SCI 발표논문

1. 1912024

   제1저자 임수, 배재현 · 교신저자 임수

   Lim S^*, Bae JH^*, Oh H, Hwang IC, Yoon YE, Cho GY

   Effect of ertugliflozin on left ventricular function in type 2 diabetes and pre-heart failure: the Ertu-GLS randomized clinical trial.

   Cardiovasc Diabetol. 2024;23(1):373.

   Abstract

   BACKGROUND The therapeutic effects of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcome are not fully understood. This study aimed to evaluate the efficacy and safety of ertugliflozin on cardiac function in people with type 2 diabetes and pre-heart failure.

   METHODS We conducted a 24-week randomized, double-blind, placebo-controlled trial involving individuals with type 2 diabetes inadequately controlled with antidiabetic medications. Participants with left ventricular hypertrophy, E/e' >15, or impaired left ventricular global longitudinal strain (LVGLS) were randomized 1:1 to receive either ertugliflozin (5 mg once daily) or a placebo. The primary outcome was the change in LVGLS. Secondary outcomes included changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Prespecified exploratory outcomes, including angiotensin-converting enzyme 2 (ACE2) and angiotensin (1-7) levels, were also assessed.

   RESULTS A total of 102 individuals (mean age, 63.9 ± 9.2 years; 38% women) were included. The ertugliflozin group showed a significant improvement in LVGLS (- 15.5 ± 3.1% to - 16.6 ± 2.8%, P = 0.004) compared to the placebo group (- 16.7 ± 2.7% to - 16.4 ± 2.6%, P = 0.509), with a significant between-group difference (P = 0.013). Improvements in LVMI and LVEF were also observed. Additionally, significant reductions in HbA_1c, systolic blood pressure, whole-body and visceral fat, uric acid, proteinuria, N-terminal pro-B-type natriuretic peptide, and lipoprotein(a) were noted. ACE2 and angiotensin (1-7) levels significantly increased in the ertugliflozin group compared to the placebo group and correlated with changes in LVGLS [r = 0.456, P < 0.001 for ACE2; r = 0.541, P < 0.001 for angiotensin (1-7)]. Adverse events were similar between the two groups.

   CONCLUSIONS This study demonstrated that ertugliflozin has beneficial effects on left ventricular function in individuals with type 2 diabetes and pre-heart failure, and it provided insights into potential underlying mechanisms.

   CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03717194.

   PubMed IF 15.6 내분비대사내과
2. 1902024

   제1저자 Ian J Neeland · 교신저자 임수, Jean-Pierre Després

   Neeland IJ, Lim S, Tchernof A, Gastaldelli A, Rangaswami J, Ndumele CE, Powell-Wiley TM, Després JP

   Metabolic syndrome.

   Nat Rev Dis Primers. 2024;10(1):77.

   Abstract

   The metabolic syndrome (MetS) is a multiplex modifiable risk factor for cardiovascular disease, type 2 diabetes mellitus and other health outcomes, and is a major challenge to clinical practice and public health. The rising global prevalence of MetS, driven by urbanization, sedentary lifestyles and dietary changes, underlines the urgency of addressing this syndrome. We explore the complex underlying mechanisms, including genetic predisposition, insulin resistance, accumulation of dysfunctional adipose tissue and ectopic lipids in abdominal obesity, systemic inflammation and dyslipidaemia, and how they contribute to the clinical manifestations of MetS. Diagnostic approaches vary but commonly focus on abdominal obesity (assessed using waist circumference), hyperglycaemia, dyslipidaemia and hypertension, highlighting the need for population-specific and phenotype-specific diagnostic strategies. Management of MetS prioritizes lifestyle modifications, such as healthy dietary patterns, physical activity and management of excess visceral and ectopic adiposity, as foundational interventions. We also discuss emerging therapies, including new pharmacological treatments and surgical options, providing a forward-looking perspective on MetS research and care. This Primer aims to inform clinicians, researchers and policymakers about MetS complexities, advocating for a cohesive, patient-centred management and prevention strategy. Emphasizing the multifactorial nature of MetS, this Primer calls for integrated public health efforts, personalized care and innovative research to address this escalating health issue.

   PubMed IF 79.8 내분비대사내과
3. 1892024

   제1저자 곽순구, 김지훈 · 교신저자 김형관, 이상철

   Kwak S, Kim J, Park CS, Lee HJ, Park JB, Lee SP, Kim YJ, Kim HK, Lee SC

   Distinct Phenotypic Groups and Related Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

   J Am Heart Assoc. 2024;13(20):e036245.

   Abstract

   BACKGROUND Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes.

   METHODS AND RESULTS This retrospective study analyzed 1231 consecutive patients with HCM from 2 tertiary hospitals. We performed latent class analysis to categorize patients into phenotypic groups. Three distinct phenotypic groups were identified using latent class analysis. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular events, 133 all-cause mortality events, and 70 noncardiovascular mortality events were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 versus 2 versus 3: 0.8% versus 8.2% versus 4.0%, respectively, P<0.001), and cardiovascular events were more frequent in Groups 2 and 3 compared with Group 1. All-cause and noncardiovascular mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance.

   CONCLUSIONS This study identified 3 distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.

   PubMed IF 6 순환기내과
4. 1882024

   제1저자 오송지, 고재문 · 교신저자 김태민

   Oh S^*, Koh J^*, Kim TM, Kim S, Youk J, Kim M, Keam B, Jeon YK, Ku JL, Kim DW, Chung DH, Heo DS

   Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer.

   Clin Cancer Res. 2024;30(20):4729-4742.

   Abstract

   PURPOSE Histologic transformation from EGFR-mutant non-small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.

   EXPERIMENTAL DESIGN We conducted whole-transcriptome analysis of 59 regions of interest through the spatial profiling of formalin-fixed, paraffin-embedded tissues obtained from 10 patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; and t-SCLC, 30 regions of interests). Transcriptomic profiles and differentially expressed genes were compared between pre- and post-transformed tumors.

   RESULTS Following EGFR-TKI treatment, 93.7% (15/16) of t-SCLC components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, histone deacetylase inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the histone deacetylase inhibitor fimepinostat were validated in both in vitro and in vivo models.

   CONCLUSIONS Our study demonstrated that most t-SCLC cases showed neuronal subtypes with low EGFR expression. Differentially expressed gene analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

   PubMed IF 10.9 혈액종양내과
5. 1872024

   제1저자 장성혜, 정세영, 채정준 · 교신저자 이은영, 이정석

   Chang SH, Jung S, Chae JJ, Kim JY, Kim SU, Choi JY, Han HJ, Kim HT, Kim HJ, Kim HJ, Park WY, Sparks JA, Lee EY, Lee JS

   Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation.

   EBioMedicine. 2024;108:105339.

   Abstract

   BACKGROUND Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial.

   METHODS Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD.

   FINDINGS Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment.

   INTERPRETATION These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor.

   FUNDING This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.

   PubMed IF 11.2 류마티스내과
6. 1862024

   제1저자 최종욱, 공성혜 · 교신저자 오창명, 문신제

   Choi JW^*, Kong SH^*, Kim YJ, Chung HS, Yu JM, Park JS, Lee CH, Park JH, Kim DS, Oh CM, Moon S

   Effect of low muscle mass on total mortality related to metabolic disease in chronic kidney disease patients.

   Sci Rep. 2024;14(1):22837.

   Abstract

   Low muscle mass is a risk factor for mortality in patients with chronic kidney disease (CKD). However, it is not clear to what extent low muscle mass contributes to this risk, either independently or in combination with metabolic abnormalities and frailty. This study used data from the National Health and Nutrition Examination Survey 1999-2006 and 2011-2018. Low muscle mass was defined as Appendicular Skeletal Mass Index < 7 kg/m² in men or < 5.5 kg/m² in women. The follow-up duration was from the first anthropometric and clinical measurements to death or the last follow-up. This study enrolled 2072 patients with CKD. Low muscle mass was associated with a lower risk of metabolic abnormalities, but was associated with an elevated mortality risk. Conversely, central obesity was associated with a higher likelihood of metabolic abnormalities and frailty, yet showed no significant association with mortality risk. Subsequently conducted mediation analysis indicated that the effect of low muscle mass on mortality was direct, not mediated by frailty and metabolic abnormalities. In spite of the inverse relationship between low muscle mass and metabolic abnormalities, low muscle mass are directly associated with an increased risk of all-cause mortality. Low muscle mass may directly contribute to mortality in patients with CKD, independent of metabolic abnormalities and frailty in these patients.

   PubMed IF 4.9 내분비대사내과
7. 1852024

   제1저자 박찬순 · 교신저자 오세일

   Park CS, Choi J, Choi J, Lee KY, Ahn HJ, Kwon S, Lee SR, Choi EK, Kwak SH, Oh S

   Alcohol is neither a risk factor nor a protective factor for sudden cardiac death and/or fatal ventricular arrhythmia: A population-based study with genetic traits and alcohol consumption in the UK Biobank.

   Heart Rhythm. 2024;21(10):1820-1826.

   Abstract

   BACKGROUND The association between alcohol consumption and the risk of sudden cardiac death and/or fatal ventricular arrhythmia remains controversial.

   OBJECTIVE We analyzed the association between alcohol consumption, genetic traits for alcohol metabolism, and the risk of sudden cardiac death and/or fatal ventricular arrhythmia.

   METHODS We identified 397,164 individuals enrolled between 2006 and 2010 from the UK Biobank database and followed them until 2021. Alcohol consumption was categorized as current nondrinkers (nondrinkers and ex-drinkers), mild drinkers, moderate drinkers, or heavy drinkers. Genetic traits of alcohol metabolism were stratified according to the polygenic risk score tertiles. The primary and secondary outcomes were a composite of sudden cardiac death and fatal ventricular arrhythmia as well as their individual components.

   RESULTS During follow-up (median 12.5 years), 3543 cases (0.89%) of clinical outcomes occurred. Although mild, moderate, and heavy drinkers showed deceased risks of outcomes compared with current nondrinkers, there was no prognostic difference among nondrinkers, mild drinkers, moderate drinkers, and heavy drinkers. Ex-drinkers showed an increased risk in univariate analysis, but the significance was attenuated after adjusting covariates (hazard ratio 1.19; 95% confidence interval 0.94-1.50). As a continuous variable, alcohol consumption was not associated with clinical outcomes (hazard ratio 1.01; 95% confidence interval 0.99-1.02). Consistent with these findings, there was no association between genetic traits for alcohol metabolism and the risk of clinical outcomes.

   CONCLUSION Alcohol consumption was neither a protective factor nor a risk factor for sudden cardiac death or fatal ventricular arrhythmia. Genetic traits of alcohol metabolism were not associated with the clinical prognosis.

   PubMed IF 7 순환기내과
8. 1842024

   제1저자 이현진, 곽윤진 · 교신저자 조수정, 김필남, 김진영

   Lee HJ, Kwak Y, Na YS, Kim H, Park MR, Jo JY, Kim JY, Cho SJ, Kim P

   Proteomic Heterogeneity of the Extracellular Matrix Identifies Histologic Subtype-Specific Fibroblast in Gastric Cancer.

   Mol Cell Proteomics. 2024;23(10):100843.

   Abstract

   Gastric cancer (GC) is a highly heterogeneous disease regarding histologic features, genotypes, and molecular phenotypes. Here, we investigate extracellular matrix (ECM)-centric analysis, examining its association with histologic subtypes and patient prognosis in human GC. We performed quantitative proteomic analysis of decellularized GC tissues that characterizes tumorous ECM, highlighting proteomic heterogeneity in ECM components. We identified 20 tumor-enriched proteins including four glycoproteins, serpin family H member 1 (SERPINH1), annexin family (ANXA3/4/5/13), S100A family (S100A6/8/9), MMP14, and other matrisome-associated proteins. In addition, histopathological characteristics of GC reveals differential expression in ECM composition, with the poorly cohesive carcinoma-not otherwise specified (PCC-NOS) subtype being distinctly demarcated from other histologic subtypes. Integrating ECM proteomics with single-cell RNA sequencing, we identified crucial molecular markers in the PCC-NOS-specific stroma. PCC-NOS-enriched matrisome proteins and gene expression signatures of adipogenic cancer-associated fibroblasts (CAF_adi) are closely linked, both associated with adverse outcomes in GC. Using tumor microarray analysis, we confirmed the CAF_adi surface marker, ATP binding cassette subfamily A member 8 (ABCA8), predominantly present in PCC-NOS tumors. Our ECM-focused analysis paves the way for studies to determine their utility as biomarkers for patient stratification, offering valuable insights for linking molecular and histologic features in GC.

   PubMed IF 6.1 소화기내과
9. 1832024

   제1저자 곽수헌 · 교신저자 박경수

   Kwak SH, Han KA, Kim ES, Choi SH, Won JC, Yu JM, Oh S, Yoo HJ, Kim CH, Kim KS, Chun S, Kim YH, Cho SA, Kim DH, Park KS

   Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

   Diabetes Obes Metab. 2024;26(10):4203-4212.

   Abstract

   AIMS To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM).

   MATERIALS AND METHODS Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52.

   RESULTS A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively.

   CONCLUSIONS Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

   PubMed IF 6.1 내분비대사내과
10. 1822024

    제1저자 이희진, 박찬순 · 교신저자 김형관

    Lee H^*, Park CS^*, Kim B, Rhee TM, Lee H, Kim YJ, Han K, Kim HK

    Real-world efficacy of fimasartan vs. other angiotensin receptor blockers in combination with calcium channel blockers: a nationwide cohort study.

    Clin Hypertens. 2024;30(1):28.

    Abstract

    BACKGROUND The antihypertensive efficacy of fimasartan was assessed based on the transition rate from a combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) to three-drug combination therapy, as compared to other ARBs.

    METHODS This nationwide cohort study used data obtained from the Korean National Health Insurance Service database. Patients who had received national health checkups within 2 years prior to January 1, 2017, and were concurrently prescribed ARBs and CCBs for > 30 days during the 6 months from January 1, 2017, to June 30, 2017 were included in the study. Patients were categorized into the 'fimasartan group' (those prescribed fimasartan) and the 'non-fimasartan group' (those prescribed ARBs other than fimasartan). The index date was set as the last day of a 30-day prescription period for ARBs and CCBs, with a subsequent 2.5-year follow-up to observe the potential addition of a third drug, such as beta-blockers or diuretics.

    RESULTS The study included 34,422 patients with a mean age of 60.3 years and 58.3% being male. The fimasartan group constituted 2.7% (n = 928) of the total, and the non-fimasartan group, 97.3% (n = 33,494). During the follow-up period, 38 patients in the fimasartan group (14.3 per 1,000 person-years) and 3,557 patients in the non-fimasartan group (42.8 per 1,000 person-years) required additional antihypertensive medications. After multivariate adjustment for age, sex, diabetes mellitus, dyslipidemia, cancer, heart failure, systolic blood pressure, and diastolic blood pressure, the fimasartan group showed a significantly lower rate of adding a third medication (hazard ratio 2.68, 95% confidence interval 1.95-3.69) compared to that of the non-fimasartan group.

    CONCLUSIONS Fimasartan is associated with a lower need for additional antihypertensive drugs compared to other ARBs. This implies its greater effectiveness in hypertension management, potentially enhancing cardiovascular outcomes, and minimizing polypharmacy.

    PubMed IF 6.2 순환기내과
11. 1812024

    제1저자 Amal Magdy, 김희진 · 교신저자 김원, 김미랑

    Magdy A, Kim HJ, Go H, Lee JM, Sohn HA, Haam K, Jung HJ, Park JL, Yoo T, Kwon ES, Lee DH, Choi M, Kang KW, Kim W, Kim M

    DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.

    Clin Mol Hepatol. 2024;30(4):824-844.

    Abstract

    BACKGROUND/AIMS Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.

    METHODS Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.

    RESULTS Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.

    CONCLUSION Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.

    PubMed IF 21.7 소화기내과
12. 1802024

    제1저자 백선경, 이승훈 · 교신저자 김정희

    Baek SK, Lee SH, Park SS, Ahn CH, Kong SH, Kim WW, Lee YM, Kim SJ, Song DE, Sung TY, Lee KE, Kim JH, Jung KC, Koh JM

    The Modified S-GRAS Scoring System for Prognosis in Korean with Adrenocortical Carcinoma.

    Endocrinol Metab (Seoul). 2024;39(5):803-812.

    Abstract

    BACKGRUOUND Adrenocortical carcinomas (ACCs) are rare tumors with aggressive but varied prognosis. Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score, based on clinical and pathological factors, was found to best stratify the prognosis of European ACC patients. This study assessed the prognostic performance of modified S-GRAS (mS-GRAS) scores including modified grade (mG) by integrating mitotic counts into the Ki67 index (original grade), in Korean ACC patients.

    METHODS Patients who underwent surgery for ACC between January 1996 and December 2022 at three medical centers in Korea were retrospectively analyzed. mS-GRAS scores were calculated based on tumor stage, mG (Ki67 index or mitotic counts), resection status, age, and symptoms. Patients were divided into four groups (0-1, 2-3, 4-5, and 6-9 points) based on total mS-GRAS score. The associations of each variable and mS-GRAS score with recurrence and survival were evaluated using Cox regression analysis, Harrell's concordance index (C-index), and the Kaplan-Meier method.

    RESULTS Data on mS-GRAS components were available for 114 of the 153 patients who underwent surgery for ACC. These 114 patients had recurrence and death rates of 61.4% and 48.2%, respectively. mS-GRAS score was a significantly better predictor of recurrence (C-index=0.829) and death (C-index=0.747) than each component (P<0.05), except for resection status. mS-GRAS scores correlated with shorter progression-free survival (P=8.34E-24) and overall survival (P=2.72E-13).

    CONCLUSION mS-GRAS scores showed better prognostic performance than tumor stage and grade in Asian patients who underwent surgery for ACC.

    PubMed IF 5.1 내분비대사내과
13. 1792024

    제1저자 이태민 · 교신저자 곽수헌

    Rhee TM, Choi J, Lee H, Merino J, Park JB, Kwak SH

    Discrepancy Between Genetically Predicted and Observed BMI Predicts Incident Type 2 Diabetes.

    Diabetes Care. 2024;47(10):1826-1833.

    Abstract

    OBJECTIVE Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D.

    RESEARCH DESIGN AND METHODS From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication.

    RESULTS Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI 1.26-2.05, P < 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity.

    CONCLUSIONS Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.

    PubMed IF 22.6 내분비대사내과
14. 1782024

    제1저자 김순찬, 서하영 · 교신저자 이상협, 장진영, 구자록

    Kim SC^*, Seo HY^*, Lee JO, Maeng JE, Shin YK, Lee SH, Jang JY, Ku JL^*

    Establishment, characterization, and biobanking of 36 pancreatic cancer organoids: prediction of metastasis in resectable pancreatic cancer.

    Cell Oncol (Dordr). 2024;47(5):1627-1647.

    Abstract

    PURPOSE Early dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC.

    METHODS Here, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented. Whole-exome sequencing and RNA sequencing were performed and drug responses to clinically relevant 18 compounds were assessed.

    RESULTS Our results revealed that borderline resectable PDAC organoids exhibited distinct patterns according to their metastatic potency highlighted by multiple genetic and transcriptional factors and strong variances in drug responses.

    CONCLUSIONS These data suggest that the presence of metastatic PDAC can be identified by integrating molecular compositions and drug responses of borderline resectable PDAC.

    PubMed IF 5.6 소화기내과
15. 1772024

    제1저자 윤준필, 강지훈 · 교신저자 박경우

    Kang J, Yun J, Park KW, Park M, Park S, Hwang D, Han JK, Yang HM, Kang HJ, Koo BK, Angiolillo DJ, Urban P, Kim HS

    Long-term outcomes of high bleeding risk patients undergoing percutaneous coronary intervention: a Korean nationwide registry.

    Eur Heart J. 2024;45(36):3721-3731.

    Abstract

    BACKGROUND AND AIMS Patients with high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) are at increased risk of not only bleeding, but also ischaemic events. This study aimed to determine the long-term relative risk of ischaemic and bleeding events in HBR patients.

    METHODS This study was a nationwide cohort study, based on the Korean National Health Insurance Review and Assessment Service database. Patients diagnosed with stable angina or acute coronary syndrome and those who underwent PCI in Korea between 2009 and 2018 were included in the analysis. According to the Academic Research Consortium HBR criteria, the total population was divided into HBR and non-HBR groups. The co-primary outcomes were major bleeding events and ischaemic (composite of cardiac death, myocardial infarction, and ischaemic stroke) events.

    RESULTS Among a total of 325 417 patients who underwent PCI, 66 426 patients (20.4%) had HBR. During the follow-up period, HBR patients had a higher risk for major bleeding events (23.9% vs. 8.9%, P < .001) and ischaemic events (33.8% vs. 14.4%, P < .001). However, the impact of HBR was significant for major bleeding events [hazard ratio (HR) 3.12, 95% confidence interval (CI) 3.04-3.21, P < .001] and for ischaemic events (HR 2.50, 95% CI 2.45-2.56, P < .001). The HBR group was also associated with a greater risk of all-cause mortality (HR 3.73, 95% CI 3.66-3.79, P < .001). The average annual rate of major bleeding events within the first year after PCI was 5.5% for a single major criterion, and 2.9% for a single minor criterion.

    CONCLUSIONS Among patients undergoing PCI, those with HBR were at increased long-term risk for both bleeding and ischaemic events, with a greater risk of mortality compared to non-HBR patients.

    PubMed IF 45.3 순환기내과
16. 1762024

    제1저자 권순일 · 교신저자 서장원, 최의근

    Kwon S, Suh J, Choi EK, Kim J, Ju H, Ahn HJ, Kim S, Lee SR, Oh S, Rhee W

    Classification of underlying paroxysmal supraventricular tachycardia types using deep learning of sinus rhythm electrocardiograms.

    Digit Health. 2024;10:20552076241281200.

    Abstract

    BACKGROUND Obtaining tachycardia electrocardiograms (ECGs) in patients with paroxysmal supraventricular tachycardia (PSVT) is often challenging. Sinus rhythm ECGs are of limited predictive value for PSVT types in patients without preexcitation. This study aimed to explore the classification of atrioventricular nodal reentry tachycardia (AVNRT) and concealed atrioventricular reentry tachycardia (AVRT) using sinus rhythm ECGs through deep learning.

    METHODS This retrospective study included patients diagnosed with either AVNRT or concealed AVRT, validated through electrophysiological studies. A modified ResNet-34 deep learning model, pre-trained on a public ECG database, was employed to classify sinus rhythm ECGs with underlying AVNRT or concealed AVRT. Various configurations were compared using ten-fold cross-validation on the training set, and the best-performing configuration was tested on the hold-out test set.

    RESULTS The study analyzed 833 patients with AVNRT and 346 with concealed AVRT. Among ECG features, the corrected QT intervals exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.602. The performance of the deep learning model significantly improved after pre-training, showing an AUROC of 0.726 compared to 0.668 without pre-training (p < 0.001). No significant difference was found in AUROC between 12-lead and precordial 6-lead ECGs (p = 0.265). On the test set, deep learning achieved modest performance in differentiating the two types of arrhythmias, with an AUROC of 0.708, an AUPRC of 0.875, an F1-score of 0.750, a sensitivity of 0.670, and a specificity of 0.649.

    CONCLUSION The deep-learning classification of AVNRT and concealed AVRT using sinus rhythm ECGs is feasible, indicating potential for aiding in the non-invasive diagnosis of these arrhythmias.

    PubMed IF 3.9 순환기내과
17. 1752024

    제1저자 강지훈, 박상현 · 교신저자 박경우, 구본권

    Kang J, Park SH, Park KW, Koo BK, Lee H, Han M, Hwang D, Yang HM, Chae IH, Shin WY, Oh JH, Kim YH, Park TH, Kim BS, Han JK, Shin ES, Kim HS

    Clopidogrel Versus Aspirin as Chronic Maintenance Antiplatelet Monotherapy in Patients After Percutaneous Coronary Intervention With Chronic Kidney Disease: A Post Hoc Analysis of the HOST-EXAM Trial.

    J Am Heart Assoc. 2024;13(18):e035269.

    Abstract

    BACKGROUND Clopidogrel monotherapy improved clinical outcomes compared with aspirin monotherapy during a chronic maintenance period in patients who underwent coronary stenting in the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial. However, it is uncertain whether the beneficial effect of clopidogrel over aspirin is different according to the renal function.

    METHODS AND RESULTS We conducted a post hoc analysis of the HOST-EXAM trial. Chronic kidney disease (CKD) was defined as baseline estimated glomerular filtration rate <60 mL/min per 1.73 m². The primary end point was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium bleeding type ≥3, during the 2-year follow up. Among the 5438 patients enrolled in the HOST-EXAM trial, 4844 patients (mean age, 63.3±10.6 years; 74.9% men) with a baseline creatinine value were analyzed in this study. A total of 508 (10.5%) patients had CKD, who were at higher risk of the primary end point compared with those without CKD (hazard ratio [HR], 2.01 [95% CI, 1.51-2.67]). Clopidogrel monotherapy was associated with a lower rate of the primary end point in both patients with CKD (HR, 0.74 [95% CI, 0.44-1.25]) and patients without CKD (HR, 0.71 [95% CI, 0.56-0.91]). No significant interaction was observed between the treatment effect and CKD status (P for interaction=0.889).

    CONCLUSIONS During the chronic maintenance period after coronary stenting, the risk of thrombotic and bleeding events was significantly higher in patients with CKD compared with those without CKD. There was no statistical difference in the treatment effect of clopidogrel monotherapy in those with versus without CKD.

    PubMed IF 6 순환기내과
18. 1742024

    제1저자 김동현 · 교신저자 김범석

    Kim DH, Ahn JS, Kang M, Park G, Lim Y, Hwang S, Ock CY, Koh J, Chung EJ, Kwon SK, Jeon YK, Jung KC, Ahn SH, Keam B

    Comparison of Tumor Microenvironments between Primary Tumors and Lymph Node Metastases in Head and Neck Squamous Cell Carcinoma and Their Predictive Role in Immune Checkpoint Inhibitor Treatment.

    Cells. 2024;13(18):cells13181557.

    Abstract

    The relationship between tumor microenvironments (TMEs) of regional lymph node metastases (LNMs) and primary tumors in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study compared tumor-infiltrating lymphocytes (TILs) and the immune phenotype (IP), characterized by spatial TIL distribution, between primary tumors and LNMs. Twenty-one HNSCC patients with regional LNM who received immune checkpoint inhibitors (ICIs) were included. A paired comparative analysis of TIL densities and IP between primary tumors and LNMs revealed no significant difference or correlation between TIL densities in primary tumors and LNMs. Their IPs were discordant in 12 patients (57.1%). Patients with high intratumoral TIL exhibited longer progression-free survival (PFS) than those with low intratumoral TIL in both primary tumors (median, 5.2 vs. 1.3 months, p = 0.003) and LNMs (median, 30.2 vs. 1.3 months, p = 0.012). Patients with inflamed IP exhibited longer PFS than those with non-inflamed IP in both primary tumors (median, 4.5 vs. 1.3 months, p = 0.043) and LNMs (median, 4.1 vs. 1.3 months, p = 0.037). Given the lack of correlation in TIL densities, the discrepancies in IP, and the predictive value of both TMEs, evaluating the TMEs of both primary tumors and LNMs may be beneficial for the precise use of ICIs in HNSCC. There was a significant discordance between the TME of primary tumors and LNMs, with implications in survival outcomes. Therefore, evaluating the TME of both the primary tumor and LNM could be beneficial for the precise use of ICIs in HNSCC.

    PubMed IF 6 혈액종양내과
19. 1732024

    제1저자 정성원 · 교신저자 김윤준

    Chung SW, Park MK, Zhang X, Wang T, Jemielita T, Fernandes G, Engel SS, Jang H, Lee YB, Cho EJ, Lee JH, Yu SJ, Yoon JH, Kim YJ

    The Predictive Value of Time-Varying Noninvasive Scores on Long-Term Prognosis of NAFLD in South Korea.

    Can J Gastroenterol Hepatol. 2024;2024:5667986.

    Abstract

    BACKGROUND This study aimed to examine whether repeated measurements on noninvasive fibrosis scores during follow-up improve long-term nonalcoholic fatty liver disease (NAFLD) outcome prediction.

    METHODS A cohort study of 2,280 NAFLD patients diagnosed at the Seoul National University Hospital from 2001 to 2015 was conducted. Multivariable Cox regression models with baseline and designated time-point measurements of the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were used to assess the association between these scores and overall mortality, liver-related outcomes, and cardiovascular events.

    RESULTS Higher baseline NFS (high versus low probability for advanced fibrosis groups) was associated with higher risk of mortality (adjusted hazard ratio (aHR), (95% confidence interval (CI)), 2.80, [1.39-5.63]) and liver-related outcomes (3.70, [1.27-10.78]). Similar findings were observed for the association of baseline FIB-4 with mortality (2.49, [1.46-4.24]) and liver-related outcomes (11.50, [6.17-21.44]). In models considering designated time-point measurements of the scores, stronger associations were noted. For NFS, a higher time-point measurement was associated with a significantly higher risk of mortality (3.01, [1.65-5.49]) and liver-related outcomes (6.69, [2.62-17.06]). For FIB-4, higher time-point measurements were associated with significantly higher mortality (3.01, [1.88-4.82]) and liver-related outcomes (13.26, [6.89-25.53]). An annual increase in FIB-4 (2.70, [1.79-4.05]) or NFS (4.68, [1.52-14.44]) was associated with an increased risk of liver-related outcomes. No association between NFS/FIB-4 and risk of cardiovascular events was observed in both models.

    CONCLUSIONS Higher aHRs describing the associations of FIB-4/NFS with overall mortality and liver-related outcomes were observed in the models that included designated time-point measurements of the scores. In addition to the baseline measurement, a routine monitoring on these scores may be important in predicting prognosis of NAFLD patients.

    PubMed IF 2.5 소화기내과
20. 1722024

    제1저자 김의주 · 교신저자 이상협, 정민규

    Kim EJ, Lee SH, Jung MK, Jang DK, Jo JH, Lee JM, Choe JW, Han SY, Choi YH, Kim SH, Park JM, Paik KH

    Current Diagnosis and Treatment of Acute Pancreatitis in Korea: A Nationwide Survey.

    Gut Liver. 2024;18(5):897-905.

    Abstract

    BACKGROUND/AIMS Acute pancreatitis (AP) is a leading cause of emergency hospitalization. We present the current diagnostic and therapeutic status of AP as revealed by analysis of a large multicenter dataset.

    METHODS The medical records of patients diagnosed with AP between 2018 and 2019 in 12 tertiary medical centers in Korea were retrospectively reviewed.

    RESULTS In total, 676 patients were included, of whom 388 (57.4%) were male, and the mean age of all patients was 58.6 years. There were 355 (52.5%), 301 (44.5%), and 20 (3.0%) patients with mild, moderate, and severe AP, respectively, as assessed by the revised Atlanta classification. The most common etiologies of AP were biliary issues (41.6%) and alcohol consumption (24.6%), followed by hypertriglyceridemia (6.8%). The etiology was not identified in 111 (16.4%) patients at the time of initial admission. The overall mortality rate was 3.3%, increasing up to 45.0% among patients with severe AP. Notably, 70.0% (14/20) of patients with severe AP and 81.5% (154/189) of patients with systemic inflammatory response syndrome had received <4 L per day during the initial 24 hours of admission. Only 23.8% (67/281) of acute biliary pancreatitis patients underwent cholecystectomy during their initial admission. In total, 17.8% of patients experienced recurrent attacks during follow-up. However, none of the patients with acute biliary pancreatitis experienced recurrent attacks if they had undergone cholecystectomy during their initial admission.

    CONCLUSIONS This study provides insights into the current status of AP in Korea, including its etiology, severity, and management. Results reveal disparities between clinical guidelines and their practical implementation for AP treatment.

    PubMed IF 4.1 소화기내과
21. 1712024

    제1저자 임석아 · 교신저자 임석아

    Im SA, Cortes J, Cescon DW, Yusof MM, Iwata H, Masuda N, Takano T, Huang CS, Chung CF, Tsugawa K, Park YH, Matsumoto K, Inoue K, Kwong A, Loi S, Fu W, Pan W, Karantza V, Rugo HS, Schmid P

    Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC.

    NPJ Breast Cancer. 2024;10(1):79.

    Abstract

    In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator's choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

    PubMed IF 8.4 혈액종양내과
22. 1702024

    제1저자 정광현, 조인래 · 교신저자 이상협, 한경도

    Chung KH, Cho IR, Choi YH, Cho YD, Ryu JK, Lee SH, Han K

    Association between diabetic status and risk of acute pancreatitis: A nationwide population-based study.

    J Evid Based Med. 2024;17(3):588-596.

    Abstract

    OBJECTIVE There have been several epidemiologic studies on the association between diabetes mellitus and acute pancreatitis. However, there is no solid evidence, and the effect of diabetes mellitus severity on acute pancreatitis incidence is not well known. This study aimed to evaluate the association between diabetic status and the risk of acute pancreatitis in a nationwide population-based cohort.

    METHODS Among the participants who underwent national health examinations between 2009 and 2012, patients with diabetes mellitus were included. Patients diagnosed with acute pancreatitis before the health examination or diagnosed with pancreatitis within 1 year following the examination were excluded. The association between the number of oral hypoglycemic agents (<3 or ≥3) or insulin use during examination and acute pancreatitis occurrence was analyzed after follow-up until December 31, 2018.

    RESULTS Overall, 2,444,254 patients were included in the final analysis. During the follow-up period, acute pancreatitis occurred in 10,360 patients with an incidence ratio of 0.585 per 1,000 person-years, and it was observed that the risk of acute pancreatitis sequentially increased between patients taking oral hypoglycemic agents <3 (incidence ratio = 0.546), those taking ≥3 (incidence ratio = 0.665), and those using insulin (incidence ratio = 0.872). The adjusted hazard ratios of patients taking three or more hypoglycemic agents and those using insulin were 1.196 (95% confidence interval (CI) 1.123-1.273) and 1.493 (95% CI 1.398-1.594), respectively.

    CONCLUSIONS As diabetes mellitus severity increases, the risk of acute pancreatitis increases.

    PubMed IF 4.7 소화기내과
23. 1692024

    제1저자 배지연, 박제현 · 교신저자 강창경

    Bae J, Park JH, Lee M, Jo HJ, Lee CM, Kang CK, Choe PG, Park WB, Kim NJ, Kim I, Oh MD

    Clinicomicrobiological risk factors for infective endocarditis in viridans group streptococci bacteraemia.

    J Antimicrob Chemother. 2024;79(9):2327-2333.

    Abstract

    BACKGROUND When to perform echocardiography to rule out infective endocarditis (IE) in patients with viridans group streptococci (VGS) bloodstream infections (BSIs) is unclear.

    OBJECTIVES We aimed to identify independent risk factors for IE in patients with VGS BSI.

    METHODS This retrospective study conducted at Seoul National University Hospital from January 2013 to December 2022 involved patients with VGS and nutritionally variant streptococcal BSI, excluding single positive blood cultures and polymicrobial BSI cases. Independent risk factors were identified by multivariate logistic regression and sensitivity analyses according to echocardiography results, VGS species or the inclusion of possible IE cases.

    RESULTS Of 845 VGS BSI cases, 349 were analysed and 86 IE cases were identified (24.6%). In the multivariate analysis, heart valve disease [adjusted odds ratio (aOR), 14.14, 95% CI, 6.14-32.58; P < 0.001], persistent bacteraemia (aOR, 5.12, 95% CI, 2.03-12.94; P = 0.001), age (per year, aOR, 0.98; 95% CI, 0.96-1.00; P = 0.015), solid cancer (aOR, 0.26; 95% CI, 0.13-0.53; P < 0.001) and haematologic malignancy (aOR, 0.04; 95% CI, 0.01-0.41; P = 0.006) were independently associated with IE. Sensitivity analyses yielded consistent results; also, infection by a member of the mitis group was independent risk factor for IE (aOR, 6.50; 95% CI, 2.87-14.68; P < 0.001).

    CONCLUSIONS Younger age, heart valve disease, persistent bacteraemia, absence of underlying malignancy and BSI by a member of the mitis group were independent risk factors for IE in patients with VGS BSI. Echocardiographic evaluation could be prudently considered based on these clinicomicrobiological risk factors.

    PubMed IF 3.6 감염내과
24. 1682024

    제1저자 조인래 · 교신저자 이상협

    Cho IR, Lee SH, Choi JH, Chun JW, Lee MW, Lee MH, Kim J, Lee TS, Paik WH, Ryu JK, Kim YT

    Diagnostic performance of EUS-guided elastography for differential diagnosis of gallbladder polyp.

    Gastrointest Endosc. 2024;100(3):449-456.e1.

    Abstract

    BACKGROUND AND AIMS It is difficult to differentiate between neoplastic and non-neoplastic gallbladder (GB) polyps before surgery. EUS-guided elastography (EUS-EG) is a noninvasive complementary diagnostic method. The utility of EUS-EG in the differential diagnosis of GB polyps has not been investigated. We investigated the diagnostic performance of EUS-EG for the differential diagnosis of GB polyps.

    METHODS Patients with GB polyps were prospectively enrolled from June 2020 until November 2022. EUS-EG and semiquantitative evaluation of the strain ratio (SR) were performed for differential diagnosis of GB polyps. Fifty-three eligible patients were divided into 2 groups based on the final diagnosis after surgery. Patient demographics, EUS characteristics, and SR values were compared. A receiver-operating characteristic curve analysis was performed to determine the optimal cutoff SR value that discriminates between neoplastic and non-neoplastic GB polyps.

    RESULTS The median SR value for neoplastic polyps (32.93 [interquartile range {IQR}, 22.37-69.02]) was significantly higher than for non-neoplastic polyps (5.40 [IQR, 2.36-14.44], P < .001). Significant differences were found in SR values between non-neoplastic, benign neoplastic (23.38 [IQR, 13.62-39.04]), and malignant polyps (49.25 [IQR, 27.90-82.00]). The optimal cutoff SR value to differentiate between neoplastic and non-neoplastic polyps was 18.4. In multivariable logistic regression, SR value >18.4 (odds ratio, 33.604; 95% confidence interval, 2.588-436.292) was an independent predictor of neoplastic polyps.

    CONCLUSIONS EUS-EG and SR values can be used as a supplementary method for evaluating GB polyps. (Clinical trial registration number: NCT04416763.).

    PubMed IF 8 소화기내과
25. 1672024

    제1저자 윤현동 · 교신저자 윤성수, 고영일

    Yoon H, Lee D, Song S, Koo B, Park J, Kim TK, Kim S, Kim S, Hong J, Byun JM, Shin DY, Kim I, Koh Y, Yoon SS

    Unraveling the impact of lysosomal dysfunction on myeloproliferative neoplasm.

    Cancer Med. 2024;13(18):e70238.

    Abstract

    BACKGROUND Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background.

    METHODS Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed.

    RESULTS A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV.

    CONCLUSIONS In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function.

    PubMed IF 3.5 혈액종양내과
26. 1662024

    제1저자 형권형 · 교신저자 임재준

    Hyung K, Kim SA, Kim JY, Kwak N, Yim JJ

    Rates and Risk Factors of Progression in Patients With Nontuberculous Mycobacterial Pulmonary Disease: Secondary Analysis of a Prospective Cohort Study.

    Chest. 2024;166(3):452-460.

    Abstract

    BACKGROUND The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) is varied, and a watchful waiting management strategy is appropriate for a subset of patients. Understanding disease progression and risk factors for progression is essential for deciding on an appropriate follow-up strategy.

    RESEARCH QUESTION What is the rate of NTM-PD progression, and what are the predictors of progression?

    STUDY DESIGN AND METHODS Patients with NTM-PD who were enrolled in a prospective observational cohort study between July 1, 2011, and December 31, 2022, were included in this analysis. Clinical, bacterial, laboratory, and radiographic data were collected at enrollment and then regularly during follow-up. NTM-PD progression was defined as either the initiation of treatment or the clinician's intention to treat. The rate of progression was calculated and the predictors for progression were analyzed.

    RESULTS Of the 477 patients enrolled, NTM-PD progressed in 192 patients over a median follow-up of 5.4 years. The incidence of NTM-PD progression was 11.0 cases per 100 person-years (95% CI, 9.5-12.7 cases per 100 person-years). The proportion of patients experiencing disease progression was 21.4% at 1 year, 33.8% at 3 years, and 43.3% at 5 years. The final multivariable analysis model identified female sex (adjusted hazard ratio [aHR], 1.69; 95% CI, 1.19-2.39), elevated erythrocyte sedimentation rate (aHR, 1.79; 95% CI, 1.31-2.43), FEV₁ % predicted (aHR, 0.89; 95% CI, 0.82-0.96), and the presence of a cavity (aHR, 2.78; 95% CI, 2.03-3.80) as predictors of progression.

    INTERPRETATION About one-half of patients with NTM-PD experienced progression during an observation period of > 5 years. Patients with risk factors for progression should be observed closely.

    TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01616745; URL: www.

    CLINICALTRIALS gov.

    PubMed IF 9.8 호흡기내과
27. 1652024

    제1저자 구본권, 양석훈 · 교신저자 구본권

    Koo BK, Yang S, Jung JW, Zhang J, Lee K, Hwang D, Lee KS, Doh JH, Nam CW, Kim TH, Shin ES, Chun EJ, Choi SY, Kim HK, Hong YJ, Park HJ, Kim SY, Husic M, Lambrechtsen J, Jensen JM, Nørgaard BL, Andreini D, Maurovich-Horvat P, Merkely B, Penicka M, de Bruyne B, Ihdayhid A, Ko B, Tzimas G, Leipsic J, Sanz J, Rabbat MG, Katchi F, Shah M, Tanaka N, Nakazato R, Asano T, Terashima M, Takashima H, Amano T, Sobue Y, Matsuo H, Otake H, Kubo T, Takahata M, Akasaka T, Kido T, Mochizuki T, Yokoi H, Okonogi T, Kawasaki T, Nakao K, Sakamoto T, Yonetsu T, Kakuta T, Yamauchi Y, Bax JJ, Shaw LJ, Stone PH, Narula J

    Artificial Intelligence-Enabled Quantitative Coronary Plaque and Hemodynamic Analysis for Predicting Acute Coronary Syndrome.

    JACC Cardiovasc Imaging. 2024;17(9):1062-1076.

    Abstract

    BACKGROUND A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization.

    OBJECTIVES This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA).

    METHODS Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort.

    RESULTS Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA.

    CONCLUSIONS AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328).

    PubMed IF 19 순환기내과
28. 1642024

    제1저자 윤민재, 김원세 · 교신저자 박진주, 국웅

    Yoon M^*, Kim W^*, Kook W, Park JJ, Greenberg B

    Analysis of the PARAGON-HF Study Results Using Win Ratio.

    Circ Heart Fail. 2024;17(9):e011860.

    Abstract

    BACKGROUND The PARAGON-HF study (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) investigated the effect of sacubitril-valsartan in heart failure (HF) with preserved ejection fraction. The results, which were analyzed using conventional statistical methods, did not find a significant reduction in the primary composite end point of cardiovascular death and total hospitalization for HF. Recent clinical trials used win ratio statistics that enable the incorporation of multiple outcome aspects into the primary end point and can detect positive outcomes with fewer patients. In this study, we assessed the effect of sacubitril-valsartan on outcomes using the win ratio to analyze results from patients included in the PARAGON-HF study.

    METHODS In the PARAGON-HF study, 4822 patients with HF with preserved ejection fraction were randomized either to sacubitril-valsartan or valsartan groups. In the present study, the primary outcome was a hierarchical composite of time to cardiovascular death, total number of hospitalization for HF, time to first hospitalization for HF, time to renal composite outcome, and change in the Kansas City Cardiomyopathy Questionnaire total symptom score at 8 months analyzed using a win ratio statistical model.

    RESULTS Using this approach, we found that a greater number of patients who received sacubitril-valsartan experienced clinical benefits compared with those who received valsartan (win ratio, 1.13 [95% CI, 1.04-1.23]; P=0.005). This clinical advantage was evident in patients regardless of whether the left ventricular ejection fraction was above or below the median, that is, the left ventricular ejection fraction of 57%, and regardless of sex (P_interaction=0.76 for the left ventricular ejection fraction and 0.73 for sex).

    CONCLUSIONS Employing the innovative win ratio approach, sacubitril-valsartan demonstrated significant clinical benefits among patients with HF with preserved ejection fraction. Notably, this benefit was observed irrespective of left ventricular ejection fraction and sex.

    REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

    PubMed IF 8.3 순환기내과
29. 1632024

    제1저자 박시연, 박성열 · 교신저자 김태민

    Park S, Park S, Kim TM, Kim S, Koh J, Lim J, Yi K, Yi B, Ju YS, Kim M, Keam B, Kim JS, Jeon YK, Kim DW, Kim YT, Heo DS

    Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer.

    Eur J Cancer. 2024;208:114206.

    Abstract

    BACKGROUND Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown.

    METHODS To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation.

    RESULTS EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response.

    CONCLUSIONS Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

    PubMed IF 7.9 혈액종양내과
30. 1622024

    제1저자 윤지선 · 교신저자 오도연

    Yoon J, Oh DY

    HER2-targeted therapies beyond breast cancer - an update.

    Nat Rev Clin Oncol. 2024;21(9):675-700.

    Abstract

    The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.

    PubMed IF 94.6 혈액종양내과

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