SCI 발표논문

2015년 276편

2462015

제1저자 이세원 · 교신저자 김효수

, , , , , ,
AKAP6 inhibition impairs myoblast differentiation and muscle regeneration: Positive loop between AKAP6 and myogenin.
Sci Rep. 2015;5:16523.

Abstract
Skeletal muscle regeneration occurs continuously to repair muscle damage incurred during normal activity and in chronic disease or injury. Herein, we report that A-kinase anchoring protein 6 (AKAP6) is important for skeletal myoblast differentiation and muscle regeneration. Compared with unstimulated skeletal myoblasts that underwent proliferation, differentiated cells show significant stimulation of AKAP6 expression. AKAP6 knockdown with siRNA effectively halts the formation of myotubes and decreases the expression of the differentiation markers myogenin and myosin heavy chain. When shAKAP6-lentivirus is delivered to mice with cardiotoxin (CTX)-induced muscle injury, muscle regeneration is impaired compared with that of mice injected with control shMock-lentivirus. The motor functions of mice infected with shAKAP6-lentivirus (CTX+shAK6) are significantly worse than those of mice infected with shMock-lentivirus (CTX+shMock). Mechanistic analysis showed that AKAP6 promotes myogenin expression through myocyte enhancer factor 2A (MEF2A). Notably, myogenin increases AKAP6 expression as well. The results of chromatin immunoprecipitation and luciferase assays showed that myogenin binds to an E-box site on the AKAP6 promoter. Taken together, our findings demonstrate a novel interplay between AKAP6 and myogenin, and we suggest that AKAP6 is an important regulator of myoblast differentiation, myotube formation, and muscle regeneration.
PubMed IF 4.9 순환기내과
2452015

제1저자 이창훈 · 교신저자 윤호일

, , , , , , , ,
Healthcare utilisation by pregnant patients with asthma in South Korea: a cohort study using nationwide claims data.
BMJ Open. 2015;5(11):e008416.

Abstract
OBJECTIVES Few nationwide population-based studies have examined the burden of asthma during pregnancy. Here, we investigated the burden and medical treatment of asthma during pregnancy requiring healthcare utilisation in South Korea.
DESIGN Cohort study.
SETTING Nationwide insurance claims database.
PARTICIPANTS A total of 1,306,281 pregnant women who delivered in South Korea in 2009-2011.
OUTCOMES The prevalence and exacerbation rates of asthma requiring healthcare utilisation, and the prescription of antiasthmatic drugs during pregnancy.
RESULTS The prevalence of asthma requiring healthcare utilisation was 0.43% among pregnant women. Among those with asthma requiring healthcare utilisation, 6.9% were hospitalised and treated with systemic steroids and short-acting β2-agonists during pregnancy. Oral drugs were prescribed less during the third trimester than during the first trimester (all p values for trends were <0.001). A significant number of patients with asthma were likely to stop taking antiasthmatic drugs after becoming pregnant.
CONCLUSIONS The prevalence of asthma requiring healthcare utilisation during pregnancy was not very high. However, a significant number of women were likely to stop taking antiasthmatic drugs, and those who did tended to experience exacerbations.
PubMed IF 2.5 호흡기내과
2442015

제1저자 강지연 · 교신저자 김태유

, , , , , ,
Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression.
Oncogene. 2015;34(45):5677-84.

Abstract
The CCCTC-binding factor (CTCF)/cohesin complex regulates gene transcription via high-order chromatin organization of the genome. De novo methylation of CpG islands in the promoter region is an epigenetic hallmark of gene silencing in cancer. Although the CTCF/cohesin complex preferentially targets hypomethylated DNA, it remains unclear whether the CTCF/cohesin-mediated high-order chromatin structure is affected by DNA methylation during tumorigenesis. We found that DNA methylation downregulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), which is an inducible, rate-limiting enzyme for prostaglandin synthesis, by disrupting CTCF/cohesin-mediated chromatin looping. We show that the CTCF/cohesin complex is enriched near a CpG island associated with PTGS2 and that the PTGS2 locus forms chromatin loops through methylation-sensitive binding of the CTCF/cohesin complex. DNA methylation abolishes the association of the CTCF/cohesin complex with the PTGS2 CpG island. Disruption of chromatin looping by DNA methylation abrogates the enrichment of transcriptional components, such as positive elongation factor b, at the transcriptional start site of the PTGS2 locus. These alterations result in the downregulation of PTGS2. Our results provide evidence that CTCF/cohesin-mediated chromatin looping of the PTGS2 locus is dynamically influenced by the DNA methylation status.
PubMed IF 9.1 혈액종양내과
2432015

제1저자 곽민선 · 교신저자 이창훈

, , , ,
The efficacy and safety of triple inhaled treatment in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis using Bayesian methods.
Int J Chron Obstruct Pulmon Dis. 2015;10:2365-76.

Abstract
PURPOSE Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting β-agonists are frequently prescribed together, the efficacy of "triple therapy" has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy.
METHODS We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models.
RESULTS Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29-82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group.
CONCLUSION Triple therapy with TIO and ICSs/long-acting β-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed.
PubMed IF 4.1 소화기내과
2422015

제1저자 안정남, 김영훈 · 교신저자 이정표

, , , , , , , , , , , ,
The reciprocal interaction between LV remodelling and allograft outcomes in kidney transplant recipients.
Heart. 2015;101(22):1826-33.

Abstract
OBJECTIVE This study aimed to investigate the incidence and related clinical factors of LV hypertrophy (LVH) regression after kidney transplantation and its effect on graft outcome.
METHODS Among the 3373 kidney transplant recipients who were enrolled in a multicentre cohort from 1997 to 2012, a total of 767 patients who underwent echocardiography before and after transplantation were included in this study followed for a median of 7.5 years.
RESULTS LVH regression steadily increased from 7.4% at 1 year to 35.4% at 5 year over the 5-year post-transplantation period. The probability of LVH regression decreased in the patients who received a kidney transplant due to end-stage renal disease of unknown aetiology (p=0.041) or who underwent pretransplant haemodialysis (p=0.020). The probability of LVH regression also decreased as the pretransplant LV mass index (p<0.001) and post-transplant systolic blood pressure increased (p=0.005). Conversely, LVH regression was significantly associated with the highest tertile of the pretransplant haemoglobin level (p=0.029). Furthermore, in the 5th year after transplantation, persistent LVH was independently associated with allograft failure (HR 1.95; 95% CI 1.14 to 3.33; p=0.015) and the LV mass index reliably predicted graft outcome.
CONCLUSIONS LVH consistently regressed after kidney transplantation in most patients. Persistent LVH, low haemoglobin levels and elevated blood pressure were associated with an increased risk of allograft failure in kidney transplant recipients.
PubMed IF 4.4 신장내과
2412015

제1저자 박흥우 · 교신저자 Tantisira KG

, , , , , ,
Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.
J Allergy Clin Immunol. 2015;136(5):1240-6.e1-8.

Abstract
BACKGROUND Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA).
OBJECTIVE We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma.
METHODS We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts.
RESULTS We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased.
CONCLUSIONS We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.
PubMed IF 11.2 알레르기내과
2402015

제1저자 곽민선, 유수종 · 교신저자 윤정환

, , , , , , , ,
Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model.
J Cancer Res Clin Oncol. 2015;141(11):2037-45.

Abstract
PURPOSE A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model.
METHODS An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then, doxorubicin with or without flavopiridol was injected. The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism.
RESULTS Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression.
CONCLUSIONS These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.
PubMed IF 3.3 소화기내과
2392015

제1저자 권유욱 · 교신저자 김효수

, , , , , ,
E-Ras improves the efficiency of reprogramming by facilitating cell cycle progression through JNK-Sp1 pathway.
Stem Cell Res. 2015;15(3):481-494.

Abstract
We have previously shown that pluripotent stem cells can be induced from adult somatic cells which were exposed to protein extracts isolated from mouse embryonic stem cells (mESC). Interestingly, generation of induced pluripotent stem (iPS) cells depended on the background of ES cell lines; possible by extracts from C57, but not from E14. Proteomic analysis of two different mES cell lines (C57 and E14) shows that embryonic Ras (E-Ras) is expressed differently in two mES cell lines; high level of E-Ras only in C57 mESC whose extracts allows iPS cells production from somatic cells. Here, we show that E-Ras augments the efficiency in reprogramming of fibroblast by promoting cell proliferation. We found that over-expression of E-Ras in fibroblast increased cell proliferation which was caused by specific up-regulation of cyclins D and E, not A or B, leading to the accelerated G1 to S phase transition. To figure out the common transcription factor of cyclins D and E, we used TRANSFAC database and selected SP1 as a candidate which was confirmed as enhancer of cyclins D and E by luciferase promoter assay using mutants. As downstream signaling pathways, E-Ras activated only c-Jun N-terminal kinases (JNK) but not ERK or p38. Inhibition of JNK prevented E-Ras-mediated induction of pSP1, cyclins D, E, and cell proliferation. Finally, E-Ras transduction to fibroblast enhanced the efficiency of iPS cell generation by 4 factors (Oct4/Klf4/Sox2/C-myc), which was prevented by JNK inhibitor. In conclusion, E-Ras stimulates JNK, enhances binding of Sp1 on the promoter of cyclins D and E, leading to cell proliferation. E-Ras/JNK axis is a critical mechanism to generate iPS cells by transduction of 4 factors or by treatment of mESC protein extracts.
PubMed IF 0.6 순환기내과
2382015

제1저자 장은진 · 교신저자 김덕겸

, , , , , , ,
Association between inhaler use and risk of haemoptysis in patients with non-cystic fibrosis bronchiectasis.
Respirology. 2015;20(8):1213-21.

Abstract
BACKGROUND AND OBJECTIVE Inhaled medications have been widely applied to patients with airflow limiting non-cystic fibrosis (non-CF) bronchiectasis. However, the association between the use of inhalers and the development of haemoptysis has rarely been explored. The objective of this study was to assess the association between the risk of haemoptysis and the use of inhalers in patients with non-CF bronchiectasis.
METHODS A nested case-control study was performed using a national claims database from 1 January 2009 to 31 December 2011. Inhalers including inhaled corticosteroids (ICS), long-acting β2 agonists (LABA), long-acting muscarinic antagonists (LAMA), short-acting β2 agonists (SABA), short-acting muscarinic antagonists (SAMA) and their combinations were tested for the risk of clinically significant haemoptysis events.
RESULTS Among the 62 530 eligible new users of inhalers with non-CF bronchiectasis, 6180 patients with haemoptysis and 27 486 strictly matched controls were selected. In the unadjusted analyses, SAMA, LAMA, SABA and ICS/LABA significantly increased the risk of haemoptysis. After adjustment for other inhaled respiratory medications, comorbidities, health-care utilization and concomitant medications, SAMA, SABA and LAMA consistently increased the risk of haemoptysis (SAMA: odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-1.4; LAMA: OR, 1.2; 95% CI: 1.1-1.2; SABA: OR, 1.2; 95% CI: 1.1-1.2). The association between anticholinergics (SAMA and LAMA) and risk of haemoptysis showed a dose-dependent trend (P for trend, <0.001).
CONCLUSIONS The use of SABA and inhaled anticholinergics in patients with non-CF bronchiectasis increased the risk of haemoptysis. The risk-benefit ratio of inhaled bronchodilators should be considered in the haemoptysis-susceptible population.
PubMed IF 7.2 호흡기내과
2372015

제1저자 이상학 · 교신저자 유철규

, , , , , , , , , ,
Efficacy and safety of aclidinium bromide in patients with COPD: A phase 3 randomized clinical trial in a Korean population.
Respirology. 2015;20(8):1222-8.

Abstract
BACKGROUND AND OBJECTIVE Aclidinium bromide ('aclidinium') is a novel, inhaled long-acting muscarinic antagonist. Therapeutic effects of aclidinium on chronic obstructive pulmonary disease (COPD) have been demonstrated in Caucasian populations in several clinical trials. This was a randomized, double-blind, multi-centre phase-3 clinical trial to evaluate the efficacy and safety of aclidinium in a Korean population.
METHODS A total of 263 Korean patients with moderate-to-severe COPD were randomized to receive aclidinium (400 μg, bd) (Genuai) or placebo via a dry-powder inhaler. The primary end point was change in trough forced expiratory volume in one second (FEV1 ) at 12 weeks. Other lung function measurements, COPD exacerbation, health status (St George's Respiratory Questionnaire (SGRQ), dyspnoea (Transition Dyspnea Index (TDI) and safety were assessed throughout the study period.
RESULTS A significant improvement in trough FEV1 from baseline was shown with aclidinium compared with the placebo (0.126 L, P < 0.0001). Significant improvements were also demonstrated in peak FEV1 (0.190 L, P < 0.0001), SGRQ and TDI. Furthermore, aclidinium significantly reduced the prevalence of exacerbations (aclidinium, 5.4%; placebo, 15.6%, P < 0.05), and the duration of exacerbations was shorter compared with placebo (rate ratio: 0.27; P < 0.05). Aclidinium (400 μg) was well tolerated and the prevalence of adverse events was comparable with the placebo.
CONCLUSIONS Inhaled aclidinium (400 μg) was shown to be safe and efficacious in Korean patients with moderate-to-severe COPD.
CLINICAL TRIAL REGISTRATION NCT01636401 at Clinicaltrials.gov.
PubMed IF 7.2 호흡기내과
2362015

제1저자 이수진, 김태민 · 교신저자 이지연

, , , , , , , , , ,
Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06).
Oncologist. 2015;20(11):1312-9.

Abstract
BACKGROUND KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications.
METHODS We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population.
RESULTS Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%-28.0%) and a disease control rate of 57.1% (95% CI: 42.1%-72.1%). The median duration of response was 34 weeks (range: 5-55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only.
CONCLUSION Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations.
IMPLICATIONS FOR PRACTICE KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations.
PubMed IF 4.7 혈액종양내과
2352015

제1저자 황인겸 · 교신저자 김재환

, , , , , , ,
Postoperative early thromboembolism as a prognostic indicator in patients with curatively resected pancreatic cancer.
Am J Surg. 2015;210(5):871-7.

Abstract
BACKGROUND Information regarding postoperative thromboembolism in curatively resected pancreatic cancer is limited. This study aimed to assess the incidence and significance of postoperative thromboembolism.
METHODS We retrospectively reviewed the medical records of 121 curatively resected pancreatic cancer patients. Early and late thromboembolisms were defined as events that occurred within 1 year and after 1 year, respectively.
RESULTS Twenty-two patients (18%) experienced thromboembolism. Seven thromboembolic events occurred within 1 month (7, 6%), and the incidence rate decreased over time. Ten (63%) of the 16 patients with early thromboembolism experienced thromboembolism before or at the same time as recurrence; however, 5 (83%) of the 6 patients with late thromboembolism experienced recurrence before thromboembolism (P = .005). A significant difference in recurrence-free survival (P = .016) and borderline difference in overall survival (P = .050) were observed between patients with early thromboembolism and others.
CONCLUSIONS Thromboembolic events after curative surgery are prevalent in pancreatic cancer, especially within 1 month. Thromboembolic events within 1 year of surgery should be cautiously monitored.
PubMed IF 2.3 소화기내과
2342015

제1저자 임수 · 교신저자 장학철

, , , , , , , , ,
Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis.
Atherosclerosis. 2015;243(1):107-19.

Abstract
OBJECTIVE The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPARγ might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPARγ agonist, might protect against atherosclerosis.
METHODS A rat model of balloon injury to the carotid artery, and high-fat, high-cholesterol diet-fed apolipoprotein E gene knockout (ApoE(-/-)) mice were studied.
RESULTS After the balloon injury, lobeglitazone treatment (0.3 and 0.9 mg/kg) caused a significant decrease in the intima-media ratio compared with control rats (2.2 ± 0.9, 1.8 ± 0.8, vs. 3.3 ± 1.2, P < 0.01). Consistent with this, in ApoE(-/-) mice fed a high-fat diet, lobeglitazone treatment (1, 3, and 10 mg/kg) for 8 weeks reduced atherosclerotic lesion sizes in the aorta compared with the control mice in a dose-dependent manner. Treatment of vascular smooth muscle cells with lobeglitazone inhibited proliferation and migration and blocked the cell cycle G0/G1 to S phase progression dose-dependently. In response to lobeglitazone, tumor necrosis factor alpha (TNFα)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNFα-induced nuclear factor kappa-B (NF-κB) p65 translocation into the nucleus was also blocked in endothelial cells. Insulin resistance was decreased by lobeglitazone treatment. Circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were decreased while adiponectin levels were increased by lobeglitazone in the high-fat diet-fed ApoE(-/-) mice.
CONCLUSION Lobeglitazone has antiatherosclerotic properties and has potential for treating patients with diabetes and cardiovascular risk.
PubMed IF 7.1 내분비대사내과
2332015

제1저자 장동기 · 교신저자 류지곤

, , , , , , , ,
Preoperative Diagnosis of Pancreatic Cystic Lesions: The Accuracy of Endoscopic Ultrasound and Cross-Sectional Imaging.
Pancreas. 2015;44(8):1329-33.

Abstract
OBJECTIVE This study aimed to evaluate the accuracy of endoscopic ultrasound (EUS) and cross-sectional imaging including multidetector computed tomography (MDCT) or magnetic resonance imaging (MRI) as a preoperative diagnostic modality for the pancreatic cystic lesions.
METHODS Three hundred eighteen patients with surgically proven pancreatic cystic lesions were enrolled as a study cohort from 1998 to 2011. Preoperative radiological, EUS, and final histopathologic diagnosis were correlated to measure several kinds of diagnostic performance.
RESULTS A total of 318 patients underwent preoperative MDCT, with additional imaging modalities such MRI and/or EUS in 215 (67.6%) and 108 (34.0%) patients, respectively. κ Values among the different modalities were as follows: MDCT versus pathology = 0.52 (P < 0.0001), MDCT + MRI versus pathology = 0.674 (P < 0.0001), and EUS versus pathology = 0.558 (P < 0.0001). The sensitivity and specificity in terms of ability to predict neoplastic cysts were as follows: MDCT, 83.1%/70.0%; MDCT + MRI, 94.7%/58.7%; and EUS, 88.5%/52.9%. The diagnostic accuracies of MDCT and MDCT + MRI were 61.4% (62/101) and 80.5% (173/215), respectively, and that of EUS was 70.4% (76/108).
CONCLUSIONS Magnetic resonance imaging as an additional diagnostic modality to MDCT increased the accuracy, sensitivity, and specificity, as well in terms of predicting neoplastic cysts.
PubMed IF 2.2 소화기내과
2322015

제1저자 이주명 · 교신저자 구본권

, , , , , , , , , , , , , ,
Integrated physiologic assessment of ischemic heart disease in real-world practice using index of microcirculatory resistance and fractional flow reserve: insights from the International Index of Microcirculatory Resistance Registry.
Circ Cardiovasc Interv. 2015;8(11):e002857.

Abstract
BACKGROUND The index of microcirculatory resistance (IMR) is a quantitative and specific index for coronary microcirculation. However, the distribution and determinants of IMR have not been fully investigated in patients with ischemic heart disease (IHD).
METHODS AND RESULTS Consecutive patients who underwent elective measurement of both fractional flow reserve (FFR) and IMR were enrolled from 8 centers in 5 countries. Patients with acute myocardial infarction were excluded. To adjust for the influence of collateral flow, IMR values were corrected with Yong's formula (IMRcorr). High IMR was defined as greater than the 75th percentile in each of the major coronary arteries. FFR≤0.80 was defined as an ischemic value. 1096 patients with 1452 coronary arteries were analyzed (mean age 61.1, male 71.2%). Mean FFR was 0.84 and median IMRcorr was 16.6 U (Q1, Q3 12.4 U, 23.0 U). There was no correlation between IMRcorr and FFR values (r=0.01, P=0.62), and the categorical agreement of FFR and IMRcorr was low (kappa value=-0.04, P=0.10). There was no correlation between IMRcorr and angiographic % diameter stenosis (r=-0.03, P=0.25). Determinants of high IMR were previous myocardial infarction (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.24-3.74, P=0.01), right coronary artery (OR 2.09, 95% CI 1.54-2.84, P<0.01), female (OR 1.67, 95% CI 1.18-2.38, P<0.01), and obesity (OR 1.80, 95% CI 1.31-2.49, P<0.01). Determinants of FFR ≤0.80 were left anterior descending coronary artery (OR 4.31, 95% CI 2.92-6.36, P<0.01), angiographic diameter stenosis ≥50% (OR 5.16, 95% CI 3.66-7.28, P<0.01), male (OR 2.15, 95% CI 1.38-3.35, P<0.01), and age (per 10 years, OR 1.21, 95% CI 1.01-1.46, P=0.04).
CONCLUSIONS IMR showed no correlation with FFR and angiographic lesion severity, and the predictors of high IMR value were different from those for ischemic FFR value. Therefore, integration of IMR into FFR measurement may provide additional insights regarding the relative contribution of macro- and microvascular disease in patients with ischemic heart disease.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02186093.
PubMed IF 7.2 순환기내과
2312015

제1저자 이성우 · 교신저자 나기영

, , , , , ,
Risk Factors for Acute Kidney Injury and In-Hospital Mortality in Patients Receiving Extracorporeal Membrane Oxygenation.
PLoS One. 2015;10(10):e0140674.

Abstract
BACKGROUND AND OBJECTIVES Although acute kidney injury (AKI) is the most frequent complication in patients receiving extracorporeal membrane oxygenation (ECMO), few studies have been conducted on the risk factors of AKI. We performed this study to identify the risk factors of AKI associated with in-hospital mortality.
METHODS Data from 322 adult patients receiving ECMO were analyzed. AKI and its stages were defined according to Kidney Disease Improving Global Outcomes (KDIGO) classifications. Variables within 24 h before ECMO insertion were collected and analyzed for the associations with AKI and in-hospital mortality.
RESULTS Stage 3 AKI was associated with in-hospital mortality, with a hazard ratio (HR) (95% CI) of 2.690 (1.472-4.915) compared to non-AKI (p = 0.001). The simplified acute physiology score 2 (SAPS2) and serum sodium level were also associated with in-hospital mortality, with HRs of 1.02 (1.004-1.035) per 1 score increase (p = 0.01) and 1.042 (1.014-1.070) per 1 mmol/L increase (p = 0.003). The initial pump speed of ECMO was significantly related to in-hospital mortality with a HR of 1.333 (1.020-1.742) per 1,000 rpm increase (p = 0.04). The pump speed was also associated with AKI (p = 0.02) and stage 3 AKI (p = 0.03) with ORs (95% CI) of 2.018 (1.129-3.609) and 1.576 (1.058-2.348), respectively. We also found that the red cell distribution width (RDW) above 14.1% was significantly related to stage 3 AKI.
CONCLUSION The initial pump speed of ECMO was a significant risk factor of in-hospital mortality and AKI in patients receiving ECMO. The RDW was a risk factor of stage 3 AKI.
PubMed IF 2.8 신장내과
2302015

제1저자 원기범 · 교신저자 김효수

, , , , , , , , , , , , , , , , , , , , , , , , , ,
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.
Cardiovasc Diabetol. 2015;14:141.

Abstract
BACKGROUND 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).
METHODS 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/m(2)) in 1125 stabilized DM patients.
RESULTS 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].
CONCLUSIONS 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.
PubMed IF 15.6 순환기내과
2292015

제1저자 옥찬영 · 교신저자 오도연

, , , , , , , , ,
The distinct signatures of VEGF and soluble VEGFR2 increase prognostic implication in gastric cancer.
Am J Cancer Res. 2015;5(11):3376-88.

Abstract
Recently, an anti-angiogenic strategy to treat gastric cancer (GC) has been successful with the use of ramucirumab. The comprehensive network of VEGF, soluble VEGF receptor-2 (sVEGFR2) and cytokines and other angiogenic factors (CAF) in GC has not been reported. We aimed to reveal the CAF signature associated with VEGF and sVEGFR2, and to explore their prognostic implication in GC. We measured pretreatment serum levels of 52 CAFs, including VEGF and sVEGFR2, using multiplex bead immunoassays and ELISA, in 70 GC patients treated with palliative chemotherapy. Linear regression analysis for correlating CAFs with VEGF and sVEGFR2, and survival analysis were performed. Results from the current analysis showed the VEGF signature was shown to be associated with seven CAFs (IL-7, IL-12p70, IL-2Ra, IL-10, stem cell factor, FGF2b, IL-3). The sVEGFR2 signature was associated with IL-4 and PDGFb. VEGF and sVEGFR2 showed no association with each other. High VEGF was associated with worse OS (11.2 months, high-VEGF versus 16.7 months, low-VEGF; P = 0.061). However, among patients with high-sVEGFR2, OS was not different according to VEGF (12.1 months, high-VEGF versus 15.1 months, low-VEGF; P = 0.546). In patients with low-sVEGFR2, OS was significantly different according VEGF (10.9 months, high-VEGF versus 16.8 months, low-VEGF, P = 0.036). In multivariate analysis, a high VEGF/sVEGFR2 ratio was significantly correlated with worse OS (HR 1.78 [95% CI 1.08-2.94], P = 0.024). In conclusion, VEGF and sVEGFR2 had distinct CAF signatures in GC. Consideration of both VEGF and sVEGFR2 confers more accurate prognostic implication compared with VEGF alone in GC.
PubMed IF 3.1 혈액종양내과
2282015

제1저자 강지훈 · 교신저자 조영석

, , , , , , , , , ,
Intravascular Ultrasound and Angiographic Predictors of In-Stent Restenosis of Chronic Total Occlusion Lesions.
PLoS One. 2015;10(10):e0140421.

Abstract
Despite the benefits of successful percutaneous coronary interventions (PCIs) for chronic total occlusion (CTO) lesions, PCIs of CTO lesions still carry a high rate of adverse events, including in-stent restenosis (ISR). Because previous reports have not specifically investigated the intravascular ultrasound (IVUS) predictors of ISR in CTO lesions, we focused on these predictors. We included 126 patients who underwent successful PCIs, using drug-eluting stents, and post-PCI IVUS of CTO lesions. Patient and lesion characteristics were analyzed to elucidate the ISR predictors. In each lesion, an average of 1.7 ± 0.7 (mean length, 46.4 ± 20.3 mm) stents were used. At 9 months follow-up, 14 (11%) patients demonstrated ISR, and 8 (6.3%) underwent target lesion revascularization. Multivariate logistic regression analysis showed that the independent predictors of ISR were the post-PCI minimal luminal diameter (MLD) and the stent expansion ratio (SER; minimal stent cross-sectional area (CSA) over the nominal CSA of the implanted stent), measured using quantitative coronary angiography (QCA) and IVUS, respectively. A receiver operating characteristic analysis indicated that the best post-PCI MLD and SER cut-off values for predicting ISR were 2.4 mm (area under the curve [AUC], 0.762; 95% confidence interval (CI), 0.639-0.885) and 70% (AUC, 0.714; 95% CI, 0.577-0.852), respectively. Lesions with post-PCI MLD and SER values less than these threshold values were at a higher risk of ISR, with an odds ratio of 23.3 (95% CI, 2.74-198.08), compared with lesions having larger MLD and SER values. Thus, the potential predictors of ISR, after PCI of CTO lesions, are the post-PCI MLD and SER values. The ISR rate was highest in lesions with a post-PCI MLD ≤2.4 mm and an SER ≤70%.
PubMed IF 2.8 순환기내과
2272015

제1저자 이대원 · 교신저자 한세원

, , , , , , , , , , , , ,
Prognostic influence of body mass index and body weight gain during adjuvant FOLFOX chemotherapy in Korean colorectal cancer patients.
BMC Cancer. 2015;15:690.

Abstract
BACKGROUND Asian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far.
METHODS We have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/ leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery.
RESULTS Among a total of 522 patients, 35.7 % of patients were obese (BMI ≥ 25 kg/m(2)) and 29.1 % were overweight (BMI, 23-24.9 kg/m(2)) before surgery. 18.0 % of patients gained ≥ 5 kg and 26.1 % gained 2-4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (≥5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02-4.08, p = 0.043) in overweight and obese patients (BMI ≥ 23.0 kg/m(2)).
CONCLUSION In Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients.
PubMed IF 4.1 혈액종양내과
2262015

제1저자 이하연 · 교신저자 유철규

, , , , , , , , , , ,
Effect of tiotropium on lung function decline in early-stage of chronic obstructive pulmonary disease patients: propensity score-matched analysis of real-world data.
Int J Chron Obstruct Pulmon Dis. 2015;10:2185-92.

Abstract
BACKGROUND Tiotropium failed to slow the annual rate of forced expiratory volume in 1 second (FEV1) decline in chronic obstructive pulmonary disease (COPD) patients with <70% predicted FEV1. However, the rate of FEV1 decline is known to be faster at early stages, which suggests that the effects of tiotropium may be more prominent in early-stage of COPD patients. The aim of this study was to test the hypothesis that tiotropium modifies the rate of FEV1 decline in COPD patients with an FEV1≥70%.
METHODS We retrospectively reviewed the records of COPD patients diagnosed between January 1, 2004, and July 31, 2012, at Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul Metropolitan Government-Seoul National University Boramae Medical Center. The inclusion criteria were as follows: age ≥40 years, postbron-chodilator (BD) FEV1≥70% of predicted and FEV1/FVC (forced vital capacity) <0.70, and spirometry more than two times at certain times of the year. Conversely, the exclusion criteria were as follows: asthma, lung cancer, pulmonary tuberculosis, pulmonary resection, or long-term use of a short-acting muscarinic antagonist. The annual lung function decline in patients using tiotropium was compared with that in patients not using the drug.
RESULTS Of the 587 patients enrolled in the study, 257 took tiotropium. Following propensity score matching, 404 patients were included in the analysis. The mean annual rate of post-BD FEV1 decline was 23.9 (tiotropium) and 22.5 (control) mL/yr (P=0.86); corresponding pre-BD values were 30.4 and 21.9 mL/yr (P=0.31), respectively. Mean annual rate of post-BD FVC decline was 55.1 (tiotropium) and 43.5 (control) mL/yr (P=0.33); corresponding pre-BD values were 37.1 and 33.3 mL/yr (P=0.13).
CONCLUSION Therefore, tiotropium does not reduce the rate of lung function decline in COPD patients with FEV1≥70%.
PubMed IF 4.1 호흡기내과
2252015

제1저자 최연악 · 교신저자 오도연

, , , , , , ,
Skeletal Muscle Depletion Predicts the Prognosis of Patients with Advanced Pancreatic Cancer Undergoing Palliative Chemotherapy, Independent of Body Mass Index.
PLoS One. 2015;10(10):e0139749.

Abstract
INTRODUCTION Body composition has emerged as a prognostic factor in cancer patients. We investigated whether sarcopenia at diagnosis and loss of skeletal muscle during palliative chemotherapy were associated with survival in patients with pancreatic cancer.
METHODS We retrospectively reviewed the clinical outcomes of pancreatic cancer patients receiving palliative chemotherapy between 2003 and 2010. The cross-sectional area of skeletal muscle at L3 by computed tomography was analyzed with Rapidia 3D software. We defined sarcopenia as a skeletal muscle index (SMI)< 42.2 cm2/m2 (male) and < 33.9 cm2/m2 (female) using ROC curve.
RESULTS Among 484 patients, 103 (21.3%) patients were sarcopenic at diagnosis. Decrease in SMI during chemotherapy was observed in 156 (60.9%) male and 65 (40.6%) female patients. Decrease in body mass index (BMI) was observed in 149 patients (37.3%), with no gender difference. By multivariate analysis, sarcopenia (P< 0.001), decreasedBMI and SMI during chemotherapy (P = 0.002, P = 0.004, respectively) were poor prognostic factors for overall survival (OS). While the OS of male patients was affected with sarcopenia (P< 0.001) and decreased SMI (P = 0.001), the OS of female patients was influenced with overweight at diagnosis (P = 0.006), decreased BMI (P = 0.032) and decreased SMI (P = 0.014). Particularly, while the change of BMI during chemotherapy did not have impact on OS within the patients with maintained SMI (P = 0.750), decrease in SMI was associated with poor OS within the patients with maintained BMI (HR 1.502; P = 0.002).
CONCLUSIONS Sarcopenia at diagnosis and depletion of skeletal muscle, independent of BMI change, during chemotherapy were poor prognostic factors in advanced pancreatic cancer.
PubMed IF 2.8 혈액종양내과
2242015

제1저자 오도연 · 교신저자 방영주

, , , , , , , ,
Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer.
Cancer Res Treat. 2015;47(4):687-96.

Abstract
PURPOSE This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.
MATERIALS AND METHODS Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m(2) (day 1) and capecitabine 1,000 mg/m(2) twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.
RESULTS Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months.
CONCLUSION In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.
PubMed IF 4.2 혈액종양내과
2232015

제1저자 오도연 · 교신저자 방영주

, , , , , , , , ,
Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors.
Cancer Res Treat. 2015;47(4):607-15.

Abstract
PURPOSE OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors.
MATERIALS AND METHODS Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively.
RESULTS Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression.
CONCLUSION This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.
PubMed IF 4.2 혈액종양내과
2222015

제1저자 최연악 · 교신저자 허대석

, , , , ,
Cancer Treatment near the End-of-Life Becomes More Aggressive: Changes in Trend during 10 Years at a Single Institute.
Cancer Res Treat. 2015;47(4):555-63.

Abstract
PURPOSE The purpose of this study was to investigate and compare cancer treatment near the end-of-life (EOL) over a 10-year period.
MATERIALS AND METHODS Patients with advanced solid cancer at Seoul National University Hospital who received palliative chemotherapy and had died were enrolled. We categorized the consecutive patients according to two time periods: 2002 (n=57) and 2012 (n=206). Aggressiveness of cancer treatment near the EOL was evaluated.
RESULTS The median patient age was 62, and 65.4% of patients (n=172) were male. Time from the last chemotherapy to death (TCD) was found to have been significantly shortened, from 66.0 days to 34.0 days during 10 years (p < 0.001); 17% of patients received molecular targeted agents as the last chemotherapy regimen in 2012. The proportion of patients who received intensive care unit care within the last month increased from 1.8% in 2002 to 19.9% in 2012 (p < 0.001), and emergency room visits within the last month also increased from 22.8% to 74.8% (p < 0.001). Although hospice referral increased from 9.1% to 37.4% (p < 0.001), timing of referral was delayed from median 53 days to 8 days before death (p=0.004). Use of targeted agents as the last chemotherapy for over-two-regimen users was associated with shortened TCD (hazard ratio, 2.564; p=0.002).
CONCLUSION Cancer treatment near the EOL became more aggressive over 10 years.
PubMed IF 4.2 혈액종양내과
2212015

제1저자 최의근 · 교신저자 최의근

, , , , , , , , , , , , , ,
Better outcome of ablation for sustained outflow-tract ventricular tachycardia when tachycardia is inducible.
Europace. 2015;17(10):1571-9.

Abstract
AIMS In patients presenting with spontaneous sustained ventricular tachycardia (VT) from the outflow-tract region without overt structural heart disease ablation may target premature ventricular contractions (PVCs) when VT is not inducible. We aimed to determine whether inducibility of VT affects ablation outcome.
METHODS AND RESULTS Data from 54 patients (31 men; age, 52 ± 13 years) without overt structural heart disease who underwent catheter ablation for symptomatic sustained VT originating from the right- or left-ventricular outflow region, including the great vessels. A single morphology of sustained VT was inducible in 18 (33%, SM group) patients, and 11 (20%) had multiple VT morphologies (MM group). VT was not inducible in 25 (46%) patients (VTni group). After ablation, VT was inducible in none of the SM group and in two (17%) patients in the MM group. In the VTni group, ablation targeted PVCs and 12 (48%) patients had some remaining PVCs after ablation. During follow-up (21 ± 19 months), VT recurred in 46% of VTni group, 40% of MM inducible group, and 6% of the SM inducible group (P = 0.004). Analysis of PVC morphology in the VTi group further supported the limitations of targeting PVCs in this population.
CONCLUSION Absence of inducible VT and multiple VT morphologies are not uncommon in patients with documented sustained outflow-tract VT without overt structural heart disease. Inducible VT is associated with better outcomes, suggesting that attempts to induce VT to guide ablation are important in this population.
PubMed IF 10.2 순환기내과
2202015

제1저자 황인겸, 김혜령 · 교신저자 황진혁

, , , , , , ,
Presence of pancreatic intraepithelial neoplasia-3 in a background of chronic pancreatitis in pancreatic cancer patients.
Cancer Sci. 2015;106(10):1408-13.

Abstract
The clinical significance of pancreatic intraepithelial neoplasia (PanIN) lesions in non-neoplastic pancreata of pancreatic ductal adenocarcinoma (PDAC) patients remains controversial. As chronic inflammation has been recently demonstrated to promote dissemination of in situ precancerous lesions, we investigated the prognostic significance of PanINs associated with chronic pancreatitis (CP) in PDAC patients. This retrospective study analyzed 125 curatively resected PDAC specimens for the presence of PanIN and CP. Univariate and multivariate analyses were performed to identify significant predictive factors for poor disease-free survival (DFS) and overall survival (OS). Immunohistochemical staining for E-cadherin and S100A4, markers of epithelial-mesenchymal transition, was performed on resected specimens containing PanIN-3 lesions. CP was observed in 27.2% (34/125) and PanIN-3 in 25.6% (32/125) of specimens. In the presence of CP, PanIN-3 was significantly associated with decreased survival (DFS: 4.3 vs 15.5 months, P = 0.021; OS: 16.3 vs 30.9 months, P = 0.004). PanIN-3 was not a prognostic factor in the absence of CP. The presence of both PanIN-3 and CP was associated with a reduced survival compared to the other cases, in both univariate (DFS: P = 0.039; OS: P = 0.023) and multivariate (DFS: P = 0.020; OS: P = 0.076) analyses. Furthermore, E-cadherin loss and S100A4 expression were more frequently observed in PanIN-3 lesions of CP specimens than in those of non-CP specimens, although not statistically significant. PanIN-3 in association with CP is a significant prognostic factor for decreased survival in PDAC patients, suggesting that chronic inflammation may accelerate the progression of preinvasive high-grade PanIN.
PubMed IF 4.9 소화기내과
2192015

제1저자 이혁, 민병훈 · 교신저자 이상협

, , , , , ,
Covered metallic stents with an anti-migration design vs. uncovered stents for the palliation of malignant gastric outlet obstruction: a multicenter, randomized trial.
Am J Gastroenterol. 2015;110(10):1440-9.

Abstract
OBJECTIVES Previous studies reported comparable stent patency between covered self-expandable metallic stents (SEMS) and uncovered SEMS (UCS) for palliation of malignant gastric outlet obstruction (GOO). The aim of this study was to evaluate the efficacy and safety of the newly developed WAVE-covered SEMS (WCS), which has an anti-migration design, compared with UCS in gastric cancer patients with symptomatic GOO.
METHODS A total of 102 inoperable gastric cancer patients with symptomatic GOO were prospectively enrolled from five referral centers and randomized to undergo UCS or WCS placement. Stent patency and recurrence of obstructive symptoms were assessed at 8 weeks and 16 weeks after stent placement.
RESULTS At the 8-week follow-up, both stent patency rates (72.5% vs. 62.7%) and re-intervention rates (19.6% vs. 19.6%) were comparable between the WCS and the UCS groups. Both stent stenosis (2.4% vs. 8.1%) and migration rates (9.5% vs. 5.4%) were comparable between WCS and UCS groups. At the 16-week follow-up, however, the WCS group had a significantly higher stent patency rate than the UCS group (68.6% vs. 41.2%). Re-intervention rates in the WCS and UCS groups were 23.5% and 39.2%, respectively. Compared with the UCS group, the WCS group had a significantly lower stent restenosis rate (7.1% vs. 37.8%) and a comparable migration rate (9.5% vs. 5.4%). Overall stent patency was significantly longer in the WCS group than in the UCS group. No stent-associated significant adverse events occurred in either the WCS or UCS groups. In the multivariate analysis, WCS placement and chemotherapy were identified as independent predictors of 16-week stent patency.
CONCLUSIONS WCS group showed comparable migration rate and significantly more durable long-term stent patency compared with UCS group for the palliation of GOO in patients with inoperable gastric cancer.
PubMed IF 7.6 소화기내과
2182015

제1저자 김지연 · 교신저자 김상균

, , , , ,
Clinical outcomes of esophageal stents in patients with malignant esophageal obstruction according to palliative additional treatment.
J Dig Dis. 2015;16(10):575-84.

Abstract
OBJECTIVE To evaluate the efficacy and feasibility of esophageal self-expanding metal stents (SEMS) insertion for malignant esophageal obstruction (MEO) in patients with or without additional palliative treatment.
METHODS We retrospectively reviewed the medical records of the patients with SEMS for MEO. Baseline characteristics, changes in Mellow-Pinkas dysphagia score, and adverse events were collected and compared according to the presence and absence of additional palliative treatment.
RESULTS Altogether 192 patients underwent 236 SEMS insertion procedures. Esophageal, gastric cardiac and lung cancers were seen in 46.4%, 33.3% and 15.1% of the patients, respectively. Their Mellow-Pinkas score significantly decreased within one week and one month after the SEMS insertion (1.66 ± 0.79 and 1.71 ± 0.87 vs 3.09 ± 0.79, respectively, P = 0.000). Complications occurred in 54 (22.9%) of 236 SEMS insertion; there were 28 (11.9%) stent obstruction, 5 (2.1%) perforation (2.1%), 10 (4.2%) stent migration, 5 (2.1%) tracheoesophageal fistula, but no procedure-related death. Most complications were managed by inserting additional SEMS. The risk of stent obstruction was significantly higher in uncovered stents than in covered SEMS (OR 3.56, 95% CI 1.39-9.12, P = 0.006). Mean duration to the development of complications was 74.8 ± 111.1 days. Overall survival (169.0 ± 127.8 days vs 96.4 ± 90.6 days, P = 0.000) and stent patency (143.3 ± 123.9 days vs 67.6 ± 71.3 days, P = 0.000) were significantly favorable in patients with SEMS and additional palliative treatments compared with those with SEMS alone.
CONCLUSION SEMS insertion is effective and safe for treating MEO, and additional palliative treatment might lengthen stent patency by prolonging the patient's survival.
PubMed IF 2.7 소화기내과
2172015

제1저자 정재우 · 교신저자 강혜련

, , , , , , , , , ,
An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing.
Genet Med. 2015;17(10):807-14.

Abstract
PURPOSE This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinol-induced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients.
METHODS HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study.
RESULTS Among a total of 401 study subjects, no SCARs were noted in HLA-B*58:01-positive patients with application of the tolerance induction protocol (n = 30) or alternative medications (n = 16), nor were any SCARs observed in HLA-B*58:01-negative patients who started allopurinol at the usual dose (n = 355). Compared with the previous retrospective cohort study, a significant reduction in SCARs was observed in HLA-B*58:01-positive patients (0 vs. 18%; P = 0.002).
CONCLUSION This study shows the usefulness of HLA-B*58:01 screening in identifying patients at high risk for the development of allopurinol-induced SCARs and suggests that application of a tolerance induction protocol or alternative medications could be an effective strategy to prevent allopurinol-induced SCARs in HLA-B*58:01-positive patients.
PubMed IF 6.2 알레르기내과

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