy and 18FDG positron emission tomography with computed tomography. Mean follow-up after reintervention was 6.5 ± 3.7 years. Thirty patients (68%) showed at least 1 PSMA-positive lesion (IRS ≥ 2) with similar proportions in RAI-positive and RAI-negative patients (75% vs 66%). In RAI-negative patients, however, the proportion of PSMA-positive disease (79% vs 25%, P < 0.01) and the mean IRS (4.0 vs 1.0, P = 0.01) were higher in 18FDG-positive than in 18FDG-negative patients. Furthermore, mean IRS was higher in patients ≥ 55 years, large primary tumors (>40 mm) or aggressive subtypes, and was correlated with structural disease at last follow-up. Strong PSMA expression (IRS ≥ 9) was associated with shorter progression-free survival (PFS). Our findings show that PSMA expression was present in two-thirds of patients with neck PRD, that it was related to poor prognostic factors and that very high expression was associated with poorer PFS. This preliminary study may offer new perspectives for the management of RAI-refractory DTC.

Clinical predictors of I-131 therapy failure in differentiated thyroid cancer by machine learning: A single-center experience.

Well-differentiated thyroid carcinoma is predominantly a slow-growing malignancy, amendable to treatment, and has an excellent prognosis following thyroidectomy and radioiodine (RAI) therapy. However, patients who fail the initial RAI treatment attempt may require repeated RAI or other treatments and with this, comes an associated impact on patient quality of life. Therefore, the anticipation of patients in whom there is a higher risk of RAI failure may help in patient risk stratification and subsequent management. We conducted a retrospective review to determine the factors associated with initial RAI therapy failure in well-differentiated thyroid cancer patients. Using scikit-learn from Python, we implemented a machine-learning algorithm to determine the clinical patient factors associated with a higher likelihood of treatment resistance. We found that clinical factors such as tumor focality (P = 0.026) and lymph node invasion at surgical resection (P = 0.0135) were significantly associated with initial treatment failure following RAI. Elevated serum thyroglobulin (Tg) and Tg antibody levels following surgery but before RAI were also associated with treatment resistance (P < 0.0001 and P = 0.011 respectively). Less expected factors such as decreased time from surgery to RAI were also associated with treatment failure, however not to a statistically significant degree (P > 0.064). Clinical outcomes following RAI can be stratified by identifying factors that are associated with initial treatment failure. These findings can help restratify patients for RAI treatment and change patient management in certain cases. Such stratification will ultimately help to optimize successful treatment outcomes and improve patient quality of life.

Characterization of Graves' disease development after partial thyroidectomy for thyroid cancer.

BackgroundGraves’ disease (GD) is the most common cause of hyperthyroidism, and it rarely develops in patients who undergo partial thyroid removal for thyroid cancer. The present study characterized and analyzed the GD development mechanism after partial thyroidectomy for thyroid cancer and suggested optimized treatments for the condition.MethodsA retrospective study from January 2013 to March 2017 was conducted in patients where GD occurred after partial thyroidectomy for thyroid cancer. Reviewed laboratory data included free 3,5,3'-triiodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), anti-Tg antibody, anti-peroxidase antibody, and TSH receptor antibody levels. All laboratory indicators included preoperative and postoperative data. In addition, we collected patient neck ultrasound examination records and radioiodine (RAI) uptake test data.ResultsAmong 5,600 patients diagnosed with GD, 5 (0.09%) met the inclusion criteria and were enrolled. Patient mean age was 47.4±9.6 years, and all were female with a papillary thyroid carcinoma stage I diagnosis. The interval between partial thyroidectomy and hyperthyroidism onset ranged from 2 to 25 months. We proposed possible mechanisms for this medical condition and identified several factors accelerating the disease course. To treat GD, a low RAI (30 mCi) dose was prescribed to patients. All exhibited hypothyroidism at a 3- or 6-month follow-up, with stable clinical status at 1-year follow-up.ConclusionsGD rarely develops after partial thyroidectomy for thyroid cancer. We recommend a low RAI dose to manage GD and ablate the remnants of thyroid cancer.

Ameliorating effects of N-acetyl cysteine against early liver damage of radioiodine in rats.

The present study was aimed to explore the potential ameliorating effects of N-acetyl cysteine (NAC) against radioiodine (RAI)-induced early liver damage. Thirty Wistar Albino male rats were arbitrarily allocated into three groups each containing 10 rats: the control group (group 1); the RAI group (group 2), oral 111 MBq/kg radioiodine was administered to rats; the RAI + NAC group (group 3), 150 mg/kg/day intraperitoneal NAC treatment was initiated 3 days prior to the RAI administration and continued for 10 days. Liver samples were obtained 24 h after the last dose of NAC therapy for biochemical and histopathologic evaluation. In the RAI + NAC group, the histopathologic damage was found significantly less than in the RAI group for whole parameters except inflammatory cell infiltration (P < 0.05). Unlike the RAI group which had marked histopathologic damage, the RAI + NAC group had only mild histologic activity index scores with no granuloma formation observed. Oxidative stress parameters were demonstrated that the NAC treatment significantly decreased the tissue malondialdehyde (MDA) and catalase levels and increased the total sulfhydryl (total sulfhydryl) levels when compared to the RAI group (P < 0.01). The outcomes of the study exhibited that the NAC treatment improved RAI-induced early liver damage. This improving effect considered to be caused by its antioxidant, anti-inflammatory, and likely vasodilator properties of NAC. Having advantages such as inexpensive, easy access, and tolerability, the NAC can be used as a radioprotective agent, especially in patients with liver diseases and requiring RAI treatment.

Ablation rate after radioactive iodine therapy in patients with differentiated thyroid cancer at intermediate or high risk of recurrence: a systematic review and a meta-analysis

PurposeWe performed a systematic review and a meta-analysis to investigate the successful ablation rate after radioiodine (RAI) administration in patients with differentiated thyroid cancer (DTC) at intermediate-high risk of recurrence.MethodsA comprehensive literature search of the PubMed, Scopus, and Web of Science databases was conducted according to the PRISMA statement.ResultsThe final analysis included 9 studies accounting for 3103 patients at intermediate-high risk of recurrence. In these patients, the successful ablation rates ranged from 51 to 94% with a 71% pooled successful ablation and were higher in intermediate (72%) than in high (52%)-risk patients. Despite the rigorous inclusion standards, a significant heterogeneity among the evaluated studies was observed. Higher administered RAI activities are associated with a lower successful ablation rate in the whole population and in the subgroup of high-risk patients. Furthermore, pooled recurrence rate in intermediate-risk patients achieving successful ablation was only 2% during the subsequent 6.4-year follow-up while the pooled recurrence rate was 14% in patients who did not achieve a successful ablation.ConclusionIn a large sample of 3103 patients at intermediate-high risk of persistent/recurrent disease, 71% of patients achieved a successful ablation. In these intermediate-risk patients, the probability of subsequent recurrence is low and most recurrence occurred in those with already abnormal findings at the first control.

Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial.

6001 Background: Cabozantinib (C), an inhibitor of VEGFR2, MET, AXL, and RET, showed clinical activity in patients (pts) with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) in phase 1/2 studies (Cabanillas 2017; Brose 2018). This phase 3 study (NCT03690388) evaluated the efficacy and safety of C vs placebo (P) in pts with RAI-refractory DTC who had progressed during/after prior VEGFR-targeted therapy for whom there is no standard of care. Methods: In this double-blind, phase 3 trial, pts were randomized 2:1 to receive C (60 mg QD) or P, stratified by prior lenvatinib treatment (L; yes, no) and age (≤65, &gt; 65 yr). Pts with RAI-refractory DTC must have received L or sorafenib for DTC and progressed during or following treatment with ≤ 2 prior VEGFR inhibitors. Pts randomized to P could cross over to open-label C upon disease progression per blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (ORR) in the first 100 randomized pts and progression-free survival (PFS) in all randomized pts. PFS and ORR were assessed by BIRC per RECIST v1.1. The study was designed to detect an ORR for C vs P (2-sided α = 0.01) and a hazard ratio (HR) for PFS of 0.61 (90% power, 2-sided α = 0.04). A prespecified interim PFS analysis was planned for the ITT population at the time of the primary ORR analysis. Results: As of 19 Aug 2020,125 vs 62 pts had been randomized to the C and P arms, respectively; median age was 66 yr, 55% were female and 63% received prior L. Median (m) follow-up was 6.2 months (mo). At the planned interim analysis, the trial met the primary endpoint of PFS with C demonstrating significant improvement over P (HR 0.22, 96% CI 0.13–0.36; p &lt; 0.0001). mPFS was not reached for C vs 1.9 mo for P; PFS benefit was observed in all prespecified subgroups including prior L (yes, HR 0.26; no, HR 0.11) and age (≤65 yr, HR 0.16; &gt; 65 yr, HR 0.31). ORR was 15% for C vs 0% for P (p = 0.0281) but did not meet the prespecified criteria for statistical significance (p &lt; 0.01). A favorable OS trend was observed for C vs P (HR 0.54, 95% CI 0.27–1.11). Treatment-emergent adverse events (AEs) of any grade with higher occurrences in the C vs P arm included diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%); grade 3/4 AEs were experienced by 57% of pts with C vs 26% with P. Dose reductions due to any grade AEs occurred in 57% of pts with C vs 5% with P. Treatment discontinuations due to AEs not related to disease progression occurred in 5% of pts with C vs 0% with P. No treatment-related deaths occurred in either arm. Conclusions: C showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. C may represent a new standard of care in pts with previously treated DTC. Clinical trial information: NCT03690388.

New Treatment Strategy Targeting Galectin-1 against Thyroid Cancer.

Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer.

Successful Management of Hyperthyroidism With Lithium and Radioiodine in a Patient With Previous Methimazole-Induced Agranulocytosis

Introduction: Antithyroid drug (ATD) therapy is the first-line treatment of Graves’ hyperthyroidism. Agranulocytosis, although rare, is a life-threatening condition associated with ATD therapy. For patients who recovered from ATD-induced agranulocytosis, surgery or radioiodine (RAI) therapy are adequate options to restore the patient’s euthyroid state. Here we report a case of ATD-related agranulocytosis where lithium therapy was used before RAI to control thyrotoxicosis and prevent worsening of hyperthyroidism. Case Report: A 74-year-old female with a previous history of hypertension presented with a 2-month history of weight loss (12 lbs), palpitations and shortness of breath. She was afebrile with a heart rate of 110, a blood pressure of 149/80, a fine tremor and a moderate diffuse goiter. She had a normal eye exam. Laboratory evaluation demonstrated TSH <0.01 uIU/mL (0.35-5.5), FT4 3.11 ng/dL (0.51-1.65) and TSH receptor antibody (TRAb) 40 (<1,0 U/L), consistent with thyrotoxicosis due to Graves’ disease. She was started on methimazole (MMI) 15mg and metoprolol. After four weeks, symptoms resolved and thyroid function tests (TFT) improved. However, after two months of treatment, she was hospitalized for fever, diarrhea and abdominal pain. White blood cell count (WBC) was 650/μL, and neutrophil count was 90/μL. A diagnosis of gastroenteritis and agranulocytosis was made and MMI was stopped. After seven days, symptoms resolved, the neutrophil count was 2200/ul and TFT were acceptable (FT4 1.25, ng/dL TT3 1.67 ng/ml, TSH < 0.02 uIU/mL). She was discharged without ATDs and a RAI dose of 20 mCi was scheduled. However, RAI therapy had to be postponed due to COVID-19 pandemic restrictions. After 3 weeks, TFT worsened and therapy with lithium carbonate 300 mg TID was started as the patient refused thyroidectomy. Lithium was initiated 12 days before RAI therapy and was maintained 7 days after the procedure. No side effects associated with lithium treatment were reported. TFT 7 days after RAI were FT4 1.43, ng/dL TT3 2.05 ng/ml and TSH < 0.02 uIU/mL. One month later, the patient was euthyroid without need for thyroid medication and remains on follow up. Discussion: Serum thyroid hormone (TH) concentrations usually increase after RAI therapy for Graves’ disease, a worrisome fact in patients with increased risk for cardiovascular complications. Previous studies report that pre-RAI treatment with lithium prevents changes in serum TH concentrations and enhances RAI therapy’s effectiveness. Here, treatment with lithium was used to control thyrotoxicosis and prevent further increase in TH levels associated with RAI therapy. Lithium is particularly suitable for patients with ATD-related side effects before definitive therapy (radioiodine or thyroidectomy). The antithyroid effect of lithium in this setting should be further studied.

Molecular Testing Can Impact Clinical Decision Making and Therapeutic Approach in Thyroid Cancer

Abstract We present the case of a patient with a thyroid nodule of indeterminate cytology on fine-needle aspiration (FNA) biopsy whose molecular profile significantly impacted clinical decision making and treatment. A 77-year-old woman with a history of hyperthyroidism presented to our clinic for a second opinion regarding management of a recently discovered right thyroid nodule. Thyroid ultrasound (US) 6 months prior showed a 2.6 cm, heterogeneous nodule with peripheral vascular flow; not characterized based on ATA or TIRADS criteria. Family history was significant for papillary thyroid cancer in daughter at age 35 years. The patient had no history of head or neck irradiation. She had no compressive symptoms or manifestations of hyper or hypothyroidism. FNA biopsy of the nodule was done twice in 4 months, and cytology was consistent with follicular lesion of undetermined significance (FLUS, Bethesda III) in both occasions. Repeat FNA biopsy at our institution showed follicular neoplasm (FN, Bethesda IV), and molecular testing using ThyroSeq v3 was positive for HRAS and TERT mutations, which conferred a &amp;gt;95% risk of cancer. Patient was referred to Endocrine Surgery and total thyroidectomy was recommended based on nodule’s molecular profile and associated hyperthyroidism. No suspicious lymph nodes were noted on preoperative US. No gross local invasion observed intraoperatively. Surgical pathology showed intrathyroidal FN without invasion. However, given disparity between pathology findings and molecular markers, specimen was sent for outside blinded pathology review which concluded to be a follicular thyroid carcinoma with capsular invasion but no angiolymphatic invasion or extrathyroidal extension. Based on these findings, along with the known HRAS and TERT mutations, it was advised to proceed with radioiodine (RAI) remnant ablation. Patient was prepared with thyrotropin alfa and received 29 millicuries of RAI. Post-treatment scan showed focal neck uptake consistent with ablated thyroid tissue and no distant metastases. Patient had an excellent response to therapy, without evidence of biochemical or structural recurrence 2 years later. Molecular testing of cytologically indeterminate thyroid nodules (Bethesda III, IV) has become an important tool to better refine risk of malignancy. Furthermore, the presence of certain mutations or mutation combinations, such as RAS and TERT co-occurrence, suggests a more aggressive behavior associated with worse outcomes. As a result, a more aggressive approach might be recommended. Our case illustrates how molecular testing can significantly influence therapeutic decisions such as extent of surgery, interpretation of surgical pathology and/or use of RAI. Further research is needed to determine if its routine use may lead to improved cancer-related outcomes or if it is cost-effective in the risk stratification of differentiated thyroid cancer.

A Unique Presentation of Metastatic Follicular Thyroid Cancer Associated with Hyperthyroidism and an Active Graves’ Orbitopathy

Background: Graves orbitopathy (GO) developing in a thyroidectomized patient with hormonally active metastatic follicular thyroid cancer (FTC) is an extremely rare event. We report a unique patient with GO and hyperthyroidism developing 13 years after FTC diagnosis. Case: A 79-year-old Caucasian female diagnosed with FTC T3N0M1 with lung metastases in 2005, was treated with total thyroidectomy and cumulative radioiodine (RAI) activity of 700 mCi between 2005 and 2010, with post-treatment scans revealing RAI-avid disease. Despite RAI treatment-associated stable disease in the lungs, the patient developed bone metastases and required external beam radiation (EBRT; 30 Gy in 10 fractions) to the left acetabular lesion in 2011. In 2015, she presented with clinically symptomatic tumor growth in the lungs and bones and biochemical disease progression with thyroglobulin levels rising from 255 ng/ml in 2014 to 273141 ng/mL in 2019. The patient completed repeat EBRT to the left iliac bone in December 2019 (30 Gy in 10 fractions). She was on weight-based suppressive levothyroxine treatment between 2005 and 2019 until she developed atrial fibrillation with a rapid ventricular response and was diagnosed with thyrotoxicosis with TSH < 0.01 mIU/mL (normal0.36 - 5.60) and free T4 5.93 ng/dL (normal 0.9 - 1.7). An iatrogenic cause of thyrotoxicosis was ruled out on the basis of persistent clinical and biochemical hyperthyroidism after reduction, and subsequently, cessation of levothyroxine treatment. Further workup was significant for elevated thyroid stimulated immunoglobulin (TSI) of 23.9 IU/l (normal: < 1.3) and thyrotropin receptor antibodies (TRAb) of 10.39 IU/L (< or =1.75), consistent with Graves’ disease. The patient achieved and maintained euthyroidism on methimazole treatment. In April 2019, she was diagnosed with active GO and was treated with intravenous methylprednisolone, which was discontinued four weeks later due to steroids-induced severe myopathy. Given a high clinical activity score of 6 and magnetic resonance imaging of the orbits revealing a significant bilateral symmetric extraocular muscle enlargement and increased retro-orbital fat with no evidence of optic nerve compromise, she underwent radiation therapy to the orbits (20 Gy in 10 fractions), which was completed in December 2019. Subsequently, in 2020, the patient underwent 8 cycles of treatment with a monoclonal antibody against insulin-like growth factor I receptor - teprotumumab. Subjectively, she reported improved eye swelling and no vision changes, but developed drug-induced partial hearing loss, which is thought to be reversible. Conclusion: Metastatic, progressive FTC can be associated with an autoimmune response, leading to stimulation of well-differentiated cancer tissue to overproduce thyroid hormones resulting in overt hyperthyroidism, as well as retroorbital fibroblasts activation leading to GO.

Can shear wave elastography determine remnant thyroid tissue in the early postoperative period in patients with differentiated thyroid carcinoma?

This study aims to investigate the usability of ultrasonography (US) and shear wave elastography (SWE) in detecting remnant thyroid tissue (RTT) within the first three postoperative months in patients who underwent total thyroidectomy (TT) for differentiated thyroid cancer (DTC) and who were scheduled for radioiodine (RAI) ablation therapy. Sixty-nine patients who underwent a TT operation due to DTC were included in the study. The participant's thyroid surgical bed was first evaluated by thyroid scintigraphy and then by greyscale US and SWE to investigate RTT. The participants were divided into two groups, those with and those without RTT. SWE quantitative data were compared between the two groups. Receiver operating characteristic (ROC) curve analysis was performed to determine the best cut-off values for stiffness and velocity in distinguishing RTT. A total of 149 regions were analysed in 69 participants (43 females, 26 males). The average time elapsed after the operation was 65.2 ± 24.1days. RTT was determined by scintigraphy and US-SWE in 38 (55%) patients. The stiffness and velocity values were significantly higher in the group with RTT than in the group without RTT. To distinguish RTT from the thyroid bed, the best cut-off values for stiffness and velocity were 15.7kPa and 2.12m/s, respectively. US with SWE can detect RTT in the early postoperative period in patients who have undergone TT due to DTC and who are scheduled for RAI treatment. The use of US and SWE will be particularly beneficial in patients with RTT but who have false-negative Tg levels and RTT that is not I-131 avid.

Decline in radioiodine use but not total thyroidectomy in thyroid cancer patients treated in the United Arab Emirates - A retrospective study

ObjectivesTo assess the trend of clinicopathological features and treatment modalities in patients with thyroid cancer (TC) in the largest oncology center in the United Arab Emirates (UAE). MethodsA retrospective analysis of patients with TC presenting to a tertiary care hospital in Al Ain, UAE between September 2008 and December 2018 identified using ICD 9 & 10 codes was performed. Data on demographics, histopathology, surgical extent, and use of Radioiodine (RAI) were extracted. Exact logistic and ordinal logistic regressions were performed to analyze the annual trend in features and management of TC, and logistic regression analysis was performed to identify predictors of total thyroidectomy and RAI use. ResultsA total of 762 patients were included in the analysis (mean age: 39.6 ± 12.6 years, 45 (60%) women). The majority (92.2%) were diagnosed with papillary thyroid cancer (PTC) and 83.9% had tumor size of <4 cm. All patients underwent surgery (93.8% total thyroidectomy, 6.2% lobectomy) and 77.4% received RAI therapy overall with a significant (p < 0.001) decline from 100% in 2008 to 60% in 2018. In multivariate analysis, nationality, and lymph node (LN) involvement were significant predictors of total thyroidectomy, while nationality, LNs, year of diagnosis, and tumor size significantly predicted RAI use. ConclusionMost patients in our cohort were diagnosed with localized PTC with no significant change in the extent of surgical approach but a substantial decline in RAI therapy administration over time. Nationality and LN involvement were significant predictors of surgical extent and RAI use.

Bulky Mediastinal Metastasis in Neglected Follicular Thyroid Carcinoma: A Case Report

Follicular carcinoma of thyroid usually behaves in an indolent manner with low metastatic potential. Distant metastases as initial presentation are rare in follicular carcinoma, especially in young patients. Blood borne metastasis is common with spread to lung, bone and other solid organs. However, metastatic mediastinal tumors are rare. Here, a neglected case of follicular carcinoma of thyroid (FTC) is reported. The patient is a 43 year old female who was referred to the Thyroid Division of NINMAS for radioiodine therapy for an inoperable metastatic FTC. She was presented with fever, shortness of breath and chest discomfort. 99mTc scan showed concentration of most of the isotope in the big metastatic mediastinal mass. Because of the sheer volume of the mass, a plan was undertaken to first reduce her tumor burden with external beam radiation therapy (EBRT) and then considered adjuvant therapy with radioiodine after manageable regression in size of the metastatic tumor. She had a history of thyroidectomy for FTC 14years back without radio iodine ablation. Negligence about proper management for FTC may result in poor outcome like huge mediastinal mass as in this reported case. Radioiodine therapy is usually the first line approach for functional metastasis, but in exceptional cases when the tumor size is very big, EBRT may be considered first. Radiotherapy (RT) is effective in relieving compression symptoms and may improve the quality of life in these patients.&#x0D; Bangladesh J. Nuclear Med. 22(2): 141-145, Jul 2019

Incidence of microcytosis in hyperthyroid cats referred for radioiodine treatment.

ObjectivesThe study aimed to document the incidence of erythrocyte microcytosis in a population of hyperthyroid cats referred for radioiodine (RAI) treatment. Microcytosis has been observed but not described in feline hyperthyroid patients and is associated with hyperthyroidism in humans.MethodsRetrospective clinicopathological data were collected for cats undergoing RAI between January and December 2017. Microcytosis was defined as mean cell volume (MCV) <41.3 fl using the ADVIA 2120 haematology analyser (Siemens) and identified on blood smear examination by a haematology laboratory scientist or board-certified specialist in veterinary clinical pathology. Hyperthyroidism was classified as mild (total thyroxine [TT4] 60–124.9 nmol/l), moderate (TT4 125–250 nmol/l) or severe (TT4 ⩾251 nmol/l) immediately before RAI. Data were analysed descriptively and using a Pearson correlation coefficient to test the relationship between TT4 and microcytosis, and time elapsed between first diagnosis and MCV.ResultsThere were 41 female and 37 male cats with an age range of 7.2–20.8 years. Most cats were non-pedigree (98.7%). Microcytosis (median MCV 39.8 fl, interquartile range 32.3–41.2) was present in 29.5% (23/78) of the cats. Of the 23 microcytic samples, 86.9% (20/23) were confirmed as such on smear examination. Of mildly, moderately and severely hyperthyroid cats, 23% (6/26), 28.1% (9/32) and 40% (8/20) were microcytic, respectively. Two microcytic cats had low red blood cell counts (<6 × 1012/l) and low haemoglobin concentration (<8.2 g/dl). There was no correlation between TT4 or time elapsed from first diagnosis and MCV. Microcytosis resolved in 77.7% (7/9) of cases with follow-up. One microcytic cat had significant comorbidities (portosystemic shunt).Conclusions and relevanceMicrocytosis was present in a significant proportion of hyperthyroid cats, most without clinically significant comorbidities, and resolved in some following RAI.

Relationship between clinicopathologic factors and FDG avidity in radioiodine-negative recurrent or metastatic differentiated thyroid carcinoma

BackgroundIn this study, we investigated the relationship between clinicopathologic factors, BRAFV600E mutation status and [18F] F-fluoro-2-deoxyglucose (FDG) avidity in patients with radioiodine (RAI)-negative recurrent or metastatic differentiated thyroid cancer (DTC).MethodsFrom 2015 to 2018 all patients with suspected recurrent or metastatic radioiodine-negative DTC patients who underwent FDG positron emission tomography/computed tomography (PET/CT) were retrospectively reviewed. Suspected lesions on FDG PET/CT were biopsied and underwent BRAFV600E mutation testing by immunohistochemistry and real-time PCR. Tumor size, recurrent versus metastatic disease, histopathologic features including classical type versus aggressive subtypes (poorly differentiated, tall cell, columnar cell, hobnail variants) and BRAFV600E mutation status were correlated with the SUVmax of highest hypermetabolic lesions on FDG PET/CT by the univariate analysis using logistic regression.ResultsSixty-three consecutive patients, 55 (87.3%) female, with median age of 48 (range 17–81) were included. The majority of patients had BRAFV600E mutation and classical subtype, 55/63 (87.3%) and 45/63(71.4%), respectively. Thyroglobulin at the time of suspected recurrence was 262.7 ng/ml (range 16.3–1000) and patients received a median 3 prior RAI treatments. Fifty-four patients (85.7%) had local recurrence. The majority of patients 58/63 (92.1%) had FDG-avid disease on PET/CT. On univariate analysis, tumor size aggressive histopathologic types and distant metastasis are the significant factors for predicting FDG uptake, p = 0.04, p = 0.001 and p = 0.004 respectively. Although FDG uptake of BRAFV600E bearing recurrent/metastatic RAIR DTC lesions was higher than those without the mutation, the difference did not reach statistical significance, SUVmax of 7.11 versus 4.91, respectively, p = 0.2.ConclusionThe majority of recurrent or metastatic RAI-negative DTC have BRAFV600E mutation and detectable disease on FDG PET/CT. FDG avidity of the recurrent or metastatic RAI-negative DTC is independently associated with the aggressive histopathologic features.

Primary lung cancer with radioiodine avidity: A thyroid cancer cohort study.

BACKGROUNDA proportion of lung cancers show sodium/iodide symporter (NIS) expression. Lung cancers with NIS expression may uptake radioiodine (RAI) and show RAI-avid lesions on RAI scan for differentiated thyroid cancer (DTC) surveillance.AIMTo investigate the possibility of RAI uptake by lung cancer in a cohort with thyroid cancer.METHODSRAI-avid lung cancers were analyzed using a prospectively maintained database of patients with thyroid cancer who were registered at a medical center between December 1, 1976 and May 28, 2018. NIS expression in lung cancer was assessed using immunohistochemical staining.RESULTSOf the 5000 patients with thyroid cancer from the studied dataset, 4602 had DTC. During follow-up, 33 patients developed primary lung cancer. Of these patients, nine received an iodine-131 (131I) scan within 1 year before the diagnosis of lung cancer. One of these nine lung cancers was RAI-avid. NIS expression was evaluated, and three of the eight available lung cancers revealed NIS expression. The proportions of lung cancer cells with NIS expression were 60%, 15%, and 10%. The RAI-avid lung cancer had the highest level of expression (60%). The RAI-avid lung cancer had a spiculated border upon single-photon emission computed tomography/computed tomography, which led to an accurate diagnosis.CONCLUSIONA proportion of lung cancer demonstrates NIS expression and is RAI-avid. Clinicians should be aware of this possibility in the interpretation of RAI scintigraphy.