FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature.

(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.

Tumor Burden of Iodine-Avid Bone Metastatic Thyroid Cancer Identified via 18F-Sodium Fluoride PET/CT Imaging.

BACKGROUND: Patients with differentiated thyroid cancer (DTC) are referred to radioactive 131I (RAI) therapy and post-therapy 131I whole-body scintigraphy (WBS) to identify local and/or remote metastases. Positron emission tomography (PET)/computed tomography (CT) imaging with 18F-fluoro-D-glucose (FDG) or 18F-sodium fluoride (NaF) may also be used with these patients for the evaluation of bone metastases. We compared the role of 18F-NaF PET/CT and 18F-FDG-PET/CT in patients with DTC and documented bone metastases at post-therapy WBS. METHODS: Ten consecutive DTC patients with iodine avid bone metastasis at post-therapy WBS referred to 18F-NaF PET/CT and 18F-FDG PET/CT were studied. The findings of the three imaging procedures were compared for abnormal detection rates and concordance. RESULTS: At post-therapy 131I WBS, all patients had skeletal involvement with a total of 21 bone iodine avid lesions. At 18F-FDG PET/TC, 19 bone lesions demonstrated increased tracer uptake and CT pathological alterations, while 2 lesions did not show any pathological finding. At 18F-NaF PET/CT, the 19 bone lesions detected at 18F-FDG PET/TC also demonstrated abnormal tracer uptake, and the other 2 bone iodine avid foci did not show any pathological finding. CONCLUSIONS: In patients with DTC, 18F-NaF PET/CT did not obtain more information on the metastatic skeletal involvement than post-therapy 131I WBS and 18F-FDG PET/CT.

Emerging Role of Nuclear Medicine in Prostate Cancer: Current State and Future Perspectives.

Prostate cancer is the most frequent epithelial neoplasia after skin cancer in men starting from 50 years and prostate-specific antigen (PSA) dosage can be used as an early screening tool. Prostate cancer imaging includes several radiological modalities, ranging from ultrasonography, computed tomography (CT), and magnetic resonance to nuclear medicine hybrid techniques such as single-photon emission computed tomography (SPECT)/CT and positron emission tomography (PET)/CT. Innovation in radiopharmaceutical compounds has introduced specific tracers with diagnostic and therapeutic indications, opening the horizons to targeted and very effective clinical care for patients with prostate cancer. The aim of the present review is to illustrate the current knowledge and future perspectives of nuclear medicine, including stand-alone diagnostic techniques and theragnostic approaches, in the clinical management of patients with prostate cancer from initial staging to advanced disease.

Head-to-Head Comparison of FDG and Radiolabeled FAPI PET: A Systematic Review of the Literature.

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.

Efficacy of Empirical Radioiodine Therapy in Patients with Differentiated Thyroid Cancer and Elevated Serum Thyroglobulin without Evidence of Structural Disease: A Propensity Score Analysis.

We assessed the outcome of administration of empiric radioactive iodine (RAI) therapy to patients with differentiated thyroid cancer (DTC), in a propensity-score-matched cohort of patients with biochemical incomplete response (BIR) and without evidence of structural disease. We retrospectively evaluated 820 DTC patients without distant metastases, who underwent total thyroidectomy followed by RAI therapy, with available BIR at 12 months and follow-up evaluations. The patients were categorized according to the administration of empiric therapy (ET). To account for differences between patients with (n = 119) and without (n = 701) ET, a propensity-score-matched cohort of 119 ET and 119 no-ET patients was created. The need for additional therapy and the occurrence of structural disease were considered as end-points. During a median follow-up of 53 months (range 3-285), 57 events occurred (24% cumulative event rate). The rate of events was significantly higher in the no-ET compared to the ET patients (30% vs. 18% p < 0.001). The multivariate Cox analysis identified age (p < 0.01), pre-therapy Tg (p < 0.05) and empiric RAI therapy (p < 0.01) as predictors of outcome. The Kaplan-Meier analysis found that progression-free survival was lower in no-ET patients compared to the ET group (p < 0.01). In patients with DTC treated with surgery and RAI, and with biochemical incomplete response at the 12-month evaluation, their prognosis seemed to be affected by Tg values and the empiric treatment. The identification of candidates for this approach may improve prognosis.

Diagnosis, Management and Theragnostic Approach of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms.

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.

Submandibular gland involvement in oral cavity squamous cell carcinoma: a retrospective multicenter study.

BACKGROUND: The submandibular gland (SMG) is routinely excised during neck dissection. Given the importance of the SMG in saliva production, it is important to understand its involvement rate by cancer tissue and the feasibility of its preservation. METHODS: Retrospective data were collected from five academic centers in Europe. The study involved adult patients affected by primary oral cavity carcinoma (OCC) undergoing tumor excision and neck dissection. The main outcome analyzed was the SMG involvement rate. A systematic review and a meta-analysis were also conducted to provide an updated synthesis of the topic. RESULTS: A total of 642 patients were enrolled. The SMG involvement rate was 12/642 (1.9%; 95% CI 1.0-3.2) when considered per patient, and 12/852 (1.4%; 95% CI 0.6-2.1) when considered per gland. All the glands involved were ipsilateral to the tumor. Statistical analysis showed that predictive factors for gland invasion were: advanced pT status, advanced nodal involvement, presence of extracapsular spread and perivascular invasion. The involvement of level I lymph nodes was associated with gland invasion in 9 out of 12 cases. pN0 cases were correlated with a reduced risk of SMG involvement. The review of the literature and the meta-analysis confirmed the rare involvement of the SMG: on the 4458 patients and 5037 glands analyzed, the involvement rate was 1.8% (99% CI 1.1-2.7) and 1.6% (99% CI 1.0-2.4), respectively. CONCLUSIONS: The incidence of SMG involvement in primary OCC is rare. Therefore, exploring gland preservation as an option in selected cases would be reasonable. Future prospective studies are needed to investigate the oncological safety and the real impact on quality of life of SMG preservation.

Prognostic value of 12-month response to therapy in pediatric patients with differentiated thyroid cancer.

PURPOSE: In pediatric patients with differentiated thyroid cancer (DTC) we assessed the prognostic value of the 12-month response to therapy after initial treatment with surgery and radioactive iodine (RAI). METHODS: We retrospectively evaluated 94 pediatric patients with DTC, treated with surgery and RAI who were initially classified as low, intermediate or high risk of relapse of disease according to the American Thyroid Association (ATA) guidelines. Twelve months after RAI administration the response to therapy was assessed by serum thyroglobulin (Tg) measurement and neck ultrasound and patients were classified as having excellent response (ER) or no-ER. RESULTS: At the 12 months evaluation, 62 (66%) patients had ER and 32 (34%) no-ER. During a mean follow-up time of 86 months (range 9-517), 19 events occurred (20% cumulative event rate). Events occurred more frequently in younger patients (p < 0.05), in those at ATA intermediate/high risk (p < 0.01) and with a pre-RAI therapy Tg level > 10 ng/mL (p < 0.001), and in those with no-ER (p < 0.001). At multivariate analysis, the evidence of no-ER was the only independent predictor of events. CONCLUSION: In pediatric patients with DTC, the response to therapy evaluated 12 months after initial treatment has an independent prognostic impact and is able to predict mid-term outcome. Patients with no-ER at 12 months after RAI therapy should be closely followed-up.

Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = -0.45, p = 0.0002, 95% confidence interval [CI] -0.63 to -0.23; Ala/Thr r = -0.39, p = 0.0012, CI -0.60 to -0.67; and Ala/Ala r = -0.30, p = 0.2347; CI -0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

Prognostic Value of Hybrid PET/MR Imaging in Patients with Differentiated Thyroid Cancer.

Background: Hybrid positron emission tomography (PET)/magnetic resonance (MR) is an emerging imaging modality with great potential to provide complementary data acquired at the same time, under the same physiological conditions. The aim of this study was to evaluate the prognostic value of hybrid 18F-fluorodeoxyglucose (FDG) PET/MR in patients with differentiated thyroid cancer (DTC) who underwent total thyroidectomy and radioactive iodine therapy for suspicion of disease relapse. Methods: Between November 2015 and February 2017, 55 patients underwent hybrid 18F-FDG PET/MR. Assessment of positive MR was made considering all sequences in terms of malignancy based on the morphological T2-weighted features and the presence of restricted diffusivity on diffusion-weighted imaging images and both needed to be positive on the same lesion. Both foci with abnormal 18F-FDG uptake, which corresponded to tissue abnormalities on the MR, and tracer accumulation, which did not correspond to normal morphological structures, were considered positive. Results: During follow-up (mean 42 ± 27 months), 29 patients (53%) had disease recurrence. In the Cox univariate regression analysis age, serum Tg level ≥ 2 ng/mL, positive short tau inversion recovery (STIR), and positive PET were significant predictors of DTC recurrence. Kaplan−Meier survival analyses showed that patients with Tg ≥ 2 ng/mL had poorer outcomes compared to those with serum Tg level < 2 ng/mL (p < 0.05). Similarly, patients with positive STIR and positive PET had a worst outcome compared to those with negative STIR (p < 0.05) and negative PET (p < 0.005). Survival analysis performed in the subgroup of 36 subjects with Tg level ≥ 2 ng/mL revealed that patients with positive PET had a worst outcome compared to those with negative PET (p < 0.05). Conclusions: Age, serum Tg level ≥ 2 ng/mL, positive STIR, and positive 18F-FDG PET were significant predictors of DTC recurrence. However, the serum Tg level was the only independent predictor of DTC. Hybrid PET/MR imaging may have the potential to improve the information content of one modality with the other and would offer new opportunities in patients with DTC. Thus, further studies in a larger patient population are needed to understand the additional value of 18F-FDG PET/MR in patients with DTC.

Intramedullary Spinal Cord Metastases from Differentiated Thyroid Cancer, a Case Report.

Intramedullary spinal cord metastases (ISCM) are uncommon metastases of the spinal cord. Magnetic resonance (MR) plays an important role in surgical planning when ISCM is suspected in the differential diagnosis. The incidence of ISCM is expected to increase due to the longer survival of cancer patients as well as the widespread use of MR in the diagnosis of neurological syndromes. The management of these patients is controversial because of the multiple clinical presentations and lack of controlled studies on the efficacy of different therapeutic approaches. Increased awareness of this rare entity may lead to an earlier diagnosis with novel imaging approaches at a stage when neurological deficits are reversible. A case of ISCM in a 49-year-old patient with differentiated thyroid cancer is reported.

Risk of primary breast cancer in patients with differentiated thyroid cancer undergoing radioactive iodine therapy: a systematic review and meta-analysis.

PURPOSE: Although it has been proven that radioactive iodine (RAI) treatment is an effective and well-tolerated procedure in patients with differentiated thyroid cancer (DTC), there is still some concern regarding the risk of developing a second primary malignancy after RAI administration. We performed a systematic review and meta-analysis to investigate the risk of primary breast cancer in patients with DTC undergoing RAI therapy. METHODS: A comprehensive literature search of the PubMed, Scopus, and Web of Science databases was conducted according to the PRISMA statement. RESULTS: The final analysis included 14 studies accounting for a total of 200,247 patients with DTC (98,368 treated with RAI and 101,879 not treated with RAI). The relative risk of primary breast cancer in patients with DTC treated with RAI to those not treated with RAI among studies ranged from 0.45 to 2.55, the pooled relative risk was 0.83 (95% confidence interval, 0.70-0.99), and the heterogeneity was 71.5%. CONCLUSION: The present meta-analysis indicates that patients with DTC treated with RAI do not have a higher risk of primary breast cancer compared to those not treated with RAI. These findings suggest that RAI therapy does not increase the risk of breast cancer.

Second Primary Malignancies in Patients with Differentiated Thyroid Cancer after Radionuclide Therapy: A Retrospective Single-Centre Study.

Second primary malignancies (SPM) are described as any primary, not synchronous, malignancy arising in a different anatomical district, with confirmed histological diagnosis. Age at diagnosis, previous non-thyroidal primary malignancy, and radioactive iodine (RAI) therapy have been proposed as independent risk factors for SPM. RAI therapy is a standard treatment for moderate-high risk differentiated thyroid cancer (DTC), and its effect on the development of SPM has become a critical topic in DTC treatment. The purpose of this retrospective single-center study was to investigate the occurrence and the possible association of non-thyroidal SPM diagnosed after DTC and RAI therapy in a cohort of 1326 consecutive DTC patients referred at our Institution for RAI treatment from 1993 to 2009. Eighty-nine patients with ages ≤ 18 years at the time of DTC diagnosis or with a follow-up of ≤12 months were excluded from the final analysis. All patients underwent a complete clinical and hematological follow-up every 6 months for a minimum of 12 months. During follow-up (mean 89 ± 73 months), 25 patients (2%) had an SPM diagnosis (mean 133 ± 73 months). The most common site of the second malignancy was the breast, accounting for 32% of all SPM, followed by colon-rectal cancer (16%), leukemia, and gynecological and kidney cancer (4%). At Cox univariable regression analysis, age at DTC diagnosis (p < 0.001), age ≥55 years (p < 0.001) and follow-up duration (p < 0.004) were associated with SPM onset, while no significant association was observed with the administered activity of radioiodine. In conclusion, our data suggest that the older a person gets, the more sharply the likelihood of developing additional diseases, such as PMS, increases. Similarly, for follow-up, the more a patient is followed up clinically over time, the higher the risk of new diagnoses increases.

Whole-Body Radioiodine Effective Half-Life in Patients with Differentiated Thyroid Cancer.

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.