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Fine-needle aspiration cytology (FNAC), used in suspicious cervical lymph nodes of unknown origin is frequently inconclusive and prone to false negatives. In order to evaluate the usefulness of measuring thyroglobulin in the washing with saline solution of the puncture needle for the diagnosis of metastasis of papillary carcinoma of the thyroid, an optimal thyroglobulin cutting point has to be calculated, being positive or negative depending on whether the thyroglobulin levels are higher or lower than the cutting point. We have retrospectively studied 33 patients (19 women and 14 men) with an average age of 49.3 years, with papillary carcinoma of the thyroid and suspected lymph node metastasis. Of them 16 (47.1%) had a positive FNAC. To determine thyroglobulin predictive capacity with regards to the metastasis of papillary carcinoma of the thyroid a ROC analysis was carried out with an under curve area UCA: 0.987 (CI 95%: 0.808-1.000) obtaining, using Youden's J statistic, 0.4 ng/ml as the thyroglobulin cutting point with best predictive capacity. The study of the relationship between thyroglobulin and the preservation/non-preservation of the thyroid showed statistically significant differences (P=.023). Our results validate 0.4 ng/ml of thyroglobulin as an optimal cutting point of the presence of metastasis of papillary carcinoma of the thyroid in lymph nodes. When reviewing the bibliography, a great diversity of cutting points may be found, which is explained mainly by the great inter-observer and inter-assay variability. That is why we recommend calculating each laboratory's own optimal cutting point; and determine in subsequent studies two cutting points depending on whether or not thyroid is preserved., (Copyright © 2024 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The purpose of this study was to evaluate the efficacy and clinical value of US, FNAC,FNA-Tg and FNAC + FNA-Tg, as well as the cutoff values of FNA-Tg to evaluate LN metastasis., Methods: We analyzed the diagnostic value of different US signs, the efficiency of US, FNAC, FNA-Tg and FNAC + FNA-Tg among the LN- and LN + groups, and the cutoff value of FNA-Tg to evaluate LN metastasis. We punctured LNs multiple times and measured the levels of FNA-Tg. Furthermore, the LNs were marked with immunohistochemical Tg and LCA to distinguish the presence of Tg in the para-cancerous tissue of the LNs., Results: The s-Tg and FNA-Tg of the LN + group were higher than those of the LN- group (P = 0.018, ≤ 0.001). The LN + group had more abnormal US signs than the LN- group. The cutoff value of FNA-Tg was 3.2 ng/mL. US had a high sensitivity (92.42), but the specificity was not satisfactory (55.1). FNA-Tg had a higher sensitivity (92.42 vs. 89.39), specificity (100 vs. 93.88), and accuracy (92.42 vs. 83.27) than FNAC. However, the sensitivity of FNAC + FNA-Tg increased further, while the specificity and accuracy decreased slightly. The presence of Tg in the normal lymphocytes adjacent to the cancer was confirmed., Conclusion: Ultrasonography provides a noninvasive, dynamic, multidimensional assessment of LNs. With a cutoff value of 3.2 ng/mL, FNA-Tg has higher accuracy and a lower false-negative rate than various single diagnoses. However, FNAC combined with FNA-Tg does not cause additional pain to patients and offers a higher diagnostic efficacy and clinical value., (© 2024. The Author(s).)

Objective: The aim of this study was to prospectively evaluate the quality of postoperative neck ultrasound (POU) for thyroid cancer patients after implementing European Thyroid Association (ETA) guideline-based POU assessment., Methods: Our analysis involved 672 differentiated thyroid cancer patients. POU report quality was compared between the implementation radiology group (IRG), which implemented ETA guideline-based assessment in 2018, and all non-implementation radiology groups (NIRG). Differences in POU quality were evaluated before and after the implementation of guideline-based assessment. Additionally, we evaluated the ability of serum thyroglobulin (Tg) level <0.2 ng/mL or between 0.21 and 0.99 ng/mL and normal POU lesion status at 1-year follow-up to predict the absence of persistent disease or relapse at 3-year follow-up., Results: IRG had significantly higher mean utility scores for POU reports of abnormal thyroid bed nodules compared to NIRG (P < 0.001). IRG's POU reports for suspicious nodules and lymph nodes were considered sufficient in 94% and 85% of cases, respectively, compared to 45% and 68% for NIRG. For patients with normal US lesion status and Tg <0.2 ng/mL or Tg 0.21-0.99 ng/mL at 1-year follow-up, the negative predictive values were 96% for both., Conclusions: Implementation of 2013 ETA POU-reporting guidelines allowed for the provision of high-quality POU reports, which may lead to increased accuracy in assessing the response to treatment and in estimating the risk of recurrence of thyroid cancer and likely reduce unnecessary repeat POU or FNA.

Background: It has been suggested that small metastatic lymph nodes (LNs) detected after initial surgery in patients with differentiated thyroid cancer (DTC) can be managed with active surveillance (AS). However, there is still concern regarding the clinical outcomes of these patients. The main aims of our study were as follows: (1) to assess the frequency of growth and the need of additional treatment in a group of patients with LN recurrences selected for AS, and (2) to determine predictive factors of LN progression. Methods: We retrospectively reviewed 856 clinical records from our DTC patient's database (May 2010 to January 2022). Eighty patients had suspicious cervical LNs on consecutive ultrasound (US) after initial surgery, but we included 50 patients with cytological confirmation of metastatic disease and at least 12 months follow-up. Exclusion criteria were as follows: any LN ≥2 cm or multiple LNs ≥1.5 cm in size, proximity to vital structures, PET-positive disease (standard uptake value ≥5), aggressive histology, and distant metastasis. Patients were followed with thyroglobulin (Tg) and thyroglobulin antibodies measurements on suppressive therapy and neck US every 6-12 months. LN growth was defined as an increase of ≥3 mm in any of its diameters. Results: A total of 50 patients had a median age of 41 years (range, 18-75). Most patients were women (80%) and had classical papillary thyroid cancer (86%). The mean size of the LNs was 10.1 ± 4.4 mm. After a median follow-up of 29 months (range, 12-144), 12 patients (24%) had an increase in size of the metastatic LN, 7 (58%) of whom were surgically removed. None of these seven patients had a structural incomplete response at the end of follow-up. The only variable that predicted an increase in LN size was a rise in Tg levels ≥0.5 ng/mL ( p  = 0.016). Based on a multivariate analysis, patients with increase in Tg levels ≥0.5 ng/mL had a significantly higher chance of developing LN growth (odds ratio [OR] 16.2 [confidence interval, CI 1.5-120.2], p  = 0.020). The median progression-free survival rate was 6.6 years [CI 5.6-9.5]. Conclusion: AS of small LNs could be a feasible alternative to immediate surgery in properly selected patients.

Background: The measurement of plasma thyroglobulin (Tg) is widely used in the monitoring of differentiated thyroid cancer (CDT). In recent years, its value as a prognostic marker prior to ablation with radioiodine has increased, demonstrating its high negative predictive value. Recent studies indicate that a wide variety of factors could potentially influence pre-ablative Tg values, including residual tumor burden and stimulation modality., Aim: To relate the value of pre-ablative Tg with the amount of preoperative disease burden, lymph node metastases, treatment, and presence of residual disease., Material and Methods: Retrospective observational study of 70 patients with CDT treated between 2012 and 2018. The amount of disease burden was defined as the sum of largest diameter of individual tumors in each patient, and as the individually largest tumor per patient and number of metastatic lymph nodes., Results: A smaller tumor size and absence of remnant tissue was associated with lower Tg values, although the association was not always significant. Furthermore, no significant difference was found between Tg levels measured within or more than 14 days after the surgical procedure. Thus, an early measurement of pTg after surgery would allow an initial therapeutic decision making., Conclusions: A statistical association between pre-ablative Tg levels and the amount of preoperative tumor tissue burden was found in some subgroups of patients.

Aim: Therapy success in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine therapy (RIT) is proven by permanent decrease in human thyroglobulin (hTg) to <1 ng/mL. In this retrospective analysis hTg development before, during and after pregnancy were analyzed. Material and methods: A descriptive analysis of hTg courses in 47 women with 57 pregnancies under levothyroxine substitution was performed after treatment of DTC without evidence of residual or recurrent disease. We compared hTg levels before, during and after pregnancies. A median of four measurements were performed during pregnancy. Results: In five out of the 47 patients at least one hTg increase to ≥1.0 ng/mL occurred during pregnancy (P1: 1.1; P2: 1.75; P3: 1.0; P4: 1.1; P5: 1.07 ng/mL). In another three cases an increase to ≥0.5 ng/mL occurred. After delivery, all patients returned to undetectable hTg levels. Human Tg maxima during pregnancy were significantly elevated according to Friedman´s Chi2 and p Holm−Bonferroni. Conclusion: In women with ablative thyroid therapy after DTC, a temporary elevation in hTg levels during pregnancy may occur. The reason therefore remains unclear and requires further investigation.

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., (© 2021. Italian Society of Endocrinology (SIE).)

Objective: To study the optimal cut-off value of thyroglobulin measurement in a fine-needle aspiration (FNA-Tg) in diagnosing malignant lymph nodes and benign lymph nodes (LNs) according to the thyroid tissue status. Methods: A total of 517 LNs were aspirated: 401 preoperative LNs, 42 LNs after subtotal thyroidectomy and 74 suspected LNs after total thyroidectomy. The cut-off value of FNA-Tg was obtained from receiver operating characteristic (ROC) analysis. The cut-off value with the best diagnostic performance was then obtained by comparing different cut-off values from other studies. Results: LN FNA-Tg levels differed between preoperative and total thyroid disease ( p < 0.001) and subtotal thyroidectomy and total thyroidectomy ( p = 0.03), but not between preoperative and subtotal thyroidectomy ( p = 1.00). Accordingly, those 443 LNs with preoperative and subtotal thyroidectomy were compared to those 74 without thyroid tissue. The optimal cut-off value in thyroid tissue group was 19.4 ng/ml and the area under the ROC curve (AUC) was 0.95 (95% CI 0.92-0.97). The optimal cut-off value in thyroid tissue absence group was 1.2 ng/ml and the AUC was 0.93 (0.85-0.98). After the analysis and comparison of multiple cut-off values, the optimal diagnostic performance was still found to be 19.4 ng/ml and 1.2 ng/ml. Conclusion: The influential factors of FNA-Tg are still controversial, and the optimal cut-off value of FNA-Tg can be determined based on the presence or absence of thyroid tissue. FNA-Tg can be used as an important auxiliary method for diagnosing cervical metastatic LNs of thyroid cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhai, Jiang, Zang, Gao, Jiang, Tian and Zhao.)

Objectives: To analyze whether thyroglobulin (Tg) and anti-Tg antibody (TgAb) detection in fine-needle aspiration (FNA) of cervical lymph node (LN; LN-FNA-Tg and LN-FNA-TgAb) can predict LN metastasis and obtain the best cutoff value. Methods: The patients admitted to our hospital from January 2020 to March 2021 were prospectively enrolled. The LNs were sampled by FNA. All patients underwent thyroid surgery and neck dissection. LN-FNA-Tg, LN-FNA-TgAb, and blood Tg and TgAb were measured. The receiver operating characteristic curve analysis was used to determine the best cutoff points for positive LN. Results: There were 29 participants in the LN metastasis group and 42 in the nonmetastasis group. Compared with the nonmetastasis group, the participants in the metastasis group had higher LN-FNA-Tg (median: 1897 vs 7.74 ng/mL, P  < .001), higher LN-FNA-TgAb (median: 15.65 vs 8.21 IU/mL, P  < .001), and higher serum Tg (median: 25.4 vs 18.81 ng/mL); there were no differences in serum TgAb (median: 26.6 vs 28.6 IU/mL, P  = .477). The best accuracy (87.5%) was observed with LN-FNA-Tg of >227.1 ng/mL, resulting in an area under the curve of 0.927, 84.5% sensitivity, and 89.5% specificity. LN-FNA-TgAb >10.85 IS/mL had an accuracy of 79.6%, sensitivity 64.8%, and specificity 89.5%. Serum Tg and TgAb had the lowest accuracy, with 64.2% and 57.4%, respectively, sensitivity of 53.5% and 67.6%, and specificity of 71.4% and 50.5%. Similar results were observed in first-operation participants and postoperative participants. Conclusions: LN-FNA-Tg has high accuracy, sensitivity, and specificity for detecting cervical LN in patients with papillary thyroid cancer.

The highly sensitive detection of serum thyroglobulin (Tg) is essential in the post-treatment follow-up of patients with differentiated thyroid cancer undergoing total or partial thyroidectomy and radioactive iodine ablation and requires sensitive, accurate and stable methods. This work proposes an electrochemical immunosensor for the detection of serum Tg antigen, making use of innovative nanocomposites including polyvinylidene fluoride (PVDF) microparticles coated with streptavidin (MP) and gold nanoparticles (AuNPs). The functionalized polymer matrices were characterized by UV-Vis, FTIR, XPS, SEM, dynamic light scattering, and free surface energy. Immobilization of biotin-labeled anti-thyroglobulin monoclonal antibodies was achieved by binding these to the polymer nanocomposite via streptavidin proteins. The analytical response was measured in quintuplicate and had a linear profile from 2.0 to 10.0 ng/mL Tg, with r 2 of 0.985. The limits of detection and quantification were excellent, equal to 0.015 and 0.047 ng/mL, respectively. In addition, the recovery factor was equal to 95.4% (1.0 ng/mL Tg). Overall, the innovative polymer-based nanocomposite used herein enabled the production of an electrochemical-based immunosensor with excellent sensitivity, selectivity, and reproducibility. It evidenced the remarkable potential of determining low levels of Tg in in vitro assays, thereby suggesting that it may be considered for the analyzes of serum patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Fine-needle aspiration cytology (FNAC) is a basic diagnostic tool for thyroid nodules. However, 15-30% of nodules are cytologically indeterminate. Midkine (MK), a pleiotropic growth factor, is often upregulated in patients with cancers. This study aimed to evaluate the role of MK and its ratios in fine-needle aspirates (FNA) for predicting thyroid malignancy., Methods: This retrospective study included patients with thyroid nodules who underwent preoperative FNA and/or thyroidectomy between April 2017 and September 2017. MK levels in FNA washout were measured by enzyme-linked immunosorbent assay, and thyroglobulin (TG) and free thyroxine (FT4) levels in FNA washout were measured by chemiluminescent immunometric assays., Results: A total of 217 patients with 242 nodules were included in this study. The concentrations of TG, FT4, MK/TG, MK/FT4, and FT4/MK were significantly different between papillary thyroid carcinomas and benign thyroid nodules. Both MK/TG and MK/FT4 ratios were positively correlated with maximum tumor diameter, extrathyroidal extension, and T and N stages. The area under the curve for MK/TG was 0.719 with a cutoff value of 55.57 ng/mg, while the area under the curve for MK/FT4 was 0.677 with a cutoff value of 0.11 μg/pmol. FNAC in combination with MK/FT4 had a higher sensitivity (95% vs. 91%) and accuracy (96% vs. 92%) than FNAC alone for cytologically indeterminate specimens, those of unknown significance, or those suspected of malignancy., Conclusions: MK/FT4 and MK/TG may have diagnostic utility for evaluation of papillary thyroid carcinomas, particularly for cytologically indeterminate thyroid nodules., (© 2021. The Author(s).)

Benign ectopic thyroid tissue within the parotid gland is very rare with only one case reported till date in the world literature. We report a case of ectopic thyroid in the left parotid gland with an orthotopic thyroid in an elderly female, who was presented to us with the simultaneous onset of right-sided thyroid swelling and left parotid swelling for 6 months. Fine-needle aspiration cytology (FNAC) was done from both the swellings and a diagnosis of Hurthle cell neoplasm metastasizing to the left parotid gland was initially made. However, histopathological examination along with the immunohistochemistry (IHC) panel proved it to be an ectopic thyroid in the parotid. The case is being documented here for its rarity as well as an unusual presentation so that the readers are aware of this entity and the complete workup required to prevent diagnostic pitfalls.

Thyroglobulin is a secreted 660 kDa glycoprotein produced by thyroid follicular cells used in diagnostic pathology to secure or exclude a thyroidal origin of metastases of unknown primary tumors. This study was performed to estimate specificity of thyroglobulin immunohistochemistry. 9974 tumor samples from 109 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Thyroglobulin was strongly expressed in all normal thyroid samples but not in any other normal tissues. Thyroglobulin immunostaining was detected in 99.1% of 106 thyroid adenomas, 98.1% of 364 papillary, 95.2% of 147 follicular, and 7.5% of 40 anaplastic thyroid cancers. Twelve of 15 thyroid samples that were thyroglobulin negative on TMAs showed at least a weak focal thyroglobulin positivity in corresponding large sections, suggesting higher sensitivity of large section analysis. Thyroglobulin positivity in one diffuse large B-cell lymphoma of the thyroid, one chondrosarcoma metastasis to the thyroid, and 42.4% of 92 medullary thyroid cancers was considered to be caused by diffusion of thyroidal colloid from destroyed or even intact adjacent follicles. Thyroglobulin positivity was, however, not seen in 6403 extrathyroidal tumors from 104 different tumor types and subtypes. Our data demonstrate a complete specificity of positive thyroglobulin immunostaining for thyroid origin in tumor tissues obtained from extrathyroidal locations. However, for all tumors located within the thyroid, false positivity can occur as a result of tissue contamination by thyroglobulin rich thyroid colloid from adjacent normal tissue., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. Materials and Methods: Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. Results: Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. Conclusions: A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.

Single- domain antibodies (SdAbs) have been deployed in various biomedical applications in the recent past. However, there are no reports of their use in the immunoradiometric assays (IRMA) for thyroglobulin (Tg). Tg is the precursor molecule for the biosynthesis of thyroid hormones: thyroxine and triiodothyronine, which are essential for the regulation of normal metabolism in all vertebrates. Patients with differentiated thyroid cancer (DTC) require periodic monitoring of their serum thyroglobulin levels, as it serves as a prognostic marker for DTC. Here, we report a methodology to produce SdAbs against human-Tg, by a hybrid immunization/directed-evolution approach by displaying the SdAb gene-repertoire derived from a hyperimmune camel in the T7 phage display system. We have demonstrated the immunoreactivity of anti-Tg-SdAb (KT75) in immunoassays for thyroglobulin and measured its affinity by surface plasmon resonance (K D  ~ 18 picomolar). Additionally, we have shown the quantitative-binding property of SdAb for the first time in IRMA for thyroglobulin. The serum Tg values obtained from SdAb-Tg-IRMA and in-house assay using murine anti-Tg-monoclonal antibody as tracer significantly correlated, r = 0.81, p < 0.05. Our results highlight the scope of using the T7 phage display system as an alternative for the conventional M13-phage to construct single-domain antibody display libraries., (Copyright © 2021 Elsevier B.V. All rights reserved.)

History: A patient presented with a cystic mass in the lateral triangle of the neck., Findings and Diagnosis: After ultrasound and MRI, a fine needle aspiration cytology (FNAC) was performed. It did not reveal malignant disease. By virtue of repeated FNAC and detection of thyroglobin in the cyst fluid, the diagnosis of thyroid carcinoma was firmly established., Therapy and Course: The necessary surgery could be performed in a single step intervention. Three weeks after surgery, radioiodine therapy with 3.7 GBq I131 was performed., Conclusion: Swelling of the cervical lymph nodes may have many causes, and rarely may be the metastasis of a thyroid carcinoma. We present a simple way to detect lymphatic metastatic thyroid carcinoma with the help of a case report., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Introduction: Clinical indications of immune checkpoint inhibitors have expanded to a variety of malignancies. Approximately one in six patients with hepatocellular carcinoma respond to programmed death 1 inhibitors nivolumab and pembrolizumab., Case Report: We report herein a patient with synchronous metastatic hepatocellular carcinoma and advanced papillary thyroid carcinoma treated with nivolumab in the second-line therapy.Management and outcome: The hepatocellular carcinoma showed a durable response to the second-line agent nivolumab. Remarkably, the patient's papillary thyroid carcinoma also responded to this programmed death 1 inhibitor., Discussion: To our knowledge, this is the first case report showing the efficacy of nivolumab in the treatment of metastatic papillary thyroid carcinoma. Further studies with immune checkpoint inhibitors in papillary thyroid carcinoma seem warranted.

Introduction: Approximately 35% patients with papillary thyroid carcinoma (PTC) and 13% with follicular thyroid carcinoma (FTC) present with metastases of cervical lymph nodes (LNs) at the time of diagnosis. In addition, 15-20% of patients treated with total thyroidectomy develop, after an interval of five years, metastases to the neck LNs on ultrasound examination. Fine-needle aspiration biopsy (FNAB) represents the gold standard technique for the detection of cervical LNs metastases. The aim of the study was to evaluate the diagnostic performance of the technique of thyroglobulin (Tg) measurement of washout FNAB (FNAB-Tg) in diagnostics of LNs metastases in different groups of patients with differentiated thyroid carcinoma (DTC)., Material and Methods: Two hundred FNAB-Tg samples from 200 patients [158 women; 42 men; mean age 51.37 ± 16.77 (53)] diagnosed with DTC were examined for the assessment of the diagnostic utility of FNAB-Tg from suspicious LNs. FNAB-Tg ranged from 1.96 to 5000 ng/mL in metastatic LNs [mean; 1510 ± 1486 ng/mL (958.5)] and from 0.04 to 635.9 ng/mL in nonmetastatic LNs [mean; 57.86 ± 319.19 ng/mL (1.96)], p < 0.001., Results: The most accurate diagnostic performance was displayed for the concentration of 33.28 ng/mL in FNAB-Tg with AUC of 0.91 and high sensitivity and specificity (0.92 and 0.93). FNAB-Tg in conjunction with the cytopathological examination of suspicious LNs in differentiated thyroid carcinoma (DTC) patients increases the diagnostic accuracy of FNAB (sensitivity 0.99; specificity 0.99; AUC 1.00)., Conclusions: FNAB-Tg may be particularly useful in detecting LN metastases in DTC patients, and in differential diagnosis of various LN metastasizing malignancies. The combination of FNAB and FNAB-Tg measurement has high specificity and sensitivity in the detection of LN metastases of DTC.

Nasopharyngeal carcinoma (NPC) has a distinctive geographical distribution in China, especially southern China. There are several risk factors for NPC, such as Epstein-Barr virus, genetics, and environmental exposures. Although the incidence of eye metastasis (EM) is lower than metastasis in other body parts, it often indicates poor prognosis.We assessed several serum biomarkers for their ability to predict EM in NPC. Patients with NPC were selected (n = 963), and were separated into two groups, EM and no eye metastasis. Ten factors were analyzed in both groups including triglyceride (TG), high-density lipoprotein, low-density lipoprotein, alkaline phosphatase, alpha fetoprotein, carbohydrate antigen-199, cancer antigen-153, apolipoproteins AI, apolipoprotein B, and cytokeratin fragment 19 (CYFRA21-1). Independent t tests, binary logistic regression, and receiver operating characteristic curves were used to assess the data.The EM group had significantly higher CYFRA21-1 and lower TG compared with the no eye metastasis group. Areas under the curve for CYFRA21-1, TG and CYFRA21-1/TG were 0.966, 0.771, and 0.976, respectively. The corresponding cut-off values were 12.12 ng/ml, 0.41 mmol/L, and 13.5. The sensitivity and specificity of CYFRA21-1/TG were 100% and 92.2%, respectively.The increased ratio of CYFRA21-1 to TG can be an accurate method to detect EM in patients with NPC.

Papillary thyroid carcinoma (PTC) generally has a good prognosis, but disease recurs in 25% to 30% of PTC patients and significantly reduces the survival rate. Lymph node metastasis (LNM) is reported in 20% to 50% of PTC patients, mainly in the neck, and 20% originates from recurrence. LNM of papillary thyroid carcinoma are a plausible prognostic factor to determine disease recurrence. Currently, fine needle lymph node aspiration for cytology (LN-FN-cytology) is the best modality to diagnose LNM but is limited by diagnostic sensitivity and sample error. Fine needle lymph node aspiration for thyroglobulin measurement (LN-FNA-Tg) could offer a reliable and quantitative diagnostic method for LNM. The combination of LN-FNA-cytology and LN-FNA-Tg could achieve almost 100% diagnostic sensitivity and specificity for LNM. Both treatment guidelines of the American Thyroid Association and European Thyroid Association recommend LN-FNA-Tg to diagnose LNM after total thyroidectomy. Diagnostic accuracy of the LN-FNA-Tg depends on optimal equipment, scanning protocol, skill, and experience of operators. Normal saline is mainly used for aspiration needle wash-out and buffer solution. And radioimmunoassay or immunoradiometric assay are widely used for the LN-FNA-Tg measurement. So far, there is no consensus about the diagnostic threshold of LN-FNA-Tg for positive LNM, but high LN-FNA-Tg, especially higher than 10 ng/mL, strongly favors LNM., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Background: Iodine is an essential nutrient for human health throughout the life cycle, especially during early stages of intrauterine life and infancy, to ensure adequate neurocognitive development. The growing global reliance on desalinated iodine-diluted water raises the specter of increased iodine deficiency in several regions. The case of Israel may be instructive for exploring the link between iodine status and habitual iodine intake in the setting of extensive national reliance on desalinated water. The aim of this study was to explore the relationship between iodine intake, including iodized salt and iodine-containing supplements intake, and iodine status among pregnant women residing in a sub-district of Israel that is highly reliant on desalinated iodine-diluted water., Methods: A total of 134 consecutive pregnant women were recruited on a voluntary basis from the obstetrics department of the Barzilai University Medical Center during 2018. Blood was drawn from participants to determine levels of serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroglobulin (Tg). An iodine food frequency questionnaire (sIFFQ) was used to assess iodine intake from food, IS and ICS. A questionnaire was used to collect data on demographic and health characteristics., Results: A total of 105 pregnant women without known or reported thyroid disease were included in the study. Elevated Tg values (≥ 13 μg/L), were found among 67% of participants, indicating insufficient iodine status. The estimated iodine intake (median, mean ± SD 189, 187 ± 106 μg/d by sIFFQ) was lower than the levels recommended by the World Health Organization and the Institute of Medicine (250 vs. 220 μg/day respectively). The prevalence of iodized salt intake and iodine containing supplement intake were 4 and 52% (respectively). Values of Tg > 13 μg/L were inversely associated with compliance with World Health Organization and Institute of Medicine recommendations., Conclusions: While the Israeli Ministry of Health has recommended the intake of iodized salt and iodine containing supplements, this is apparently insufficient for achieving optimal iodine status among Israeli pregnant women. The evidence of highly prevalent probable iodine deficiency in a sample of pregnant women suggests an urgent need for a national policy of iodized salt regulation, as well as guidelines to promote iodine containing supplements and adherence to them by caregivers. In addition, studies similar to this one should be undertaken in additional countries reliant on desalinated iodine-diluted water to further assess the impact of desalinization on maternal iodine status.

Background: Poorly differentiated thyroid cancer (PDTC) is a rare but aggressive type of thyroid cancer (TC) and the main cause of death from non-anaplastic follicular cell-derived TC. Although the Turin criteria are well defined, the pathological features that could serve as diagnostic and prognostic factors remain controversial., Materials and Methods: Forty-nine consecutive PDTC cases were identified in a single cancer center between 2000 and 2018. We analyzed the impact of routine histopathological and immunohistochemical features and several parameters that are not routinely included in pathology reports such as the presence of atypical mitoses, the amount of necrosis, or insulin-like growth factor-II mRNA-binding protein 3 immunostaining on the survival of patients with PDTC. Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method., Results: Of the 49 PDTC 34 (69.4%) showed the insular pattern of growth. The median of poorly differentiated area was 95% (range, 1-100), and 30 (61.2%) patients had a predominant (>50%) insular area. The 5-year OS and DSS rates at a median follow-up of 57 months were 60.6% and 64.3%, respectively. Univariate analysis showed that tumor size >4 cm, presence of atypical mitoses, Ki-67 >5%, and thyroglobulin (Tg)-negative immunostaining were associated with a higher risk of PDTC-related death. Atypical mitoses and Tg negativity were independent factors of worse DSS in multivariate analysis. Patients with insular and predominant insular areas showed a 3- and 6-fold higher risk of PDTC death when they displayed atypical mitoses., Conclusions: In PDTC, the presence of atypical mitoses may be helpful in identifying patients with poorer outcome and worth including in pathology reports, particularly in tumors with a dominant insular pattern of growth. Additionally, the inclusion of Tg immunostaining may be considered in a prognostic context, and not only as a diagnostic feature., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Although frequently used as an adjunct to cytology in patients with differentiated thyroid cancers, interpretation of thyroglobulin washout remains unclear. We aim to compare the utility of different analytic tools to develop recommendations for use in post-total thyroidectomy follow-up., Methods: This is an institutional review board-approved retrospective study of patients who underwent lymph node fine needle aspiration biopsy with thyroglobulin washout between 2012 and 2018, during the post-total thyroidectomy follow-up of differentiated thyroid cancer. The utilities of thyroglobulin washout concentration, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content were compared., Results: Sixty-four patients underwent 79 fine needle aspirations with thyroglobulin washout of cervical lymph nodes. Fifty-two lymph nodes were found to be metastatic and 27 benign. One patient had a pathologically confirmed lymph node metastasis despite a thyroglobulin washout of 0. The optimal cutoffs of thyroglobulin washout, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content to predict metastatic involvement were 2.5 ng/ml (94% sensitive, 100% specific), 0.1 (100% sensitive and specific), and 12.5 (94% sensitive, 100% specific), respectively. The second measure lacked utility in patients with undetectable serum thyroglobulin., Conclusion: The use of thyroglobulin washout concentration or thyroglobulin washout/serum thyroglobulin ratio has drawbacks based on variations in technique and clinical scenario. Absolute thyroglobulin content is an alternative that may be a more objective expression of thyroglobulin washout., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of the work was to carry out an immunocytochemical (ICC) study of thyroid peroxidase (TPO) and thyroglobulin (Tg) expression in the punctates of the radioiodine (RI) refractory and RI uptake metastases of thyroid papillary carcinoma (PTC), on the basis of which it is possible to develop new methods of preoperative prediction of RI resistance and RI therapy efficiency for thyroid papillary carcinoma metastases., Materials and Methods: The ICC research was carried out on a fine needle aspiration biopsy material of 104 metastases that were found after thyroidectomy and RI therapy, i.e. in postoperative period (79 - radioiodine-refractory metastases, 25 - radioiodine-uptake metastases). The ICC analysis of TPO and Tg expression in PTC was performed with the use of monoclonal antibodies against TPO and Tg., Results: RI-refractory (RIRM) and RI-uptake metastases of PTC significantly differ by the percentage of cells expressing TPO and Tg (p < 0.05, and p < 0.05 respectively). The effectiveness of RI therapy was different for patients with different percentages of TPO-positive cells., Conclusion: A statistically significant difference was demonstrated in the expression of TPO in a punctates of RI-resistant and RI-sensitive metastatic TPC, based on which a new method for preoperative prediction of RI resistance and RI therapy efficiency was developed. It was shown that ICC determination of Tg expression in metastases is effective in preoperative monitoring of RI resistance of PTC if the part of Tg-positive cells in punctates is lower than 56%. The comprehensive study of the ICC profile of thyrocytes in RI-uptake metastases punctates allows us to develop a personified approach to prediction, monitoring and therapy of patients with PTC.

Background: To investigate the diagnostic performance of cytology (fine-needle aspiration cytology [FNAC]), thyroglobulin (fine-needle aspiration thyroglobulin [FNA-Tg]), and combination of them in the washout of fine-needle aspiration for those patients who have suspicious metastatic lymph nodes of differentiated thyroid cancer., Methods: Databases, including PubMed, EMbase, Web of Science and Cochrane Library were searched up to June 2019. The quality assessment of diagnostic accuracy scale-2 was used to conduct quality assessments, and publication bias was evaluated using the Deeks funnel plot. STATA version 14.0 was used to perform the meta-analysis., Results: A total of 2257 patients with 2786 samples of suspicious metastatic lymph nodes of differentiated thyroid cancer were included in the meta-analysis. The results showed that the diagnostic value for detecting lymph node metastasis of differentiated thyroid cancer was as follows: combination of FNAC and FNA-Tg > FNA-Tg > FNAC. All differences of superiority among them are statistically significant. The sensitivity of the combination was 0.968 (95% confidence interval [CI]: 0.942-0.983), the specificity was 0.932 (95% CI: 0.856-0.969), the diagnostic score was 6.036 (95% CI: 4.892-7.181), the diagnostic odds ratio was 418.424 (95% CI: 133.167-1314.729), and the score of summary receiver operating characteristic was 0.99 (95% CI: 0.97-0.99)., Conclusions: The combination of FNAC and FNA-Tg is an excellent procedure in diagnosis of lymph nodes metastasis of patients with differentiated thyroid cancer, which should be highly recommended.

Purpose: This is a longitudinal study of retrospective data aimed at verifying whether repeated measurements of serum non-stimulated thyroglobulin (Tg) allow the prediction of persistent disease in patients with differentiated thyroid cancer (DTC) and indeterminate response., Methods: We examined 145 DTC patients with indeterminate response to therapy followed up for a median time of 68 months. Tg measurements and neck ultrasound (US) were performed every 6-12 months. The changes over time of repeated measurements of basal Tg were analyzed through the multilevel linear regression., Results: Seventy (48.3%) out of 145 patients spontaneously achieved an excellent response, while persistent indeterminate response was observed in 62 (42.7%) patients. The remaining 13 (9.0%) patients had progression: 3/13 with biochemical disease and 10/13 with structural disease. Tg steadily increased in patients with progressive disease (mean percentage change + 27.1% at each follow-up visit), while Tg decreased in patients without any evidence of progression (mean percentage change - 8.8%). This different trend between the two groups was not related to either different values of median TSH at baseline (0.32 vs 0.28 mIU/l, respectively) or to different trend of TSH during follow-up (p = 0.76). Basal Tg values did not increase in three out of ten patients with structural disease that was identified by neck US., Conclusions: The importance of the study is that, in DTC patients with indeterminate response, rising values of unstimulated Tg, independently from the basal levels, may be useful to identify patients with progressive disease. These results are also useful to avoid unnecessary TSH stimulation.

Ultrasonography (USG)-guided fine needle aspiration (FNA) is widely used for diagnosis of lymph node (LN) metastasis in papillary thyroid cancer (PTC). However, FNA cytology sometimes shows inconclusive results. Recently, the measurement of thyroglobulin (Tg) in FNA washout fluid (aspirate-Tg) has been widely adopted, but there are some difficulties in the preparation of the sample and standardization of the procedure. Here, we examined serum Tg after FNA as a new predictive marker for LN metastasis of PTC. We performed USG-guided FNA cytology and examined aspirate-Tg in PTC patients showing suspicious metastatic LNs during follow-up. We measured baseline serum thyroid stimulating hormone (TSH), Tg, and Tg antibody levels before FNA, and serum Tg level within an hour after FNA. We defined aspirate-Tg level above 0.9 ng/mL as positive, and a 30% increase in serum Tg level after FNA compared to the baseline as elevation of serum Tg. Twenty-two patients were included in our study. Nine patients (40.9%) showed elevation of Tg level after FNA, and the mean value of Tg elevation was 24.8 ± 48.0 ng/mL. Among these 9 patients, 8 were diagnosed with PTC and 1 patient showed cellular atypia on cytopathology. All these patients showed positive aspirate-Tg. Thirteen patients (59.1%) did not show elevation of Tg level after FNA. Among these patients, 2 had PTC, 2 had cellular atypia, and 9 yielded negative results for malignancy on cytopathology. Elevation of serum Tg level after FNA might have a diagnostic role for predicting LN metastasis of PTC.

Background: The multicriteria decision method (MCDM) aims to find conflicts among alternatives by comparing and evaluating them according to various criteria to reach the best compromise solution. The evaluation of a new health technology is extremely important in the health sciences field. The aim of this work is to evaluate a new health technology to assay thyroglobulin in patients with differentiated thyroid cancer to improve its service from an organizational point of view, by planning new and appropriate training activities, ensuring proper use of resources and satisfying the needs of different users., Methods: The evaluation was performed using two methodologies: the analytic hierarchy process (AHP) and the Likert scale. The AHP is a multicriteria decision approach that assigns a weight to each evaluation criterion according to the decision maker's pairwise comparisons of the criteria. The Likert scale is a psychometric scale employed to study the degree of user satisfaction by measuring opinions., Results: Results show the need of particularly improving clinical efficiency, effectiveness, and return on sales (ROS) related to the technology; technological safety, human resources and other parameters do not need to be improved because of the high satisfaction results of the users., Conclusions: The application of both methods provided the necessary information to improve the quality of the service, allowing the decision maker to identify the most valuable service features and to improve these to ensure user satisfaction and to identify possible service improvements.

Background: To study the application value of thyroid ultrasound combined with thyroglobulin (Tg) in the diagnosis of postoperative recurrence of thyroid cancer, so as to provide a reference for clinical practice., Methods: Eighty patients with thyroid cancer who underwent operative treatment for more than 2 times in our hospital from January 2014 to December 2016 were selected as the objects of study. After operation, residual thyroid tissues were removed via131Iodine (131I) treatment, the serum Tg and thyroid globulin antibody (TgAb) were detected, and the cervical ultrasound was performed. At 1 week after 131I treatment, the systemic single photon emission computed tomography (SPECT) was performed. Finally, the application values of serum Tg, TgAb and ultrasound in the diagnosis of postoperative recurrence of thyroid cancer were analyzed., Results: The sensitivity, specificity and accuracy of Tg level in detecting of recurrence and metastasis of differentiated thyroid cancer were 78.5%, 73.3% and 77.5%, respectively, and it was difficult to show whether the postoperative recurrence and metastasis of thyroid cancer occurred through the expression level of serum TgAb. Moreover, TgAb in different concentrations had an effect on the diagnosis of metastasis of differentiated thyroid cancer via Tg. When the TgAb level ≥100 IU/mL, the sensitivity, specificity and accuracy of Tg diagnosis were 51.9%, 50.0% and 51.7%, respectively. When the TgAb level <100 IU/mL, the sensitivity, specificity and accuracy of Tg diagnosis were 94.6%, 71.4% and 88.2%, respectively. Besides, the sensitivity, specificity and accuracy of ultrasonic diagnosis of lymphatic metastasis after the treatment of differentiated thyroid cancer were 78.5%, 60.0% and 75.0%, respectively. The sensitivity, specificity and accuracy of ultrasound combined with Tg in the diagnosis of thyroid cancer were 97.4%, 75.0% and 93.6%, respectively. The difference in the metastasis rate of thyroid cancer was not statistically significant between patients with papillary carcinoma and patients with follicular carcinoma after treatment (P>0.05)., Conclusions: Thyroid ultrasound combined with Tg is of high clinical value in the diagnosis of postoperative recurrence of thyroid cancer, which can significantly improve the sensitivity, specificity and accuracy of clinical diagnosis. The TgAb level can be detected when Tg is used to monitor the postoperative recurrence and metastasis of thyroid cancer, providing a reference for the clinical prevention and treatment.

Objective: To investigate the diagnostic performance of fine-needle aspiration (FNA) cytology for the detection of lateral lymph node metastases in patients with papillary thyroid carcinoma (PTC). Methods: A total of 109 lateral lymph nodes with suspicious metastases from 85 patients were retrospectively subjected to FNAC, fine-needle aspiration thyroglobulin measurement (FNATg), and FNATg/SerumTg measurement. Lymph node pathological results after surgery were taken as the gold standard. Using Mann-Whitney U test, Pearson linear model and ROC curve were used for data analysis. Results: The sensitivity, specificity and accuracy of FNATg for the diagnosis of lateral neck lymph node metastasis were respectively 93.7%, 90.0% and 93.3% and those of FNATg/SerumTg were respectively 89.9%, 90.0% and 93.2% respectively, the threshold values for FNATg and FNATg/SerumTg were 0.925 ng/ml and 1.007, respectively. The sensitivity, specificity and accuracy of FNATg combined with FNAC were respectively 91.0%,93.5% and 94.4%. The existence of thyroid tissue and the expression of serum Tg did not affect the expression of lymph node FNATg. The FNATg cutoff value of 0.925 ng/ml showed the best diagnostic performance in patients with a thyroid gland, while the FNATg/SerumTg cutoff ratio of 14.95 showed the best diagnostic performance in patients without a thyroid gland. The serum TgAb significantly interfered with the expression of FNATg in the lateral neck metastatic lymph nodes ( P =0.049). Conclusions: FNATg alone or the combination of FNATg with FNAC are highly reliable in the diagnosis of lateral neck lymph node metastases in patients with PTC. The expression of TgAb may interfere with the accuracy of the diagnostic performance of FNATg.

Fine-needle aspiration (FNA) cytology coupled with needle-wash thyroglobulin (FNA-Tg) testing is recommended for cervical lymph node (LN) biopsies in patients with a history of papillary thyroid carcinoma (PTC). However, the procedure has not been standardized with the assay for FNA-Tg testing. A standard operating procedure (SOP) has been generated at our facility for cervical LN FNAs with Tg reflex testing on patients with a history of PTC. The procedure requires FNA cytology to be reviewed first, and all cases not positive for PTC are reflexed for FNA-Tg testing with the Beckman Access thyroglobulin assay. The thyroglobulin cutoff value is ≤ 1.0 ng/mL. From 2016 to 2017, 117 patients, including 71 women and 46 men, were identified as having a history of PTC. Patients' clinical characteristics were collected from medical records. A total of 143 LN biopsies were investigated for these patients. The results show that four out of 11 (36.4%) non-diagnostic LNs and five out of five (100%) atypical/suspicious LNs tested positive for FNA-Tg. Among these nine patients with positive thyroglobulin testing, LN metastases were proven histologically for all nine patients, and two patients were treated with LN ablation. Out of 68 LNs positive for PTC, three had FNA-Tg results. FNA-Tg testing was ordered for unknown reasons on two positive LNs (> 5000 ng/mL thyroglobulin) from one patient. The third LN was tested due to non-classic morphology, and the result was less than the cutoff value. Three patients with negative LN biopsies were tested to have elevated (> 1.0 ng/mL) thyroglobulin levels. One patient (FNA-Tg ng/mL) was proven to have multiple metastatic LNs through follow-up surgery. However, no positive LN was identified for the other two patients who had FNA-Tg level of 4.1 ng/mL and 37 ng/mL respectively. This is likely due to contamination, as these two patients had intact thyroids. In our practice, the FNA-Tg test is a very useful adjunct test to LN FNA specimens with a non-positive diagnosis in patients with a history of PTC. Furthermore, FNA-Tg testing increases diagnostic sensitivity among non-diagnostic and atypical/suspicious LNs. However, FNA-Tg testing should not substitute conventional cytology due to the following reasons: (1) false-negative thyroglobulin lab results; (2) PTC with loss of thyroglobulin expression; (3) LN metastasis from other origins; and (4) false-positive thyroglobulin testing due to blood contamination in patients who are not completely athyrotic.

Importance: One-third of patients with papillary thyroid cancer (PTC) develop persistent or recurrent disease after initial therapy. Most patients with persistent or recurrent disease undergo reoperation, but the role of treatment with radioactive iodine (RAI) after reoperation is unclear., Objective: To determine whether receipt of RAI after reoperation for recurrent PTC is associated with improved outcomes., Design, Setting, and Participants: This retrospective cohort study included electronic health record data from 102 patients who underwent neck reoperation for persistent or recurrent PTC at a tertiary referral center from April 2006 to January 2016; 50 patients received RAI after reoperation, and 52 did not receive RAI after reoperation. Data analysis was performed from September 1, 2017, to December 1, 2017., Main Outcomes and Measures: Suppressed thyroglobulin (Tg) levels were compared between patients who underwent reoperation and received RAI and patients who underwent reoperation without receipt of RAI at the following time points: before reoperation (Tg0), after reoperation (Tg1), and after RAI or a comparable time interval among patients whose cases were managed without RAI (Tg2). Outcomes were biochemical response and structural recurrence after reoperation., Results: The cohort comprised 102 patients who underwent neck reoperation for persistent or recurrent PTC (median age, 44 years [interquartile range, 33-54 years; SD, 14 years]; 67 [66%] female), 50 of whom received treatment with RAI after reoperation. Clinicopathologic characteristics of the patients at the time of the initial surgical procedure were similar between the reoperation with RAI group and the reoperation without RAI group with the exception of tumor (T) stage (T3 and T4, 28 of 50 [56%] vs 19 of 52 [37%]). Although median Tg levels were similar between the reoperation with RAI group and the reoperation without RAI group (Tg0, 3.3 ng/mL vs 2.4 ng/mL; Tg1, 0.6 ng/mL vs 0.2 ng/mL; and Tg2, 0.5 ng/mL vs 0.2 ng/mL; all differences were nonsignificant), the rate of excellent response at Tg1 was lower in the reoperation with RAI group (4 of 33 [12%] vs 24 of 51 [47%]; P = .007). Structural recurrence after reoperation occurred in 18 of 50 patients (36%) in the reoperation with RAI group and 10 of 52 patients (19%) in the reoperation without RAI group. In multivariable analysis accounting for clinicopathologic characteristics and Tg0, receipt of RAI after reoperation was not associated with the rate of a second structural recurrence. In subset analyses limited to patients with incomplete response to reoperation and patients with T3 or T4 tumors, no association between receipt of RAI and the risk of a second recurrence was found., Conclusions and Relevance: Patients who received RAI after reoperation had outcomes similar to those in patients who underwent reoperation alone. RAI after reoperation was not associated with a significant clinical benefit in this limited series. Larger multicenter studies are required to determine whether receipt of RAI after reoperation improves outcomes among patients with recurrent PTC.

Background: Papillary thyroid carcinoma (PTC) is often associated with cervical lymph node metastasis (LNM), which may cause poor prognosis. Both fine-needle aspiration cytology (FNAC) and thyroglobulin measurement with fine-needle aspiration (Tg-FNA) have high diagnostic efficacy, but the diagnostic values and relationships among BRAF v600e mutation (BRAF MUT ) testing, FNAC and FNA-Tg are unclear., Methods: We enrolled 145 patients with confirmed PTC and lymph nodes (LNs) that were suspected to be metastatic based on ultrasound findings, who were treated from May 2017 to April 2018, and underwent FNAC, Tg-FNA and BRAF MUT tests. Diagnostic efficacy was calculated by diagnostic and chi-square tests., Results: Diagnostic values were FNAC-sensitivity: 67%, specificity: 100%, PPV: 100%, NPV: 66%, accuracy: 80%; and FNA-Tg (at a cut-off of 2.23 ng/mL)-sensitivity: 97.3%, specificity: 87.8%, PPV: 87.8%, NPV: 97.3%, accuracy: 92.3%. In the BRAF MUT + group, sensitivities and specificities were FNAC: 68.6% and 100%, Tg-FNA: 94.4% and 85.7%; compared with FNAC: 75% and 90.9%, Tg-FNA: 80% and 100% in the BRAF MUT - group., Conclusion: The combination of Tg-FNA + FNAC is useful in diagnosing metastatic PTC. BRAF mutational status does not affect the diagnostic performance of FNAC or Tg-FNA., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objective: To investigate the influential factors of efficacy of the first (131)I ablation therapy for thyroid remnant in papillary thyroid microcarcinoma (PTMC) patients after thyroidectomy. Methods: Eighty-nine PTMC patients who underwent twice (131)I ablation therapy and (131)I whole body follow-up scan ((131)I-WBS) within 5 to 8 months in our department from September 2007 to October 2016 were identified and enrolled in present study. Patients were divided into complete-ablation group and uncomplete-ablation group according to whether or not radioactivity was detected at the thyroid bed in (131)I-WBS. The χ (2) test and multi-variance Binary logistic regression were performed for the factors which might affect the therapeutic efficacy. Results: The first (131)I ablation therapy was successful in 41 of 89 patients (46.07%). Residual thyroid weight was found to be associated with therapeutic efficacy ( P <0.05), while gender, age, surgical method, lesions'maximum diameter, with or without LN metastasis, with or without distant metastasis, time of operation from first (131)I treatment, lesions'number, thyroid stimulating hormone (TSH), thyroglobulin (Tg), the consistency of (131)I-WBS and (99)Tc(m)-pertechnatate, TNM stage, ATA risk, Tg/TSH ratio were not significant associated with therapeutic efficacy. Binary logistic regression analysis was performed in these respects and it indicated that residual thyroid weight and ATA risk were not statistically significant independent variable ( P >0.05). Conclusions: Residual thyroid weight might affect efficacy of the first (131)I ablation therapy on thyroid remnant in PTMC patients after thyroidectomy, but it is not an independent factor. Multiple interrelated factors should be considered when predicting the efficacy of the first (131)I ablation therapy.

Thyroid plays an important role in the endocrine system of the human body. Its characterization by diffuse optics can open new path ways in the non-invasive diagnosis of thyroid pathologies. Yet, the absorption spectra of tyrosine and thyroglobulin-key tissue constituents specific to the thyroid organ-in the visible to near infrared range are not fully available. Here, we present the optical characterization of tyrosine (powder), thyroglobulin (granular form) and iodine (aqueous solution) using a time domain broadband diffuse optical spectrometer in the 550-1350 nm range. Various systematic errors caused by physics of photo migration and sample inherent properties were effectively suppressed by means of advanced time domain diffuse optical methods. A brief comparison with various other known tissue constituents is presented, which reveals key spectral regions for the quantification of the thyroid absorbers in an in vivo scenario.

Objective: A highly sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here, we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, CA, USA)., Design: Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management., Participants: All DTC cases diagnosed, treated and followed up in four tertiary referral centres for thyroid cancer since January 2005 (n = 1456) were retrieved, and predefined selection criteria were applied to prevent relevant enrolment biases. A series of 204 patients was finally selected for this study., Measurements: Samples had been stored at -80°C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory., Results: Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC), and 81.4% showed no evidence of disease (NED) at the end of follow-up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH-stimulated Tg cut-offs to detect sREC were 0.41 μg/L and 1.82 μg/L for Elecsys® and 0.36 μg/L and 1.62 μg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse., Conclusions: Using appropriate assay-specific cut-offs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well-established Access® Tg assay., (© 2017 John Wiley & Sons Ltd.)

Ultrasound is critical in detection, diagnosis, and management of thyroid nodules. Ultrasound detection of regional nodal metastatic disease is based on abnormal nodal morphology rather than size and is critical to initial surgical and long-term management of thyroid cancer. Fine-needle aspiration biopsy is the gold standard for malignancy diagnosis in thyroid cancer. Thyroglobulin assay of nodal aspirates improves accuracy in diagnosis of metastases. Reporting lexicons assign risk levels to thyroid nodules with the goal of improving and standardizing patient management. Surveillance ultrasound in papillary microcarcinomas is being evaluated and compared with surgical management., (Published by Elsevier Inc.)

Objective: Sortilin, a Vps10p family member, is expressed by thyroid epithelial cells (TEC), where it binds to internalized thyroglobulin (Tg) molecules. Premature binding of Tg to sortilin during biosynthesis may cause intracellular retention of Tg. Such a premature interaction may be prevented by one or more inhibitor/s. Because both sortilin and Tg bind to the low-density lipoprotein receptor-associated protein (RAP), we investigated whether RAP serves such a function., Methods: Immunofluorescence staining for sortilin, Tg, and RAP was performed in FRTL-5 cells. Co-immunoprecipitation experiments were performed in extracts from FRTL-5 or COS-7 cells, the former co-transfected with Tg and/or RAP and/or sortilin, or in thyroid extracts from RAP KO mice., Results: Tg and sortilin did not co-localize in FRTL-5 cells following inhibition of protein synthesis, suggesting that newly synthesized, endogenous sortilin and Tg do not interact, in confirmation of which an anti-sortilin antibody did not co-precipitate Tg in FRTL-5 cells. In contrast, Tg co-localized with RAP in FRTL-5 cells. Co-immunoprecipitation of Tg with an anti-sortilin antibody in COS-7 cells transfected with sortilin and Tg was abolished when cells were co-transfected with RAP, indicating that RAP prevents binding of Tg to sortilin during biosynthesis, in confirmation of which an anti-sortilin antibody co-precipitated Tg in thyroid extracts from RAP KO mice to a greater extent than in thyroid extracts from WT mice., Conclusions: Tg does not bind prematurely to sortilin because of its interaction with RAP during protein biosynthesis. These findings add new information to the knowledge of thyroid physiology.

This article summarizes the main principles for the appropriate use of laboratory testing in the diagnosis and management of thyroid disorders, as well as controversies that have arisen in association with some of these biochemical tests. To place a test in perspective, its sensitivity and accuracy should be taken into account. Ordering the correct laboratory tests facilitates the early diagnosis of a thyroid disorder and allows for timely and appropriate treatment. This article focuses on a comprehensive update regarding thyroid-stimulating hormone, thyroxine/triiodothyronine, thyroid autoantibodies, thyroglobulin, and calcitonin. Clinical uses of these biochemical tests are outlined., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Stable isotopically labeled (SIL) tryptic peptides, cleavable SIL peptides, and a full-length SIL protein were compared for internal calibration (i.e., as internal calibrators) and external calibration (i.e., as internal standards) when quantifying three forms of unlabeled, human thyroglobulin (Tg) by bottom-up protein analysis. All SIL materials and human proteins were standardized by amino acid analysis to ensure traceability of measurements and allow confident assignment of accuracy. The three forms of human Tg quantified were (1) the primary reference material BCR457-a native protein purified from human thyroids, (2) a commercially available form also purified from human thyroids, and (3) a full-length recombinant form expressed and purified from a human embryonic kidney 293 cell-line. Collectively, the results unequivocally demonstrate the lack of commutability of tryptic and cleavable SIL peptides as internal calibrators across various bottom-up assays (i.e., denaturing/digestion conditions). Further, the results demonstrate the potential during external calibration for surrogate protein calibrators (i.e., recombinant proteins) to produce inaccurate concentration assignments of native protein analytes by bottom-up analysis due to variance in digestion efficiency, which is not alleviated by altering denaturation/digestion stringency and indicates why protein calibrators may not be commutable in bottom-up protein assays. These results have implications regarding the veracity of "absolute" protein concentration assignments by bottom-up assays using peptide calibrators, as well as protein calibrators, given that absolute accuracy was not universally observed. Nevertheless, these results support the use of recombinant SIL proteins as internal standards over SIL peptides due to their ability to better mimic the digestion of human-derived proteins and mitigate bias due to digestion-based matrix effects that were observed during external calibration.

Different imaging tools, circulating endocrine markers, and fine-needle aspiration (FNA) cytology are of great importance in the diagnosis and follow-up of different thyroid and parathyroid diseases. Sometimes, however, they are conflicting or inconclusive: interestingly, measuring endocrine markers (i.e. thyroglobulin, calcitonin, parathyroid hormone) in fluids from FNA proved to be a very useful complementary diagnostic tool in such cases. The determination of endocrine markers in fluids other than serum/plasma has been developed in the last years. Although studies have reported overall satisfactory results, a good standardization of procedures has not yet been reached, and further efforts should be made in order to better define pre-analytical, analytical, and post-analytical aspects. Here we reviewed critically the literature on the measurement of FNA endocrine markers, focusing on laboratory issues, such as preparation of the sample, choice of solution, and technical features of determination of these markers. Indeed, information for use of FNA-Tg, FNA-CT, and FNA-PTH in clinical practice was also provided.

Objective: To evaluate two variables affecting Thyroglobulin stability in the washout of fine needle aspiration biopsies of thyroid nodules and metastatic lymph nodes., Materials and Methods: Thyroglobulin stability after storage at -20 °C up to 14 days was studied in washout performed with normal saline solution and further dilutions with normal saline solution from five metastatic thyroid nodes and six benign thyroid nodules. We also studied thyroglobulin stability in diluents compared with normal saline solution: 4% bovine serum albumin in normal saline solution and diluents free from thyroglobulin or Calcitonin or parathyroid hormone in paired and simultaneous thyroglobulin measurements of washout dilutions from 5/6 benign thyroid nodules and 2/5 metastatic lymph nodes. Thyroglobulin and Thyroglobulin antibodies were measured by a chemiluminescent assay. Positive samples with thyroglobulin antibodies in serum and/or washout were excluded., Results: Thyroglobulin decreased with storage in washout or dilutions of washout performed in normal saline solution (p < 0.05). Lower thyroglobulin concentrations, close to the commonly used cut-off (1.1 ng/mL), showed the highest decrease as soon as after 1 day of storage. Diluents other than normal saline solution stabilized thyroglobulin in dilutions of all washout., Conclusions: The results suggest that the reliability of thyroglobulin measurements in washout of fine needle aspirates could be preserved by immediate measure of thyroglobulin or the use of stabilizing diluents to perform washout.

The aim of this study was to evaluate the pre-analytical factors contributing to uncertainty in thyroglobulin measurement in fluids from fine-needle aspiration (FNA) washout of cervical lymph nodes. We studied pre-analytical stability, in different conditions, of 41 samples prepared with concentrated solutions of thyroglobulin (FNA washout or certified standard) diluted in physiological saline solution or buffer containing 6% albumin. In this buffer, over time, no changes in thyroglobulin concentrations were observed in all storage conditions tested. In albumin free saline solution, thyroglobulin recovery rates depended on initial sample concentrations and on modalities of their conservation (in conventional storage tubes, recovery mean was 56% after 3 hours-storage at room temperature and 19% after 24 hours-storage for concentrations ranged from 2 to 183 μg/L; recovery was 95%, after 3 hours or 24 hours-storage at room temperature, for a concentration of 5,656 μg/L). We show here that these results are due to non-specific adsorption of thyroglobulin in storage tubes, which depends on sample protein concentrations. We also show that possible contamination of fluids from FNA washout by plasma proteins do not always adequately prevent this adsorption. In conclusion, non-specific adsorption in storage tubes strongly contributes to uncertainty in thyroglobulin measurement in physiological saline solution. It is therefore recommended, for FNA washout, to use a buffer containing proteins provided by the laboratory.

Objective: Graves disease (GD) is commonly seen in endocrine clinical practice. The objective of this study was to evaluate the current diagnosis and management of patients with GD in the Middle East and North Africa (MENA)., Methods: An electronic survey on GD management was performed using an online questionnaire of a large pool of practicing physicians. Responses from 352 eligible and willing physicians were included in this study. They were mostly endocrinologists (157) and internal medicine physicians (116)., Results: In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request serum antithyroid peroxidase antibody and TSH-receptor autoantibody (50% and 46%, respectively), whereas serum antithyroglobulin antibodies would be ordered by fewer respondents (36%). Thyroid ultra-sound would be requested by a high number of respondents (63.7%), while only a small percentage would order isotopic thyroid studies. Antithyroid drug (ATD) therapy was the preferred first-line treatment (52.7%), followed by radio-iodine (RAI) treatment (36.8%), β-blockers alone (6.9%), thyroidectomy (3.2%), and no therapy (1.3%). When RAI treatment was selected in the presence of mild Graves orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis was frequently used. The preferred ATD in pregnancy was propylthiouracil in the first trimester and carbimazole in the second and third trimesters. On most issues, choices of the MENA physicians fell between European and American practices., Conclusion: Hybrid practices are seen in the MENA region, perhaps reflecting training and affiliations. Management approaches most suitable for patients in this region are needed., Abbreviations: ATD = antithyroid drug CBZ = carbimazole FT3 = free T3 FT4 = free T4 GD = Graves disease GO = Graves orbitopathy MENA = Middle East and North Africa MMI = methimazole RAI = radioactive iodine RAIU = RAI uptake T3 = tri-iodothyronine T4 = thyroxine TG Ab = antithyroglobulin antibodies TRAb = TSH-receptor autoantibody TSH = thyroid-stimulating hormone PTU = propylthiouracil TID = thrice daily UAE = United Arab Emirates US = ultrasound.

Objective: To study the role of fine-needle aspiration biopsy and thyroglobulin measurement (FNAB-Tg) in diagnosing cervical lymph node (CLN) metastases in patients with papillary thyroid cancer (PTC) before thyroidectomy., Methods: Ultrasonography (US)-guided FNAB was performed on 92 patients with PTCs with 105 CLNs before surgery. The wash-out of the FNAB-Tg level was detected., Results: Based on the final pathology, 67 lymph nodes (LNs) were positive for metastasis, and 38 LNs were negative for metastasis. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FNAB-Tg in thyroidectomized patients was 100%, 86.8%, 95.2%, 97.3%, and 95.2%, respectively., Conclusions: FNAB-Tg is a useful technique for diagnosing CLN metastasis of PTC before thyroidectomy.
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Background: Differentiated thyroid carcinomas (DTCs) account for about 1% of all human malignancies. Cervical lymph nodes metastases and recurrences in the thyroid bed frequently occur. Furthermore, about 10-15% of patients develop distant metastases. Therefore, patients must undergo life-long follow-up., Objective: The aim of this study was to evaluate the usefulness of Thyroglobulin measurement in FNAB washout (FNAB-Tg) in the detection of local metastasis in patients affected by or evaluated for thyroid cancer., Materials and Methods: In a 3-year period, a total of 83 consecutive patients coming to our attention at the Ear-Nose-Throat (ENT) Outpatients Service of the National Cancer Research Center &quot;Istituto Tumori Giovanni Paolo II&quot; of Bari, Italy, because of the finding of one or more cervical lymph node(s), were enrolled in the study. After collection of the cytological specimen, the needle used for performing FNAB was then washed in 1 ml of normal saline. 89 FNAB washouts were collected from the same number of lymph nodes and subsequently investigated for Thyroglobulin levels using a sequential chemiluminescent-immunometric assay., Results: Comparing the cytological or, when performed, histological diagnoses with the results of FNAB-Tg, we found that in 24 cases of lymph node metastases from PTC (19 lymph nodes from patients at the first diagnoses and 5 lymph nodes from PTC patients in follow up) the mean level of Thyroglobulin was 1840.11 ng/ml; range: <0,2 to 11440 ng/ml. In the group of PTC patients (27 lymph nodes) with lymph nodes negative for metastatic involvement at cytology (i.e. no lymph node recurrence at follow-up), as well as in the cases of subjects without PTC and submitted to FNAB because of the appearance of lymph node(s) classified as reactive at cytology (37 lymph nodes), FNAB-Tg was lower than or equal to 0.2 ng/ml. As expected, the Thyroglobulin level was not detectable (< 0.2 ng/ml) also in a lymph node FNAB from a case of anaplastic thyroid carcinoma., Conclusion: In our study, FNAB-Tg was not detectable in all node negative patients showing, when considering together all the lymph node metastases, a 96% sensitivity and 100% specificity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We describe the development and validation of multianalyte immunoassays (MAIA) for three analytes, viz., thyroxine (T4), thyroid stimulating hormone (TSH), and thyroglobulin (Tg) essential for assessment of thyroid function but having widely varying molecular weights. Using polycarbonate (PC) track-etched membranes (TEM) as an immobilization support and 125 I as the tracer, both competitive assay for T4 and non-competitive assay for TSH and Tg were performed on the same TEM. MAIA was found to be highly sensitive and precise with clinically useful working range and correlated very well with individual analyte immunoassays. While we have demonstrated this assay format with radiotracer, it can be used with non-isotopic tracers equally well.