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1.  The Utility of Segmental Analysis in Cardiac I-123 MIBG SPECT in Parkinson’s Disease 
Cardiac images using I-123 metaiodobenzylguanidine (MIBG) are widely used to evaluate cardiac sympathetic denervation in Parkinson’s disease (PD). The aim of this study was to evaluate the utility of segmental analysis on cardiac MIBG SPECT in PD patients.
Materials and Methods
In total, 36 patients with PD (n = 26) or essential tremor (ET, n = 10) who underwent MIBG cardiac SPECT were enrolled. The heart-to-mediastinum (H/M) ratios of MIBG uptake were acquired on planar images. For the segmental analysis of SPECT images, we evaluated the summed defect score (SDS) using a 17-segment model. The diagnostic abilities of H/M ratios and segmental parameters on MIBG SPECT were assessed by ROC curve analysis.
The H/M ratios were significantly lower in PD than in ET patients (p < 0.05). On segmental analysis, SDS was significantly higher in PD patients than in the ET group (7.04 ± 4.09 vs. 2.90 ± 2.80; p = 0.006). The defect score of the anteroseptal region showed a significant difference between the groups (p = 0.002). The ROC analysis suggested only SDS (AUC = 0.785, p = 0.0003) and defect scores in the anteroseptal (AUC = 0.800, p < 0.0001) and inferior (AUC = 0.667, p = 0.013) regions showed significant diagnostic ability to differentiate PD from ET.
Segmental parameters from cardiac MIBG SPECT images can provide additional information to differentiate PD from ET patients. Beyond H/M ratios from planar images, we recommend an MIBG SPECT study to evaluate sympathetic denervation in PD.
PMCID: PMC4630334  PMID: 26550049
I-123 MIBG; Heart; SPECT; Parkinson’s disease; Segmental analysis
2.  Efficacy and safety of two fixed-dose combinations of S-amlodipine and telmisartan (CKD-828) versus S-amlodipine monotherapy in patients with hypertension inadequately controlled using S-amlodipine monotherapy: an 8-week, multicenter, randomized, double-blind, Phase III clinical study 
To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy.
Patients and methods
Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] ≥90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings.
After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were −9.67±6.50/−12.89±11.78, −10.72±6.19/−13.79±9.41, and −4.93±7.26/−4.55±11.27 mmHg in the CKD-828 2.5/40 mg (P<0.0001/P<0.0001), CKD-828 2.5/80 mg (P<0.0001/P<0.0001), and S-amlodipine 2.5 mg (P<0.0001/P=0.0027) groups, respectively, which were all significant BP reductions. At Week 8, the CKD-828 2.5/40 mg (sitDBP/SBP: P=0.0002/P<0.0001) and CKD-828 2.5/80 mg (sitDBP/SBP: P=0.0001/P<0.0001) showed superior BP-lowering effects to S-amlodipine 2.5 mg (P<0.001). At Week 4, all groups showed significant antihypertensive effects but both CKD-828 combinations (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) exhibited superior BP-lowering effects to that of S-amlodipine 2.5 mg (sitDBP/SBP: P=0.0028/P=0.0001 and P<0.0001/P=0.0012, respectively). The adverse event incidence was significantly lower in the CKD-828 2.5/40 mg (9.52%, P=0.0086) than in the S-amlodipine 2.5 mg group (27.87%) and increasing the telmisartan dose induced no unexpected adverse events, suggesting the safety of CKD-828.
CKD-828 is an effective and safe option for patients with inadequate responses to S-amlodipine monotherapy.
PMCID: PMC5125808  PMID: 27920497
blood pressure; antihypertensive; calcium channel blocker; angiotensin receptor blocker; efficacy; safety
3.  Impact of low high-density lipoprotein-cholesterol level on 2-year clinical outcomes after acute myocardial infarction in patients with diabetes mellitus 
It is still unclear whether low high-density lipoprotein cholesterol (HDL-C) affects cardiovascular outcomes after acute myocardial infarction (AMI), especially in patients with diabetes mellitus.
A total of 984 AMI patients with diabetes mellitus from the DIabetic Acute Myocardial InfarctiON Disease (DIAMOND) Korean multicenter registry were divided into two groups based on HDL-C level on admission: normal HDL-C group (HDL-C ≥ 40 mg/dL, n = 519) and low HDL-C group (HDL-C < 40 mg/dL, n = 465). The primary endpoint was 2-year major adverse cardiovascular events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), and target vessel revascularization (TVR).
The median follow-up duration was 730 days. The 2-year MACE rates were significantly higher in the low HDL-C group than in the normal HDL-C group (MACE, 7.44% vs. 3.49%, p = 0.006; cardiac death, 3.72% vs. 0.97%, p = 0.004; non-fatal MI, 1.75% vs. 1.55%, p = 0.806; TVR, 3.50% vs. 0.97%, p = 0.007). Kaplan-Meier analysis revealed that the low HDL-C group had a significantly higher incidence of MACE compared to the normal HDL-C group (log-rank p = 0.013). After adjusting for conventional risk factors, Cox proportional hazards analysis suggested that low HDL-C was an independent risk predictor for MACE (hazard ratio [HR] 3.075, 95% confidence interval [CI] 1.034-9.144, p = 0.043).
In patients with diabetes mellitus, low HDL-C remained an independent risk predictor for MACE after adjusting for multiple risk factors during 2-year follow-up of AMI.
Trial registration
This study was the sub-analysis of the prospective multi-center registry of DIAMOND (Diabetic acute myocardial infarction Disease) in Korea. This is the observational study supported by Bayer HealthCare, Korea. Study number is 15614. First patient first visit was 02 April 2010 and last patient last visit was 09 December 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-016-0374-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5116186  PMID: 27863493
High-density lipoprotein cholesterol; Major adverse cardiovascular events; Acute myocardial infarction; Diabetes mellitus
4.  Temporal trends and in-hospital outcomes of primary percutaneous coronary intervention in nonagenarians with ST-segment elevation myocardial infarction 
Data regarding the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in nonagenarians are very limited. The aim of the present study was to evaluate the temporal trends and in-hospital outcomes of primary PCI in nonagenarian STEMI patients.
We retrospectively reviewed data from the Korea Acute Myocardial Infarction Registry (KAMIR) from November 2005 to January 2008, and from the Korea Working Group on Myocardial Infarction (KorMI) from February 2008 to May 2010.
During this period, the proportion of nonagenarians among STEMI patients more than doubled (0.59% in KAMIR vs. 1.35% in KorMI), and the rate of use of primary PCI also increased (from 62.5% in KAMIR to 81.0% in KorMI). We identified 84 eligible study patients for which the overall in-hospital mortality rate was 21.4% (25.0% in KAMIR vs. 20.3% in KorMI, p = 0.919). Multivariate analysis identified two independent predictors of in-hospital mortality, namely a final Thrombolysis in Myocardial Infarction (TIMI) flow < 3 (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.2 to 59.0; p < 0.001) and cardiogenic shock during hospitalization (OR, 6.7; 95% CI, 1.5 to 30.3; p = 0.013).
The number of nonagenarian STEMI patients who have undergone primary PCI has increased. Although a final TIMI flow < 3 and cardiogenic shock are independent predictors of in-hospital mortality, primary PCI can be performed with a high success rate and an acceptable in-hospital mortality rate.
PMCID: PMC4642011  PMID: 26552457
In-hospital outcomes; Aged, 90 and over; Myocardial infarction; Percutaneous coronary intervention
5.  The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers 
Molecular carcinogenesis  2014;54(10):1172-1180.
Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in one hundred forty six (146) cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
PMCID: PMC4286524  PMID: 25043748
histone modification; EZH2; UTX; cancer; prognosis
6.  Comparison of 2-year clinical outcomes between diabetic versus nondiabetic patients with acute myocardial infarction after 1-month stabilization 
Medicine  2016;95(25):e3882.
Supplemental Digital Content is available in the text
This study assessed the 2-year clinical outcomes of patients with diabetes mellitus (DM) after acute myocardial infarction (AMI) in a cohort of the DIAMOND (DIabetic Acute Myocardial infarctiON Disease) registry. Clinical outcomes were compared between 1088 diabetic AMI patients in the DIAMOND registry after stabilization of MI and 1088 nondiabetic AMI patients from the KORMI (Korean AMI) registry after 1 : 1 propensity score matching using traditional cardiovascular risk factors. Stabilized patients were defined as patients who did not have any clinical events within 1 month after AMI. Primary outcomes were the 2-year rate of major adverse cardiac events (MACEs), a composite of all-cause death, recurrent MI (re-MI), and target vessel revascularization (TVR). Matched comparisons revealed that diabetic patients exhibited significantly lower left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate and smaller stent size. Diabetic patients exhibited significantly higher 2-year rates of MACE (8.0% vs 3.7%), all-cause death (3.9% vs 1.4%), re-MI (2.8% vs 1.2%), and TVR (3.5% vs 1.3%) than nondiabetic patients (all P < 0.01), and higher cumulative rates in Kaplan–Meier analyses of MACE, all-cause death, and TVR (all P < 0.05). A multivariate Cox regression analysis revealed that chronic kidney disease, LVEF < 35%, and long stent were independent predictors of MACE, and large stent diameter and the use of drug-eluting stents were protective factors against MACE. The 2-year MACE rate beyond 1 month after AMI was significantly higher in DM patients than non-DM patients, and this rate was associated with higher comorbidities, coronary lesions, and procedural characteristics in DM.
PMCID: PMC4998313  PMID: 27336875
acute myocardial infarction; diabetes mellitus; major adverse cardiac events
7.  Prospective and Systematic Analysis of Unexpected Requests for Non-Cardiac Surgery or Other Invasive Procedures during the First Year after Drug-Eluting Stent Implantation 
Yonsei Medical Journal  2014;55(2):345-352.
Unexpected requests for non-cardiac surgery requiring discontinuation of dual antiplatelet therapy (DAPT) frequently occur in daily clinical practice. The objectives of this study were to evaluate prevalence, timing and clinical outcomes of such unexpected requests for non-cardiac surgery or other invasive procedures during the first year after drug-eluting stents (DESs) implantation.
Materials and Methods
We prospectively investigated the prevalence, timing and clinical outcomes of unexpected requests for non-cardiac surgery or other procedures during the first year after DESs implantation in 2117 patients.
The prevalence of requested non-cardiac surgery or invasive procedures was 14.6% in 310 requests and 12.3% in 261 patients. Among 310 requests, those were proposed in 11.3% <1 month, 30.0% between 1 and 3 months, 36.8% between 4 and 6 months and 21.9% between 7 and 12 months post-DES implantation. The rates of actual discontinuation of DAPT and non-cardiac surgery or procedure finally performed were 35.8% (111 of 310 requests) and 53.2% (165 of 310 requests), respectively. On multivariate regression analysis, the most significant determinants for actual discontinuation of DAPT were Endeavor zotarolimus-eluting stent implantation with 3-month DAPT (OR=5.54, 95% CI 2.95-10.44, p<0.001) and timing of request (OR=2.84, 95% CI 1.97-4.11, p<0.001). There were no patients with any death, myocardial infarction, or stent thrombosis related with actual discontinuation of DAPT.
Those unexpected requests with premature discontinuation of DAPT were relatively common and continuously proposed during the first year following DES implantation. No death, myocardial infarction or stent thrombosis occurred in patients with actual discontinuation of DAPT.
PMCID: PMC3936620  PMID: 24532502
Antiplatelet therapy; drug-eluting stents; coronary artery disease
8.  The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress 
BMC Cancer  2016;16:319.
Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy.
Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event.
This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy.
Trial registration Identifier NCT00912548. Registered May 31 2009. Korean Breast Cancer Society Study Group Register KBCSG005. Registered October 26 2009.
PMCID: PMC4872354  PMID: 27197523
Ovarian function suppression; Goserelin; Tamoxifen; Adjuvant endocrine therapy; Premenopause; Breast cancer
9.  Age and prognosis of papillary thyroid carcinoma: retrospective stratification into three groups 
We investigated the prognosis according to age in papillary thyroid carcinoma (PTC) patients.
We retrospectively evaluated 2,890 patients who underwent thyroidectomy due to PTC between May 2004 and Aug 2008. We divided patients into 3 groups: young (≤35 years old), middle (between 35 and 54 years old), and old (≥55 years old).
Median age was 47.0 years old (range, 15 to 82 years). Within a follow-up period median of 50 months, there were 148 (5.1%) locoregional recurrences, 6 (0.2%) PTC-related deaths, and 18 (0.6%) PTC-unrelated deaths. Outcomes were more favorable in the young group, with no PTC-related death despite the frequent locoregional recurrence. In the old group compared to the middle, there was a higher proportion of male, and more aggressive types as T3 or N1b, higher mean tumor number, more multiplicity, and bilaterality. The old group of ≥55 years did not show a significant difference in PTC-related deaths than other age groups in Cox analysis (OR, 0.9; P = 0.677), but a significant cutoff age in PTC-related deaths at 62.5 years was determined in ROC analysis (area under curve = 0.912).
We showed that the ≤35 years group shows favorable prognosis despite the frequent locoregional recurrence and ≥62.5 years group shows a poor prognosis regardless of other factors such as male sex or tumor aggressiveness. Further multiinstitutional studies are needed to elucidate the prognosis according to patient's age.
PMCID: PMC3491227  PMID: 23166884
Age; Prognosis; Papillary thyroid carcinoma
10.  Observational study of central metastases following thyroid lobectomy without a completion thyroidectomy for papillary carcinoma 
There are no guidelines for the optimal timing of the decision of when to perform completion thyroidectomy, and controversy exists regarding how the timing of completion thyroidectomy impacts survival patterns. We investigated the legitimacy of an observational strategy in central node metastasis after thyroid lobectomy for papillary thyroid cancer (PTC).
We retrospectively evaluated 522 consecutive patients who underwent thyroid lobectomy. Of the 69 patients with central metastasis, 61 patients (88.4%) were included in an observational study under cautious evaluation with informed consent by the patients, and compared with an observation arm of 180 postlobectomy N0 (node negative proven) patients.
Of the 522 patients, six (1.1%) thyroid, five (0.9%) central, and two (0.4%) lateral recurrences were observed. Lateral recurrences occurred in the immediate completion N0 and Nx groups but not in the N1a observation arms. There were two (3.3%) central recurrences without thyroid or lateral recurrence on the observation arm of N1a observation patients. But two (1.1%) thyroid and three (1.7%) central recurrences were on the observation arm of N0 patients. In Kaplan-Meier survival curves for central or lateral recurrences between observation arms for the N1a and N0 groups, no significant difference was found between the N1a and N0 observation arms (P = 0.365).
The timing of when to perform completion thyroidectomy in central metastases-proven patients after lobectomy for PTC should be based on the patient's risk category.
PMCID: PMC3467385  PMID: 23091791
Observation; Lymphatic metastasis; Thyroid neoplasms; Thyroidectomy
11.  Thyroid gland metastasis arising from primary liver cholangiocarcinoma: The first case report involving surgical operation 
A primary cancer causing thyroid metastasis is extremely rare. In western countries, the most common primary tumors causing thyroid metastases include kidney, lung, breast, and gastrointestinal cancers. In contrast, breast is the most common primary site, followed by kidney, colon, and lung cancers in Korea. To the best of our knowledge, surgically confirmed thyroid metastasis from cholangiocarcinoma has not been reported. Herein, we report the first case of thyroid metastasis secondary to cholangiocarcinoma on which surgery was performed.
Presentation of case
A 55-year-old man was diagnosed with hepatic malignancy in December 2008. He subsequently received 2 cycles of transarterial chemoembolization and 4 cycles of radio-frequency ablation between 2008 and 2010. At follow-up in January 2011, brain metastasis was identified in the right parietal area secondary to cholangiocarcinoma. In April 2011, the patient was found to have palpable masses on the left thyroid and lateral neck. The patient subsequently underwent total thyroidectomy followed by left radical neck dissection. Intraoperatively, an ill-defined mass measuring 6.0 cm was found infiltrating the subcutaneous tissue into the prevertebral fascia. Microscopic and immunohistochemical findings confirmed that the thyroid masses and lymph nodes were metastatic cholangiocarcinoma.
Positive immunohistochemical staining for cytokeratin 7, cytokeratin 19, and AFP and negative results for TG, TTF-1, and cytokeratin 20 can be definitely helpful in arriving at a correct diagnosis.
To the best of our knowledge, this is the first case report on surgically resected thyroid and lateral neck metastases secondary to cholangiocarcinoma.
PMCID: PMC3267264  PMID: 22288052
Neoplasm metastasis; Thyroid metastasis; Cholangiocarcinoma
12.  Comparing Two-Stent Strategies for Bifurcation Coronary Lesions: Which Vessel Should be Stented First, the Main Vessel or the Side Branch? 
Journal of Korean Medical Science  2011;26(8):1031-1040.
This study compared two-stent strategies for treatment of bifurcation lesions by stenting order, 'main across side first (A-family)' vs 'side branch first (S-family). The study population was patients from 16 centers in Korea who underwent drug eluting stent implantation with two-stent strategy (A-family:109, S-family:140 patients). The endpoints were cardiac death, myocardial infarction (MI), stent thrombosis (ST), and target lesion revascularization (TLR) during 3 years. During 440.8 person-years (median 20.2 months), there was 1 cardiac death, 4 MIs (including 2 STs), and 12 TLRs. Cumulative incidence of cardiac death, MI and ST was lower in A-family (0% in A-family vs 4.9% in S-family, P = 0.045). However, TLR rates were not different between the two groups (7.1% vs 6.2%, P = 0.682). Final kissing inflation (FKI) was a predictor of the hard-endpoint (hazard ratio 0.061; 95% CI 0.007-0.547, P = 0.013), but was not a predictor of TLR. The incidence of hard-endpoint of S-family with FKI was comparable to A-family, whereas S-family without FKI showed the poorest prognosis (1.1% vs 15.9%, retrospectively; P = 0.011). In conclusion, 'A-family' seems preferable to 'S-family' if both approaches are feasible. When two-stent strategy is used, every effort should be made to perform FKI, especially in 'S-family'.
PMCID: PMC3154338  PMID: 21860553
Bifurcation; Coronary Artery Disease; Drug-Eluting Stents; Percutaneous Coronary Intervention
13.  Comparison of 2-year mortality according to obesity in stabilized patients with type 2 diabetes mellitus after acute myocardial infarction: results from the DIAMOND prospective cohort registry 
After acute myocardial infarction (AMI), the replicated phenomenon of obesity paradox, i.e., obesity appearing to be associated with increased survival, has not been evaluated in stabilized (i.e., without clinical events within 1 month post AMI) Asian patients with diabetes mellitus (DM).
Among 1192 patients in the DIabetic Acute Myocardial InfarctiON Disease (DIAMOND) Korean multicenter registry between April 2010 and June 2012, 2-year cardiac and all-cause death were compared according to obesity (body mass index ≥25 kg/m2) in 1125 stabilized DM patients.
Compared with non-obese DM patients (62 % of AMI patients), obese DM patients had: higher incidence of dyslipidemia (31 vs. 24 %, P < 0.01); lower incidence of chronic kidney disease (26 vs. 33 %) (P < 0.01); higher left ventricular ejection fraction after AMI (53 ± 11 vs. 50 ± 12 %, P < 0.001); and lower 2-year cardiac and all-cause death occurrence (0.7 vs. 3.6 % and 1.9 vs. 5.2 %, both P < 0.01) and cumulative incidence in Kaplan–Meier analysis (P < 0.005, respectively). Likewise, both univariate and multivariate Cox hazard regression analyses adjusted for the respective confounders showed that obesity was associated with decreased risk of both cardiac [HR, 0.18 (95 % CI 0.06–0.60), P = 0.005; and 0.24 (0.07–0.78), P = 0.018, respectively] and all-cause death [0.34 (0.16–0.73), P = 0.005; and 0.44 (0.20–0.95), P = 0.038].
In a Korean population of stabilized DM patients after AMI, non-obese patients appear to have higher cardiac and all-cause mortality compared with obese patients after adjusting for confounding factors.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0305-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4608118  PMID: 26471283
Type 2 diabetes mellitus; Acute myocardial infarction; Obesity; Survival
14.  A Longitudinal Study of BDNF Promoter Methylation and Depression in Breast Cancer 
Psychiatry Investigation  2015;12(4):523-531.
Brain-derived neurotrophic factor (BDNF) is investigated in depression related to medical disorders and its secretion is influenced by epigenetic factors. We investigated the association between BDNF promoter methylation and depression following mastectomy for breast cancer.
In total, 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 (79%) were followed up 1 year later. Depression was diagnosed (major or minor depressive disorder) according to DSM-IV criteria and depression severity was estimated by Montgomery-Asberg Depression Rating Scale (MADRS). We assessed BDNF promoter methylation using leukocyte DNA. The effects of BDNF methylation on depression diagnosis and severity were investigated using multivariate logistic and linear regression models, respectively. The two-way interaction between BDNF methylation and the val66met polymorphism on depression was also evaluated using multivariate logistic regression models.
Higher BDNF methylation was independently associated with depression diagnosis and with more severe symptoms at both 1 week and 1 year after mastectomy. No significant methylation-genotype interactions were found.
A role for BDNF in depression related to breast cancer was supported. Indeed, the association between depression and BDNF methylation may be useful for identifying patients who are at high risk for depression and for suggesting directions for promising drug research.
PMCID: PMC4620310  PMID: 26508964
Breast cancer; Depression; BDNF; DNA methylation; Epigenetics
15.  The neutrophil to lymphocyte ratio can discriminate anaplastic thyroid cancer against poorly or well differentiated cancer 
We evaluated the capability of the neutrophil to lymphocyte ratio (NLR) as a diagnostic tool to discriminate between poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) from well differentiated thyroid cancer (WDTC).
The NLR of 3,870 patients with benign and malignant thyroid tumors were analyzed. There were 436 benign, 3,364 papillary, 15 medullary, 34 follicular or hurthle type, 14 PDTC, and 7 ATC type neoplasms. Patients were divided into two groups: a high NLR group and a low NLR group.
The NLR of all 3,870 patients was a normal distribution, and the median value was 1.57. Advanced stage cancer, such as T3 or T4 was high (30.4% vs. 26.5%, P = 0.027), and cancer-specific deaths were also high (1.2% vs. 0.4%, P = 0.018) in the high NLR group. The proportion of PDTC (0.6% vs. 0.1%) and ATC (0.3% vs. 0.1%) was higher in the high NLR group. The NLR can discriminate between PTC, PDTC, and ATC (P = 0.035, P = 0.002, and P = 0.025, respectively), and the cutoff value was 3.8 between PDTC versus ATC. None of the NLR of PDTC exceeded the cutoff value of 3.8.
NLR can play a relevant role as a discriminating tool and may be considered as a new diagnostic criterion in discriminating as well as in selecting therapeutic approaches to these aggressive forms of thyroid cancer.
PMCID: PMC4384286  PMID: 25844352
Neutrophils; Lymphocytes; Thyroid neoplasms; Inflammation
16.  A Phase I/II Trial to Evaluate the Technical Feasibility of Partial Breast Irradiation with Three-Dimensional Conformal Radiation Therapy in Korean Women with Stage I Breast Carcinoma: An Initial Report of the Korean Radiation Therapy Oncology Group (KROG) Study 0804 
This prospective study was designed to verify the technical feasibility of partial breast irradiation in breast cancer patients with small breasts, which are commonly encountered in Korean women.
Materials and Methods
A total of 40 Gy, administered in 10 fractions on consecutive days (one fraction per day), was prescribed to the isocenters of the fields using three-dimensional conformal radiotherapy (3-DCRT). For all patients, treatment planning and dose parameters strictly adhered to the constraints set forth in the Radiation Therapy Oncology Group (RTOG) 0319 protocol. This study was designed such that if fewer than five of the first 42 evaluable patients received unacceptable scores, the treatment would be considered reproducible.
Ten treatment plans (23.8%) were determined to have major variations. There was no major variation in planning target volume (PTV) coverage. The ipsilateral and contralateral breast dose limitations were not met in four (9.5%) and four cases (9.5%), respectively. Major variations in ipsilateral and contralateral lung dose limitations were observed in two cases (4.8%). Major variations in the heart and thyroid dose limitations were observed in one (2.4%) and one case (2.4%), respectively. In multivariate analysis, a ratio of PTV to ipsilateral breast volume (PTV/IB) > 0.16 was the only significant factor that statistically affected major variations.
We concluded that partial breast irradiation using 3-DCRT could not be reproduced in Korean breast cancer patients, particularly small-volumed breast surrogated as PTV/IB > 0.16. The dominant cause was the major variation in surrounding normal breast tissues.
PMCID: PMC4296846  PMID: 25143050
Breast neoplasms; Partial breast irradiation; Conformal radiotherapy
17.  Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer 
BMC Cancer  2014;14:959.
Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.
Tissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.
Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.
We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.
PMCID: PMC4301952  PMID: 25510449
Breast cancer; Molecular subtype; Immunohistochemistry; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase
18.  Validation of Risk Assessment Models for Predicting the Incidence of Breast Cancer in Korean Women 
Journal of Breast Cancer  2014;17(3):226-235.
The Gail model is one of the most widely used tools to assess the risk of breast cancer. However, it is known to overestimate breast cancer risk for Asian women. Here, we validate the Gail model and the Korean model using Korean data, and subsequently update and revalidate the Korean model using recent data.
We validated the modified Gail model (model 2), Asian American Gail model, and a previous Korean model using screening patient data collected between January 1999 and July 2004. The occurrence of breast cancer was confirmed by matching the resident registration number with data from the Korean Breast Cancer Registration Program. The expected-to-observed (E/O) ratio was used to validate the reliability of the program, and receiver operating characteristics curve analysis was used to evaluate the program's discriminatory power. There has been a rapid increase in the incidence of breast cancer in Korea, and we updated and revalidated the Korean model using incidence and mortality rate data from recent years.
Among 40,229 patients who were included in the validation, 161 patients were confirmed to have developed breast cancer within 5 years of screening. The E/O ratios and 95% confidence intervals (CI) were 2.46 (2.10-2.87) for the modified Gail model and 1.29 (1.11-1.51) for the Asian American Gail model. The E/O ratio and 95% CI for the Korean model was 0.50 (0.43-0.59). For the updated Korean model, the E/O ratio and 95% CI were 0.85 (0.73-1.00). In the discriminatory power, the area under curve and 95% CI of the modified Gail model, Asian American Gail model, Korean model and updated Korean model were 0.547 (0.500-0.594), 0.543 (0.495-0.590), 0.509 (0.463-0.556), and 0.558 (0.511-0.605), respectively.
The updated Korean model shows a better performance than the other three models. It is hoped that this study can provide the basis for a clinical risk assessment program and a future prospective study of breast cancer prevention.
PMCID: PMC4197352  PMID: 25320620
Breast neoplasms; Risk assessment; Validation studies
19.  Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR) 
BMC Cancer  2014;14:170.
Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer.
Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively.
This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer.
Trial registration Identifier NCT01589367
PMCID: PMC3984742  PMID: 24612502
Metformin; Letrozole; Neoadjuvant; Estrogen receptor-positive Breast cancer
20.  Atypia of undetermined significance on thyroid fine needle aspiration: surgical outcome and risk factors for malignancy 
This study was performed to analyze the surgical pathology results of the "atypia of undetermined significance" (AUS) category from thyroid fine needle aspiration (FNA) and to describe the characteristics to distinguish a malignant from a benign nodule.
A retrospective analysis was done on 116 patients who underwent thyroid surgery from December 2008 to December 2012, following a diagnosis of AUS from preoperative thyroid FNA. We investigated the age, gender, size and site of the nodules, ultrasonographic criteria, cytological features, the number of atypia results after repeated FNAs, surgical method, and final pathologic results.
Sixty-five out of 116 patients underwent total thyroidectomy and the rest had partial thyroidectomy. The final pathologic results were 41 malignancies (35.3%) and 75 benign diseases (64.7%). AUS was divided into group 1: 'cannot rule out malignancy' or group 2: 'cannot rule out follicular neoplasm'. After surgery, group 1 revealed papillary thyroid cancer in most cases and group 2 revealed follicular adenoma in most cases. Age over 40 years, ultrasonographic findings suggestive of malignancy, more than 2 results of atypia from repeated FNAs and nodules less than 2 centimeters were risk factors for malignancy on univariate analysis. Multivariate analysis showed that ultrasonographic findings suggestive of malignancy was a significant risk factor for malignancy.
For proper evaluation of the risk for malignancy in thyroid AUS patients, the ultrasonographic criteria should be considered along with other clinicopathological findings such as age, nodule size, number of atypia, cytologic features.
PMCID: PMC3994624  PMID: 24761418
Atypia of undetermined significance; Fine needle aspiration; Thyroid neoplasms
21.  Prognostic Significance of Metabolic Tumor Volume Measured by 18F-FDG PET/CT in Operable Primary Breast Cancer 
We investigated whether PET indices measured by 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) can predict prognosis in patients with operable primary breast cancer.
We reviewed 53 patients with operable primary breast cancer who underwent pretreatment FDG PET/CT. PET indices, maximum standardized uptake value (SUV) and metabolic tumor volume (MTV), were measured in the primary breast tumor (P), metastatic lymph nodes (N) and total tumor (T). The Cox proportional hazards model was used with age, tumor size, clinical lymph node status, method of surgery, presence or absence of neoadjuvant chemotherapy, histological type, histological grade, hormone receptors and HER2 status to predict disease-free survival (DFS) and overall survival (OS).
Median follow-up period was 50 months (range, 17–73 months), during which 17 patients had recurrent disease and nine of whom died. The univariate analysis showed that high SUV of N (NSUV, P = 0.011), MTV of N (NMTV, P = 0.011) and MTV of T (TMTV, P = 0.045) as well as high histological grade (P = 0.008), negative estrogen (P = 0.045) and negative progesterone (P = 0.029) receptor status were associated with shorter DFS. High NSUV (P = 0.035), NMTV (P = 0.035) and TMTV (P = 0.035) as well as high histological grade (P = 0.012) and negative estrogen receptor status (P = 0.009) were associated with shorter OS. NSUV, NMTV and TMTV were found to be significantly associated with high histological grade (P = 0.005). However, those failed to be statistically significant prognostic factors on multivariate analysis.
PET indices seem to be useful in the preoperative evaluation of prognosis in patients with operable primary breast cancer. NSUV, NMTV and TMTV might be considerable factors associated with patient outcome in operable breast cancer.
PMCID: PMC4043062  PMID: 24900075
Breast cancer; FDG PET/CT; Maximum standardized uptake value; Metabolic tumor volume; Prognosis
22.  Malignant thyroid bed mass after total thyroidectomy 
Ultrasonographic (US) criteria on malignant thyroid bed mass have been suggested, including taller than wide shape, loss of echogenic hilum, abnormal vascularity, and microcalcification. The relationship between fine-needle aspiration (FNA) cytology findings and US findings on thyroid bed mass is unknown. We have retrospectively assessed the malignant thyroid bed mass after total thyroidectomy due to papillary thyroid carcinoma (PTC).
We retrospectively evaluated 2,048 patients who underwent total thyroidectomy due to PTC. FNA was performed in 97 patients on the thyroid bed under US surveillance. The 97 suspicious thyroid bed masses were divided into two groups: metastatic thyroid bed group (n = 34) and nonmetastatic group (n = 63). The groups were evaluated according to various clinical, serologic, and US findings.
Within a median 47.0 months of follow-up, the proportion of malignant thyroid bed mass was high in large tumor size (1.37 cm vs. 1.03 cm), isthmic position (10.3% vs. 3.9%), and previous N1a (55.9% vs. 34.9%). US findings revealed that the presence of microcalcification or macrocalcification (47.1% vs. 19.0%) and thyroid bed mass height (5.4 mm vs. 3.9 mm) were the only discriminable criteria for central compartment recurrence. But, degree of echogenicity, loss of hilum, and irregularity of margin failed to discriminate malignant thyroid bed mass.
US findings on malignant thyroid bed mass were different from previously reported general criteria on lateral metastatic nodes. Additional FNA cytology should be performed on patients, even low-risk patients, who present the above findings.
PMCID: PMC3764368  PMID: 24020017
Ultrasonography; Fine-needle biopsy; Thyroidectomy; Papillary thyroid cancer
23.  Trans-Radial versus Trans-Femoral Intervention for the Treatment of Coronary Bifurcations: Results from Coronary Bifurcation Stenting Registry 
Journal of Korean Medical Science  2013;28(3):388-395.
Trans-radial (TR) approach is increasingly recognized as an alternative to the routine use of trans-femoral (TF) approach. However, there are limited data comparing the outcomes of these two approaches for the treatment of coronary bifurcation lesions. We evaluated outcomes of TR and TF percutaneous coronary interventions (PCI) in this complex lesion. Procedural outcomes and clinical events were compared in 1,668 patients who underwent PCI for non-left main bifurcation lesions, according to the vascular approach, either TR (n = 503) or TF (n = 1,165). The primary outcome was major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR) in all patients and in 424 propensity-score matched pairs of patients. There were no significant differences between TR and TF approaches for procedural success in the main vessel (99.6% vs 98.6%, P = 0.08) and side branches (62.6% vs 66.7%, P = 0.11). Over a mean follow-up of 22 months, cardiac death or MI (1.8% vs 2.2%, P = 0.45), TLR (4.0% vs 5.2%, P = 0.22), and MACE (5.2% vs 7.0%, P = 0.11) did not significantly differ between TR and TF groups, respectively. These results were consistent after propensity score-matched analysis. In conclusion, TR PCI is a feasible alternative approach to conventional TF approaches for bifurcation PCI ( number: NCT00851526).
PMCID: PMC3594602  PMID: 23486858
Bifurcation; Percutaneous Coronary Intervention; Trans-Radial Approach
24.  Recurrent Syncope Triggered by Temporal Lobe Epilepsy: Ictal Bradycardia Syndrome 
Korean Circulation Journal  2012;42(5):349-351.
Ictal asystole is potentially lethal, and known to originate from the involvement of limbic autonomic regions. Appropriate treatment must include an antiepileptic drug and the implantation of a pacemaker. We report the case of a 54-year-old male with recurrent syncope secondary to ictal asystole triggered by temporal lobe epilepsy. This was confirmed by combined Holter and video-electroencephalogram monitoring.
PMCID: PMC3369968  PMID: 22701136
Bradycardia; Syncope; Electrocardiography
25.  The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial: study protocol for a randomized controlled trial 
Trials  2012;13:29.
Second-generation drug-eluting stents (DES) have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES) is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES). In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI). A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT)) was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS) patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT)) is used more commonly than doubling the dose of clopidogrel in high-risk patients.
In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES) and antiplatelet regimen (TAT vs DDAT). The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen.
The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI.
Trial registration number NCT01267734.
PMCID: PMC3342216  PMID: 22463698
Cilostazol; cobalt chromium; coronary heart disease; everolimus-eluting stent; platinum chromium; zotarolimus-eluting stent

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