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BACKGROUND: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAF(V600E) mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. METHODS: Patients with BRAF(V600E) RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 ((124)I) positron emission tomography–computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate (124)I uptake on the second PET/CT then received therapeutic radioactive iodine ((131)I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic (131)I. RESULTS: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic (131)I. At 6 months, 2 patients achieved partial response after (131)I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. CONCLUSIONS: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Background: Patients with Graves' disease are commonly treated with radioiodine. There remains controversy over whether the aim of treatment should be to achieve euthyroidism or hypothyroidism, and whether treatments should be administered with standard levels of radioactivity or personalized according to the radiation absorbed doses delivered to the thyroid. The aim of this review was to investigate whether a relationship exists between radiation absorbed dose and treatment outcome. Methods: A systematic review and meta-analysis of all reports published before February 13, 2020, were performed using PubMed, Web of Science, OVID MEDLINE, and Embase. Proportion of patients achieving nonhyperthyroid status was the primary outcome. Secondary outcomes were proportion of patients who were specifically euthyroid or hypothyroid. A random-effects meta-analysis of proportions was performed for primary and secondary outcomes, and the impact of the radiation absorbed dose on treatment outcome was assessed through meta-regression. The study is registered with PROSPERO (CRD42020175010). Results: A total of 1122 studies were identified of which 15, comprising 2303 Graves' disease patients, were eligible for the meta-analysis. A strong association was found between radiation absorbed dose and nonhyperthyroid and hypothyroid outcomes (odds ratio [OR] = 1.11 [95% confidence interval {CI} 1.08–1.14] and OR = 1.09 [CI 1.06–1.12] per 10 Gy increase). Higher rates of euthyroid outcome were found for radiation absorbed doses within the range 120–180 Gy when compared with outside this range (n = 1172, OR = 2.50 [CI 1.17–5.35], p = 0.018). A maximum euthyroid response of 38% was identified at a radiation absorbed dose of 128 Gy. Conclusions: The presented radiation absorbed dose–response relationships can facilitate personalized treatment planning for radioiodine treatment of patients with Graves' disease. Further studies are required to determine how patient-specific covariates can inform personalized treatments.

Background: Refining the risk of malignancy in patients presenting with thyroid nodules with indeterminate cytology (IC) is a critical challenge. We investigated the performances of 18F-fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) to predict malignancy. Methods: Between May 2016 and March 2019, 107 patients presenting with a thyroid nodule ≥15 mm with IC and eligible for surgery were included in this prospective study. Head-and-neck PET/CT acquisitions were performed 20 and 60 minutes after injection of 1.5 MBq/kg of FCH. PET/CT acquisition was scored positive when maximal standardized uptake value in the IC nodule was higher than in the thyroid background. Pathology was the gold standard for diagnosis. Results: At pathology, 19 (18%) nodules were malignant, 87 were benign, and one was a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Sensitivity, specificity, accuracy, positive-predictive value (PPV), and negative-predictive value (NPV) of FCH PET/CT in detecting cancer or NIFTP were 90%, 50%, 55%, 29%, and 96% at 20 minutes and 85%, 49%, 67%, 28%, and 94% at 60 minutes, respectively. Higher specificity (58% vs. 33%, p = 0.01) was observed in nononcocytic (n = 72) than in oncocytic IC nodules (n = 35). The pre-PET/CT probability of cancer or NIFTP in Bethesda III–IV nodules was 11% and the post-PET/CT probability was 19% in PET-positives and 0% in PET-negatives. In retrospective analysis, 42% of surgeries would have been unnecessary after PET/CT and 81% before (p

Background: Whether radioactive iodine ((131)I) treatments for differentiated thyroid cancer should be performed as an outpatient or inpatient remains controversial. The objective of this study was to survey selected aspects of radiation safety of patients treated with (131)I for differentiated thyroid cancer as an outpatient. Methods: An e-mail invitation was sent to over 15,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. to complete a web-based survey on selected aspects of radiation safety regarding their last outpatient (131)I treatment. Results: A total of 1549 patients completed the survey. Forty-five percent (699/1541) of the respondents reported no discussion on the choice of an inpatient or outpatient treatment. Moreover, 5% (79/1541) of the respondents reported that their insurance company made the decision. Survey respondents recalled receiving oral and written radiation safety instructions 97% (1459/1504) and 93% (1351/1447) of the time, respectively. Nuclear medicine physicians delivered oral and written instructions to 54% (807/1504) and 41% (602/1462) of the respondents, respectively. Eighty-eight percent (1208/1370) of the respondents were discharged within 1 hour after receiving their (131)I treatment, and 97% (1334/1373) traveled in their own car after being released from the treating facility. Immediately post-therapy, 94% (1398/1488) of the respondents stayed at their own home or a relative's home, while 5% (76/1488) resided in a public lodging. The specific recommendations received by patients about radiation precautions varied widely among the respondents. Ninety-nine percent (1451/1467) of the respondents believed they were compliant with the instructions. Conclusion: This is the largest, patient-based survey published regarding selected radiation safety aspects of outpatient (131)I treatment. This survey suggests several concerns about radiation safety, such as the decision process regarding inpatient versus outpatient treatment, instructions about radiation safety, transportation, and lodging after radioiodine therapy. These concerns warrant further discussion, guidelines, and/or policies.

Background: (131)I treatment (tx) of differentiated thyroid cancer (DTC) is associated with hematopoietic toxicity. It was hypothesized that metformin could have radioprotective effects on bone-marrow function. The objective was to determine whether metformin prevents (131)I-induced changes in complete blood counts (CBC) in patients with DTC. Methods: A retrospective analysis was performed of CBC values in DTC patients who were (40 patients: metformin group) or were not taking metformin (39 patients: control group) at the time of administration of (131)I. Repeated measures analysis of variance was used for the analysis of the differences in the averages of CBC that were documented at baseline and at 1, 6, and 12 months post (131)I tx. Results: The groups were comparable in terms of age, sex, stage of DTC, (131)I dose administered, and baseline CBC values. In the control group, the decrease in white blood cells (WBC) was 35.8% (p

Background and aim: Atherosclerosis evolves or accelerates when arteries are exposed to ionizing radiation, both early and late after exposure. Radioiodine therapy of benign thyroid disease exposes the carotid arteries to 4–50 Gy, and may thereby increase the risk of atherosclerosis. Increased risk of cerebrovascular events has been reported after radioiodine therapy. This study aimed to examine whether atherosclerosis develops early or late after radioiodine therapy of benign thyroid disease. Method: Patients treated for benign thyroid disorders (nontoxic goiter, adenoma, and hyperthyroidism) were examined with ultrasound for the main outcome, carotid intima media thickness (CIMT), and for plaque presence (plaque presence only in late damage). Signs of early damage from radioiodine were studied in 39 radioiodine-treated patients, who were examined before treatment and at 1, 3, 6, and 12 months after treatment. Late changes were studied in a cross-sectional case-control design, with radioiodine-treated patients as cases (n = 193) and patients treated with surgery as controls (n = 95). Data were analyzed with repeated measurement for longitudinal data, and with multivariate regression for cross-sectional data. Results were adjusted for age, sex, cholesterol, smoking status, known atherosclerotic disease, and body mass index. Results: No changes in CIMT were found in the patients followed prospectively for one year after treatment with radioactive iodine for benign thyroid disease (p = 0.58). In the study on late effects, there was no difference in CIMT (p = 0.25) or presence of plaques (p = 0.70) between those treated with radioactive iodine and those treated with surgery (9.8 and 5.6 years since treatment, respectively). Furthermore, the level of thyrotropin (TSH) did not influence these atherosclerosis markers. Conclusion: No early changes in CIMT were detected in patients treated with radioactive iodine for benign thyroid disease. No signs of late effects of radioactive iodine on CIMT or plaque presence were found after 10 years of follow-up. The radiation to the carotid arteries by radioactive iodine therapy for benign thyroid disease may therefore have no or low effect on atherosclerotic burden of the carotid arteries in general.

Initial management recommendations of papillary thyroid carcinoma (PTC) are very dependent on preoperative studies designed to evaluate the presence of PTC with aggressive features. The purpose of this study was to evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) before surgery can be used as a tool to stratify tumor aggressiveness in patients with PTC.In this prospective study, 28 patients with PTC underwent DW-MRI studies on a three Tesla MR scanner prior to thyroidectomy. Due to image quality, 21 patients were finally suitable for further analysis. Apparent diffusion coefficients (ADCs) of normal thyroid tissues and PTCs for 21 patients were calculated. Tumor aggressiveness was defined by surgical histopathology. The Mann-Whitney U test was used to compare the difference in ADCs among groups of normal thyroid tissues and PTCs with and without features of tumor aggressiveness. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative specificity, sensitivity, and accuracy of and determine the cutoff value for the ADC in stratifying PTCs with tumor aggressiveness.There was no significant difference in ADC values between normal thyroid tissues and PTCs. However, ADC values of PTCs with extrathyroidal extension (ETE; 1.53±0.25×10(-3) mm2/s) were significantly lower than corresponding values from PTCs without ETE (2.37±0.67×10(-3) mm2/s; p0.005). ADC values identified 3 papillary carcinoma patients with extrathyroidal extension that would have otherwise been candidates for observation based on ultrasound evaluations. The cutoff value of ADC to discriminate PTCs with and without ETE was determined at 1.85×10(-3) mm2/s with a sensitivity of 85%, specificity of 85%, and ROC curve area of 0.85.ADC value derived from DW-MRI before surgery has the potential to stratify ETE in patients with PTCs.

The ability of thyroid follicular cells to take up iodine enables the use of radioactive iodine (RAI) for imaging and targeted killing of RAI-avid thyroid cancer following thyroidectomy. To facilitate identifying novel strategies to improveA customized mouse cradle was designed and used for microSPECT/CT image acquisition at 1 hour (t1) and 24 hours (t24) post injection ofThe customized mouse cradle facilitates consistent tissue configuration among image acquisitions such that rigid body registration can be applied to align serial images of the same mouse via the in-house CTViewer software. CTViewer is designed specifically to streamline SPECT/CT image analysis with functions tailored to quantify thyroid radioiodine uptake. Automatic segmentation of thyroid volumes of interest (VOI) from adjacent salivary glands in t1 images is enabled by superimposing the thyroid VOI from the t24 image onto the corresponding aligned t1 image. The extent of heterogeneity inMicroSPECT/CT image acquisition and analysis for thyroidal RAI uptake is greatly improved by the cradle and the CTViewer software, respectively. Furthermore, the approach of superimposing thyroid VOIs from t24 images to select thyroid VOIs on corresponding aligned t1 images can be applied to studies in which the target tissue has differential radiotracer retention from surrounding tissues.

Gallium-68 (Ga-68) DOTATATE is a radiolabeled peptide-imaging modality that targets the somatostatin receptor (SSTR), especially subtype 2 (SSTR2). Benign and malignant thyroid tumors have been observed to express SSTR. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical thyroid uptake as detected by Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT).A retrospective analysis was conducted of a prospective study in which 237 patients underwent Ga-68 DOTATATE PET/CT as part of a work-up for metastatic and unknown primary neuroendocrine tumors. The types of uptake in the thyroid gland (focal/diffuse) and maximum standardized uptake value (SUVmax) levels were evaluated and compared with the background uptake in the liver and salivary glands.Of 237 patients, 26 (11%) had atypical thyroid uptake as detected by Ga-68 DOTATATE PET/CT. There were no significant clinical or biochemical variables associated with atypical thyroid uptake. Fourteen (54%) patients had positive focal uptake, and 12 (46%) patients had diffuse uptake. Of the 14 patients with atypical focal uptake, 10 (71%) had thyroid nodules on the corresponding side, as detected by anatomic imaging. Three of 10 patients (21%) were found to have papillary thyroid cancer, and seven (70%) had adenomatoid nodules. Of the 12 patients with diffuse increased uptake, six (50%) had a history of hypothyroidism, five (42%) had chronic lymphocytic thyroiditis, and one (8%) had nontoxic multinodular goiter.Patients with an incidental focal abnormal thyroid uptake on Ga-68 DOTATATE PET/CT scan should have further clinical evaluation to exclude a diagnosis of thyroid cancer.

Micro-single-photon emission computed tomography (SPECT) provides a noninvasive way to evaluate the effects of genetic and/or pharmacological modulation on sodium-iodide symporter (NIS)-mediated radionuclide accumulation in mouse thyroid and salivary glands. However, parameters affecting image acquisition and analysis of mouse thyroids and salivary glands have not been thoroughly investigated. In this study, we investigated the effects of region-of-interest (ROI) selection, collimation, scan time, and imaging orbit on image acquisition and quantification of thyroidal and salivary radionuclide accumulation in mice.The effects of data window minima and maxima on thyroidal and salivary ROI selection using a visual boundary method were examined in SPECT images acquired from mice injected with (123)I NaI. The effects of collimation, scan time, and imaging orbit on counting linearity and signal intensity were investigated using phantoms filled with various activities of (123)I NaI or Tc-99m pertechnetate. Spatial resolution of target organs in whole-animal images was compared between circular orbit with parallel-hole collimation and spiral orbit with five-pinhole collimation. Lastly, the inter-experimental variability of the same mouse scanned multiple times was compared with the intra-experimental variability among different mice scanned at the same time.Thyroid ROI was separated from salivary glands by empirically increasing the data window maxima. Counting linearity within the range of 0.5-14.2 μCi was validated by phantom imaging using single- or multiple-pinhole collimators with circular or spiral imaging orbit. Scanning time could be shortened to 15 minutes per mouse without compromising counting linearity despite proportionally decreased signal intensity. Whole-animal imaging using a spiral orbit with five-pinhole collimators achieved a high spatial resolution and counting linearity. Finally, the extent of inter-experimental variability of NIS-mediated radionuclide accumulation in the thyroid and salivary glands by SPECT imaging in the same mouse was less than the magnitude of variability among the littermates.The impacts of multiple variables and experimental designs on micro-SPECT imaging and quantification of radionuclide accumulation in mouse thyroid and salivary glands can be minimized. This platform will serve as an invaluable tool to screen for pharmacologic reagents that differentially modulate thyroidal and salivary radioiodine accumulation in preclinical mouse models.

Background: Dietary iodine is often restricted before radioactive iodine (RAI) scanning or treatment of welldifferentiated thyroid cancer. Our objective was to examine the impact of a low-iodine diet (LID) before RAI treatment or scanning on the following outcomes: (i) the efficacy of thyroid remnant ablation (or residual disease elimination), (ii) urinary iodine measurements, (iii) RAI kinetics, and (iv) long-term thyroid cancer outcomes. Methods: We performed a systematic review of the English literature. We searched four electronic databases and conducted a hand search. Two reviewers independently screened citations and reviewed full-text articles and reached consensus on included articles. Two reviewers independently abstracted data. Results: We reviewed 76 abstracts or citations and 26 full-text articles. Eight studies were included in the review. The most commonly studied diets allowed � 50mg/day of iodine for 1‐2 weeks. In one study, 6-month successful remnant ablation rates were higher in patients following an LID than in controls. However, in another study, there was no significant benefit of an LID. LIDs reduce urinary iodine measurements and appear to increase I-131 uptake or lesional radiation compared to regular diets. No studies have examined long-term recurrence or mortality rates. Conclusions: Given that LIDs reduce urinary iodine measurements, increase I-131 uptake, and possibly improve efficacy of I-131 treatment, we currently favor the use of a 1‐2-week LID before I-131 therapy or scanning. However, more research is needed to clarify the role of this dietary intervention.

We examined outcomes in patients treated for radioactive iodine-induced sialadenitis (RAIS) and xerostomia with sialendoscopy.Data was prospectively collected for all patients undergoing sialendoscopy for RAIS from a single institution. Interventional details and intraoperative findings were recorded. Qualitative data were obtained through patient examination, telephone interviews, and use of a standard quality of life questionnaire, Xerostomia Questionnaire. Quantitative data were obtained from patients who underwent sialometry.Twenty-six patients (24 women and 2 men; median age, 43 years; age range, 19-57 years) underwent interventional sialendoscopy after conservative management of symptoms proved unsuccessful. Sialadenitis was present in 25 patients and xerostomia in 22 patients. Mucus plugging in the duct of the gland was the most common finding (22 patients) followed by stenosis (18 patients), inflammation (eight patients), and erythema (eight patients). Median follow-up time was 23.4±12.1 months. Sixteen patients (64%) reported complete resolution; seven (28%), partial resolution; one (4%), no change in symptoms; and one (4%), regression in RAIS-related symptoms. Patients subjectively noted the following regarding their xerostomia symptoms: seven (31.8%) had complete resolution; 10 (45.5%), partial resolution; four (18.2%), no change; and one (4.5%), regression. Statistical analysis of the available sialometry data revealed a statistically significant difference in saliva production at 6 months following sialendoscopy for unstimulated saliva production (p=0.028).Sialendoscopy is an effective treatment option for the management of RAIS and xerostomia refractory to conservative therapy and medical management. Patients in our cohort report durable improvement in symptoms after intervention.

The long-term sequelae of radioactive iodine (RAI) for differentiated thyroid cancer (DTC) in pediatric and young adult patients are not well-defined. Epidemiologic analyses of second primary malignancy (SPM) risk have only been performed in the adult population. Existing data are limited to case series with limited follow-up. The objective of this study was to analyze the elevated risk of SPM attributable to RAI in young patients treated for DTC.Population-based analysis of 3850 pediatric and young adult patients (25 years old) undergoing treatment with surgery with/without RAI for DTC, followed in the Surveillance, Epidemiology, and End Results cancer registry (1973-2008), equating to 54,727 person-years at risk (PYR). The excess risk of SPM was calculated relative to a reference population and expressed as standardized incidence ratio (SIR) and excess absolute risk (EAR) per 10,000 PYR. Excess risk was compared in RAI-treated and non-RAI-treated patients.A total of 1571 patients (40%) received RAI. The percentage of patients treated with RAI increased over time, from 4% in 1973 to 62% in 2008 (p0.001). Among patients who received RAI, 26 SPMs were observed, and 18.3 were expected. The relative risk of SPM at any site was significantly elevated (SIR=1.42), corresponding to 4.4 excess cases per 10,000 PYR. SPM risk was not elevated in the non-RAI-treated cohort (SIR=1.01, EAR=0). Patients treated with RAI were at dramatically elevated risk for development of a salivary malignancy (SIR=34.1), corresponding to 1.7 excess cases per 10,000 PYR. The risk of leukemia in RAI-treated patients was elevated (SIR=4.0, EAR=0.9) but did not reach statistical significance. There was no elevated risk of salivary cancer or leukemia in the non-RAI-treated cohort.Pediatric and young adult patients who receive RAI for DTC experience an elevated risk of SPM, mainly salivary gland cancer. These risks appear to be only slightly higher than in adult patients. Over a decade, approximately 1 in 227 RAI-treated patients will develop an SPM, and 1 in 588 RAI-treated patients will develop a salivary cancer, attributable to RAI. Because the expected survival time for young DTC patients is long, it is critical to weigh the benefits of RAI carefully against the small, but real, increase in SPM risk.

Background: Thyroid nodules are a common finding in the general population, and their detection is increasing with the widespread use of ultrasound (US). Thyroid cancer is found in 5–15% of cases depending on sex, age, and exposure to other risk factors. Some US parameters have been associated with increased risk of malignancy. However, no characteristic seems sufficiently reliable in isolation to diagnose malignancy. The objective of this meta-analysis was to evaluate the diagnostic performance of US features for thyroid malignancy in patients with unselected thyroid nodules and nodules with indeterminate fine-needle aspiration (FNA) cytology. Methods: Electronic databases were reviewed for studies published prior to July 2012 that evaluated US features of thyroid nodules and reported postoperative histopathologic diagnosis. A manual search of references of review and key articles, and previous meta-analyses was also performed. A separate meta-analysis was performed including only nodules with indeterminate cytology. Analyzed features were solid structure, hypoechogenicity, irregular margins, absence of halo, microcalcifications, central vascularization, solitary nodule, heterogeneity, taller than wide shape, and absence of elasticity. Results: Fifty-two observational studies (12,786 nodules) were included. Nine studies included nodules with indeterminate cytology as a separate category, comprising 1851 nodules. In unselected nodules, all US features were significantly associated with malignancy with an odds ratio varying from 1.78 to 35.7, and microcalcifications, irregular margins, and a taller than wide shape had high specificities (Sp; 87.8%, 83.1%, 96.6%) and positive likelihood ratios (LHR; 3.26, 2.99, 8.07). Absence of elasticity was the single feature with the best diagnostic performance (sensitivity 87.9%, Sp 86.2%, and positive LHR 6.39). The presence of central vascularization was the most specific US feature in nodules with indeterminate cytology (Sp 96% and positive LHR 2.13). Conclusions: US features in isolation do not provide reliable information to select nodules that should have a FNA performed. A combination of US characteristics with higher likelihood ratios and consequently with higher post-test probabilities of malignancy—microcalcifications, or a taller than wide shape, or irregular margins, or absence of elasticity—will probably identify nodules with an increased risk for malignancy. Further studies are required to standardize elastography techniques and evaluate outcomes, especially in nodules with an indeterminate cytology.

Rebound thymic hyperplasia (RTHP) is not an uncommon finding after radiation or chemotherapy in patients with various malignancies. However, there are limited case reports of this phenomenon after radioactive iodine ablation therapy (RIAT) in differentiated thyroid cancer (DTC). The goal of this study was to evaluate the incidence, patterns, and factors affecting RTHP after RIAT using (18)F-FDG PET/CT.The study design was a retrospective review of 2550 patients (568 men, 1982 women; age 13-79 years) who underwent FDG PET/CT imaging after total thyroidectomy and RIAT from June 2009 through June 2012. Patients were divided into four age-related subgroups. Overall incidence, age-related incidences, and sex distribution were evaluated in patients with thymic FDG uptake on PET/CT (RTHP+). The correlation between incidence of RTHP and age was assessed using the Cochran-Armitage trend test. The Wilcoxon rank-sum test and multiple regression were applied to investigate the effect of applied dose of radioactive iodine (RAI) and age on the incidence of RTHP. Correlations of standardized uptake value (SUV) and thymic volume with age and morphologic type were also evaluated.Overall incidence of RTHP after RIAT was 1.49%, and all of the RTHP+ patients except one were female. The Cochran-Armitage trend test revealed significantly decreased incidence from the second to fifth decade (8.84%, 1.74%, 0.98%, and 0.39% respectively; p0.001). In each age-related subgroup, the RAI dose was significantly higher in the RTHP+ than RTHP- group (p0.001), while there was no difference in RAI dose in RTHP+ patients among age-related subgroups (p=0.838). SUVmean and SUVmax of RTHP revealed no meaningful correlation with RAI dose or age. There were no differences among morphologic patterns of RTHP in age distribution and ablation dose.RTHP after RIAT showed a strong female predominance, despite the higher administration dose of RAI in male patients. Although the decreased incidence of RTHP after RIAT with age is similar to the pattern of RTHP induced by other causes, the fact that older patients, even sixth decade patients, can present with RTHP after RIAT is noteworthy in the management of DTC.

Salivary and lacrimal side effects of radioiodine therapy have been carefully described. However, nasal side effects are rarely described. The objective of this study was to document the frequency of nasal side effects in comparison to the already well-documented lacrimal side effects and to determine contributing risk factors.A retrospective review of the medical records of 807 patients with differentiated thyroid cancer who received care at an academic medical center was conducted. Four hundred eleven patients who received treatment with radioactive iodine (RAI) were identified and included in the analysis. The frequency of both nasal and lacrimal side effects was ascertained. Factors that may have contributed to patients sustaining nasal damage after RAI therapy were also documented. These factors included radioactive iodine dose, method of preparation for receiving RAI therapy, and patient characteristics.The mean dose of RAI administered was 109 mCi. Forty-three patients (10.5%) and 40 patients (9.7%) developed nasal and lacrimal side effects, respectively, following RAI treatment. The mean time of onset of nasal symptoms was 11 days, compared with 10 months for lacrimal symptoms. Radioiodine dose and body mass index were significantly positively and negatively correlated, respectively, with sustaining nasal side effects (p values of 0.04 and 0.01, respectively). Similarly, both RAI dose and body mass index were significantly correlated, positively and negatively, respectively, with sustaining lacrimal side effects (p values of 0.02 and 0.01). Preparation for treatment using a withdrawal protocol was associated with increased risk of both nasal and lacrimal side effects, compared with a recombinant human thyrotropin (rhTSH) protocol (p values of0.01 and 0.01). The odds ratios (95% confidence interval [CI]) for nasal and lacrimal side effects with recombinant rhTSH preparation were 0.22 [0.11-0.44] and 0.37 [0.18-0.76], respectively. Instructions to maintain adequate hydration and development of lacrimal symptoms were only associated with nasal symptoms in unadjusted analyses.Both nasal and lacrimal dysfunction occurred at an approximately 10% frequency. Although it cannot be determined whether acute nasal side effects are followed by long-term ramifications, these consequences of RAI could potentially add to the reasons to carefully evaluate the benefits and risks of RAI therapy on an individual basis.

The management of patients with differentiated thyroid cancer (DTC) who have elevated serum thyroglobulin (Tg) levels and negative (131)I or (123)I scans is problematic, and the decision regarding whether or not to administer (131)I therapy (a "blind" therapy) is also problematic. While (124)I positron emission tomography (PET) imaging has been shown to detect more foci of residual thyroid tissue and/or metastases secondary to DTC than planar (131)I images, the utility of a negative (124)I PET scan in deciding whether or not to consider performing blind (131)I therapy is unknown. The objective of this study was to determine whether a negative (124)I pretherapy PET scan in patients with elevated serum Tg levels and negative (131)I or (123)I scans predicts a negative (131)I posttherapy scan.Several prospective studies have been performed to compare the radiopharmacokinetics of (124)I PET versus (131)I planar imaging in patients who 1) had histologically proven DTC, 2) were suspected to have metastatic DTC (e.g., elevated Tg, positive recent fine-needle aspiration cytology, suspicious enlarging mass), and 3) had (131)I planar and (124)I PET imaging performed. Using these criteria, we retrospectively identified patients who had an elevated Tg, a negative diagnostic (131)I/(123)I scan, a negative diagnostic (124)I PET scan, therapy with (131)I, a post-therapy (131)I scan, and a prior (131)I therapy with a subsequent positive post-(131)I therapy scan. For each scan, two readers categorized every focus of (131)I and (124)I uptake as positive for thyroid tissue/metastases or physiological.Twelve patients met the above criteria. Ten of these 12 patients (83%) had positive foci on (131)I posttherapy scan.In our selected patient population, (131)I posttherapy scans are frequently positive in patients with elevated serum Tg levels, a negative diagnostic (131)I or (123)I scan, and a negative (124)I PET scan. Thus, for a patient with elevated serum Tg level, negative diagnostic (131)I planar scan, and a prior post-(131)I therapy scan that was positive, a negative (124)I PET scan will have a low predictive value for a negative post-(131)I therapy scan and should not be used to exclude the option of blind (131)I therapy.

Background: Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. Methods: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAFV600E, or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. Results: We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAFV600E and in primary cultured thyroid tumor cells from TRβPV/PV mice. Conclusion: Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.

Background: Differentiated thyroid carcinomas originating from thyroid follicular cells are frequent tumors of the thyroid with relatively good prognosis due to improved surgical techniques and follow-up procedures. Poorly differentiated thyroid cancers, which lose iodine uptake ability, in most cases still express thyrotropin (TSH) receptors (TSHR). Therefore, the aim of this study was to radiolabel a superagonist recombinant human TSH (rhTSH) analogue for imaging poorly differentiated thyroid cancer.Methods: The TSHR superagonist, TR1401, was labeled with Tc-99m using an indirect method via succinimidyl-6-hydrazinonicotinate hydrochloride conjugation. In vitro quality controls included SDS-PAGE, cysteine challenge, and cell-binding assay on TSHR positive cell lines (JP09 and ML-1). In vivo studies included tumor targeting experiments in athymic nude CD-1 mice xenografted with several different TSHR positive cells (JP09, K1, and ML-1) and TSHR negative cells (JP02) as control.Results: The superagonist rhTSH analogue TR1401 was labeled with high labeling efficiency (>95%) and high specific activity (9250 MBq/mg). The labeled molecule retained its biologic activity and structural integrity. In tumor targeting experiments, a focal uptake of radiolabeled TR1401 was observed in TSHR positive cells but not in TSHR negative cells. The same observation was made in a dog with spontaneous intraglandular thyroid cancer.Conclusions: We were able to radiolabel the rhTSH superagonist analogue TR1401 with Tc-99m efficiently with retention of in vitro and in vivo binding capacity to TSHR. The relative role of such novel radiopharmaceutical versus I-131 scanning of thyroid cancer will require future histopathologic and clinical studies, but it may open new perspectives for presurgical staging of thyroid cancer, and diagnosis of radioiodine negative local relapses and/or distant metastases.

Background: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ( 131I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with 131I therapy. Methods: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2±9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0mL; range 31.9-242.2mL) were randomized to receive placebo (n=32), 0.01mg MRrhTSH (n=30), or 0.03mg MRrhTSH (n=33) 24 hours before a calculated 131I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. Results: At six months, TV reduction was enhanced in the 0.03mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44±12.7% (SD) in the placebo group, 41±21.0% in the 0.01mg MRrhTSH group, and 53±18.6% in the 0.03mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03mg MRrhTSH group, the subset of patients with basal 131I uptake 131I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤0.03mg, indicating that the lower threshold for efficacy is around this level.

Ablation of the thyroid tissue using radioactive iodine (RAI) after the surgical removal of well-differentiated thyroid cancer can induce radiation-related salivary gland (SG) dysfunction. However, in vivo changes of SGs after RAI administration in appropriate animal models are not well described in the literature. This study was undertaken to document morphometric and functional changes during the 12 months after RAI administration in a murine model of RAI-induced SG dysfunction.Four-week-old female C57BL/6 mice (n = 60) were divided into an RAI-treated group (n = 30) that received RAI orally (0.01 mCi/g body weight) and an unexposed control group (n = 30). Mice in both groups were divided into five subgroups (n = 6 per subgroup) and euthanized at 1, 2, 3, 6, and 12 months post-RAI administration. Salivary flow rates and salivary lag times were measured at 1, 2, 3, 6, and 12 months after RAI administration. Morphological and histological examinations and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed. In addition, changes in salivary (99m)Tc pertechnetate uptake and excretion were observed by single-photon emission computed tomography.In RAI-treated mice, the SGs were significantly lighter than those of unexposed controls at all study time points. Lag times to salivation in the RAI-treated group were greater than in the unexposed controls, but mean salivary flow rates were lower. Histologic examinations of SGs in the RAI group showed pale cytoplasm, atypical ductal configuration, septal widening, cytoplasmic vacuolization with pleomorphism, lymphocyte infiltration, and increased fibrosis. Furthermore, more apoptotic cells were observed in acini and ducts in the RAI group. In addition, patterns of (99m)Tc pertechnetate uptake and excretion in the RAI group were quite different from those observed in controls at 1 and 12 months post-RAI.Various histological alterations were observed in mice exposed to RAI, that is, an increase in apoptotic acini and ductal cells and functional SG deterioration. The murine model of RAI-induced SG dysfunction used in the present study appears to be applicable to preclinical research on RAI-induced sialadenitis in patients with well-differentiated thyroid cancer.

A low-iodine diet (LID) is usually recommended for a week or two before radioactive iodine (RAI) ablation therapy in papillary thyroid cancer (PTC) patients after total thyroidectomy. However, it is still controversial whether an LID affects ablation outcomes. We therefore evaluated the association between urinary iodine excretion and the rate of successful ablation and investigated the determinants of successful RAI ablation outcomes.We retrospectively reviewed the records of 295 consecutive patients with PTC who received 1110 MBq RAI remnant ablation therapy with thyroid hormone withdrawal after total thyroidectomy. Successful ablation was defined as either no visible or faint uptake on a follow-up scan (definition 1), or no visible or faint uptake on a follow-up scan and a stimulated thyroglobulin level2 ng/mL (definition 2).The proportion of patients with appropriate LID status (defined as a urinary iodine concentration [UIC]66.2 μg iodine/g creatinine [μg/gCr]) was significantly higher in the successfully ablated group (81% vs. 67%, p=0.03). Based on definition 1, 80.3% (237/295) of patients were successfully ablated. The ablation rate was significantly lower in patients who had a UIC250 μg/gCr at the time of RAI ablation (p0.05). In multivariate analysis, a UIC250 μg/gCr was the only significant variable associated with ablation failure (p=0.002, odds ratio [OR] 4.74 [95% confidence interval (CI) 1.78-12.63]). Based on definition 2, 74.9% (221/295) of patients were successfully ablated. A UIC250 μg/gCr at RAI administration showed a significant association with ablation failure (p0.05). The OR of a UIC250 μg/gCr for ablation failure was 3.88 [CI 1.42-10.57] (p=0.008).Excessive iodine intake (UIC250 μg/gCr) was associated with poor RAI ablation outcomes. Because this amount of iodine is very high, we propose that the level of strictness of the LID protocol should be modified according to the region that the patient is from and the food that the patient is accustomed to eating. Even in those areas where iodine intake is high, overly strict compliance with an LID protocol is not necessary and simple recommendations to avoid iodine-rich foods would be appropriate.

There is variation in the use of radioactive iodine (RAI) as treatment for well-differentiated thyroid cancer. The factors involved in physician decision-making for RAI remain unknown.We surveyed physicians involved in postsurgical management of patients with thyroid cancer from 251 hospitals. Respondents were asked to rate the factors important in influencing whether a thyroid cancer patient receives RAI. Multivariable analyses controlling for physician age, gender, specialty, case volume, and whether they personally administer RAI, were performed to determine correlates of importance placed on patients' and physicians' worry about death from cancer and differences between low- versus higher-case-volume physicians.The survey response rate was 63% (534/853). Extent of disease, adequacy of surgical resection, patients' willingness to receive RAI, and patients' age were the factors physicians were most likely to report as quite or very important in influencing recommendations for RAI to patients with thyroid cancer. Interestingly, both physicians' and patients' worry about death from thyroid cancer were also important in determining RAI use. Physicians with less thyroid cancer cases per year were more likely than higher-volume physicians to report patients' (p0.001) and physicians' worry about death (p=0.016) as quite or very important in decision-making. Other factors more likely to be of greater importance in determining RAI use for physicians with lower thyroid cancer patient volume versus higher include the accepted standard at the affiliated hospital (p=0.020), beliefs about RAI expressed by colleagues comanaging patients (p=0.003), and patient distance from the nearest facility administering RAI (p=0.012).In addition to the extent of disease and adequacy of surgical resection, physicians place importance on physician and patient worry about death from thyroid cancer when deciding whether to treat a patient with RAI. The factors important to physician decision-making differ based on physician thyroid-cancer case-volume, with worry about death being more influential for low-case-volume physicians. As the mortality from thyroid cancer is low, the importance placed on death in decision making may be unwarranted.

Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation.SGS was performed just before RAI ablation (pre-SGS) and ∼5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs. Xerostomia was assessed and compared with the SGS findings.Worsening of the U score was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients had a worsening U score for at least one of four salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least one of the four salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, p0.05). The number of dysfunctional salivary glands was correlated with xerostomia (p0.01).About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI. While parotid glands are more susceptible to (131)I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.

There is a concern regarding the use of iodinated contrast agents (ICA) for chest and neck computed tomography (CT) to localize metastatases in patients with differentiated thyroid cancer (DTC). This is because the iodine in ICA can compete with (131)I and interfere with subsequent whole scans or radioactive iodine treatment. The required period for patients to eliminate the excess iodine is not clear. Therefore, knowing the period for iodine levels to return to baseline after the injection of ICA would permit a more reliable indication of CT for DTC patients. The most widely used marker to assess the plasmatic iodine pool is the urinary iodine (UI) concentration, which can be collected over a period of 24 hours (24U) or as a single-spot urinary sample (sU). As 24U collections are more difficult to perform, sU samples are preferable. It has not been established, however, if the measurement of iodine in sU is accurate for situations of excess iodine.We evaluated 25 patients with DTC who received ICA to perform chest or neck CT. They collected 24U and sU urinary samples before the CT scan and 1 week and 1, 2, and 3 months after the test. UI was quantified by a semiautomated colorimetric method.Baseline median UI levels were 21.8 μg/dL for 24U and 26 μg/dL for sU. One week after ICA, UI median levels were very high for all patients, 800 μg/dL. One month after ICA, however, UI median levels returned to baseline in all patients, 19.0 μg/dL for 24U and 20 μg/dL for sU. Although the values of median UI obtained from sU and 24U samples were signicantly different, we observed a significant correlation between samples collected in 24U and sU in all evaluated periods.One month is required for UI to return to its baseline value after the use of ICA and for patients (after total thyroidectomy and radioiodine therapy) to eliminate the excess of iodine. In addition, sU samples, although not statistically similar to 24U values, can be used as a good marker to evaluate patients suspected of contamination with iodine.

The role for pre-thyroidectomy (pre-Tx) imaging with F-18 flurodeoxyglucose (FDG) positron emission tomography (PET), FDG PET-computed tomography (CT), in differentiated thyroid cancer is controversial as is the significance of positive and negative FDG uptake in this setting. We reviewed the records of patients with papillary thyroid carcinoma (PTC) who had pre-Tx FDG PET-CT to determine whether FDG uptake was associated with features noted on pre-Tx ultrasonography (US) and parameters determined after post-Tx.Patients were selected for a retrospective review of their records if they had a total Tx with central lymph node dissection for PTC and pre-Tx FDG PET-CT and US between 2006 and 2009. Sixty patients who met these criteria were studied. Patients who had a history of head and neck irradiation, surgery, or sclerotherapy with ethanol in the last 3 months were excluded. The clinicopathologic factors-age, sex, size, tumor-node-metastasis (TNM) staging, the presence of extrathyroidal extention, multifocality, cervical lymph node metastases (CLNM), Hashimoto thyroiditis, and US characteristics-were evaluated to determine whether they were associated with positive pre-Tx FDG uptake.Forty-three (71.6%) of patients in the study had positive FDG uptake. Larger tumors and the presence of CLNM were associated with a greater likelihood of positive FDG uptake. The sensitivity, specificity, positive predictive value, and negative predictive value for CLNM detection by FDG PET-CT showed low statistical values. When considering the excellence of US for evaluating a thyroid nodule size and the presence of CLNM, the clinical value of pre-Tx FDG PET-CT is comparatively limited.Pre-Tx FDG PET is not recommended for routine use in patients with PTC.

Salivary dysfunction is the most common side effect associated with (131)I therapy in patients with differentiated thyroid cancer. The purpose of this study was to evaluate the effect of parotid gland (PG) massage on radioisotope accumulation in the salivary gland.Sixty patients were included in this study. Using Tc-99m pertechnetate, two salivary scans were performed in all patients. In 30 patients, PG massage was performed between the two salivary gland scans, whereas in the other 30 patients no massage was performed between the two scans. Total counts of both PGs and accumulation ratios were calculated.In the patients who received massage, no difference was observed between the mean PG counts of first and second images (8556.9±3333.4 count vs. 8598.3±3341.3 count, p=0.39). In the patients who did not receive massage, the mean PG count on second images was significantly higher than that on first images (8581.2±3618.0 count vs. 9096.4±3654.0 count, p0.01). Mean accumulation ratio in the patients who received massage was significantly lower than in the patients who did not receive massage (0.5%±3.3% vs. 6.8%±3.8%, p0.01). Further, among the patients who received massage there was a higher percentage of patients with a negative accumulation ratio than among the patients who did not receive massage (43.3% vs. 0%, p0.01).PG massage can reduce Tc-99m pertechnetate accumulation in the PG, and thus, should be helpful to prevent salivary damage associated with (131)I therapy.