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Theranostics define diagnostic evaluations directing patient-specific therapeutic decisions. Molecular theranostics involves genomic, transcriptomic, proteomic, metabolomic and finally phenonic definitions thyroid cancer differentiation. It is the functional differentiation that determines the sensitivity and accuracy of RAI imaging as well as the effectiveness of RAI treatment. Total thyroidectomy is performed to empower an anticipated RAI treatment. A preoperative determination of the genomic and transcriptomic profile of the tumor is a strong predictor of response to therapeutic interventions. This article discusses the oncopathophysiologic basis of the theranostic risk stratification approach.

Radioactive iodine (RAI) is a cornerstone therapy for differentiated thyroid cancer, but many tumours—especially those with the BRAF[sup.V600E] mutation—become RAI-refractory and stop taking up iodine. We analysed patient tissues and public datasets and found that Gadd45B is consistently reduced in RAI-refractory disease. Using thyroid cancer cell lines and mouse models (including patient-derived xenografts), we show that restoring Gadd45B re-sensitises tumours to RAI, increases uptake, and slows growth. Mechanistically, Gadd45B modulates two complementary axes: it interacts with MAP3K4 to dampen MAPK signalling, and it restrains MYCBP–c-Myc–TERT activity. Together, these effects upregulate iodine-handling genes (e.g., NIS, TPO, Tg) and improve tumour differentiation. Clinically, low Gadd45B correlates with poor outcomes, supporting its potential as a biomarker and therapeutic target. While intratumoural recombinant Gadd45B showed benefit in vivo, we did not directly confirm its cellular entry; future studies will test delivery strategies and validate safety in patients.

Purpose Although most patients with differentiated thyroid carcinoma (DTC) have an excellent prognosis, a subset will experience radioactive iodine refractory (RAI-R) disease, associated with recurrence, distant metastases and worse prognosis. In recent years, redifferentiation has emerged as an attractive approach for patients with RAI-R DTC, a strategy to induce iodine uptake in RAI-R DTC tumor cells and ultimately prolong time to initiation of systemic therapy. Methods An overview and critical appraisal of the existing literature on redifferentiation will be presented in this review under the lens of the genotype-specific targeted therapy administered with redifferentiation intent. Results/conclusions Due to the significant heterogeneity across studies, it will be key to harmonize research methodology and support future larger, multicenter prospective trials in order to identify the most suitable candidates for this therapeutic strategy.

A Iodine-131 ( I) whole body scan (WBS) is performed to evaluate the treatment response after radioactive iodine (RAI) therapy. Despite the clinical relevance of RAI-refractory differentiated thyroid cancer, a consensus on its precise definition remains lacking. This study investigates the potential utility of hepatic I accumulation as an early predictor for tumor recurrence or progression after RAI administration. Of 814 patients receiving care at our institution, we enrolled 225 patients who exhibited no accumulation of RAI in the remnant tissues or other lesions on I WBS. We quantified the hepatic uptake ratio [defined as (hepatic uptake/background uptake (H/B)] from WBS. All patients were categorized into group A (H/B ≤1.5) and group B (H/B >1.5), and we assessed between-group differences. The Kaplan-Meier method and Log-rank test were used to analyze the progression-free survival (PFS). Using the Cox proportional hazards model, we identified independent prognostic factors from among the seven known prognostic factors, i.e., H/B, thyroglobulin, sex, age, stage, total I dose, and final therapeutic dose. The 5-year and median PFS were 98.8% and 114.7 months in group A (n: 171) compared with 24.1% and 42.7% months in group B (n: 54), respectively. Group B showed a significant correlation with poor prognosis (p<0.00001). Of the seven prognostic factors, H/B exhibited the highest impact on patient outcomes (hazards ratio for recurrence/disease progression, 42.156; 95% confidence interval: 8.750-203.106). Quantitative evaluation of hepatic uptake on I WBS provides a marker that may help identify patients with differentiated thyroid cancer who are at a high risk of disease progression/recurrence immediately after RAI therapy.

Radioactive iodine therapy is a mainstay for recurrent and metastatic differentiated thyroid cancer. However, a substantial portion of differentiated thyroid cancer patients exhibits dedifferentiation status with a lack of sodium iodide symporter functionality and expression, as well as downregulated thyroid-specific proteins and transcription factors. Eventually, this status is connected to the failure of radioactive iodine therapy with an overall poor prognosis. Selenium, an essential trace element, has antitumor, antioxidant, immunomodulatory, and antiviral activities and is required for thyroid hormone synthesis and metabolism, and it was reported that sodium selenite induces radioactive iodine uptake in thyroid tissue in rats. However, the relationship between sodium selenite and differentiation markers in differentiated thyroid cancer remains unclear. We investigated whether sodium selenite enhances radioactive iodine avidity and reinforces I therapeutic effects in papillary thyroid cancer cells. We also analyzed changes in selected signaling pathways and factors induced by sodium selenite treatment. Sodium iodide symporter, thyroid-specific proteins, and transcription factors were upregulated by sodium selenite, increasing radioactive iodine avidity and radioactive iodine-mediated cytotoxicity in papillary thyroid cancer cells. Sodium selenite downregulated the MAPK, PI3K-AKT, and GSK-3β/β-catenin signaling pathways. Sodium selenite may serve as a promising adjunct to enhance radioactive iodine avidity in papillary thyroid cancer cells.

Liver dysfunction is a common complication of Graves’ disease (GD) that may be caused by excessive thyroid hormone (TH) or anti-thyroid drugs (ATDs). Radioactive iodine (RAI) therapy is one of the first-line treatments for GD, but it is unclear whether it is safe and effective in patients with liver dysfunction. 510 consecutive patients with GD receiving first RAI were enrolled in the study, and followed up at 3-, 6- and 12-month. Liver dysfunction was recorded in 222 (43.5%) patients. GD patients with liver dysfunction had higher serum levels of free triiodothyronine (FT3) (median 27.6 vs. 20.6 pmol/L, p  < 0.001) and free thyroxine (FT4) (median 65.4 vs. 53.5 pmol/L, p  < 0.001) levels than those with normal liver function. Binary logistic regression analysis showed that duration of disease (OR = 0.951, 95% CI: 0.992–0.980, p  = 0.001) and male gender (OR = 1.106, 95% CI: 1.116–2.384; p  = 0.011) were significant differential factors for liver dysfunction. Serum TSH levels were higher in patients with liver dysfunction at all 3 follow-up time points ( p  = 0.014, 0.008, and 0.025 respectively). FT3 level was lower in patients with liver dysfunction at 3-month follow-up ( p  = 0.047), but the difference disappeared at 6 and 12 months ( p  = 0.351 and 0.264 respectively). The rate of euthyroidism or hypothyroidism was higher in patients with liver dysfunction than in those with normal liver function at 3 months (74.5% vs 62.5%; p  = 0.005) and 6 months (82.1% vs 69.1%; p  = 0.002) after RAI treatment, but the difference did not persist at 12-month follow-up (89.6% vs 83.2%, p  = 0.081).There were no statistically significant differences in treatment efficacy (94.48% vs 90.31%, p  = 0.142), incidence of early-onset hypothyroidism (87.73% vs 83.67%, p  = 0.277), and recurrence rate (4.91% vs 7.14%, p  = 0.379) between the 2 groups at 12-month follow-up. In conclusion, the efficacy of RAI was comparable in GD patients with liver dysfunction and those with normal liver function.

Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in theranostic power of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in “differentiated thyroid cancers” remains a clinical problem despite optimized RAI administration protocols. Functional mis-differentiation and associated RAI-indifference are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory mis-differentiated thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols.

Standard therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is multi-targeted kinase inhibitors (m-TKIs), represented by sorafenib and lenvatinib. One of the main target molecules of m-TKIs is vascular endothelial growth factor receptor (VEGF-R). m-TKIs are known to cause adverse reactions such as hypertension and proteinuria as a class effect. In particular, proteinuria is thought to result from vascular endothelial damage and podocytopathy in glomeruli, and the development of thrombotic microangiopathy (TMA) has been reported for VEGF inhibitors. We encountered a patient with RAI-refractory (RR) papillary thyroid carcinoma (PTC) who developed proteinuria and renal dysfunction due to lenvatinib. Renal biopsy demonstrated that these changes were caused by TMA. To our knowledge, this is the first reported case of TMA due to lenvatinib in a Japanese patient with RR-PTC. A 70-year-old woman developed proteinuria, renal impairment and hypertension while receiving lenvatinib for RR-PTC. Her proteinuria and renal damage continued to worsen despite dose reductions and dose interruptions. Renal biopsy was consistent with the chronic type of TMA. These findings indicate that TMA is a possible cause of proteinuria due to lenvatinib, as has been reported for the VEGF inhibitors.

Radiation exposure from patients treated with radioactive iodine (.sup.131I) represents a radiation hazard to children and adolescents, representing the most vulnerable group of household contacts. Our aim was to calculate the cumulative radiation exposure (CRE) figures to children and adolescents sharing the same home with outpatients treated with low-dose .sup.131I. The secondary aim was to study the demographic and educational factors that may significantly affect radiation exposure to them. The whole number of household contacts less than 18 years was 99, out of them 49 [less than or equal to] 12 years. CRE level to children and adolescents ranged from 79 to 934 uSv. The mean, median, and 75th percentile figures were 284 ± 178 uSv, 215 uSv, and 334 uSv, respectively. The compliance of this group of contacts to radiation exposure constraint (1 mSv) was 100%. All CRE values were below this figure with 75% of them below half of this constraint. Thirteen adolescents from 12 to 18 years and 17 mothers of 23 household contacts [less than or equal to] 12 years got radiation safety instructions (RSI) directly from a radiation safety officer (RSO). This group had a significantly lower mean CRE value (184 ± 93 uSv) compared to those who got RSI from the patient or from other family members (298 ± 185 uSv) with a significant p value. The compliance of adolescents and children to the 1-mSv radiation exposure constraint is 100%. It is advised for adolescents and mothers of children in contact with .sup.131I-treated patients to get direct RSI from the RSO, which is the only factor associated with significantly lower radiation exposure figures.

Radioactive iodine (RAI, 131 I) has been used as a therapeutic agent for differentiated thyroid cancer (DTC) with over 50 years of history. Recently, it is now attracting attention in medical fields as one of the molecular targeting therapies, which is known as targeted radionuclide therapy. Radioactive iodine therapy (RIT) for DTC, however, is now at stake in Japan, because Japan is confronting several problems, including the recent occurrence of the Great East Japan Disaster (GEJD) in March 2011. RIT for DTC is strictly limited in Japan and requires hospitalization. Because of strict regulations, severe lack of medical facilities for RIT has become one of the most important medical problems, which results in prolonged waiting time for Japanese patients with DTC, including those with distant metastasis, who wish to receive RIT immediately. This situation is also due to various other factors, such as prolonged economic recession, super-aging society, and subsequent rapidly changing medical environment. In addition, due to the experience of atomic bombings in Hiroshima and Nagasaki, Japanese people have strong feeling of “radiophobia”. There is fear that GEJD and related radiation contamination may worsen this feeling, which might be reflected in more severe regulation of RIT. To overcome these difficulties, it is essential to collect and disclose all information about the circumstances around this therapy in Japan. In this review, we would like to look at this therapy through several lenses, including historical, cultural, medical, and socio-economic points of view. We believe that clarifying the problems is sure to lead to the resolution of this complicated situation. We have also included several recommendations for future improvements.