Lobectomy in patients with differentiated thyroid cancer: experience of a Chilean tertiary center.

PURPOSE: Thyroid lobectomy (TL) is an appropriate treatment for up to 4 cm intrathyroidal differentiated thyroid cancer (DTC). There is scarce data regarding TL outside first-world centers. Our aim is to report a cohort of patients with DTC treated with TL in Chile. METHODS: We included DTC patients treated with TL, followed for at least 6 months, characterized their clinicopathological features and classified their risk of recurrence and response to treatment. RESULTS: Eighty-two patients followed for a median of 2.3 years (0.5-7.0). Seventy-three (89%) patients had papillary, 8 (9.8%) follicular and 1 (1.2%) high-grade DTC. The risk of recurrence was low in 56 (68.3%) and intermediate in 26 (31.7%). Eight (9.8%) patients required early completion thyroidectomy and radioiodine. At last follow-up, 52 (70.3%) had excellent, 19 (25.7%) had indeterminate, and 1 (1.4%) had structural incomplete response. CONCLUSION: In a developing country, TL is an adequate option for appropriately selected DTC patients.

Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment.

Objective: Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). Subjects and methods: We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. Results: After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-riskto high-risk patients with postoperative s-Tg > 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. Conclusion: The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based ondynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

Rhipicephalus microplus thyropin-like protein: Structural and immunologic analyzes.

Tick saliva has a pivotal function in parasitism. It has pharmacological and immunomodulatory properties, with several proteins reported in its composition. Thyroglobulin type-1 domain protease inhibitor (thyropin)-like proteins are found in tick saliva, but their function, properties and structures are poorly characterized. It has been reported that thyropins are capable of inhibiting cysteine peptidases present in antigen-presenting cells. To elucidate the role of thyropin-like proteins in ticks, we conducted in silico analysis and cloned an open reading frame from a thyropin-like protein found in Rhipicephalus microplus. The recombinant protein was successfully expressed, followed by immunological characterization and a vaccine trial against Rhipicephalus sanguineus in rabbits. Several differences are observed between thyropin-like proteins from hard and soft ticks, especially the number of thyroglobulin domains and predicted glycosylation pattern. Thyropin-like proteins also differ between postriata and metastriata ticks, the latter having a coil-domain at the C-terminal region and high number of predicted glycosylation sites. Overall, the data suggested divergence in thyropin-like proteins functions among ticks. The recombinant thyropin-like protein is immunogenic and the antibodies against it are able to recognize the native protein in tick saliva and tissues. While the recombinant protein does not elicit a protective response against R. sanguineus infestation, its characterization paves the way for further investigations aimed at determining the precise function of this protein in tick physiology.

Stimulated thyroglobulin and diagnostic 131-iodine whole-body scan as a predictor of distant metastasis and association with response to treatment in pediatric thyroid cancer patients.

INTRODUCTION: Differentiated thyroid carcinoma (DTC) is a rare oncological disease in the pediatric population, presenting with a more aggressive form. Stimulated thyroglobulin (sTg) and the 131-iodine whole-body scans (WBSs) are known adult markers related to the presence of distant metastasis. Little is known about their roles in the pediatric population. PURPOSE: To evaluate sTg levels and diagnostic WBS (DxWBS) as predictors of distant metastasis after thyroidectomy and to correlate with the response to treatment at the end of follow-up in pediatric DTC. MATERIALS AND METHODS: Patients under 19 years old diagnosed with DTC from 1980 to 2022 were retrospectively evaluated. sTg values and WBS were assessed after thyroidectomy and prior radioiodine treatment (RIT) and correlated with the possibility of finding distant metastasis and response to treatment at the end of follow-up. RESULTS: In a total of 142 patients with a median age of 14.6 (4-18) years who were followed for 9.5 ± 7.2 years and classified according to the ATA risk of recurrence as low (28%), intermediate (16%), and high risk (56%), 127 patients had their sTg evaluated. A sTg value of 21.7 ng/dl yielded a sensitivity of 88% compared to 30% for DxWBS in predicting distant metastasis. Specificity was 60% and 100% respectively. 42% of patients obtained discordant results between DxWBS and RxWBS. In high-risk patients, sTg levels were particularly able to differentiate those who would have distant metastasis with better diagnostic accuracy than the WBSs. CONCLUSIONS: The sTg level had better performance in detecting distant metastases in pediatric DTC than the DxWBS. DxWBS's low performance suggests that caution should be taken in interpreting their findings in terms of the underdiagnosis for metastatic disease, especially when the sTg level already suggests distant disease.

Basal or stimulated thyroglobulin in evaluating response to treatment in papillary thyroid carcinoma? A retrospective cohort study.

OBJECTIVE: It is not clear whether response to initial treatment in papillary thyroid carcinoma (PTC) patients is best evaluated by measuring thyroglobulin (Tg) in the presence of levothyroxine (BTg) or when stimulated by elevated TSH (STg). The aim of this study was to evaluate whether response to therapy 1 year after initial treatment changes with the use of STg in relation to BTg in PTC patients treated with total thyroidectomy (TT) and radioiodine (131I), and, if observed, to assess which response is better associated with clinical course. SUBJECTS AND METHODS: This is a retrospective study of 148 PTC patients submitted to TT and 131I. We analyzed the response to therapy (excellent, biochemical incomplete, or indeterminate) at 1 year after initial treatment, using BTg or STg, and compared which method was better associated with "excellent response at final evaluation." RESULTS: Twenty-eight patients (20.4%) presented change in response to therapy, with 17 of these (60.7%) presenting a worse response. Response using STg was 1.6 times better associated with proposed outcome [odds ratio (OR) = 4.61; confidence interval 95% (IC95%): 2.13-9.98] than with BTg (OR = 2.84; IC95%: 1.33-6.06). CONCLUSION: Response to therapy at 1 year using STg was altered in approximately 20% of cases and therefore proved to be a better predictor of excellent response in the last evaluation.

Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment

ABSTRACT Objective: Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). Subjects and methods: We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. Results: After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-risk to high-risk patients with postoperative s-Tg ≥ 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. Conclusions: The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based on dynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

The Usefulness of Thyroid Antibodies in the Diagnostic Approach to Autoimmune Thyroid Disease.

Autoimmune thyroid disease (AITD) refers to a spectrum of various diseases, with two extremes of clinical presentation, hypothyroidism (Hashimoto's thyroiditis (HT) and hyperthyroidism (Graves-Basedow disease (GBD)). Both conditions are characterized by presenting a cellular and humoral autoimmune reaction, with an increase in the synthesis and secretion of antibodies directed toward various thyroid antigens, together with a phenomenon of thyrocyte necrosis and apoptosis (in HT) and a persistent thyrotropin-receptor stimulation (in GBD). The diagnosis of both entities is based on clinical, laboratory, and imaging findings. Three major anti-thyroid antibodies have been described, those directed against the TSH receptor (TRAb), against thyroid peroxidase (TPOAb), and against thyroglobulin (TgAb). Each of these autoantibodies plays a fundamental role in the diagnostic approach of autoimmune thyroid disease. TRAbs are the hallmark of GBD, and additionally, they are predictors of response to disease treatment, among other utilities. Likewise, TPOAb and TgAb allow for identifying individuals with a higher risk of progression to hypothyroidism; the positivity of one or both autoantibodies defines the presence of thyroid autoimmunity. In this review, the usefulness of anti-thyroid antibodies in the diagnostic approach to autoimmune thyroid disease is described.

The p.Cys1281Tyr variant in the hinge module/flap region of thyroglobulin causes intracellular transport disorder and congenital hypothyroidism.

Congenital hypothyroidism (CH) due to thyroglobulin (TG) variants causes very low serum TG levels with normal or enlarged thyroid glands, depending on the severity of the defect, and with autosomal recessive inheritance. The purpose of this study was to functionally characterize p.Cys1281Tyr variant in the TG gene in order to increase our knowledge of the molecular mechanisms associated with CH. In order to find evidence that support the hypothesis that the p.Cys1281Tyr variant would affect the TG folding were performed amino acid prediction, 3D modeling and transient expression analysis in HEK293T cells. 18 of the 21″in silico" algorithms predict a deleterious effect of the p.Cys1281Tyr variant. The full-length 3D model p.Cys1281Tyr TG showed disulfide bond cleavage between the cysteines at positions 1249 and 1281 and rearrangement of the TG structure, while transient expression analysis indicated that p.Cys1281Tyr causes retention of the protein inside the cell. Consequently, these results show that this pathogenic variant makes it impossible for TG to fulfill its function in the biosynthesis process of thyroid hormones, causing CH. In conclusion, our results confirm the pathophysiological importance of misfolding of TG as a consequence of p.Cys1281Tyr variant located in the hinge module/flap region of TG.

Improving Iodine Intake in Rural Haiti through Social Enterprise: A Cross-Sectional Study in the Central Plateau.

Iodine intake in Haiti has increased in recent years thanks to the "Bon Sel" social enterprise approach to salt fortification and distribution by the market segment. However, it was uncertain whether this salt reached remote communities. This cross-sectional study aimed to assess the iodine status of school-age children (SAC) and women of reproductive age (WRA) in a remote region of the Central Plateau. A total of 400 children (9-13 years) and 322 women (18-44 years) were recruited through schools and churches, respectively. Urinary iodine (UIC) and urinary creatinine (UCC) concentrations were measured in spot samples, and thyroglobulin (Tg) on dried blood spots. Their iodine intake was estimated, and dietary information collected. The median (IQR) UIC in SAC was 130 µg/L (79-204, n = 399), and in WRA, 115 µg/L (73-173, n = 322). The median (IQR) Tg in SAC was 19.7 µg/L (14.0-27.6, n = 370), and in WRA, 12.2 µg/L (7.9-19.0, n = 183); 10% of SAC had Tg > 40 µg/L. Estimated iodine intake was 77 µg/day and 202 µg/day in SAC and WRA, respectively. Iodized table salt was rarely consumed, though bouillon was used daily; this is hypothesized to be a major contributor to dietary iodine intake. Iodine intake in this remote region seems to have improved considerably since the 2018 national survey, though SAC remain at risk. These results point to the potential effectiveness of using social business principles to deliver humanitarian solutions.

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.

Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify and functionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanisms responsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with marked alteration of TG synthesis were studied. The two families were previously analysed in our laboratory, only one deleterious allele, in each one, was detected after sequencing the TG gene (c.2359 C > T [p.Arg787*], c.5560 G > T [p.Glu1854*]). These findings were confirmed in the present studies by Next-Generation Sequencing. The single nucleotide coding variants of the TG gene were then analyzed to predict the possible variant causing the disease. The p.Pro2232Leu (c.6695 C > T), identified in both families, showing a low frequency population in gnomAD v2.1.1 database and protein homology, amino acid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently express p.Pro2232Leu in a full-length rat TG cDNA clone and confirmed that this point variant was sufficient to cause intracellular retention of mutant TG in HEK293T cells. Consequently, each family carried a compound heterozygous for p.Arg787*/p.Pro2232Leu or p.Glu1854*/p.Pro2232Leu variants. In conclusion, our results confirm the pathophysiological importance of altered TG folding as a consequence of missense variants located in the ChEL domain of TG.

[Factitious hyperthyroidism due to intake of herbal supplements for weight reduction]. / Hipertiroidismo facticio por ingesta de suplementos herbales para reducción de peso.

Factitious thyrotoxicosis is characterized by the intentional or accidental intake of excess thyroid hormones or their derivatives. We describe 6 cases of patients who developed thyrotoxicosis and adverse effects by weight-reducing herbal medicines. Currently there is a lot of publicity about supplements that "help to lose weight", which are over-the-counter and widely distributed in health food stores or online, which is why it is common to have patients who consume them, without many noticing their possible risks. If factitious hyperthyroidism is suspected, we should request thyroglobulin and anti-thyroglobulin tests, as well as a thyroid scan or uptake curve. To make the differential diagnosis between intake of thyroxine (T4) or triiodothyronine (T3) or its derivatives, we must request the measurement of T4 and T3. In case of ingestion of T4, T4 and T3 will be elevated, but in case of ingestion of triodothyronine or its derivatives, T4 will be decreased with elevated T3.

La tirotoxicosis facticia se caracteriza por la ingesta de un exceso de hormonas tiroideas o derivados de las mismas de forma intencional o accidental. Describimos 6 casos clínicos de pacientes que desarrollaron tirotoxicosis y efectos adversos con la ingesta de suplementos de herbales de venta libre para descenso de peso. Actualmente existe mucha publicidad sobre suplementos que "ayudan al descenso de peso", los cuales son de venta libre y distribuidos ampliamente en tiendas de dietéticas o por internet por lo cual es habitual tener pacientes que los consumen, sin que muchos reparen en sus posibles riesgos. En caso de sospechar un hipertiroidismo facticio debemos solicitar tiroglobulina y anticuerpos anti tiroglobulina así como centellograma tiroideo o curva de captación. Para realizar el diagnóstico diferencial entre ingesta de tiroxina (T4) o triiodotironina (T3) o sus derivados debemos solicitar medición de T4 y T3. En caso de ingesta de T4, la T4 y T3 se encontrarán elevadas, pero en caso de ingesta de triodotironina o sus derivados la T4 se encontrará descendida con una T3 elevada.

Hipertiroidismo facticio por ingesta de suplementos herbales para reducción de peso / Factitious hyperthyroidism due to intake of herbal supplements for weight reduction

Resumen La tirotoxicosis facticia se caracteriza por la ingesta de un exceso de hormonas tiroideas o derivados de las mismas de forma intencional o accidental. Describimos 6 casos clínicos de pacientes que desarrollaron tirotoxicosis y efectos adversos con la ingesta de suplementos de herbales de venta libre para descenso de peso. Actualmente existe mucha publicidad sobre suplementos que "ayudan al descenso de peso", los cuales son de venta libre y distribuidos ampliamente en tiendas de dietéticas o por internet por lo cual es habitual tener pacientes que los consumen, sin que muchos reparen en sus posibles riesgos. En caso de sospechar un hipertiroidismo facticio debemos solicitar tiroglobulina y anticuerpos anti tiroglobulina así como centellograma tiroideo o curva de captación. Para realizar el diagnóstico diferencial entre ingesta de tiroxina (T4) o triiodotironina (T3) o sus derivados debemos solicitar medición de T4 y T3. En caso de ingesta de T4, la T4 y T3 se encontrarán elevadas, pero en caso de ingesta de triodotironina o sus derivados la T4 se encontrará descendida con una T3 elevada.

Abstract Factitious thyrotoxicosis is characterized by the intentional or accidental intake of excess thyroid hormones or their derivatives. We describe 6 cases of patients who developed thyrotoxicosis and adverse effects by weight-reducing herbal medicines. Currently there is a lot of publicity about supplements that "help to lose weight", which are over-the-counter and widely distributed in health food stores or online, which is why it is com mon to have patients who consume them, without many noticing their possible risks. If factitious hyperthyroidism is suspected, we should request thyroglobulin and anti-thyroglobulin tests, as well as a thyroid scan or uptake curve. To make the differential diagnosis between intake of thyroxine (T4) or triiodothyronine (T3) or its deriva tives, we must request the measurement of T4 and T3. In case of ingestion of T4, T4 and T3 will be elevated, but in case of ingestion of triodothyronine or its derivatives, T4 will be decreased with elevated T3.

Second Adjuvant Radioiodine Therapy after Reoperation for Locoregionally Persistent or Recurrent Papillary Thyroid Carcinoma.

Introduction Differentiated thyroid carcinoma (DTC) has increased incidence. Intermediate- and high-risk patients have lymph node relapse rate ranging from 10 to 50%, and receive multiple reinterventions, increasing the morbidity of the disease. Currently, there are no established guidelines for the use of second radioactive iodine (RAI) therapy after the reintervention for local recurrence. Materials and Methods This is a retrospective review of the medical records of 1,299 patients treated from January 2016 to July 2019 with DTC. We included 48 patients who received total thyroidectomy, RAI remnant ablation, surgery to remove the locally recurrent/persistent papillary thyroid carcinoma (PTC), and received a second RAI therapy. Results There were no significant differences between thyroglobulin (Tg) levels before reoperation (Tg0), Tg levels postoperatively (Tg1), and Tg levels after 6 months of second adjuvant RAI therapy (Tg2). However, we evidenced a 69.79% drop in first Tg levels (Tg0: 24.7 vs. Tg1: 7.56, p =0.851) and 44.4% decrease in second Tg levels (Tg1: 7.56 vs. Tg2: 4.20, p =0.544). Also, 77.1% of the patients did not have another documented recurrence. The median relapse-free time was 10.9 months (range: 1.3-58.2 months). Conclusion The results of the study cannot assess that a second RAI treatment after reoperation for locoregionally persistent or recurrent disease have a significant impact on treatment outcomes in intermediate- or high-risk patients with PTC. However, the 77.1% of patients have not presented a second documented recurrence and the median values of Tg and TgAb levels showed a substantial decrease after surgery and second RAI treatment.

Rol de la dosificación de tiroglobulina en el líquido de lavado de la punción por aguja fina para el diagnóstico de metástasis ganglionares en el seguimiento de cáncer de tiroides en el Hospital de Clínicas de Montevideo, Uruguay / The role of thyroglobulin detection in washout fluid from fine-needle aspiration biopsies to diagnose gland metastases in thyroid cancer follow up / Rol de dosificação de tiroglobulina no líquido de lavado da punção por agulha fina para o diagnóstico de metástases ganglionares no seguimento de câncer de tiroides

La recurrencia del cáncer diferenciado de tiroides (CDT) a nivel del cuello ocurre en 5%-20% de los casos. El estudio citológico mediante punción de adenopatías ha sido utilizado para confirmar los hallazgos ecográficos sospechosos de malignidad, su sensibilidad varía entre 75%-85%. El objetivo del estudio es evaluar la utilidad de la tiroglobulina (Tg) medida en la punción por aspiración de aguja fina (PAAF) (Tg-PAAF), en el diagnóstico de metástasis ganglionares de pacientes en seguimiento por CDT mayores de 18 años. Se realizó un estudio retrospectivo, descriptivo y observacional en una muestra de 14 pacientes predominantemente de sexo femenino (71,4%), con edad promedio 40,9 ± 2,9 años. Resultados: la variante CDT unifocal fue la más frecuente. De los 22 ganglios sospechosos la mitad tuvieron Tg-PAAF ≥ 1 ng/ml. Todas las adenitis reactivas tuvieron un resultado < 1 ng/ml, en cambio las adenopatías metastásicas obtuvieron un resultado ≥ 1 ng/ml. El 85,7% de pacientes tuvieron anticuerpos anti-Tg ≥10 UI/ml (5 pacientes con valores de Tg-PAAF ≥1 ng/ml y siete pacientes con Tg-PAAF < 1 ng/ml) y 14,3% tuvieron valores < 10 UI/ml (todos con Tg-PAAF <1 ng/ml). Se realizaron cuatro vaciamientos ganglionares, en todas se encontró metástasis de CDT. Conclusiones: la Tg-PAAF es un buen estudio para el diagnóstico de metástasis ganglionares en pacientes en seguimiento de CDT. Dado los resultados obtenidos en este trabajo, apoyado en la búsqueda bibliográfica, el uso de la Tg-PAAF tiene un gran valor diagnóstico para detectar metástasis ganglionares en el seguimiento del CDT por lo que se recomienda su uso junto con la citología y/o la anatomía patológica.

Recurrence of differentiated thyroid cancer (DTC) in the cervix is 5-20% of cases. Fine-needle aspiration cytology of adenopathies has been used to confirm ultrasound findings when suspicions of being malignant. The study aims to evaluate usefulness of fine-needle aspiration of lymph gland to diagnose gland metastases in patients over 18 years old under papillary thyroid cancer follow-up. Retrospective, descriptive and observational study in a 14-patient-sample, mainly female (71,4%), with an average age of 40.9 ± 2.9 years old. Results: single tumor focus papillary thyroid cancer was the most common type of thyroid cancer found. 50% of the 22 suspicious glands had FNATg ≥1ng/ml. All reactive adenitis had measurements < 1ng/ml, whereas metastatic adenopathies results were ≥ 1ng/ml. 85.7% of patients had anti-TG Ac ≥ 1ng/ml (5 patients with FNATg values ≥1ng/ml and 7 patients with FNATg < 1ng/ml), 14.3% of which obtained results < 10 UI/ml (all of them with FN1 ng/ml). Gland emptying was performed in 4 cases, and papillary thyroid cancer metastases was found in all of them. Conclusions: FNATg is a good study to diagnose gland metastases in patients under differentiated thyroid cancer follow-up. Given the results of this study, supported by a bibliographic search, the use of FNATg has a great diagnostic value to detect gland metastases in the follow up of differentiated thyroid cancer, and thus it is recommended along with cytological and/or pathology studies.

A recorrência do câncer diferenciado de tiroides (CDT) no nível do pescoço, ocorre em 5-20% dos casos. O estudo citológico mediante punção de linfadenopatia foi utilizado para confirmar os achados ecográficos suspeitos de malignidade; sua sensibilidade varia entre 75-85%. O objetivo do estudo era avaliar a utilização da tiroglobulina (Tg) medida na punção por aspiração por agulha fina (PAAF) (Tg-PAAF), no diagnóstico de metástase ganglionar de pacientes em seguimento por CDT maiores de 18 anos. Realizou-se um estudo retrospectivo, descritivo e observacional em uma amostra de 14 pacientes predominantemente de sexo feminino (71,4%), com idade média de 40,9 ± 2,9 anos. Resultados: a variante CPT unifocal foi a mais frequente. Dos 22 linfonodos suspeitos, a metade apresentou Tg-PAAF ≥ 1ng/ml. Todas as adenites reativas apresentaram um resultado < 1ng/ml, no entanto as linfadenopatias metastásicas tiveram um resultado ≥ 1ng/ml. 85,7% dos pacientes apresentam Ac anti-Tg ≥10 UI/ml (5 pacientes com valores de Tg-PAAF ≥1ng/ml e 7 pacientes com Tg-PAAF < 1ng/ml) e 14,3% valores < 10 UI/ml (todos com Tg-PAAF <1 ng/ml). Foram feitos 4 esvaziamentos ganglionares, em todos foram encontradas metástases da CPT. Conclusões: o Tg-PAAF é um bom método para o diagnóstico de metástase ganglionar em pacientes em seguimento de CDT. Considerando os resultados obtidos neste trabalho, apoiado na bibliografia, o uso do Tg-PAAF tem um grande valor diagnóstico para detectar metástase ganglionar no seguimento do CDT; por essa razão recomenda-se seu uso junto com a citologia e/ou anatomia patológica.

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect.

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.

Análisis de tiroglobulina preablativa y cáncer diferenciado de tiroides preoperatorio / Analysis of pre-ablative and preoperative thyroglobulin in differentiated thyroid cancer

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.

Is there a role for diagnostic scans in the management of intermediate-risk thyroid cancer?

Radioiodine (RAI) is selectively recommended for intermediate-risk differentiated thyroid carcinomas (DTC). The information gleaned from pretherapy stimulated thyroglobulin levels (sTg) and diagnostic 131I whole-body scans (DxWBS) to guide therapy remains controversial. The present study aimed at evaluating the impact of preablation sTg and DxWBS in the management of intermediate-risk DTC. A retrospective analysis of 301 intermediate-risk DTC patients submitted to total thyroidectomy and RAI therapy was performed. Pretherapy sTg and DxWBS and post-therapy WBS (RxWBS) findings were analyzed and compared to outcomes. Fifty-two patients (17.3%) had metastases diagnosed by DxWBS and/or RxWBS. The DxWBS identified 10.6% of patients with functioning metastases, including unexpected distant metastases. If combined with SPECT-CT, DxWBS detected RAI-avid metastases more frequently, particularly lymph node metastases (13.1% vs 4.2% planar WBS, P = 0.015). The DxWBS findings modified patient management in 8.3%. A pretherapy sTg <1 ng/mL was associated with a low false-negative rate for the presence of metastases (5.2%), and its performance in excluding metastasis was improved by a negative DxWBS (2.7% of patients with both negative exams had metastases in RxWBS). A sTg <1 ng/mL predicted statistically significant lower rates of recurrent/persistent disease and biochemical/structural incomplete responses. In conclusion, preablation sTg and DxWBS contribute to the detection of unknown or persistent metastatic disease in intermediate-risk DTC patients. A sTg <1 ng/mL in combination with a negative DxWBS is highly suggestive of the absence of remaining malignant disease, and one may consider deferring RAI ablation if both exams are negative. A stunning effect is rarely observed and it does not impair proper treatment of metastases.

Natural history, predictive factors of apparent disease (structural or biochemical) and spontaneous excellent response in patients with papillary thyroid carcinoma and indeterminate response to initial therapy with radioiodine.

BACKGROUND: About 20% of patients with papillary thyroid carcinoma (PTC) submitted to total thyroidectomy followed by radioactive iodine (RAI) exhibit an indeterminate response to therapy. The aim was to evaluate the natural history, predictive factors of apparent disease (structural or biochemical), and spontaneous excellent response in patients with PTC and an initial indeterminate response to RAI therapy defined based on unstimulated Tg (u-Tg). METHODS: We evaluated 164 patients who were initially treated with total thyroidectomy and RAI and who had an indeterminate response to therapy (u-Tg between 0.2 and 1 ng/ml, undetectable anti-Tg antibodies [TgAb], and neck ultrasonography [US] without anomalies). None of the patients received empirical therapy with RAI. The patients were followed up for 24 to 144 months (median 72 months). RESULTS: Apparent disease occurred in 16 patients (9.7%), including 13 with structural disease and 3 with u-Tg elevation > 1 ng/ml, but no tumor was detected by the imaging methods (biochemical disease). A higher frequency of disease was observed in patients with >3 lymph node metastases (LNM) and initial u-Tg >0.35 ng/ml. The frequency was only 2% among patients with ≤3 LNM and u-Tg ≤0.35 ng/ml and 9.7% among patients with > 3 LNM or u-Tg >0.35 ng/ml, while the frequency was 27% in patients with >3 LNM and u-Tg >0.35 ng/ml. In the absence of any additional therapy, u-Tg was <0.2 ng/ml (excellent response) in the last assessment in 70 patients (42.7%). Only initial u-Tg was associated with a higher probability of spontaneously achieving an excellent response: 40/72 patients (55.5%) with u-Tg ≤0.35 ng/ml versus 30/92 patients (32.6%) with u-Tg >0.35 ng/ml. CONCLUSIONS: A minority of patients with PTC and an initial indeterminate response to RAI defined based on u-Tg develop apparent disease (structural or biochemical) and many spontaneously achieve an excellent response. The risk of disease can be refined based on parameters such as the extent of lymph node involvement and initial Tg concentration.

Value of stimulated pre-ablation thyroglobulin as a prognostic marker in patients with differentiated thyroid carcinoma treated with radioiodine.

OBJECTIVE: To determine which Thyroglobulin (Tg) level after levothyroxine (LT4) withdrawal (stimulated thyroglobulin - sTg) measured before radioiodine therapy (RAIT) is able to predict incomplete response to treatment of differentiated thyroid carcinoma (DTC) with greater sensitivity and specificity one year after initial treatment with I131. METHODS: A chart review was performed in which 375 patients with DTC treated with RAIT were included. The sTg was measured in all patients prior to treatment with I131. Follow up were then performed one year later. Initial sTg levels were associated to DTC outcomes. A receiver operating characteristic (ROC) curve was performed to achieve a sTg level able to predict which patients would have a greater chance of having an incomplete response to RAIT. RESULTS: Incomplete response to treatment was found in 122 patients (32.5%), this group had a mean sTg of 23.2 ng/mL. ROC curve showed that the optimal cut-off sTg level was 4.4 ng/mL. (sensitivity: 72.1%; specificity: 72.3%; accuracy: 72.2%; positive predictive value of 55.7%; and negative predictive value: 84.3%). CONCLUSION: sTg pre-ablation is a valuable predictor of DTC incomplete response to treatment one year after RAIT. Levels of 4.4 ng/ml or more showed higher accuracy to predict this outcome.

Indication for radioactive iodine in patients with papillary thyroid carcinoma without apparent disease after total thyroidectomy but with elevated antithyroglobulin antibodies.

OBJECTIVE: To evaluate a criterion for the selective indication of radioactive iodine (RAI) based on the short-term behaviour of antithyroglobulin antibodies (TgAb) in patients with papillary thyroid carcinoma (PTC) who have negative thyroglobulin (Tg) and neck ultrasonography (US) without abnormalities after total thyroidectomy but elevated TgAb. DESIGN: This was a prospective study that evaluated 216 patients with low- or intermediate-risk PTC who had nonstimulated Tg ≤ 0.2 ng/ml and no US abnormalities but elevated TgAb 3 months after thyroidectomy. RAI was not indicated in patients with negative TgAb or a >50% reduction in TgAb concentrations 6 months after initial assessment followed by a negative test or an additional reduction (also >50%) after 12 months. RESULTS: Only two of the 114 patients who did not receive RAI developed recurrences; another 108 patients met the criterion of an excellent response to therapy in the last assessment and TgAb persisted in four patients but there was an additional reduction in their concentration during follow-up. Among the 102 patients who received RAI, post-therapy whole-body scanning (RxWBS) detected persistent disease in 8 (8%). Two of the 94 patients without persistent disease on RxWBS developed recurrences. In the last assessment, in the absence of additional treatment, 54/92 patients (58.7%) without structural recurrence had negative TgAb. CONCLUSIONS: The indication for RAI can be based on the short-term behaviour of TgAb in patients with PTC and elevated TgAb after thyroidectomy who are not high risk and who do not have apparent disease (nonstimulated Tg ≤ 0.2 ng/ml and no US abnormalities).