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Bisphenol A (BPA) is a prevalent environmental contaminant found in plastics and known for its endocrine-disrupting properties, posing risks to both human health and the environment. Despite its widespread presence, the impact of BPA on papillary thyroid cancer (PTC) progression, especially under realistic environmental conditions, is not well understood. This study examined the effects of BPA on PTC using a 3D thyroid papillary tumor spheroid model, which better mimicked the complex interactions within human tissues compared to traditional 2D models. Our findings demonstrated that BPA, at environmentally relevant concentrations, could induce significant changes in PTC cells, including a decrease in E-cadherin expression, an increase in vimentin expression, and reduced thyroglobulin (TG) secretion. These changes suggest that BPA exposure may promote epithelial-mesenchymal transition (EMT), enhance invasiveness, and reduce cell differentiation, potentially complicating treatment, including by increasing resistance to radioiodine therapy. This research highlights BPA's hazardous nature as an environmental contaminant and emphasizes the need for advanced in vitro models, like 3D tumor spheroids, to better assess the risks posed by such chemicals. It provides valuable insights into the environmental implications of BPA and its role in thyroid cancer progression, enhancing our understanding of endocrine-disrupting chemicals.

Background: Various postoperative staging systems were developed to assess the outcome of differentiated thyroid cancer from initial risk after surgery to dynamic changing prognosis during follow-up. The objective of our retrospective cohort study was to identify risk factors contributing to macroscopic positive surgical margin (R2 resection) and parameters in discriminating the treatment responses and prognosis among R2 patients., Methods: In total, 242 differentiated thyroid cancer patients with extrathyroidal extension who underwent a thyroidectomy at Kaohsiung Chang Gung Memorial Hospital between January 2013 and July 2018, were included. The patients were grouped according to the presence or absence of gross residual disease (R2). The R2 patients were further classified into two categories according to their treatment response into excellent and nonexcellent groups. The parameters and treatment outcomes were compared between these groups., Results: The mean follow-up time was 45.3 months. Two hundred seven (85.5%) patients had either surgery-free or microscopic margins (R0/R1), while 35 (14.5%) had R2 resection. In the R2 group (n = 35), 15 (42.9%) patients achieved an excellent response, while 20 (57.1%) achieved a nonexcellent response. Statistically significant differences were observed in the extent of neck dissection, TSH-Tg level, post-RAI Tg level, nodal status, and recurrence between the two groups. The Kaplan-Meier curves for 5-year local and distant recurrence-free survival of R0/R1 versus R2 patients were 90.0% versus 66.3%, and 98.4% versus 90.7%, respectively ( p < 0.001). Among the R2 patients, the excellent responders had a higher local recurrence-free survival than nonexcellent responders (93.3% vs. 45.1%, p = 0.008)., Conclusion: There are significant disparities in recurrence-free survival among R2 patients with different treatment responses. The nodal status of papillary thyroid cancer and thyroglobulin level after thyroidectomy and RAI were factors contributing to difference in their treatment responses., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Purpose: The treatment of recurrent thyroid cancer with critical organ invasion is challenging. The combination of radiofrequency ablation (RFA) and external beam radiation therapy (EBRT) has been proposed as an effective option. This study evaluates outcomes for inoperable residual/recurrent differentiated thyroid cancer (rDTC) patients treated with RFA followed by EBRT., Materials and Methods: Patients with rDTC treated with RFA followed by EBRT were retrospectively studied. RFA was performed using a free-hand, 'moving-shot' technique under US or CT guidance. For lesions invading critical structures intolerant to 'en bloc' high-temperature RFA, limited-field EBRT using 6- or 10-MV photons was used for adjuvant treatment at a dose of 66 Gy in 33 daily fractions. Toxicities and outcomes were reviewed., Results: Between April 2020 and January 2022, 11 patients with 14 rDTC lesions underwent RFA followed by EBRT. Five patients had metastatic lesions at rDTC diagnosis. With a median follow-up period of 33.7 months, all patients maintained locoregional control, while achieving a 2-year survival rate of 90.9%. This combined treatment achieved a volume reduction ratio of 92.1% ± 5.1%. The mean nadir thyroglobulin level in patients without initial distant metastases after treatment was 1.40 ± 0.81 ng/ml. Regarding treatment-related complications, one patient (9%) experienced temporary hoarseness after RFA, grade 2 radiation dermatitis occurred in 3 patients (27.2%), and grade 2 dysphagia was noted in 4 patients (36.4%). No grade 3 or greater toxicities occurred., Conclusions: Salvage RFA followed by EBRT is feasible, effective and safe for patients with rDTC.

Context: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Dysregulated expression of miR-146b and androgen receptor (AR) has been shown to play critical roles in tumorigenesis in PTC. However, the mechanistic and clinical association between AR and miR-146b is not fully understood., Objective: The purpose was to investigate miR-146b as the potential AR target miRNA and its involvement in advanced tumor characteristics of PTC., Methods: Expression of AR and miR-146b were assessed in frozen and formalin-fixed paraffin-embedded tissue samples from PTC and adjacent normal thyroid specimens by quantitative real-time polymerase chain reaction, and their correlation was examined. Human thyroid cancer cell lines BCPAP and TPC-1 were used to evaluate the effect of AR on miR-146b signaling. Chromatin immunoprecipitation (ChIP) assays were performed to determine whether AR binds to the miR-146b promoter region., Results: Pearson correlation analysis confirmed significant inverse correlation between miR-146b and AR expression. Overexpressing AR BCPAP and TPC-1 cells showed relatively lower miR-146b expression. ChIP assay revealed that AR might bind to the androgen receptor element located on the promoter region of miRNA-146b gene, and overexpression of AR suppresses miR-146b-mediated tumor aggressiveness. The low AR/high miR-146b PTC patient group was associated with advanced tumor characteristics, including higher tumor stage, lymph node metastasis, and worse treatment response., Conclusion: To sum up, miR-146b is a molecular target of AR transcriptional repression; therefore, AR suppresses miR-146b expression to reduce PTC tumor aggressiveness., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The purpose of this study was to evaluate the feasibility of radiofrequency ablation (RFA) for thyroid nodules with cytological atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS, Bethesda III)., Materials and Methods: A total of 28 adults presenting with 30 initial Bethesda III nodules underwent thyroid RFA at a single medical center. Thyroid nodules with Bethesda IV or V according to the second aspiration were excluded. All RFA procedures were performed using the free-hand, 'moving-shot' technique under local anesthesia. Clinical features and demographics, RFA details, nodule volume reduction rate (VRR), and complications were analyzed., Results: The mean age of patients was 47.6 years, 82.1% of whom were females. Mean nodule volumes at pre-RFA, and at 6 months and 12 months post-RFA were 7.92, 2.42, and 1.25 mL, respectively, with a VRR of 77.9% at 6 months, and 87.4% at 12 months. Post-RFA complications were noted in two patients, one with transient vocal cord palsy and another with isthmus minor rupture., Conclusion: RFA may be another safe alternative except for active surveillance or surgical excision for AUS/FLUS nodules with low-suspicion Thyroid Imaging Reporting and Data System features for patients who are unsuitable or strongly refuse surgery. Long-term results remain uncertain, thus further follow-up study is necessary.

This retrospective study was designed to compare the treatment response of patients with differentiated thyroid cancer (DTC) prepared for radioiodine ablation (RIA) with thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH) stimulation. Patients with DTC were followed-up retrospectively between 2013 and 2018 in Kaohsiung Chang Gung Memorial Hospital, Taiwan. We compared the excellent response ratios between THW (49.9%) and rhTSH (50.1%) stimulation. Patients were then divided into subgroups, on the basis of age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage, for analysis. In all, 647 patients were followed-up after RIA. The ratios of THW or rhTSH use in the different subgroups were not statistically significant. In all the patients, the excellent response rate with THW and rhTSH was 80% and 76.5%, respectively, which was not statistically significant. The subgroup analysis, including age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage (low and high risk), showed similar results. Furthermore, the logistic regression analysis revealed no statistically significant differences among the subgroups. The multivariate analysis showed extrathyroidal extension, lymph node metastasis, and high I 131 dose were the prognostic factors affecting the excellent response rate. In conclusion, the THW and rhTSH preparations for RIA were similar in terms of the excellent response rates and subgroup clinical outcomes., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Objective: The application of radiofrequency ablation (RFA) for recurrent thyroid cancer has been demonstrated to effectively manage lesions at critical locations, such as abutting the trachea, with limited complications. Comprehensive investigation of both biochemical (B) and structural (S) change after RFA remains limited. We herein present the first single-center experience of RFA for the treatment of locoregional recurrent thyroid cancer in Taiwan., Design: 23 patients were enrolled, and the treatment responses after RFA were divided into four groups ( E , S(+) , B(+) , and SB(+) ), and then compared. The RFA technique, follow-up strategy, changes in pre-and post-operative status, and complications are presented. The volume reduction rate at 1, 3, and 6 months, and the differing responses between lesions abutting/not abutting the trachea are also discussed., Results: In patients with pre-RFA structural and biochemical incomplete ( SB(+) ) status, presenting with lesion with an initial maximum diameter of >3.2cm, a higher rate of structural incomplete status at the 6-month follow-up was noted in ROC analysis, with a sensitivity of 57% and specificity of 91%. Favorable structural remission after RFA was noted, and 60.9% of patients achieved biochemical complete status. No significant correlation was noted between the trachea-abutted lesion number and complete remission (p= 0.474). No significant difference in RFA efficacy was noted between the lesions abutting/not abutting the trachea., Conclusions: This retrospective study reveals that RFA can achieve both structural and biochemical improvements for locoregionally recurrent thyroid cancer, with a low complication rate. Nearly half of the patients achieved an excellent response after RFA, while a favorable treatment response can be achieved despite the lesion abutting the trachea, with a mean VRR of 84.74%., 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 Chen, Chou, Chang, Chiang, Lim, Chi, Luo and Lin.)

Background: The incidence of papillary thyroid microcarcinoma (PTMC) has increased rapidly in recent decades, with a favorable overall prognosis. We aimed to evaluate the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) for treating low-risk PTMC in Taiwan., Methods: This prospective study included patients with PTMC who were ineligible or refused surgery and underwent US-guided RFA between October 2018 and June 2020. US and computed tomography (CT) were performed before RFA to assess tumor lesions and exclude cervical lymph node metastasis. Sequential US follow-up following RFA was performed after 1, 3, 6, and 12 months, and yearly thereafter. Volume reduction ratio (VRR) and complete disappearance rate of tumor at one year were evaluated., Results: 13 PTMCs in 12 patients were enrolled with a mean follow-up of 16.2 ± 8.1 months (range, 1-24 months). The median largest tumor diameter and tumor volume before RFA were 0.76 cm and 0.15 ml (range, 0.02-0.37 ml). The median (interquartile range, IQR) volume and VRR at 12 months post-RFA were 0 (0, 0.03) ml (p = 0.033) and 100% (84.26%, 100%) (p = 0.008). Eight tumors (61.54%) were completely disappeared at 12 months post-RFA and no tumor recurrence, lymph nodes, or distant metastasis were noted. All tumors were successfully treated without complications., Conclusion: Minimally invasive US-guided RFA is an effective and safe alternative for low-risk PTMC, resulting a satisfied VRR., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Papillary thyroid carcinomas (PTC), which is derived from thyroid follicular cells, is the most commonly differentiated thyroid cancer with sex disparity. However, the role of estrogen receptors (ERs) in the pathogenesis of PTC remains unclear. The present study aimed to determine the association of ER mRNA expression levels with clinicopathologic features in PTC. To that aim, the mRNA levels of ESR1 (ERα66), ESR1 (ERα36), ESR2 , and G-protein-coupled estrogen receptor 1 ( GPER1 ) in snap-frozen tissue samples from PTCs and adjacent normal thyroid tissues were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the correlation between ER mRNA expression levels and clinicopathologic features was analyzed. The expression of ERα66, ERα36, ERβ, and GPER1 was lower in PTC specimens than in adjacent normal thyroid tissues. Moreover, low GPER1 expression was associated with extrathyroidal extension. There was no obvious difference in expression of ERs between PTC specimens from male and female patients. In conclusion, our findings highlight the importance of ERs in PTC tumorigenesis.

Differentiated thyroid cancer (DTC) survivors are at increased risk of developing double primary malignancy (DPM). The aim of this study was to investigate clinicopathological characteristics and survival in DTC patients diagnosed with DPM. A total of 975 patients with DTC diagnosed between 2013 and 2017, treated, and followed at a medical center in Taiwan were retrospectively reviewed. Data from enrolled patients were analyzed for differences in prognosis dependent on the presence of DPM, and which clinicopathological variables affected their prognosis. Among 975 thyroid cancer patients, 94 (9.6%) were diagnosed with DPMs and 16 (1.6%) patients died of any cause. DPM patients had a greater proportion of males, had a higher mean age, more commonly presented with a thyroid mass incidentally by imaging and cervical lymph node metastases, showed a more advanced thyroid cancer stage, and had a higher proportion of lymph node metastases. Overall survival (OS) was significantly lower in patients diagnosed with DPM. Male gender (hazard ratio [HR] = 4.597), two or more DPMs (HR = 8.071), and shorter time interval between two cancers occurrences (HR = 7.101) were significantly risk factors for DPM-related death. In conclusion, the risk of developing DPM in DTC patients was elevated in older, male patients with an advanced tumor-node-metastasis stage. DPM adversely affected the OS of thyroid cancer patients. Male gender, two or more DPMs, and shorter time interval between occurrences were significant risk factors for OS in DPM patients., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Objectives: To evaluate the feasibility of radiofrequency ablation (RFA) on follicular neoplasm with low standard uptake value (SUV) in a Positron emission tomography (PET/CT) study., Methods: From January 2018 to July 2019, 86 consecutive patients were diagnosed with follicular neoplasm. Of the patients, 28 with PET/CT scans were enrolled in this study. All patients received ultrasound, fine/core needle aspiration, and PET/CT scan prior to treatment. In accordance with previous studies, we recommended 6 patients who had follicular neoplasm with SUVmax ≥5 undergo surgical resection due to an elevated suspicion of malignancy. For 22 patients SUVmax <5, RFA was performed using the moving shot technique. Ultrasound was performed 6 to 12 months after each procedure., Results: Statistically significant volume reductions during follow-up between values prior to RFA and 12 months post RFA were demonstrated (12.6 ± 20.9 vs. 2.4 ± 3.0 cm 3 , p  < 0.001). Volume reduction ratios at 6-12 months (mean: 10.1 months) after RFA were 73.3% ± 17.7%. One patient presented with vocal cord palsy and recovered within 3 months after RFA. No postprocedural hypothyroidism occurred in the RFA patients., Conclusions: By using PET/CT, we can select patients with low SUV follicular neoplasm. RFA offers a safe and feasible alternative treatment option for patients unsuitable or unwilling to undergo surgery.KEY POINTSBy using positron emission tomography-computed tomography, we can distinguish low SUV follicular neoplasm for radiofrequency ablation.For low SUV follicular neoplasm, RF ablation offers a safe and effective alternative treatment option for patients unsuitable or unwilling to undergo surgery.

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET /PTC- RAS - BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial. MicroRNAs (miRNAs) have been labeled as promising molecular prognostic markers in several tumor types. Our recent studies demonstrated that microRNA-146b (miR-146b) deregulation is associated with PTC aggressiveness and prognosis. Here we summarize the current knowledge related to the functional roles, regulated target genes, and clinical applications of miR-146b in PTC and discuss how these studies provide insights into the key role of miR-146b as an oncogenic regulator promoting cellular transformation as well as a prognosis marker for tumor recurrence in PTC. In conjunction with the current perspectives on miRNAs in a wide variety of human cancers, this review will hopefully translate these updated findings on miR-146b into more comprehensive diagnostic or prognostic information regarding treatment in PTC patients before surgical intervention and follow up strategies.

Context: MicroRNA (miR)-146b is overexpressed in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal invasion, advanced tumor stage, and poor prognosis. However, the underlying mechanism of miR-146b in relation to its oncogenic behavior in PTC and its putative targets remain unknown., Objective: The purpose was to investigate IL-1 receptor-associated kinase 1 (IRAK1) as the potential miR-146b target gene and its involvement in PTC., Design: We used genome-wide microarray, computational analysis, and 3' UTR reporter gene assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were further performed to determine the effects of IRAK1 on proliferation, colony formation, and wound-healing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via qRT-PCR., Results: Microarray expression profile revealed that the mRNA level of IRAK1 gene was down-regulated by miR-146b. The 3' UTR of IRAK1 mRNA was found to be a molecular target of miR-146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by down-regulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA was significantly lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens., Conclusion: Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities. In conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis may provide a potential approach for PTC management.

Context: Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model., Methodology: Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined., Results: Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis., Conclusions: Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.

Background: Papillary thyroid carcinoma (PTC) are clinicopathogenetically heterogeneous. Micro-RNAs (miRNAs) are involved in the pathogenesis of diverse human cancers, including PTC. Information regarding associations between clinicopathological features of PTC with the expression of specific miRNAs, however, is sparse. In this study, we compared expression of deregulated miRNAs in PTCs to assess this was associated with selected clinicopathogenetic features., Methods: We analyzed the expression levels of three reported deregulated miRNAs (miR-221, miR-222, and miR-146b) using quantitative real-time polymerase chain reaction in 100 cases of PTCs with distinct clinicopathogenetic characteristics and 16 paired normal controls. The tumor samples were categorized into low- and high-risk groups on the basis of the tumor-node-metastasis staging system., Results: The expression levels of miR-221, miR-222, and miR-146b were significantly associated with extrathyroidal invasion (p = 0.013, 0.05, and 0.003, respectively). The expression levels of miR-221 and miR-146b were significantly higher in the high-risk PTC group (p = 0.01 and 0.042, respectively). The miR-146b expression levels in PTCs with BRAF mutation were significantly higher than those without this mutation (p < 0.0001). There were no other associations between the expression of these miRNAs and other clinicopathological parameters., Conclusions: Our results show the potential importance of miR-221, miR-222, and miR-146b in determining the aggressive properties of PTCs and highlight the need to identify the gene targets of these miRNAs.