SCI 발표논문

2019년 297편

2372019

제1저자 안정남, 현진성, 이정표, 황금숙 · 교신저자 이정표, 황금숙

, , , , , , , , , , , , , ,
Urinary myo-inositol is associated with the clinical outcome in focal segmental glomerulosclerosis.
Sci Rep. 2019;9(1):14707.

Abstract
Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) have similar initial histological findings; however, their prognoses are distinct. Therefore, it is of great importance to discriminate FSGS from MCD in the early phase of disease and predict clinical prognosis. A discovery set of 184 urine samples (61 healthy control, 80 MCD, and 43 FSGS) and a validation set of 61 urine samples (12 healthy control, 26 MCD, and 23 FSGS) were collected at the time of kidney biopsy. Metabolic profiles were examined using nuclear magnetic resonance spectroscopy. Of 70 urinary metabolites, myo-inositol was significantly higher in FSGS patients than in control patients (discovery set, 2.34-fold, P < 0.001; validation set, 2.35-fold, P = 0.008) and MCD patients (discovery set, 2.48-fold, P = 0.002; validation set, 1.69-fold, P = 0.042). Myo-inositol showed an inverse relationship with the initial estimated glomerular filtration rate (eGFR) and was associated with the plasma level of soluble urokinase-type plasminogen activator receptor in FSGS patients. Myo-inositol treatment ameliorated the decreased expression of ZO-1 and synaptopodin in an in vitro FSGS model, and as myo-inositol increased, myo-inositol oxygenase tissue expression decreased proportionally to eGFR. Furthermore, urinary myo-inositol exhibited an increase in the power to discriminate FSGS patients, and its addition could better predict the response to initial treatment. In conclusion, urinary myo-inositol may be an important indicator in the diagnosis and treatment of FSGS patients.
PubMed IF 4.9 신장내과
2362019

제1저자 이희선 · 교신저자 김형관

, , , , , , , , , ,
Risk of end-stage renal disease in patients with hypertrophic cardiomyopathy: A nationwide population-based cohort study.
Sci Rep. 2019;9(1):14565.

Abstract
Although hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, has mortality rate as low as general population, previous studies have focused on identifying high-risk of sudden cardiac death. Thus, long-term systemic impact of HCM is still unclear. We sought to investigate the association between HCM and end-stage renal disease (ESRD). This was a nationwide population-based cohort study using the National Health Insurance Service database. We investigated incident ESRD during follow-up in 10,300 adult patients with HCM (age 62.1 years, male 67.3%) and 51,500 age-, sex-matched controls. During follow-up (median 2.8 years), ESRD developed in 197 subjects; 111 (1.08%) in the HCM, and 86 (0.17%) in the non-HCM (incidence rate 4.14 vs. 0.60 per 1,000 person-years, p < 0.001). In the HCM, the incidence rate for ESRD gradually increased with age, but an initial peak and subsequent plateau in age-specific risk were observed. HCM was a significant predictor for ESRD (unadjusted HR 6.90, 95% CI 5.21-9.15, p < 0.001), as comparable to hypertension and diabetes mellitus. Furthermore, after adjusting for all variables showing the association in univariate analysis, HCM itself remained a robust predictor of ESRD development (adjusted HR 3.93, 95% CI 2.82-5.46, p < 0.001). The consistent associations between HCM and ESRD were shown in almost all subgroups other than smokers and subjects with a history of stroke. Conclusively, HCM increased the risk of ESRD, regardless of known prognosticators. It provides new insight into worsening renal function in HCM, and active surveillance for renal function should be considered.
PubMed IF 4.9 순환기내과
2352019

제1저자 김태현 · 교신저자 김원, 김상건

, , , , , , , , , , , ,
Overproduction of inter-α-trypsin inhibitor heavy chain 1 after loss of Gα13 in liver exacerbates systemic insulin resistance in mice.
Sci Transl Med. 2019;11(513):11/513/eaan4735.

Abstract
The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα₁₃) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα₁₃ caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα₁₃ and its reversal by ITIH1 neutralization.
PubMed IF 15.6 소화기내과
2342019

제1저자 황영재, 박선미 · 교신저자 김나영

, , , , ,
Accuracy of an administrative database for pancreatic cancer by international classification of disease 10th codes: A retrospective large-cohort study.
World J Gastroenterol. 2019;25(37):5619-5629.

Abstract
BACKGROUND Korean National Health Insurance (NHI) claims database provides large-cohort. However, studies regarding accuracy of administrative database for pancreatic cancer (PC) have not been reported. We aimed to identify accuracy of NHI database regarding PC classified by international classification of disease (ICD)-10 codes.
AIM To identify the accuracy and usefulness of administrative database in PC and the accurate ICD codes for PC with location.
METHODS Study and control groups were collected from 2003 to 2016 at Seoul National University Bundang Hospital. Cases of PC were identified in NHI database by international classification of diseases, 10th revision edition (ICD-10 codes) supported with V codes. V code is issued by medical doctors for covering 95% of medical cost by Korean government. According to pathologic reports, definite or possible diagnoses were defined using medical records, images, and pathology.
RESULTS A total of 1846 cases with PC and controls were collected. Among PC, only 410 (22.2%) cases were identified as specific cancer sites including head in 234 (12.7%) cases, tail in 104 (5.6%) cases and body in 72 (3.9%) cases. Among PC, 910 (49.3%) cases were diagnosed by definite criteria. Most of these were adenocarcinoma (98.0%). The rates of definite diagnosis of PC were highest in head (70.1%) followed by body (47.2%) and tail (43.3%). False-positive cases were pancreatic cystic neoplasm and metastasis to the pancreas. In terms of the overall diagnosis of PC, sensitivity, specificity, positive predictive value, and negative predictive value were 99.95%, 98.72%, 98.70%, and 99.95%, respectively. Diagnostic accuracy was similar both in terms of diagnostic criteria and tumor locations.
CONCLUSION Korean NHI claims database collected according to ICD-10 code with V code for PC showed good accuracy.
PubMed IF 7.7 소화기내과
2332019

제1저자 문인기, 이소령 · 교신저자 최의근

, , , , , , , ,
Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation and Valvular Heart Disease.
J Clin Med. 2019;8(10):jcm8101624.

Abstract
BACKGROUND There are limited data for non-vitamin K antagonist oral anticoagulants (NOACs) impact on outcomes for patients with atrial fibrillation (AF) and valvular heart diseases (VHDs).
METHODS We identified patients with AF and associated Evaluated Heartvalves, Rheumatic or Artificial (EHRA) type 2 VHDs, and who had been naïve from the oral anticoagulants in the Korean National Health Insurance Service database between 2014 and 2016 (warfarin: n = 2671; NOAC: n = 3058). For analyzing the effect of NOAC on primary prevention, we excluded those with a previous history of ischemic stroke, intracranial hemorrhage (ICH), and gastrointestinal (GI) bleeding events. To balance covariates, we used the propensity score weighting method. Ischemic stroke, ICH, GI bleeding, major bleeding, all-cause death, and their composite outcome and fatal clinical events were evaluated.
RESULTS During a follow-up with a mean duration of 1.4 years, NOACs were associated with lower risks of ischemic stroke (hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.53-0.96), GI bleeding (HR: 0.50, 95% CI: 0.35-0.72), fatal ICH (HR: 0.28, 95% CI: 0.07-0.83), and major bleeding (HR: 0.61, 95% CI: 0.45-0.80) compared with warfarin. Overall, NOACs were associated with a lower risk of the composite outcome (HR: 0.68, 95% CI: 0.58-0.80).
CONCLUSIONS In this nationwide Asian AF population with EHRA type 2 VHDs, NOAC use was associated with lower risks of ischemic stroke, major bleeding, all-cause death, and the composite outcome compared to warfarin use.
PubMed IF 3.3 순환기내과
2322019

제1저자 김유정 · 교신저자 김범석

, , , , , , , , , , ,
A phase II study of pembrolizumab and paclitaxel in patients with relapsed or refractory small-cell lung cancer.
Lung Cancer. 2019;136:122-128.

Abstract
OBJECTIVE Patients with etoposide/platinum-refractory extensive disease (ED) small-cell lung cancer (SCLC) have a dismal prognosis. We aimed to evaluate the efficacy and safety of pembrolizumab and paclitaxel combination therapy in these patients.
METHODS In this multi-center, phase II study, ED-SCLC patients who showed progression after etoposide/platinum chemotherapy received paclitaxel 175 mg/m² every 3 weeks for up to six cycles. Pembrolizumab 200 mg was added from the second cycle and continued until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses including programmed death-ligand 1 (PD-L1) expression, next-generation sequencing, and flow cytometric analysis of peripheral blood cells.
RESULTS Of the 26 patients enrolled, the confirmed ORR was 23.1% (95%CI: 6.9%-39.3%); complete response: 3.9%, confirmed partial response [PR]: 19.2%, stable disease: 57.7%, progressive disease: 7.7%, and not evaluable: 11.5%. Including 4 cases of unconfirmed PRs, 38.5% of patients were responding and the disease control rate was 80.7%. The median PFS and OS were 5.0 months (95% CI: 2.7-6.7) and 9.1 months (95% CI: 6.5-15.0), respectively. The grade 3 or 4 adverse events observed included febrile neutropenia (7.7%), neutropenia (7.7%), asthenia (7.7%), hyponatremia (7.7%), and type I diabetes (7.7%). Targeted gene sequencing identified no specific genetic alterations correlated with the treatment, except for theMET copy number gain (PFS 10.5 versus 3.4 months, p = 0.019).
CONCLUSIONS Pembrolizumab and paclitaxel combination therapy showed a moderate activity with acceptable toxicity in patients with refractory ED-SCLC.
PubMed IF 5.3 혈액종양내과
2312019

제1저자 김희진 · 교신저자 김나영, 이혜승

, , ,
The clinical meaning of the "indefinite for atrophy" lesions within gastric mucosa biopsy specimens in a region with a high prevalence of gastric cancer.
Helicobacter. 2019;24(5):e12605.

Abstract
BACKGROUND The diagnosis of gastric atrophy is important in the regions where the prevalence of Helicobacter pylori (H. pylori) is high. The assessment of gastric atrophy is impossible in subjects with severe gastric inflammation or inadequate biopsy samples, leading these cases to be categorized as indefinite for atrophy. The aim of this study was to evaluate clinical characteristics of cases reported as indefinite for atrophy.
MATERIALS AND METHODS We reviewed 3192 gastric biopsies obtained at a single medical center between 2003 and 2017. Cases categorized as indefinite atrophy (n = 1,292) were compared with three groups, the absent atrophy group (n = 755), Operative Link on Gastric Atrophy (OLGA) I-II group (n = 925), and OLGA III-IV group (n = 220), by considering age, sex, smoking, alcohol drinking, salty and spicy food diet, ABO blood type, family history of gastric cancer (GC), and H. pylori infection that are known atrophic gastritis-associated risk factors.
RESULTS Subjects aged ≥65 years (34.9% vs 26.4%, P < 0.001), male (58.9% vs 49.1%, P < 0.001), and H. pylori infected subjects (82.5% vs 63.3%, P < 0.001) were significantly more likely to be categorized into the indefinite atrophy group than absent atrophy group. Subjects with family history of GC (21.9% vs 25.7%, P = 0.031) and positive H. pylori infection (82.5% vs 86.2%, P = 0.019) were significantly less likely to be in the indefinite atrophy group than low-risk OLGA group. Subjects aged ≥65 years (34.9% vs 52.3%, P < 0.001) and current/past smoker (50.9% vs 70.0%, P < 0.001) were significantly more likely to be in the high-risk OLGA group than indefinite atrophy group.
CONCLUSIONS The pathological report of indefinite for atrophy suggests a higher plausibility of gastric atrophy than nonassessment due to a simple technical error.
PubMed IF 4.6 소화기내과
2302019

제1저자 박세훈, 고현정 · 교신저자 이하정, 문경철

, , , , , , , , , , , , ,
Clinical importance of the updated Oxford classification in allograft IgA nephropathy.
Am J Transplant. 2019;19(10):2855-2864.

Abstract
With the recent update to the Oxford classification for allograft IgA nephropathy (IgAN), additional investigations on the clinical significance of the updated components are warranted. We performed a retrospective cohort study at two tertiary hospitals. Kidney transplant recipients diagnosed with allograft IgAN were included in the study after additional review by specialized pathologists. We applied the updated Oxford classification and determined the MEST-C scores of the patients. The main study outcome was death-censored graft failure within 10 years after the establishment of allograft IgAN diagnosis and was assessed using the Cox regression analysis. Three hundred thirty-three allograft IgAN patients were reviewed: 100 patients with confirmed native IgAN and 233 patients with other, clinical, or unknown primary causes for end-stage renal disease (ESRD). The updated Oxford classification for allograft IgAN demonstrated prognostic value for graft failure, and patients with multiple MEST-C components had worse outcomes. M, E, S, and C were significantly associated with the prognosis of recurred IgAN and T was the only independent prognostic parameter for allograft IgAN without confirmed native IgAN. Therefore, we suggest reporting MEST-C scores in allograft biopsies and careful interpretation of the results according to the primary cause of ESRD.
PubMed IF 8.1 신장내과
2292019

제1저자 김경진 · 교신저자 김학령

, , , , , , , ,
Correlations between invasively measured aortic pressures and left ventricular end-diastolic pressure in patients undergoing coronary angiography.
Blood Press Monit. 2019;24(5):241-247.

Abstract
OBJECTIVE Data on ventricular-arterial coupling using invasive hemodynamic studies are limited. This study was performed to clarify the interaction between aortic pressures and left ventricular end-diastolic pressure (LVEDP) using invasive catheterization.
PATIENTS AND METHODS A total of 104 consecutive stable patients (mean age, 65.8 ± 10.0 years; 56% men) undergoing invasive coronary angiography (ICA) were prospectively evaluated. LVEDP and central aortic pressures [systolic blood pressure (aSBP) and diastolic blood pressure (aDBP)] were sequentially measured using a pigtail catheter before ICA. Aortic pulse pressure (aPP) was defined by the difference between aSBP and aDBP.
RESULTS A total of 82 patients (79%) had obstructive coronary artery disease (≥50% stenosis). The mean LVEDP value was 18.7 ± 6.4 mmHg. Univariable analyses showed that aSBP (r = 0.309, P = 0.001) and aPP (r = 0.286, P = 0.003) significantly correlated with LVEDP, whereas aDBP was not correlated with LVEDP (P > 0.05). Multivariable analysis revealed that aSBP (β = 0.345, P = 0.001) and aPP (β = 0.276, P = 0.018) remained independent predictors of LVEDP even after controlling for potential confounders.
CONCLUSION Invasively measured aSBP and aPP were independently associated with invasively measured LVEDP in patients undergoing ICA. This result provides additional evidence of a close interaction between central aortic pressure and LV diastolic function in this population.
PubMed IF 1 순환기내과
2282019

제1저자 손경희 · 교신저자 한정규, 강혜련

, , , , , ,
Immediate and delayed hypersensitivity after intra-arterial injection of iodinated contrast media: a prospective study in patients with coronary angiography.
Eur Radiol. 2019;29(10):5314-5321.

Abstract
OBJECTIVES While hypersensitivity reactions (HSR) to intravenously administered iodinated contrast media (ICM) have been well studied, not much is known about HSR to intra-arterially administered ICM.
METHODS A prospective observational study was performed to evaluate coronary angiography (CAG)-induced ICM hypersensitivity in patients who underwent CAG using ICM including ioversol, a low-osmolar non-ionic monomer, and iodixanol, an iso-osmolar non-ionic dimer. The HSR were investigated through in-patient monitoring after CAG and telephone interview after discharge.
RESULTS A total of 714 patients were enrolled during the observation period, of whom 26 (3.6%) showed immediate HSR and 108 (15.1%) showed delayed HSR. With regard to severity, proportion of immediate HSR grades 1, 2, and 3 was 57.7%, 38.5%, and 3.8%, respectively, whereas that of delayed HSR grades 1, 2, and 3 was 85.2%, 13.9%, and 0.9%, respectively. Multivariate analysis revealed that previous intra-arterial exposure to ICM was an independent risk factor for immediate HSR (odds ratio (OR) 2.92, 95% confidence interval (CI) 1.22-6.96; p = 0.015). Iodixanol was a significant risk factor for delayed HSR (OR 1.61, 95% CI 1.07-2.43; p = 0.024) and correlated with a higher incidence of delayed HSR within 24-h post-ICM administration compared to ioversol.
CONCLUSION The incidence rate of immediate and delayed HSR in intra-arterially administered ICM was 3.6% and 15.1%, respectively. Previous exposure to intra-arterially administered contrast media was a significant risk factor for immediate HSR. Compared to ioversol, iodixanol was associated with relatively earlier and more frequent delayed HSR.
KEY POINTS • In this prospective study, the incidence of immediate and delayed hypersensitivity in intra-arterial injection of contrast media during coronary angiography was 3.6% and 15.1%, respectively. • Delayed hypersensitivity reactions were more common but less severe than immediate hypersensitivity reactions during coronary angiography. • Previous exposure to ICM via intra-arterial route was a significant risk factor for immediate hypersensitivity to intra-arterial contrast medium.
PubMed IF 6 알레르기내과
2272019

제1저자 이의재 · 교신저자 최의근

, , , , , , ,
Increased risk of atrial fibrillation in patients with Behçet's disease: A nationwide population-based study.
Int J Cardiol. 2019;292:106-111.

Abstract
BACKGROUND Chronic inflammation plays a role in the pathophysiology of atrial fibrillation (AF). However, there is a paucity of information about whether Behçet's disease (BD) is associated with an increased risk of AF. This population-based study aimed to determine the risk of AF in patients with BD.
METHODS A total of 6636 newly diagnosed BD patients without a history of AF were included from the Korean National Health Insurance Service database between 2010 and 2014. Newly diagnosed non-valvular AF was identified using the claims data. An age- and sex-matched non-BD subjects were extracted at a ratio of 1:5 (n = 31,040). The incidence and risk of AF were compared between groups.
RESULTS During a mean follow-up of 3.6 ± 1.5 years, AF was newly diagnosed in 173 patients (51 in the BD group, 122 in the control group). The incidence was 2.3 and 1.1 per 1000 person-years, respectively. After adjustment, the BD group showed a 1.8-fold higher risk of AF compared to the control group. Patients with BD aged ≤40 years had a higher risk of AF, while patients aged ≥65 years showed a similar risk. Men with BD had a 2.5-fold increased risk of AF, whereas women with BD did not. Severe BD had a higher risk for AF compared to non-severe BD and controls.
CONCLUSIONS BD was associated with an increased risk of AF, particularly in men and young patients. Active surveillance and treatment are needed in BD patients and those with arrhythmic symptoms.
PubMed IF 3.3 순환기내과
2262019

제1저자 김학령 · 교신저자 김명아

, , , , , , , , , , , , ,
Gender difference in the impact of coexisting diabetes mellitus on long-term clinical outcome in people with heart failure: a report from the Korean Heart Failure Registry.
Diabet Med. 2019;36(10):1312-1318.

Abstract
AIM Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure.
METHODS A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission.
RESULTS People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P < 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P > 0.05).
CONCLUSIONS In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.
PubMed IF 3.3 순환기내과
2252019

제1저자 정재훈, 김학령 · 교신저자 김명아

, , , , , ,
Association between invasively measured aortic pulse pressure and orthostatic hypotension in patients undergoing invasive coronary angiography.
J Hypertens. 2019;37(10):1966-1973.

Abstract
OBJECTIVE Underlying pathophysiology of orthostatic hypotension has been poorly understood. We hypothesized that aortic pulse pressure (APP) reflecting aortic stiffness may be involved in the development of orthostatic hypotension.
METHODS A total of 200 patients (age 64.3 ± 10.9 years, 62.5% men) who underwent invasive coronary angiography (ICA) were prospectively recruited. Orthostatic hypotension was defined as SBP drop at least 20 mmHg or DBP drop at least 10 mmHg within 3 min of the standing position compared with the supine position. Hemodynamic parameters were measured at the ascending aorta using a pig-tail catheter immediately before ICA. APP was calculated as a difference between the aortic peak systolic pressure and the end-diastolic pressure.
RESULTS A total of 156 patients (78.0%) had obstructive coronary artery disease on ICA. Orthostatic hypotension was present in 58 patients (29.0%). Diabetes mellitus was more prevalent in patients with orthostatic hypotension than those without (48.3% vs. 23.2%; P < 0.001). Other clinical parameters including age, cardiovascular risk factors, laboratory findings and concomitant medications were not different between patients with and without orthostatic hypotension (P > 0.05 for each). In hemodynamic parameters, APP was higher in patients with orthostatic hypotension than those without (78.4 ± 25.8 vs. 68.3 ± 21.3 mmHg; P = 0.005). Higher APP was significantly associated with the presence of orthostatic hypotension even after controlling for potential confounders (odds ratio, 2.99; 95% confidence interval 1.15-7.78; P = 0.025).
CONCLUSION In patients undergoing ICA, APP was associated with increased risk of orthostatic hypotension. Central aortic stiffness may play a role in the development of orthostatic hypotension.
PubMed IF 5.6 순환기내과
2242019

제1저자 최윤진 · 교신저자 이동호

, , , , , , ,
Patients with inflammatory bowel disease have an increased risk of myocardial infarction: a nationwide study.
Aliment Pharmacol Ther. 2019;50(7):769-779.

Abstract
BACKGROUND Inflammatory bowel disease (IBD) is accompanied by various extraintestinal manifestations including systemic inflammation and hypercoagulability, which may increase the risk of atherosclerosis and ischaemic heart disease.
AIM To investigate whether IBD is associated with an increased risk of myocardial infarction (MI), stroke or death METHODS: The International Classification of Disease, 10th edition codes and the claim codes for rare diseases were used to identify candidates from National Health Insurance Service (NHIS) of South Korea. Patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 2006 and 2009 were age-matched 1:3 with NHIS enrolees without IBD. The primary outcomes included newly developed MI, stroke and death. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models.
RESULTS We identified 10 708 patients diagnosed with CD and 26 769 with UC. MI risk was higher in CD patients than in controls (incidence ratio (IR) 1.64 per 1000 person-years, HR, 1.80; 95% CI, 1.47-2.21), and this trend was more prominent among patients aged <40 years (IR 0.69 per 1000 person-years, HR, 2.96; 95% CI, 1.96-4.47) and among female patients (IR 2.35 per 1000 person-years, HR, 2.18; 95% CI, 1.61-2.94). In contrast, only female patients with UC had an increased risk of MI (IR 2.01 per 1000 person-years, HR, 1.33; 95% CI, 1.13-1.56).
CONCLUSIONS The risk of MI risk is higher in patients with CD than in the general population, and this trend is stronger in female patients and those aged <40 years.
PubMed IF 6.8 소화기내과
2232019

제1저자 김형준 · 교신저자 이춘택

, , , , , , , , , , ,
Clinical Significance of Pleural Attachment and Indentation of Subsolid Nodule Lung Cancer.
Cancer Res Treat. 2019;51(4):1540-1548.

Abstract
PURPOSE Lung cancers presenting as subsolid nodule commonly have peripheral location, making the cancer-pleura relationship noteworthy. We aimed to evaluate the effect of pleural attachment and/or indentation on visceral pleural invasion (VPI) and recurrence-free survival.
MATERIALS AND METHODS Patients who underwent curative resection of lung cancer as subsolid nodules from April 2007 to January 2016 were retrospectively evaluated. They were divided into four groups according to their relationship with the pleura. Clinical, radiographical, and pathological findings were analyzed.
RESULTS Among 404 patients with malignant subsolid nodule, 120 (29.7%) had neither pleural attachment nor indentation, 26 (6.4%) had attachment only, 117 (29.0%) had indentation only, and 141 (34.9%) had both. VPI was observed in nodules of 36 patients (8.9%), but absent in nonsolid nodules and in those without pleural attachment and/or indentation. Compared to subsolid nodules with concurrent pleural attachment and indentation, those with attachment only (odds ratio, 0.12; 95% confidence interval [CI], 0.02 to 0.98) and indentation only (odds ratio, 0.10; 95% CI, 0.03 to 0.31) revealed lower odds of VPI. On subgroup analysis, the size of the solid portion was associated with VPI among those with pleural attachment and indentation (p=0.021). Such high-risk features for VPI were associated with earlier lung cancer recurrence (adjusted hazard ratio, 3.31; 95% CI, 1.58 to 6.91).
CONCLUSION Concurrent pleural attachment and indentation are risk factors for VPI, and the odds increase with larger solid portion in subsolid nodules. Considering the risk of recurrence, early surgical resection could be encouraged in these patients.
PubMed IF 4.2 호흡기내과
2222019

제1저자 리우준, 홍준식 · 교신저자 윤성수

, , , , , , , , , ,
ERK-dependent IL-6 positive feedback loop mediates resistance against a combined treatment using danusertib and BKM120 in Burkitt lymphoma cell lines.
Leuk Lymphoma. 2019;60(10):2532-2540.

Abstract
This study was conducted to define the synergistic effect of the PI3K inhibitor BKM120 with the pan-Aurora kinase inhibitor danusertib and the potential mechanism of resistance to the combined inhibitor treatment in Burkitt lymphoma cell lines. The combination of danusertib and BKM120 showed a synergistic effect on Namalwa cells but not on BJAB cells. The combined treatment led to ERK hyperactivation and induced IL-6 secretion in BJAB cells but not in Namalwa cells. A blockade of ERK signaling with trametinib suppressed the combination treatment-induced ERK activation, reduced IL-6 mRNA expression, and downregulated IL-6R mRNA expression, resulting in an improvement in the antitumor effect. We stepwise treated Namalwa cells with both inhibitors using on-and-off treatment cycles and found that Namalwa cells gained chemoresistance by activating the ERK/IL-6 feedback loop, suggesting that the ERK-dependent IL-6 positive feedback loop can compensate for AKT inactivation and is closely associated with adaptive resistance and relapse.
PubMed IF 2.1 혈액종양내과
2212019

제1저자 강은정 · 교신저자 오국환

, , , , , , , , ,
Association Between High-Sensitivity Cardiac Troponin T and Echocardiographic Parameters in Chronic Kidney Disease: Results From the KNOW-CKD Cohort Study.
J Am Heart Assoc. 2019;8(18):e013357.

Abstract
Background It is unclear whether high-sensitivity troponin T (hs-TnT) is associated with subclinical cardiac changes in chronic kidney disease (CKD). We evaluated the relationship between hs-TnT and left ventricular structure and function in a CKD population, according to estimated glomerular filtration rate. Methods and Results We analyzed 2017 patients with CKD stages 1 to 5 (predialysis) in the KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) cohort. The predictor was hs-TnT level measured at baseline, and the outcomes were left ventricular hypertrophy (LVH) and systolic and diastolic dysfunction shown by echocardiography at baseline and after 4 years. Participants were categorized into quartiles according to hs-TnT levels. The associations between quartiles of hs-TnT and outcomes were assessed using multivariable logistic regression analysis with confounders including demographics, medical history, and laboratory findings. A receiver operating characteristic curve was used to assess the diagnostic power of hs-TnT for the outcomes as a continuous variable. For subgroup analysis, patients were stratified based on an estimated glomerular filtration rate of 60 mL/min per 1.73 m². Elevated hs-TnT was associated with LVH and diastolic dysfunction at baseline in an adjusted model but was not associated with systolic dysfunction. These associations remained significant for both estimated glomerular filtration rate subgroups. Receiver operating characteristic curve analysis showed that hs-TnT as a continuous variable exhibited fair significance for detection of LVH (area under the curve: 0.689) and diastolic dysfunction (area under the curve: 0.744). Multivariable analysis showed that higher hs-TnT levels at baseline were related to development of LVH but not diastolic dysfunction (n=864). Conclusions In CKD patients, hs-TnT is strongly associated with alterations of left ventricular structure and diastolic dysfunction for both estimated glomerular filtration rate strata. Baseline hs-TnT levels are predictive of new LVH on follow-up.
PubMed IF 6 신장내과
2202019

제1저자 김용철, 이정훈 · 교신저자 양승희, 이정표

, , , , , , , , , , , , , , ,
Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis.
Sci Rep. 2019;9(1):13495.

Abstract
Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.
PubMed IF 4.9 신장내과
2192019

제1저자 이소령, 이태민 · 교신저자 오세일, 그레고리 립

, , , , ,
Meta-Analysis of Oral Anticoagulant Monotherapy as an Antithrombotic Strategy in Patients With Stable Coronary Artery Disease and Nonvalvular Atrial Fibrillation.
Am J Cardiol. 2019;124(6):879-885.

Abstract
Guidelines recommend oral anticoagulant (OAC) monotherapy without antiplatelet therapy (APT) in patients with nonvalvular atrial fibrillation (AF) with stable coronary artery disease (CAD) of >1 year after myocardial infarction or percutaneous coronary intervention. More evidences are required for the safety and efficacy of OAC monotherapy compared with OAC plus APT. PubMed, EMBASE, and Cochrane Database of Systematic Reviews were systematically searched up to February 2019. Nonrandomized studies and randomized clinical trials comparing OAC monotherapy with OAC plus single APT (SAPT) for patients with stable CAD and nonvalvular AF. The primary end point was major adverse cardiovascular events (composite of ischemic or thrombotic events) and secondary outcomes included major bleeding, stroke, all-cause death, and net adverse events (composite of ischemic, thrombotic, or bleeding events). From 6 trials, 8,855 patients were included. There was no significant difference in major adverse cardiovascular event in patients with AF treated using OAC plus SAPT compared with those treated with OAC monotherapy (hazard ratio [HR] 1.09; 95% confidence interval [CI] 0.92 to 1.29). OAC plus SAPT was associated with a significantly higher risk of major bleeding compared with OAC monotherapy (HR 1.61; 95% CI 1.38 to 1.87), as well as in terms of net adverse event (HR 1.21; 95% CI 1.02 to 1.43). There were no significant differences in rates of stroke and all-cause death. In conclusion, in this meta-analysis, OAC monotherapy and OAC plus SAPT treatment showed similar effectiveness, but OAC monotherapy was significantly associated with a lower risk of bleeding compared with OAC plus SAPT in patients with nonvalvular AF and stable CAD.
PubMed IF 2.5 순환기내과
2182019

제1저자 최진호 · 교신저자 이상협

, , , , , , , , ,
Step-wise endoscopic approach to palliative bilateral biliary drainage for unresectable advanced malignant hilar obstruction.
Sci Rep. 2019;9(1):13207.

Abstract
The ideal type of stent utilized at index endoscopic retrograde cholangiopancreatography (ERCP) in management of malignant hilar obstruction (MHO) remains unclear. We aimed to determine the ideal stent choice in patients with MHO. In this retrospective study, patients with unresectable MHO were separated into the plastic stent (PS) group and the self-expandable metal stent (SEMS) group. The primary outcome was the risk and rate of rescue percutaneous transhepatic biliary drainage (PTBD). The secondary outcomes were the progression-free survival, the overall survival and the PTBD-free period (days). Thirty-six patients in the PS group and 38 patients in the SEMS group were enrolled. The risk for PTBD was higher in SEMS group (HR = 2.205, 95% C.I. 0.977-4.977, P = 0.057). The rate of PTBD was significantly lower in the PS group. (22.2% vs 50.0%, P = 0.017) There were no differences in overall survival and progression-free survival (410 and 269 in the PS group, 395 and 266 in the SEMS group, P = 0.663 and P = 0.757). The PTBD-free period was significantly longer in the PS group. (836.43 vs 586.40, P = 0.039) Although comparable in clinical efficacy, utilization of PS at index ERCP may reduce patient's discomfort by avoiding PTBD and prolonging PTBD-free period in patients with MHO.
PubMed IF 4.9 소화기내과
2172019

제1저자 이현정, 김학령 · 교신저자 김명아

, , , , , ,
Subclinical alterations in left ventricular structure and function according to obesity and metabolic health status.
PLoS One. 2019;14(9):e0222118.

Abstract
BACKGROUND Obesity and metabolic syndrome (MetS) are associated with high risk of cardiac dysfunction and heart failure. We assessed the effect of obesity and metabolic health status on left ventricular (LV) structure and function in subjects without overt heart disease.
METHODS In 789 subjects (58.8±13.0 years, 50.7% males) without overt heart disease, LV morphology and function were compared among 6 groups stratified by body mass index (BMI) (normal weight, overweight and obese) and metabolic health status (meeting ≤1 criterion of MetS excluding waist circumference defined as metabolically healthy; otherwise, metabolically unhealthy).
RESULTS LV ejection fraction (LVEF) was not different among the 6 groups (P>0.05). However, high BMI and poor metabolic health were associated with poorer global longitudinal strain (GLS), higher LV mass index (LVMI) and higher E/e' (P<0.001). Poor metabolic health status was associated with greater adverse changes in LV structure and function than obesity, and among MetS components, high systolic blood pressure (SBP) showed the greatest impact. Higher SBP, BMI and triglycerides were independently associated with worse GLS, and higher SBP was also associated with worse LVMI and E/e´. GLS, LVMI and E/e´ worsened in proportion to the number of MetS criteria or continuous MetS scores. Adverse myocardial changes associated with obesity were significant in the metabolically healthy group, but not in the metabolically unhealthy group.
CONCLUSIONS Obesity and poor metabolic health status were associated with subclinical decrement in LV systolic and diastolic function, and higher LV mass, but not with LVEF, in subjects without overt heart disease.
PubMed IF 2.8 순환기내과
2162019

제1저자 박세훈, 백충희 · 교신저자 이하정

, , , , , , , , , , ,
Possible beneficial association between renin-angiotensin-aldosterone-system blockade usage and graft prognosis in allograft IgA nephropathy: a retrospective cohort study.
BMC Nephrol. 2019;20(1):354.

Abstract
BACKGROUND Although immunoglobulin A nephropathy (IgAN) is associated with an increased risk of renal allograft failure, evidences for its treatment, including renin-angiotensin-aldosterone system blockade (RAASB) usage, remain limited.
METHODS In this bi-center retrospective cohort study, we included patients who were recently diagnosed with IgAN through allograft biopsies. We identified their 6-month antihypertensive medication prescriptions and investigated the association between the medication types, albuminuria changes, and risk of 5-year death-censored-graft-failure (DCGF). The mixed effect model and cox regression analysis were used.
RESULTS A total of 464 allograft IgAN patients were included: 272, 38, 33, and 121 patients in the no antihypertensive medication, single agent RAASB, single agent beta blocker (BB)/calcium channel blocker (CCB), and combination therapy groups, respectively. High-degree albuminuria after 6 months of allograft IgAN diagnosis was an important prognostic parameter and a partial mediator for the association between the subgroups and 5-year DCGF. The usage of single RAASB was associated with decrement of albuminuria from allograft IgAN diagnosis (P for interaction = 0.03). The single BB/CCB group demonstrated significantly worse prognosis than the single RAASB group (adjusted hazard ratio, 2.76 [1.09-6.98]; P = 0.03).
CONCLUSIONS In conclusion, RAASB may be beneficial for graft prognosis in early allograft IgAN patients who require single antihypertensive medication therapy, by means of reducing albuminuria. Further investigation of treatment strategy in allograft IgAN is warranted.
PubMed IF 2.9 신장내과
2152019

제1저자 정미향, 김학령 · 교신저자 김응주

, , , , , , , , ,
Heart failure awareness in the Korean general population: Results from the nationwide survey.
PLoS One. 2019;14(9):e0222264.

Abstract
BACKGROUND For a better heart failure outcome, it is fundamental to improve the awareness of heart failure at the general population level. We conducted this study to identify the current status of awareness of heart failure in the Korean general population.
METHODS This cross-sectional nationwide survey recruited a total of 1,032 participants aged 30 years or older, based on a stratification systematic sampling method. A 23-item questionnaire was surveyed through telephone interviews.
RESULTS Although 80% of the participants had heard of heart failure, 47% exactly defined what heart failure is. A minority of participants correctly recognized the lifetime risk of developing heart failure (21%) as well as the mortality (16%) and readmission risk (18%) of heart failure and the cost burden of heart failure admission (28%). Regarding preferred treatment options, 71% of the participants chose a treatment option that could improve the quality of life. Approximately two-thirds of the participants agreed that current medical treatment could reduce mortality and improve the quality of life. More than half of the participants (59%) thought that heart failure patients should live quietly and reduce all physical activities. Across survey items, we found a lower awareness state in the elderly groups and people at lower income and educational levels.
CONCLUSIONS The current awareness status of heart failure in the Korean general population is still low. Proactive educational efforts should be made to improve public awareness with special attention to individuals with lower disease awareness.
PubMed IF 2.8 순환기내과
2142019

제1저자 장영, 조유리 · 교신저자 이정훈

, , , , , , , , , , , , , , , ,
Comparison of Models for Tumor Recurrence after Liver Transplantation for the Patients with Hepatocellular Carcinoma: A Multicenter Long-Term Follow-Up Study.
Cancers (Basel). 2019;11(9):cancers11091295.

Abstract
BACKGROUND AND AIMS Several models have been developed to predict tumor the recurrence of hepatocellular carcinoma (HCC) after liver transplantation besides the conventional Milan criteria (MC), including the MoRAL score. This study aimed to compare the prognostication power of the MoRAL score to most models designed so far in the Eastern and Western countries.
METHODS This study included 564 patients who underwent living donor liver transplantation (LDLT) in three large-volume hospitals in Korea. The primary and secondary endpoints were time-to-recurrence, and overall survival (OS), respectively. The performance of the MoRAL score was compared with those of other various Liver transplantation (LT) criteria, including the Milan criteria, University of California San Francisco (UCSF) criteria, up-to-seven criteria, Kyoto criteria, AFP model, total tumor volume/AFP criteria, Metroticket 2.0 model, and Weill Cornell Medical College group model.
RESULTS The median follow-up duration was 78.1 months. Among all models assessed, the MoRAL score showed the best discrimination function for predicting the risk of tumor recurrence after LT, with c-index of 0.78, compared to other models (all p < 0.001). The MoRAL score also represented the best calibration function by Hosmer-Lemeshow test (p = 0.15). Especially in the beyond-MC sub-cohort, the MoRAL score predicted tumor recurrence (c-index, 0.80) and overall survival (OS) (c-index, 0.70) significantly better than any other models (all p < 0.001). When the MoRAL score was low (<314.8), the five-year cumulative risks of tumor recurrence and death were excellent in beyond-MC (27.8%, and 20.5%, respectively) and within-MC (16.3%, and 21.1%, respectively) sub-cohorts.
CONCLUSIONS The MoRAL score provides the most refined prognostication for predicting HCC recurrence after LDLT.
PubMed IF 4.8 소화기내과
2132019

제1저자 공성혜, 김정희 · 교신저자 조남한

, , , , ,
Dehydroepiandrosterone Sulfate and Free Testosterone but not Estradiol are Related to Muscle Strength and Bone Microarchitecture in Older Adults.
Calcif Tissue Int. 2019;105(3):285-293.

Abstract
The study aimed to elucidate the relationship between sex steroids and muscle mass, muscle strength, and trabecular bone score (TBS) in a community-dwelling aged population. We analyzed 922 men > 60 years of age and 1244 postmenopausal women. Weak muscle strength was defined as hand grip strength < 26 kg for men and < 18 kg for women, whereas degraded bone microarchitecture was defined as a TBS ≤ 1.2. The mean age was 70.2 ± 6.8 years for men and 71.2 ± 6.7 years for women. Participants within higher dehydroepiandrosterone sulfate (DHEAS) and free testosterone (FT) tertiles were likely to be younger, have greater muscle mass, and have stronger hand grip strength. Based on logistic regression models, men within the lowest FT tertile had weaker muscle strength compared to those in the highest tertile (adjusted odds ratio [OR] 2.28; 95% confidence interval [CI] 1.33-3.91). Women within the lowest DHEAS and FT tertile had weaker muscle strength compared to those in the highest tertile (adjusted OR for DHEAS 1.42; 95% CI 1.02-1.99; adjusted OR for FT 1.77, 95% CI 1.26-2.48). Moreover, men within the lowest FT tertile exhibited degraded bone microarchitecture compared to those in the highest tertile (adjusted OR 2.57, 95% CI 1.46-4.51). However, estradiol was not related to muscle strength or bone microarchitecture in both sexes. In conclusion, in aged men, serum FT was closely associated with muscle strength and bone microarchitecture and in postmenopausal women, serum DHEAS and FT were related to muscle strength.
PubMed IF 3.5 내분비대사내과
2122019

제1저자 김동완 · 교신저자 김동완

, , , , , , , , , , , , , , , , , , , ,
Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial.
Lung Cancer. 2019;135:66-72.

Abstract
OBJECTIVES The aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy.
MATERIALS AND METHODS Phase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [EGFR T790 M mutation-positive patients]; 2B: 500 mg twice daily [EGFR T790 M mutation-positive]; 3: 800 mg once daily [EGFR T790 M mutation-negative]). In phase 2, EGFR T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2'). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters.
RESULTS Overall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6-67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6-9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%).
CONCLUSION Olmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.
PubMed IF 5.3 혈액종양내과
2112019

제1저자 이유수 · 교신저자 김태민

, , , , , , ,
Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations.
J Thorac Oncol. 2019;14(9):1556-1566.

Abstract
INTRODUCTION NSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of first- to third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations.
METHODS We developed seven EGFR exon 20 insertion-mutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and N-ethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion-mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared.
RESULTS EGFR exon 20 insertion-mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to first-generation EGFR TKIs (concentration that inhibits 50% [IC₅₀], 1.1 ± 0.067 to 5.4 ± 0.115 μM). Mutants were sensitive to second-generation EGFR TKIs (IC₅₀, 0.02 ± 0.0002 to 161.8 ± 18.7nM), except EGFR H773insH (IC₅₀, 46.3 ± 8.0 to 352.5 ± 22.7nM). The IC₅₀ ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion-mutant cells (IC₅₀, 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion-mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation.
CONCLUSIONS Osimertinib is active against EGFR exon 20 insertion-mutant NSCLC and flexibly binds within drug-binding pockets in preclinical models.
PubMed IF 23.3 혈액종양내과
2102019

제1저자 김영찬, 이상언, 김솜이, 장현덕 · 교신저자 김효수

, , , , , , , ,
Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation.
Nat Chem Biol. 2019;15(9):907-916.

Abstract
Toll-like receptor (TLR)/myeloid differentiation primary response protein (MYD88) signaling aggravates sepsis by impairing neutrophil migration to infection sites. However, the role of intracellular fatty acids in TLR/MYD88 signaling is unclear. Here, inhibition of fatty acid synthase by C75 improved neutrophil chemotaxis and increased the survival of mice with sepsis in cecal ligation puncture and lipopolysaccharide-induced septic shock models. C75 specifically blocked TLR/MYD88 signaling in neutrophils. Treatment with GSK2194069 that targets a different domain of fatty acid synthase, did not block TLR signaling or MYD88 palmitoylation. De novo fatty acid synthesis and CD36-mediated exogenous fatty acid incorporation contributed to MYD88 palmitoylation. The binding of IRAK4 to the MYD88 intermediate domain and downstream signal activation required MYD88 palmitoylation at cysteine 113. MYD88 was palmitoylated by ZDHHC6, and ZDHHC6 knockdown decreased MYD88 palmitoylation and TLR/MYD88 activation upon lipopolysaccharide stimulus. Thus, intracellular saturated fatty acid-dependent palmitoylation of MYD88 by ZDHHC6 is a therapeutic target of sepsis.
PubMed IF 15.8 순환기내과
2092019

제1저자 김률 · 교신저자 김범석

, , , , , , ,
First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non-small-cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Clin Lung Cancer. 2019;20(5):331-338.e4.

Abstract
BACKGROUND This study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non-small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.
MATERIALS AND METHODS A search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.
RESULTS A total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.
CONCLUSIONS For patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.
PubMed IF 3.9 혈액종양내과
2082019

제1저자 박지은, 김미화 · 교신저자 오도연

, , , , , , ,
GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer.
Gastric Cancer. 2019;22(5):932-940.

Abstract
BACKGROUND EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC.
METHODS GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml.
RESULTS GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model.
CONCLUSION Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.
PubMed IF 6.1 혈액종양내과

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