Alginate-based 3D cell culture technique to evaluate the half-maximal inhibitory concentration: an in vitro model of anticancer drug study for anaplastic thyroid carcinoma

Background Three-dimensional (3D) cell culture methods are identified for simulating the biological microenvironment and demonstrating more similarity to in vivo circumstances. Anaplastic thyroid carcinoma (ATC) is a lethal endocrine malignancy. Despite different treatment approaches, no improvement in the survival rate of the patients has been shown. In this study, we used the 3D in vitro ATC model to investigate the cytotoxic effect of BI-847325 anticancer drug in two-dimensional (2D)- and 3D- cultured cells. Methods Human ATC cell lines, C643 and SW1736, were cultured in one percentage (w/v) sodium alginate. Spheroids were incubated in medium for one week. The reproducibility of the fabrication of alginate beads was evaluated. Encapsulation of the cells in alginate was examined by DAPI (4′,6-diamidino-2-phenylindole) staining. Survival of alginate-encapsulated cells was evaluated by CFSE (5,6-Carboxyfluorescein N-hydroxysuccinimidyl ester) staining. The population doubling times of C643 and SW1736 cell lines cultured in 2D monolayer as well as in 3D system were calculated. The cytotoxic effect of BI-847325 on 2D- and 3D- cultured cell lines was assessed for 24–72 h by MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] assay. Finally, the 3D culture results were compared with the 2D culture method. Results The half-maximal inhibitory concentration (IC50) values of BI-847325 were higher in 3D culture compared to 2D culture. The cytotoxicity data indicated that 3D in vitro models were more resistant to chemotherapy agents. Conclusions The findings of this study are beneficial for developing in vitro ATC 3D models to analyze the efficacy of different chemotherapy drugs and formulations.

Is Hashimoto thyroiditis associated with increasing risk of thyroid malignancies? A systematic review and meta-analysis

Background and purpose Hashimoto thyroiditis (HT) is the most common inflammatory autoimmune thyroid disease and also the most common cause of hypothyroidism in developed countries. There is evidence of the role of HT in developing thyroid cancers (TCs). This study investigated the association between HT and different types of TCs. Methods Results of a comprehensive search in three major databases, as well as hand searching, were screened in title/abstract and full-text stages and the relevant data were extracted from the studies that met the inclusion criteria. Risk of bias (RoB) was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis software. Results Out of 4785 records, 50 studies were included in the systematic review, and 27 of them met the criteria for quantitative synthesis. The results indicated a significant role for HT in developing papillary TC (OR: 1.65; 95% CI: 1.04 to 2.61), medullary TC (OR: 2.70; 95% CI: 1.20 to 6.07) and lymphoma (OR:12.92; 95% CI: 2.15 to 77.63); but not anaplastic TC (OR: 1.92; 95% CI: 0.29 to 1.90) and follicular TC (OR: 0.73; 95% CI: 0.41 to 1.27). Also, this study found a significant association between HT and thyroid malignancies (OR: 1.36; 95% CI: 1.05 to 1.77). Conclusion Although we found a significant association between HT and some types of TCs, High RoB studies, high level of heterogeneity, and the limited number of well-designed prospective studies, suggested the need for more studies to reach more reliable evidence.

Nutritional iodine status and obesity

Iodine is an essential component of the thyroid hormones, thyroxine and triiodothyronine. Its availability strictly depends on iodine content of foods, which may vary from very low to very high. Inadequate iodine intake (deficiency or excess) may affect thyroid function resulting in hypothyroidism or hyperthyroidism. Based on median urinary iodine concentrations, epidemiological criteria have been established for the categorization and monitoring of nutritional iodine status of a population (or subgroups of populations). Additional methods for iodine intake assessment include measurement of thyroid size (by thyroid palpation or ultrasonography) and of biochemical parameters, such as neonatal thyroid stimulating hormone, thyroglobulin and thyroid hormones.Recent studies carried out in overweight/obese children and adults provide evidence that body mass index (BMI) may significantly influence the above indicators, thus theoretically affecting the epidemiological evaluation of nutritional iodine status in populations.In this short review, we analyze current knowledge on the effects of overweight and obesity on indicators of adequacy and monitoring of iodine status, namely urinary iodine excretion and thyroid volume and echogenicity.Data on urinary iodine excretion in overweight/obese children are divergent, as both increased and reduced levels have been reported in overweight/obese children compared to normal-weight controls.Whether gastrointestinal surgery may affect iodine absorption and lead to iodine deficiency in patients undergoing bariatric surgery has been evaluated in a limited number of studies, which excluded iodine deficiency, thus suggesting that supplements usually recommended after bariatric surgery do not need to include iodine.Albeit limited, evidence on thyroid volume and obesity is consistent with a direct relationship between thyroid volume and BMI, irrespective of nutritional iodine status. Finally, a higher frequency of thyroid hypoechoic pattern has been described in overweight/obese children. This finding has been recently related to an increased adipocyte infiltration and thyroid parenchyma imbibition mediated by inflammatory cytokines and should be considered when the frequency of thyroid hypoechoic pattern is used as non-invasive marker to indirectly assess thyroid autoimmunity in monitoring Universal Salt Iodization programs. Further studies, specifically addressing the role of schoolchildren body mass index as a factor potentially influencing iodine intake indicators are needed.

Poorly differentiated thyroid carcinoma arising from a lithium-induced goiter in a patient with schizophrenia: a case report

Background Lithium use causes goiter by increasing serum thyroid-stimulating hormone levels through the inhibition of thyroid hormone release. However, there are no reports of poorly differentiated thyroid carcinoma resulting from lithium-induced goiter. Herein, we report the case of a patient with schizophrenia who developed poorly differentiated thyroid carcinoma arising from a lithium-induced goiter. Case presentation A 61-year-old woman who was taking lithium for schizophrenia, visited the thyroid-endocrine center with a 10 × 12 cm anterior neck mass. She had a slowly growing goiter approximately 30 years ago; however, when she came to the hospital for diabetes diagnosis 2 years ago, she had no accompanying symptoms and refused evaluation. Three months before her visit, her dysphagia and dyspnea worsened as the size of her goiter increased rapidly. A neck ultrasound and enhanced thyroid computed tomography (CT) examination revealed a 10.9 × 9.2 × 12.8 cm size multi-lobulated mass on the right thyroid gland, leading to a leftward deviation of the trachea. Diagnostic total thyroidectomy was performed, and microscopic findings and immunohistochemical staining results indicated poorly differentiated thyroid carcinoma (PDTC) in the right thyroid mass. Mutation analyses for BRAF and the telomerase reverse transcriptase (TERT) promoter was performed. No BRAF gene mutations were detected; however, TERT promoter C228T point mutation was present in the PDTC. The patient underwent radioactive iodine therapy two months after the surgery. At a recent follow-up 4 months postoperatively, she was taking thyroid hormone replacement and remained in a relatively good health with a serum thyroglobulin level of 0.55 ng/ml. Conclusions Thyroid examination of psychiatric patients who develop goiter due to long-term lithium treatment should be monitored regularly, and appropriate investigations and surgery should be performed in a timely manner if the goiter is growing rapidly.

Undetectable thyroglobulin makes 123I whole-body scan and stimulated thyroglobulin obsolete in follow-up care of differentiated thyroid cancer: a retrospective study

Background Differentiated thyroid cancer (DTC) is a common malignancy with increasing incidence. Follow-up care for DTC includes thyroglobulin (Tg) measurement and ultrasound (US) of the neck, combined with 131I remnant ablation when indicated. Diagnostic precision has evolved with the introduction of the new high-sensitive Tg-assays (sensitivity ≤0.1 ng/mL). The aim of the study was to determine the prognostic utility of high-sensitive Tg and the need for other diagnostic tests in DTC. Methods This was a retrospective, observational study. Patients with pathologically confirmed DTC, treated with total thyroidectomy and 131I remnant ablation, who had their complete follow-up care in our institution were selected (October 2013–December 2018). Subjects with possible thyroglobulin autoantibody interference were excluded. Statistical analysis was performed using the IBM SPSS® Statistics 24 software package. Results Forty patients were eligible for analysis. A total of 24 out of the 40 patients (60%) had an undetectable high-sensitive Tg 6 months after total thyroidectomy. None of these patients had a stimulated Tg above 1 ng/mL, or remnant on the 123I Whole-Body Scan (WBS) after 1 year of follow-up. Ultrasound of the neck, performed between 6 and 12 months postoperative, was negative in 21 out of the 24 patients. Conclusions This study shows that an undetectable high-sensitive Tg can change the management of patients with DTC and decrease the use and need of stimulated Tg and 123I WBS.

The relationship between thyroid function and ovarian reserve: a prospective cross-sectional study

Background Thyroid dysfunction can affect fertility and miscarriage risk by affecting the process of follicular growth, embryo development, implantation, and placental formation. It has been suggested that thyroid disorders are associated with ovarian reserve by affecting the follicular process. The aim of the present study was to investigate the relationship between thyroid hormone levels and ovarian reserve. Methods Three hundred fourteen women with infertility due to various etiologies were enrolled in this study (172 individuals with Anti-Mullerian hormone (AMH) level ≥ 1.1 ng/ml and 142 individuals with AMH < 1.1 ng/ml). Serum levels of follicle-stimulating hormone (FSH), estradiol (E2) on day 2–4 of menstrual cycles, AMH, Thyroid-stimulating hormone (TSH), and thyroxine (free T4) were evaluated. Results In participants with age over 35 years, median TSH level in women with AMH < 1.1 ng/ml was significantly higher than those with AMH ≥1.1 ng/ml (P-value =0.037). There was no significant difference in body mass index (BMI) in patients with age older than 35 years and younger than 35 years sub-groups based on AMH level (P-value = 0.102, and P-value = 0.909 respectively). With one unit increase in TSH level, the odds of having AMH < 1.1 ng/ml increases by 1.25 times or by 25% (P-value =0.017). Receiver operator characteristic (ROC) curve analysis showed a TSH cut-off point of 1.465 mIU/L in participants over 35 years in identifying decreased AMH level. Conclusion Our study supports the relationship between TSH level and ovarian reserve so that with an increase in TSH from a certain level is associated with a decrease in ovarian function.

Association between thyroid disorders and COVID-19: a protocol for a systematic review and meta-analysis

Background The novel coronavirus (COVID-19) epidemic initially appeared in Wuhan, Hubei Province, China, on 31 December 2019 and was spread rapidly worldwide. Most underlying diseases reported with COVID-19 patients are diabetes, hypertension, coronary heart diseases, and cerebrovascular disease. We do not know whether individuals with thyroid disease are at increased risk of COVID-19 infection. Methods Two experienced researchers will conduct an electronic search of the databases including PubMed/MEDLINE, the Cochrane Reviews, and the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, and ProQuest, for articles published since October 2019. Clinical trials and observational studies will be included. Studies will be screened after de-duplication. A standardized data extraction form will be developed through discussions with the review team and will be revised after piloting. An appropriate risk of bias assessment tool will be used to assess the quality of studies. Two independent reviewers will assess the eligibility, extraction of detailed information, and quality assessment of studies. The results will be pooled for meta-analysis, subgroup analysis and/or descriptive analysis based on the included data conditions. Conclusion Results of this study will provide current evidence on the association of COVID-19 diseases with any thyroid disorders such as hypothyroidism, thyrotoxicosis, and thyroid cancer with or without radioiodine therapy. Findings will be disseminated in peer-reviewed publications and conference presentations. Trial registration PROSPERO registration number: CRD42020184289. https://www.crd.york.ac.uk/PROSPERO/#recordDetails

Recurrence of carcinoma showing thymus-like differentiation (CASTLE) involving the thyroid gland

Background Carcinoma showing thymus-like differentiation (CASTLE) in the thyroid gland is a rare disease with generally a favorable prognosis. Treatment with surgery and adjuvant radiotherapy has been shown to improve local control and long-term survival rates. In this report, we present a case of a recurrent thyroid gland CASTLE and review the literature on the diagnosis and treatment of this disease. Case presentation A 60-year-old woman, who was diagnosed with a CASTLE thyroid tumor in 2015, had a total thyroidectomy and was maintained on thyroid hormone replacement (levothyroxine). After 5 years, the patient had a recurrence, in an advanced stage unsuitable for surgery. As the patient declined to undergo radiotherapy, she was followed up without intervention and is currently stable after 15 months. Conclusions CASTLE is a rare disease, diagnosed based on postoperative pathology and immunohistochemistry analysis, especially upon CD5 marker. In case of relapse, treatment options include surgery and radiotherapy; however conservative management without intervention is an acceptable alternative in some cases.

Development of metastatic poorly differentiated thyroid cancer from a sub-centimeter papillary thyroid carcinoma in a young patient with a germline MET mutation – association or random chance?

Background Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed. Case presentation A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion. Conclusions The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.

How to use thionamide anti-thyroid drug in the young– what’s new?

The excess thyroid hormone secretion that characterises Graves’ disease (GD) is generated when stimulatory antibodies bind to the thyroid stimulating hormone receptor on the follicular cell of the thyroid gland.This underlying mechanism cannot easily be abolished and the mainstay of Graves’ disease (GD) management in the young remains thionamide anti-thyroid drug (ATD). Unfortunately, GD will usually recur after a 2 or 3 year course of ATD, even when the stimulatory antibody titres have fallen. The diagnosis of GD therefore usually signals the start of a lengthy period of out-patient assessments and associated venepuncture. Careful, more protracted administration of ATD may increase the likelihood of longer-term remission and reduce the likelihood of the patient developing ATD side-effects. An understanding of how best to use ATD and an awareness of the less well-known consequences of GD and its’ treatment - such as excessive weight-gain and long-term hypothyroidism – are also of fundamental importance.Recent clinical studies have shed light on how best to manage the young patient with GD and the associated new information will help to answer some of the questions posed by the young person and their family at diagnosis. This new knowledge is the focus of this article about ATD therapy in the young.