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Purpose: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131 I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124 I PET., Methods: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUV max  > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI- 124 I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUV max and activity in microcurie per gram, from a single imaging timepoint., Results: In the 169 lesions (in 15 patients) that received 131 I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUV max was the best predictor of lesion radiation dose and permitted calculation of the 131 I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals., Conclusions: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124 I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124 I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center., Trial Registration: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018., (© 2023. The Author(s).)

Purpose: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC., Patients and Methods: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc., Results: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation., Conclusions: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC., (©2023 American Association for Cancer Research.)

Most patients with differentiated thyroid cancer have a good prognosis after radioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University., Methods: RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated., Results: Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% ( n = 15) and the objective response rate (ORR) was 26.9% ( n  = 7). Most patients with disease control had thyroglobulin decreases of more than 60% ( p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis ( p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS ( p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS ( p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS., Conclusions: Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ling, Xiong, Luo, Zou, Chen, Pan, Long, Feng and Ouyang.)

Context: Whether radioactive iodine therapy (RAIT) is necessary for intermediate-risk papillary thyroid cancer (PTC) after total thyroidectomy is still lacking reliable evidence, especially for patients with low postoperative thyroglobulin (Tg) levels., Objective: This study conducted a propensity score matching (PSM) analysis to investigate whether RAIT is effective in reducing the recurrence of intermediate-risk PTC with low Tg levels., Methods: In total, 1487 patients with intermediate-risk PTC with unstimulated Tg ≤ 1 ng/mL or stimulated Tg ≤ 10 ng/mL after total thyroidectomy were enrolled retrospectively. The clinicopathological characteristics were compared between the non-RAIT and RAIT groups before and after PSM (1:4 matching). The impact of RAIT on biochemical recurrence and structural recurrence was evaluated., Results: Overall, 1349 (90.7%) patients underwent RAIT, and 138 (9.3%) did not. After a median follow-up time of 51 months, 30 patients presented with recurrence, including 11 structural and 19 biochemical recurrences. After PSM, the non-RAIT group had a higher rate of structural recurrence (5/138 vs 5/552, P = .046) and biochemical recurrence (6/138 vs 4/552, P = .005) than the RAIT group. Multivariate analysis showed that not receiving RAIT was an independent risk factor for structural recurrence (hazard ratio [HR] 10.572, 95% CI 2.439-45.843, P = .002) and biochemical recurrence (HR 16.568, 95% CI 3.670-74.803, P < .001). Kaplan-Meier analysis showed that the non-RAIT group had more unfavorable recurrence-free survival (structural and biochemical, all P < .05)., Conclusion: RAIT could decrease the recurrence risk of intermediate-risk PTC in patients with unstimulated Tg ≤ 1 ng/mL or stimulated Tg ≤ 10 ng/mL. Further prospective randomized studies are needed to confirm these findings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: A decrease in the use of radioactive iodine (RAI) treatment for thyroid cancer has been described in the last decade in the US following subsequent updates of the American Thyroid Association guidelines. By contrast, population-based data from European countries are lacking. The study aims to assess the frequency and long-term trends in the use of RAI in Italy., Methods: From the Italian national hospital discharge database, the proportion of RAI treatment after total thyroidectomy with thyroid cancer diagnosis has been assessed by sex and age class during 2001-2018., Results: Throughout the whole study period, RAI was performed after 58% of 149,419 total thyroidectomies. The use of RAI was higher for men and younger patients; it peaked in 2007 (64% in women and 68% in men) and declined thereafter (2018: 46% in women and 53% in men), with a similar pattern observed across all ages and areas., Conclusion: National data show that in Italy trends in RAI treatment paraleled those observed in the US. Further monitoring of the use of RAI is warranted in Italy, as elsewhere, to assess the impact of international guidelines on real-life clinical management of thyroid cancer.

This study aimed to assess recurrence-free survival (RFS) rates and recurrence-related factors of patients who received adjuvant therapy (AT) with radioactive iodine (RAI) for differentiated thyroid cancer (DTC) following thyroidectomy. We evaluated 284 patients who underwent AT between January 2011 and July 2020 at our hospital. Recurrence was defined as visible recurrent lesions on image analysis or need for repeat surgery with pathologically confirmed recurrent lesions. RFS rate and prognostic factors were statistically evaluated. The median observation period was 30.2 months (range, 5.7-294 months). Overall, 192 patients were female and 92 were male, and the median age was 54 years (range, 9-85 years). Initial assessment revealed 39 recurrence cases. The 3-year RFS rate was 85.8% (95% confidence interval: 81.1-90.9%). Univariate analysis revealed that histology (except for papillary carcinoma), Tg level > 4 ng/dL before AT, and AT result significantly exacerbated the RFS rate. In multivariate analysis, histology and AT result were also important contributors to the worsening RFS rate. Results of AT can be determined relatively early and are important in predicting future recurrence in patients with DTC. Increasing the success rate of AT may lead to an improved prognosis., (© 2023. The Author(s).)

Precise dosimetry has gained interest for interpreting the response assessments of novel therapeutic radiopharmaceuticals, as well as for improving conventional radiotherapies such as the "one dose fits all" approach. Although radioiodine as same-element isotope theranostic pairs has been used for differentiated thyroid cancer (DTC), there are insufficient studies on the determination of its dosing regimen for personalized medicine and on extrapolating strategies for companion diagnostic radiopharmaceuticals. In this study, DTC xenograft mouse models were generated after validating iodine uptakes via sodium iodine symporter proteins (NIS) through in vitro assays, and theranostic surrogacy of companion radiopharmaceuticals was investigated in terms of single photon emission computed tomography (SPECT) imaging and voxel-level dosimetry. Following a Monte Carlo simulation, the hypothetical energy deposition/dose distribution images were produced as [ 123 I]NaI SPECT scans with the use of 131 I ion source simulation, and dose rate curves were used to estimate absorbed dose. For the tumor, a peak concentration of 96.49 ± 11.66% ID/g occurred 2.91 ± 0.42 h after [ 123 I]NaI injection, and absorbed dose for 131 I therapy was estimated as 0.0344 ± 0.0088 Gy/MBq. The absorbed dose in target/off-target tissues was estimated by considering subject-specific heterogeneous tissue compositions and activity distributions. Furthermore, a novel approach was proposed for simplifying voxel-level dosimetry and suggested for determining the minimal/optimal scan time points of surrogates for pretherapeutic dosimetry. When two scan time points were set to T max and 26 h and the group mean half-lives were applied to the dose rate curves, the most accurate absorbed dose estimates were determined [-22.96, 2.21%]. This study provided an experimental basis to evaluate dose distribution and is expected hopefully to improve the challenging dosimetry process for clinical use.

Purpose: An accurate postoperative assessment is pivotal to inform postoperative 131 I 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 131 I administration and select patients requiring curative rather than adjuvant 131 I therapy schedules., (© 2023. The Author(s).)

Radioactive iodine is well established as a successful treatment for differentiated thyroid cancer (DTC), although around 15% of patients have local recurrence or develop distant metastases and may become refractory to radioactive iodine (RAI). A personalized approach to treatment, based on the absorbed radiation doses delivered and using treatments to enhance RAI uptake, has not yet been developed. Methods: We performed a multicenter clinical trial to investigate the role of selumetinib, which modulates the expression of the sodium iodide symporter, and hence iodine uptake, in the treatment of RAI-refractory DTC. The iodine uptake before and after selumetinib was quantified to assess the effect of selumetinib. The range of absorbed doses delivered to metastatic disease was calculated from pre- and posttherapy imaging, and the predictive accuracy of a theranostic approach to enable personalized treatment planning was investigated. Results: Significant inter- and intrapatient variability was observed with respect to the uptake of RAI and the effect of selumetinib. The absorbed doses delivered to metastatic lesions ranged from less than 1 Gy to 1,170 Gy. A strong positive correlation was found between the absorbed doses predicted from pretherapy imaging and those measured after therapy ( r = 0.93, P < 0.001). Conclusion: The variation in outcomes from RAI therapy of DTC may be explained, among other factors, by the range of absorbed doses delivered. The ability to assess the effect of treatments that modulate RAI uptake, and to estimate the absorbed doses at therapy, introduces the potential for patient stratification using a theranostic approach. Patient-specific absorbed dose planning might be the key to more successful treatment of advanced DTC., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Purpose: False-positive radioiodine uptake can sometimes be observed with post-radioiodine treatment (RIT) whole body scanning. Radioiodine pitfall has often been reported as being caused by benign or inflammatory disease, or, in some cases, by tumor lesions. This paper reviews the possible causes of such false-positive imaging, and suggests possible reasons for suspecting these pitfalls., Methods and Results: Online databases, including MEDLINE (via PubMed), Embase, ISI Web of Science, Google Scholar, and Scopus, were systematically examined, using different keyword combinations: "radioiodine false-positive imaging", "131 I false-positive imaging" and " RAI false-positive imaging". An illustrative case was described. Excluding cases in which SPECT/CT was not performed, a total of 18 papers was found: 17 case reports and one series regarding false-positive iodine-131 uptake after RIT., Conclusions: The prevalence of radioiodine pitfall was significantly reduced through the use of SPECT/CT imaging, though its possible presence has always to be taken into account. Inflammation, passive iodine accumulation, other tumors, and, sometimes, unknown causes can all potentially generate false-positive imaging. Missing detection of false-positive imaging could result in over-staging and inappropriate RIT or it could lead to the non-detection of other cancers. We examine the reasons for these possible pitfalls., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study aimed to evaluate neutrophil to lymphocyte ratio (NLR) as a laboratory biomarker in radioactive iodine-refractory (RAIR) locally advanced and/or metastatic differentiated thyroid cancer (DTC) and determine its correlation with overall survival (OS)., Methods: We retrospectively included 172 patients with locally advanced and/or metastatic RAIR DTC admitted between 1993 and 2021 at INCA. Age at diagnosis, histology, presence of distant metastasis (DM), DM site, neutrophil-to- lymphocyte ratio (NLR), imaging studies such as PET/CT results, progression free survival (PFS) and overall survival (OS) data were analyzed. NLR was calculated at the time of locally advanced and/or metastatic disease diagnosis and the cutoff value was 3. Survival curves were established using the Kaplan-Meier method. The confidence interval is 95%, and a p-value of less than 0.05 was considered statistically significant RESULTS: Out of 172 patients, 106 were locally advanced, and 150 presented DM at some point during follow-up. Regarding NLR data, 35 had NLR over 3 and 137 had NLR under 3. Higher NLR at was associated with shorter OS (6 vs. 10; p = 0.05) and with highest SUV on FDG PET-CT (15.9 vs. 7.7, p = 0.013). We found no association between higher NLR and age at diagnosis, DM or final status., Conclusion: NLR higher than 3 at the time of locally advanced and/or metastatic disease diagnosis is an independent fator for shorter OS in RAIR DTC patients. Noteworthy higher NLR was also associated with highest SUV on FDG PET-CT in this population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of radioiodine (I-131) in the management of patients suffering differentiated thyroid cancer (DTC) has changed little in the past 40 years. The use of a standardized approach has served the majority of patients well over that time. However, there have been recent doubts concerning this approach in some low risk patients and if so, how can these patients recognized and which patients who may need more intensive treatment. A number of clinical trials have questioned the paradigms used in the treatment of DTC including what activity of I-131 should be used for ablation and which low risk patients should be treated with I-131 especially as there remains some doubts as to the long-term safety of I-131. Should a dosimetric approach be used to optimize the use of I-131 even though at present this approach has not been shown to improve outcomes in a formal clinical trial. The era of precision oncology represents a challenge and opportunity to nuclear medicine with a move away from a regime of standard care to one of highly individualized care based on the genetic profiling of the patient and their cancer. The treatment of DTC with I-131 is about to become very interesting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Exposure to therapeutic radioactive iodine (RAI) is associated with an increased relative risk of myeloid malignancies. Clonal hematopoiesis (CH) is a precursor state that can be detected in blood of healthy individuals decades before overt development of leukemia. We prospective studied the effects of RAI on CH., Design: Prospective cohort study., Patients and Measurements: We examined the effect of RAI on CH in 20 patients exposed to RAI for thyroid carcinoma and 20 age-matched unexposed controls. CH status was determined at baseline, 6, 12, 18 and 24 months. We also examined the effect of CH on structural progression of disease., Results: No CH mutations were observed in the patient population that were not present at baseline. Using a variant allelic fraction (VAF) of 2% to define CH, 6/20 older patients (55-80 years old) had CH compared to 2/20 younger patients (20-40 years old) (p = 0.11). Six patients exposed to RAI had CH compared to two patients not exposed to RAI (30% vs. 10%, p = 0.11). There was no significant difference in CH VAF increase in patients treated with RAI compared to untreated age-matched controls (3.8% vs. 1.2%, p = 0.2). CH was significantly associated with somatic BRAFV600E mutations and with worse progression-free survival in the overall cohort as well as among BRAFV600E-mutant tumors., Conclusions: There was no increase in CH in patients treated with RAI over a 2-year follow-up period. Larger studies with longer follow-up periods are needed to investigate the association between RAI and clonal dynamics. The presence of CH is associated with worse structural progression in both BRAFV600E-mutant and wild-type thyroid cancers., (© 2023 John Wiley & Sons Ltd.)

Objectives: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients., Methods: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1 , ATM , ATG16L2 , ATG10 , TGFB1 , and TNF polymorphisms were determined by allele-specific realtime-PCR., Results: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy., Conclusions: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

In clinical settings, an estimated 10% differentiated thyroid cancer (DTC) cases become radioactive iodide refractory (RAIR), which lack a molecular marker and have fewer treatment selections. A higher uptake of 18F-fluorodeoxyglucose (18F-FDG) might indicate poor prognosis for DTC. This study aimed to evaluate the clinical value of 18F-FDG psitron emission tomography/computed tomography (PET/CT) for the early diagnosis of RAIR-DTC and high-risk DTC. A total of 68 DTC patients were enrolled and underwent 18F-FDG PET/CT for the detection of recurrence and/or metastasis. 18F-FDG uptake was evaluated in patients with different postoperative recurrence risks or TNM stages and compared between RAIR and non-RAIR-DTC based on its maximum standardized uptake value and tumor/liver (T/L) ratio. The final diagnosis was judged by histopathology and follow-up data. Of 68 DTC cases, 42 were RAIR and 24 non-RAIR, with 2 not determined. A total of 263 of 293 lesions detected on 18F-FDG PET/CT were confirmed to be locoregional or metastatic after follow-up. The T/L ratio was significantly higher for RAIR than for non-RAIR (median 5.18 vs 1.44; P < .01) and also significantly higher in postoperative patients at high-risk of recurrence than at low to medium risk (median 4.90 vs 2.16; P < .01). 18F-FDG PET/CT exhibited a sensitivity of 83.3% and specificity of 87.5% for identifying RAIR, with a cutoff T/L value of 2.98. 18F-FDG PET/CT has the potential to diagnose RAIR-DTC early and identify the high-risk DTC. The T/L ratio is a useful parameter for the detection of RAIR-DTC patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

Background: Faecalibacterium prausnitzii , one of the most important bacteria of the human gut microbiota, produces butyrate (a short-chain fatty acid). Short-chain fatty acids are known to influence thyroid physiology and thyroid cancer's response to treatment. We aimed to analyze the relative abundance of Faecalibacterium prausnitzii on the gut microbiota of differentiated thyroid cancer patients compared to controls and its variation after radioiodine therapy (RAIT)., Methods: Fecal samples were collected from 37 patients diagnosed with differentiated thyroid cancer before and after radioiodine therapy and from 10 volunteers. The abundance of F. prausnitzii was determined using shotgun metagenomics., Results: Our study found that the relative abundance of F. prausnitzii is significantly reduced in thyroid cancer patients compared to volunteers. We also found that there was a mixed response to RAIT, with an increase in the relative and absolute abundances of this bacterium in most patients., Conclusions: Our study confirms that thyroid cancer patients present a dysbiotic gut microbiota, with a reduction in F. prausnitzii's relative abundance. In our study, radioiodine did not negatively affect F. prausnitzii , quite the opposite, suggesting that this bacterium might play a role in resolving radiation aggression issues.

Background: We aimed to investigate whether the risk of second primary malignancy (SPM) in patients with thyroid cancer (TC) receiving radioactive iodine (RAI) therapy rises in a cumulative, dose-dependent manner compared with those not undergoing RAI., Methods: Using the Korean National Health Insurance Service National Health Information Database (2002-2019), we investigated hazard ratios of SPM associated with RAI in TC. SPM was defined as a second primary malignancy diagnosed at least 1 year after TC diagnosis., Results: Of 217 777 patients with TC (177 385 women and 40 392 men; mean [SD] age, 47.2 [11.6] years), 100 448 (46.1%) received RAI therapy. The median (IQR) follow-up duration was 7.7 (5.5-10.3) years, and the median (IQR) cumulative RAI dose was 3.7 (1.9-5.6) GBq. From 2004 to 2019, SPM incidence rates were 7.30 and 6.56 per 1000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted hazard ratio of 1.09 (95% confidence interval = 1.05 to 1.13); this rate remained at 1.08 (95% confidence interval = 1.04 to 1.13) after adjustment for multiple clinical confounding factors. Notably, SPM risk increased significantly, from 3.7 GBq with full adjustments, and a strong linear association between cumulative RAI dose and SPM was observed in the restricted cubic spline analysis. Regarding cancer subtypes, myeloid leukemia and salivary gland, trachea, lung and bronchus, uterus, and prostate cancers were the most significantly elevated risks in patients who underwent RAI therapy., Conclusions: This study identified that SPM risk increased linearly in a dose-dependent manner in patients with TC undergoing RAI therapy compared with those not undergoing RAI therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: We evaluated the efficacy and safety of postoperative radiotherapy (PORT) for differentiated thyroid cancer (DTC) with high risk features., Materials and Methods: This retrospective study analyzed 187 patients treated for DTC from 1985 to 2019. DTC referred to nonanaplastic thyroid cancer originating from follicular cells. PORT was defined as the administration of external beam radiation to the thyroid and regional lymph nodes following surgery for initially diagnosed DTC. The patients were included in the analysis if they received PORT or exhibited any of the following features: (a) pT4 or pN1b according to the 8th American Joint Committee on Cancer, (b) poorly differentiated thyroid cancer (PDTC), or (c) unfavourable variants such as anaplastic foci and etc. After 1:1 propensity matching, a total of 108 patients were analyzed according to PORT receipt. The median follow-up duration of the matched group was 10.4 years., Results: After matching, most of the variables became balanced, but the PORT group still had more PDTC and DTC with anaplastic foci. Radioactive iodine (RAI) was less frequently administered in the PORT group. PORT yielded a significantly higher 5-year locoregional recurrence free survival (LRFS) than the No PORT group (5-year LRFS 86.1% vs. 72.7%, p = 0.022), but the 10-year cancer specific survival (CSS) was similar between them (97.8% vs. 85.9%, p = 0.122). The multivariable analysis indicated that PORT was a favourable prognostic factor (Hazard ratio 0.3, 95% Confidence interval 0.1-0.8, p = 0.02) for LRFS, but not for CSS. Among 133 patients without PORT for initial disease, 39 of them received salvage surgery followed by salvage PORT. No severe toxicity after PORT was reported., Conclusion: PORT reduced locoregional recurrence in DTC patients without severe toxicity. PORT can be an effective and safe treatment to improve locoregional control in DTC with high risk features. However, further study is warranted to identify those who can benefit from PORT., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Abstract: A 31-year-old woman with a history of papillary thyroid cancer underwent ablative 131I therapy. Posttherapeutic whole-body 131I scintigraphy revealed abnormally increased activity in the neck. Additional SPECT/CT images localized the activity in the bilateral peripheral fascia of the platysma., Competing Interests: Conflicts of interest and sources of funding: The authors have no conflicts of interest to report. This project was supported by the Natural Science Foundation of Sichuan Province No.2023NSFSC0635., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Objective: This study aimed to investigate the long-term effect of radioiodine (RAI) treatment on thyroid functions and ultrasonographic changes in the thyroid gland and toxic nodules., Methods: Thyroid function tests and ultrasonography reports of patients diagnosed with toxic adenoma (TA) or toxic multinodular goitre (TMNG) between 2000 and 2021 were retrospectively analysed., Results: We included 100 patients whom thyroid function and ultrasonography results were obtained from our outpatient clinic before and at least 36 months post-RAI. At the end of the follow-up period, the mean thyroid volume reduction in patients with TA and TMNG was 56.6% ± 3.1% and 51.1% ± 6.7%, respectively; the mean volume decrease of all toxic nodules was 80.5% ± 1.9%. The volume of the thyroid and toxic nodules was significantly reduced up to 12 years (p < 0.01). Between 3 and 10 years after RAI therapy, the annual incidence of hypothyroidism was 2.0% and 1.5% in the TA and TMNG groups, respectively. Toxic nodules were more frequently solid and hypoechoic in post-RAI ultrasounds (p < 0.01)., Conclusions: The volume of thyroid gland and toxic nodules continuously decreases, as the risk of hypothyroidism increases up to 10 years after RAI treatment. After RAI treatment, patients should be followed up to check their thyroid functions. In post-RAI examinations, toxic nodules may show ultrasonographic features suspicious for malignancy. History taking should include previous RAI therapies and old scintigraphy scans should be evaluated to avoid unnecessary procedures and non-diagnostic biopsy results., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Background: Aim of the present study was to evaluate the clinical impact of fluorine- 18 F-fluorodeoxyglucose PET/CT ( 18 F-FDG-PET/CT) concurrent with post-therapeutic whole-body radioiodine scan (TxWBS) after first radioiodine (RAI) treatment in patients with high-risk differentiated thyroid carcinoma (DTC)., Methods: This was a retrospective, single-center study including 39 patients with DTC (22 females, 17 males, median age 54; IQR: 35-60 years, 87% papillary thyroid cancer, 13% follicular thyroid cancer). All patients underwent 18 F-FDG-PET/CT and RAI treatment, both performed off L-T4 about 3 months after total thyroidectomy. TxWBS was obtained 3 days afterwards using planar technique and SPECT/CT of neck and thorax regions. Semiquantitative analysis was performed on positive 18 F-FDG-PET/CT scans to assess SUVmax, SUVratio, MTV and TLG values in target lesions (hottest 18 F-FDG-positive lesion present in each patient). Receiver operating characteristics (ROC) curve analysis was obtained to establish a cut-off point for SUVmax able to predict the presence of RAI nonavid lesions. Univariate and multivariate analyses were executed to find out predictive factors for abnormal 18 F-FDG-PET/CT imaging., Results: In 11 (28%) patients 18F-FDG-PET/CT and TxWBS were both negative and in 9 (23%) both positive, showing loco-regional or distant metastases. In 14 patients (36%) 18 F-FDG-PET/CT showed more lesions than TxWBS, while in 5 (13%) patients more lesions were present at TxWBS than 18F-FDG-PET/CT. Overall, 23 patients (59%) showed 18 F-FDG avid lesions and 18 F-FDG-PET/TC changed the management in 14 (36%), including the choice to perform RAI therapy with higher activities than expected, lymph-node dissection for loco-regional metastases, direct therapy for solitary bone metastases. Through ROC curve analysis, a value superior to 7.25 of SUVmax was able to predict the presence of RAI non-avid lesion at TxWBS. Serum stimulated thyroglobulin and extranodal invasion resulted to be risk factors for abnormal 18 F-FDG-PET/CT imaging. However, only extranodal invasion turned out to be an independent risk factor for abnormal 18 F-FDG-PET/CT., Conclusions: The present study demonstrated the clinical value of RAI-concurrent 18 F-FDG-PET/CT in patients with high-risk DTC. However, some questions remain open, including the pretherapeutic thyroglobulin level to use as indication to 18 F-FDG-PET/CT and the predictive value of 18 F-FDG-PET/CT semiquantitative parameters.

Background: In patients with low-risk differentiated thyroid cancer (DTC), remnant ablation with radioiodine (RA) after total thyroidectomy (TT) is controversial. No benefits have been demonstrated in terms of mortality or disease-free survival. Recent evidence found that RA did not improve mid-term outcomes., Purpose: To evaluate initial response to treatment and long-term follow-up status in low-risk DTC patients after TT vs. TT + RA with 131 I 1.11 GBq (30 mCi)., Methods: Prospective multicenter non-randomized study; 174 low-risk DTC that underwent TT were recruited an divided in two groups according to RA (87 ablated and 87 non-ablated). Response to treatment was evaluated at 6-18 months after thyroidectomy and at the end of follow-up with measurements of thyroglobulin, and anti-thyroglobulin antibodies levels, and neck ultrasonography., Results: Baseline characteristics of both groups were similar. Ablated patients: median age 45.5 years, 84% females, 95.4% papillary thyroid carcinoma (PTC), mean tumor size 16 mm; non-ablated: median age 45 years, 88.5% females, 96.6% PTC, mean tumor size 14 mm. Response to initial treatment was similar between both groups, with < 2% of structural incomplete response. Final status was evaluated in 139 cases (median follow-up of 60 months). Among ablated patients, 82.8% had no evidence of disease (NED), 12% had an indeterminate response (IR) and 5% a biochemical incomplete response (BIR). Non-ablated patients had NED in 90%, IR in 8.7% and BIR in 1.2%. No statistical difference was found between groups (p = 0.29). No patient had evidence of structural disease at the end of follow-up., Conclusions: Our findings support the recommendation against routine RA in low-risk DTC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This viewpoint highlights the contributions of Dr. Ernest Mazzaferri, a prominent figure in the field of thyroid cancer care, who made significant contributions to the diagnosis and treatment of this disease. Dr. Mazzaferri's first paper on thyroid cancer, published in 1977, established fundamental principles that remain fundamental to differentiated thyroid cancer management. He was an advocate of total thyroidectomy and of postoperative radioiodine therapy and contributed to improving thyroid fine needle aspiration techniques. Dr. Mazzaferri's leadership in developing guidelines for the management of thyroid cancer and thyroid nodules has been influential and widely accepted. His groundbreaking work established a systematic and data-driven approach to the diagnosis and treatment of thyroid cancer that continues to shape the field of thyroid cancer care today. This Viewpoint reflects on his lasting impact ten years after his death., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The role of adjuvant external-beam radiotherapy (EBRT) in the treatment of locally advanced papillary thyroid carcinoma (PTC) remains controversial due to the lack of prospective data and the conflicting retrospective data. This study aimed to determine the benefits of adjuvant EBRT in patients with PTC and other organ invasions using propensity score matching to reduce the heterogeneity of the patient population., Methods: Data from patients with PTC with other organ invasions but no distant metastases who underwent surgery and adjuvant radioactive iodine (RAI) alone (Non-EBRT group) or adjuvant EBRT plus RAI (EBRT group) were retrospectively reviewed. Propensity matching was used to reduce heterogeneity. Survival outcomes and toxicities associated with EBRT were evaluated., Results: Between January 2005 and December 2019, 102 patients in the Non-EBRT group and 26 patients in the EBRT group were evaluated. In the 48 propensity score-matched patients, no significant differences in baseline characteristics between the Non-EBRT and EBRT groups were detected. The locoregional recurrence-free survival (LRRFS) and recurrence-free survival (RFS) rates were significantly higher in the EBRT group compared with the rates in the Non-EBRT group (5y-LRRFS: 100% vs. 74%, p = 0.003, 5y-RFS: 91% vs. 74%, p = 0.035). EBRT was well-tolerated, with no grade ≥ 3 toxicity, and all patients completed the therapy as planned., Conclusion: Adjuvant EBRT plus RAI exhibited acceptable toxicity and improved LRRFS and RFS in patients with PTC with other organ invasions compared with RAI alone., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patterns of utilization of external beam radiation therapy (EBRT) in thyroid cancer are incompletely described. We characterize therapeutic intent, complications, and survival in thyroid cancer treated with EBRT., Methods: In this retrospective study of 105 thyroid cancer patients treated with EBRT at one institution (2008-2018), the primary outcome was overall survival. Secondary outcomes included incomplete treatment, emergency department (ED) visits, weight change, and gastrostomy placement., Results: Dominant histopathology was differentiated (44%), anaplastic (45%) and poorly-differentiated (11%) disease. EBRT was mainly utilized for locoregional control (differentiated 87%, poorly-differentiated 75%, anaplastic 92%). Palliative EBRT was more common in poorly-differentiated disease (42%). Weight loss was greater in aggressive/advanced disease (differentiated 10 lb, poorly-differentiated 27 lb, anaplastic 18 lb). Anaplastic cancer had higher rates of gastrostomy (34%) and lowest rates of treatment completion (83%). ED encounters were common (differentiated 44%, poorly-differentiated 50%, anaplastic 45%). Gastrostomy was associated with mortality on multivariable analysis in non-anaplastic malignancy., Conclusions: EBRT was most frequently administered for locoregional control in thyroid cancer. Despite complications, the majority of patients completed EBRT therapy., Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) are not amenable to novel 131 I therapy due to the reduced expression of sodium iodide symporter (Na+/I- symporter, NIS) and/or the impairment of NIS trafficking to the plasma membrane. RAIR-TC patients have a relatively poor prognosis with a mean life expectancy of 3-5 years, contributing to the majority of TC-associated mortality. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging for clinicians. In this review, we demonstrate the updated clinical scenarios or the so-called "definitions" of RAIR-TC suggested by several associations based on 131 I uptake ability and tumor response post- 131 I therapy. We also discuss current knowledge of the molecular alterations involved in membrane-localized NIS loss, which provides a preclinical basis for the development of targeted therapies, in particular, tyrosine kinase inhibitors (TKIs), redifferentiation approaches, and immune checkpoint inhibitors., (© 2021 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Background: Residual/recurrent lymph node metastase (LNM) is often found after differentiated thyroid cancer (DTC) surgery. This study aimed to investigate whether patients complicated with radioiodine-avid ( 131 I+) lymph nodes from DTC on the initial posttherapy scan (PTS) need repeated 131 I therapy., Methods: From June 2013 to August 2022, DTC patients with 131 I+ lymph nodes on the initial PTS who received at least two cycles of 131 I therapy were retrospectively enrolled. They were divided into a complete response (CR) group and an incomplete response (IR) group according to their response to the initial 131 I therapy based on the 2015 American Thyroid Association (ATA) guidelines., Results: A total of 170 DTC patients with 131 I+ lymph nodes on the initial PTS were included; 42/170 (24.7%) patients were classified into the CR group and 128/170 (75.9%) were classified into the IR group according to their response to the initial 131 I therapy. None of the 42 CR patients had disease progression at the subsequent follow-up, and 37/170 (21.8%) IR patients improved after repeated therapy. Univariate analysis showed that N stage ( P= 0.002), stimulated thyroglobulin (sTg) level before initial 131 I therapy ( P <0.001), LNM size ( P <0.001), number of total residual/recurrent LNM ( P= 0.021), radioiodine-nonavid ( 131 I-) LNM ( P= 0.002) and ultrasound features ( P <0.001) were related to the initial treatment response. On multivariate analysis, sTg level ( OR =1.186, P <0.001) and LNM size ( OR =1.533, P =0.004) were independent risk factors for IR after initial 131 I therapy. The optimal sTg level and LNM size cutoff value for predicting the treatment response after initial 131 I therapy were 18.2 µg/l and 5mm., Conclusion: This study suggested that approximately one-quarter of patients with 131 I+ lymph nodes on initial PTS, especially those with N0 or N1a stage, lower sTg level, smaller LNM size, ≤2 residual/recurrent LNMs, negative ultrasound features and no 131 I- LNM, remain stable after one cycle of 131 I therapy and do not need repeated therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiang, Liu, Qiu, Huo, Zhang, Cai, Lv and Ma.)

Use of radioactive iodine (RAI) for thyroid cancer patients is accompanied by elevated risks of radiation-induced adverse effects due to significant radiation exposure of normal tissues or organs other than the thyroid. The health risk estimation for thyroid cancer patients should thus be preceded by estimating normal tissue doses. Although organ dose estimation for a large cohort often relies on absorbed dose coefficients (i.e. absorbed dose per unit activity administered, mGy MBq -1 ) based on population models, no data are available for thyroid cancer patients. In the current study, we calculated absorbed dose coefficients specific for adult thyroid cancer patients undergoing RAI treatment after recombinant human TSH (rhTSH) administration or thyroid hormone withdrawal (THW). We first adjusted the transfer rates in the biokinetic model previously developed for THW patients for use in rhTSH patients. We then implemented the biokinetic models for thyroid cancer patients coupled with S values from the International Commission on Radiological Protection (ICRP) reference voxel phantoms to calculate absorbed dose coefficients. The biokinetic model for rhTSH patients predicted the extrathyroidal iodine decreasing noticeably faster than in the model for THW patients (calculated half-times of 12 and 15 h for rhTSH administration and THW, respectively). All dose coefficients for rhTSH patients were lower than those for THW patients with the ratio (rhTSH administration/THW) ranging from 0.60 to 0.95 (mean = 0.67). The ratio of the absorbed dose coefficients in the current study to the ICRP dose coefficients, which were derived from models for normal subjects, varied widely from 0.21 to 7.19, stressing the importance of using the dose coefficients for thyroid cancer patients. The results of this study will provide medical physicists and dosimetrists with scientific evidence to protect patients from excess exposure or to assess radiation-induced health risks caused by RAI treatment., (© 2023 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Context: Using response to surgery when tailoring radioiodine (RAI) therapy for papillary thyroid cancer (PTC) is valued but lacks prospective validation., Objective: To spare RAI thyroid remnant ablation among patients with intermediate-risk PTCs using 3-tiered assessments with response to surgery highlighted, in addition to the risk of the recurrence stratification and TNM staging., Methods: Patients with no evidence of disease (NED) identified as excellent response (ER) or indeterminate response (IDR) to surgery were spared from RAI thyroid remnant ablation after informed consent and prospectively enrolled under active surveillance. Those involved in other trials or without sufficient follow-up data were excluded. Dynamic responses were followed and compared longitudinally. The main outcome measures were NED presenting as durable ER or IDR for over 12 months., Results: Of the enrolled 215 patients, 47.4% (102/215) ER and 52.6% (113/215) IDR were identified regarding RAI decision-making. After a median of 23.6 (interquartile range 13.8-31.6) months, the share of ER increased to 82.8% (178/215) and IDR decreased to 16.3% (35/215), with 85 patients shifting from IDR to ER over time, only 0.5% (1/215) structural incomplete response and 0.5% (1/215) biochemical incomplete response observed. Successful remnant ablation was observed in 27.7% (26/94) of the patients completing 2 diagnostic whole-body scans after a median interval of 13.0 months, indicating a theranostic effect. In the 173 patients followed for over 12 months, the NED rate did not differ between ER and IDR subgroups (100% vs 97.9%, P = .20)., Conclusion: Through the 3-tiered assessments with response to surgery highlighted, postoperative ER and IDR spared from RAI remnant ablation may indicate similar favorable responses in intermediate-risk patients with PTC during 23.6 months of follow-up., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To analyze the influencing factors of tumor volume, body immunity, and poor prognosis after 125 I particle therapy for differentiated thyroid cancer., Methods: A total of 104 patients with differentiated TC who were treated with 125 I particles during January 2020 to January 2021 was picked. These subjects were graded as low-dose group (80Gy-110Gy) and high-dose group (110Gy-140Gy) according to the minimum dose received by 90% of the target volume (D90) after surgery. The tumor volume before and after treatment was compared, and fasting venous blood was collected before and after treatment. The content of thyroglobulin (Tg) was detected by electrochemiluminescence immunoassay. The levels of absolute lymphocyte count (ALC), lymphocytes, neutrophils, and monocytes were detected on automatic blood cell analyzer. The lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ration (PLR) were calculated. The changes in the condition of patients were closely observed, and the occurrence of adverse reactions in the two groups were compared. The risk factors influencing the efficacy of 125 I particle therapy for differentiated TC were analyzed through multivariate logistic regression analysis., Results: The total effective rate of patients in the low- and high-dose groups was 78.85% and 82.69%, respectively ( P > 0.05). Compared with the pretreatment period, the tumor volume and Tg level in both groups were much lower ( P < 0.05), and the differences in tumor volume and Tg level had no statistically significant difference between the two groups before and after treatment ( P > 0.05). At 1 week of the treatment, the total incidence of adverse reactions such as nausea, radiation gastritis, radiation parotitis, and neck discomfort was obviously higher in the high-dose group than in the low-dose group ( P < 0.05). At 1 month of treatment, the incidence of adverse reactions such as nausea was markedly higher in the high-dose group than in the low-dose group ( P < 0.05). After treatment, serum NLR and PLR contents were memorably elevated and LMR level was sharply decreased in both groups, and serum NLR and PLR contents were higher and LMR content was lower in the high-dose group than in the low-dose group ( P < 0.05). Multivariate logistic regression analysis showed that the pathological type of follicular adenocarcinoma, tumor size ≥ 2 cm, clinical stage of III~IV, distant metastasis, and high TSH level before 125 I particle treatment were all risk factors related to the efficacy of 125 I particle treatment of TC ( P < 0.05)., Conclusion: The efficacy of low-dose and high-dose 125 I particles in the treatment of differentiated thyroid cancer is comparable, among which low-dose 125 I particles have fewer adverse effects and have less impact on the immunity of the body, which is well tolerated by patients and can be widely used in clinical practice. In addition, the pathological type of follicular adenocarcinoma, tumor size ≥ 2 cm, clinical stage III~IV, distant metastasis, and high TSH level before 125 I particle treatment are all risk factors that affect the poor effect of 125 I particles on thyroid cancer treatment, and early monitoring of the above index changes can help evaluate the prognosis., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Liling Tan et al.)

Background: Thyroid carcinoma >4 cm in size is staged as T3a. The current American Thyroid Association guidelines recommend subtotal/total thyroidectomy and consideration for postoperative radioactive iodine (RAI) treatment for these tumors. In this retrospective cohort study, we aimed to explore the clinical course of large encapsulated thyroid carcinoma without other risk factors. Methods: Eighty-eight patients with large (>4 cm) encapsulated well-differentiated thyroid carcinoma resected between 1995 and 2021 were included in this retrospective cohort study. Exclusion criteria were tall cell variant, any extent of vascular invasion, extrathyroidal extension (microscopic or gross), high-grade histology, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), infiltrative tumors, positive resection margin, and cases with follow-up <1 year. The primary outcomes are risk of nodal metastasis at the initial resection, disease-free survival (DFS), and disease-specific survival (DSS). Results: The tumor histotype was follicular carcinoma ( n  = 18, 21%), oncocytic (Hurthle cell) carcinoma ( n  = 8, 9%), and papillary thyroid carcinoma (PTC; n  = 62, 70%). Among PTC, 38 were encapsulated follicular variant, 20 classic type, and 4 solid variant. Four cases had extensive capsular invasion (CI), 61 (69%) had focal CI, whereas 23 did not have CI. Thirty-two cases (36%) were treated with lobectomy/hemithyroidectomy alone, and 55 patients (62%) did not receive RAI. Five patients had nodal metastasis at the time of primary resection, all of whom had classic-type PTC. The median follow-up period was 4.8 years (interquartile range: 3.2-9.7 years). No recurrence, being local, regional, or distant, was observed in the entire cohort, including those patients treated with lobectomy alone without RAI. The 10-year DFS and DSS were 100%, respectively. Conclusion: Large intrathyroidal encapsulated well-differentiated thyroid carcinoma without vascular invasion follow an extremely indolent clinical course with negligible risk of recurrence. Lobectomy alone without RAI may be the appropriate treatment strategy for this selected group of patients.

Clinical Pathways are care plans that are applied to clinical processes with a predictable course, with the intention of protocolizing these processes and reducing the variability in their management. Our objective was to develop a clinical pathway for 131 I metabolic therapy in its application to differentiated thyroid cancer. A work team was organized consisting of doctors (Endocrinology and Nuclear Medicine), nursing staff (Hospitalization Unit and Nuclear Medicine), Radiophysics and the Clinical Management and Continuity of Care Support Service. For the design of the clinical pathway, several team meetings were held, in which the literature reviews were pooled and the design and development of the clinical pathway was undertaken in accordance with current clinical guidelines. This team achieved consensus on the development of the care plan, establishing its key points and drafting the different documents that make up the Clinical Pathway: Timeframe-based schedule, Clinical Pathway Variation Record Document, Patient Information Documents, Patient Satisfaction Survey, Pictogram Brochure, Quality Assessment Indicators. Finally, the clinical pathway was presented to all the clinical departments involved and to the Medical Director of the Hospital and is now being implemented in clinical practice., (Copyright © 2023 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies., Competing Interests: Conflict of interest The authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This is the story of how one man's life's work allowed for Iodine-131 (I-131) to become a therapy for hyperthyroidism and thyroid cancer. What is now a standard in our times arose from Saul Hertz's rather challenging and humble beginnings. Thyroid lobectomy and total thyroidectomy were therapeutic mainstays for thyroid disease until Hertz treated his first patient with radioactive iodine (RAI) ablation therapy at Massachusetts General Hospital (MGH) on March 31, 1941. His concepts for using beta particle emission from RAI to ablate thyroid tissue were revolutionary. Hertz's RAI therapy translated to research with thyroid cancer by the mid-1940s. The high-energy beta particles produced cytolethal effects on remnant thyroid tissue left behind by total thyroidectomy, thereby accomplishing completion thyroidectomy in some patients. Progressive surgeons from the Hertz era incorporated RAI into their practice. MGH surgery resident Francis Moore took sabbatical from clinical training to do translational research with RAI and other radioisotopes. Irving Ariel of New York became known as a nuclear surgeon in the wake of Hertz's work. George Crile Jr of Cleveland became an RAI advocate for the surgical community, implementing several paradigm-changing concepts in thyroid disease along the way. Hertz was a visionary who sparked this movement, predicting many of the molecular dilemmas with RAI-tumor avidity that clinical researchers continue to navigate today. This timely history for surgical oncologists and endocrine surgeons traces the development of RAI therapy through the life of Saul Hertz, a biographical window influenced by social stigma, political controversy, and mainstream media.

Objective: Chronic sialadenitis is the most common complication of radioactive iodine (RAI) treatment. The aim of the study was to ascertain sonographic features of the major salivary glands in patients with papillary thyroid cancer (PTC) treated with RAI., Methods: The database of a tertiary medical center was retrospectively searched for consecutive patients who underwent total thyroidectomy for PTC in 2011-2020 with ultrasound follow-up after 1 year. Changes in ultrasound features of the major salivary glands were compared between patients treated or not treated with RAI postoperatively., Results: The cohort included 158 patients, of whom 109 (69%) were treated postoperatively with RAI (mean dose, 131 mCi) and 49 were not (control group). Sonographic changes were observed in the major salivary glands in 43% of the study group and 18% of the control group (p = 0.002), including coarse echotexture, decreased echogenicity, fibrosis, and atrophy. Higher RAI doses were significantly correlated with the prevalence and severity of glandular changes (p < 0.0001)., Conclusion: RAI treatment following thyroidectomy is associated with a dose-response effect and adverse changes in the major salivary glands and should be prescribed carefully., Level of Evidence: 4 Laryngoscope, 133:1271-1275, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

This study aimed to assess the impact of adjuvant external beam radiotherapy (EBRT) on the survival of patients with locally invasive papillary thyroid carcinoma. This retrospective study used data from the Surveillance, Epidemiology, and End Results database for the diagnosis of papillary thyroid carcinoma, using Cox models to screen for adverse prognostic factors. The prognostic value of using adjuvant external beam radiotherapy in papillary thyroid carcinoma was further evaluated, based on the competing risk model and propensity score matching. Based on the competitive risk model, the sub-distribution hazard ratio (SHR) of the multivariate analysis of patients receiving EBRT alone versus those receiving radioiodine-131 alone was 9.301 (95% CI 5.99-14.44) (P < 0.001), and the SHR of the univariate analysis was 1.97 (95% CI 1.03-3.78) (P = 0.042). In the propensity score-matched Kaplan-Meier analysis, patients who received EBRT still had worse OS (6-year OS, 59.62% vs 74.6%; P < 0.001) and DSS (6-year DSS, 66.6% vs 78.2%; P < 0.001) than patients who did not receive EBRT. Patients who received EBRT had a higher cumulative risk of death due to thyroid cancer after PSM (P < 0.001). Adjuvant EBRT was not associated with survival benefit in the initial management of locally invasive papillary thyroid cancer., (© 2023. The Author(s).)

Background: Anaplastic thyroid carcinoma has a very poor prognosis. We analyzed the effect of surgery, radiotherapy and chemotherapy on survival time and side effects in patients with ATC., Methods: We retrospectively analyzed all patients (n = 63) with histologically confirmed ATC who presented at our clinic between 1989 and 2020. We analyzed the survival with Kaplan-Meier curves and cox proportional hazard models and acute toxicities with logistic regression models., Results: Out of 63 patients, 62 received radiotherapy, 74% underwent surgery and 24% received combined chemotherapy. A median radiation dose of 49 Gy (range 4-66 Gy) was applied. In 32% of the cases opposing-field technique was used, in 18% 3D-conformal, in 27% a combination of opposing field and 3D-conformal technique and 21% obtained IMRT (intensity modulated radiotherapy) or VMAT (volumetric modulated arc radiotherapy). Median overall survival (OS) was 6 months. We identified five predictive factors relevant for survival: absence of distant metastases at the time of diagnosis (OS 8 months), surgery (OS 9.8 months), resection status R0 (OS 14 months), radiation dose of 50 Gy or higher (OS 13 months) and multimodal therapy (surgery, radiotherapy and chemotherapy) with a median OS of 9.7 months., Conclusion: In spite of the dismal outcome, longer survival can be achieved in some patients with ATC using surgery and radiotherapy with a high radiation dose. Compared to our previous study, there are no significant advantages in overall survival. Trial registration Retrospectively registered., (© 2023. The Author(s).)

Purpose: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness., Experimental Design: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio., Results: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity., Conclusions: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy., (©2023 American Association for Cancer Research.)

Patients treated with radionuclide therapy usually require restrictions on certain activities for a period of time following treatment to optimise protection of the public and ensure the legal dose limit is not exceeded. Software may be used to calculate necessary restriction periods for an individual based on longitudinal dose rate measurements from the time of radiopharmaceutical administration. A spreadsheet program has been used for this purpose in Australian hospitals for the last two decades. However, this spreadsheet has a limitation in that it uses an approximation in the calculation of dose from a contact pattern, which affects the calculated restriction period. A computer program called Dorn was developed that provides the same functionality as the spreadsheet but without this approximation. Proffered radiation safety advice from Dorn and the spreadsheet were compared. Advice from the spreadsheet and Dorn were compared for 55 patients who underwent iodine-131 therapy for differentiated thyroid cancer. The restriction periods for caring for infants, close contact with children and sleeping with a partner were typically about 13 h longer in Dorn than in the spreadsheet, but in some cases were over a week shorter or a month longer. If the Dorn program is used clinically in place of the spreadsheet, some patients will enjoy shorter restriction periods and the therapy provider can be more confident in their compliance with regulatory requirements and best practice. Dorn is freely available fromhttps://doi.org/jg5f., (© 2023 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Purpose: Radioactive iodine ( 131 I) therapy is a conventional post-surgery treatment widely used for papillary thyroid carcinoma (PTC). Since 131 I is orally administered, we hypothesize that it may affect gut microbiome. This study aims to investigate alterations of intestinal microbiome caused by 131 I therapy in PTC patients and explore its association with response to 131 I therapy., Methods: Fecal samples of 60 PTC patients pre- and post- 131 I therapy were collected to characterize the 131 I therapy-induced gut microbiota alterations using 16S rRNA gene sequencing. According to the inclusion criteria, sequence data of 40 out of the 60 patients, divided into excellent response (ER) group and non-excellent response (NER) group, were recruited to investigate the possible connection between gut microbiota and response to 131 I therapy. Multivariate binary logistic regression was employed to construct a predictive model for response to 131 I therapy., Results: Microbial richness, diversity, and composition were tremendously altered by 131 I therapy. A significant decline of Firmicutes to Bacteroides (F/B) ratio was observed post- 131 I therapy. 131 I therapy also led to changes of gut microbiome-related metabolic pathways. Discrepancies in β diversity were found between ER and NER groups both pre- and post- 131 I therapy. Furthermore, a predictive model for response to 131 I therapy with a p value of 0.003 and an overall percentage correct of 80.0% was established, with three variables including lymph node metastasis, relative abundance of g&#95;Bifidobacterium and g&#95;Dorea. Among them, g&#95;Dorea was identified to be an in independent predictor of response to 131 I therapy (p = 0.04)., Conclusion: For the first time, the present study demonstrates the gut microbial dysbiosis caused by 131 I therapy in post-surgery PTC patients and reveals a previously undefined role of gut microbiome as predictor for 131 I ablation response. G&#95;Dorea and g&#95;Bifidobacterium may be potential targets for clinical intervention to improve response to 131 I in post-operative PTC patients., Trial Registration: ChiCTR2100048000. Registered 28 June 2021., (© 2022. The Author(s).)

Background: Radioiodine (RAI) is commonly used for thyroid cancer treatment, although its therapeutic benefits are restricted to iodine-avid tumors. The RAI-refractory disease develops with tumor dedifferentiation involving loss of sodium-iodine symporter (NIS). Thyroid cancers driven by ALK fusions are prone to dedifferentiation, and whether targeted ALK inhibition may enhance RAI uptake in these tumors remains unknown. The aim of this study was to determine the levels of NIS expression during the progression of ALK fusion-driven thyroid cancer, assess the effects of ALK activation on NIS-mediated RAI uptake, and test pharmacological options for its modulation. Methods: The expression of NIS at different stages of ALK-driven carcinogenesis was analyzed using a mouse model of STRN-ALK-driven thyroid cancer. For in vitro experiments, a system of doxycycline-inducible expression of STRN-ALK was generated using PCCL3 normal thyroid cells. The STRN-ALK-induced effects were evaluated with quantitative reverse transcription polymerase chain reaction, Western blot, immunofluorescence, RNA sequencing, and gene sets pathways analyses. RAI uptake was measured using 131 I. Treatment experiments were done with FDA-approved ALK inhibitors (crizotinib and ceritinib), MEK inhibitor selumetinib, and JAK1/2 inhibitor ruxolitinib. Results: We found that Nis downregulation occurred early in ALK-driven thyroid carcinogenesis, even at the stage of well-differentiated cancer, with a complete loss in poorly differentiated thyroid carcinomas. Acute STRN-ALK expression in thyroid cells resulted in increased MAPK, JAK/STAT3, and PI3K/AKT/mTOR signaling outputs associated with significant ALK-dependent downregulation of the majority of thyroid differentiation and iodine metabolism/transport genes, including Slc5a5 ( Nis ), Foxe1 , Dio1 , Duox1/2 , Duoxa2 , Glis3 , Slc5a8 , and Tg . Moreover, STRN-ALK expression in thyroid cells induced a significant loss of membranous NIS and a fourfold decrease of the NIS-mediated RAI uptake, which were reversed by ALK inhibitors crizotinib and ceritinib. In addition, a strong dose-dependent restoration of NIS with its membranous redistribution in STRN-ALK-expressing thyroid cells was observed after inhibition of MAPK signaling with selumetinib, which exhibited a cumulative effect with JAK1/2 inhibitor ruxolitinib. Conclusions: The findings of this preclinical study showed that ALK fusion-induced downregulation of NIS, the prerequisite of RAI refractoriness, could be reversed in thyroid cells by either direct inhibition of ALK or its downstream signaling pathways.

Radiation therapy is a critical strategy for the treatment of malignant tumors. X-ray external radiation has been successfully used to treat head and neck cancer. On the other hand, 131 I internal radiation has been effective in managing differentiated thyroid cancer. However, these therapies cause radiation damage to salivary glands. Radiation sialadenitis is the most common complication associated with radiotherapy applied to the head and neck and it severely affects patients' quality of life. Since DNA is the main intracellular target of radiation, and the integrity of the DNA structure is critical to genomic stability and the cellular survival of salivary glands, regulating radiation-induced DNA damage offers great promise in preventing and managing radiation sialadenitis. In this review, we summarize recent progress in DNA damage and repair in irradiated salivary glands., (© 2021 Wiley Periodicals LLC.)

Background/aim: Radioactive iodine (RAI) treatment is a cornerstone of treatment of differentiated thyroid carcinoma. Although serious RAI-related complications are uncommon, there have been reports of airway emergencies. Here, a life-threatening airway complication after RAI treatment is reported and previously reported cases are reviewed., Case Report: A 79-year old man with Hürthle cell carcinoma and a remnant thyroid lobe after surgery developed an edema compromising the airway two days after receiving radioactive iodine treatment. An emergency awake intubation and tracheostomy were performed. He could be successfully de-cannulated 17 days later with no long-term complications., Conclusion: Although rare, life-threatening airway complications after radioactive iodine treatment, especially with high dose treatment in patients with remaining thyroid tissue, can occur and these patients should be supervised where these complications can be managed., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Papillary thyroid carcinoma (PTC) with other organ invasions is directly related to patient prognosis and quality of life; however, studies on the clinical outcomes of adjuvant radioactive iodine (RAI) for PTC with other organ invasions are limited. This study aimed to clarify the clinical outcomes and prognostic factors for patients with PTC with other organ invasions after adjuvant RAI., Methods: Patients with PTC with other organ invasions without distant metastases who underwent surgery and adjuvant RAI were retrospectively reviewed. We evaluated the initial responses based on the American Thyroid Association guidelines and survival rates. Prognostic factors for locoregional recurrence-free survival (LRRFS) were analyzed., Results: Between January 2005 and December 2019, 102 patients were included in the study. Their median age was 55 years. The median follow-up duration was 92 months (range; 30-231 months). The excellent response rate after RAI was 42%. The 7-year overall survival, LRRFS, and recurrence-free survival rates were 100%, 75%, and 75%, respectively. Metastatic lymph node size, resection margin status, and post-RAI suppressed thyroglobulin level were the independent prognostic factors for LRRFS., Conclusion: We demonstrated that 75% of patients with PTC with other organ invasions could achieve long-term survival without recurrence after adjuvant RAI. Future development of effective treatment strategies for large metastatic lymph nodes, gross residual tumors, and high serum thyroglobulin levels is warranted., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)