The History of Thyroid Ultrasound: Past, Present, and Future Directions.

The rapid evolution of ultrasound (US) technology has dramatically changed the medical field. Ideally suited for evaluation of anatomic disorders of the thyroid, coupled with its ease of use at the bedside, US has become an essential tool for endocrinologists over the last 50 years. This noninvasive technology provides a sensitive and specific instrument for malignancy risk prediction of thyroid nodules, surveillance for recurrent thyroid cancer, and diagnosis of autoimmune thyroid disorders. While US has proven invaluable for such diagnostic purposes, its extensive use also has resulted in important negative consequences. This review will discuss the evolution of US equipment for the evaluation of thyroid disorders, its use in interventional procedures, and the unintended outcomes from the widespread adoption of this technology. Finally, this article will explore the potential future applications for US technology and its related advancements.

Defining the Functional Sensitivity for the Siemens Atellica Calcitonin Assay: Insight From a Single-Center Study.

BACKGROUND: Detectable, and especially rising postthyroidectomy serum calcitonin and carcinoembryonic antigen levels, as per American Thyroid Association guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent medullary thyroid carcinoma. Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making. METHODS: A retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between September 27, 2022 and August 11, 2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. Carcinoembryonic antigen results were also reviewed. RESULTS: Precision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent medullary thyroid carcinoma confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity. CONCLUSIONS: Our findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy.

International Expert Consensus on US Lexicon for Thyroid Nodules.

Multiple US-based systems for risk stratification of thyroid nodules are in use worldwide. Unfortunately, the malignancy probability assigned to a nodule varies, and terms and definitions are not consistent, leading to confusion and making it challenging to compare study results and craft revisions. Consistent application of these systems is further hampered by interobserver variability in identifying the sonographic features on which they are founded. In 2018, an international multidisciplinary group of 19 physicians with expertise in thyroid sonography (termed the International Thyroid Nodule Ultrasound Working Group) was convened with the goal of developing an international system, tentatively called the International Thyroid Imaging Reporting and Data System, or I-TIRADS, in two phases: (phase I) creation of a lexicon and atlas of US descriptors of thyroid nodules and (phase II) development of a system that estimates the malignancy risk of a thyroid nodule. This article presents the methods and results of phase I. The purpose herein is to show what has been accomplished thus far, as well as generate interest in and support for this effort in the global thyroid community.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. METHODS: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches Laryngology Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSION: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.

BACKGROUND: The objective of this study is the validation and proof of clinical relevance of a novel electrochemiluminescence immunoassay (ECLIA) for the determination of serum calcitonin (CT) in patients with medullary thyroid carcinoma (MTC) and in different diseases of the thyroid and of calcium homeostasis. METHODS: This was a multicenter prospective study on basal serum CT concentrations performed in 9 US and European referral institutions. In addition, stimulated CT concentrations were measured in 50 healthy volunteers after intravenous calcium administration (2.5 mg/kg bodyweight). RESULTS: In total, 1929 patients and healthy controls were included. Limits of blank, detection, and quantification for the ECLIA were 0.3, 0.5, and 1 ng/L, respectively. Highest intra- and interassay coefficients of variation were 7.4% (CT concentration, 0.8 ng/L) and 7.0% (1.1 ng/L), respectively. Medians (interval) of serum CT concentrations in 783 healthy controls were 0.8 ng/L (<0.5-12.7) and 3 ng/L (<0.5-18) for females and males, respectively (97.5th percentile, 6.8 and 11.6 ng/L, respectively). Diagnostic sensitivity and specificity were 100%/97.1% and 96.2%/96.4%, for female/males, respectively. Patients (male/female) with primary hyperparathyroidism, renal failure, and neuroendocrine tumors showed CT concentrations >97.5th percentile in 33%/4.7%, 18.5%/10%, and 8.3%/12%, females/males, respectively. Peak serum CT concentrations were reached 2 min after calcium administration (161.7 and 111.8 ng/L in males and females, respectively; P < 0.001). CONCLUSIONS: Excellent analytical performance, low interindividual variability, and low impact of confounders for increased CT concentrations in non-MTC patients indicate that the investigated assay has appropriate clinical utility. Calcium-stimulated CT results suggest good test applicability owing to low interindividual variability.

LONG-TERM NONOPERATIVE RATE OF THYROID NODULES WITH BENIGN RESULTS ON THE AFIRMA GENE EXPRESSION CLASSIFIER.

OBJECTIVE: The primary objective was to assess the operative rate in patients with a benign result from the Afirma gene expression classifier (GEC) during long-term follow-up at nonacademic medical facilities. The secondary endpoint of this study was the treating physician's opinion regarding the safety of GEC use compared to the hypothetical situation of providing thyroid nodule management without the GEC. METHODS: This was a retrospective study of nonacademic medical practices utilizing the GEC. Those clinicians utilizing the GEC testing who had three or more 'benign' results during the data collection period (September 2010 through June 2014) were invited to participate. Operative status and patient demographics were documented for patients with GEC testing at least 36 months (± 3 months) prior to the date of data collection. A survey also was administered to the treating physicians to assess their perceived safety of using the GEC in patient care. RESULTS: During 36 months (± 3 months) of follow-up, 17 of 98 patients (17.3%) with a 'benign' GEC result underwent surgery. Within the first 2 years after a 'benign' GEC, 88% of surgeries were performed. Regarding safety of the GEC, the treating physicians reported that patient safety was improved by using the GEC compared to not using the GEC in 78 of 91 cases (86%). CONCLUSION: It appears that a 'benign' result on the GEC is associated with a reduction in the rate of thyroid surgeries compared to published data when patients are followed for 36 months after testing. A nonoperative approach to follow-up was felt to be a safe alternative to diagnostic surgery by the majority of responsible physicians in the study. ABBREVIATIONS: AUS = atypia of undetermined significance FLUS = follicular lesion of undetermined significance FN = follicular neoplasm FNA = fine-needle aspiration GEC = gene expression classifier.

Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

Ultrasound Features and Performance of Afirma Gene Sequencing Classifier in Cytologically Indeterminate Thyroid Nodules.

Background: Cytologically indeterminate thyroid nodules (ITN) pose a management challenge. Here we analyze if adding ultrasound characteristics to Afirma Genome Sequence Classifier (GSC) results increases GSC diagnostic performance. Methods: We retrospectively analyzed 237 GSC-tested Bethesda III/IV ITNs between July 2017 and December 2019 and classified them by American Thyroid Association (ATA) and the Thyroid Imaging Reporting and Data System (TIRADS) of the American College of Radiology. Results: The benign call rate was higher in Bethesda III ITNs with TIRADS <5 vs TIRADS 5 (89% vs 68%. P = .015). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of GSC in ATA high-risk Bethesda III ITNs vs lower were 100% vs 80% (P = 1), 89.5% vs 91.5% (P = .67), 66.7% vs 25% (P = .13), and 100% vs 99.2% (P = 1), respectively, and for TIRADS 5 vs <5 were 100% vs 80% (P = 1), 88.2% vs 91.4% (P = .65), 71.4% vs 23.5% (P = .06), and 100% vs 99.3% (P = 1). The sensitivity, specificity, PPV, and NPV of GSC in high-risk ATA Bethesda IV ITNs vs lower were 66.7% vs 100% (P = .42), 83.3% vs 85.7% (P = 1), 66.7% vs 64.3% (P = 1), and 83.3% vs 100% (P = .3), respectively, and for TIRADS 5 vs <5 were 66.7% vs 90% (P = .42), 88.9% vs 83.8% (P = 1), 66.7% vs 60% (P = 1), and 88.9% vs 96.9% (P = .39). Conclusion: Sensitivity, specificity, NPV, and PPV of GSC were not significantly different in ATA high-risk and TIRADS 5 ITNs compared to ATA < high-risk and TIRADS 1-4 ITNs.

Indolent Behavior of Malignant Bethesda III Nodules Compared to Bethesda V/VI Nodules.

BACKGROUND: The Bethesda system classifies all fine-needle aspiration specimens into 1 of 6 categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior. METHODS: This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology. RESULTS: A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with a predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs 41 days, P < .001) (Fig. 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62% vs 46%, P < .03), a lower possibility of recurrence (8% vs 24%, P < .001), and a shorter interval to achieve remission (median 1218 vs 1682 days, P = .02) compared to Bethesda V/VI, which did not change after adjusting for age, sex, radioactive iodine therapy, mode of surgery, and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis. CONCLUSION: Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

Beyond malignancy risk stratification: FNAC report anticipates thyroid cancer staging. Insights from recent studies.

Fine-needle-aspiration-cytology (FNAC) is safe and cost-effective procedure for evaluating thyroid nodules. The non-negligible rate of indeterminate cytology (ITN), warrants diagnostic surgery for histological assessment, in some cases. Two recent studies (from Europe and the U.S.) reported that the clinical behavior of a histologically proven thyroid cancer (TC) varies according to its pre-surgical FNAC results. Despite differences in study design, inclusion criteria, and the use of different cytology classification systems (Italian and Bethesda), the overall results were comparable. In order to further discuss these results and to provide additional perspective on the topic, the senior authors of the two studies invited other thyroid experts and cytologists not involved in the previous studies to participate in the present commentary. The strong, consistent clinical message that emerges, especially regarding PTC, is that TC with an initial diagnosis of ITN has a less aggressive clinical presentation, lower rates of: i) lymph-node metastasis; ii) more aggressive variants; iii) BRAFV600E mutations, as compared with DTC with an initial diagnosis of "suspicious for malignancy" or "malignant". These results were consistent in both studies and strongly point toward a more indolent clinical phenotype of DTC with a preoperative diagnosis of ITN as opposed to suspicious for malignancy or malignant. Further understanding the clinical implications of these data appears of clinical relevance and will be discussed from both the endocrinologist and cytologist point of view. The here overviewed data provide the foundation for beginning to examine the impact of less aggressive therapies for TC with an initial ITN diagnosis.

Molecular testing in thyroid cancer diagnosis and management.

Molecular diagnostic testing has had a profound impact on the diagnosis and management of thyroid nodules and thyroid cancer. Based on the tremendous expansion of knowledge of the genomic landscape of thyroid cancer over the past few decades, tests have been developed, analyzed, modified, and implemented into clinical practice. Genomic testing of thyroid nodules to improve preoperative diagnosis has become an important component supporting decision-making in clinical care, reducing the need for diagnostic surgeries and improving accuracy of cancer risk assessment. In addition, a role for molecular testing of established thyroid cancers to assist in selection of therapeutic options for patients with advanced and/or progressive disease has been established. Research is ongoing to determine if molecular results should affect management of less aggressive forms of thyroid cancer earlier in clinical management. This review will outline the various commercial platforms for molecular diagnostics for nodules emphasizing their performance parameters and indications for use, as well as discuss the use of genomic analysis for progressive thyroid cancer and highlight opportunities for further research.

Neoadjuvant dabrafenib and trametinib for functional organ preservation in recurrent BRAF V600E-mutated papillary thyroid cancer.

OBJECTIVES: To describe the first reported use of neoadjuvant dabrafenib and trametinib specifically to permit organ conservation surgery in locally advanced recurrent differentiated thyroid carcinoma. PATIENTS AND METHODS: A patient presented with locally recurrent, radioiodide-resistant DTC with a BRAF V600E mutation invading the laryngotrachea. Definitive treatment would require a total laryngectomy. She was offered neoadjuvant dabrafenib and trametinib prior to surgery. RESULTS: A significant radiographic response permitted partial laryngectomy, enabling preservation of voice, early resumption of oral feeding, and avoidance of permanent tracheostomy. At 9 months, she remained free of disease. CONCLUSION: Neoadjuvant tyrosine kinase inhibitor treatment prior to definitive surgery for locally-invasive recurrent DTC is a potential approach that may limit the degree of surgery and associated morbidity.

Coronary Artery and Peripheral Vascular Disease in a Patient with Poorly Differentiated Thyroid Cancer Treated with the Tyrosine Kinase Inhibitor Lenvatinib.

A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.

Thyroglobulin Cutoff Values for Detecting Excellent Response to Therapy in Patients With Differentiated Thyroid Cancer.

Context: Serum thyroglobulin (Tg) is a biochemical marker for detecting persistent or recurrent differentiated thyroid carcinoma (DTC) post-thyroidectomy. Tg can indicate DTC before structural disease (SD) is visible with imaging procedures. Objective: This work aimed to evaluate the clinical performance of the Elecsys® Tg II assay at a Tg cutoff of 0.2 ng/mL for ruling out SD in adults with DTC after total/near-total thyroidectomy, with or without radioiodine ablation (RAI). Methods: Patients were enrolled into 2 cohorts: longitudinal (Tg assessed every 6 months over 2 years under thyroid-stimulating hormone [TSH] suppression therapy following thyroidectomy with or without RAI) and cross-sectional with confirmed SD (Tg assessed once >12 weeks after thyroidectomy). Analyses were performed for both cohorts combined and in the longitudinal cohort. Results: The study included 530 clinically evaluable samples, the majority (n = 424 samples) from patients who had not received RAI treatment. Following correction for SD prevalence (4.97% in the longitudinal cohort), an Elecsys Tg II cutoff of 0.2 ng/mL ruled out SD with a negative predictive value of 99.9% (95% CI, 99.5%-100%). The assay had excellent sensitivity (98.5%-100%) and acceptable specificity (53.4%-53.5%) for detecting SD (Tg ≥ 0.2 ng/mL) for both cohorts combined and in the longitudinal cohort, with similar findings in RAI-treated and non-RAI-treated subgroups. Conclusion: In this cohort of DTC patients post-thyroidectomy, a Tg cutoff of 0.2 ng/mL was highly effective for ruling out the presence of SD under TSH-suppressed conditions, including in patients who had not received RAI treatment.

The Future of Thyroid Nodule Risk Stratification.

Clinical evidence supports the association of ultrasound features with benign or malignant thyroid nodules and serves as the basis for sonographic stratification of thyroid nodules, according to an estimated thyroid cancer risk. Contemporary guidelines recommend management strategies according to thyroid cancer risk, thyroid nodule size, and the clinical scenario. Yet, reproducible and accurate thyroid nodule risk stratification requires expertise, time, and understanding of the weight different ultrasound features have on thyroid cancer risk. The application of artificial intelligence to overcome these limitations is promising and has the potential to improve the care of patients with thyroid nodules.

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial.

Background: Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer (DTC), and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib + trametinib therapy in patients with BRAF-mutated radioactive iodine refractory DTC. Methods: In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory DTC with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 13 months before enrollment were eligible. Patients were randomly assigned to receive dabrafenib alone or dabrafenib + trametinib. The primary endpoint was objective response rate by modified RECIST (minor response of -20% to -29%, partial and complete response) within the first 24 weeks of therapy. Trial Registration Number: NCT01723202. Results: A total of 53 patients were enrolled. The objective response rate (modified RECIST) was 42% (11/26 [95% confidence interval {CI} 23-63%]) with dabrafenib versus 48% (13/27 [CI 29-68%]) with dabrafenib + trametinib (p = 0.67). Objective response rate (RECIST 1.1) was 35% (9/26 [CI 17-56%]) with dabrafenib and 30% (8/27 [CI 14-51%]) with dabrafenib + trametinib. Most common treatment-related adverse events included skin and subcutaneous tissue disorders (17/26, 65%), fever (13/26, 50%), hyperglycemia (12/26, 46%) with dabrafenib alone and fever (16/27, 59%), nausea, chills, fatigue (14/27, 52% each) with dabrafenib + trametinib. There were no treatment-related deaths. Conclusions: Combination dabrafenib + trametinib was not superior in efficacy compared to dabrafenib monotherapy in patients with BRAF-mutated radioiodine refractory progressive DTC.

Na+/I- symporter expression, function, and regulation in non-thyroidal tissues and impact on thyroid cancer therapy.

For the past 80 years, radioiodine (131I) has been used to ablate thyroid tissue not removed by surgery or to treat differentiated thyroid cancer that has metastasized to other parts of the body. However, the Na+/I- symporter (NIS), which mediates active iodide uptake into thyroid follicular cells, is also expressed in several non-thyroidal tissues. This NIS expression permits 131I accumulation and radiation damage in these non-target tissues, which accounts for the adverse effects of radioiodine therapy. We will review the data regarding the expression, function, and regulation of NIS in non-thyroidal tissues and explain the seemingly paradoxical adverse effects induced by 131I, the self-limited gastrointestinal adverse effects in contrast to the permanent salivary dysfunction that is seen after 131I therapy. We propose that prospective studies are needed to uncover the time-course of pathological processes underlying development and progression or ultimate resolution of 131I-induced salivary ductal obstruction and nasolacrimal duct obstruction. Finally, preventive measures and early therapeutic interventions that can be applied potentially to eliminate or alleviate long-term radioiodine adverse effects will be discussed.

Personalized radioiodine therapy for thyroid cancer patients with known disease.

Radioactive iodine (RAI) 131I is a targeted therapy for patients with RAI-avid follicular cell-derived thyroid cancer. However, the responsiveness to 131I therapy varies among thyroid cancer patients mainly owing to differential RAI uptake and RAI radiosensitivity among patients' lesions. A personalized approach to maximize 131I therapeutic efficacy is proposed based on recent scientific advances and future opportunities.