Molecular imaging of thyroid and parathyroid diseases.

INTRODUCTION: Molecular imaging of thyroid and parathyroid diseases has changed in recent years due to the introduction of new radiopharmaceuticals and new imaging techniques. Accordingly, we provided an clinicians-oriented overview of such techniques and their indications. AREAS COVERED: A review of the literature was performed in the PubMed, Web of Science, and Scopus without time or language restrictions through the use of one or more fitting search criteria and terms as well as through screening of references in relevant selected papers. Literature up to and including December 2023 was included. Screening of titles/abstracts and removal of duplicates was performed and the full texts of the remaining potentially relevant articles were retrieved and reviewed. EXPERT OPINION: Thyroid and parathyroid scintigraphy remains integral in patients with thyrotoxicosis, thyroid nodules, differentiated thyroid cancer and, respectively, hyperparathyroidism. In the last years positron-emission tomography with different tracers emerged as a more accurate alternative in evaluating indeterminate thyroid nodules [18F-fluorodeoxyglucose (FDG)], differentiated thyroid cancer [124I-iodide, 18F-tetrafluoroborate, 18F-FDG] and hyperparathyroidism [18F-fluorocholine]. Other PET tracers are useful in evaluating relapsing/advanced forms of medullary thyroid cancer (18F-FDOPA) and selecting patients with advanced follicular and medullary thyroid cancers for theranostic treatments (68Ga/177Ga-somatostatin analogues).

Thyroglobulin measurement is the most powerful outcome predictor in differentiated thyroid cancer: a decision tree analysis in a European multicenter series.

OBJECTIVES: An accurate prognostic assessment is pivotal to adequately inform and individualize follow-up and management of patients with differentiated thyroid cancer (DTC). We aimed to develop a predictive model for recurrent disease in DTC patients treated by surgery and 131I by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), administered 131I activities and post-therapy whole body scintigraphy (PT-WBS) were identified as potential predictors and put into regression algorithm (conditional inference tree, c-tree) to develop a risk stratification model for predicting persistent/recurrent disease over time. RESULTS: The PT-WBS pattern identified a partition of the population into two subgroups (PT-WBS positive or negative for distant metastases). Patients with distant metastases exhibited lower disease-free survival (either structural, DFS-SD, and biochemical, DFS-BD, disease) compared to those without metastases. Meanwhile, the latter were further stratified into three risk subgroups based on their Tg values. Notably, Tg values >63.1 ng/mL predicted a shorter survival time, with increased DFS-SD for Tg values <63.1 and <8.9 ng/mL, respectively. A comparable model was generated for biochemical disease (BD), albeit different DFS were predicted by slightly different Tg cutoff values (41.2 and 8.8 ng/mL) compared to DFS-SD. CONCLUSIONS: We developed a simple, accurate and reproducible decision tree model able to provide reliable information on the probability of structurally and/or biochemically persistent/relapsed DTC after a TTA. In turn, the provided information is highly relevant to refine the initial risk stratification, identify patients at higher risk of reduced structural and biochemical DFS, and modulate additional therapies and the relative follow-up.

Diagnostic, Theranostic and Prognostic Value of Thyroglobulin in Thyroid Cancer.

Thyroglobulin (Tg) is an iodinated glycoprotein, which is normally stored in the follicular colloid of the thyroid, being a substrate for thyroid hormone production. Since it is produced by well-differentiated thyroid cells, it is considered a reliable tumor marker for patients with differentiated thyroid carcinoma (DTC) during their follow-up after total thyroidectomy and radioiodine ablation. It is used to monitor residual disease and to detect recurrent disease. After total thyroid ablation, unstimulated highly sensitive Tg measurements are sufficiently accurate to avoid exogenous or endogenous thyrotropin (TSH) stimulation and provide accurate diagnostic and prognostic information in the great majority of DTC patients. Adopting sophisticated statistical analysis, i.e., decision tree models, the use of Tg before radioiodine theranostic administration was demonstrated to be useful in refining conventional, pathology-based risk stratification and providing personalized adjuvant or therapeutic radioiodine administrations. The follow-up of DTC patients aims to promptly identify patients with residual or recurrent disease following primary treatment. Our review paper covers the diagnostic, theranostic and prognostic value of thyroglobulin in DTC patients.

Theranostics of Thyroid Cancer.

Molecular imaging is pivotal in evaluating and managing patients with different thyroid cancer histotypes. The existing, pathology-based, risk stratification systems can be usefully refined, by incorporating tumor-specific molecular and molecular imaging biomarkers with theranostic value, allowing patient-specific treatment decisions. Molecular imaging with different radioactive iodine isotopes (ie, I131, I123, I124) is a central component of differentiated carcinoma (DTC)'s risk stratification while [18F]F-fluorodeoxyglucose ([18F]FDG) PET/CT is interrogated about disease aggressiveness and presence of distant metastases. Moreover, it is particularly useful to assess and risk-stratify patients with radioiodine-refractory DTC, poorly differentiated, and anaplastic thyroid cancers. [18F]F-dihydroxyphenylalanine (6-[18F]FDOPA) PET/CT is the most specific and accurate molecular imaging procedure for patients with medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells. In addition, [18F]FDG PET/CT can be used in patients with more aggressive clinical or biochemical (ie, serum markers levels and kinetics) MTC phenotypes. In addition to conventional radioiodine therapy for DTC, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC. Moreover, peptide receptor theranostics showed promising results in patients with advanced and metastatic radioiodine-refractory DTC and MTC, respectively. The current appropriate role and future perspectives of molecular imaging and theranostics in thyroid cancer are discussed in our present review.

Nodal metastasis in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

The term noninvasive tumor with a follicular growth pattern and nuclear features of papillary thyroid cancer (NIFTP) is used to describe a tumor currently considered as a pre-malignant lesion for which a conservative therapeutic approach (i.e., lobectomy without radioiodine therapy) is strongly suggested. However, some patients with NIFTP and loco-regional or distant metastases have been already reported. We present an adult male patient with a final histological diagnosis of NIFTP and lymph node metastasis noted at post-therapy whole-body scintigraphy performed some days after radioiodine therapy.

Radioiodine versus radiofrequency ablation to treat autonomously functioning thyroid nodules: a systematic review and comparative meta-analysis.

PURPOSE: Radioiodine (RAI) is a well-established first-line therapy for autonomously functioning thyroid nodules (AFTN). Radiofrequency ablation (RFA) is a minimally invasive procedure that has been proposed as an alternative treatment option for hyperthyroidism caused by AFTN. Although RFA has been shown to be useful for reducing nodule volume and improving TSH levels in AFTN, no comprehensive comparative clinical studies have been proposed to evaluate the overall response to RFA treatment. The aim of this comparative systematic review and meta-analysis was to evaluate the response of RAI and RFA treatments in AFTN. METHODS: A systematic search strategy was applied in PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov until July 2023 without time or language restrictions. Studies investigating the response to RAI and/or RFA treatment in AFTN patients 6 and/or 12 months after treatment were included. The risk of bias was assessed based on the study design. Random-effect models were used for the meta-analysis. RESULTS: Twenty-three articles (28 reports) met the inclusion criteria and were included in the study. Overall, RAI therapy was found to have a significantly higher treatment response (94%) than RFA (59%), although the volume of AFTNs was reduced to a similar extent. In the direct comparison (n = 3 studies), RFA showed a higher risk of non-response than RAI (RR, 1.24; 95% CI, 0.94-1.63; z = 1.55; p = 0.12). CONCLUSIONS: Our results demonstrate the superiority of RAI over RFA in terms of success rates and safety profile and confirm RAI as the first choice for the treatment of AFTNs.

Integrated Diagnostics of Thyroid Nodules.

Thyroid nodules are common findings, particularly in iodine-deficient regions. Our paper aims to revise different diagnostic tools available in clinical thyroidology and propose their rational integration. We will elaborate on the pros and cons of thyroid ultrasound (US) and its scoring systems, thyroid scintigraphy, fine-needle aspiration cytology (FNAC), molecular imaging, and artificial intelligence (AI). Ultrasonographic scoring systems can help differentiate between benign and malignant nodules. Depending on the constellation or number of suspicious ultrasound features, a FNAC is recommended. However, hyperfunctioning thyroid nodules are presumed to exclude malignancy with a very high negative predictive value (NPV). Particularly in regions where iodine supply is low, most hyperfunctioning thyroid nodules are seen in patients with normal thyroid-stimulating hormone (TSH) levels. Thyroid scintigraphy is essential for the detection of these nodules. Among non-toxic thyroid nodules, a careful application of US risk stratification systems is pivotal to exclude inappropriate FNAC and guide the procedure on suspicious ones. However, almost one-third of cytology examinations are rendered as indeterminate, requiring "diagnostic surgery" to provide a definitive diagnosis. 99mTc-methoxy-isobutyl-isonitrile ([99mTc]Tc-MIBI) and [18F]fluoro-deoxy-glucose ([18F]FDG) molecular imaging can spare those patients from unnecessary surgeries. The clinical value of AI in the evaluation of thyroid nodules needs to be determined.

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.

Molecular Theranostics in Radioiodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and has an excellent overall prognosis. However, metastatic DTC in certain cases may have a poor prognosis as it becomes radioiodine-refractory. Molecular imaging is essential for disease evaluation and further management. The most commonly used tracers are [18F]FDG and isotopes of radioiodine. Several other radiopharmaceuticals may be used as well, with different diagnostic performances. This review article aims to summarize radiopharmaceuticals used in patients with radioiodine-refractory DTC (RAI-R DTC), focusing on their different molecular pathways. Additionally, it will demonstrate possible applications of the theranostics approach to this subgroup of metastatic DTC.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

The Influence of Food Regimes on Oxidative Stress: A Permutation-Based Approach Using the NPC Test.

(1) Background: This paper aims to assess the existence of significant differences between two dietary regimes (omnivorous vs. semi-vegetarian) with reference to some oxidative stress markers (SOD, GPx, TRxR, GR, AGEs, and AOPPs) using non-parametric combination methodology based on a permutation test. (2) Methods: At the endocrinology unit of Messina University Hospital, two hundred subjects were asked to fill out a questionnaire about their dietary habits. None were under any pharmacological treatment. Using the NPC test, all comparisons were performed stratifying patients according to gender, age (≤40 or >40 years), BMI (normal weight vs. overweight), physical activity (sedentary vs. active lifestyle), TSH, FT4 levels in quartiles, and diagnosis of Hashimoto's thyroiditis. We evaluated differences in oxidative stress parameters in relation to two examined dietary regimes (omnivorous vs. semi-vegetarian). (3) Results: The antioxidant parameters GPx and TRxR were significantly lower in subjects with an omnivorous diet than in semi-vegetarians, particularly in females, both age groups, subjects with normal weight, those not affected by Hashimoto's thyroiditis, and both the sedentary and active lifestyle groups. Finally, the AGE and AOPP markers were significantly lower in semi-vegetarians. (4) Conclusion: Thanks to the NPC methodology, we can state that dietary patterns exert a significant influence on some oxidative stress parameters.

The EANM guideline on radioiodine therapy of benign thyroid disease.

This document provides the new EANM guideline on radioiodine therapy of benign thyroid disease. Its aim is to guide nuclear medicine physicians, endocrinologists, and practitioners in the selection of patients for radioiodine therapy. Its recommendations on patients' preparation, empiric and dosimetric therapeutic approaches, applied radioiodine activity, radiation protection requirements, and patients follow-up after administration of radioiodine therapy are extensively discussed.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Thyroglobulin Value Predict Iodine-123 Imaging Result in Differentiated Thyroid Cancer Patients.

Background: In differentiated thyroid cancer (DTC) patients, the response to initial treatments is evaluated 6-12 months after radioiodine therapy (RIT) according to the 2015 American Thyroid Association (2015 ATA) criteria. In selected patients, diagnostic 131-radioiodine whole-body scintigraphy (Dx-WBS) is recommended. We evaluated the diagnostic performance of 123I-Dx-WBS-SPECT/CT imaging in detecting incomplete structural responses in the early follow-up of DTC patients and, additionally, derived optimized basal-Tg value as a yardstick for scintigraphic imaging. Methods: We reviewed the records of 124 low or intermediate-risk DTC patients with negative anti-thyroglobulin antibody. All patients had undergone (near)-total-thyroidectomy followed by RIT. The response to initial treatments was evaluated 6-12 months after RIT. Results: According to the 2015 ATA criteria, 87, 19 and 18 DTC patients were classified to have excellent response (ER), indeterminate/incomplete biochemical response (BIndR/BIR) or structural incomplete response (SIR), respectively. Among patients with less than ER, 18 had a positive 123I-Dx-WBS-SPECT/CT. Metastatic disease at 123I-Dx-WBS-SPECT/CT mainly involved lymph nodes within the central compartment, and corresponding neck ultrasound examinations were negative. The ROC curve analysis was performed to define the best basal-Tg cut-off (i.e., 0.39 ng/mL; AUC = 0.852) able to discriminate patients with and without positive 123I-Dx-WBS-SPECT/CT, respectively. The overall sensitivity, specificity, accuracy, PPV and NPV were 77.8%, 89.6%, 87.9%, 56.0% and 95.9%, respectively. Basal-Tg cut-off was an independent risk factor for having a positive 123I-Dx-WBS-SPECT/CT. Conclusion:123I-Dx-WBS-SPECT/CT identified lymph node metastases in 14/37 patients with less than ER and a negative neck ultrasound, thus modifying the management of such patients. The diagnostic performance of 123I-Dx-WBS-SPECT/CT significantly increased in patients with basal-Tg values ≥ 0.39 ng/mL.

Add-on radioiodine during long-term BRAF/MEK inhibition in patients with RAI-refractory thyroid cancers: a reasonable option?

Dual modulation of the MAPK pathway with BRAF (e.g., dabrafenib) and MEK (e.g., trametinib) inhibitors has the potential to re-establish radioiodine (RAI) sensitivity in BRAF-mutated RAI-refractory (RAI-R)-differentiated thyroid carcinoma (DTC) cells. Here we showed that (1) double BRAF/MEK inhibition may still reach a significant redifferentiation in patients with a long-history RAI-R DTC and multiple previous treatments; (2) the addition of high RAI activities may obtain a significant structural response in such patients; and (3) a divergence between increasing thyroglobulin and structural response may be a reliable biomarker or redifferentiation. Accordingly, the add-on prescription of high activities of 131I should be considered in RAI-R patients under multikinase inhibitors with stable or responding structural disease and divergent increase of Tg levels.

Prognostic role of early prostate specific antigen changes after [177 Lu]Lu-PSMA radioligand therapy of metastasized prostate cancer: A meta-analysis.

BACKGROUND: Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [177 Lu]Lu-prostate-specific membrane antigen (PSMA) is an emerging treatment for metastasized mCRPC and its efficacy is assessed not only but also by prostate specific antigen (PSA) measurement after 12 weeks or more after treatment. Our aim was to evaluate the role of early PSA measurement after RLT in predicting overall survival (OS) of mCRPC patients. METHODS: A systematic search on PubMed, Web Of Science and Scopus was performed from January to December 2022. PRISMA guidelines for prognostic studies was adopted. Risk of bias was assessed using quality of prognostic studies (QUIPS). RESULTS: Twelve studies at low-intermediate risk of bias, were included in the meta-analysis (1646 patients, mean age 70 years). About 50% of patients showed a PSA decline after 1-2 of [177 Lu]Lu-PSMA, and more than 30% reported a PSA decline ≥50%. The median OS range for patients with any PSA decline was 13-20 months, while for patients with stable or increased PSA, the median OS fell to 6-12 months. The OS rate for a PSA decline after the one-two [177 Lu]Lu-PSMA cycles was 0.39 (95% CI: 0.31-0.50), while OS for a PSA decline ≥50% was 0.69 (95% CI: 0.57-0.83). CONCLUSIONS: A PSA decline is observed in almost 50% of mCRPC patients after 1-2 [177 Lu]Lu-PSMA cycles, with a significantly longer OS compared to stable or increased PSA levels, respectively. Accordingly, any PSA decline after 1-2 cycles of therapy should be regarded as a favourable prognostic factor for OS.

Comparison of 1.1 GBq and 2.2 GBq Activities in Patients with Low-Risk Differentiated Thyroid Cancer Requiring Postoperative 131I Administration: A Real Life Study.

OBJECTIVES: To compare the efficacy of low and moderate 131I activities in low-risk differentiated thyroid carcinoma (DTC) patients requiring postoperative thyroid remnant ablation in a real-world clinical setting. METHODS: We retrospectively reviewed the records of 299 low-risk DTC patients (pT1-T2, Nx(0) Mx) who had undergone (near)-total thyroidectomy followed by 131I therapy, using either low (1.1 GBq) or moderate (2.2 GBq) radioiodine activities. The response to initial treatments was evaluated after 8-12 months, and patient responses were classified according to the 2015 American Thyroid Association guidelines. RESULTS: An excellent response was observed in 274/299 (91.6%) patients, specifically, in 119/139 (85.6%) and 155/160 (96.9%) patients treated with low and moderate 131I activities, respectively (p = 0.029). A biochemically indeterminate or incomplete response was observed in seventeen (22.2%) patients treated with low 131I activities and three (1.8%) patients treated with moderate 131I activities (p = 0.001). Finally, five patients showed an incomplete structural response, among which three and two received low and moderate 131I activities, respectively (p = 0.654). CONCLUSIONS: When 131I ablation is indicated, we encourage the use of moderate instead of low activities, in order to reach an excellent response in a significantly larger proportion of patients, including patients with the unexpected persistence of the disease.