131I Uptake Research Articles

MiR-221-3p and miR-222-3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer.

The expression levels of microRNA (miR)-221-3p and miR-222-3p in thyroid cancer have been found to be upregulated compared with those in normal tissues. The present study aimed to determine the effects and potential underlying mechanisms of miR-221-3p and miR-222-3p on the regulation of radioactive iodine (131I) uptake and radiosensitivity of thyroid cancer cells. The potential regulatory target genes of miR-221-3p and miR-222-3p were predicted by bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction was used to verify miR-221-3p, miR-222-3p and target gene expression levels in thyroid cancer tissues and cell lines. Overexpression of miR-221-3p or miR-222-3p in cell models was performed using lentivirus infection. Knockdown of miR-221-3p and miR-222-3p in cells was achieved using oligonucleotide inhibitor transfection. Western blotting was used to analyze the expression levels of target proteins. In addition, the effects of miR-221-3p and miR-222-3p on the radiosensitivity of thyroid cancer cells were verified using a colony formation assay. The results of the present study revealed that the expression levels of miR-221-3p and miR-222-3p were significantly upregulated, while the expression levels of suppressor of cytokine signaling 3 (SOCS3) were downregulated in thyroid cancer tissues. Furthermore, miR-221-3p and miR-222-3p overexpression downregulated the expression levels of SOCS3, E-cadherin and solute carrier family 5 member 5 (NIS), and upregulated the expression levels of phosphorylated STAT3 and vimentin. Following the overexpression of miR-221-3p or miR-222-3p in the FTC133 and TPC1 cell lines, their radiosensitivity was suppressed. In conclusion, the findings of the present study suggested that miR-221-3p and miR-222-3p may downregulate the expression levels of NIS and promote radioresistance. The potential mechanism was hypothesized to be associated with the miR-221-3p and miR-222-3p targeting of the SOCS3 gene, which may subsequently activate the STAT3 signaling pathway.

Abstract PO-006: Exploiting non-canonical pathways of NIS regulation to enhance radioiodide uptake and identify predictive markers of recurrence in thyroid cancer

Abstract For >75 years radioiodide (RAI) has been used to target metastases and safely and specifically destroy remaining thyroid cancer cells post-surgery. Despite this, activity of the sodium iodide symporter (NIS) – the sole conduit for cellular iodide uptake – is diminished in 25-50% of thyroid cancers, limiting adequate RAI uptake for effective therapeutic ablation. Thus, identifying targetable processes that govern NIS function is urgently needed to enhance RAI uptake and diminish recurrent thyroid cancer. Here we utilized the mutated yellow fluorescent protein (YFP) as a surrogate biosensor of intracellular iodide and screened 1200 drugs (95% FDA approved), allowing us to identify putative candidate drugs which increased iodide uptake. Categorization revealed a high proportion of drugs that modulate the proteostasis network (20/50 top candidate drugs; 40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 compounds based on their pharmacologic properties (AUC, EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1-50 uM). Dose-dependent increases in 125I uptake were apparent across multiple cancer cell models, as well as human primary thyrocytes, implying that proteostatic and related pathways are central to the innate control of NIS function. Subsequent mechanistic insight allowed us to evolve entirely novel combinatorial drug strategies, routinely leading to robust and significant > 5-fold increases in RAI uptake (all p < 0.001). Appraisal of TCGA to study the clinical relevance of proteostasis modulators identified significant dysregulation of 13 core proteostasis genes linked to recurrence in RAI-treated papillary thyroid cancer (PTC) compared to non-recurrent controls (all p < 0.05). Critically, a predictive risk model based on these 13 genes showed that RAI-treated PTC patients at high risk had a significantly worse prognosis than those at low risk [Hazard Ratio (HR) = 35.87, 95% CI 4.81-267.41; p < 0.001; n =137]. By comparison, there was no difference in the prognosis of non-RAI treated PTC patients stratified into risk groups. Moreover, after controlling for age, gender, disease stage, tumor stage and node status, multivariate analysis showed that the 13 proteostasis gene risk score classifier was the sole independent predictive factor for thyroid cancer recurrence (HR = 4.55, 95% CI 2.38-8.70; p < 0.001) in the entire TCGA cohort (n = 438). Whilst oncogene activation can suppress NIS expression and function, our study has identified new non-canonical pathways that govern radioiodide uptake. Collectively, we therefore propose a new model for the targetable steps of intracellular processing of NIS, with translatable potential to address the current lack of clinical options for patients treated with RAI who typically have poorer clinical outcomes. Citation Format: Martin L. Read, Katie Brookes, Caitlin E.M. Thornton, Hannah R. Nieto, Alice Fletcher, Patricia Borges de Souza, Mohammed Alshahrani, Ling Zha, Jamie R.M. Webster, Luke J. Alderwick, Kristien Boelaert, Vicki E. Smith, Christopher J. McCabe. Exploiting non-canonical pathways of NIS regulation to enhance radioiodide uptake and identify predictive markers of recurrence in thyroid cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-006.

Radioiodine therapy of thyroid autonomy.

Radioiodine therapy (RIT) of thyroid functional autonomy (TFA) is rapidly evolving, though it has been recognized for decades as a very effective treatment of toxic nodular varieties. Indeed, TFA is a frequent cause of persistent subclinical hyperthyroidism, which should be regarded as a new metabolic syndrome, with well-established adverse cardio-vascular consequences. Sensitive TSH assays and multiparametric ultrasounds are not accurate enough to reliably diagnose TFA and identify its main variants, unifocal, multifocal (UFA/MFA) and disseminated autonomy (DISA). Modern diagnostic tools are extensively presented and rely upon Thyroid Scan imaging and quantification. A new relationship allows predicting at baseline, an excess of 123I uptake as compared to the TSH stimulation in compensated TFA. Suppressed TS are useful with either isotope, otherwise. Diagnosis of the DISA variant is presented as compared to Graves' disease. Dosimetry has some specificity in TFA work-up. Indeed, the spatial distribution of the dose is as important as the mean value itself and can be eventually controlled by adjusting the TSH level with the smart use of LT3 or antithyroid drug therapy (ATD). A review of the different ways to determine the target mass from anatomical to functional approaches is presented. Main clinical and dosimetric published results of RIT are summarized according to clinical goals. Endogenous TSH stimulation using an ATD preparation has promising results in reducing big autonomously functioning goiters. Finally, we report preliminary successful results of preventive RIT using short term LT3 suppression in compensated TFA, with low administered activities and low rate of hypothyroidism.

Clinical applications of single-photon emission computed tomography/computed tomography in post-ablation 131iodine scintigraphy in children and young adults with differentiated thyroid carcinoma.

The utility of integrated single-photon emission computed tomography/computed tomography (SPECT/CT) in children and young adults with differentiated thyroid carcinoma is incompletely studied. To determine the value of adding SPECT/CT to conventional whole-body scintigraphy in post-ablation iodine-131 (131I) scintigraphy for children and young adults with differentiated thyroid carcinoma. Planar scintigraphy and SPECT/CT were performed on 42 post-surgical children and young adults (32 female, 10 male; mean age 14.3±4.9years, range 7-20years) with differentiated thyroid carcinoma (39 papillary, 2 follicular, 1 mixed) 5days after the therapeutic administration of 1.9-7.4GBq of 131I. Planar and SPECT/CT images were interpreted independently, and sites of uptake were categorized as positive or equivocal with respect to thyroid bed, lymph node and distant metastasis uptake. An experienced thyroid endocrinologist used a combination of surgical histopathology and scintigraphic findings to determine whether the addition of SPECT/CT would change patient management. Planar scintigraphy evidenced 88 radioiodine-avid foci and SPECT/CT confirmed all foci. No additional foci were disclosed by SPECT/CT. SPECT/CT correctly classified 16/88 (18%) foci that were unclear or wrongly classified at planar scintigraphy. Globally, SPECT/CT showed an incremental value over planar scintigraphy in 9 (21.4%) patients and changed therapeutic management in 3 (7.1%; 95% confidence interval, 2-20%) patients. SPECT/CT improved localization and characterization of focal 131I uptake on post-ablation whole-body scintigraphy in children and young adults with differentiated thyroid carcinoma. Further prospective evaluation in a larger series is justified to prove the effect of post-ablation SPECT/CT-based management decisions.

Muscarinic inhibition of salivary glands with glycopyrronium bromide does not reduce the uptake of PSMA-ligands or radioiodine

RationaleSalivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium—iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands.MethodsTen patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared.ResultsNo significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46).ConclusionMuscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies.

Outcomes following I-131 treatment with cumulative dose exceeding or equal to 600 mCi in differentiated thyroid carcinoma patients.

To evaluate treatment outcomes following radioactive iodine (RAI) treatment with a cumulative dose of ≥≥600 mCi in differentiated thyroid carcinoma (DTC) patients, a retrospective review of medical records was done in 176 DTC patients with a cumulative dose of ≥600 mCi from January 1993 to December 2013. All patients were followed up for at least 2 years after receiving 600 mCi of I-131 treatment. Remission criteria were no clinical and imaging evidence of disease and low serum thyroglobulin levels during thyroid-stimulating hormone suppression of <0.2 ng/ml or of <1 ng/ml after stimulation in the absence of interfering antibodies. A total of 176 patients were included in the study: 137 – papillary thyroid cancer, 29 – follicular thyroid cancer, 9 – mixed papillary and follicular thyroid cancer, and 1 – Hurthle cell carcinoma. Most of the patients (118, 67%) had locoregional metastasis, whereas 48 patients (27%) had distant metastases at presentation. The median cumulative dose was 900 mCi (range: 600–2200 mCi). The mean follow-up period was 82.84 ± 42.41 months. Only 16 patients (9.1%) met remission criteria at the end of treatment. The rest of patients (160, 90.9%) were not remitted: stable disease in 94 (53.4%), at least 1 metastasis without I-131 uptake in 34 (19.3%), progressive disease in 21 (11.9%), and death during the whole follow-up period in 11 (6.3%). Two patients (1.1%) developed second primary malignancy. Eighteen cases were suspected of bone marrow suppression (14 cases [7.9%] had anemia and 5 cases [2.8%] had neutropenia). Seven patients (3.9%) developed permanent salivary gland dysfunction. Although the complications after receiving RAI treatment with a cumulative dose of ≥≥600 mCi were low and not severe, the patients with remission were in <10%. Our study suggests that the decision to administer further treatments should be made on an individual basis because beneficial effects may be controversial.

Extracellular Vesicles Act as Nano-Transporters of Tyrosine Kinase Inhibitors to Revert Iodine Avidity in Thyroid Cancer.

A new approach for using extracellular vesicles (EVs) to deliver tyrosine kinase inhibitors (TKIs) to enhance iodine avidity in radioactive iodine-refractory thyroid cancer is needed. We isolated and characterized primary human adipose-derived stem cells (ADSCs) and isolated their EVs. The EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. A new TKI was loaded into the EVs by incubation (37 °C; 10 min) or sonication (18 cycles; 4 s per cycle) with 2 s intervals and a 2 min ice bath every six cycles. TKI loading was confirmed and measured by mass spectrometry. EV uptake into radioactive iodine-refractory thyroid cancer cells (SW1736 cells) was confirmed by microscopy. We treated the SW1736 cells with vehicle, TKI, or TKI-loaded EVs (sonication TKI-loaded EVs [EVsTKI(S)]) and examined the expression of iodide-metabolizing proteins and radioiodine uptake in the SW1736 cells. ADSCs cells showed >99% of typical stem cell markers, such as CD90 and CD105. The EVs displayed a round morphology, had an average size of 211.4 ± 3.83 nm, and were positive for CD81 and Alix and negative for cytochrome c. The mass spectrometry results indicate that the sonication method loaded ~4 times more of the TKI than did the incubation method. The EVsTKI(S) were used for further experiments. Higher expression levels of iodide-metabolizing mRNA and proteins in the EVsTKI(S)-treated SW1736 cells than in TKI-treated SW1736 cells were confirmed. EVsTKI(S) treatment enhanced 125I uptake in the recipient SW1736 cells compared with free-TKI treatment. This is the first study that demonstrated successful delivery of a TKI to radioactive iodine-refractory thyroid cancer cells using EVs as the delivery vehicle. This approach can revert radioiodine-resistant thyroid cancer cells back to radioiodine-sensitive thyroid cancer cells.

Tunicamycin as a Novel Redifferentiation Agent in Radioiodine Therapy for Anaplastic Thyroid Cancer.

The silencing of thyroid-related genes presents difficulties in radioiodine therapy for anaplastic thyroid cancers (ATCs). Tunicamycin (TM), an N-linked glycosylation inhibitor, is an anticancer drug. Herein, we investigated TM-induced restoration of responsiveness to radioiodine therapy in radioiodine refractory ATCs. 125I uptake increased in TM-treated ATC cell lines, including BHT101 and CAL62, which was inhibited by KClO4, a sodium-iodide symporter (NIS) inhibitor. TM upregulated the mRNA expression of iodide-handling genes and the protein expression of NIS. TM blocked pERK1/2 phosphorylation in both cell lines, but AKT (protein kinase B) phosphorylation was only observed in CAL62 cells. The downregulation of glucose transporter 1 protein was confirmed in TM-treated cells, with a significant reduction in 18F-fluorodeoxyglucose (FDG) uptake. A significant reduction in colony-forming ability and marked tumor growth inhibition were observed in the combination group. TM was revealed to possess a novel function as a redifferentiation inducer in ATC as it induces the restoration of iodide-handling gene expression and radioiodine avidity, thereby facilitating effective radioiodine therapy.

The Influence of H2-Receptor Antagonist Administration to the 24-h Uptake of I-131 in the Thyroid Gland.

The aim of this study was to determine the influence of H2RAs to the 24-h I-131 uptake in the thyroid gland. A prospective study with quasi-experimental pre- and post-study design was done. Subjects with normal fT4 level who fulfilled the inclusion criteria were selected. All subjects received 0.2mCi of I-131 orally, and the thyroid uptake calculations were performed at 24h later. The same procedure was performed 4weeks later. All of the subjects were asked to consume H2RAs 1h before the administration of I-131 of the second procedure. Both 24-h thyroid uptakes were statistically analysed. A total of 14 subjects were enrolled in this study. Most of them were women (78%) with an average age of 37.6years old (range: 20-55). This study showed a median of 24-h thyroid uptake of I-131 before and after H2-receptor antagonist of 20.6% (range: 11.1-57.8%) and 16.7% (range: 8.1-39.4%) respectively. H2-receptor antagonist caused a significance reduction of 24-h I-131 uptake value in the thyroid gland.

The diagnostic incremental value of 131I SPECT-CT scan compared to planar 131I WBS for differentiated thyroid carcinoma: A single institutional experience

ABSTRACT This study investigated the usefulness of iodine-131 (131I) single-photon emission computed-tomography/computed-tomography (SPECT-CT) in conjunction with whole-body scan (WBS) planar imaging for the management of a patient presenting with differentiated thyroid carcinoma (DTC). A total of 100 patients with DTC post-total thyroidectomy were included in the study. The foci of 131I uptake were classified as neck site and outside the neck site by WBS planar and SPECT-CT imaging. SPECT-CT incrementally identified 141 neck sites and 217 distant neck foci compared to 139 at the neck site and 197 at the outside neck site identified by planar imaging. For the neck site, SPECT-CT downstaged 27 foci of 32 for indeterminate thyroid remnants at the neck site. Regarding sites distant to the neck, the SPECT-CT analysis led to the correct downstaging of two false-positive foci of suspicious uptake within the lung and bone, which were noted as metastases on planar images. SPECT-CT correctly upstaged one focus of iodine activity observed in the left arm as contamination on planar images, subsequently corrected as a metastatic bone lesion. The use of 131I SPECT-CT scans increased the incremental diagnostic data compared with 131I WBS planar scan imaging alone, which could change patient management.

Valores pronósticos de la captación en estrella de 131I en pacientes con cáncer diferenciado de tiroides

ObjectiveAfter 131I treatment in patients with differentiated thyroid carcinoma (DTC), we sometimes find a star-shaped intense uptake of 131I on therapeutic whole body scans (Rx-WBS), called star artifacts. Therefore, we analyzed the relevant clinical factors and prognostic value of star artifacts in DTC patients. Methods809 DTC patients who received 131I treatment were retrospectively evaluated and divided into 2 groups of patients with and without star artifacts. We evaluated the therapeutic response which was divided into excellent response (ER), biochemical incomplete response (BIR), indeterminate response (IR), and structural incomplete response (SIR). Clinical factors for the presence of star artifacts were analyzed. We also compared the rate of ER, BIR, IR, SIR and recurrence rate between group 1 and group 2. ResultsThe major clinical factors included stimulated thyroglobulin (sTg)>1.8ng/ml, 24h radioiodine uptake (RAIU)>2.2%, and positive 99mTcO4− thyroid imaging for the presence of star artifacts. In patients with sTg levels>10ng/ml, patients in group 1 had a higher rate of ablation success and ER than patients in group 2 (80.2% vs 65.6%, P=0.038, 31.6% vs 13.1%, P=0.008, respectively) and had a similar rate of BIR, IR, SIR. Recurrence rate was similar between group 1 and group 2 (5.2% vs 3.1%, P=0.13). ConclusionMore remnant thyroid tissue is one of the factors associated with the presence of star artifacts on Rx-WBS. Patients with star artifacts exhibit a better therapeutic response (ER) when sTg levels are >10ng/ml. However, star artifacts have no effect on the recurrence rate.

Feasibility of Bone Marrow Mesenchymal Stem Cell-Mediated Synthetic Radiosensitive Promoter-Combined Sodium Iodide Symporter for Radiogenetic Ovarian Cancer Therapy.

Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12-24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane glycoprotein and can concentrate 131I, which is important for radionuclide therapy and nuclear medicine imaging in recent years. However, the rapid iodine efflux has become a bottleneck for NIS-mediated radionuclide gene therapy. Our previous studies found that the early growth response-1 (Egr1) promoter containing CC(A/T)6GG (CArG) elements had an 131I radiation-positive feedback effect on the NIS gene. Other research showed the synthesized Egr1 promoter containing four CArG elements, E4, was nearly three times as sensitive as the Egr1 promoter. In our study, BMSC-E4-NIS was engineered to express NIS under the control of E4 promoter using lentivirial vectors. After BMSC-E4-NIS implantation, no tumors were seen in BALB/c nude mice and BMSC-E4-NIS did not promote the growth of SKOV3 tumor. BMSCs migrated toward ovarian cancer samples in chemotaxis assays and to ovarian tumors in mice. Using micro-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, we found that E4 promoter produced a notable increase in 125I uptake after 131I irradiation, the radionuclide uptake is almost three and six times more than Egr1 and cytomegalovirus (CMV) promoters. These studies confirmed the feasibility of using BMSCs as carriers for lentivirus-mediated E4-NIS gene therapy for ovarian cancer. Further research on BMSC-E4-NIS gene therapy for ovarian cancer in vivo will also be carried on, and if successful, this might provide a new adjuvant therapeutical option for platinum-resistant ovarian cancer patients and provide a new method for dynamic evaluation of curative effect.

Predictors of the efficacy of radioiodine therapy of Graves' disease in children and adolescents

Insufficient world-wide clinical experience in radioiodine therapy (RIT) for Graves' disease (GD) in children and adolescents, and limited knowledge of the predictors of RIT efficacy. Analysis and identification of the most significant predictors of the efficacy of RIT in children and adolescents with Graves' disease. A total of 55 patients (48 females and 7 males) aged from 8 to 18 years receiving primary RIT for GD were enrolled. RIT planning was based on the dosimetric method. Analyzed parameters included gender, age, ultrasound thyroid volume before and 6 months after treatment, the presence of endocrine ophthalmopathy, duration of antithyroid drug (ATD) therapy, relapse of thyrotoxicosis after ATD dose reduction, blood fT3, fT4 and TSH levels initially and at 1, 3, 6 months after treatment, TSH receptor Ab initially and at 3 and 6 months after treatment, thyroid99mTc-pertechnetate uptake at 10-20 minutes (%), maximum thyroid 131I uptake (%), specific131I uptake (MBq/g) and therapeutic131I activity (MBq). Fisher exact test, non-parametric Mann-Whitney test, Wilcoxon signed-rank test, logistic regression modelling, ROC-analysis, proportional hazard model (the Cox regression), the Kaplan-Meier method and log-rank test were used for statistical analysis as appropriate. Six months after RIT, hypothyroidism was achieved in 45 (81.8%), euthyroid state - in 2 (3.6%), and in 8 (14.6%) patients thyrotoxicosis persisted. On univariate statistical analysis, the smaller thyroid volume, higher fT4 and lower TSH receptor Ab levels, lower 99mTc-pertechnetate uptake and higher specific 131I uptake were associated with hypothyroidism. On multivariate logistic regression analysis, the older patient's age (p=0.011), smaller thyroid volume (p=0.003) and higher fT4 (p=0.024) were independent predictors of RIT efficacy. Thyroid volume was also the only variable associated with achievement of hypothyroidism in time after RIT (p=0.011). The efficacy of dosimetry-based RIT in children and adolescents with GD 6 months after treatment was 81.2%. Older patients' age, smaller thyroid volume and higher fT4 level were independent predictors of therapy success. Smaller thyroid volume was also a predictor of the favorable time-related outcome. Statistical models obtained in this work may be used to prospectively estimate the chance of efficient RIT for GD in pediatric patients.

FDG PET Predicts the Effects of 131I and Prognosis for Patients with Bone Metastases from Differentiated Thyroid Carcinoma.

Background18F-FDG PET and 131I scans are important in the detection of metastases from differentiated thyroid carcinoma (DTC). The relationship of FDG and radioiodine (RAI) metabolism in bone metastases (BMs) from DTC and its prognostic value on RAI treatment is not clear.MethodsThe retrospective study included DTC patients with BMs from two medical centers, who underwent 18F-FDG PET/CT scans and RAI therapy. Therapeutic response was evaluated by serum thyroglobulin (Tg) levels and anatomical imaging changes.ResultsThe analyses were performed on 30 patients with 72 BMs. Forty-two (42/72, 58%) lesions displayed simultaneous 131I and 18F-FDG uptake. BMs with positive 18F-FDG uptake had a less favorable response to RAI therapy in comparison to those with negative 18F-FDG uptake (p = 0.018), even in 131I-avid lesions (p = 0.033). Sixteen (53%) patients had disease progression with a median PFI of 26 months (range: 3 to 89 months). Compared to those with 131I-avid but non-FDG-avid BMs, patients presenting with 18F-FDG-avid BMs had shorter PFI, whether with 131I uptake (p = 0.002) or without (p = 0.002).ConclusionMore than half of BMs (58%) from DTC show simultaneous 18F-FDG and 131I uptakes which are contrary to the flip-flop phenomenon (131I negative and 18F-FDG positive). Regardless of 131I uptake, 18F-FDG uptake of BMs portends a less favorable therapeutic response and poorer prognosis for patients with DTC.

Firm mass in thyroid of an elderly patient: not always cancer.

In elderly patients presenting with a solid thyroid mass, the differential diagnosis between benign and malignant lesion is not always straightforward. We present the case of an 85-year-old woman with fever and an enlarged, firm and painful thyroid mass. Blood exams documented a mild thyrotoxicosis with a moderate inflammatory status. Thyroid scintiscan showed an absent uptake of 131I. Ultrasound and CT scan documented a 3 cm hypoechoic nodule with infiltration of the sternocleidomastoid muscle, very suspicious for neoplastic nature. Fine-needle aspiration and tru-cut biopsy were performed. During biopsy, the lesion was partially drained and a brownish fluid was extracted. The culture resulted positive for Klebsiella pneumoniae whereas the pathological analysis of the specimen was not conclusive due to the presence of an intense inflammatory response. A targeted oral antibiotic therapy was then initiated, obtaining only a partial response thus, in order to achieve a definite diagnosis, a minimally invasive hemithyroidectomy was performed. The pathological analysis documented acute suppurative thyroiditis and the clinical conditions of the patient significantly improved after surgical removal of thyroid abscess. In elderly patients with a solid thyroid mass, although neoplastic origin is quite frequent, acute suppurative thyroiditis should be considered as a differential diagnosis. A solid and rapidly growing thyroid mass in elderly patients can hide a multifaceted variety of diseases, both benign and malign. A multidisciplinary team (endocrinologist, surgeon, radiologist and pathologist) could be necessary in order to perform a correct differential diagnosis and therapeutic approach. Surgery can be decisive not only to clarify a clinically uncertain diagnosis, but also to rapidly improve the clinical conditions of the patient.

A prospective comparative study of two methods for the individual calculation of 131I activity in the treatment of hyperthyroidism

ObjectiveRadioiodine (131I) is an established modality of definitive treatment of hyperthyroidism. In spite of the vast experience available, there are still several aspects to be clarified, such as whether fixed or calculated doses should be used. The aim of this study was to assess whether efficacy of this treatment could be improved by implementing a simple dosimetric calculation method including ultrasonographic estimation of thyroid volume and a single measurement of 24-h 131I thyroid uptake. MethodsA prospective non-inferiority study was designed to compare two procedures to calculate radioiodine activity: the “semi-fixed” dose method (A), and the “calculated” dose method (B). The first consisted of activity escalation (185MBq steps) based on etiology of hyperthyroidism, 131I uptake, and treatment objective. The second method was based on the “dosimetric compromise” concept, considering 24-h uptake and thyroid volume as the only factors and using a standard half-life of 5.5 days. The target absorbed dose was 150Gy, but after a preliminary analysis (first 100 cases) it was increased to 200Gy in diffuse toxic goiters (DTGs). ResultsA total of 212 patients were included. Method B was at least as effective in terms of final and functional outcome, with a trend to more success and less hypothyroidism. In addition, activities administered were significantly lower. ConclusionIn radioiodine therapy of hyperthyroidism, a simple dosimetric method that provided results at least equal to those of a fixed dose-based method, with lower administered activities, could be implemented.

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy

The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated invivo in subcutaneous HuH7 mousexenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48h after or 24-48h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced bycombining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

Least Significant Changes and Reproducibility of 131I Uptake Test.

Radioactive iodine uptake (RAIU) is one of the important tests performed in the departments of nuclear medicine, testing thyroid function by measuring the amount of 131I uptake after oral administration. A RAIU value measured 4 and 24 h after administration has been widely used for differential diagnosis of thyroid function and for the calculation of treatment dose. This study was performed to define practical methods for reproducibility and least significant change (LSC) values replicating thyroid measurements. In the study were 119 patients referred to the nuclear medicine department for examination of thyroid gland function with the diagnosis of Graves' disease (60), toxic multinodular goiter (29), thyroiditis (10), thyroid cancer (6), and unknown etiology (14). The level of thyroid stimulating hormone (TSH) among the patients was 2.07 ± 6.74 μIU mL-1. RAIU measurements were carried out by two different technicians, who have performed an equal number of measurements from each diagnosis in reference to the clinical diagnosis. Measurement of each patient was performed twice at 4 and 24 h after the administration under stable geometry and counting conditions using a standard procedure. Data were evaluated using statistical methods. For assessment of the reproducibility, three parameters were used: reproducibility coefficient (RC), the root-mean-square standard deviation (SDRMS), and the least significant change values. The average RAIU values of the first and second measurements were found as 23.71 ± 16.52% and 23.94 ± 16.64% at 4 h (p >0.05), and 35.33 ± 19.22% and 35.49 ± 19.19% at 24 h (p >0.05), respectively. For thyroid uptake values repeated at 4 and 24 h after radioiodine administration, the mean difference was found to be -0.24 ± 0.62% [limits of agreement (%); -1.44 to 0.97] at 4 h and -0.16 ± 0.44% [limits of agreement (%); -1.02 to 0.70] at 24 h. Confidence intervals were within the limits of agreement (d̅-1.96 SD and d̅+1.96 SD). When the correlation between the repeated RAIU measurements was examined taking the differences and averages into account, there was a negative correlation between 4-h measurement pairs (r=-0.203, p <0.05). On the other hand, a significant correlation was not found between the 24-h measurement pairs (r=0.074, p >0.05). RC, SDRMS, and LSC were calculated as 0.70%, 0.46%, and 1.29% for the 4 h measurements and 0.54%, 0.33%, and 0.91% for the 24-h measurements, respectively. Although there was a minor difference between measurement pairs at 4 and 24 h post-administration, the difference appeared to be insignificant without an apparent effect in the clinical settings.

Postablative 131I SPECT/CT Is Much More Sensitive Than Cervical Ultrasonography for the Detection of Thyroid Remnants in Patients After Total Thyroidectomy for Differentiated Thyroid Cancer

Evaluation of utility of cervical ultrasound (US) for detection of thyroid remnants (ThR) in patients after thyroidectomy for differentiated thyroid cancer. Included were 154 consecutive patients (17-89 years, 123 female and 31 male patients), without known cancer residues or cervical lymph nodes metastases, admitted for ThR ablation with I, 14 to 20 weeks after surgery. Neck uptake of I (Tup) and thyroglobulin were determined, and location and volume of ThR detected by cervical US were recorded. On days 3 to 4 after ablation (1.7-4.6GBq, 46-124.3 mCi I), neck SPECT/CT was performed, and I uptake foci were assigned to one of the regions as described below. The anterior neck was divided into 2 compartments: superior and inferior to lower margin of thyroid cartilage, and each compartment was subdivided into middle and lateral regions (in SPECT/CT, posterolateral and anterolateral regions were also marked out). I uptake sites and ThR detected by US, if congruent with SPECT/CT, were counted and analyzed. In total, 341 I uptake foci were found in 150 patients (97.4%) by SPECT/CT and 213 corresponding ThR in 118 patients (76.6%) by US. Ultrasound detected 30% to 46% of I uptake foci in superior lateral regions, 49% in pyramidal lobe/thyroglossal duct area (both P < 0.05), 74% to 77% in inferior lateral regions, and 22% in isthmus (both P > 0.05). Correlation between ThR volume and Tup was strong (r = 0.79), and that between ThR volume and thyroglobulin was weak (r = 0.24). Ultrasound is less sensitive than I posttherapy scans for ThR detection in patients after thyroidectomy, especially for remnants located above the lower margin of thyroid cartilage.

Influence of Short-Term Dietary and Therapeutic Iodine Restriction on the Therapeutic Effects of Radioactive Iodine Therapy in Patients with Graves' Disease.

Background: Several studies have investigated the factors affecting the effects of radioactive iodine (131I) treatment (RAIT) in patients with Graves' disease. However, the influence of dietary or therapeutic iodine on the effect of RAIT has not been fully elucidated yet. The aim of this study was to investigate whether dietary or therapeutic iodine before RAIT influences the therapeutic effects of RAIT with a fixed-dose regimen and a short-term restriction of iodine intake in an iodine-sufficient area. Materials and Methods: We retrospectively analyzed 81 Japanese patients with Graves' disease treated with the following RAIT regimen: dietary iodine restriction for 7 days as well as discontinuation of antithyroid drugs (ATDs), potassium iodine (KI), or both for 5 days before RAIT. On the day of RAIT, we measured urinary iodine content to estimate daily iodine intake. After RAIT, we adjusted the dose of ATDs, KI, or both according to serum thyroid hormone levels every 1-2 months. Using the data from these patients, we investigated the effect of dietary and therapeutic iodine on the therapeutic effects of RAIT. The therapeutic effects at 1 year after RAIT were evaluated based on the necessity of ATDs, KI, or both. Results: Dietary iodine intake was weakly correlated with 131I uptake (RAIU), but the dose of therapeutic iodine was not correlated with RAIU. The therapeutic effects of RAIT were strongly negatively associated with estimated thyroid volume before RAIT. Neither dietary iodine intake nor therapeutic iodine before RAIT affected this association. Conclusion: This study did not find an association between short-term dietary or therapeutic iodine restriction before RAIT and the therapeutic effects of RAIT in an iodine-sufficient area.