Tae Hyuk Kim

The association of the BRAFV600E mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer

The effects of the BRAFV600E mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta‐analysis to assess the strength of associations between these conditions and the BRAFV600E mutation.

Hemoglobin A1c as a diagnostic tool for diabetes screening and new-onset diabetes prediction: a 6-year community-based prospective study.

OBJECTIVE Various cutoff levels of hemoglobin A1c (A1C) have been suggested to screen for diabetes, although more consensus about the best level, especially for different ethnicities, is required. We evaluated the usefulness of A1C levels when screening for undiagnosed diabetes and as a predictor of 6-year incident diabetes in a prospective, population-based cohort study. RESEARCH DESIGN AND METHODS A total 10,038 participants were recruited from the Ansung-Ansan cohort study. All subjects underwent a 75-g oral glucose tolerance test at baseline and at each biennial follow-up. Excluding subjects with a previous history of diabetes (n = 572), the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of the A1C cutoff. The Cox proportional hazards model was used to predict diabetes at 6 years. RESULTS At baseline, 635 participants (6.8%) had previously undiagnosed diabetes. An A1C cutoff of 5.9% produced the highest sum of sensitivity (68%) and specificity (91%). At 6 years, 895 (10.2%) subjects had developed incident diabetes. An A1C cutoff of 5.6% had the highest sum of sensitivity (59%) and specificity (77%) for the identification of subsequent 6-year incident diabetes. After multivariate adjustment, men with baseline A1C ≥5.6% had a 2.4-fold increased risk and women had a 3.1-fold increased risk of new-onset diabetes. CONCLUSIONS A1C is an effective and convenient method for diabetes screening. An A1C cutoff of 5.9% may identify subjects with undiagnosed diabetes. Individuals with A1C ≥5.6% have an increased risk for future diabetes.

Pericardial Fat Amount Is an Independent Risk Factor of Coronary Artery Stenosis Assessed by Multidetector-Row Computed Tomography: The Korean Atherosclerosis Study 2

Pericardial fat surrounding the heart and coronary arteries might aggravate vessel wall inflammation and stimulate the progression of coronary atherosclerosis. However, there has been little comprehensive evaluation of the effects of pericardial fat on coronary artery disease (CAD). We investigated the relationship between pericardial fat volume and the severity of coronary artery stenosis assessed by computed tomography and angiography among patients with suspected CAD. Participants from the cohort of the Korean Atherosclerosis Study 2 (n = 402, mean age of 54 years, 57.0% men) underwent 64‐slice multidetector‐row computed tomography (MDCT) to assess pericardial fat amount, coronary artery calcium score (CACS), severity of coronary artery stenosis, and plaque characteristics. Patients with atherosclerotic lesion had significantly larger volume of pericardial fat than patients without atherosclerosis (308 ± 96 cm3 vs. 251 ± 93 cm3; P < 0.01). In a multivariate regression analysis adjusting for age, gender and BMI, subjects with more pericardial fat had a higher risk for significant (>50%) stenosed coronary vessels (odds ratio (OR) = 1.012; 95% confidence interval (CI) 1.001–1.030; P = 0.017). This association remained after adjusting for hypertension, diabetes, smoking status, and lipid profiles (OR = 1.007; 95% CI 1.001–1.014; P = 0.042). In conclusion, an increased pericardial fat volume was an independent risk factor for stenotic CAD and could be helpful in assessing subclinical CADs.

The Frequency and Clinical Implications of the BRAFV600E Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades

Background Over the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC) as well as a number of changes in the clinicopathological characteristics of this disease. BRAFV600E, which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAFV600E mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed. Methods The present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAFV600E mutation status of each patient was confirmed using the polymerase chain reaction-restriction fragment length polymorphism method or by the direct sequencing of DNA. Results The prevalence of the BRAFV600E mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001) over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE) and lymph node metastasis in 2009 to 2012 patients with the BRAFV600E mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAFV600E mutation (P=0.047). Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAFV600E mutation status. Conclusion The BRAFV600E mutation rate in Korean PTC patients has been persistently high (approximately 70%) over the past two decades and continues to increase. The present findings demonstrate that BRAFV600E-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAFV600E mutation status may be a useful prognostic factor for PTC in patients recently diagnosed with this disease.

Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status.

CONTEXT The widespread use of thyroid tests in asymptomatic individuals identifies many patients with transient subclinical hypothyroidism. OBJECTIVE Our objective was to determine the effect of seasonal change on serum TSH levels and the transition between subclinical hypothyroid and euthyroid status. DESIGN, SETTING, AND SUBJECTS This was a retrospective longitudinal study of 1751 subclinical hypothyroid and 28 096 euthyroid subjects aged over 18 years who underwent serial thyroid function tests at a health screening center between October 2003 and May 2011. MAIN OUTCOME MEASURES Age-adjusted geometric mean values of the TSH level by month were calculated using linear mixed models. Adjusted odds ratios of test season and multiple baseline clinical factors were determined using generalized estimating equations. RESULTS During a median 36 months of follow-up, 57.9% of subclinical hypothyroid subjects reverted to euthyroidism, and 4.3% of euthyroid subjects developed subclinical hypothyroidism. The monthly distribution of follow-up TSH levels indicated a biphasic pattern, ie, an increase during the winter-spring season and a decrease during the summer-fall season, with a maximal TSH difference of 0.69 mIU/L in subclinical hypothyroid and 0.30 mIU/L in euthyroid subjects. Normalization of subclinical hypothyroidism was increased 1.4-fold in follow-up tests during the summer-fall follow-up, whereas subclinical hypothyroidism increased 1.4-fold in euthyroid subjects during the winter-spring follow-up. CONCLUSIONS The season in which thyroid testing was performed was independently related to the transition between subclinical hypothyroid and euthyroid status. Seasonal variations in TSH concentration should be considered before deciding on treatment of subclinical hypothyroidism, particularly in the areas with a wide annual temperature range.

Comprehensive screening for PD-L1 expression in thyroid cancer

PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. The reported frequency of PD-L1 positivity varies in thyroid carcinomas, and multiple factors may contribute to the variability in PD-L1 positivity. We evaluated the PD-L1 expression in various thyroid cancers on a large scale. A total of 407 primary thyroid cancers with a median 13.7-year of follow-up were included. We evaluated the frequency of PD-L1 expression using a rabbit monoclonal antibody (clone SP142). In addition, we analyzed the relationships between PD-L1 expression and clinicopathologic factors, including TERT promoter, BRAF status and disease progression. Tumoral PD-L1 was expressed in 6.1% of papillary thyroid carcinomas, 7.6% of follicular thyroid carcinomas and 22.2% of anaplastic thyroid carcinomas. The distribution of PD-L1 positivity was different according to cancer histology types (P < 0.001). All PD-L1-positive cases of follicular thyroid carcinoma and anaplastic thyroid carcinoma showed strong intensity. The proportions of positivity in PD-L1 positive anaplastic thyroid carcinomas were more than 80%. PD-L1 in immune cells was positive in 28.5% of papillary thyroid carcinoma, 9.1% of follicular thyroid carcinomas and 11.1% of anaplastic thyroid carcinomas. There was no significant association between clinicopathologic variables, disease progression, oncogenic mutation and PD-L1 expression. PD-L1 was highly expressed in a subset of patients with advanced thyroid cancer, such as follicular and anaplastic thyroid carcinoma. Identification of PD-L1 expression may have direct therapeutic relevance to patients with refractory thyroid cancer.

TERT promoter mutations and long-term survival in patients with thyroid cancer

TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16-81 years) and median follow-up of 13 years (interquartile range 11-16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77-18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03-66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85-17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

Tumor Size and Age Predict the Risk of Malignancy in Hürthle Cell Neoplasm of the Thyroid and Can Therefore Guide the Extent of Initial Thyroid Surgery

BACKGROUND The majority of patients having a diagnosis of Hürthle cell neoplasm (HCN) on fine-needle aspiration (FNA) of a thyroid nodule have a diagnostic thyroid lobectomy to make the final diagnosis. If the nodule is malignant, they require a completion thyroidectomy. The objective of this study was to devise a simple clinical scheme capable of predicting malignancy in patients with cytologic diagnosis of HCN and, therefore, guide the extent of initial thyroid surgery. METHODS A total of 57 patients who underwent thyroid surgery after an FNA diagnosis of HCN were retrospectively studied. The patients were examined for clinical features, preoperative imaging studies, and pathology reports. The risk of malignancy was calculated using a multiple logistic regression model. RESULTS The overall rate of malignancy in patients with HCN was 46% (26/57). The predictors of malignancy based on multiple logistic regression analysis were tumor size >1.5 cm (odds ratio [95% confidence interval] = 8.0 [1.9-33.4]) and patient age >45 years (odds ratio [95% confidence interval] = 2.3 [0.6-8.6]). In patients with nodules larger than 1.5 cm, the predicted probability of malignancy was greater in patients over 45 years than in younger patients (65% for >45 years vs. 44% for ≤45 years). In patients with a nodule 1.5 cm or less, the probability of malignancy was relatively low and not significantly different between the two age categories (18% for >45 years vs. 10% for ≤45 years). CONCLUSIONS This study suggests that tumor size and age can be integrated into decision making for patients with an FNA diagnosis of HCN to facilitate patient selection for surgical referral and, particularly, to determine in which patients a thyroidectomy rather than a lobectomy should be the initial surgery.

Polymorphisms in KCNQ1 Are Associated with Gestational Diabetes in a Korean Population

Background: Recent genome-wide association studies in East Asians have identified polymorphisms in KCNQ1 as new type 2 diabetes risk variants. The aim of this study was to investigate whether variants in KCNQ1 are associated with development of gestational diabetes mellitus (GDM) and measures of oral glucose tolerance test (OGTT) at the time of diagnosis of GDM. Methods: Three candidate single nucleotide polymorphisms (rs2074196, rs2237892, and rs2237895) were genotyped in 869 Korean GDM women and 632 nondiabetic control subjects. Insulin resistance was estimated by homeostasis model assessment and pancreatic β-cell function by the insulinogenic index at 1 h. Results: rs2074196 and rs2237892 were associated with the risk of GDM (OR 1.17, 95% CI 1.01–1.36, p = 0.039; OR 1.24, 95% CI 1.07–1.45, p = 0.0049). Furthermore, rs2237892 and rs2237895 were nominally associated with a decreased insulinogenic index at the time of GDM diagnosis (p = 0.025 and p = 0.037), whereas no association was observed with measures of insulin resistance. Conclusions: The single nucleotide polymorphisms in KCNQ1 showed a significant association with GDM in the Korean population. Although the mechanism is not yet clear, it could be possible that variants in KCNQ1 confer a risk for GDM by altering pancreatic β-cell function.

Follicular and Hurthle cell carcinoma of the thyroid in iodine-sufficient area: retrospective analysis of Korean multicenter data

Background/Aims Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) of the thyroid are relatively uncommon thyroid malignancies in iodine-sufficient areas. In this study we evaluated the clinical behavior, prognostic factors and treatment outcomes of FTC and HCC in Korea. Methods This multicenter study included 483 patients with FTC and 80 patients with HCC who underwent an initial surgery between 1995 and 2006 in one of the four tertiary referral hospitals in Korea. We evaluated clinicopathological factors associated with distant metastases and recurrence during a median of 6 years of follow-up. Results HCC patients were significantly older (49 years vs. 43 years; p < 0.001) and had more lymphovascular invasions (22% vs. 14%; p = 0.03) compared with FTC patients. Distant metastases were confirmed in 40 patients (8%) in the FTC group and in two patients (3%) in the HCC group (p = 0.07). Distant metastases were significantly associated with older age, widely invasive cancer and extrathyroidal invasion. Only 14 patients (3%) had recurrent disease and there was no significant difference between FTC and HCC groups (p = 0.38). Recurrence was associated with larger tumor size and cervical lymph node metastasis. Conclusions HCC patients were older and had more lymphovascular invasions than FTC patients. However, FTC and HCC patients had similar initial clinicopathological features. Older age, wide invasiveness and extrathyroidal invasion were independent risk factors for predicting distant metastases in FTC and HCC patients.