Autoimmune Thyroid Diseases.

Autoimmune thyroid diseases (AITDs) include a wide spectrum of thyroid diseases affecting more commonly women than men. The most frequent forms are Graves' Disease (GD) and Hashimoto's thyroiditis / Autoimmune Thyroiditis (AIT), but there are also other immunogenic destructive forms of thyroiditis, that is, silent and postpartum thyroiditis. In the last decade, AITDs and other inflammatory thyroid diseases related to anti-tumor molecular drugs are more frequently seen due to the widespread use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICPIs). Autoimmune thyroiditis related to SARS-CoV-2 infection has been a novel entity in recent years. Graves' Disease and AIT may shift from hyperthyroidism to hypothyroidism, which may complicate the differential diagnosis and further treatment strategy. Moreover, all AITDs may manifest with thyrotoxicosis (a clinical condition marked with high serum levels of thyroid hormones) which has to be distinguished from hyperthyroidism (increased thyroid hormone production and secretion as a result of hyperfunctioning thyroid gland) due to different therapeutic approaches. Nuclear medicine techniques, such as radioiodine uptake (RAIU) and thyroid scintigraphy, using 99mTc- pertechnetate (Na[99mTc]TcO4) or 123-Iodine (Na[123I]I), have a crucial role in the differential diagnosis. Measurement of thyroid antibodies, e.g. thyroid peroxidase antibodies (TPO) and thyrotropin receptor antibodies (TRAb), as well as thyroid ultrasound, are complementary methods in the evaluation of thyroid disorders.

Postoperative thyroglobulin as a yard-stick for radioiodine therapy: decision tree analysis in a European multicenter series of 1317 patients with differentiated thyroid cancer.

PURPOSE: An accurate postoperative assessment is pivotal to inform postoperative 131I treatment in patients with differentiated thyroid cancer (DTC). We developed a predictive model for post-treatment whole-body scintigraphy (PT-WBS) results (as a proxy for persistent disease) by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, TSH, and Tg were identified as potential predictors and were put into regression algorithm (conditional inference tree, ctree) to develop a risk stratification model for predicting the presence of metastases in PT-WBS. RESULTS: The lymph node (N) stage identified a partition of the population into two subgroups (N-positive vs N-negative). Among N-positive patients, a Tg value > 23.3 ng/mL conferred a 83% probability to have metastatic disease compared to those with lower Tg values. Additionally, N-negative patients were further substratified in three subgroups with different risk rates according to their Tg values. The model remained stable and reproducible in the iterative process of cross validation. CONCLUSIONS: We developed a simple and robust decision tree model able to provide reliable informations on the probability of persistent/metastatic DTC after surgery. These information may guide post-surgery 131I administration and select patients requiring curative rather than adjuvant 131I therapy schedules.

EANM enabling guide: how to improve the accessibility of clinical dosimetry.

Dosimetry can be a useful tool for personalization of molecular radiotherapy (MRT) procedures, enabling the continuous development of theranostic concepts. However, the additional resource requirements are often seen as a barrier to implementation. This guide discusses the requirements for dosimetry and demonstrates how a dosimetry regimen can be tailored to the available facilities of a centre. The aim is to help centres wishing to initiate a dosimetry service but may not have the experience or resources of some of the more established therapy and dosimetry centres. The multidisciplinary approach and different personnel requirements are discussed and key equipment reviewed example protocols demonstrating these factors are given in the supplementary material for the main therapies carried out in nuclear medicine, including [131I]-NaI for benign thyroid disorders, [177Lu]-DOTATATE and 131I-mIBG for neuroendocrine tumours and [90Y]-microspheres for unresectable hepatic carcinoma.

Variations in Radioiodine Therapy in Europe: Decision-Making after Total Thyroidectomy.

The role of radioiodine therapy (RIT) (used as ablation therapy or adjuvant therapy) following total thyroidectomy for differentiated thyroid cancer (DTC) changed. Major revisions of the American Thyroid Association (ATA) Guidelines in 2015 resulted in significant differences in treatment recommendations in comparison to the European Association of Nuclear Medicine (EANM) 2008 guidelines. Recently, we presented the effects on daily practice for RIT among Swiss Nuclear Medicine centres. We now performed a study at the European level and hypothesized that there is also considerable variability among European experts. We performed a decision-tree-based analysis of management strategies from all members of the EANM thyroid committee to map current practice among experts. We collected data on whether or not RIT is administered, on which criteria these decisions are based and collected details on treatment activities and patient preparation. Our study shows discrepancies for low-risk DTC, where "follow-up only" is recommended by some experts, while RIT with significant doses is used by other experts. E.g., for pT1b tumours without evidence of metastases, the level of agreement for the use of RIT is as low as 50%. If RIT is administered, activities of I-131 range from 1.1 GBq to 3.0 GBq. In other constellations (e.g., pT1a), experts diverge from current clinical guidelines as up to 75% administer RIT in certain cases. For intermediate and high-risk patients, RIT is generally recommended. However, dosing and treatment preparation (rhTSH vs. thyroid hormone withdrawal) vary distinctly. In comparison to the Swiss study, the general level of agreement is higher among the European experts. The recently proposed approach on the use of RIT, based on integrated post-surgery assessment (Martinique article) and results of ongoing prospective randomized studies are likely to reduce uncertainty in approaching RIT treatment. In certain constellations, consensus identified among European experts might be helpful in formulating future guidelines.

Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade.

BACKGROUND: Since the last major review of literature on the benefit of I-131 therapy, the continued debate on postoperative radioiodine treatment (RIT) in differentiated thyroid carcinoma (DTC) has led to a number of further studies being published on this topic. AIM: The aim of the present paper is to report the results of an updated structured review of the literature pertaining to the prognostic benefits of postoperative RIT in DTC in terms of recurrence-free and disease-specific survival. METHODS: A systematic search of the literature was performed using the Medline and Cochrane Library database. The search period started in August 2007 and ended on December 6, 2017. Search terms used included "differentiated thyroid cancer" and "radioiodine therapy" amended by specific terms for recurrence/disease-free survival or overall and/or cancer-specific survival. Included in the search were systematic reviews, randomized clinical trials, or cohort studies consisting of both patients who underwent postoperative RIT and patients treated by surgery alone. RESULTS: Eleven retrospective cohort studies met the defined inclusion criteria and were included in the present review. Results of the studies were mixed, with some showing a benefit of RIT even in microcarcinoma whereas others showed no benefit at all. CONCLUSION: Literature published in the last decade offers data that support adjuvant postoperative RIT in DTC patients with a tumor diameter exceeding 1 cm. Therefore, at least until randomized prospective studies prove otherwise, the prescription of adjuvant I-131 treatment to all DTC patients with a primary tumor diameter exceeding 1 cm remains a reasonable option.

Controversies, Consensus, and Collaboration in the Use of 131I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association.

BACKGROUND: Publication of the 2015 American Thyroid Association (ATA) management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer was met with disagreement by the extended nuclear medicine community with regard to some of the recommendations related to the diagnostic and therapeutic use of radioiodine (131I). Because of these concerns, the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging declined to endorse the ATA guidelines. As a result of these differences in opinion, patients and clinicians risk receiving conflicting advice with regard to several key thyroid cancer management issues. SUMMARY: To address some of the differences in opinion and controversies associated with the therapeutic uses of 131I in differentiated thyroid cancer constructively, the ATA, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association each sent senior leadership and subject-matter experts to a two-day interactive meeting. The goals of this first meeting were to (i) formalize the dialogue and activities between the four societies; (ii) discuss indications for 131I adjuvant treatment; (iii) define the optimal prescribed activity of 131I for adjuvant treatment; and (iv) clarify the definition and classification of 131I-refractory thyroid cancer. CONCLUSION: By fostering an open, productive, and evidence-based discussion, the Martinique meeting restored trust, confidence, and a sense of collegiality between individuals and organizations that are committed to optimal thyroid disease management. The result of this first meeting is a set of nine principles (The Martinique Principles) that (i) describe a commitment to proactive, purposeful, and inclusive interdisciplinary cooperation; (ii) define the goals of 131I therapy as remnant ablation, adjuvant treatment, or treatment of known disease; (iii) describe the importance of evaluating postoperative disease status and multiple other factors beyond clinicopathologic staging in 131I therapy decision making; (iv) recognize that the optimal administered activity of 131I adjuvant treatment cannot be definitely determined from the published literature; and (v) acknowledge that current definitions of 131I-refractory disease are suboptimal and do not represent definitive criteria to mandate whether 131I therapy should be recommended.

Role of 18F-Choline Positron Emission Tomography/Computed Tomography to Detect Structural Relapse in High-Risk Differentiated Thyroid Cancer Patients.

BACKGROUND: This study aimed to evaluate the role of 18F-choline (18F-FCH) positron emission tomography (PET)/computed tomography (CT) in high-risk differentiated thyroid cancer (DTC) patients with suspected relapse. It also compared 18F-FCH-PET/CT results with those of fludeoxyglucose (18F-FDG)-PET/CT and evaluated the additional diagnostic value and clinical impact of the combined use of these two tracers. Finally, it assessed the association between the clinical, biochemical, and histological parameters and 18F-FCH-PET/CT and 18F-FDG-PET/CT results. METHODS: The study prospectively enrolled high-risk DTC patients treated with thyroidectomy and radioactive iodine therapy and presenting high/increasing thyroglobulin levels under thyrotropin suppression, negative/inconclusive neck ultrasound, and negative 131I whole-body scan. All patients underwent 18F-FDG-PET/CT and 18F-FCH-PET/CT within 30 days of each other. Experienced nuclear medicine physicians examined the images of both procedures, and an integrated analysis of the two PET/CT modalities was also conducted. For each modality, a patient-based analysis (PBA) and lesion-based-analysis (LBA) was performed. On PBA, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. On LBA, only sensitivity was calculated. The standard of reference was based on clinical, imaging, and histological data. RESULTS: Twenty-five high-risk DTC patients were included; DTC relapse/persistence was confirmed in 23 patients. On PBA, 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the integrated evaluation of the two imaging modalities showed the following rates: sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 69.6%, 100%, 22.2%, 100%, and 72% versus 56.5%, 100%, 16.7%, 100%, and 60% versus 82.6%, 100%, 33.3%, 100%, and 84%, respectively. When compared with 18F-FDG-PET/CT, the integrated analysis of these two imaging procedures changed the clinical management in 4/23 (17%) patients. On LBA, the sensitivity rates of 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the combined evaluation of the two modalities were 58.7%, 38.1%, and 66.7%, respectively; when only lymph node involvement was considered, the rates were 56.3%, 53.1%, and 68.8%, respectively. Serum thyroglobulin doubling time (Tg-DT) <12 months was significantly associated with positive 18F-FCH-PET/CT. A trend toward a significant association was also found between positive 18F-FDG-PET/CT and both Tg-DT <12 months and DTC aggressive subtypes. CONCLUSION: 18F-FCH-PET/CT may add important information during the follow-up of high-risk DTC patients. 18F-FCH-PET/CT may be considered a useful complementary tool in patients affected by non-aggressive DTC subtypes, with Tg-DT <12 months, high risk of lymph node spreading, and negative or doubtful 18F-FDG-PET/CT.

Differentiated Thyroid Cancer lymph-node relapse. Role of adjuvant radioactive iodine therapy after lymphadenectomy.

PURPOSE: Our purpose as to evaluate the impact of adjuvant radioactive iodine therapy (RAI) on prognosis, as assessed by progression-free survival (PFS) and overall survival (OS), in patients affected by differentiated thyroid carcinoma (DTC) lymph-node relapse and previously treated with lymphadenectomy. METHODS: We retrospectively evaluated DTC patients treated with lymph-node dissection for disease relapse. All patients had previously undergone total thyroidectomy and radioiodine remnant ablation (RRA). We used clinical and histological data obtained during follow-up to assess response and outcome. By means of univariate and multivariate time-to-event analyses, we assessed the impact of RAI on outcome (PFS and OS) and the prognostic role of thyroglobulin (Tg) levels under suppression with levothyroxine (Tg-on) measured 1-3 months after lymphadenectomy and of other risk factors. RESULTS: We evaluated 113 patients (age at diagnosis: median 41 years, interquartile range: 31-59), 64 of whom were treated with RAI. Over a median follow-up time of 5.7 years, 27 patients showed disease progression and 13 died. Kaplan-Meier PFS and OS curves showed that age on diagnosis, tumor histology, tumor size, DTC aggressive variant, and Tg-on were associated with prognosis. Patients with Tg-on ≥1 ng/ml treated with RAI showed a better PFS (Log-rank pp 0.001) and OS (p = 0.005) than untreated patients, while no effect of RAI was observed in patients with Tg-on <1 ng/ml. Multivariate models showed that age, Tg-on (≥1 vs. < 1 ng/ml, HR: 18.2, 95% CI: 5.09-64.8, p = 0.001) and RAI (Yes vs. No, HR: 0.36,95%CI: 0.15-0. 9, p = 0.02) remained the only independent factors associated with PFS, but only age and Tg-on remained significantly associated with OS (HR: 8.31, 95%CI:1.56-44.3, p = 0.01). Nonetheless, patients treated with RAI showed a lower risk of mortality (HR: 0.34, 95%CI: 0.1-1.15 p = 0.08) than untreated patients. CONCLUSIONS: RAI after lymphadenectomy for DTC relapse is significantly associated with better PFS only in patients with Tg-on ≥1 ng/ml.

Hashimoto's encephalopathy: A rare proteiform disorder.

Hashimoto's encephalopathy (HE) is a rare not well understood, progressive and relapsing multiform disease, characterized by seizures, movement disorders, subacute cognitive dysfunction, psychiatric symptoms and responsiveness to steroid therapy. The disorder is generally associated with thyroid diseases and the most common feature is the presence of anti-thyroperoxidase antibodies (TPOAb). Patients are usually euthyroid or mildly hypothyroid at presentation. All age groups can be affected. The pathophysiology is still unclear, especially the link between elevated serum TPOAb and the encephalopathy. Most reported cases occurred in women and girls. Unspecific symptoms, non-pathognomonic laboratory neurophysiology and neuroimaging features make its diagnosis a real challenge for clinicians. The case of a 16 year old boy, with a clinical picture of HE associated with hypothyroidism, demonstrating an excellent response to high dose steroids is presented together with a systematic review of the literature.

Positron emission tomography/computed tomography in patients treated for differentiated thyroid carcinomas.

Differentiated thyroid cancer (DTC) generally has a favorable prognosis; however, the chance of a recurrence in patients with DTC is 20%, and 8% of patients with recurrence will subsequently die of the disease. After thyroid remnant ablation, detectable serum thyroglobulin levels are a sensitive marker for residual or recurrent disease, while imaging procedures, primarily neck ultrasound and an iodine-131 (131I) or iodine-123 diagnostic whole-body scan, are useful to localize recurrent disease. However, ultrasound cannot identify lesions outside the neck, and diagnostic whole-body scan is of limited value if progressive dedifferentiation of thyroid carcinoma cells occurs. In these patients, fluorine-18 (18F)-fluorodeoxyglucose PET/computed tomography (18FDG-PET/CT) has been shown to improve detection and localization of tumor foci. Additionally, 18FDG-PET/CT is also of value in selecting patients unlikely to benefit from additional 131I therapy and those at highest risk of disease-specific mortality, which may prompt more alternative therapies. Recently, iodine-124 (124I)-PET/CT was proved to perform better than low-dose diagnostic 131I scans. Additionally, 124I PET/CT succesfully predicts the results of subsequent high-dose post-treatment 131I scans and allows lesion-based dosimetric calculations. The present article reviews the utility and limitations of PET/CT techniques in DTC management and offers practical recommendations.