Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.

BACKGROUND: Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined. METHODS: A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1 year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups. RESULTS: The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33 GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2 GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7 GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality. CONCLUSIONS: In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2 GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.

Predictive Value of a Prognostic Model Based on Lymphocyte-to-Monocyte Ratio Before Radioiodine Therapy for Recurrence of Papillary Thyroid Carcinoma.

BACKGROUND: The aim of this study was to investigate the predictive value of a prognostic model based on the lymphocyte-to-monocyte ratio (LMR) before radioiodine treatment for the recurrence of papillary thyroid carcinoma (PTC). METHODS: Clinicopathological data of 441 patients with papillary thyroid cancer were collected retrospectively. The Receiver operating characteristic (ROC) was used to determine the optimal cut-off value for predicting PTC recurrence by LMR before radioiodine treatment. Recurrence was the endpoint of the study, and survival was estimated by the Kaplan-Meier method, and any differences in survival were evaluated with a stratified log-rank test. Univariate and multifactorial analyses were performed using Cox proportional-hazards models to identify risk factors associated with PTC recurrence. RESULTS: The ROC curve showed that the best cut-off value of LMR before radioiodine treatment to predict recurrence in patients with PTC was 6.61, with a sensitivity of 54.1%, a specificity of 73%, and an area under the curve of 0.628. The recurrence rate was significantly higher in the low LMR group (16%) than in the high LMR group (5%) (P = 0.001, χ2 = 12.005). Multifactorial analysis showed that LMR < 6.61 (P = 0.006; HR = 2.508) and risk stratification (high risk) (P = 0.000; HR = 5.076) before radioiodine treatment were independent risk factors predicting recurrence in patients with PTC. Patients with preoperative LMR < 6.61 and high risk stratification had the lowest recurrence-free survival rate and the shortest recurrence-free survival time. CONCLUSIONS: The LMR-based prognostic model before radioactive iodine treatment is valuable for early prediction of PTC recurrence and it can be used in clinical practice as a supplement to risk stratification and applied in combination to help screen out patients with poorer prognosis early.

Parathyroid Changes After RAI in Patients With Differentiated Thyroid Carcinoma.

Objective: The purpose of this study was to investigate parathyroid hormone (PTH), serum calcium, phosphorus, and 25-hydroxyvitamin D (25-OH-VD) changes before and after radioactive iodine (RAI) in differentiated thyroid carcinoma (DTC) patients at different time points. Methods: A total of 259 DTC patients who received RAI were prospectively enrolled. We evaluated PTH, serum calcium, phosphorus, and 25-OH-VD levels at baseline pre-RAI, five days, six weeks, and six months post-RAI, respectively. We analyzed the risk factors of hypocalcemia at five days post-RAI. Results: The mean PTH, serum calcium and phosphorus values decreased five days post-RAI compared with pre-RAI (PTH 4.18 ± 1.23 pmol/L vs. 3.95 ± 1.41 pmol/L; calcium 2.27 ± 0.09 mmol/L vs. 2.20 ± 0.11 mmol/L; phosphorus 1.25 ± 0.17 vs. 0.98 ± 0.20 mmol/L, P < 0.05), and the differences were statistically significant. The mean 25-OH-VD levels did not significantly decrease at five days post-RAI. 21.2% (55/259) of patients had hypocalcemia at five days post-RAI, and all of them were given oral calcium supplements. At six weeks post-RAI, all of the above parameters were higher than those at five days post-RAI. Multivariate regression analysis showed that baseline pre-RAI serum calcium < 2.27 mmol/L, PTH < 4.18 pmol/L and negative 99mTcO4- thyroid imaging were risk factors for hypocalcemia at five days post-RAI. Conclusion: For DTC patients with normal PTH and serum calcium levels at pre-RAI, their PTH, serum calcium, and phosphorus levels decreased at five days post-RAI. About one-fifth of patients could have hypocalcemia at five days post-RAI. Lower baseline pre-RAI serum calcium and PTH levels and negative 99mTcO4- thyroid imaging were risk factors for hypocalcemia five days post-RAI.

Decline in anti-Müllerian hormone concentrations following radioactive iodine treatment in women with differentiated thyroid cancer: A systematic review and meta-analysis.

AIM: Radioactive iodine (RAI) is frequently used as adjuvant therapy in patients with differentiated thyroid cancer (DTC). However, its effect on ovarian reserve has not been fully elucidated, with studies yielding inconsistent results. The aim of this study was to systematically review and meta-analyze the best available evidence regarding the effect of RAI on ovarian reserve in premenopausal women with DTC. METHODS: A comprehensive literature search was conducted in PubMed, Cochrane and Scopus, through to December 6th, 2020. Data were expressed as weighted mean difference (WMD) with a 95% confidence interval (CI). The I2 index was used to assess heterogeneity. RESULTS: Four prospective studies were included in the qualitative and quantitative analysis. Anti-Müllerian hormone (AMH) concentrations decreased at three (WMD -1.66 ng/ml, 95% CI -2.42 to -0.91, p<0.0001; I2 0%), six (WMD -1.58, 95% CI -2.63 to -0.52, p=0.003; I2 54.7%) and 12 months (WMD -1.62 ng/ml, 95% CI -2.02 to -1.22, p<0.0001; I2 15.5%) following a single RAI dose compared with baseline (three studies; n=104). With respect to follicle-stimulating hormone (FSH) concentrations, no difference was observed at six (WMD +3.29 IU/l, 95% CI -1.12 to 7.70, p=0.14; I2 96.8%) and 12 months (WMD +0.13 IU/l, 95% CI -1.06 to 1.32, p=0.83; I2 55.2%) post-RAI compared with baseline (two studies; n=83). No data were available for antral follicle count. CONCLUSIONS: AMH concentrations are decreased at three months and remain low at 6 and 12 months following RAI treatment in women with DTC. No difference in FSH concentrations post-RAI is observed.

What is the experience of our patients with transient hypoparathyroidism after total thyroidectomy?

BACKGROUND: We sought to better understand the experience of patients with transient hypoparathyroidism using patient interviews and quality of life surveys. METHODS: This is a prospective analysis of 62 patients after total thyroidectomy at a high-volume institution. Semistructured patient interviews and quality of life surveys were conducted preoperatively and postoperatively at 2 weeks, 6 weeks, 6 months, and 1 year and compared based on postoperative parathyroid hormone levels. RESULTS: Postoperative parathyroid hormone levels were <10 pg/mL in 32% of patients (n = 20), 10 to 20 pg/mL in 19% (n = 12), and >20 pg/mL in 48% (n = 30). Hypocalcemic symptoms at 2 weeks were reported in 28 of 55 patients (51%), but patients felt "well prepared" and reported it "wasn't a big deal." If symptoms persisted at 6 weeks, they became more bothersome. At 6 months and 1 year, patients reported calcium supplementation prevented most symptoms and did not interfere with daily activities. Quality of life as measured by the European Organization for Research and Treatment of Cancer and the 12-Item Short Form Survey demonstrated a slight improvement at 1 year postoperatively regardless of parathyroid hormone level. CONCLUSION: Early postoperative transient hypoparathyroidism is common but when appropriately managed did not have a substantial negative impact on the overall quality of life.

Blood prognostic predictors of treatment response for patients with papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is a very common malignant disease with high morbidity. We needed some pretreatment indicators to help us predict prognosis and guide treatment. We conducted a study about some pretreatment prognostic indicators. METHODS: This clinical study recruited 705 postoperative PTC patients (211 males, 494 females). Clinical data before radioactive iodine (RAI) treatment were collected. Patients' response to therapy were classified into two categories: 'Good Prognosis Group' (GPG) and 'Poor Prognosis Group' (PPG), according to '2015 American Thyroid Association Guidelines'. Differences of indicators between different prognosis groups were compared. Odds ratios (ORs) were calculated by univariate/multiple binary logistic regression models. Difference of body mass index (BMI) changes before and after RAI treatment between different prognosis groups was also compared. RESULTS: A total of 546 (77.45%) belonged to GPG, and 159 (22.55%) belonged to PPG. Platelet (PLT), neutrophil (NEUT), PLT subgroups, and combination of red blood cell distribution width (RDW) and BMI (COR-BMI) were different between two prognosis groups. The significance of the difference between the two groups of BMI disappeared after the Bonferroni correction. PLT and PLT subgroups had detrimental effects on the risk of PPG; T stage had a positive effect on the risk of PPG. PLT subgroup showed a detrimental effect on the risk of PPG when we included additional covariates. CONCLUSIONS: We found that lower pretreatment PLT levels may indicate a poor prognosis for PTC. The relationship between platelet-derived growth factor (PDGF) and radiation sensitivity may be the key to this association.

Association between clinical and tumor features with postoperative thyroglobulin in pediatric papillary thyroid cancer.

BACKGROUND: Why certain patients after total thyroidectomy for thyroid cancer who do not have distant metastasis have increased serum stimulated thyroglobulin (s-Tg) is unknown. The aim of our study was to systematically investigate the associations of preablation s-Tg with clinical and tumor characteristics in children and young adults less than 20 years old after total thyroidectomy for papillary thyroid cancer. METHODS: We performed a retrospective analysis of 93 children and young adults younger than 20 years old who had undergone total thyroidectomy and were without known distant metastases who underwent remnant ablation. Before any remnant preablation, we assessed the association of s-Tg after thyroid hormone withdrawal with the clinical and histopathologic characteristics according to the American Thyroid Association pediatric initial risk classification system. RESULTS: The median age was 18 years, and the majority of patients were female (80%). The preablation s-Tg ranged from 0.02 to 902.00 ng/mL, with a median of 9.2 ng/mL. Forty-five (48%) patients had an increased preablation s-Tg >10 ng/mL. In multivariate analyses of clinical and tumor characteristics, high-risk stratification and high neck uptake (>2%) were the independent predictive factors for the presence of an increased preablation s-Tg. CONCLUSION: Children and young adults younger than 20 years old with high-risk stratification and high neck uptake are likely to present a high level of preablation s-Tg after total thyroidectomy for papillary thyroid cancer. Continued long-term surveillance is necessary in this cohort of patients to confirm the role of preablation s-Tg as a biomarker for monitoring postoperative residual disease.

Plasma branched chain amino acids are lower in short-term profound hypothyroidism and increase in response to thyroid hormone supplementation.

Branched chain amino acids (BCAA) are implicated in the pathogenesis of cardiometabolic diseases conceivably by affecting insulin resistance and mitochondrial dysfunction. Circulating BCAA levels may predict (subclinical) atherosclerosis, diabetes and hypertension development but the factors involved in BCAA regulation are incompletely understood. Given the key role of thyroid hormones on many metabolic processes including protein metabolism, we aimed to determine effects of thyroid dysfunction on circulating BCAA. Effects of short-term profound hypothyroidism on plasma BCAA were determined in 17 patients who had undergone total thyroidectomy for differentiated thyroid carcinoma. Patients were studied during hypothyroidism, i.e. after thyroidectomy, and after thyroid hormone supplementation. Plasma BCAA (sum of valine, leucine and isoleucine) and alanine were measured by nuclear magnetic resonance spectroscopy. During hypothyroidism (median thyroid-stimulating hormone 81 (IQR 67-120.5) mU/L), plasma BCAA were lower (255 (IQR 222-289) µmol/L) compared to a euthyroid reference population (n = 5579; 377 µmol/L (2.5th to 97.5th percentile 258-548), p < 0.001). After 20 weeks of thyroid hormone supplementation (thyroid-stimulating hormone 0.03 (IQR 0.01-0.14 mU/L) plasma BCAA had increased (328 (IQR 272-392) µmol/L, p = .001), but plasma alanine concentrations were unaltered (p = .50). Changes in body weight in response to thyroid hormone supplementation were correlated with changes in plasma BCAA (r = 0.721 p = .001, but not with changes in cholesterol or glucose (p > .80). In conclusion, plasma BCAA concentrations are lower during short-term profound hypothyroidism in humans, and increase in response to thyroid hormone supplementation. Changes in BCAA and in body weight after reversal of the hypothyroid state appear to be interrelated.

Comparison of thyroid hormone withdrawal and recombinant human thyroid-stimulating hormone administration for adjuvant therapy in patients with intermediate- to high-risk differentiated thyroid cancer.

OBJECTIVE: To compare the clinical outcome in patients who received adjuvant therapy with radioactive iodine (RAI) using different preparation methods, namely, thyroid hormone withdrawal (THW) and recombinant human thyroid-stimulating hormone (rhTSH), after undergoing thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma (DTC) according to the American Thyroid Association criteria. METHODS: Between May 2012 and October 2018, 136 patients who underwent adjuvant therapy with high-dose (3700 MBq) RAI for DTC without any metastatic lesions or macroscopic residual lesions after surgical resection were retrospectively selected. Patients were excluded if distant metastasis was confirmed during adjuvant therapy or if the outcome could not be confirmed; thus, 112 patients were finally evaluated. Patients underwent either a 3-week I restriction with thyroxine withdrawal or a 2-week I restriction with rhTSH administration. The serum thyroglobulin (Tg) concentration was measured, and 131I scintigraphy (370 MBq) was performed 6-12 months after adjuvant therapy. The definition of the initial achievement of adjuvant therapy was the disappearance of the uptake of 131I at the thyroid bed and serum Tg concentration < 2.0 ng/mL. The results of the adjuvant therapy between the groups were compared using the Fisher's exact test, and the TSH levels and estimated glomerular filtration rate (eGFR) were compared using the Welch's t test. RESULTS: The THW and rhTSH groups included 47 and 65 patients, respectively, and the intermediate- and high-risk groups included 63 and 49 patients, respectively. No patient was assigned to the low-risk group. In the THW and rhTSH groups, the initial RAI adjuvant therapy goal was achieved in 30/47 (63.8%) and 46/65 patients (70.8%), respectively (p = 0.54); mean ± standard deviation of the TSH levels was 123.8 ± 46.4 µIU/mL and 274.5 ± 97.7 µIU/mL, respectively (p < 0.01), and eGFR (treatment/pre-treatment) was 0.81 and 0.99, respectively (p < 0.01). In the intermediate- and high-risk groups, the initial RAI adjuvant therapy goal was achieved in 43/63 patients (68.3%) and 33/49 (67.3%), respectively (p = 1.0). CONCLUSION: No significant differences were observed between the preparation methods in the initial achievement of RAI adjuvant therapy. However, patients in the rhTSH group demonstrated higher TSH levels and retained eGFR.

Serum Matrix metalloproteinase-9 (MMP-9) can help identify patients with papillary thyroid cancer at high risk of persistent disease: Value and limitations of a potential marker of neoplasia.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an important mediator of invasion and metastasis in neoplasia. In thyroid cancer expression levels correlate with aggressiveness but data on peripheral MMP-9 levels are less definitive. OBJECTIVE: Prospective study evaluating serum MMP-9 in the diagnosis and prognosis of papillary thyroid cancer. METHODS: Serum samples of MMP-9 were drawn before surgery in 185 consecutively enrolled patients with nodular thyroid disease, stratified on pathology as benign disease (N= 88) and papillary thyroid cancer (N= 97). Serum MMP-9 was measured by an immunometric assay. RESULTS: MMP-9 levels were not different between benign vs malignant pathology (p= 0.3). In papillary thyroid cancer there was no significant difference in MMP-9 levels between histologies, TNM stage and invasive/non-invasive cancers. High-risk patients with multiple features of aggressiveness had significantly higher MMP-9 levels compared to low-intermediate risk patients (767.5 ± 269.2 ng/ml vs 563.7 ± 228.4 ng/ml, p= 0.019). A cut-off of 806 ng/ml distinguished high from low-intermediate risk patients with a sensitivity of 60% and a specificity of 87.36%, p= 0.018. In patients with available follow-up data (N= 78), MMP-9 was higher in patients who required ⩾ 2 doses of 131I therapy (p= 0.009) and in those with biochemical evidence of persistent disease/who required additional therapy to achieve disease-free status (p= 0.017). CONCLUSION: Serum MMP-9 is not useful in the diagnosis of PTC, but preliminary data shows that high pre-surgical serum MMP-9 levels may identify patients at higher risk of persistent disease who require intensive treatment. Large volume prospective studies are required to confirm this observation.

Levothyroxine Therapy in Thyrodectomized Patients.

Administration of the optimal dose of levothyroxine (LT4) is crucial to restore euthyroidism after total thyroidectomy. An insufficient or excessive dosage may result in hypothyroidism or thyrotoxicosis, either one associated with a number of symptoms/complications. Most literature regarding the LT4 dosage deals with the treatment of primary hypothyroidism, whereas a limited number of studies handle the issue of thyroxin replacement after total thyroidectomy. A literature review was performed focusing on all papers dealing with this topic within the last 15 years. Papers that reported a scheme to calculate the proper LT4 dose were collected and compared to set up a review exploring limits and drawbacks of LT4 replacement therapy in the wide population of patients who had undergone thyroidectomy. Most of the methods for monitoring and adjusting thyroid hormone replacement after thyroidectomy for benign disease use LT4 at an empirical dose of approximately 1.6 µg/kg, with subsequent changes according to thyroid function test results and assessments of the patient's symptoms. Approximately 75% of patients require a dose adjustment, suggesting that factors other than body weight play a role in the determination of the proper LT4 dose. Hence, several schemes are reported in the literature for the proper initial dose of LT4. An inadequate level of thyroid hormone levels in these patients can be due to several factors. The most common ones that lead to the necessity of LT4 dose adjustments include lack of compliance, changes in LT4 formulation, dosage errors, increased serum levels of T4-binding globulin, body mass changes, and dietary habits. Moreover, concomitant ingestion of calcium supplements, ferrous sulfate, proton-pump inhibitors, bile acid sequestrants, and sucralfate might influence LT4 absorption and/or metabolism. Furthermore, some gastrointestinal conditions and their treatments can contribute to suboptimal LT4 performance by altering gastric acidity and thereby reducing its bioavailability, particularly in the solid form. Beyond the classic tablet form, new formulations of LT4, such as a soft gel capsule and an oral solution, recently became available. The liquid formulation is supposed to overcome the food and beverages interference with absorption of LT4 tablets.

Estimating the Growth Rate of Lung Metastases in Differentiated Thyroid Carcinoma: Response Evaluation Criteria in Solid Tumors or Doubling Time?

Background: Estimating the growth rate of lung metastases for the treatment of patients with metastases of differentiated thyroid carcinoma (DTC) is important. This study aimed to evaluate survival outcomes according to different criteria for estimating the growth rate of lung metastases. Methods: Patients with macronodular (≥1 cm) lung metastases of DTC who underwent total thyroidectomy and high-dose radioactive iodine therapy between 1995 and 2013 were enrolled. The time to progressive disease (PD) by the Response Evaluation Criteria in Solid Tumors (RECIST), average tumor volume doubling time of the two dominant target lung lesions (midDT), and thyroglobulin doubling time (TgDT) were measured in each patient, and their association with disease-specific survival (DSS) was evaluated. Results: Forty-four patients with target lung metastatic nodules with an initial maximal diameter of 1.3 cm (median) were followed-up for a median of 6.8 years after the diagnosis of lung metastases. Based on RECIST, 12 patients (27.3%) showed fast tumor progression, with time to PD <1 year. When assessed by midDT, nine patients (20.5%) had midDT ≤1 year, showing rapid tumor progression. Seven of 33 patients (21.2%) who were negative for thyroglobulin antibody had midDT <1 year. Growth rates assessed by all three criteria were significantly associated with DSS. However, midDT had the highest predictive value for DSS, with a proportion of variation explained of 33.6%. Five-year DSS was 29.6% in patients with midDT ≤1 year, 50.0% in patients with time to PD <1 year, and 42.9% in patients with TgDT <1 year. Conclusions: Among the different criteria for estimating the growth rate of metastases in patients with lung metastases of DTC, midDT was the most powerful for predicting DSS, in comparison with RECIST and TgDT. Performing at least three serial chest computed tomography scans during the first year from the diagnosis of lung metastases can facilitate early detection of patients with rapid tumor progression and provide objective guidance for initiation of systemic therapy.

The most reliable time point for intact parathyroid hormone measurement to predict hypoparathyroidism after total thyroidectomy with central neck dissection to treat papillary thyroid carcinoma: a prospective cohort study.

PURPOSE: We assessed the optimal time for intact parathyroid hormone (iPTH) measurement for early detection of post-total thyroidectomy (TT) hypocalcemia in patients with papillary thyroid carcinoma (PTC). METHODS: In this single-center prospective cohort study, 143 patients who underwent TT with central neck dissection with or without lateral neck dissection for PTC were included. Biochemical profiles including iPTH, corrected total calcium, and ionized calcium within 24 h after surgery were analyzed. RESULTS: The 4-h postoperative iPTH was the most reliable predictor of post-TT transient or permanent hypoparathyroidism (cutoff for hypocalcemia was 3.75 pg/mL, AUC = 0.885, P < 0.001, sensitivity 81.6%, specificity 86.0%; cutoff for permanent hypocalcemia was 2.48 pg/mL, AUC = 0.819, P < 0.001, sensitivity 100%, specificity 57.8% calculated using ROC curves). CONCLUSIONS: The 4-h postoperative iPTH can most accurately predict hypoparathyroidism after TT with central neck dissection to treat PTC and facilitate the early discharge of low-risk postoperative hypoparathyroidism patients and decrease unnecessary overnight observation and calcium supplementation.

Selenium and thyroid cancer: a systematic review.

The aim of the study was to investigate the association between blood and tissue levels of selenium and thyroid cancer through a systematic review. We searched for observational studies written in English, Spanish, and Portuguese indexed in PubMed, LILACS, and Scielo without date restriction, that evaluated the association between selenium levels in whole-blood, serum, or plasma and/or thyroid tissue and thyroid cancer, both in individuals with cancer of thyroid as in healthy individuals. Then data were extracted and analyzed. Of the 570 articles identified, five cross-sectional studies were included in the review. In one study, lower concentrations of selenium were found in whole-blood (0.543 µg/ml) and in the thyroid (0.88 µg/g) of thyroid cancer patients compared to controls. Another study showed a decrease in serum selenium concentrations in patients with follicular carcinoma and papillary types (0.077 ± 0.021 µg/ml and 0.080 ± 0.020 µg/ml, respectively). On the other hand, other studies showed no difference in plasma selenium content or glutathione peroxidase activity among patients and healthy volunteers. The available evidence on this issue is inconclusive. Additional studies are needed to elucidate the association between serum and/or tissue levels of selenium and the development of thyroid cancer.

Associations of telomerase reverse transcriptase rs10069690 and rs2736100 polymorphisms with papillary thyroid carcinoma.

Papillary thyroid carcinoma is one of the most common endocrine malignancies. Telomerase reverse transcriptase rs10069690 and rs2736100 polymorphisms have been studied in thyroid carcinomas with different ethnicity, but the results were inconsistent. Therefore, we evaluated the relationship between rs10069690 and rs2736100 polymorphisms and papillary thyroid carcinoma risk and furtherly investigated the associations of these polymorphisms with stimulated thyroglobulin (sTg) positivity and adverse reactions of I treatment in papillary thyroid carcinoma. Four hundred thirty-six papillary thyroid carcinoma patients and 345 controls of Chinese Han population were included in our study. Rs10069690 and rs2736100 were genotyped using improved multiple ligase detection reactions. Analysis of inheritance model was performed using the unconditional logistic regression. In our study, rs10069690 and rs2736100 were associated with papillary thyroid carcinoma risk, especially in females over 45 years of age (P = 0.002 and P = 0.032, respectively). Rs10069690 was associated with sTg positivity and with an rs10069690-related occurrence risk order of thyroglobulin antibody (Tg-Ab)(+) + Tg(+) > Tg-Ab(+) + sTg(-) > Tg-Ab(-) + sTg(+). Patients with the homozygous TT genotype of rs10069690 had an increased risk of neck discomfort (P = 0.033), while the homozygous CC genotype of rs2736100 had a decreased risk of gastrointestinal toxicity (P = 0.048). Our data demonstrated that rs10069690 and rs2736100 might be bio-indicators related to papillary thyroid carcinoma risk in females over 45 years of age and I treatment-related toxicity. In addition, rs10069690 may be a predictor of bad clinicopathological features and poor prognosis from a serological point of view.

Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial.

PURPOSE: The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION. EXPERIMENTAL DESIGN: Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes. RESULTS: Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38-2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37-3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52-2.71; P < 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57-2.87; P < 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P < 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40-0.94), P = 0.022; placebo = 0.49 (0.29-0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit. CONCLUSIONS: We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

Targeting EZH2 as a novel therapeutic strategy for sorafenib-resistant thyroid carcinoma.

Thyroid carcinoma is the most common endocrine malignancy. Surgery, post-operative selective iodine-131 and thyroid hormone suppression were the most common methods for the therapy of thyroid carcinoma. Although most patients with differentiated thyroid carcinoma (DTC) showed positive response for these therapeutic methods, some patients still have to face the radioactive iodine (RAI)-refractory problems. Sorafenib is an oral multikinase inhibitor for patients with advanced RAI refractory DTC. However, the side effects and drug resistance of sorafenib suggest us to develop novel drugs and strategies for the therapy of thyroid carcinoma. In this study, we firstly found that patients with sorafenib resistance showed no significant change in rapidly accelerated fibrosarcoma and VEGFR expression levels compared with sorafenib sensitive patients. Moreover, a further miRNAs screen by qRT-PCR indicated that miR-124-3p and miR-506-3p (miR-124/506) were remarkably reduced in sorafenib insensitive patients. With a bioinformatics prediction and functional assay validation, we revealed that enhancer of zeste homolog 2 (EZH2) was the direct target for miR-124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH2 intervention with miR-124/506 overexpression or EZH2 inhibitor treatment in vitro and in vivo, which will lead to the decreased tri-methylation at lysine 27 of histone H3 (H3K27me3) and increased acetylated lysine 27 of histone H3 (H3K27ac) levels. Therefore, we conclude that the suppression of EZH2 represents a potential target for thyroid carcinoma therapy.

Role of 18F-Choline Positron Emission Tomography/Computed Tomography to Detect Structural Relapse in High-Risk Differentiated Thyroid Cancer Patients.

BACKGROUND: This study aimed to evaluate the role of 18F-choline (18F-FCH) positron emission tomography (PET)/computed tomography (CT) in high-risk differentiated thyroid cancer (DTC) patients with suspected relapse. It also compared 18F-FCH-PET/CT results with those of fludeoxyglucose (18F-FDG)-PET/CT and evaluated the additional diagnostic value and clinical impact of the combined use of these two tracers. Finally, it assessed the association between the clinical, biochemical, and histological parameters and 18F-FCH-PET/CT and 18F-FDG-PET/CT results. METHODS: The study prospectively enrolled high-risk DTC patients treated with thyroidectomy and radioactive iodine therapy and presenting high/increasing thyroglobulin levels under thyrotropin suppression, negative/inconclusive neck ultrasound, and negative 131I whole-body scan. All patients underwent 18F-FDG-PET/CT and 18F-FCH-PET/CT within 30 days of each other. Experienced nuclear medicine physicians examined the images of both procedures, and an integrated analysis of the two PET/CT modalities was also conducted. For each modality, a patient-based analysis (PBA) and lesion-based-analysis (LBA) was performed. On PBA, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. On LBA, only sensitivity was calculated. The standard of reference was based on clinical, imaging, and histological data. RESULTS: Twenty-five high-risk DTC patients were included; DTC relapse/persistence was confirmed in 23 patients. On PBA, 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the integrated evaluation of the two imaging modalities showed the following rates: sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 69.6%, 100%, 22.2%, 100%, and 72% versus 56.5%, 100%, 16.7%, 100%, and 60% versus 82.6%, 100%, 33.3%, 100%, and 84%, respectively. When compared with 18F-FDG-PET/CT, the integrated analysis of these two imaging procedures changed the clinical management in 4/23 (17%) patients. On LBA, the sensitivity rates of 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the combined evaluation of the two modalities were 58.7%, 38.1%, and 66.7%, respectively; when only lymph node involvement was considered, the rates were 56.3%, 53.1%, and 68.8%, respectively. Serum thyroglobulin doubling time (Tg-DT) <12 months was significantly associated with positive 18F-FCH-PET/CT. A trend toward a significant association was also found between positive 18F-FDG-PET/CT and both Tg-DT <12 months and DTC aggressive subtypes. CONCLUSION: 18F-FCH-PET/CT may add important information during the follow-up of high-risk DTC patients. 18F-FCH-PET/CT may be considered a useful complementary tool in patients affected by non-aggressive DTC subtypes, with Tg-DT <12 months, high risk of lymph node spreading, and negative or doubtful 18F-FDG-PET/CT.

30mCi radioactive iodine achieving comparative excellent response in intermediate/high-risk nonmetastatic papillary thyroid cancer: a propensity score matching study.

OBJECTIVE: To determine the efficacy of low-dose radioactive iodine (RAI) therapy (30 mCi, 1110 MBq) in Chinese patients with intermediate- to high-risk papillary thyroid cancer (PTC) without distant metastasis. DESIGN AND METHODS: This large retrospective study included Chinese patients with PTC that tested negative for thyroglobulin antibodies. Patients were categorized into low-dose (30 mCi, 1110 MBq) and high-dose (>100 mCi, 3700 MBq) RAI groups. Ablation rate and long-term response were compared between groups using propensity score matching (PSM) to minimize bias and confounding. RESULTS: In total, we included 446 patients. No significant difference in ablation success rate was found between groups (P = 0.305) before or after PSM (N = 162; P = 0.200). Excellent response (ER) rate was not significant between groups before (P = 0.917) or after PSM (P = 0.798). Efficacy of low-dose RAI was similar to that of high-dose RAI in N0- (P = 1.000), N1a- (P = 0.981), and N1b-stage (P = 0.903) patients. Low- and high-dose RAI groups achieved similar ER rates in pre-ablative stimulated thyroglobulin level (≤1 ng/mL, P = 1.000; 1 < ps-Tg ≤ 5 ng/mL, P = 0.444; 5 < ps-Tg ≤ 10 ng/mL, P = 0.665; >10 ng/mL, P = 1.000) and BRAFV600E-positive (P = 0.324) subgroups. CONCLUSIONS: Efficacy of low-dose RAI therapy was similar to that of high-dose for ablation and achieving ER in Chinese nonmetastatic intermediate- to high-risk PTC patients. High-dose RAI could not rectify ablation failure or non-ER rates in PTC patients with BRAFV600E, lymph node metastases, or unfavorable thyroglobulin levels.