SCI 발표논문

2016년 247편

1272016

제1저자 윤도란, 구혜림 · 교신저자 김남중

, , , , , , , , , ,
The purpose and appropriateness of carbapenem use in a single university hospital, 2009-2013.
Expert Rev Clin Pharmacol. 2016;9(6):863-5.

Abstract
This is a retrospective review study to investigate changes in carbapenem consumption and to evaluate the proportion of inappropriate empirical use of carbapenem in the months of September and October of 2009, 2011, and 2013 in a single university-affiliated hospital. Total carbapenem use was classified into 3 categories: prophylactic, directed, and empirical. If an empirical prescription was continued without documentation of any eligible etiologic microorganism, we defined this as 'inappropriate' use. We also considered it 'inappropriate' when a patient's culture revealed no pathogen and the patient was initially not in severe sepsis or septic shock and did not have a history of admission to a health-care facility or of colonization with a pathogen eligible for carbapenem within 3 months. The total amount was 48.1, 51.1, and 91.0 defined daily doses/1000 patient-days in 2009, 2011, and 2013, respectively. Empirical use accounted for 78.4% of all prescriptions. The proportion of inappropriate empirical use ranged from 15.0 to 38.9% of the empirical carbapenem prescriptions.
PubMed IF 3.6 감염내과
1262016

제1저자 배은진 · 교신저자 이하정

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Lower serum uric acid level predicts mortality in dialysis patients.
Medicine (Baltimore). 2016;95(24):e3701.

Abstract
We evaluated the impact of serum uric acid (SUA) on mortality in patients with chronic dialysis. A total of 4132 adult patients on dialysis were enrolled prospectively between August 2008 and September 2014. Among them, we included 1738 patients who maintained dialysis for at least 3 months and had available SUA in the database. We categorized the time averaged-SUA (TA-SUA) into 5 groups: <5.5, 5.5-6.4, 6.5-7.4, 7.5-8.4, and ≥8.5 mg/dL. Cox regression analysis was used to calculate the hazard ratio (HR) of all-cause mortality according to SUA group. The mean TA-SUA level was slightly higher in men than in women. Patients with lower TA-SUA level tended to have lower body mass index (BMI), phosphorus, serum albumin level, higher proportion of diabetes mellitus (DM), and higher proportion of malnourishment on the subjective global assessment (SGA). During a median follow-up of 43.9 months, 206 patients died. Patients with the highest SUA had a similar risk to the middle 3 TA-SUA groups, but the lowest TA-SUA group had a significantly elevated HR for mortality. The lowest TA-SUA group was significantly associated with increased all-cause mortality (adjusted HR, 1.720; 95% confidence interval, 1.007-2.937; P = 0.047) even after adjusting for demographic, comorbid, nutritional covariables, and medication use that could affect SUA levels. This association was prominent in patients with well nourishment on the SGA, a preserved serum albumin level, a higher BMI, and concomitant DM although these parameters had no significant interaction in the TA-SUA-mortality relationship except DM. In conclusion, a lower TA-SUA level <5.5 mg/dL predicted all-cause mortality in patients with chronic dialysis.
PubMed IF 2 신장내과
1252016

제1저자 박진주, 채인호 · 교신저자 최동주

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Renal function, serum sodium level, and outcomes in hospitalized systolic heart failure patients: An analysis of the COAST study.
Medicine (Baltimore). 2016;95(25):e3898.

Abstract
Both renal function and serum sodium level are well-known prognostic markers in heart failure (HF) patients. We investigated the prognostic value of the renal impairment (RI) stratified by the serum sodium level in systolic HF patients.The Clinical Characteristics and Outcomes in Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) Study enrolled hospitalized systolic HF patients (ejection fraction<45%) in South Korea, Taiwan, and China. Twelve-month mortality was stratified according to the renal function and serum sodium level.Of 1462 enrolled patients, 716 patients (49%) had RI (GFR<60 mL/min/1.73 m), and they had higher 12-month mortality than those without RI (22.8% vs. 10.9%, P<0.001). Furthermore, 676 patients (46%) had low sodium level defined as Na<median, that was, 139 mmol/L. The mortality rate was lowest in patients with normal renal function and high sodium level (7.4%), but highest in those with RI and low sodium level (26.1%) (P<0.001). Patients with both RI and low sodium level had a 3.8-times increased hazard for 12-month mortality (HR 3.80, 95% CI 2.06-7.05), whereas the low sodium level (HR, 2.95; 95% CI, 1.51-5.75) and RI (HR 3.08; 95% CI, 1.63-5.82) had similar hazard, suggesting that they might be equivalent risk factors.In hospitalized Asian HF-patients both RI and low sodium level are independent risk factors. Patients with both RI and low serum sodium level are at the highest risk and may require meticulous medical care.
PubMed IF 2 순환기내과
1242016

제1저자 허승호 · 교신저자 김효수

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Comparison of 2-year clinical outcomes between diabetic versus nondiabetic patients with acute myocardial infarction after 1-month stabilization: Analysis of the prospective registry of DIAMOND (DIabetic acute myocardial infarctiON Disease) in Korea: an observational registry study.
Medicine (Baltimore). 2016;95(25):e3882.

Abstract
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.
PubMed IF 2 순환기내과
1232016

제1저자 한승석 · 교신저자 이정표

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Posttransplant Hyponatremia Predicts Graft Failure and Mortality in Kidney Transplantation Recipients: A Multicenter Cohort Study in Korea.
PLoS One. 2016;11(5):e0156050.

Abstract
Although hyponatremia is related to poorer outcomes in several clinical settings, its significance remains unresolved in kidney transplantation. Data on 1,786 patients who received kidney transplantations between January 2000 and December 2011 were analyzed. The patients were divided into two groups according to the corrected sodium values for serum glucose 3 months after their transplantations (<135 mmol/L vs. ≥135 mmol/L). Subsequently, the hazard ratios (HRs) for biopsy-proven acute rejection, graft failure, and all-cause mortality were calculated after adjustments for several immunological and non-immunological covariates. 4.0% of patients had hyponatremia. Patients with hyponatremia had higher risks for graft failure and all-cause mortality than did the counterpart normonatremia group; the adjusted HRs for graft failure and mortality were 3.21 (1.47-6.99) and 3.03 (1.21-7.54), respectively. These relationships remained consistent irrespective of heart function. However, hyponatremia was not associated with the risk of acute rejection. The present study addressed the association between hyponatremia and graft and patient outcomes in kidney transplant recipients. Based on the study results, our recommendation is to monitor serum sodium levels after kidney transplantations.
PubMed IF 2.8 신장내과
1222016

제1저자 안창호 · 교신저자 조영민

, , , , ,
Evaluation of Non-Laboratory and Laboratory Prediction Models for Current and Future Diabetes Mellitus: A Cross-Sectional and Retrospective Cohort Study.
PLoS One. 2016;11(5):e0156155.

Abstract
BACKGROUND Various diabetes risk scores composed of non-laboratory parameters have been developed, but only a few studies performed cross-validation of these scores and a comparison with laboratory parameters. We evaluated the performance of diabetes risk scores composed of non-laboratory parameters, including a recently published Korean risk score (KRS), and compared them with laboratory parameters.
METHODS The data of 26,675 individuals who visited the Seoul National University Hospital Healthcare System Gangnam Center for a health screening program were reviewed for cross-sectional validation. The data of 3,029 individuals with a mean of 6.2 years of follow-up were reviewed for longitudinal validation. The KRS and 16 other risk scores were evaluated and compared with a laboratory prediction model developed by logistic regression analysis.
RESULTS For the screening of undiagnosed diabetes, the KRS exhibited a sensitivity of 81%, a specificity of 58%, and an area under the receiver operating characteristic curve (AROC) of 0.754. Other scores showed AROCs that ranged from 0.697 to 0.782. For the prediction of future diabetes, the KRS exhibited a sensitivity of 74%, a specificity of 54%, and an AROC of 0.696. Other scores had AROCs ranging from 0.630 to 0.721. The laboratory prediction model composed of fasting plasma glucose and hemoglobin A1c levels showed a significantly higher AROC (0.838, P < 0.001) than the KRS. The addition of the KRS to the laboratory prediction model increased the AROC (0.849, P = 0.016) without a significant improvement in the risk classification (net reclassification index: 4.6%, P = 0.264).
CONCLUSIONS The non-laboratory risk scores, including KRS, are useful to estimate the risk of undiagnosed diabetes but are inferior to the laboratory parameters for predicting future diabetes.
PubMed IF 2.8 내분비대사내과
1212016

제1저자 이슬기 · 교신저자 김윤준

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17β-estradiol exerts anticancer effects in anoikis-resistant hepatocellular carcinoma cell lines by targeting IL-6/STAT3 signaling.
Biochem Biophys Res Commun. 2016;473(4):1247-1254.

Abstract
17β-Estradiol (E2) has been proven to exert protective effects against HCC; however, its mechanism on HCC proliferation and suppression of invasion remains to be further explored. Because HCC up-regulates serum Interleukin-6 (IL-6) levels and Signal Transducer and Activator of Transcription 3 (STAT3), molecular agents that attenuate IL-6/STAT3 signaling can potentially suppress HCC development. In this study, we examined involvement of E2 in anoikis resistance that induces invasion capacities and chemo-resistance. Huh-BAT and HepG2 cells grown under anchorage-independent condition were selected. The anoikis-resistant (AR) cells showed stronger chemo-resistance against sorafenib, doxorubicin, 5-fluorouracil and cisplatin compared to adherent HCC cells. AR HCC cells exhibited decreased expression of E-cadherin and increased expression of the N-cadherin and vimentin compared to adherent HCC cells. We then demonstrated that E2 suppressed cell proliferation in AR HCC cells. IL-6 treatment enhanced invasive characteristics, and E2 reversed it. Regarding mechanism of E2, it decreased in the phosphorylation of STAT3 that overexpressed on AR HCC cells. The inhibitory effect of E2 on cell growth was accompanied with cell cycle arrest at G2/M phase and caspase-3/9/PARP activation through c-Jun N-terminal Kinase (JNK) phosphorylation. Taken together, these findings suggested that E2 inhibited the proliferation of AR HCC cells through down-regulation of IL-6/STAT3 signaling. Thus, E2 can be a potential therapeutic drug for treatment of metastatic or chemo-resistant HCC.
PubMed IF 2.5 소화기내과
1202016

제1저자 조영윤 · 교신저자 김윤준

, , , , , , , , ,
Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis.
PLoS One. 2016;11(5):e0154986.

Abstract
BACKGROUND/AIMS Limited treatment options are available for patients with hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Transarterial radioembolization using Yttrium-90 microspheres is a new treatment modality for HCC with PVT. For this analysis, we compared responses to treatment with radioembolization and with sorafenib.
METHODS We evaluated 32 patients who were part of a multicenter retrospective cohort. All patients had PVT without extrahepatic metastasis and were treated with radioembolization in one of six tertiary referral hospitals in Korea. We retrospectively enrolled another 31 consecutive PVT patients without extrahepatic metastasis from a single center who received sorafenib treatment to serve as the control group. We used inverse probability weighting (IPW) using propensity scores to adjust for the between-group differences in baseline characteristics.
RESULTS At 3 months, the response rate and disease control rate were 32.1% (9/32) and 57.1% (16/32), respectively, in the radioembolization group and 3.2% (1/31) and 41.9% (13/31) in the sorafenib group. Median overall survival (OS) and time to progression (TTP) were not significantly different between the radioembolization group and the sorafenib group (13.8 months and 10.0 months, P = 0.22; and 6.0 months and 6.0 months, P = 0.08; respectively). No differences in OS (P = 0.97) or TTP (P = 0.34) were observed after IPW was applied to balance the population characteristics. The sorafenib group showed significantly more grade 3/4 adverse effects than the radioembolization group (P < 0.01).
CONCLUSION HCC patients with PVT who underwent radioembolization achieved comparable survival to patients who received sorafenib, even after application of IPW. The radioembolization group also experienced fewer severe adverse effects. Radioembolization can be considered a new treatment option for patients with HCC with PVT.
PubMed IF 2.8 소화기내과
1192016

제1저자 김학령, 김명아 · 교신저자 심완주

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Reproductive Factors Predicting Angiographic Obstructive Coronary Artery Disease: The KoRean wOmen'S Chest Pain rEgistry (KoROSE).
J Womens Health (Larchmt). 2016;25(5):443-8.

Abstract
BACKGROUND Whether reproductive factors are associated with coronary artery disease (CAD) has been debated. The aim of this study was to investigate etiologic associations of a wide range of reproductive factors of women with the presence of angiographic obstructive CAD.
MATERIALS AND METHODS Study data were obtained from a nationwide registry that enrolled 687 Korean women (59.9 ± 11.4 years) with chest pain undergoing invasive coronary angiography (ICA). Obstructive CAD was defined as ≥50% luminal stenosis of one or more epicardial coronary arteries in ICA. Information on reproductive history, including ages at menarche and menopause, duration of reproductive capacity, number of pregnancies, hormonal replacement therapy, and history of twin pregnancy, was obtained using a standardized questionnaire.
RESULTS A total of 178 women (25.9%) had obstructive CAD. Multivariable logistic regression analysis identified that later age at menarche (odds ratio [OR] = 1.265, 95% confidence interval [CI] = 1.064-1.504, p = 0.008, per year) and increased number of pregnancies (OR = 1.223, 95% CI = 1.026-1.457, p = 0.025, per pregnancy) were the independent predictors of obstructive CAD even after controlling for potential confounders, including age, diabetes mellitus, hypertension, dyslipidemia, renal function, high-density lipoprotein level, white blood cell count, hemoglobin, and E/e'.
CONCLUSIONS Later age at menarche and increased number of pregnancies may be reproductive risk factors for angiographic obstructive CAD, suggesting the important role of hormonal status in the development of CAD.
PubMed IF 1.8 순환기내과
1182016

제1저자 송영신, 임정아 · 교신저자 박영주, 박도준

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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;122(9):1370-9.

Abstract
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.
PubMed IF 5.6 내분비대사내과
1172016

제1저자 옥찬영 · 교신저자 김범석

, , , , , , , , ,
Pan-Cancer Immunogenomic Perspective on the Tumor Microenvironment Based on PD-L1 and CD8 T-Cell Infiltration.
Clin Cancer Res. 2016;22(9):2261-70.

Abstract
PURPOSE There is currently no reliable biomarker to predict who would benefit from anti-PD-1/PD-L1 inhibitors. We comprehensively analyzed the immunogenomic properties in The Cancer Genome Atlas (TCGA) according to the classification of tumor into four groups based on PD-L1 status and tumor-infiltrating lymphocyte recruitment (TIL), a combination that has been suggested to be a theoretically reliable biomarker of anti-PD-1/PD-L1 inhibitors.
EXPERIMENTAL DESIGN The RNA expression levels of PD-L1 and CD8A in the samples in the pan-cancer database of TCGA (N = 9,677) were analyzed. Based on their median values, the samples were classified into four tumor microenvironment immune types (TMIT). The mutational profiles, PD-L1 amplification, and viral association of the samples were compared according to the four TMITs.
RESULTS The proportions of TMIT I, defined by high PD-L1 and CD8A expression, were high in lung adenocarcinoma (67.1%) and kidney clear cell carcinoma (64.8%) among solid cancers. The number of somatic mutations and the proportion of microsatellite instable-high tumor in TMIT I were significantly higher than those in other TMITs, respectively (P < 0.001). PD-L1 amplification and oncogenic virus infection were significantly associated with TMIT I, respectively (P < 0.001). A multivariate analysis confirmed that the number of somatic mutations, PD-L1 amplification, and Epstein-Barr virus/human papillomavirus infection were independently associated with TMIT I.
CONCLUSIONS TMIT I is associated with a high mutational burden, PD-L1 amplification, and oncogenic viral infection. This integrative analysis highlights the importance of the assessment of both PD-L1 expression and TIL recruitment to predict responders to immune checkpoint inhibitors. Clin Cancer Res; 22(9); 2261-70. ©2016 AACRSee related commentary by Schalper et al., p. 2102.
PubMed IF 10.9 혈액종양내과
1162016

제1저자 이정훈, 조유리 · 교신저자 서경석, 윤정환

, , , , , , , , , , , , , , , ,
Serum Tumor Markers Provide Refined Prognostication in Selecting Liver Transplantation Candidate for Hepatocellular Carcinoma Patients Beyond the Milan Criteria.
Ann Surg. 2016;263(5):842-50.

Abstract
OBJECTIVE To develop and validate a model to predict tumor recurrence after living donor liver transplantation (LDLT) (MoRAL) for hepatocellular carcinoma (HCC) beyond the Milan criteria (MC).
BACKGROUND Some subgroups of HCC exceeding the MC experience substantial benefit from LDLT.
METHODS This multicenter study included a total of 566 consecutive patients who underwent LDLT in Korea: the beyond-MC cohort (n = 205, the derivation [n = 92] and validation [n = 113] sets) and the within-MC cohort (n = 361). The primary endpoint was time-to-recurrence.
RESULTS Using multivariate Cox proportional hazard model, we derived the MoRAL score using serum levels of protein induced by vitamin K absence-II and alpha-fetoprotein, which provided a good discriminant function on time-to-recurrence (concordance index = 0.88). Concordance index was maintained similarly on both internal and external validations (mean 0.87 and 0.84, respectively). At cut off of 314.8 (75th percentile value), a low MoRAL score (≤314.8) was associated with significantly longer recurrence-free (versus > 314.8, HR = 5.29, P < 0.001) and overall survivals (HR = 2.59, P = 0.001) in the beyond-MC cohort. The 5-year recurrence-free and overall survival rates of beyond-MC patients with a low MoRAL score were as high as 66.3% and 82.6%, respectively. The within-MC patients with a high MoRAL score showed a higher risk of recurrence than beyond-MC patients with a low MoRAL score (HR = 2.56, P = 0.035). The MoRAL score was significantly correlated with explant histology.
CONCLUSIONS This new model using protein induced by vitamin K absence-II and alpha-fetoprotein provides refined prognostication. Among beyond-MC HCC patients, those with a MoRAL score ≤314.8 and without extrahepatic metastasis might be potential candidates for LDLT.
PubMed IF 7.4 소화기내과
1152016

제1저자 이반석 · 교신저자 이상협

, , , , , , , ,
Belching during gastroscopy and its association with gastroesophageal reflux disease.
Dis Esophagus. 2016;29(4):342-9.

Abstract
Belching may result from transient lower esophageal sphincter relaxation; therefore, it has been proposed that belching may be a manifestation of gastroesophageal reflux disease (GERD). This study was conducted to investigate the frequency of belching during esophagogastroduodenoscopy (EGD) and its association with GERD. A retrospective review was performed on prospectively collected clinical and endoscopic data from 404 subjects who underwent EGD without sedation from December 2012 to May 2013 in a training hospital in Korea. All detectable belching events during endoscopy were counted. Frequency and severity of belching events were compared between the group with and without GERD using an ordinal logistic regression model. There were 145 GERD patients (26 erosive reflux disease and 119 nonerosive reflux disease [NERD]). In the multivariable analysis, GERD was significantly associated with a higher frequency of belching events (odds ratio = 6.59, P < 0.001). Central obesity, female, and younger age were also risk factors for frequent belching during EGD. Subgroup analyses were performed in subjects without erosive reflux disease (n = 378) and NERD (n = 293). NERD was also a predictive factor for frequent belching during EGD (odds ratio = 6.61, P < 0.001), and the frequency of belching was significantly correlated with GERD severity according to the Los Angeles classification (P < 0.05). Frequent belching during EGD was associated with GERD, including NERD. Future research should focus on its adjuvant role in the diagnosis of GERD/NERD and the necessity for applying differentiated endoscopy strategies for GERD patients, leading to less discomfort during EGD in patients at risk for intolerability.
PubMed IF 2.4 소화기내과
1142016

제1저자 박준빈 · 교신저자 이승표

, , , , , , , , ,
Quantification of Right Ventricular Volume and Function Using Single-Beat Three-Dimensional Echocardiography: A Validation Study with Cardiac Magnetic Resonance.
J Am Soc Echocardiogr. 2016;29(5):392-401.

Abstract
BACKGROUND Because of the unique geometry of the right ventricle, assessment of right ventricular (RV) volume and function is clinically challenging. The aim of this study was to investigate the feasibility of single-beat three-dimensional echocardiography (sb3DE) for RV volume and functional assessment in patients with dilated right ventricles.
METHODS Fifty-two patients with severe tricuspid regurgitation or atrial septal defects were enrolled. Fifty patients underwent sb3DE and cardiac magnetic resonance (CMR) within 24 hours under a euvolemic state, and the results of sb3DE were compared with those of CMR, the reference method. Fifteen normal subjects were also recruited for a broader validation of sb3DE.
RESULTS Of the 67 individuals, data from 59 study participants (44 patients and 15 normal subjects) with adequate image quality were analyzed (mean age, 46.9 ± 19.3 years; 58% women). The correlation was excellent between sb3DE and CMR for measuring RV volumes and RV ejection fraction (RVEF) (r = 0.96, r = 0.93, and r = 0.93 [P < .001 for all] for RV end-diastolic volume, RV end-systolic volume, and RVEF, respectively). Bland-Altman analysis revealed that RV volumes, but not RVEF, tended to be slightly underestimated by sb3DE (-5.8 ± 9.6%, -3.8 ± 14.1%, and -1.2 ± 9.4% for RV end-diastolic volume, RV end-systolic volume, and RVEF, respectively). Intra- and interobserver variability was acceptable for all indices (4.9% and 6.1% for RV end-diastolic volume, 4.2% and 7.9% for RV end-systolic volume, and 5.7% and 2.8% for RVEF, respectively). Among patients with RV dilation, the difference in RVEF between sb3DE and CMR was more pronounced in patients with atrial fibrillation than those in sinus rhythm (-5.9% vs 0.9%, P = .041).
CONCLUSIONS In patients with dilated right ventricles and in normal subjects, assessment of RV volume and systolic function by sb3DE is feasible in terms of accuracy and reproducibility. RV analysis using sb3DE can be performed in patients with atrial fibrillation, with the possibility of RVEF underestimation.
PubMed IF 8.3 순환기내과
1132016

제1저자 안동원, 박영수 · 교신저자 이상협

, , , , , , , ,
Clinical outcome of acute nonvariceal upper gastrointestinal bleeding after hours: the role of urgent endoscopy.
Korean J Intern Med. 2016;31(3):470-8.

Abstract
BACKGROUND/AIMS This study was performed to investigate the clinical role of urgent esophagogastroduodenoscopy (EGD) for acute nonvariceal upper gastrointestinal bleeding (ANVUGIB) performed by experienced endoscopists after hours.
METHODS A retrospective analysis was performed for consecutively collected data of patients with ANVUGIB between January 2009 and December 2010.
RESULTS A total of 158 patients visited the emergency unit for ANVUGIB after hours. Among them, 60 underwent urgent EGD (within 8 hours) and 98 underwent early EGD (8 to 24 hours) by experienced endoscopists. The frequencies of hemodynamic instability, fresh blood aspirate on the nasogastric tube, and high-risk endoscopic findings were significantly higher in the urgent EGD group. Primary hemostasis was achieved in all except two patients. There were nine cases of recurrent bleeding, and 30-day mortality occurred in three patients. There were no significant differences between the two groups in primary hemostasis, recurrent bleeding, and 30-day mortality. In a multiple linear regression analysis, urgent EGD significantly reduced the hospital stay compared with early EGD. In patients with a high clinical Rockall score (more than 3), urgent EGD tended to decrease the hospital stay, although this was not statistically significant (7.7 days vs. 12.0 days, p > 0.05).
CONCLUSIONS Urgent EGD after hours by experienced endoscopists had an excellent endoscopic success rate. However, clinical outcomes were not significantly different between the urgent and early EGD groups.
PubMed IF 2.2 소화기내과
1122016

제1저자 김형준 · 교신저자 이춘택

, , , , , , , , ,
Outcome of incidentally detected airway nodules.
Eur Respir J. 2016;47(5):1510-7.

Abstract
Low-dose chest computed tomography (LDCT) screening increased detection of airway nodules. Most nodules appear to be secretions, but pathological lesions may show similar findings. The National Comprehensive Cancer Network (NCCN) recommends repeating LDCT after 1 month and proceeding to bronchoscopy if the nodules persist. However, no reports exist about incidentally detected airway nodules. We investigated the significance of airway nodules detected by LDCT screening.We screened patients with incidental airway nodules detected by LDCT in the Seoul National University Hospital group. The characteristics of computed tomography, bronchoscopy, pathology and clinical findings were analysed.Among 53 036 individuals who underwent LDCT screening, 313 (0.6%) had airway nodules. Of these, 186 (59.4%) were followed-up with chest computed tomography and/or bronchoscopy. Seven (3.8%) cases had significant lesions, including leiomyoma (n=2), endobronchial tuberculosis (n=2), chronic inflammation (n=1), hamartoma (n=1) and benign granuloma (n=1). The remaining 179 lesions were transient, suggesting that they were secretions.The use of LDCT for lung cancer screening demonstrated the low incidence of airway lesions. Most lesions were transient secretions. True pathological lesions were rare, and no malignant lesion was found. The current recommendation of the NCCN guideline is a reasonable approach that can avoid unnecessary bronchoscopy.
PubMed IF 23.8 호흡기내과
1112016

제1저자 이민호, 박진주 · 교신저자 윤창환, 채인호

, , , , , , , , , , , , , , ,
Impact of smoking status on clinical outcomes after successful chronic total occlusion intervention: Korean national registry of CTO intervention.
Catheter Cardiovasc Interv. 2016;87(6):1050-62.

Abstract
OBJECTIVES We sought to evaluate the effect of cigarette smoking on long-term outcomes after successful percutaneous coronary intervention for chronic total occlusion (CTO) lesions.
BACKGROUND Cigarette smoking promotes the progression of atherosclerosis but enhances the antiplatelet effect of clopidogrel.
METHODS The Korea National Registry of CTO Intervention included 2,167 patients with CTO lesions from 26 centers who were successfully revascularized with drug-eluting stents from 2007 to 2009. Thrombotic events were defined as the composite of cardiac death, nonfatal myocardial infarction, and stent thrombosis.
RESULTS Current-smokers had more favorable baseline characteristics such as a younger age and lower prevalence of hypertension and diabetes mellitus. At 1 year, current-smokers had a significantly lower thrombotic event rate (1.1% vs. 2.7%, P = 0.034), but a significantly higher target vessel revascularization (TVR) rate (7.2% vs. 4.2%, P = 0.017) compared with never-smokers. After adjustment, current-smoking was independently associated with a 72% decreased risk for thrombotic events, and 73% increased risk for TVR.
CONCLUSIONS In patients with a revascularized CTO lesion, cigarette smoking is associated with fewer thrombotic events but with a higher incidence of TVR. Patients with CTO may benefit from smoking cessation to reduce TVR in conjunction with the use of new more potent antiplatelet agents whose effect is independent of cigarette smoking to improve thrombotic events. © 2015 Wiley Periodicals, Inc.
PubMed IF 1.9 순환기내과
1102016

제1저자 최윤진 · 교신저자 김나영

, , , , , , ,
Familial Clustering of Gastric Cancer: A Retrospective Study Based on the Number of First-Degree Relatives.
Medicine (Baltimore). 2016;95(20):e3606.

Abstract
This comprehensive cross-sectional study aimed to identify factors contributing to familial aggregation of gastric cancer (GC). A total of 1058 GC patients and 1268 controls were analyzed separately according to the presence or absence of a first-degree relative of GC (GC-relative). Logistic regression analysis adjusted for age, gender, residence during childhood, smoking, alcohol intake, monthly income, spicy food ingestion, Helicobacter pylori status and host cytokine polymorphisms was performed. Cytotoxin-associated gene A (cagA) positivity was a distinctive risk factor for GC in the family history (FH)-positive group (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.42-4.00), while current/ex-smoker, moderate to strong spicy food ingestion, and non-B blood types were more closely associated with GC in the FH-negative group. Among the FH-positive group, alcohol consumption showed a synergistic carcinogenic effect in the at least 2 GC-relatives group compared to the 1 GC-relative group (1.71 vs. 9.58, P for interaction = 0.026), and this was dose-dependent. In the subjects with ≥2 GC-relatives, TGFB1-509T/T was a risk factor for GC (OR 23.74; 95% CI 1.37-410.91), as were rural residency in childhood, alcohol consumption, spicy food ingestion, and cagA positivity. These results suggest that subjects with FH may be a heterogeneous group in terms of gastric cancer susceptibility. Especially, subjects with ≥2 GC-relatives should undergo risk stratification including TGFB1-509T/T and alcohol consumption.
PubMed IF 2 소화기내과
1092016

제1저자 최윤진 · 교신저자 김나영

, , , , ,
Upregulation of Vanilloid Receptor-1 in Functional Dyspepsia With or Without Helicobacter pylori Infection.
Medicine (Baltimore). 2016;95(19):e3410.

Abstract
The etiological basis of functional dyspepsia (FD) is incompletely understood. The aim of this study was to evaluate the involvement of nociceptor-related genes and Helicobacter pylori (HP) in the pathogenesis of FD. The expression of nociceptor-related genes was measured in gastric cell lines that were co-cultured with HP. FD patients (n = 117) and controls (n = 55) were enrolled from a tertiary hospital gastroenterology clinic. Expression of the genes nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the gastric mucosa were detected by reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemical staining of TRPV1 was analyzed. These measurements were repeated after 1 year. TRPV1, GDNF, and NGF expression was elevated in gastric cell lines co-cultured with HP. TRPV1 immunostaining was stronger in HP-positive than HP-negative subjects. The FD group showed higher expression levels of TRPV1, GDNF, and NGF and increased TRPV1 immunostaining compared with those of the control group (all P < 0.05). Among 61 subjects who were followed up at 1 year, controls with successful HP eradication and patients whose symptoms had improved both showed significant reductions in the expression of TRPV1 and NGF (all P < 0.05) compared with controls without HP eradication and patients whose symptoms had not improved, respectively. The expression of NGF, GDNF, and TRPV1 may be associated with the pathogenesis of FD. Since HP infection may induce the increased expression of these genes, anti-HP therapy could be beneficial for HP-positive patients with FD.
PubMed IF 2 소화기내과
1082016

제1저자 이정환 · 교신저자 임춘수

, , , , , , , , , , ,
Factors Affecting the Referral Time to Nephrologists in Patients With Chronic Kidney Disease: A Prospective Cohort Study in Korea.
Medicine (Baltimore). 2016;95(19):e3648.

Abstract
Timely referral to nephrologists is important for improving clinical outcomes and reducing costs during transition periods. We evaluated the impact of patients' demographic, clinical, and social health characteristics on referral time.A total of 1744 CKD patients who started maintaining dialysis were enrolled in a Korean prospective cohort. The early referral (ER) and late referral group (LR) were defined as patients who were referred to a nephrologist more than or less than 1 year prior to dialysis initiation, respectively.A total of 1088 patients (62.3%) were in the ER, and 656 patients (37.6%) were in the LR. Among the patients in the LR, 398 patients (60.7%) were referred within the 3 months prior to the start of dialysis (ultralate referral group [ULR]). The ER was younger at the time of referral than the LR; however, the ER was older at the start of dialysis. Patients with diabetes or hypertension as the cause of kidney disease were more common in the LR, whereas patients with glomerulonephritis, females, and nonsmokers were more common in the ER. The ER had more well-controlled blood pressure, lower phosphorus levels, and higher hemoglobin levels at the start of dialysis. Congestive heart failure (CHF) was more common in the LR. In the multivariate analysis, male sex (odds ratio [OR] 1.465, 95% confidence interval [CI] 1.034-2.076), underlying kidney disease (diabetes mellitus [OR 1.507, 95% CI 1.057-2.148] and hypertension [OR 1.995, 95% CI 1.305-3.051]), occupation (mechanician [OR 2.975, 95% CI 1.445-6.125], laborer [OR 3.209, 95% CI 1.405-7.327], and farmer [OR 5.147, 95% CI 2.217-11.953]), CHF (OR 2.152, 95% CI 1.543-3.000), and ambulatory status (assisted-walks, OR 2.072, 95% CI 1.381-3.111) were proved as the independent risk factor for late referral.Patients with hypertensive or diabetic kidney disease are referred later than those with glomerulonephritis. Male patients with physically active occupations exhibiting CHF and restricted ambulation were associated with a late referral. Considering the various factors associated with late referral, efforts to increase early referrals should be emphasized, particularly in patients with hypertension, diabetes, or congestive heart failure.
PubMed IF 2 신장내과
1072016

제1저자 이정환 · 교신저자 이정표

, , , , , , , , , , ,
Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation: A Multicenter Cohort Study in Korea.
Medicine (Baltimore). 2016;95(21):e3671.

Abstract
Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs.Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 ± 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation.Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155-4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289-6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341-3.426; P = 0.001).KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver function is within the normal range.
PubMed IF 2 신장내과
1062016

제1저자 이창훈, 김지민 · 교신저자 윤호일

, , , , , , , ,
Inhaled Corticosteroids Use Is Not Associated With an Increased Risk of Pregnancy-Induced Hypertension and Gestational Diabetes Mellitus: Two Nested Case-Control Studies.
Medicine (Baltimore). 2016;95(22):e3627.

Abstract
There have been concerns that systemic corticosteroid use is associated with pregnancy-induced hypertension (PIH) and diabetes mellitus. However, the relationship between inhaled corticosteroids (ICSs) and the risk of PIH has not been fully examined, and there was no study investigating the association between ICS use and the development of gestational diabetes mellitus (GDM). The aims of the study are to determine whether the use of ICSs during pregnancy increases the risk of PIH and GDM in women.We conducted 2 nested case-control studies utilizing the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea), in which 1,306,281 pregnant women who delivered between January 1, 2009 and December 31, 2011 were included. Among them, PIH cases and GDM cases were identified and matched controls were included. Conditional logistic regression analyses adjusted by other concomitant drugs use during and before pregnancy and confounding covariates including comorbidities were performed.Total 43,908 PIH cases and 219,534 controls, and 34,190 GDM cases and 170,934 control subjects were identified. When other concomitant drugs use during pregnancy was adjusted, ICS use was associated with an increased rate of PIH (adjusted odds ratio, 1.40 [95% CI, 1.05-1.87]). ICS medication possession ratios and cumulative doses were associated with an increased risk of PIH. However, the statistical significance was not found in other models. In both unadjusted and adjusted multivariable models, ICSs use was not associated with increase in the risk of GDM.ICSs use is not associated with an increased risk of PIH and GDM.
PubMed IF 2 호흡기내과
1052016

제1저자 박진균, 변주연 · 교신저자 이은봉, 이영미

, , , , , , , , , , , ,
HM71224, a novel Bruton's tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis.
Arthritis Res Ther. 2016;18:91.

Abstract
BACKGROUND Bruton's tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.
METHODS The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA).
RESULTS HM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.
CONCLUSIONS HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.
PubMed IF 5.4 류마티스내과
1042016

제1저자 현민경 · 교신저자 이창훈

, , , ,
Effect of inhaled drugs on anxiety and depression in patients with chronic obstructive pulmonary disease: a prospective observational study.
Int J Chron Obstruct Pulmon Dis. 2016;11:747-54.

Abstract
OBJECTIVE We investigated the effect of treatment with inhaled drugs on changes in mood, focusing on depression and anxiety during treatment in patients with newly diagnosed chronic obstructive pulmonary disease (COPD).
METHODS We prospectively selected new COPD patients from three Seoul National Hospitals. Participants underwent face-to-face interviews to evaluate clinical characteristics and drug use, and completed questionnaires using the Hospital Anxiety and Depression Scale (HADS) at the start of the project, the 4th week, and the 12th week. We compared changes in HADS scores both between inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) users and non-ICS/LABA users, as well as between long-acting muscarinic antagonist (LAMA) users and non-LAMA users. The general linear mixed model was applied for multivariate analysis.
RESULTS Ninety new COPD patients participated in the study. Of these 90 patients, 84 completed face-to-face interviews. In the univariate analysis, those who were treated by ICS/LABA or LAMA showed a significant increase in HADS-A at the 4-week evaluation (0.73±2.56, P=0.038), but the statistical significance was lost in the multivariable analysis. No significant difference was found in the change in HADS scores between ICS/LABA users and non-ICS/LABA users, or between LAMA users and non-LAMA users in multivariate general linear mixed model analyses.
CONCLUSION In this prospective observational study, we found no significant effects of inhaled treatment on mood problems among new COPD patients. Further research should be conducted to identify the association between anxiety and depression and inhaled drugs for COPD treatment.
PubMed IF 4.1 호흡기내과
1032016

제1저자 허진 · 교신저자 김효수

, , , , , , , , , , , , , , , , ,
CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages.
Cell Stem Cell. 2016;18(4):508-21.

Abstract
Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82(-/-) mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC(+) BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.
PubMed IF 23.3 순환기내과
1022016

제1저자 구보경 · 교신저자 이창훈

, , , ,
Prevalence of Gestational Diabetes Mellitus in Korea: A National Health Insurance Database Study.
PLoS One. 2016;11(4):e0153107.

Abstract
AIMS/INTRODUCTION This study aimed to estimate the prevalence of gestational diabetes mellitus (GDM) and use of anti-diabetic medications for patients with GDM in Korea, using data of the period 2007-2011 from the Health Insurance Review and Assessment (HIRA) database, which includes the claims data of 97% of the Korean population.
MATERIALS AND METHODS We used the Healthcare Common Procedure Coding System codes provided by the HIRA to identify women with delivery in the HIRA database between 2009 and 2011. GDM was defined according to ICD-10 codes, and patients with pre-existing diabetes between January 1, 2007 and pregnancy were excluded. A Poisson regression was performed to evaluate the trends in annual prevalence rates.
RESULTS The annual numbers of deliveries in 2009-2011 were 479,160 in 2009, 449,747 in 2010, and 377,374 in 2011. The prevalence of GDM during that period was 7.5% in 2009-2011: 5.7% in 2009, 7.8% in 2010, and 9.5% in 2011. The age-stratified analysis showed that the prevalence of GDM was highest in women aged 40-44 years, at 10.6% in 2009-2011, and that the annual prevalence significantly increased even in young women aged 20-29 years during that period (P < 0.05). More than 95% of the patients with GDM did not take any anti-diabetic medication. Among the anti-diabetic medications prescribed for patients with GDM, insulin was most commonly prescribed (for >98% of the patients with GDM on medication).
CONCLUSIONS The prevalence of GDM in Korean women recently reached 5.7-9.5% in recent years. This represents a public health concern that warrants proper screening and medical care for GDM in women during the childbearing years.
PubMed IF 2.8 호흡기내과
1012016

제1저자 김동완 · 교신저자 Shaw AT

, , , , , , , , , , , , , , , , , , , ,
Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial.
Lancet Oncol. 2016;17(4):452-463.

Abstract
BACKGROUND ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.
METHODS ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516.
FINDINGS Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7-15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3-non-estimable [NE]) in ALK inhibitor-naive patients and 8·3 months (6·8-9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1-NE) in ALK inhibitor-naive patients and 6·9 months (5·6-8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis.
INTERPRETATION The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases.
FUNDING Novartis Pharmaceuticals Corporation.
PubMed IF 33.7 혈액종양내과
1002016

제1저자 박성열, 남수정 · 교신저자 김범석

, , , , , , , , , , ,
VEGF and Ki-67 Overexpression in Predicting Poor Overall Survival in Adenoid Cystic Carcinoma.
Cancer Res Treat. 2016;48(2):518-26.

Abstract
PURPOSE The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC).
MATERIALS AND METHODS A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS).
RESULTS In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS.
CONCLUSION High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.
PubMed IF 4.2 혈액종양내과
992016

제1저자 옥찬영 · 교신저자 김범석

, , , , , , , , , , , , , , , ,
Identification of genomic mutations associated with clinical outcomes of induction chemotherapy in patients with head and neck squamous cell carcinoma.
J Cancer Res Clin Oncol. 2016;142(4):873-83.

Abstract
PURPOSE We performed deep sequencing of target genes in head and neck squamous cell carcinoma (HNSCC) tumors to identify somatic mutations that are associated with induction chemotherapy (IC) response.
METHODS Patients who were diagnosed with HNSCC were retrospectively identified. Patients who were treated with IC were divided into two groups: good responders and poor responders by tumor response and progression-free survival. Targeted gene sequencing for 2404 somatic mutations of 44 genes was performed on HNSCC tissues. Mutations with total coverage of <500 were excluded, and the cutoff for altered allele frequency was >10 %.
RESULTS Of the 71 patients, 45 were treated upfront with IC. Mean total coverage was 1941 per locus, and 42.2 % of tumors had TP53 mutations. Thirty-three mutations in TP53, NOTCH3, FGFR2, FGFR3, ATM, EGFR, MET, PTEN, FBXW7, SYNE1, and SUFU were frequently altered in poor responders. Among the patients who were treated with IC, those with unfavorable genomic profiles had significantly poorer overall survival than those without unfavorable genomic profiles (hazard ratio 6.45, 95 % confidence interval 2.07-20.10, P < 0.001).
CONCLUSIONS Comprehensive analysis of mutation frequencies identified unfavorable genomic profiles, and the patients without unfavorable genomic profiles can obtain clinical benefits from IC in patients with HNSCC.
PubMed IF 3.3 혈액종양내과
982016

제1저자 전미성 · 교신저자 김태유

, , , , , ,
Aberrant Epigenetic Modifications of LPHN2 Function as a Potential Cisplatin-Specific Biomarker for Human Gastrointestinal Cancer.
Cancer Res Treat. 2016;48(2):676-86.

Abstract
PURPOSE Epigenetic alterations of specific genes have recently been identified as diagnostic biomarkers for human cancers. However, there are currently no standardized epigenetic biomarkers for drug sensitivity in human gastrointestinal cancer. Therefore, the aim of this study is to identify a novel epigenetic biomarker in gastrointestinal cancer.
MATERIALS AND METHODS Using bisulfite sequencing and pyrosequencing analysis, DNA methylation patterns of gastric, colon primary tissues and their cancer cells were analyzed, and histone modifications were analyzed using chromatin immunoprecipitation assay. In addition, cancer cells were exposed to cisplatin and treated with a DNA methyltransferase inhibitor.
RESULTS We report that in human gastric and colon cancers, latrophilin 2 (LPHN2) is silenced by epigenetic modifications, including CpG island methylation and aberrant histone modifications. We also confirmed that LPHN2 was silenced by DNA hypermethylation in primary gastric and colon tumor tissues compared to their normal counterparts. Interestingly, we found that cancer cells with methylated LPHN2 showed higher sensitivity to cisplatin. Also, 5-aza- 2'-deoxycytidine combined with cisplatin decreased the cytotoxicity of cisplatin in cancer cells with methylated LPHN2. In addition, LPHN2 knockdown in cancer cells with high LPHN2 expression sensitized these cells to the anti-proliferative effects of cisplatin.
CONCLUSION In human gastrointestinal cancer, we found that LPHN2 is regulated by epigenetic modifications, and that cancer cells with lower LPHN2 expression show higher sensitivity to cisplatin. Therefore, the methylation status of LPHN2 is a potential novel epigenetic biomarker for cisplatin treatment in human gastric and colon cancers.
PubMed IF 4.2 혈액종양내과

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