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

FAPI-based radiopharmaceuticals are a novel class of tracers, mainly used for PET imaging, which have demonstrated several advantages over [¹⁸F]FDG, especially in the case of low-grade or well-differentiated tumors. We conducted this systematic review to evaluate all the studies where a head-to-head comparison had been performed to explore the potential utility of FAPI tracers in clinical practice. FAPI-based radiopharmaceuticals have shown promising results globally, in particular in detecting peritoneal carcinomatosis, but studies with wider populations are needed to better understand all the advantages of these new radiopharmaceuticals.

(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to ¹³¹I, becoming more aggressive. In this scenario, [¹⁸F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8–21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: “FAP” or “FAPi” or “Fibroblast activating protein” and “thyroid” or “thyroid cancer”, in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [¹⁸F]FDG and a promising theranostic tool. However, further studies with a larger population are needed.

This study assessed the long-term predictive value of the response to therapy, evaluated by serum thyroglobulin (Tg) determination and neck ultrasound, and estimated the potential additional impact of diagnostic whole-body scan (WBS) in patients with differentiated thyroid cancer (DTC) treated with surgery and radioactive iodine (RAI) therapy. We retrospectively evaluated 606 DTC patients treated with surgery and RAI. Response to ¹³¹I therapy at 12 months was assessed by serum Tg measurement, neck ultrasound, and diagnostic WBS. According to American Thyroid Association (ATA) guidelines, patients were classified as having a low, intermediate or high risk of recurrence and at 12 months as having an excellent response (ER) or no-ER. Follow-up was then performed every 6–12 months with serum Tg determination and imaging procedures. With a median follow-up of 105 months (range 10–384), 42 (7%) events requiring further treatments occurred. Twenty-five patients had additional RAI therapy, 11 with structural disease in the thyroid bed, eight in both thyroid bed and neck lymph nodes, four had lung metastases and two had bone metastases. The other 17 patients had additional surgery for nodal disease followed by RAI therapy. The ATA intermediate and high risk of recurrence, post-operative and pre-RAI therapy Tg ≥ 10 ng/mL, and the absence of ER at 12 months were independent predictors of events. Diagnostic WBS at 12 months permitted the identification of only five recurrences among the 219 ER patients according to serum Tg levels and ultrasound. In DTC patients, the response to therapy at 12 months after RAI therapy could rely on serum Tg measurement and neck ultrasound, while diagnostic WBS was not routinely indicated in patients considered in ER.

Background: Radioactive ¹³¹I (RAI) therapy is used in patients with differentiated thyroid cancer (DTC) after total thyroidectomy for remnant ablation, adjuvant treatment or treatment of persistent disease. ¹³¹I retention data, which are used to indicate the time at which a ¹³¹I treated DTC patient can be released from the hospital, may bring some insights regarding clinical factors that prolong the length of hospitalization. The aim of this study was to investigate the ¹³¹I whole-body retention in DTC patients during ¹³¹I therapy. Methods: We monitored 166 DTC patients to follow the ¹³¹I whole-body retention during ¹³¹I therapy with a radioactivity detector fixed on the ceiling of each protected room. A linear regression fit permitted us to estimate the whole-body ¹³¹I effective half-life in each patient, and a relationship was sought between patients’ clinical characteristics and whole-body effective ¹³¹I half-life. Results: The effective ¹³¹I half-life ranged from 4.08 to 56.4 h. At multivariable analysis, longer effective ¹³¹I half-life was related to older age and extensive extra-thyroid disease. Conclusions: ¹³¹I effective half-life during ¹³¹I treatment in DTC patients is highly variable among patients and is significantly longer in older and in patients with RAI uptake in large thyroid remnants or in extrathyroidal disease that significantly prolongs the whole-body retention of ¹³¹I.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) constitute an ideal target for radiolabeled somatostatin analogs. The theragnostic approach is able to combine diagnosis and therapy by the identification of a molecular target that can be diagnosed and treated with the same radiolabeled compound. During the last years, advances in functional imaging with the introduction of somatostatin analogs and peptide receptor radionuclide therapy, have improved the diagnosis and treatment of GEP-NENs. Moreover, PET/CT imaging with ¹⁸F-FDG represents a complementary tool for prognostic evaluation of patients with GEP-NENs. In the field of personalized medicine, the theragnostic approach has emerged as a promising tool in diagnosis and management of patients with GEP-NENs. The aim of this review is to summarize the current evidence on diagnosis and management of patients with GEP-NENs, focusing on the theragnostic approach.