Thyroglobulin Antibodies and Tumor Epitope-Specific Cellular Immunity in Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients.

Preoperative Serum Thyroglobulin Levels Predict Radioiodine Therapy Outcome in Papillary Thyroid Microcarcinoma Patients.

Our previous study showed that elevated preoperative thyroglobulin (pre-Tg) level predicted the risk of developing radioiodine refractory in PTC patients. In the present study, we aimed to evaluate the prognostic value of pre-Tg in papillary thyroid microcarcinoma (PTMC). After a specific inclusion and exclusion criteria were applied, a total of 788 PTMCs were enrolled from Jiangyuan Hospital affiliated to Jiangsu Institute of Nuclear Medicine between Jan 2015 and Dec 2019. Among them, 107 PTMCs were treated with radioiodine therapy (RAIT) and the response to therapy was grouped as excellent response (ER), and non-excellent response (NER: indeterminate response, IDR and biochemical incomplete response, BIR). Multivariable logistic regression was used to identify predictors for the response of RAIT in PTMCs. Higher pre-Tg levels were detected in PTMCs with RAIT as compared with PTMCs without RAIT (p=0.0018). Higher levels of pre-Tg were also found in patients with repeated RAIT as compared with patients with single RAIT (p<0.0001). Furthermore, pre-Tg level was higher in PTMC with IDR (n=16) and much higher in BIR (n=9) as compared with patients with ER (n=82, p=0.0003) after RAIT. Multivariate analysis showed that pre-Tg level over 16.79 ng/ml [OR: 6.55 (2.10-20.39), p=0.001] was the only independent predictor for NER in PTMC with RAIT. We found that high level of pre-Tg predicted a poor RAIT outcome in PTMC. Our finding explores a prospective way in identifying high-risk PTMCs with poor response to RAIT.

Predictors of response to Radioactive Iodine Therapy in Intermediate and high risk patients with papillary thyroid carcinoma.

BACKGROUND: Radioactive iodine (RAI) therapy is the standard treatment approach after total thyroidectomy in patients with papillary thyroid carcinoma (PTC). We aimed to identify predictive factors of response to the treatment in intermediate and high-risk patients with PTC. In addition, the impact of multiple RAI treatments was explored. METHODS: In a 3-year retrospective study, data from intermediate and high-risk patients with PTC who received RAI therapy following total thyroidectomy, were analyzed by the end of year-one and year-three. Demographic data, tumor size, capsular/vascular invasion, extrathyroidal extension, local or distant metastasis, initial dose and cumulative dose of RAI, serum thyroglobulin(Tg), antithyroglobulin antibody(TgAb), and imaging findings were investigated. Patients with an excellent response to a single dose of RAI treatment, after three years of follow-up were classified as the "Responder group". Excellent response was defined as stimulated serum Tg less than 1 ng/ml, or unstimulated serum Tg less than 0.2 ng/ml in TgAb-negative patients with negative imaging scans. RESULTS: 333 patient records with a complete data set were analyzed in this study. After three years of initial treatment, 271 patients were non-responders (NR) and 62 were responders (R). At baseline, the median pre-ablation serum Tg level was 5.7 ng/ml in the NR group, and 1.25 ng/ml in the R group (P < 0.001). TSH-Stimulated serum Tg greater than 15.7 ng/ml, was associated with response failure even after multiple RAI therapy, AUC: 0.717(0.660-0.774), sensitivity: 52.5%, specificity: 89.47%, P < 0.001. On the other hand, multiple RAI therapy was associated with excellent response in 16.2% of the patients. The chance of ER was decreased by 74% if initial post-operation ultrasound imaging confirmed the presence of locoregional involvement, OR 0.26, (95% CI: 0.12-0.55), P < 0.001. CONCLUSION: Stimulated serum Tg and locoregional involvement after total thyroidectomy are predictive factors of non-response to RAI therapy in intermediate and high-risk patients with PTC. In addition, a minority of patients achieve excellent response after multiple RAI therapy.

Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer.

OBJECTIVE: We aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. METHODS: Ten eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. RESULTS: Structurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was -15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. CONCLUSION: Anlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

The Effect of Mediterranean Diet on Thyroid Gland Activity.

The main goal of this research was to determine whether there is a correlation between adherence to the Mediterranean diet (assessed by the Mediterranean Diet Serving Score (MDSS)) and parameters indicating thyroid gland activity, such as concentration of thyroid-stimulating hormone (TSH), thyroid hormones (free triiodothyronine (fT3), free thyroxine (fT4)), thyroglobulin (Tg), antibodies to thyroid proteins (thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb)), and calcitonin (CT) in plasma and serum samples. An additional objective was to investigate whether there are differences in the values of the MDSS among clinical groups (euthyroid individuals, euthyroid individuals with positive TgAb and/or TPOAb, and hypothyroid and hyperthyroid participants). This cross-sectional study included 4620 participants over 18 years of age from the islands of Korcula and Vis, and the mainland city of Split. The MDSS was assessed from a food frequency questionnaire (FFQ). MDSS values were significantly higher in females compared to males and showed a positive association with the age of the participants. There was no significant difference in the MDSS values among the examined clinical groups. In the group of subjects with euthyroidism, a significant positive association was found between fT3 and the MDSS, while in the group of subjects with subclinical hypothyroidism, a significant positive association was observed between the MDSS and both fT3 and fT4. CT levels were also positively associated with the MDSS. Considering the significant positive association of the MDSS and both fT3 and fT4 levels in patients with subclinical hypothyroidism, the results of this study could be used to create guidelines for selecting an appropriate, potentially protective diet for these patients.

The impact of intraoperative neural monitoring during papillary thyroid cancer surgery on completeness of thyroidectomy and thyroglobulin response: a propensity-score matched study.

BACKGROUND: Intraoperative neural monitoring (IONM) has been utilized for a variety of thyroid pathologies, including papillary thyroid carcinoma (PTC). Remnant thyroid tissue following total thyroidectomy (TT) in patients with PTC is associated with increased recurrence. The aim of this study is to investigate whether the use of IONM in PTC surgery has an impact on the completeness of thyroidectomy. METHODS: Retrospectively, patients with preoperative diagnosis of PTC, who underwent TT in a tertiary center were reviewed. They were grouped based on the IONM usage, and 1:1 propensity-score match was performed. Primary outcome was the completeness of thyroidectomy, determined by measuring postoperative stimulated thyroglobulin levels (sTg). RESULTS: Among 274 clinically node-negative PTC patients who underwent TT and ipsilateral prophylactic central lymph-node dissection, a total of 170 patients (85:85) were matched. Postoperative sTg levels were significantly lower in the IONM group (1 ng/dL vs. 0.4 ng/dL; p < 0.01) with higher percentage of the patients with sTg levels <1 ng/ml (50.6% vs. 69.4%; p = 0.01). More patients in the no-IONM group received RAI ablation with significantly higher doses (mean mci: 120 vs. 102; p = 0.02). CONCLUSION: The use of IONM during thyroidectomy provides improvement in the completeness of thyroidectomy and reduction in postoperative sTg levels which can be used as a guide by clinicians to avoid RAI ablation in selected PTC patients and to adjust low ablative doses in patients who are scheduled for remnant ablation.

Markedly elevated serum preoperative thyroglobulin predicts radioiodine-refractory thyroid cancer.

BACKGROUND: Repeated radiotherapy brings limited benefits and significant side effects for differentiated thyroid cancer patients (DTC) with radioiodine refractory (RAIR). However, the prognostic role of preoperative thyroglobulin (pre-Tg) in predicting RAIR is unclear. METHODS: In the present study, data were retrospectively reviewed from 5173 patients who underwent radiotherapy in the Jiangyuan Hospital from January 2006 to December 2020. RESULTS: A total of 1,102 patients with or without repeated radiotherapy were compared (repeated vs. single radiotherapy; n = 199 vs. n = 903). Pre-Tg was significantly elevated in patients with repeated radiotherapy. After the classification of RAIR (non-RAIR, n = 786 vs. RAIR, n = 90), elevated pre-Tg was also correlated with RAIR after univariate and multivariate analyses. According to the receiver operating characteristic curve analysis, elevated pre-Tg well predicted RAIR (AUC = 0.76, CI: 0.71-0.82, p < 0.0001). To control the selection bias, the propensity score matching was used. Pre-Tg level was found to be an independent predictor of RAIR (p < 0.001, HR = 7.25, CI: 2.55-20.62). CONCLUSION: Our results indicate that markedly elevated pre-Tg level can be served as an independent predictor of RAIR-DTC, which can guide a more precise treatment strategy and/or an active surveillance during surgery and follow-ups.

Iodine deficiency in pregnancy along a concentration gradient is associated with increased severity of preeclampsia in rural Eastern Cape, South Africa.

BACKGROUND: Preeclampsia is a leading cause of maternal mortality and morbidity in South Africa. Iodine deficiency in pregnancy, which is amenable to correction through iodine supplementation, has been reported to increase the risk of preeclampsia. However, the association of iodine nutrition status with preeclampsia in South Africa has not been studied. METHODS: We enrolled 51 randomly selected normotensive pregnant controls at term together with 51 consecutively selected cases of preeclampsia and 51 cases of severe preeclampsia/eclampsia, all in the third trimester, from Mthatha Regional and Nelson Mandela Academic Hospital in the Eastern Cape Province. Urinary iodine concentration (UIC), serum thyroid-stimulating hormone (TSH), triiodothyronine (FT3), thyroxine (FT4) and thyroglobulin (Tg) levels were compared between cases and controls. RESULTS: The respective chronological and gestational ages at enrolment for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were: age 23, 24 and 19 years (p = 0.001), and gestational age 38, 34, and 35 weeks (p < 0.001). The median gravidity was 1 for all three groups. The median UIC, FT4, FT3 revealed a decreasing and Tg a rising trend with the severity of preeclampsia (p < 0.05). TSH had a non-significant rising trend (p > 0.05). The respective median values for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were UIC 217.1, 127.7, and 98.8 µg/L; FT4 14.2, 13.7, and 12. pmol/L; FT3 4.8, 4.4, and 4.0 pmol//L; Tg 19.4, 21.4, and 32. Nine microgram per liter; TSH 2.3, 2.3, and 2.5 mIU/L. UIC < 100 µg/L, Tg > 16 µg/L and FT4 < 11.3 pmol/L were independent predictors of preeclampsia/eclampsia syndrome. CONCLUSION: Women with severe preeclampsia/eclampsia had significantly low UIC and high Tg, suggesting protracted inadequate iodine intake. Inadequate iodine intake during pregnancy severe enough to cause elevated Tg and FT4 deficiency was associated with an increased risk of severe preeclampsia/eclampsia.

Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7.

PURPOSE: To date, many genes have been associated with congenital hypothyroidism (CH). Our aim was to identify the mutational spectrum of 23 causative genes in Turkish patients with permanent CH, including thyroid dysgenesis (TD) and dyshormonogenesis (TDH) cases. METHODS: A total of 134 patients with permanent CH (130 primary, 4 central) were included. To identify the genetic etiology, we screened 23 candidate genes associated with CH by next-generation sequencing. For confirmation and to detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. RESULTS: Possible pathogenic variants were found in 5.2% of patients with TD and in 64.0% of the patients with normal-sized thyroid or goiter. In all patients, variants were most frequently found in TSHR, followed by TPO and TG. The same homozygous TSHB variant (c.162 + 5G > A) was identified in four patients with central CH. In addition, we detected novel variants in the TSHR, TG, SLC26A7, FOXE1, and DUOX2. CONCLUSION: Genetic causes were determined in the majority of CH patients with TDH, however, despite advances in genetics, we were unable to identify the genetic etiology of most CH patients with TD, suggesting the effect of unknown genes or environmental factors. The previous studies and our findings suggest that TSHR and TPO mutations is the main genetic defect of CH in the Turkish population.

Preoperative platelet distribution width-to-platelet ratio combined with serum thyroglobulin may be objective and popularizable indicators in predicting papillary thyroid carcinoma.

OBJECTIVES: The incidence of papillary thyroid carcinoma (PTC) has increased more rapidly than that of any other cancer type in China. Early indicators with high sensitivity and specificity during diagnosis are required. To date, there has been a paucity of studies investigating the relationship between preoperative platelet distribution width-to-platelet count ratio (PPR) and PTC. This study thus aimed to assess the diagnostic value of PPR combined with serum thyroglobulin (Tg) in patients with PTC. METHODS: A total of 1001 participants were included in our study. 876 patients who underwent surgery for nodular goiter were divided into the PTC group or benign thyroid nodule (BTN) group according to pathology reports, and 125 healthy controls (HCs) were included. Preoperative hemogram parameters and serum Tg levels were compared among three groups. Receiver operating characteristic (ROC) curve was used to evaluate the value of PPR combined with serum Tg for diagnosing PTC. RESULTS: Platelet distribution width (PDW) and PPR levels were higher in the PTC group than in the BTN and HC groups (both p < 0.05) but did not significantly differ between the BTN and HC groups. PDW and PPR levels significantly differed in the presence/absence of lymph node metastasis, the presence/absence of capsule invasion (p = 0.005), and TNM stages (p < 0.001). Multivariable analyses indicated that high serum Tg levels [adjusted odds ratio (OR), 1.007; 95% confidence interval (CI), 1.004-1.009; p < 0.001], high neutrophil-to-lymphocyte ratio (NLR,adjusted OR, 1.928; 95% CI, 1.619-2.295; p < 0.001), and high PPR (adjusted OR, 1.378; 95% CI, 1.268-1.497; p < 0.001) were independent risk factors for PTC. In ROC analysis, the areas under the curves (AUCs) of serum Tg, PDW, PPR, and NLR for predicting PTC were 0.603, 0.610, 0.706, and 0.685, respectively. PPR combined with serum Tg (PPR + Tg) had a higher diagnostic value (AUC, 0.738; sensitivity, 60%; specificity, 74.7%) compared with PDW + Tg (AUC, 0.656; sensitivity, 64.4%; specificity, 59.9%) and NLR + Tg (AUC, 0.714; sensitivity, 61.6%; specificity, 71.1%). CONCLUSIONS: Preoperative PPR combined with serum Tg may be objective and popularizable indicators for effective predicting PTC.

Postoperative Surveillance in Older Adults With T1N0M0 Low-risk Papillary Thyroid Cancer.

BACKGROUND: The frequency and cost of postoperative surveillance for older adults (>65 y) with T1N0M0 low-risk papillary thyroid cancer (PTC) have not been well studied. METHODS: Using the SEER-Medicare (2006-2013) database, frequency and cost of surveillance concordant with American Thyroid Association (ATA) guidelines (defined as an office visit, ≥1 thyroglobulin measurement, and ultrasound 6- to 24-month postoperatively) were analyzed for the overall cohort of single-surgery T1N0M0 low-risk PTC, stratified by lobectomy versus total thyroidectomy. RESULTS: Majority of 2097 patients in the study were white (86.7%) and female (77.5%). Median age and tumor size were 72 y (interquartile range 68-76) and 0.6 cm (interquartile range 0.3-1.1 cm), respectively; 72.9% of patients underwent total thyroidectomy. Approximately 77.5% of patients had a postoperative surveillance visit; however, only 15.9% of patients received ATA-concordant surveillance. Patients who underwent total thyroidectomy as compared with lobectomy were more likely to undergo surveillance testing, thyroglobulin (61.7% versus 24.8%) and ultrasound (37.5% versus 29.2%) (all P < 0.01), and receive ATA-concordant surveillance (18.5% versus 9.0%, P < 0.001). Total surveillance cost during the study period was $621,099. Diagnostic radioactive iodine, ablation, and advanced imaging (such as positron emission tomography scans) accounted for 55.5% of costs ($344,692), whereas ATA-concordant care accounted for 44.5% of costs. After multivariate adjustment, patients who underwent total thyroidectomy as compared with lobectomy were twice as likely to receive ATA-concordant surveillance (adjusted odds ratio 2.0, 95% confidence interval: 1.5-2.8, P < 0.001). CONCLUSIONS: Majority of older adults with T1N0M0 low-risk PTC do not receive ATA-concordant surveillance; discordant care was costly. Total thyroidectomy was the strongest predictor of receiving ATA-concordant care.

Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum.

OBJECTIVES: Matrix differences among serum samples from non-pregnant and pregnant patients could bias measurements. Standard Reference Material 1949, Frozen Human Prenatal Serum, was developed to provide a quality assurance material for the measurement of hormones and nutritional elements throughout pregnancy. METHODS: Serum from non-pregnant women and women in each trimester were bottled into four levels based on pregnancy status and trimester. Liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed and applied to the measurement of thyroid hormones, vitamin D metabolites, and vitamin D-binding protein (VDBP). Copper, selenium, and zinc measurements were conducted by inductively coupled plasma dynamic reaction cell MS. Thyroid stimulating hormone (TSH), thyroglobulin (Tg), and thyroglobulin antibody concentrations were analyzed using immunoassays and LC-MS/MS (Tg only). RESULTS: Certified values for thyroxine and triiodothyronine, reference values for vitamin D metabolites, VDBP, selenium, copper, and zinc, and information values for reverse triiodothyronine, TSH, Tg, and Tg antibodies were assigned. Significant differences in serum concentrations were evident for all analytes across the four levels (p≤0.003). TSH measurements were significantly different (p<0.0001) among research-only immunoassays. Tg concentrations were elevated in research-only immunoassays vs. Federal Drug Administration-approved automated immunoassay and LC-MS/MS. Presence of Tg antibodies increased differences between automated immunoassay and LC-MS/MS. CONCLUSIONS: The analyte concentrations' changes consistent with the literature and the demonstration of matrix interferences in immunoassay Tg measurements indicate the functionality of this material by providing a relevant matrix-matched reference material for the different stages of pregnancy.

Iodine supplementation for pregnant women: a cross-sectional national interventional study.

BACKGROUND: Although Iran has been considered iodine replete since 2000, the first national survey of iodine intake among Iranian pregnant women in 2014 indicated that despite the adequate intake of iodine by the general population, this vulnerable group has moderate iodine deficiency. Therefore, in this national cross-sectional interventional study, we aimed to assess the iodine intake and thyroid function of Iranian pregnant women 2 years after implementing national iodine supplementation for this vulnerable group. MATERIALS AND METHODS: In this cross-sectional study, we conducted a national interventional survey of pregnant women. A total of 1200 pregnant women (400 women from each trimester) from 12 provinces of Iran were recruited from the antenatal care clinics from October 2018 to March 2019. The median urinary iodine concentration (MUIC), as an indicator of iodine status in three spot urine samples, was measured, along with the serum total T4 (TT4), thyrotropin (TSH), thyroglobulin (Tg), thyroid peroxidase antibody (TPO-Ab), and iodine content of household salt. RESULTS: The mean age of the cohort was 28 ± 6.2 years, with the mean gestational age of 22.7 ± 13.0 weeks. The overall MUIC (IQR) of pregnant women was 188 µg/L (124.2-263 µg/L). Also, the MUICs in the three trimesters of pregnancy were 174 µg/L (110-254), 175 µg/L (116-251), and 165 µg/L (114-235), respectively. The MUICs ≥ 150, 100-149, and < 100 µg/L were found in 63, 19.8, and 16.2% of the subjects, respectively. The mean TT4 level was 12 ± 4.5 µg/dL, and the median (IQR) level of TSH was 2.37 mIU/L (1.66-3.18 mIU/L). According to our local reference range, 118 (10.5%) pregnant women had subclinical hypothyroidism, 6 (0.53%) women had isolated hypothyroxinemia, and 65 (5.7%) women were TPO-Ab positive. Also, the median (IQR) level of Tg was 10.08 µg/dL (5.7-20.4 µg/dL), and the median iodine content of household salt was 29.6 µg/g; the iodine content was ≥ 30 µg/g in 85% of household salt. The results showed that more than 95% of households were under iodized salt coverage. CONCLUSION: The results of this study indicated that iodine supplementation with at least 150 µg of iodine per day improved the iodine intake of pregnant women. Except for subclinical hypothyroidism, the prevalence of clinical hypothyroidism, clinical/subclinical thyrotoxicosis, TPO-Ab positivity, and isolated hypothyroxinemia decreased significantly, which emphasizes the importance of iodine supplementation during pregnancy.

Serum thyroglobulin is associated with orbitopathy in Graves' disease.

PURPOSE: Serum thyroglobulin levels are often elevated in Graves' disease (GD) and in most cases decrease during treatment. Its relation to Graves' orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). METHODS: We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen. RESULTS: At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30-555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5-287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ. CONCLUSION: The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.

A case of postpartum thyroiditis following SARS-CoV-2 infection.

Postpartum thyroiditis (PPT) is characterized by mild thyrotoxicosis occurring within one year of parturition commonly followed by transient hypothyroidism. Having genetic background of autoimmune thyroid disorders is a risk factor for it because the immune reactivation during postpartum period is a trigger for PPT. Pandemic of COVID-19: caused by SARS-CoV-2 infection is a global health problem, and occurrence of Graves' disease and Hashimoto's thyroiditis after the viral infection have been reported but occurrence of PPT with COVID-19 has never been reported. A 29-year-old woman developed general fatigue four and a half months after parturition, and was diagnosed as having PPT: one month before, she had COVID-19. Hereafter, we define the date of delivery as Day 0 to make timeline clear. SARS-CoV-2 infection was diagnosed by PCR on Day 103, its disappearance from the upper airway confirmed on Day 124, and the thyroiditis diagnosed on Day 136. She had been euthyroid on Day 0 and 95, but thyrotoxic on Day 136. Serum thyroglobulin (Tg) concentration was normal in the presence of anti-Tg antibody, other thyroid-related autoantibodies were negative, and by ultrasonography, the thyroid gland was normal in size and no evidence of increased vascularity. Thyroid function returned to normal by Day 172 without any specific drug therapy. In conclusion, although a clear causal relationship could not be found, we documented the world's first case of PPT developed following COVID-19.

High Iodine Nutrition May Be a Risk Factor for Cervical Lymph Node Metastasis in Papillary Thyroid Cancer Patients.

PURPOSE: The aim of this study was to retrospectively identify the effect of iodine on the papillary thyroid cancer (PTC) process and investigate the risk clinicopathologic characteristics of cervical lymph node metastasis (CLNM) for achieving a better preventive strategy of PTC. METHODS: Totally 187 patients with CLNM and 279 without CLNM (NCLNM) were enrolled, and their urinary iodine concentration (UIC) and serum iodine concentration (SIC) were measured. Logistic regressions were used to reveal the effects of iodine nutrition on the CLNM status of PTC. RESULTS: The levels of thyroid-stimulating hormone (TSH) and thyroglobulin (TG) were higher in the CLNM group than in the NCLNM group. UIC and SIC were positively correlated, and both of them were correlated with TSH, free thyroxine, and TG. The proportions of UIC >300 µg/L and of SIC >90 µg/L were higher in the CLNM than in the NCLNM. Logistic analysis showed that SIC >90 µg/L was an independent predictor for CLNM in PTC. Additionally, age ≥45, female, TG, multifocality, and diameter of cancer invasion >1 cm also affected CLNM status in PTC, and their logistic regression model showed a certain diagnostic accuracy (area under the receiver-operating characteristic curve = 0.72). CONCLUSIONS: Relatively high iodine nutrition seemed to be a significant risk factor for the occurrence of CLNM in PTC and may promote lymphatic metastasis in PTC.

Comparison between a new thyroglobulin assay with the well-established Beckman Access immunoassay: A preliminary report.

OBJECTIVES: Measurement of serum thyroglobulin (Tg) plays a key role in the post-thyroidectomy management of differentiated thyroid carcinoma (DTC). In this context, the performance of new-generation thyroglobulin assay has clinical implications in the follow-up of DTC patients. Aim of this study was to compare the new highly sensitive Liaison Tg II (Tg-L) with the well-established Tg Access assay (Tg-A). MATERIALS AND METHODS: A total of 91 residual serum samples (23 positive and 68 negatives for Tg auto-antibodies) were tested by the Beckman Access and Diasorin Liaison assays. Study samples were from 21 patients with pathologically proven DTC and control samples from 70 (16 patients with benign thyroid disease and 54 apparently healthy subjects). RESULTS: Our results showed that Tg-L was highly correlated with Tg-A for both values ranging between 0.2 and 50 ng/mL (Pearson's r = 0.933 [95%CI 0.894-0.958], P < .001) and higher than 50 ng/mL (Pearson's r = 0.849 [95%CI 0.609-0.946], P < .001). For Tg values lower than 0.2 ng/mL, the overall concordance rate was 92%. Moreover, we tested 7 fine-needle aspiration washout fluids (FNA), showing an overall concordance rate in discriminating negative and positive of 100%. Finally, we found no interference by Tg auto-antibodies (TgAbs) for both Tg-L and Tg-A. Conversely, rheumatoid factor (RF) interferes with Tg-A, but not with Tg-L in one patient with no relapsing thyroid carcinoma. CONCLUSIONS: Liaison Tg II demonstrated a good correlation with Access Tg assay both for sera and FNAs. Further studies on larger population are needed to evaluate Tg-L clinical impact on DTC patient's follow-up.

Predictors of thyroglobulin in the lymph nodes recurrence of papillary thyroid carcinoma undergoing total thyroidectomy.

BACKGROUND: To investigate the association between postoperative lymph nodes (LNs) recurrence and distinct serum thyroglobulin (Tg) levels in patients with papillary thyroid carcinoma (PTC). METHODS: This study included PTC patients who underwent total thyroidectomy (TT) with at least central neck dissection and then re-operated due to recurrence of LNs between January 2013 and June 2018. These patients were grouped by negative or positive serum Tg levels according to the American Thyroid Association guidelines. RESULTS: Of the 60 included patients, 49 underwent radioactive iodine (RAI) treatment. Maximum unstimulated Tg (uTg) ≥ 0.2 ng/mL were associated with larger diameter of recurrent LNs (P = 0.027), and higher rate of metastatic LNs (P < 0.001). Serum-stimulated Tg (off-Tg) ≥ 1 ng/mL (P = 0.047) and unstimulated Tg (on-Tg) ≥ 0.2 ng/Ml (P = 0.013) were associated with larger diameter of recurrent LNs. Number of metastatic LNs ≥ 8 was an independent predictor for postoperative maximum uTg ≥ 0.2 ng/mL (OR = 8.767; 95% CI = 1.392-55.216; P = 0.021). Ratio of metastatic LNs ≥ 25% was an independent predictor for off-Tg ≥ 1 ng/mL (OR = 20.997; 95% CI = 1.649-267.384; P = 0.019). CONCLUSION: Postoperative Tg-positive status was associated with larger size of recurrent LNs. Number of metastatic LNs ≥ 8 and ratio of metastatic LNs ≥ 25% were independent predicators for uTg-positive and off-Tg-positive status, respectively.

Stimulated serum thyroglobulin but not RAIU level is a prognostic factor for ablation efficacy with a 3.7GBq (100mCi) fixed 131I dose in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of this study was to determine prognostic value of radioactive iodine uptake (RAIU) and stimulated thyroglobulin (sTg) regarding the ablation efficacy in patients with differentiated thyroid cancer. SUBJECTS AND METHODS: We studied 466 differentiated thyroid cancer (DTC) patients without distant metastases after thyroidectomy who underwent iodine-131 (131I) ablation and were pre-therapy assessed by RAIU. The patients were divided into four groups according to the RAIU result, including: A) RAIU<2%, B) 2%≤RAIU<5%, C) 5%≤RAIU<10% and D) RAIU≥10%. Every group was divided into four subgroups according to sTg levels, namely: 1) sTg<2ng/mL, 2) 2ng/mL≤sTg<5ng/mL, 3) 5ng/mL≤sTg<10ng/mL and 4) sTg≥10ng/mL subgroup. The ablation success was defined as a negative scan 6 months to 1 year and other imaging like US did not detect anything suspicious after ablation. Excellent response was considered as: sTg<1ng/mL with negative thyroglobulin antibodies (TgAb) and negative image scans. RESULTS: The rate of successful ablation was 88.3%, 88.7%, 88.4% and 79% between group A to D, respectively (P=0.779). There was also no significant difference about the excellent response rate (64.5% vs 63.6% vs 48.8% vs 57.1%, P=0.256) between group A to D. The ablation success rate did not differ significantly between subgroups 1 to 4 in every group. However, the rates of excellent response were 86.8%, 52.1%, 25% and 15.2% between subgroups 1 to 4 for group A, respectively (P<0.001). Similarly, there was a significant difference about excellent response rate between subgroups 1 to 4 for groups B, C and D. CONCLUSION: After total thyroidectomy, not RAIU but sTg is a prognostic factor for ablation efficacy with a 3.7GBq (100mCi) fixed 131I dose in patients with DTC.

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.

Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1ß, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.