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Papillary thyroid cancer (PTC) is one of the most treatable forms of cancer, with many cases being fully curable. However, resistance to anticancer drugs often leads to metastasis or recurrence, contributing to the failure of cancer therapy and, ultimately, patient mortality. The mechanisms underlying molecular differences in patients with metastatic or recurrent PTC, particularly those resistant to anticancer drugs through epigenetic reprogramming, remain poorly understood. Consequently, refractory PTC presents a critical challenge, and effective therapeutic strategies are urgently needed. Therefore, this study aimed to identify small-molecule inhibitors to enhance treatment efficacy in lenvatinib-resistant PTC. We observed an increase in sarco/endoplasmic reticulum calcium ATPase (SERCA) levels in patient-derived lenvatinib-resistant PTC cells compared with lenvatinib-sensitive ones, highlighting its potential as a therapeutic target. We subsequently identified two SERCA inhibitors [candidates 40 (isoflurane) and 42 (ethacrynic acid)] through in silico screening. These candidates demonstrated significant tumor shrinkage in a xenograft tumor model and reduced cell viability in patient-derived lenvatinib-resistant PTC cells when used in combination with lenvatinib. Our findings have potential clinical value for the development of new combination therapies to effectively target highly malignant, anticancer drug-resistant cancers.

Abstract It is important to identify risk factors for post-thyroidectomy bleeding requiring airway intervention or reoperation. Therefore, we aimed to compare the characteristics of patients with postoperative bleeding after thyroid surgery according to the period until reoperation. We conducted a retrospective study analyzing data between April 2009 and July 2022 and included 126 patients who had postoperative bleeding. The patients were grouped according to the period between thyroidectomy and reoperation due to bleeding (0 day, 1–7 days, > 7 days). We performed among-group comparisons of patient characteristics and surgical aspects, including the extent of surgery. The ratios of male–female and lateral neck dissection were higher in the post-operative bleeding group than in the group without bleeding. In the analysis of patients with postoperative bleeding, grouped according to period between thyroidectomy and reoperation, there was a significant among-group difference in the male–female ratio. The male sex was positively correlated with the reoperation period. Further, the reoperation period was also positively correlated with total thyroidectomy and lateral neck dissection and the operation time showed a significant among-group difference. Our results indicate that the male sex and lateral neck dissection are risk factors for postoperative bleeding after thyroidectomy. Furthermore, male sex, total thyroidectomy, and lateral neck dissection are risk factors for delayed bleeding. Therefore, clinicians should consider these factors for interventions against immediate or delayed bleeding after thyroidectomy.

Purpose: To investigate whether preoperative ultrasonographic (US) features of the index cancer and metastatic lymph nodes (LNs) are associated with level II LN metastasis in N1b papillary rmfthyroid carcinoma (PTC) patients. Materials and methods: We enrolled 517 patients (mean age, 42 [range, 6–80] years) who underwent total thyroidectomy and lateral compartment LN dissection between January 2009 and December 2015. We reviewed the clinicopathologic and US features of the index cancer and metastatic LNs in the lateral neck. Logistic regression analysis was performed to analyze features associated with level II LN metastasis. Results: Among the patients, 196 (37.9%) had level II metastasis on final pathology. In the preoperative model, larger tumor size (odds ratios [ORs], 1.031; 95% confidence interval [CI]: 1.011–1.051, p = 0.002), nonparallel tumor shape (OR, 1.963; 95% CI: 1.322–2.915, p = 0.001), multilevel LN involvement (OR, 1.906; 95% CI: 1.242–2.925, p = 0.003), and level III involvement (OR, 1.867; 95% CI: 1.223–2.850, p = 0.004), were independently associated with level II LN metastasis. In the postoperative model, non-conventional pathology remained a significant predictor for level II LN metastasis (OR, 1.951; 95% CI: 1.121–3.396; p = 0.018), alongside the presence of extrathyroidal extension (OR, 1.867; 95% CI: 1.060–3.331; p = 0.031), and higher LN ratio (OR, 1.057; 95% CI: 1.039–1.076; p < 0.001). Conclusions: Preoperative US features of the index tumor and LN may be helpful in guiding surgery in N1b PTC. These findings could enhance preoperative planning and decision-making, potentially reducing surgical morbidities by identifying those at higher risk of level II LN metastasis and tailoring surgical approaches accordingly.

Background This study aimed to investigate the changes of incidence and treatment of choice for hyperthyroidism from 2003 to 2018 and explore the treatment-related complications and concomitant comorbidities in South Korea using data from the National Health Insurance Service. Methods This is a retrospective observational study. Hyperthyroidism was defined as a case having two or more diagnostic codes of thyrotoxicosis, with antithyroid drug intake for more than 6 months. Results The average age-standardized incidence of hyperthyroidism from 2003 to 2018 was 42.23 and 105.13 per 100,000 men and women, respectively. In 2003 to 2004, hyperthyroidism was most often diagnosed in patients in their 50s, but in 2017 to 2018, people were most often diagnosed in their 60s. During the entire period, about 93.7% of hyperthyroidism patients were prescribed with antithyroid drugs, and meanwhile, the annual rates of ablation therapy decrease from 7.68% in 2008 to 4.56% in 2018. Antithyroid drug-related adverse events, mainly agranulocytosis and acute hepatitis, as well as complications of hyperthyroidism such as atrial fibrillation or flutter, osteoporosis, and fractures, occurred more often in younger patients. Conclusion In Korea, hyperthyroidism occurred about 2.5 times more in women than in men, and antithyroid drugs were most preferred as the first-line treatment. Compared to the general population, hyperthyroid patients may have a higher risk of atrial fibrillation or flutter, osteoporosis, and fractures at a younger age.

Abstract Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.

IntroductionMetachronous lateral neck recurrence after thyroidectomy for N1b papillary thyroid cancer is accompanied by high morbidity and increased difficulty of reoperation. From the perspective of recurrence, the objective of this study was to compare patients who underwent metachronous lateral neck dissection (mLND) despite initial thyroidectomy and patients who underwent synchronous lateral neck dissection (sLND) for papillary thyroid cancer and analyze the risk factors for recurrence after mLND.MethodThis retrospective study involved 1,760 patients who underwent lateral neck dissection for papillary thyroid cancer at the Gangnam Severance Hospital, a tertiary medical center in Korea, from June 2005 to December 2016. The primary outcome was structural recurrence, and secondary outcome measures were risk factors of recurrence in the mLND group.ResultA total of 1,613 patients underwent thyroidectomy and sLND at diagnosis. In 147 patients, thyroidectomy alone was performed at the time of diagnosis, and mLND was performed when recurrence to the lateral neck lymph node was confirmed. During a median follow-up of 102.1 months, 110 (6.3%) patients experienced a recurrence. There was no significant difference in the recurrence between the sLND and mLND groups (6.1% vs 8.2%, P=.32). The period from lateral neck dissection to recurrence was longer in the mLND group than in the sLND group (113.6 ± 39.4 months vs 87.0 ± 33.8 months, respectively, P1.45 cm (adjusted HR=4.022, 95% CI=1.036–15.611; P=.04), and lymph node ratio in the lateral compartment (adjusted HR=4.043, 95% CI=1.079–15.148; P=.04) were independent variables predictive of recurrence after mLND.ConclusionmLND is suitable for treating lateral neck recurrence in patients with N1b papillary thyroid cancer who previously underwent thyroidectomy. Lateral neck recurrence after treatment in patients who underwent mLND was predicted by age, tumor size, and lymph node ratio in the lateral compartment.

Background/objective: The diagnostic accuracy of fine needle aspiration biopsy (FNAB) seems limited in large thyroid nodules with Bethesda Cat. 2 result. We aimed to determine the incidence of carcinoma with benign cytology and the reason for the high false-positive rate in thyroid nodules ≥4 cm. Methods: The records of 103 patients with thyroid nodules ≥4 cm with preoperative cytological diagnosis of Bethesda Cat. 2 who underwent thyroidectomy were consecutively reviewed. Characteristics between patients with malignant vs. benign pathology were compared. Results: Forty patients (38.8%) had malignancy. Malignancy was subclassified into follicular variant of papillary thyroid carcinoma (43%), minimally invasive follicular thyroid carcinoma (20.0%), and minimally invasive Hurthle cell thyroid carcinoma (10.9%). Patients with malignant cytology had significantly more suspicious ultrasound findings than those with benign cytology (p = 0.001). Conclusions: Preoperative FNAB showed high false-negative rates in patients with thyroid nodules ≥4 cm with benign cytology. These nodules have a high malignancy rate with suspicious ultrasound findings.

BackgroundPrimary thyroid lymphoma (PTL) is a very rare entity accounting for 5% of all thyroid malignancies and less than 2% of lymphomas. PTLs are classified as non-Hodgkin’s B-cell lymphomas in the majority of cases, although Hodgkin’s lymphoma of the thyroid has also been identified. This study aimed to identify the clinical, biochemical, and pathological features of primary thyroid lymphomas.MethodsFrom January 2008 to December 2020, data from patients diagnosed with PTL treated at the Gangnam Severance Hospital, including clinical, biochemical, and pathological features of thyroid lymphomas, were assessed.ResultsOf 10 patients, nine women and one man, with a median age of 62 (range, 44–82) years were included. Fine needle aspiration biopsy was performed in nine patients and surgical resection was performed in one patient without biopsy. Excisional and surgical biopsies were performed in all patients, including five who underwent excisional biopsy and five who underwent thyroidectomy. Histological analyses revealed that all 10 lymphomas were non-Hodgkin B-cell lymphoma; six patients had diffuse large B-cell lymphoma, three had mucosa-associated lymphoid tissue lymphoma, and one had Burkitt lymphoma. Four patients received chemotherapy, two were treated with chemoradiation therapy, one received radiation therapy only, one did not require more treatment after surgery, one refused treatment, and one was transferred to another hospital.ConclusionsAlthough PTLs are scarce, clinicians should be aware of this rare entity and evaluate and treat PTLs on an individual basis.

BackgroundWith the recent advances in thyroid cancer surgery techniques and the increasing number of patients concerned about cosmetics, the use of transoral endoscopic thyroidectomy is increasing globally. The aim of this study was to determine whether transoral endoscopic thyroidectomy is truly a clean-contaminated surgery.MethodsFrom September 2016 to April 2018, 20 patients with thyroid cancer underwent transoral endoscopic thyroidectomy performed by a single surgeon at Gangnam Severance Hospital. Before and after surgery, the oral cavity was swabbed to obtain culture samples, and antibiotics were administered before and after surgery each once.ResultsOf the total 20 patients, no bacteria were identified before or after surgery in eight (40%) patients. Bacteria were identified both before and after surgery in seven patients (35%). In four patients (20%), bacteria were not identified before surgery, but bacteria were identified after surgery. Bacteria were identified before surgery but not after surgery in one patient (5%). No surgical site infection was observed. All the bacteria identified were normal flora of the oral cavity and skin.ConclusionsThere was no difference between the preoperative culture and postoperative culture of the oral cavity in patients undergoing TOET, and there were no postoperative surgical site infection with prophylactic pre & post-operative antibiotics use. Considering the patient's position and surgical extent in TOET, it appears to be difficult for non-indigenous bacteria to invade the surgical site in oral cavity.

Thyroid cancer is generally curable and, in many cases, can be completely treated, although it can sometimes recur after cancer therapy. Papillary thyroid cancer (PTC) is known as one of the most general subtypes of thyroid cancer, which take up nearly 80% of whole thyroid cancer. However, PTC may develop anti-cancer drug resistance via metastasis or recurrence, making it practically incurable. In this study, we propose a clinical approach that identifies novel candidates based on target identification and validation of numerous survival-involved genes in human sorafenib-sensitive and -resistant PTC. Consequently, we recognized a sarco/endoplasmic reticulum calcium ATPase (SERCA) in human sorafenib-resistant PTC cells. Based on the present results, we detected novel SERCA inhibitor candidates 24 and 31 via virtual screening. These SERCA inhibitors showed remarkable tumor shrinkage in the sorafenib-resistant human PTC xenograft tumor model. These consequences would be clinically worthwhile for the development of a new combinatorial strategy that effectively targets incredibly refractory cancer cells, such as cancer stem cells and anti-cancer drug-resistant cells.

BackgroundThe biological behavior of thyroid cancer in children has been known to be different from that in adults. We sought to understand the differences between DTC presentation in pediatric (

Background/Purpose: There has not been an international multicentric study to examine the relationship between thyroid cancer clinical outcomes and geographic location for South Korea, Colombia, and Turkey, whereas thyroid cancer is amongst the highest three cancer types seen in South Korea and Turkey. The aim of the study was to assess regional differences of T1 papillary thyroid cancer outcomes in Korea, Turkey and Colombia. Methods: This is an observational non-randomized study. A total of 2720 patients who have been operated for T1 papillary thyroid cancer between 2011 and 2014 and are on routine follow-up have been recruited. The mean follow-up was 46.4 ± 10.7 months. Data were collected in a commonly used database and analyses were conducted. Results: Patients participated in South Korea (88.2%), Turkey (9.1%) and Colombia (2.6%). Eighty percent were female. Female dominance tended to be higher in Colombia (p = 0.01). Mean age at diagnosis was 45.2 years. There was no mortality. Recurrence tended to be higher in Colombia (p

IntroductionMedullary thyroid carcinoma (MTC) is a rare cancer that accounts for 5% of thyroid cancers. Serum calcitonin is a good biomarker for MTC, which is used for diagnosis, prognosis, and monitoring of recurrence. Calcitonin-negative MTC (CNMTC) is rare but confounds diagnostic and prognostic directions. This study introduces 19 cases of CNMTC in a single center.MethodFrom 2002 March to 2020 July, more than 76,500 patients had undergone thyroid surgery due to thyroid cancer at the Severance Hospital, and a total of 320 patients were diagnosed with MTC (0.4%). Serum calcitonin levels were obtained from every patient who was suspected with MTC. These patients had undergone either bilateral total thyroidectomy or unilateral thyroidectomy with central compartment lymph node dissection, and additional modified radical lymph node dissection if lateral lymph node metastasis was positive. Postoperative monitoring and out-patient clinic follow-up were performed with obtaining the serum calcitonin levels.ResultNineteen patients tested negative for calcitonin preoperatively (6%). The mean preoperative calcitonin level was 5.1pg/mL if undetectable level is regarded as 0pg/mL. Only two patients were males, and the female bias was significant (p = 0.017). No one except two patients with modified radical neck dissection showed central compartment lymph node metastasis. Every patient’s postoperative calcitonin level remained low. The median follow-up period was 71 months. There was no recurrence and only one fatality, and the overall survival rate was 95%.ConclusionSince incidence of CNMTC is not negligible, MTC should not be ruled out in the diagnostic phase even if serum calcitonin is negative in preoperative examination. We presented 19 cases of CNMTC whose prognosis in general were favorable. Markers of serum and immunohistochemical samples other than calcitonin should be actively examined.

Abstract Background Drug repurposing has been motivated to ameliorate low probability of success in drug discovery. For the recent decade, many in silico attempts have received primary attention as a first step to alleviate the high cost and longevity. Such study has taken benefits of abundance, variety, and easy accessibility of pharmaceutical and biomedical data. Utilizing the research friendly environment, in this study, we propose a network-based machine learning algorithm for drug repurposing. Particularly, we show a framework on how to construct a drug network, and how to strengthen the network by employing multiple/heterogeneous types of data. Results The proposed method consists of three steps. First, we construct a drug network from drug-target protein information. Then, the drug network is reinforced by utilizing drug-drug interaction knowledge on bioactivity and/or medication from literature databases. Through the enhancement, the number of connected nodes and the number of edges between them become more abundant and informative, which can lead to a higher probability of success of in silico drug repurposing. The enhanced network recommends candidate drugs for repurposing through drug scoring. The scoring process utilizes graph-based semi-supervised learning to determine the priority of recommendations. Conclusions The drug network is reinforced in terms of the coverage and connections of drugs: the drug coverage increases from 4738 to 5442, and the drug-drug associations as well from 808,752 to 982,361. Along with the network enhancement, drug recommendation becomes more reliable: AUC of 0.89 was achieved lifted from 0.79. For typical cases, 11 recommended drugs were shown for vascular dementia: amantadine, conotoxin GV, tenocyclidine, cycloeucine, etc.

BackgroundIBM’s Watson for Oncology (WFO) is an artificial intelligence tool that trains by acquiring data from the Memorial Sloan Kettering Cancer Center and learns from test cases and experts. This study aimed to analyze the adequacy and effectiveness of WFO in determining the treatment method for patients with thyroid carcinoma.Materials and MethodsWe retrospectively enrolled 50 patients with thyroid cancer who underwent surgery in 2018 and entered their clinical data into WFO. The WFO treatment recommendations were compared with the surgical procedures and recommended treatments performed according to the Korean Thyroid Endocrine Surgery Association guidelines.ResultsThe overall concordance rate between WFO-recommended treatments and actual surgical treatments was 48%, and for patients with stage I, II, and III disease, these rates were 52.4, 50, and 16.7%, respectively. A lower concordance rate was observed with respect to treatment for advanced thyroid cancer.ConclusionWFO is a useful clinical aid but must be used with caution. A surgeon’s decision takes precedence over WFO recommendations in the treatment of advanced thyroid cancer.

Background: Survival rates for anaplastic thyroid cancer (ATC) have not improved in the past four decades; however, preliminary clinical data indicate that lenvatinib may provide efficacy benefits for patients with ATC. This real-world study aimed to define the potential role of lenvatinib in ATC by examining the impact of treatment administered alongside existing therapies.Methods: This was a retrospective, single-center analysis of Korean patients with confirmed ATC who received lenvatinib between October 2015 and February 2018. Eighteen patients were included (mean ± standard deviation age, 64.9 ± 11.1 years; 61.1% female). Six [33.3%] had resectable disease that progressed after a combination of surgery, radiotherapy, and chemotherapy, and 12 [66.7%] had unresectable disease that progressed after radiation treatment and chemotherapy. Study endpoints were overall survival (OS) and change in volume of the largest tumor assessed via imaging.Results: Median OS for the 18 lenvatinib-treated patients was 230 days (range 64–839 days). Survival rates at 6 months and 1 year were 61.1 and 22.2%, respectively. Three patients (16.7%) survived beyond 1 year; 15 patients died, of whom four (26.7%) had local disease and 11 (73.3%) had distant metastasis. Two patients (11.1%) had tumor volume increases of 9–10%. The other 16 patients (88.9%) had tumor volume reductions of 2–69%. Six patients (33.3%) had tumor volume reductions ≥50%.Conclusions: In patients with ATC who had progressed on prior therapy, addition of lenvatinib could improve survival duration and reduce tumor volume. Further studies of lenvatinib in ATC are warranted.

Background: Lobectomy with preservation of the contralateral lobe has already become the most preferred surgical method for patients with low-risk thyroid cancer. The incidence of and risk factors for the development of hypothyroidism after lobectomy for thyroid cancer remains unclear. The previous practice of levothyroxine supplementation post-thyroidectomy, to bring about thyroid stimulating hormone (TSH) suppression, had some serious side effects. This study aimed to evaluate the incidence of hypothyroidism and to identify the factors associated with hypothyroidism requiring thyroid hormone replacement.Methods: We retrospectively reviewed the charts of 256 consecutive patients with differentiated thyroid cancer treated with lobectomy at the Gangnam Severance Hospital between April and December 2014 who were followed-up for more than 5 years. Patients were evaluated using a thyroid function test at the time of outpatient visit every 6 months for the 1st year, with an annual follow-up thereafter.Results: After 5 years, 66.0% (169) of the patients needed levothyroxine supplementation to maintain euthyroid status. The incidence of hypothyroidism requiring levothyroxine supplementation increased until 3 years but showed no significant change in the 4 and 5th year. Recurrence showed no difference between the group with and without levothyroxine supplementation. The presence of thyroiditis and preoperative TSH levels were correlated with postoperative levothyroxine supplementation to maintain euthyroid status, in univariate and multivariate analyses.Conclusion: High preoperative TSH levels and/or thyroiditis indicate a significantly increased likelihood of developing hypothyroidism requiring thyroid hormone supplementation after a thyroid lobectomy. Patients with an increased risk of postoperative hypothyroidism must be aware of their risk factors and should undergo more intensive follow-ups.

[This corrects the article DOI: 10.1371/journal.pone.0235056.].

Globally, cancer patients obtain much of their disease information online. Online health communities allow patients to share questions and information about diseases. However, there have been few studies on the factors affecting online health community participation behavior in cancer patients. Online social networking is associated with mental health problems, and patients with thyroid cancer experience high levels of distress, anxiety and depression. The purpose of this study was to investigate factors associated with use of online health communities by patients with thyroid cancer to understand the characteristics of patients participating in such online communities. A questionnaire survey was completed by 114 thyroid cancer patients admitted for surgery at a general hospital in Seoul, Korea. General characteristics, clinical characteristics, attitude toward cancer, distress, and anxiety and depression scores of patients who joined an online health community (user group) and patients who did not (non-user group) were compared. The factors affecting online health community participation were education (p = 0.049), tumor size (p = 0.010), attitude toward cancer (p = 0.022), and anxiety and depression (p = 0.021). The average score of satisfaction with the online health community was 4.25 of 5. The user group had larger tumors, a high awareness of the risk of thyroid cancer, and high levels of anxiety and depression. Patients who actively used the online health community have relatively larger cancer size and had higher levels of mental stress. As such patients are often very anxious and depend heavily on the gathered information, the quality of this information is important. Healthcare professionals need to develop appropriate interventions for patients participating in the online health community.

Thyroid cancer (TC) includes tumors of follicular cells; it ranges from well differentiated TC (WDTC) with generally favorable prognosis to clinically aggressive poorly differentiated TC (PDTC) and undifferentiated TC (UTC). Papillary thyroid cancer (PTC) is a WDTC and the most common type of thyroid cancer that comprises almost 70–80% of all TC. PTC can present as a solid, cystic, or uneven mass that originates from normal thyroid tissue. Prognosis of PTC is excellent, with an overall 10-year survival rate >90%. However, more than 30% of patients with PTC advance to recurrence or metastasis despite anti-cancer therapy; consequently, systemic therapy is limited, which necessitates expansion of improved clinical approaches. We strived to elucidate genetic distinctions due to patient-derived anti-cancer drug-sensitive or -resistant PTC, which can support in progress novel therapies. Patients with histologically proven PTC were evaluated. PTC cells were gained from drug-sensitive and -resistant patients and were compared using mRNA-Seq. We aimed to assess the in vitro and in vivo synergistic anti-cancer effects of a novel combination therapy in patient-derived refractory PTC. This combination therapy acts synergistically to promote tumor suppression compared with either agent alone. Therefore, genetically altered combination therapy might be a novel therapeutic approach for refractory PTC.

Abstract Background In the last decade, several tyrosine kinase inhibitors (TKIs), which disrupt pathways involved in the proliferation and tumorigenesis of thyroid cancer, have been extensively studied. Two different TKIs, lenvatinib and sorafenib, were recently approved by both the US FDA and European Medicine Agency. Until date, the duration of the TKI response is not sufficient and resistance eventually occurs. The goal of this study was to investigate a new treatment protocol, SoLAT, using sorafenib and lenvatinib alternatively on refractory thyroid cancer. Methods Patient-derived aggressive papillary thyroid cancer (PTC) cell lines from patients with biochemical and histologically proven aggressive RAI-refractory papillary thyroid cancer were exposed to sorafenib and lenvatinib alternatively. Human thyroid cancer cell xenografts were obtained by injecting patient-derived aggressive PTC cell lines into the flank of female BALB/c nude mice. Tumor-bearing mice were treated with sorafenib and lenvatinib alternatively. Cell viability assay, immunofluorescence analysis, confocal imaging, immunoblot analysis, flow cytometry analysis of cell cycle and a tube formation assay were performed. Results SoLAT was more effective for advanced PTC cell lines than individual treatment. Immunoblot analysis showed that SoLAT markedly increased levels of cell cycle inhibitors (p53 and p21), and pro-apoptotic factors (Apaf-1 and cleaved caspase 3) and decreased levels of positive cell cycle regulators (cyclin D1, CDK4, CDK6) and anti-apoptotic factors (p-NFκB, Bcl-2). Increased sub-G0/G1 population was observed in the SoLAT group, leading to apoptosis, cell cycle arrest, and strong inhibition of advanced PTC cell viability. SoLAT reduced the level of EMT markers such as vimentin, E-cadherin, Snail and Zeb1 by FGFR inhibition. In the xenograft model, individual treatment with sorafenib or lenvatinib did not markedly suppress patient-derived aggressive PTC cell xenograft tumors, whereas SoLAT significantly suppressed the proliferation of these tumors. Conclusions SoLAT was more effective than individual treatment with sorafenib or lenvatinib in inhibiting PTC progression by inducing cell cycle arrest. Studies using both in vitro cell culture and an in vivo xenograft model provided evidence of tumor shrinkage with SoLAT. We suggest that these effects may be due to reduced EMT-mediated drug resistance in the aggressive PTC model.

Anaplastic thyroid cancer (ATC) constitutes less than 2% of total thyroid cancers but accounts for 20–40% of thyroid cancer-related deaths. Cancer stem cell drug resistance represents a primary factor hindering treatment. This study aimed to develop targeted agents against thyroid malignancy, focusing on individual and synergistic effects of HNHA (histone deacetylase), lenvatinib (FGFR), and sorafenib (tyrosine kinase) inhibitors. Patients with biochemically and histologically proven papillary thyroid cancer (PTC) and ATC were included. Cell samples were obtained from patients at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. PTC and ATC cells were treated with lenvatinib or sorafenib, alone or in combination with HNHA. Tumor-bearing mice (10/group) were administered 10 mg/kg lenvatinib (p.o.) or 40 mg/kg sorafenib (p.o.), alone or in combination with 25 mg/kg HNHA (i.p.) once every three days. Gene expression in patient-derived PTC and ATC cells was compared using a microarray approach. Cellular apoptosis and proliferation were examined by immunohistochemistry and MTT assays. Tumor volume and cell properties were examined in the mouse xenograft model. HNHA-lenvatinib combined treatment induced markers of cell cycle arrest and apoptosis and suppressed anti-apoptosis markers, epithelial-mesenchymal transition (EMT), and the FGFR signaling pathway. Combined treatment induced significant tumor shrinkage in the xenograft model. HNHA-lenvatinib combination treatment thus blocked the FGFR signaling pathway, which is important for EMT. Treatment with HNHA-lenvatinib combination was more effective than either agent alone or sorafenib-HNHA combination. These findings have implications for ATC treatment by preventing drug resistance in cancer stem cells.

Anaplastic thyroid carcinoma (ATC) although rare is the most deadly form of thyroid cancer. The fatality rate for ATC is high-pitched, the survival rate at 1 year after diagnosis is

Background: Thyroid cancer has become the most common cancer in Korea. Generally, thyroid cancer patients have a good prognosis; however, 15–20% of patients experience recurrence or distant metastasis or are refractory to standard treatment. We assessed the safety of sorafenib and lenvatinib in patients with advanced or metastatic radioactive iodine-refractory differentiated thyroid cancers (DTC) consecutively treated at a tertiary center in South Korea.Methods: We retrospectively reviewed the charts of all consecutive patients with DTC treated during ≥6 months with lenvatinib (February 2016–April 2018) and sorafenib (January 2014–April 2018) at Gangnam Severance Hospital. Patients were treated according to the prescribing information of each drug and were followed up for 2 months. We evaluated the adverse events (AEs) reported with each drug.Results: A total of 71 medical records (lenvatinib, n = 23; sorafenib, n = 48) were reviewed. The most common histological types were papillary thyroid cancer (69.0%) and follicular thyroid cancer (22.5%). All patients (n = 23) started lenvatinib at a dose of 20 mg; 41.7% of sorafenib-treated patients received an initial dose of 800 mg daily. Four (17.4%) lenvatinib-treated patients and 26 (54.2%) sorafenib-treated patients required treatment discontinuation. The most common AEs of any grade in the lenvatinib group were diarrhea (82.6%), hypertension (78.3%), hand-foot skin reaction (56.5%), weight loss (52.2%), proteinuria (47.8%), and anorexia (43.5%). In the sorafenib group, these were hand-foot skin reaction (87.5%), diarrhea (62.5%), anorexia (60.4%), alopecia (56.3%), mucositis (52.1%), weight loss and generalized weakness (each, 50%), and hypertension (43.8%). The incidence of hand-foot skin reaction, alopecia, and rash of any grade was significantly lower (P = 0.003, P = 0.017, and P = 0.017) in patients treated with lenvatinib compared with those treated with sorafenib. The incidence of hypertension, QT prolongation, and proteinuria of any grade was significantly higher (P = 0.006, P = 0.038, and P < 0.001) in patients treated with lenvatinib compared with those treated with sorafenib. Seven deaths occurred, which were attributed to disease progression.Conclusions: No new safety concerns were identified for either drug. Most AEs were managed with dose modification and medical therapy. AEs such as hypertension and proteinuria warrant close monitoring.

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC.

Purpose: The goal of this study was to assess the clinicopathologic and ultrasonographic features of thyroid nodules with nondiagnostic results on repeat ultrasonography (US)-guided fineneedle aspiration biopsy (FNAB) according to size and the number of suspicious findings and to determine the proper management of nodules with consecutive nondiagnostic results. Methods: This retrospective study included 297 nodules with nondiagnostic results on repeat FNAB that were evaluated by US over the course of at least 12 months of follow-up, a follow-up biopsy, or an operation. We compared clinical and US variables between benign and malignant nodules in thyroid nodules with repeat nondiagnostic results. Results: The comparison of benign and malignant nodules with repeat nondiagnostic results revealed that age, marked hypoechogenicity, irregular or microlobulated margins, microcalcifications, and nonparallel shape were significantly associated with malignancy. Multivariate logistic regression analysis in malignant nodules revealed that microcalcifications and irregular or microlobulated margins were independently associated with malignancy. Among them, only irregular or microlobulated margins were independently significant as a predictor of malignancy in repeatedly nondiagnostic nodules measuring >10 mm. Using receiver operating characteristic analysis, the best cutoff value for the “number of suspicious findings” between benign and malignant nodules was three in nodules of all sizes, three in nodules measuring ≤10 mm, and two in nodules measuring >10 mm. Conclusion: Irregular or microlobulated margins may be the most frequent US features in repeatedly nondiagnostic nodules >10 mm. The presence of “two or more suspicious findings” can be used as the cutoff for distinguishing benign and malignant nodules.

BACKGROUND:Postoperative hypoparathyroidism is the most common complication after total thyroidectomy, owing to unintentional injury or decreased blood flow to the parathyroid glands. Prediction of postoperative hypoparathyroidism would be helpful for surgeons to manage postoperative hypocalcemia. In this study, we scored the discoloration of the parathyroid glands using a new parathyroid scoring system and evaluated the correlation between the parathyroid score and duration of required calcium supplementation after total thyroidectomy. METHODS:A total of 316 patients undergoing total thyroidectomy between November 2009 and April 2010 were enrolled in this retrospective study. Parathyroid scoring was performed by one experienced surgeon. The status of each of the 4 parathyroid glands was classified as normal color (3 points), slightly discolored (2 points), dark discoloration (1 point), or loss of the gland (0 points), resulting in possible total scores of 0-12. Serum parathyroid hormone (PTH), serum calcium, and ionized calcium concentrations were measured at 2 hours, 2 weeks, 3 months, 6 months, and 1 year after surgery. Patients were also divided into three groups based on the duration of required calcium supplementation: no required supplementation (n = 260, 82.3%), required supplementation for

Purpose: The increase in thyroid cancer incidence has inevitably led to an increase in thyroid cancer surgeries. This meta-regression analysis aimed to determine if the rate of post-thyroidectomy complications changes by year. Materials and Methods: PubMed and Embase databases were used to perform a systematic literature search of studies published from January 1, 2005, using the keywords "thyroidectomy" and "complication." A meta-regression was performed for post-thyroidectomy hypocalcemia and bleeding. Results: This meta-analysis included 25 studies involving 927751 individuals. Through the years of publications in this study, there was no significant difference in the proportion of post-thyroidectomy hypocalcemia and bleeding (p=0.9978, 0.6393). Conclusion: Although the number of thyroid surgeries has recently increased, the incidence of post-thyroidectomy hypocalcemia and bleeding did not significantly increase. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify the risk factors associated with the occurrence and prognosis of hypertrophic scarring following thyroidectomy. Materials and Methods: A total of 4238 patients who underwent thyroidectomy were included in this study. A multivariable logistic regression model was developed to identify the risk factors for hypertrophic scar development and its prognosis. Results: Our analysis revealed that hypertrophic scar development was associated with younger age [odds ratio (OR)=0.949, p<0.0001], male sex (OR=0.562, p<0.0001), higher body mass index (OR=1.137, p<0.0001), prominent sternocleidomastoid muscles (OR=2.522, p<0.0001), scarring located within 1 cm of the sternal notch (OR=4.345, p<0.0001), and a history of keloid development (OR=2.789, p=0.0031). Additionally, scar location within 1 cm of the sternal notch (beta=4.326, p=0.0429) and a history of keloid development (beta=23.082, p<0.0001) were found to be associated with the prognosis of hypertrophic scarring. Conclusion: The findings of this study provide valuable insights into the risk factors associated with hypertrophic scarring following thyroidectomy. Clinicians can use this information to predict the occurrence of hypertrophic scarring and its prognosis, and take preventative measures accordingly. [ABSTRACT FROM AUTHOR]

Context: Tumor size is important in determining the range of surgery in papillary thyroid carcinomas (PTCs), especially those smaller than 1 cm. Objective: We aimed to analyze the features of small PTCs with aggressive subtypes based on histological characteristics. Methods: In this retrospective study, we reviewed the medical records of 11 570 patients with PTCs smaller than or equal to 1 cm who underwent thyroidectomy between January 2009 and December 2016. Aggressive subtypes included diffuse sclerosing, solid, tall cell, columnar cell, and hobnail subtypes. Results: Among the 11 570 patients with PTCs smaller than or equal to 1 cm, 177 aggressive PTC subtypes were identified. Propensity score matching revealed 110 tumors (62.1%) with extrathyroidal extension of aggressive PTC subtypes and 451 (51.1%) nonaggressive PTC subtypes (95% CI, 0.41-0.80; P<.001). Metastatic central and lateral neck lymph nodes constituted 3.06±3.67 and 3.81± 5.39 of aggressive PTC subtypes and 1.22±2.14 and 2.85±3.79 of nonaggressive PTC subtypes, respectively (central neck nodes: 95% CI, 1.42-2.26; P<.001; lateral neck nodes: 95% CI, 2.9-5.90; P<.001). Seven patients with aggressive PTC subtypes (3.95%) and 12 with nonaggressive PTC subtypes (1.7%) exhibited recurrence. Conclusion: Aggressive subtypes of small PTC tumors smaller than or equal to 1 cm exhibited more extrathyroidal extension and neck node metastasis. This study suggests that surgeons should consider the aggressive subtypes as important factors when deciding the range of surgery in PTCs smaller than 1 cm. [ABSTRACT FROM AUTHOR]