Publications by authors named "Ka Hee Yi"

57 Publications

A national database analysis for factors associated with thyroid cancer occurrence.

Sci Rep 2020 10 20;10(1):17791. Epub 2020 Oct 20.

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.

In order to analyze the associations between thyroid cancer and environmental factors, we analyzed the national sample cohort representative of the entire population provided by the Korean National Health Insurance Service database record from 2006 to 2015. The cohort was categorized according to age, body mass index, income, residential areas, frequency of exercise, frequency of alcohol drinking, diet, presence or absence of hyperthyroidism, presence or absence of hypothyroidism, and smoking data. Age ≥ 55 years (HR 0.68, 95% CI 0.53-0.88), lower income (0.57, 0.40-0.80), and current smoking (0.69, 0.55-0.85) were associated with lower thyroid cancer occurrence among men. Body mass index (BMI) ≥ 25 kg/m2 (1.51, 1.26-1.82), higher income (1.44, 1.19-1.76), urban residence (1.24, 1.03-1.49), and presence of hypothyroidism (3.31, 2.38-4.61) or hyperthyroidism (2.46, 1.75-3.46) were associated with higher thyroid cancer occurrence among men. Age ≥ 55 years (0.63, 0.56-0.71), moderate alcohol drinking (0.87, 0.77-0.99), and current smoking (0.56, 0.37-0.85) were associated with lower thyroid cancer occurrence among women. BMI ≥ 25 kg/m2 (1.41, 1.26-1.57), frequent exercise (1.21, 1.07-1.36), higher income (1.18, 1.06-1.32), urban residence (1.17, 1.06-1.29), and presence of hypothyroidism (1.60, 1.40-1.82) or hyperthyroidism (1.38, 1.19-1.61) were associated with higher thyroid cancer occurrence among women. In conclusion, age ≥ 55 years and current smoking were associated with lower thyroid cancer occurrence, while BMI ≥ 25 kg/m2, higher income, urban residence, hypothyroidism, and hyperthyroidism were associated with higher occurrence in both men and women.
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http://dx.doi.org/10.1038/s41598-020-74546-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576121PMC
October 2020

A Phase II Multi-Center, Non-Randomized, Parallel Group, Non-Inferiority Study to Compare the Efficacy of No Radioactive Iodine Remnant Ablation to Remnant Ablation Treatment in Low- to Intermediate-Risk of Papillary Thyroid Cancer: The MOREthyroid Trial Protocol.

Endocrinol Metab (Seoul) 2020 09 22;35(3):571-577. Epub 2020 Sep 22.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: Radioactive iodine (RAI) remnant ablation is recommended in patients with papillary thyroid cancer (PTC) and extrathyroidal extension or central lymph node metastasis. However, there exists little evidence about the necessity of remnant ablation in PTC patients with low- to intermediate-risk, those have been increasing in recent decades.

Methods: This multicenter, prospective, non-randomized, parallel group clinical trial will enroll 310 eligible patients with low- to intermediate-risk of thyroid cancer. Inclusion criteria are patients who recently underwent total thyroidectomy for PTC with 3 or less tumors of size 1≤ to ≤2 cm with no microscopic extension and N0/x, or size ≤2 cm with microscopic extension and/or N1a (number of lymph node ≤3, size of tumor foci ≤0.2 cm, and lymph node ratio <0.4). Patients choose to undergo RAI ablation (131I, dose 1.1 GBq) or diagnostic whole-body scan (DxWBS) (131I or 123I, dose 0.074 to 0.222 GBq), followed by subsequent measurement of stimulated thyroglobulin (sTg) within 1 year. Survey for quality of life (QOL) will be performed at baseline and at 1 year after follow-up. The total enrollment period is 5 years, and patients will be followed up for 1 year. The primary endpoint is the non-inferiority of surgery alone to surgery with ablation in terms of biochemical remission (BCR) rate (sTg ≤2 ng/mL) without evidence of structural recurrence. The secondary endpoint was the difference of QOL.

Conclusion: This study will evaluate whether surgery alone achieves similar BCR and improved QOL compared to RAI ablation in patients with low- to intermediate-risk PTC within 1 year.
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http://dx.doi.org/10.3803/EnM.2020.681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520583PMC
September 2020

Functional Voice and Swallowing Outcome Analysis After Thyroid Lobectomy: Transoral Endoscopic Vestibular Versus Open Approach.

World J Surg 2020 Dec 11;44(12):4127-4135. Epub 2020 Aug 11.

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

Background: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a scarless remote-access thyroidectomy technique. This study compared subjective and objective voice outcomes and swallowing outcomes of patients who underwent thyroid lobectomy using the TOETVA versus conventional open thyroidectomy (OT).

Methods: In addition to questionnaires, acoustic and aerodynamic analyses were performed to compare subjective and objective voice outcomes of the two groups. Swallowing outcome analyses were conducted using Swallowing Impairment Index-6 (SIS-6) scores. Assessments were performed preoperatively and 3 and 6 months after surgery. Propensity score matching was performed to compare the outcomes of the two groups.

Results: One hundred and two patients were included in this study (52 TOETVA and 50 OT). Excluding two patients who had vocal cord palsy and open conversion in the TOETVA group, 100 patients completed 3-month postoperative surveys. There were no significant differences between the groups in VAS, GRBAS, or VHI-10 scores at the preoperative and 3- and 6-month assessments. For both groups, there were no significant changes in acoustic or aerodynamic parameters during the 3-6-month postoperative period. The TOETVA group had lower SIS-6 scores at the postoperative 6-month assessment, but the SIS-6 scores after 12 months were similar between groups before and after propensity score matching.

Conclusions: Following TOETVA lobectomy, there were no significant changes in voice outcomes 3 and 6 months after surgery, and the outcomes were comparable with those of OT. The TOETVA group also had swallowing outcomes that were comparable with the OT group.
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http://dx.doi.org/10.1007/s00268-020-05731-8DOI Listing
December 2020

Feasibility of Attachable Ring Stimulator for Intraoperative Neuromonitoring during Thyroid Surgery.

Int J Endocrinol 2020 30;2020:5280939. Epub 2020 Jan 30.

Department of Internal Medicine, Seoul National University College of Medicine and Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea.

Objective: Stimulator-attached dissecting instruments are useful for intraoperative nerve monitoring during thyroidectomy. The aim of this study was to evaluate the feasibility of an attachable ring stimulator (ARS) by comparing the electromyography (EMG) amplitudes evoked by an ARS and a conventional stimulator.

Methods: Medical records of fourteen patients who underwent thyroidectomy using intraoperative neuromonitoring between June and August 2019 were retrospectively reviewed. The amplitudes of V1, R1, R2, and V2 signals were checked using both the ARS and a conventional stimulator, at the same point.

Results: Both stimulators were tested on 20 recurrent laryngeal nerves (RLNs) and 20 vagus nerves (VNs). In all the nerves, the amplitudes of V1, R1, R2, and V2 were greater than 500 V. The mean amplitudes of V1, R1, R2, and V2 checked with the ARS were 1175, 1432, 1598, and 1279 V, respectively. The mean amplitudes of V1, R1, R2, and V2 checked with the conventional stimulator were 1140, 1425, 1557, and 1217 V, respectively. Difference between amplitudes evoked by the two stimulators for V1, R1, R2, and V2 was 77, 110, 102, and 99 V, respectively. There was no statistical difference in the amplitudes between the two groups for V1, R1, R2, and V2.

Conclusion: The ARS transferred electric stimulation as effectively as the conventional stimulator. It is an effective tool for repeated stimulation and facilitates continuous feedback regarding the functional integrity of nerves during thyroid surgery.
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http://dx.doi.org/10.1155/2020/5280939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204267PMC
January 2020

2019 Practice guidelines for thyroid core needle biopsy: a report of the Clinical Practice Guidelines Development Committee of the Korean Thyroid Association.

J Pathol Transl Med 2020 Jan 15;54(1):64-86. Epub 2020 Jan 15.

Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Ultrasound-guided core needle biopsy (CNB) has been increasingly used for the pre-operative diagnosis of thyroid nodules. Since the Korean Society of the Thyroid Radiology published the 'Consensus Statement and Recommendations for Thyroid CNB' in 2017 and the Korean Endocrine Pathology Thyroid CNB Study Group published 'Pathology Reporting of Thyroid Core Needle Biopsy' in 2015, advances have occurred rapidly not only in the management guidelines for thyroid nodules but also in the diagnostic terminology and classification schemes. The Clinical Practice Guidelines Development Committee of the Korean Thyroid Association (KTA) reviewed publications on thyroid CNB from 1995 to September 2019 and updated the recommendations and statements for the diagnosis and management of thyroid nodules using CNB. Recommendations for the resolution of clinical controversies regarding the use of CNB were based on expert opinion. These practical guidelines include recommendations and statements regarding indications for CNB, patient preparation, CNB technique, biopsy-related complications, biopsy specimen preparation and processing, and pathology interpretation and reporting of thyroid CNB.
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http://dx.doi.org/10.4132/jptm.2019.12.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986975PMC
January 2020

Longitudinal Assessment of Quality of Life According to Treatment Options in Low-Risk Papillary Thyroid Microcarcinoma Patients: Active Surveillance or Immediate Surgery (Interim Analysis of MAeSTro).

Thyroid 2019 08 12;29(8):1089-1096. Epub 2019 Jul 12.

1Department of Internal Medicine, Seoul National University Hospital and College of Medicine, Seoul, Republic of Korea.

In this ongoing multicenter prospective cohort study on active surveillance (AS) in low-risk papillary thyroid microcarcinoma (PTMC), we aimed to compare the quality of life (QoL) of participants based on their choice of treatment, that is, AS or immediate surgery (OP). QoL of 203 participants who chose AS and 192 participants who underwent OP was evaluated using a thyroid-specific QoL questionnaire at diagnosis and during follow-up (median 8 months). The mean ages of the participants in the AS and OP groups were 47.3 ± 11.7 and 45.6 ± 10.5 years ( = 0.138), respectively, and the mean tumor sizes were 5.7 ± 1.6 and 6.5 ± 2.1 mm ( = 0.065), respectively. At baseline, significantly better psychological health (7.1 ± 1.3 vs. 6.8 ± 1.6,  = 0.023) and overall health (6.8 ± 1.2 vs. 6.5 ± 1.3,  = 0.018) were observed in the AS group than in the OP group. During follow-up, significantly better physical (7.9 ± 1.1 vs. 7.4 ± 1.2,  < 0.001), psychological (7.4 ± 1.3 vs. 6.9 ± 1.6,  = 0.004), and overall health (6.9 ± 1.0 vs. 6.5 ± 1.1,  = 0.002) were observed in the AS group than in the OP group, whereas spiritual health was comparable between the two groups. Compared with the AS group, the OP group experienced more fatigue, changes in voice and appearance, less satisfaction, and low fear of recurrence. The self-assessed financial burden was similar at baseline and follow-up in both groups. The QoL of PTMC patients is different according to the type of treatment. Better psychological health at baseline and physical and psychological health at follow-up were observed in the AS group than in the OP group. However, studies with longer follow-up periods are needed.
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http://dx.doi.org/10.1089/thy.2018.0624DOI Listing
August 2019

Ultrasound image analysis using deep learning algorithm for the diagnosis of thyroid nodules.

Medicine (Baltimore) 2019 Apr;98(15):e15133

Department of Surgery, Kuma Hospital, Kobe, Japan.

Fine needle aspiration (FNA) is the procedure of choice for evaluating thyroid nodules. It is indicated for nodules >2 cm, even in cases of very low suspicion of malignancy. FNA has associated risks and expenses. In this study, we developed an image analysis model using a deep learning algorithm and evaluated if the algorithm could predict thyroid nodules with benign FNA results.Ultrasonographic images of thyroid nodules with cytologic or histologic results were retrospectively collected. For algorithm training, 1358 (670 benign, 688 malignant) thyroid nodule images were input into the Inception-V3 network model. The model was pretrained to classify nodules as benign or malignant using the ImageNet database. The diagnostic performance of the algorithm was tested with the prospectively collected internal (n = 55) and external test sets (n = 100).For the internal test set, 20 of the 21 FNA malignant nodules were correctly classified as malignant by the algorithm (sensitivity, 95.2%); and of the 22 nodules algorithm classified as benign, 21 were FNA benign (negative predictive value [NPV], 95.5%). For the external test set, 47 of the 50 FNA malignant nodules were correctly classified by the algorithm (sensitivity, 94.0%); and of the 31 nodules the algorithm classified as benign, 28 were FNA benign (NPV, 90.3%).The sensitivity and NPV of the deep learning algorithm shown in this study are promising. Artificial intelligence may assist clinicians to recognize nodules that are likely to be benign and avoid unnecessary FNA.
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http://dx.doi.org/10.1097/MD.0000000000015133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485748PMC
April 2019

Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Korean Patients with Type 2 Diabetes Mellitus in Real-World Clinical Practice.

Diabetes Metab J 2019 Oct 28;43(5):590-606. Epub 2019 Feb 28.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: This study aimed to evaluate the efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in Korean patients who had inadequately controlled type 2 diabetes mellitus (T2DM) in real-world clinical practice.

Methods: We included 410 patients who started SGLT2 inhibitors (empagliflozin or dapagliflozin) as add-on therapy or switch therapy between February 2015 and June 2017. The primary efficacy endpoint was a change in glycosylated hemoglobin (HbA1c) from baseline to week 12. The secondary endpoints were patients achieving HbA1c <7.0% and changes in the fasting plasma glucose (FPG), lipid profiles, body weight, and blood pressure (BP).

Results: The mean HbA1c at baseline was 8.5% (8.6% in the add-on group and 8.4% in the switch group). At week 12, the mean adjusted HbA1c decreased by -0.68% in the overall patients (<0.001), by -0.94% in the add-on group, and by -0.42% in the switch group. Significant reductions in FPG were also observed both in the add-on group and switch group (-30.3 and -19.8 mg/dL, respectively). Serum triglyceride (-16.5 mg/dL), body weight (-2.1 kg), systolic BP (-4.7 mm Hg), and diastolic BP (-1.3 mm Hg) were significantly improved in the overall patients. Approximately 18.3% of the patients achieved HbA1c <7.0% at week 12. A low incidence of hypoglycemia and genital tract infection was observed (6.3% and 2.2%, respectively).

Conclusion: SGLT2 inhibitors can be a suitable option as either add-on or switch therapy for Korean patients with inadequately controlled T2DM.
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http://dx.doi.org/10.4093/dmj.2018.0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834827PMC
October 2019

Comprehensive Transcriptomic and Genomic Profiling of Subtypes of Follicular Variant of Papillary Thyroid Carcinoma.

Thyroid 2018 11 16;28(11):1468-1478. Epub 2018 Oct 16.

1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea.

Background: Among subtypes of follicular variant of papillary thyroid carcinoma (FVPTC), encapsulated FVPTC (EFVPTC) shows more indolent behavior than infiltrative FVPTC (IFVPTC). In particular, noninvasive EFVPTC, now designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tends to have an excellent prognosis. However, it remains unclear whether the molecular pathogenesis or signature of the various forms of FVPTC is different. By massively parallel sequencing analysis, this study comprehensively characterized the transcriptional and mutational landscape of FVPTC and established correlations with phenotypic subtypes.

Methods: This study included 48 FVPTCs: 17 NIFTPs, 13 invasive EFVPTCs (I-EFVPTCs), and 18 IFVPTCs. For comparison, 55 classical papillary thyroid carcinomas (cPTCs) harboring a BRAF mutation, six follicular adenomas (FAs), and 15 minimally invasive follicular thyroid carcinomas (miFTCs) with RAS mutations were also included.

Results: In NIFTP, the BRAF mutation was not found, but RAS and other alterations were present in 64.7% and 17.6% of cases, respectively. However, in I-EFVPTC and IFVPTC, the proportions of BRAF mutation (38.5% and 38.9%, respectively) and of RAS mutations (38.5% and 38.9%, respectively) or other alterations (15.4% and 16.7%, respectively) were similar. On a molecular level, RAS-mutated FVPTCs were all RAS-like except for one IFVPTC case. Transcriptomic profiles of NIFTP, I-EFVPTC, and FA/miFTC were comparable, although the profile of RAS-mutated IFVPTC was altered to activate molecular pathways involved in cell adhesion and invasion. Interestingly, 80% of BRAF-mutated I-EFVPTCs were also classified as RAS-like, whereas all BRAF-mutated IFVPTCs were BRAF-like and indistinguishable from cPTC. Molecular pathways associated with cell adhesion and invasion were also differentially activated in BRAF-mutated IFVPTC.

Conclusions: Molecular profiles of NIFTP and I-EFVPTC may be shared with FA/miFTC, while IFVPTC seems to be associated with a similar profile as cPTC. Activation of cell adhesion and invasion pathways may play a key role in the development of invasive phenotypes of FVPTC.
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http://dx.doi.org/10.1089/thy.2018.0198DOI Listing
November 2018

Significance of distance between tumor and thyroid capsule as an indicator for central lymph node metastasis in clinically node negative papillary thyroid carcinoma patients.

PLoS One 2018 17;13(7):e0200166. Epub 2018 Jul 17.

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.

The aim of this study was to evaluate preoperatively identifiable clinical and ultrasonographic characteristics associated with central lymph node metastasis (CLNM) in clinically node negative papillary thyroid carcinoma (PTC) patients. Records of the patients who underwent thyroidectomy with prophylactic central lymph node dissection due to clinically node negative PTC (size, 1.0-3.0 cm) were reviewed. Of a total of 174 patients, 71 (40.8%) had CLNMs. CLNM was more associated with capsule invasion than capsule non-invasion on ultrasonography (68.4% vs. 37.4%, p = 0.009). In the 155 patients without capsule invasion, a distance from the capsule < 1.9 mm was associated with CLNM in univariable (p = 0.002) and multivariable analysis (p < 0.001). Any PTC patient with a distance from the capsule ≥ 1.9 mm did not have CLNM whereas 40.8% (58/142) of PTC patients with a distance from the capsule < 1.9 mm had CLNM. CLNM was not associated with age, gender, or tumor size on ultrasonography. Distance from capsule ≥ 1.9 mm on preoperative ultrasonography was a significant indicator for not having CLNM in clinically node negative PTC patients. Measuring distance from the capsule on preoperative ultrasonography images could help select patients with PTC who could benefit from prophylactic central lymph node dissection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049913PMC
January 2019

Study Protocol of Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro).

Endocrinol Metab (Seoul) 2018 Jun;33(2):278-286

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: The ongoing Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) aims to observe the natural course of papillary thyroid microcarcinoma (PTMC), develop a protocol for active surveillance (AS), and compare the long-term prognosis, quality of life, and medical costs between the AS and immediate surgery groups.

Methods: This multicenter prospective cohort study of PTMC started in June 2016. The inclusion criteria were suspicious of malignancy or malignancy based on fine needle aspiration or core needle biopsy, age of ≥18 years, and a maximum diameter of ≤1 cm. If there was no major organ involvement, no lymph node/distant metastasis, and no variants with poor prognosis, the patients were explained of the pros and cons of immediate surgery and AS before selecting AS or immediate surgery. Follow-up visits (physical examination, ultrasonography, thyroid function, and questionnaires) are scheduled every 6 months during the first 2 years, and then every 1 year thereafter. Progression was defined as a maximum diameter increase of ≥3, ≥2 mm in two dimensions, suspected organ involvement, or lymph node/distant metastasis.

Results: Among 439 enrolled patients, 290 patients (66.1%) chose AS and 149 patients (33.9%) chose immediate surgery. The median follow-up was 6.7 months (range, 0.2 to 11.9). The immediate surgery group had a larger maximum tumor diameter, compared to the AS group (7.1±1.9 mm vs. 6.6±2.0 mm, respectively; P=0.014).

Conclusion: The results will be useful for developing an appropriate PTMC treatment policy based on its natural course and risk factors for progression.
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http://dx.doi.org/10.3803/EnM.2018.33.2.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021306PMC
June 2018

Star-Shaped Intense Uptake of ¹³¹I on Whole Body Scans Can Reflect Good Therapeutic Effects of Low-Dose Radioactive Iodine Treatment of 1.1 GBq.

Endocrinol Metab (Seoul) 2018 Jun 4;33(2):228-235. Epub 2018 May 4.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: After initial radioactive iodine (RAI) treatment in differentiated thyroid cancer patients, we sometimes observe a star-shaped region of intense uptake of ¹³¹I on whole body scans (WBSs), called a 'star artifact.' We evaluated the clinical implications of star artifacts on the success rate of remnant ablation and long-term prognosis.

Methods: Total 636 patients who received ¹³¹I dose of 1.1 GBq for the initial RAI therapy and who did not show distant metastasis at the time of diagnosis were retrospectively evaluated. A negative second WBS was used for evaluating the ablation efficacy of the RAI therapy. Among them, 235 patients (36.9%) showed a star artifact on their first WBS.

Results: In patients with first stimulated thyroglobulin (sTg) levels ≤2 ng/mL, patients with star artifacts had a higher rate of negative second WBS compared with those without star artifacts (77.8% vs. 63.9%, P=0.044), and showed significantly higher recurrence-free survival (P=0.043) during the median 8.0 years (range, 1.0 to 10.0) of follow-up. The 5- and 10-year recurrence rates (5YRR, 10YRR) were also significantly lower in patients with star artifacts compared with those without (0% vs. 4.9%, respectively, P=0.006 for 5YRR; 0% vs. 6.4%, respectively, P=0.005 for 10YRR). However, ablation success rate or recurrence-free survival was not different among patients whose first sTg levels >2 ng/mL regardless of star artifacts.

Conclusion: Therefore, star artifacts at initial RAI therapy imply a good ablation efficacy or a favorable long-term prognosis in patients with sTg levels ≤2 ng/mL.
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http://dx.doi.org/10.3803/EnM.2018.33.2.228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021303PMC
June 2018

The prevalence of primary hyperparathyroidism in Korea: a population-based analysis from patient medical records.

Ann Surg Treat Res 2018 May 30;94(5):235-239. Epub 2018 Apr 30.

Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Because primary hyperparathyroidism (PHPT) is difficult to recognize, it has a high likelihood of being underdiagnosed. In this study, we estimated the incidence of PHPT and evaluated PHPT diagnosis in Korea.

Methods: To calculate the prevalence of PHPT, we examined the medical records of patients that were hospitalized for urolithiasis between 2013 and 2016 at a single institute, and then identified those who were diagnosed with PHPT from the same group. A Korea-wide insurance claim database was used to ascertain the number of urolithiasis patients and the number of parathyroidectomies performed in Korea. The incidence of PHPT in the Korean population was estimated using the ratio of patients who presented with urolithiasis as the initial symptom of PHPT.

Results: During the 4-year study period, 4 patients from the 925 urolithiasis patients enrolled in this study (0.4%) were diagnosed with PHPT. During this same period, there were 85,267 patients with urolithiasis in Korea, and the estimated number of PHPT patients was 341, which was 0.4% of 85,267. Considering that 12% to 23% of patients with PHPT are initially diagnosed with urolithiasis, the total number of PHPT patients was estimated to range from 1,483 to 2,842. The number of patients who underwent parathyroidectomy due to PHPT was 1,935 during the study period.

Conclusion: The number of patients we estimated to have PHPT corresponded closely with the number of patients undergoing parathyroidectomy during the study period. Considering the number of nonsymptomatic PHPT patients, PHPT may be properly diagnosed in Korea.
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http://dx.doi.org/10.4174/astr.2018.94.5.235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931933PMC
May 2018

Improvement of Glycosylated Hemoglobin in Patients with Type 2 Diabetes Mellitus under Insulin Treatment by Reimbursement for Self-Monitoring of Blood Glucose.

Diabetes Metab J 2018 Feb 28;42(1):28-42. Epub 2017 Sep 28.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: In Korea, the costs associated with self-monitoring of blood glucose (SMBG) for patients with type 2 diabetes mellitus (T2DM) under insulin treatment have been reimbursed since November 2015. We investigated whether this new reimbursement program for SMBG has improved the glycemic control in the beneficiaries of this policy.

Methods: Among all adult T2DM patients with ≥3 months of reimbursement (n=854), subjects without any changes in anti-hyperglycemic agents during the study period were selected. The improvement of glycosylated hemoglobin (HbA1c) was defined as an absolute reduction in HbA1c ≥0.6% or an HbA1c level at follow-up <7%.

Results: HbA1c levels significantly decreased from 8.5%±1.3% to 8.2%±1.2% during the follow-up (P<0.001) in all the study subjects (n=409). Among them, 35.5% (n=145) showed a significant improvement in HbA1c. Subjects covered under the Medical Aid system showed a higher prevalence of improvement in HbA1c than those with medical insurance (52.2% vs. 33.3%, respectively, P=0.012). In the improvement group, the baseline HbA1c (P<0.001), fasting C-peptide (P=0.016), and daily dose of insulin/body weight (P=0.024) showed significant negative correlations with the degree of HbA1c change. Multivariate analysis showed that subjects in the Medical Aid system were about 2.5-fold more likely to improve in HbA1c compared to those with medical insurance (odds ratio, 2.459; 95% confidence interval, 1.138 to 5.314; P=0.022).

Conclusion: The reimbursement for SMBG resulted in a significant improvement in HbA1c in T2DM subjects using insulin, which was more prominent in subjects with poor glucose control at baseline or covered under the Medical Aid system.
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http://dx.doi.org/10.4093/dmj.2018.42.1.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842298PMC
February 2018

Feasibility of sentinel lymph node dissection using Tc-99m phytate in papillary thyroid carcinoma.

Ann Surg Treat Res 2017 Nov 27;93(5):240-245. Epub 2017 Oct 27.

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Various methods of sentinel lymph node (SLN) biopsy in thyroid cancer have been introduced. Tc-99m phytate as a radiotracer has been successfully utilized for SLN biopsy in breast, cervix, and endometrial cancer. We assessed the feasibility of SLN dissection using Tc-99m phytate in papillary thyroid carcinoma (PTC).

Methods: Seventeen patients with PTC were prospectively enrolled. Ultrasound-guided peritumoral injection of 55.5 MBq Tc-99m phytate in 0.25-mL normal saline was performed. Preoperative single-photon emission-computed tomography (SPECT) and intraoperative gamma-probe were used for SLN detection during operation.

Results: Identification rate of SLNs was 70.6% (12 of 17) with SPECT, and 88.2% (15 of 17) with gamma-probe. Combined SPECT and gamma-probe had identification rates of 88.2% (15 of 17). Identification rates of SLNs in central LN compartments were 82.4% (14 of 17) and 41.2% (7 of 17) in lateral LN compartments. Overall sensitivity, specificity, positive predictive value, and negative predictive value of the results of SLN biopsy were 91.6%, 100%, 88.4%, and 100%, respectively. Eight patients (47.1%) had metastasis in SLNs; all patients had SLN metastasis in the central compartment and 2 patients had SLN metastasis in both the central and lateral compartments.

Conclusion: Combined SPECT and gamma-probe could detect SLNs with an 88.2% identification rate in PTC. SLN biopsy using Tc-99m phytate is technically feasible. Further investigation is warranted for clinical application of Tc-99m phytate in PTC.
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http://dx.doi.org/10.4174/astr.2017.93.5.240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694714PMC
November 2017

Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer.

Eur J Endocrinol 2017 Dec 1;177(6):465-473. Epub 2017 Sep 1.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Objective: Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer (FTC) over time have not been reported. Moreover, the prognostic effects of and promoter mutations in FTC have not been clearly elucidated. We investigated changes in the clinicopathological characteristics of patients with FTC over four decades, as well as the clinical significance of genetic mutations of FTC.

Design And Methods: This retrospective study included 690 patients with FTC who underwent thyroidectomy between 1973 and 2015 at the Seoul National University Hospital. In 134 samples, genetic tests for and promoter mutations and rearrangement were performed.

Results: The age at diagnosis has increased ( < 0.001) in recent decades and extrathyroidal extension of the tumor has become less common ( = 0.033). Other clinicopathological characteristics and prognosis of FTC have not significantly changed. The prevalence of mutations decreased ( = 0.042) over time, whereas that of promoter mutations remained stable. mutations were associated with distant metastasis and persistent disease, and promoter mutations were associated with distant metastasis, advanced TNM stage, recurrence and disease-specific mortality. FTC patients with coexistent and promoter mutations showed a higher recurrence risk than those with only one mutation.

Conclusions: The age at diagnosis of FTC and the frequency of extrathyroidal extension have changed over four decades. Moreover, the prevalence of mutations decreased. and promoter mutations may be associated with poor clinical outcomes in FTC, especially when the two mutations coexist.
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http://dx.doi.org/10.1530/EJE-17-0456DOI Listing
December 2017

Prevalence of thyroid nodules and their associated clinical parameters: a large-scale, multicenter-based health checkup study.

Korean J Intern Med 2018 07 7;33(4):753-762. Epub 2017 Jul 7.

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.

Background/aims: We evaluated the prevalence and characteristics of thyroid nodules detected by thyroid ultrasound (US) at health checkups and the associated clinical parameters.

Methods: A total of 72,319 subjects who underwent thyroid US at three health checkup centers in Korea from January 2004 to December 2010 were included in this study. The correlations between the presence of thyroid nodules and other clinical parameters were analyzed.

Results: The prevalence of thyroid nodules and cysts was 34.2% (n = 24,757). Thyroid nodules were more prevalent in women and older age groups. Among the subjects with thyroid nodules with size information (n = 24,686), 18,833 (76.3%) had nodules measuring ≤ 1.0 cm. Women and older age groups showed higher proportion of larger nodules. Percentage of women, age, body mass index (BMI), waist circumference, body fat composition, blood pressure, and the level of fasting glucose, total cholesterol, and low density lipoprotein cholesterol were higher in the subjects with thyroid nodules compared to those without nodules. The prevalence of metabolic syndrome and overt/subclinical thyrotoxic state was higher in the subjects with thyroid nodules. In the multivariable logistic regression analysis, women, age, BMI, metabolic syndrome, and thyrotoxicosis were independently associated with the presence of thyroid nodules.

Conclusions: The high prevalence of thyroid nodules in people who underwent thyroid US at a health checkup suggests that increased detection of thyroid nodules resulted in an increased prevalence in the general population. However, metabolic disturbances may also have contributed to the increase in thyroid nodule prevalence in Korea.
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http://dx.doi.org/10.3904/kjim.2015.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030422PMC
July 2018

Transoral endoscopic thyroidectomy for papillary thyroid microcarcinoma: initial experience of a single surgeon.

Ann Surg Treat Res 2017 Aug 28;93(2):70-75. Epub 2017 Jul 28.

Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea.

Purpose: Recently, transoral endoscopic thyroidectomy (TOET) is receiving attention because it is regarded as a true minimally invasive surgery in that it does not leave scars on any part of the body and the area of flap dissection is similar to that of open surgery. In this study, we present the surgical procedures and initial outcomes of TOET in the treatment of papillary thyroid microcarcinoma (PTMC) patients.

Methods: The medical records of patients who underwent TOET for PTMC between July 2016 and February 2017 were retrospectively reviewed. Indication of TOET was PTMC without capsular invasion or lymph node metastasis on preoperative imaging studies.

Results: Ten female patients were enrolled. Seven patients underwent thyroid lobectomy and three patients underwent isthmusectomy. The mean age and tumor size was 43.3 ± 11.5 years and 0.6 ± 0.2 cm, respectively. Operation time for lobectomy and isthmusectomy was 121.1 ± 30.7 (range, 65-148) and 90.0 ± 9.2 minutes (range, 82-100 minutes), respectively. The mean number of retrieved lymph nodes was 2.7 ± 1.7. Two patients had transient vocal cord palsy, which recovered in three months. There was no case with subcutaneous emphysema, surgical site infection, postoperative bleeding, or mental nerve injury.

Conclusion: TOET was feasible and could be performed safely for PTMC. TOET might become a new treatment option for the patients who do not want to leave visible scars on the body.
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http://dx.doi.org/10.4174/astr.2017.93.2.70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566749PMC
August 2017

The Second Antithyroid Drug Treatment Is Effective in Relapsed Graves' Disease Patients: A Median 11-Year Follow-Up Study.

Thyroid 2017 04 24;27(4):491-496. Epub 2017 Jan 24.

6 Department of Internal Medicine, Chung-Ang University College of Medicine , Seoul, Korea.

Background: Antithyroid drug (ATD) is a widely used treatment for Graves' disease (GD). However, its long-term efficiency remains unclear. This study investigated the long-term disease prognosis and predictive factors for relapse in ATD-treated GD patients.

Methods: Newly diagnosed, ATD-treated GD patients with at least four years of follow-up were recruited (n = 187). Remission was defined as maintaining a euthyroid status for more than one year after ATD withdrawal.

Results: During 11.1 years (range 4.0-23.7 years) of median follow-up, overall, 51.9% of the newly diagnosed ATD-treated GD patients achieved remission, 32.1% continued ATD treatment, and 13.4% underwent other ablation treatments. The 10-year remission rates were higher in the first (34.2%) and second (25.5%) ATD courses than in any of the other subsequent ATD courses, and decreased as ATD treatments were repeated. The 10-year relapse rate was the highest after the third ATD treatment (71.4%) compared with that after the first (60.5%) and second (58.3%) courses. Longer duration of ATD treatment (odds ratio [OR] = 1.4 [confidence interval (CI) 1.2-1.7], p < 0.001), higher number of relapses (OR = 4.7 [CI 2.3-9.8], p < 0.001), and moderate to severe Graves' ophthalmopathy (OR = 4.1 [CI 1.1-15.2], p = 0.032) were associated with persistent disease status.

Conclusions: A second course of ATD can be considered for GD patients after the first relapse because the chance of remission and the relapse rate are similar to the one after the first ATD treatment course. For GD patients with more than two relapses, or with an ATD treatment duration of more than four to five years, low-dose maintenance of ATD or ablative treatment needs to be considered.
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http://dx.doi.org/10.1089/thy.2016.0056DOI Listing
April 2017

Upregulation of SLC2 (GLUT) family genes is related to poor survival outcomes in papillary thyroid carcinoma: Analysis of data from The Cancer Genome Atlas.

Surgery 2017 01 11;161(1):188-194. Epub 2016 Nov 11.

Cancer Research Institute, Seoul National University Hospital and College of Medicine, Seoul, Korea; Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea. Electronic address:

Background: The Warburg effect describes increased glucose uptake in cancer cells, and glucose transporter proteins are overexpressed in many tumors. In this study, we evaluated the expression of 14 SLC2A genes encoding glucose transporter proteins in papillary thyroid carcinoma patients.

Methods: Clinical information and gene expression data from 499 papillary thyroid carcinoma patients were downloaded from The Cancer Genome Atlas database. Correlations between SLC2 gene family (SLC2A1-14) mRNA expression levels and clinicopathologic factors were analyzed.

Results: There were 14 mortalities during follow-up (median, 21.6 months). Patient overall mortality was associated with age ≥45 years, extrathyroidal extension, higher TNM stage, and increased expression of SLC2A1, SLC2A3, and SLC2A14 mRNA. Greater SLC2A1, SLC2A3, and SLC2A14 expression was associated with increased mortality (odds ratio: 11.692, 95% confidence interval: 3.362-36.938; odds ratio: 12.725, 95% confidence interval: 4.247-40.187; and odds ratio: 13.768, 95% confidence interval: 4.208-61.710, respectively). Kaplan-Meier survival analysis indicated that overall survival was shorter in patients with high rather than low SCL2 expression (SLC2A1, P = .003; SLC2A3, P < .001; and SLC2A14, P < .001).

Conclusion: Upregulation of the SLC2A1, SLC2A3, and SLC2A14 genes was associated with increased mortality in papillary thyroid carcinoma patients, and SLC2 gene expression levels are potentially useful prognostic indicators.
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http://dx.doi.org/10.1016/j.surg.2016.04.050DOI Listing
January 2017

Long-Term Recurrence of Small Papillary Thyroid Cancer and Its Risk Factors in a Korean Multicenter Study.

J Clin Endocrinol Metab 2017 02;102(2):625-633

Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

Context: Small papillary thyroid cancer (PTC) generally has an excellent prognosis. However, long-term recurrence is not uncommon and sometimes leads to morbidity or mortality.

Objective: To identify high-risk factors for long-term recurrence in patients with small PTC by stratifying their pathologic characteristics.

Design, Setting, And Patients: We conducted a nationwide, retrospective, multicenter study of 3282 patients with PTC sized ≤2 cm from 9 high-volume hospitals in Korea.

Main Outcome Measures: The maximally selected χ2 method was used to find the best cutoff points of tumor size, the number of metastatic lymph nodes (LNs), and the ratio of metastatic/examined LNs (LNR) to predict recurrence. Kaplan-Meier analysis and the Cox proportional hazards regression model were used to analyze recurrence and risk factors.

Results: The optimal tumor size cutoff was 1.8 cm (10-year recurrence rates for tumors sized 0.1 to 1.7 cm and 1.8 to 2.0 cm: 7.7% vs 17.2%, respectively). Metastatic LNs ≤1 and ≥2 provided optimal estimates of recurrence (10-year recurrence rates: 4.0% vs 16.8%, respectively). The LNR of 0.19 was the optimal cutoff point for predicting the risk of recurrence (10-year recurrence rates for LNRs of 0 to 0.18 and 0.19 to 1: 2.7% vs 16.2%, respectively). LN metastasis, lobectomy, tumor size ≥1.8 cm, and bilateral tumors were independent risk factors for recurrence.

Conclusions: Long-term recurrence was increased in patients who underwent lobectomy or with tumor sized ≥1.8 cm, 2 or more metastatic LNs, or bilateral tumors. For patients with these high-risk features, total thyroidectomy could be considered to avoid reoperation.
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http://dx.doi.org/10.1210/jc.2016-2287DOI Listing
February 2017

The Revised 2016 Korean Thyroid Association Guidelines for Thyroid Nodules and Cancers: Differences from the 2015 American Thyroid Association Guidelines.

Authors:
Ka Hee Yi

Endocrinol Metab (Seoul) 2016 Sep;31(3):373-378

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.

Increased detection of thyroid nodules using high-resolution ultrasonography has resulted in a world-wide increase in the incidence of differentiated thyroid cancer (DTC). Despite the steep increase in its incidence, the age-standardized mortality rate of thyroid cancer has remained stable, which leads toward a trend of more conservative treatment. The latest American Thyroid Association (ATA) guidelines for thyroid nodules and thyroid cancer revised in 2015 suggested that fine needle aspiration biopsy should be performed for thyroid nodules larger than 1 cm and lobectomy might be sufficient for 1 to 4 cm intrathyroidal DTC. In addition, active surveillance instead of immediate surgical treatment was also recommended as a treatment option for papillary thyroid microcarcinoma based on the results of a few observational studies from Japan. The Korean Thyroid Association (KTA) has organized a task force team to develop revised guidelines for thyroid nodules and DTC after an extensive review of articles and intense discussion on whether we should accept the changes in the 2015 ATA guidelines. This paper introduces and discusses the updated major issues and differences in the ATA and the KTA guidelines.
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http://dx.doi.org/10.3803/EnM.2016.31.3.373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053047PMC
September 2016

Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients.

Cancer 2016 05 11;122(9):1370-9. Epub 2016 Mar 11.

Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.

Background: Recent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes.

Methods: In all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow-up duration was 4.8 years (interquartile range, 3.4-10.6 years).

Results: TERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF-mutated nor RAS-mutated tumors, 4.8% in BRAF-mutated tumors, and 11.3% in RAS-mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high-risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42-15.18; HR for RAS, 5.36; 95% CI, 1.20-24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55-148.23; HR for RAS, 14.75; 95% CI, 1.30-167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high-risk (HR for recurrence, 5.79; 95% CI, 2.07-16.18; HR for mortality, 16.16; 95% CI, 2.10-124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19-10.85; HR for mortality, 9.06; 95% CI, 2.09-39.26).

Conclusions: The coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high-risk patients with DTC. Cancer 2016;122:1370-1379. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.29934DOI Listing
May 2016

Recombinant human thyrotropin-stimulated thyroglobulin level at the time of radioactive iodine ablation is an independent prognostic marker of differentiated thyroid carcinoma in the setting of prophylactic central neck dissection.

Clin Endocrinol (Oxf) 2016 09 23;85(3):459-65. Epub 2016 Feb 23.

Department of Internal Medicine, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam-si, Korea.

Objective: We investigated the value of the stimulated thyroglobulin (Tg) level at the time of recombinant human thyrotropin (rhTSH)-aided remnant ablation for predicting disease status 1 year later in patients with DTC who underwent total thyroidectomy with central neck dissection (CND).

Design, Setting, And Participant: This was a prospective observational study of 253 consecutive patients with DTC who underwent rhTSH-aided RAI ablation after total thyroidectomy and prophylactic CND. Patients with evidence of initial distant metastasis or positive Tg antibodies were excluded.

Major Outcome Measure: We compared rhTSH-stimulated Tg level at RAI ablation according to the disease status at 1 year and evaluated optimal cut-off value of rhTSH-stimulated Tg. Binary logistic regression analysis was performed to investigate the independent predictive factors for disease status 1 year after ablation.

Results: Among study participants, 228 (90·1%) were considered disease free at 1 year after remnant ablation. Patients with persistent or recurrent disease were more likely to be aged ≥45 years, and to have N1b stage, TNM stage III or IV, and higher rhTSH-stimulated Tg level at RAI ablation. The optimal cut-off of rhTSH-stimulated Tg for predicting persistent or recurrent disease was 1·79 ng/ml, with a negative predictive value of 99·5%. A serum rhTSH-stimulated Tg level ≥1·79 at the time of ablation was independently associated with persistent or recurrent disease 1 year later. N1b stage tended to be associated with persistent or recurrent disease.

Conclusion: A low stimulated serum Tg level at rhTSH-aided RAI ablation may be a favourable prognostic marker in the setting of prophylactic CND.
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http://dx.doi.org/10.1111/cen.13029DOI Listing
September 2016

The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease.

PLoS One 2015 9;10(12):e0144599. Epub 2015 Dec 9.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Osteoporosis-related fractures are one of the complications of Graves' disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves' disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves' disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves' disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144599PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674124PMC
April 2017

CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma.

Endocr Relat Cancer 2016 02 11;23(2):113-24. Epub 2015 Nov 11.

Department of Internal MedicineSeoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, South KoreaDepartment of PathologyBorame Medical Center 20, Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, South KoreaLee Gil Ya Cancer and Diabetes InstituteGachon University Graduate School of Medicine, 155 Gatbeol-ro, Yeonsu-ku, Incheon 406-840, Korea

Macrophages in tumor microenvironment have pivotal roles in tumor growth, metastasis, and angiogenesis. We investigated the interacting mechanism of macrophage actions in human papillary thyroid cancer (PTC). Co-cultures of macrophage/PTC significantly increased the cancer cell migration potentials, compared with the PTC culture alone. Treatment of conditioned medium (CM) of macrophage/PTC co-cultures enhanced cell invasions in 3D invasion assay. Cytokine array analysis demonstrated that CM of macrophage/PTC co-cultures contained a high level of CXCL16, while it was not found in CM of PTC culture alone. Treatment with CXCL16 enhanced the cell migration potentials in PTC cells, and blocking CXCL16 signaling using anti-CXCL16 antibody or metalloproteinase inhibitor (TAPI2) attenuated macrophage-mediated enhancement of PTC cell migration potentials. In PTC cells, CXCL16 treatment or co-cultures with macrophages increased Akt phosphorylation, and these macrophage-dependent increases of Akt phosphorylation was inhibited by anti-CXCL16 antibody. Moreover, Akt inhibitor attenuated macrophage-mediated increases of PTC cell migration potential. In macrophages, treatment of macrophage/PTC co-cultured CMs up-regulated CD163, Il10, and CD206, which were attenuated by anti-CXCL16 antibody treatment. Finally, CXCR6 and CXCL16 expressions were evaluated by immunohistochemical staining with a thyroid tissue microarray including 136 PTC. CXCR6 expressions showed positive correlation with the density of CD163(+) macrophages and associated with lymph node metastasis. In conclusion, CXCL16 signaling partly mediated macrophage actions on PTC tumor cell invasion and also changed the macrophage phenotypes into M2-macrophages in PTC tumor microenvironment. These data suggested that CXCL16 signaling, a bidirectional player in macrophage-associated tumor microenvironment, might be a potential therapeutic target of human PTC.
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http://dx.doi.org/10.1530/ERC-15-0196DOI Listing
February 2016

Influence of thyroid dysfunction on serum levels of angiopoietin-like protein 6.

Metabolism 2015 Oct 24;64(10):1279-83. Epub 2015 Jun 24.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul. Electronic address:

Angiopoietin-like protein 6 (ANGPTL6) is a novel metabolic regulator that modulates energy expenditure as well as glucose and lipid metabolism. Thyroid hormone can induce metabolic changes that are similar to those induced by ANGPTL6. Herein, we investigated whether circulating ANGPTL6 levels change according to thyroid hormone status in humans. We measured the serum levels of ANGPTL6 and metabolic parameters in 150 drug-naïve subjects with overt hyperthyroid, subclinical hyperthyroid, euthyroid, subclinical hypothyroid, or overt hypothyroid status (n=30 in each group). Serum ANGPTL6 levels were significantly higher in patients with overt hypothyroidism than in the other subjects. Women had significantly higher serum levels of ANGPTL6 than men. ANGPTL6 levels correlated positively with thyroid stimulating hormone (TSH), total cholesterol, aspartate aminotransferase, and alanine aminotransferase (ALT) and negatively with serum free thyroxine (T4) level. Multiple stepwise linear regression analysis revealed that sex, TSH, free T4, and ALT were independent predictors of serum ANGPTL6 levels. In summary, serum ANGPTL6 levels increased in patients with a hypothyroid status, and both TSH and free T4 levels are associated with ANGPLT6 levels, suggesting a possible association between thyroid function and ANGPTL6 levels. Whether the upregulated ANGPTL6 level in the hypothyroid status is primarily owing to a direct association or a compensatory mechanism remains to be determined.
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http://dx.doi.org/10.1016/j.metabol.2015.06.015DOI Listing
October 2015

Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years.

Clin Endocrinol (Oxf) 2016 04 30;84(4):587-97. Epub 2015 Jul 30.

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Context: The increase in thyroid screening in the general population may lead to earlier detection of medullary thyroid carcinoma (MTC).

Objective: We aimed to evaluate secular trends in clinicopathological characteristics and long-term prognosis of MTC and its prognostic factors.

Design: This was a retrospective analysis from 1982 to 2012.

Patients: Three hundred and thirty-one patients with MTC were included and grouped based on the year of diagnosis (1982-2000, 2001-2005, 2006-2010 and 2011-2012).

Measurements: These included recurrence and mortality as well as biochemical remission (BCR) of serum calcitonin.

Results: Mean tumour size (from 2·5 cm to 1·7 cm, P < 0·001) and percentage of extrathyroidal extension (from 52·0% to 26·0%, P = 0·026) decreased. The percentage of patients achieving BCR within six postoperative months (po-BCR) increased with time (from 39·6% to 76·1%, P < 0·001). The 5-year overall recurrence rate significantly decreased in 2006-2012 compared to 1982-2005 (10% vs 18%, respectively, P = 0·031), although the 5-year survival rate did not improve (92% vs 92%, P = 0·929). Failure to achieve po-BCR was the strongest predictive factor associated with recurrence (hazard ratio [HR] = 58·04, 95% CI 7·14-472·11; P < 0·001). Male gender (HR = 3·18, 95% CI 1·18-8·56; P = 0·022), tumour size >2 cm (HR = 18·33, 95% CI 2·35-143·06; P = 0·006) and distant metastasis (HR = 4·00, 95% CI 1·31-12·21; P = 0·015) were significant prognostic factors for mortality.

Conclusions: Clinicopathological characteristics and recurrence of MTC improved with time. Po-BCR was the best predictive factor for recurrence-free survival.
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http://dx.doi.org/10.1111/cen.12852DOI Listing
April 2016

Clinical Outcome of Remnant Thyroid Ablation with Low Dose Radioiodine in Korean Patients with Low to Intermediate-risk Thyroid Cancer.

J Korean Med Sci 2015 Jul 10;30(7):876-81. Epub 2015 Jun 10.

Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea. ; Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Tumor Microenvironment Global Core Research Center, Seoul National University College of Medicine, Seoul, Korea.

Radioiodine activity required for remnant thyroid ablation is of great concern, to avoid unnecessary exposure to radiation and minimize adverse effects. We investigated clinical outcomes of remnant thyroid ablation with a low radioiodine activity in Korean patients with low to intermediate-risk thyroid cancer. For remnant thyroid ablation, 176 patients received radioiodine of 1.1 GBq, under a standard thyroid hormone withdrawal and a low iodine diet protocol. Serum levels of thyroid stimulating hormone stimulated thyroglobulin (off-Tg) and thyroglobulin-antibody (Tg-Ab), and a post-therapy whole body scan (RxWBS) were evaluated. Completion of remnant ablation was considered when there was no visible uptake on RxWBS and undetectable off-Tg (<1.0 ng/mL). Various factors including age, off-Tg, and histopathology were analyzed to predict ablation success rates. Of 176 patients, 68.8% (n = 121) who achieved successful remnant ablation were classified into Group A, and the remaining 55 were classified into Group B. Group A presented with significantly lower off-Tg at the first radioiodine administration (pre-ablative Tg) than those of Group B (1.2 ± 2.3 ng/mL vs. 6.2 ± 15.2 ng/mL, P = 0.027). Pre-ablative Tg was the only significant factor related with ablation success rates. Diagnostic performances of pre-ablative Tg < 10.0 ng/mL were sensitivity of 99.1%, specificity of 14.0%, positive predictive value of 71.1%, and negative predictive value of 87.5%, respectively. Single administration of low radioiodine activity could be sufficient for remnant thyroid ablation in patients with low to intermediate-risk thyroid cancer. Pre-ablative Tg with cutoff value of 10.0 ng/mL is a promising factor to predict successful remnant ablation.
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http://dx.doi.org/10.3346/jkms.2015.30.7.876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479940PMC
July 2015