SCI 발표논문

2020년 305편

652020

제1저자 남준열, 장은선 · 교신저자 정숙향

, , , , , , , , , , ,
Epidemiological and Clinical Characteristics of Hepatitis C Virus Infection in South Korea from 2007 to 2017: A Prospective Multicenter Cohort Study.
Gut Liver. 2020;14(2):207-217.

Abstract
BACKGROUND/AIMS This study aimed to elucidate the epidemiological and clinical characteristics of chronic hepatitis C (CHC) patients in South Korea from 2007 to 2017 and to compare the treatment patterns between two periods before and after the first approval of direct-acting antivirals (DAA) in South Korea in 2015.
METHODS This prospective, multicenter cohort enrolled 2,758 patients with hepatitis C virus (HCV) viremia at seven tertiary centers, and clinical data were prospectively collected with questionnaire surveys focused on lifetime risk factors related to HCV infection.
RESULTS The HCV patients had a mean age of 57.3 years (50.8% male). Among them, 14.3% showed a positive history of transfusion before HCV screening and 5.6% reported intravenous drug use (IVDU), with significant differences in these risk factors between men and women. The proportions of patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) were 69.5%, 18.9%, and 11.5%, respectively. The mean alanine aminotransaminase level was within the upper normal limit at 49.9%, and the major genotypes were 1b (48.2%) and 2 (46.4%). The overall treatment rate was 53.8%, showing a rapid transition from interferon-based therapy to DAA therapy. In the post-DAA-approval era, the untreated group was older, had a higher prevalence of HCC, and had less education than the treated group.
CONCLUSIONS More than 90% of CHC patients were over 40 years old, the major genotypes were 1b and 2, and IVDU was observed in less than 6% of CHC patients. Approximately half of the patients underwent antiviral therapy even in the DAA era, showing an unmet need with regard to HCV elimination.
PubMed IF 4.1 소화기내과
642020

제1저자 조영윤 · 교신저자 김윤준

, , , , , , , ,
Long-term Nucleotide Analogue Treatment Has Higher Levels of Renal Toxicities than Does Entecavir in Patients with Chronic Hepatitis B.
Gut Liver. 2020;14(2):225-231.

Abstract
BACKGROUND/AIMS Renal toxicity is a concern in patients with chronic hepatitis B taking nucleotide analogues, such as adefovir (ADV) and tenofovir disoproxil fumarate (TDF). We sought to determine the long-term renal effects of nucleotide analogue treatment versus entecavir (ETV) treatment.
METHODS In this retrospective single-center study, we selected 87 patients who were treated with ADV and subsequently with TDF from June 2008 to December 2013. ETV-treated patients were matched by treatment duration. We analyzed the creatinine increase over 0.5 mg/dL, glomerular filtration rate (GFR) decrease over 25%, phosphorus decrease under 2.0 mg/dL, and dose reduction of antiviral agents.
RESULTS The median follow-up period was 60.0 months for both groups. The incidence of liver cirrhosis was higher in the ADV-TDF group than in the ETV group (32.2% vs 74.7%, p<0.01). Creatinine increased in both groups during follow-up, but the difference was not significant (5.7% and 2.3%, p=0.44). In addition, GFR decreased more often in the ADV-TDF group than in the ETV group (31.0% and 14.9%, p=0.01). After multivariate Cox regression analysis, ADV-TDF treatment was significantly associated with a GFR decrease over 25% (hazard ratio, 2.10; 95% confidence interval, 1.08 to 4.10; p=0.03) after adjusting for the baseline GFR decrease.
CONCLUSIONS Patients taking nucleotide analogues had a significantly higher number of renal events than did those taking ETV. Clinicians should be aware of the development of renal toxicity in this patient population. Further long-term studies are warranted.
PubMed IF 4.1 소화기내과
632020

제1저자 안소라, 김학로 · 교신저자 김유정

, , , , , , , , , , , ,
Symptom burden and characteristics of patients who die in the acute palliative care unit of a tertiary cancer center.
Ann Palliat Med. 2020;9(2):216-223.

Abstract
BACKGROUND Acute palliative care unit (APCU) is a novel inpatient program in a tertiary cancer center that provides aggressive symptom management and assists with the transition to hospice. However, patients often die in the APCU before successfully transferring to hospice. The aim of this study was to evaluate the symptom burden and characteristics of advanced cancer patients who died in the APCU.
METHODS We retrospectively reviewed the medical records of all advanced cancer patients admitted to the APCU between April 2015 and March 2016 at a tertiary cancer center in Korea. Basic characteristics and symptom burden assessed by the Edmonton Symptom Assessment System (ESAS) were retrieved. Statistical analyses were conducted to compare patients who died in the APCU with those who were discharged alive.
RESULTS Of the 267 patients, 87 patients (33%) died in the APCU. The median age of the patients was 66 years (range, 23-97 years). The most common primary cancer types were lung (21%), stomach (17%), and colorectal cancer (15%). Patients who died in the APCU had higher ESAS scores for drowsiness (6 vs. 5, P=0.002), dyspnea (4 vs. 2, P=0.001), anorexia (8 vs. 6, P=0.014) and insomnia (6 vs. 4, P=0.002) compared to patients who were discharged alive. The total symptom distress score (SDS) was also significantly higher (47 vs. 40, P=0.001) in patients who died in the APCU. In the multivariate analysis, patients who died in the APCU were more likely to be male [odds ratio (OR) 2.63, 95% confidence interval (CI): 1.49-4.64, P=0.001] and have higher ESAS scores for drowsiness (OR 2.08, 95% CI: 1.08-3.99, P=0.029) and dyspnea (OR 2.19, 95% CI: 1.26-3.80, P=0.005). Patients who died in the APCU showed significantly shorter survival after APCU admission (7 vs. 31 days, P<0.001).
CONCLUSIONS Advanced cancer patients who die in the APCU were more likely to be male and have significantly higher symptom burden including drowsiness and dyspnea. These patients showed rapid clinical deterioration after APCU admission. More proactive and timely end-of-life care is needed for these patients.
PubMed IF 1.681 혈액종양내과
622020

제1저자 이소령 · 교신저자 최의근

, , , , , , ,
Effectiveness and Safety of Direct Oral Anticoagulants in Relation to Temporal Changes in Their Use.
Circ Cardiovasc Qual Outcomes. 2020;13(3):e005894.

Abstract
Background Since the direct oral anticoagulants (DOAC) were introduced, oral anticoagulant (OAC) prescription patterns have rapidly changed in patients with atrial fibrillation (AF). We aimed to evaluate the evolving trends of OAC use in a large nationwide cohort and specifically examine the changes in patient profiles treated with warfarin or DOAC and whether the time trends in OAC use affected clinical outcomes. Methods and Results Using the Korean Health Insurance Review and Assessment database, we divided OAC naive patients with AF into 3 groups according to the enrollment period between January 2015 and December 2017 (n=35 353 in cohort 1, n=36 631 in cohort 2, and n=44 819 in cohort 3). DOAC use increased from 59% to 89%, whereas warfarin use has decreased from 41% to 11% during the study period. Patients treated with warfarin were increasingly younger from cohort 1 to cohort 3 (mean age 68-65 years, P<0.001) with lower mean CHA₂DS₂-VASc scores (3.3-2.9, P<0.001), whereas those with DOAC did not show a significant difference in clinical characteristics over the study period. Warfarin group had improved clinical outcomes over time, reflecting dynamic changes in patient characteristics. Compared with warfarin group, unadjusted hazard ratios of composite outcome for DOAC group have changed over time (hazard ratio 0.77 [95% CI, 0.69-0.85] in cohort 1, hazard ratio 0.84 [95% CI, 0.73-0.97] in cohort 2, and hazard ratio 1.00 [95% CI, 0.78-1.25] in cohort 3). After propensity score weighting between warfarin and DOAC groups in each cohort, DOAC showed consistently lower risks of the composite outcome by approximately 23% to 25% compared with warfarin across 3 different periods. Conclusions In contemporary clinical practice, OAC prescription patterns and characteristics of patients treated warfarin or DOAC have dynamically changed. Despite these changes, DOAC showed a consistent better net clinical benefit compared with warfarin across different periods.
PubMed IF 6.9 순환기내과
612020

제1저자 이동석 · 교신저자 박종규

, , ,
Clinical significance of regional lymph node enlargement in patients with EGC within the expanded criteria for ESD.
BMC Gastroenterol. 2020;20(1):51.

Abstract
BACKGROUND Lymph node (LN) metastasis is negligible in early gastric cancer (EGC) within expanded criteria for endoscopic submucosal dissection (ESD). However, regional lymph nodes in abdominal CT scans are sometimes enlarged in patients with EGC within the expanded criteria for endoscopic submucosal dissection (ESD). In this study, we investigated the clinical significance of regional lymph node enlargement on abdominal CT scan in patients with EGC within the expanded criteria for ESD.
METHODS From December 2010 to April 2015, among 301 patients with EGC within the ESD expanded criteria, 47 patients with regional lymph node enlargement shown by abdominal CT scan were prospectively enrolled. We performed surgical resection or periodic follow-up with abdominal CT scans and upper endoscopy every 6 months to evaluate whether the enlarged lymph nodes are due to metastasis or a reactive change.
RESULTS The mean age of the 47 patients (38 males, 9 female) was 64.8 years. The enlarged lymph nodes were usually single (26/47, 44.6%) and sized as follows: 11 nodes were ≤ 5 mm, 19 were 6-10 mm, and 17 were ≥ 10 mm. Four of the 47 patients initially underwent surgical resection, and 8 patients underwent surgical resection after ESD. However, there was no lymph node metastasis in surgical specimens. Thirty-five patients received ESD and periodically followed up at a median duration of 56 months (IQR: 44-59 month). The enlarged lymph node disappeared in 12 of 35 patients, decreased in 9 patients and remained the same size in 13 patients, and increased in 1 patient.
CONCLUSION Regional lymph node enlargement on abdominal CT scan in patients within expanded criteria for ESD of ECG may be not due to metastasis but a reactive change.
PubMed IF 3.2 소화기내과
602020

제1저자 조남한, 구유정 · 교신저자 김윤지, 최성희

, , , , , , , , ,
Estimated Association Between Cytokines and the Progression to Diabetes: 10-year Follow-Up From a Community-Based Cohort.
J Clin Endocrinol Metab. 2020;105(3):e381-9.

Abstract
CONTEXT The long-term association between multiple cytokines and progression to diabetes is still uncertain.
OBJECTIVE To identify which cytokines could predict progression to prediabetes and type 2 diabetes over 10 years.
METHODS The study included 912 participants aged 40 to 69 years at baseline from the Ansung cohort, part of the Korea Genome Epidemiology Study. At baseline, a 75-g oral glucose tolerance test and 8 cytokines were measured: plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumor necrosis factor alpha, retinol binding protein 4 (RBP4), and adiponectin. People with normal glucose tolerance (NGT, n = 241) and prediabetes (n = 330) were followed-up biennially for 10 years. Multinomial logistic regression analysis was used to evaluate the predictability of cytokines on the new-onset prediabetes and type 2 diabetes.
RESULTS At 10 years, 38 (15.8%) and 82 (34.0%) of those with NGT had converted to prediabetes and type 2 diabetes, respectively. Of those with prediabetes, 228 (69.1%) had converted to type 2 diabetes. In people with NGT or prediabetes at baseline, the highest tertile of RBP4 was associated with a 5.48-fold and 2.43-fold higher risk of progression to type 2 diabetes, respectively. The odds for converting from NGT to prediabetes in the highest tertile of PAI-1 and the lowest tertile of adiponectin were 3.23 and 3.37, respectively. In people with prediabetes at baseline, those in the highest tertile of resistin were 2.94 time more likely to develop type 2 diabetes (all P < 0.05).
CONCLUSIONS In this 10-year prospective study, NGT with higher serum RBP4 and PAI-1, and with lower adiponectin were associated with new-onset prediabetes and type 2 diabetes.
PubMed IF 5.4 내분비대사내과
592020

제1저자 진은효 · 교신저자 정성애

, , , , , ,
A Novel Susceptibility Locus Near GRIK2 Associated With Erosive Esophagitis in a Korean Cohort.
Clin Transl Gastroenterol. 2020;11(3):e00145.

Abstract
INTRODUCTION The male-predominant sex difference through the spectrum of erosive esophagitis to Barrett's esophagus is widely known. We conducted a genome-wide association study (GWAS) stratified by sex for identifying factors that can predict the endoscopically diagnosed erosive esophagitis.
METHODS Erosive esophagitis was diagnosed by endoscopy and assessed for severity. We identified genetic factors associated with erosive esophagitis that accounted for the sex differences in a cohort of 4,242 participants via a GWAS. After quality control and imputation, genetic associations with erosive esophagitis were investigated by multivariate linear regression in 3,620 subjects. Single-nucleotide polymorphisms (SNPs) with P < 5.0 × 10 were considered significant genome wide, and a genetic risk score was constructed for the prediction of erosive esophagitis risk.
RESULTS Six genome-wide significant SNPs near the GRIK2 gene on chromosome 6 were found to be associated with erosive esophagitis only in male subjects. These were predictive of severity through a genetic risk score (P < 0.05), and the findings were validated in a cohort of 622 subjects (P < 0.05).
DISCUSSION This is the first GWAS of erosive esophagitis, and we identified 6 genome-wide significant SNPs in male subjects. These SNPs could help explain the pathogenesis of erosive esophagitis and contribute to the understanding of sex differences. Further genetic investigation could allow for the prediction of high risk for erosive esophagitis and development of new treatment options.
PubMed IF 3.6 소화기내과
582020

제1저자 조유리, 최윤이 · 교신저자 김원

, , , , , , , , ,
Point shear wave elastography predicts fibrosis severity and steatohepatitis in alcohol-related liver disease.
Hepatol Int. 2020;14(2):270-280.

Abstract
BACKGROUND Point shear wave elastography (pSWE) is a convenient noninvasive tool for assessing liver fibrosis in chronic liver disease. However, there is little information on the correlation between pSWE and the histological findings of alcohol-related liver disease (ALD). Thus, we investigated the diagnostic performance of pSWE in discriminating the fibrosis stage of patients with ALD.
METHODS A total of 251 Korean patients with ALD were prospectively enrolled. The diagnostic performance of pSWE was evaluated on the basis of histological fibrosis severity according to Kleiner/Brunt et al.'s criteria and the Laennec classification.
RESULTS Median liver stiffness on pSWE significantly increased as liver fibrosis stage increased (p < 0.001). Liver stiffness measurement proved to be an excellent diagnostic indicator in the evaluation of a ≥ F2 stage (area under the receiver operating characteristics curve [AUROC] 0.93; cutoff > 1.46 m/s), ≥ F3 stage (AUROC 0.90; cutoff > 1.47 m/s), and F4 stage (AUROC 0.91; cutoff > 1.66 m/s). Compared with noninvasive serum fibrosis tests, pSWE had the highest AUROC for predicting ≥ F2, ≥ F3, and = F4 stages and the highest Obuchowski index (0.931 ± 0.007; all p < 0.001). The AUROC for discriminating steatohepatitis from simple steatosis was 0.93 (> 1.49 m/s) and the AUROC for discriminating cirrhosis with steatohepatitis from cirrhosis without steatohepatitis was 0.92 (> 2.52 m/s).
CONCLUSION pSWE not only gives an accurate indication of liver fibrosis stage in ALD, but also can allow patients with severe alcoholic steatohepatitis to begin corticosteroid treatment without exposing them to the risks of liver biopsy.
CLINICAL TRIAL REGISTRATION Clincialtrials.gov Identifier NCT01943318.
PubMed IF 7.8 소화기내과
572020

제1저자 이정석, 안요한, 윤종수 · 교신저자 이은영, 주영석

, , , , , , , , , ,
Germline gain-of-function mutation of STAT1 rescued by somatic mosaicism in immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like disorder.
J Allergy Clin Immunol. 2020;145(3):1017-1021.

PubMed IF 11.2 류마티스내과
562020

제1저자 박창희 · 교신저자 김미소

, , , , , , , , ,
Clinical Application of Next-Generation Sequencing-Based Panel to BRAF Wild-Type Advanced Melanoma Identifies Key Oncogenic Alterations and Therapeutic Strategies.
Mol Cancer Ther. 2020;19(3):937-944.

Abstract
Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with BRAF wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E-negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1-mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92-1.00; P = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, P = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.
PubMed IF 6.9 혈액종양내과
552020

제1저자 홍수정 · 교신저자 김지현

, , , , , , , , , , , , , , , , , , , , ,
Polypharmacy, Inappropriate Medication Use, and Drug Interactions in Older Korean Patients with Cancer Receiving First-Line Palliative Chemotherapy.
Oncologist. 2020;25(3):e502-e511.

Abstract
BACKGROUND Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially inappropriate medication (PIM) use, and drug-drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes.
SUBJECTS, MATERIALS, AND METHODS This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first-line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first-line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi-comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment-related toxicity, and hospitalization using logistic regression and Cox regression analyses.
RESULTS In total, 301 patients (median age 75 years; range, 70-93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0-14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 [1.18-2.55], p < .01). Neither polypharmacy nor PIM use showed association with treatment-related toxicity.
CONCLUSION Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period.
IMPLICATIONS FOR PRACTICE This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug-drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer.
PubMed IF 4.7 혈액종양내과
542020

제1저자 공성혜, 김정희 · 교신저자 조남한

, , , , , ,
Low free T3 to free T4 ratio was associated with low muscle mass and impaired physical performance in community-dwelling aged population.
Osteoporos Int. 2020;31(3):525-531.

Abstract
UNLABELLED In aged population, the association of thyroid hormones on physical performance, especially within their normal range, has yet to be elucidated. In this study, individuals with low serum free T3/free T4 were likely to have low muscle mass and impaired physical performance.
PURPOSE We aimed to evaluate the associations of muscle mass, strength, and physical performance with thyroid hormone in an aged euthyroid population from a community-based cohort.
METHODS We examined 918 men aged over 60 years and 1215 postmenopausal women from the Ansung cohort study. Appendicular skeletal muscle mass divided by square of height (ASM/ht²) was used as the muscle mass index. Hand grip strength was measured using a hydraulic dynamometer. Physical performance was assessed using the short physical performance battery (SPPB).
RESULTS Participants with higher tertiles of free T3 and free T3/free T4 were younger and had higher ASM/ht², stronger hand grip strength, and higher SPPB scores than those in the lower tertiles. In adjusted models, men within higher tertiles of free T3 had higher ASM/ht² compared with those within lower tertiles (p = 0.033), whereas subjects with higher tertiles of free T4 had lower ASM/ht² compared with those within lower tertiles (p = 0.043). Subjects within higher tertiles of free T3/free T4 had higher ASM/ht² (p < 0.001) and better physical performance (p = 0.048) than those within lower tertiles after adjustments. However, free T3, free T4, or free T3/free T4 was not related to hand grip strength after adjustment for covariates.
CONCLUSION Our results thus indicate that in an aged euthyroid population, low serum free T3/free T4 was a better index for low muscle mass and impaired physical performance than serum free T3 or free T4 alone.
PubMed IF 5.4 내분비대사내과
532020

제1저자 김정희, 문혜미 · 교신저자 김신곤

, , , ,
Epidemiology and Prognosis of Pheochromocytoma/Paraganglioma in Korea: A Nationwide Study Based on the National Health Insurance Service.
Endocrinol Metab (Seoul). 2020;35(1):157-164.

Abstract
BACKGROUND Pheochromocytomas and paragangliomas (PPGLs) are rare endocrine tumors originating from chromaffin cells. PPGLs are associated with a high mortality rate and several complications. To date, no epidemiological studies have been conducted on PPGLs in Asia. This study aimed to investigate the epidemiology and prognosis of PPGLs in Korea using nationwide data.
METHODS Using the National Health Insurance Service Database, subjects with a principal diagnosis of PPGLs on two or more occasions between 2003 and 2014 who satisfied the operational definition of PPGLs were included. Incidence, prevalence, complications, metastasis, and mortality were investigated.
RESULTS In total, 1048 subjects with a mean age of 47.6±16.1 years were included. There was no sex preponderance. The overall prevalence of PPGLs was 2.13 per 100,000 persons, and the overall age-standardized incidence rate was 0.18 per 100,000 person-years. Malignant PPGLs accounted for 17.7% (185 of 1,048) of cases, and 94 subjects exhibited metastasis at the time of diagnosis. Among initially non-metastatic PPGLs, 9.5% (nine of 954) eventually metastasized after a mean duration of 78.1±41.4 months. The 5-year survival rates for non-metastatic and metastatic PPGLs at diagnosis were 97% and 84%, respectively. Multivariable Cox regression models adjusted for covariates showed that metastatic PPGLs were associated with a 2.40-fold higher risk of mortality than non-metastatic PPGLs (95% confidence interval, 1.38 to 4.17; P=0.002).
CONCLUSION PPGLs are rare in Korea, and the prognosis of these endocrine tumors varies depending on whether they are benign or malignant. This epidemiological study paves the way for further research on PPGLs.
PubMed IF 5.1 내분비대사내과
522020

제1저자 유승근 · 교신저자 박영주, 서정선

, , ,
Recent Improvements in Genomic and Transcriptomic Understanding of Anaplastic and Poorly Differentiated Thyroid Cancers.
Endocrinol Metab (Seoul). 2020;35(1):44-54.

Abstract
Anaplastic thyroid cancer (ATC) is a lethal human cancer with a 5-year survival rate of less than 10%. Recently, its genomic and transcriptomic characteristics have been extensively elucidated over 5 years owing to advance in high throughput sequencing. These efforts have extended molecular understandings into the progression mechanisms and therapeutic vulnerabilities of aggressive thyroid cancers. In this review, we provide an overview of genomic and transcriptomic alterations in ATC and poorly-differentiated thyroid cancer, which are distinguished from differentiated thyroid cancers. Clinically relevant genomic alterations and deregulated signaling pathways will be able to shed light on more effective prevention and stratified therapeutic interventions for affected patients.
PubMed IF 5.1 내분비대사내과
512020

제1저자 홍승욱 · 교신저자 윤혁

, , , , , ,
Clinical significance of granulomas in Crohn's disease: A systematic review and meta-analysis.
J Gastroenterol Hepatol. 2020;35(3):364-373.

Abstract
BACKGROUND AND AIM Epithelioid granuloma is one hallmark used to histologically diagnose Crohn's disease (CD). However, the clinical significance of granulomas in CD is unclear. Therefore, we performed a meta-analysis to compare the clinical features with CD according to the presence of granulomas.
METHODS A literature search in PubMed, EMBASE, and Cochrane databases was performed on manuscripts published until October 2018. We included studies that met the following inclusion criteria: (i) patient: patients with CD; (ii) exposure: granulomas on the pathology; (iii) comparator: no granulomas; and (iv) outcomes: disease location, disease behavior, perianal disease, disease activity, use of biologics, and CD-associated hospitalization, surgery.
RESULTS Nineteen studies met our inclusion criteria. Granulomas in CD patients were associated with a higher proportion of ileocolonic disease (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.21-1.83), a higher proportion of upper gastrointestinal disease (OR: 2.25, 95% CI: 1.28-3.95), a higher proportion of penetrating behavior (OR: 1.48, 95% CI: 1.09-2.01), a higher prevalence of perianal disease (OR: 2.15, 95% CI: 1.48-3.11), and a higher severity index at presentation (standardized mean difference: 0.20, 95% CI: 0.09-0.32). In addition, the use of biologics was significantly higher in CD patients with granulomas compared with without granulomas (OR: 1.66, 95% CI: 1.07-2.59). The presence of granulomas was significantly associated with CD-associated hospitalization (OR: 3.88, 95% CI: 1.44-10.49), but not with CD-associated surgery.
CONCLUSIONS Clinical features in CD patients were significantly different according to the presence of granulomas. It may indicate a more aggressive phenotype of CD.
PubMed IF 3.5 소화기내과
502020

제1저자 조영재, 신철민 · 교신저자 이동호, 한경도

, , , , , ,
Abdominal obesity increases risk for esophageal cancer: a nationwide population-based cohort study of South Korea.
J Gastroenterol. 2020;55(3):307-316.

Abstract
BACKGROUND The relationship between overall obesity, as measured by body mass index (BMI) and risk of esophageal squamous cell carcinoma (ESCC) has been reported to show a negative correlation. However, the relationship of ESCC, which accounts for around 90% of esophageal cancers in South Korea, with abdominal obesity, as measured by waist circumference (WC), may be different. Thus, we investigated the association between abdominal obesity and esophageal cancer in a nationwide population-based cohort.
METHODS A retrospective cohort study of 22,809,722 individuals who had undergone regular health check-ups provided by the National Health Insurance Corporation between 2009 and 2012 (median follow-up period, 6.4 years) in South Korea was conducted. Abdominal obesity was defined as a WC > 90 cm for men and > 85 cm for women. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using χ² test and Cox proportional hazards model adjusted for confounding factors. The primary outcome was newly developed esophageal cancer.
RESULTS After adjusting for BMI, abdominal obesity increased the risk of esophageal cancer (HR 1.29, 95% CI 1.23-1.36). WC increased the risk for esophageal cancer in a dose-dependent manner (p values for trend < 0.0001). Among overweight (BMI 23-24.9 kg/m²) and obese I (BMI 25-29.9 kg/m²) individuals, abdominal obesity was a risk factor for esophageal cancer (HR 1.22, 95% CI 1.11-1.34; HR 1.28, 95% CI 1.18-1.39, respectively).
CONCLUSION Increasing abdominal obesity may be associated with an increased risk for esophageal cancer. Further studies are warranted to confirm the relationship.
PubMed IF 5.7 소화기내과
492020

제1저자 김동희, 김원 · 교신저자 김동희, 김원

, , , , , , ,
Association between body size-metabolic phenotype and nonalcoholic steatohepatitis and significant fibrosis.
J Gastroenterol. 2020;55(3):330-341.

Abstract
BACKGROUND AND AIMS Body size-metabolic phenotype may help predict whether or not individuals with nonalcoholic fatty liver disease (NAFLD) develop advanced liver disease. We studied the association of body size-metabolic phenotype with nonalcoholic steatohepatitis (NASH) and significant fibrosis.
METHODS Our cross-sectional study included 559 subjects (mean age of 53 years; women 51%) with biopsy-proven NAFLD. Clinical, genetic, and histological characteristic features of NAFLD were evaluated. The metabolically unhealthy phenotype was defined by the presence of two or more metabolic components, while body size was categorized based on body mass index: obese (≥ 25 kg/m²) or non-obese (< 25 kg/m²). Body size-metabolic phenotypes were divided into four study groups: (1) non-obese metabolic syndrome (MS)-, (2) non-obese MS+ , (3) obese MS-, and (4) obese MS+.
RESULTS Obese MS- and non-obese MS+ groups demonstrated comparable levels of insulin resistance, adipose tissue insulin resistance indexes, and visceral adipose tissue (VAT) areas. The VAT area was significantly higher in the obese MS+ group versus obese MS- group. However, the VAT to subcutaneous adipose tissue (SAT) ratio was highest in the non-obese MS+ group. There was no difference in histology between the non-obese MS+, obese MS-, and obese MS+ groups. Multivariate analyses adjusted for age, sex, smoking status, PNPLA3, TM6SF2, and VAT/SAT areas demonstrated an independent and dose-dependent relationship between the body size-metabolic phenotype and NASH or significant fibrosis.
CONCLUSION The non-obese MS+ group displayed similar degree of hepatic histological severity compared to their obese MS- counterparts. Metabolic milieu beyond obesity may play a pathogenic role in non-obese MS+ individuals who develop NASH with significant hepatic fibrosis.
CLINICAL TRIAL NUMBER NCT02206841.
PubMed IF 5.7 소화기내과
482020

제1저자 장의진, 김택수 · 교신저자 강창경, 김인호

, , , , , , , , , , , ,
Limited Positive Predictive Value of β-d-Glucan in Hematologic Patients Receiving Antimold Prophylaxis.
Open Forum Infect Dis. 2020;7(3):ofaa048.

Abstract
BACKGROUND Diagnostic value of β-d-glucan (BDG) in populations with low prevalence of invasive fungal infection (IFI), such as hematologic patients receiving antimold prophylaxis, should be re-evaluated.
METHODS We retrospectively reviewed episodes with BDG results in hematologic patients receiving antimold prophylaxis from January 2017 to August 2019 in a tertiary hospital. The episodes were classified as true positive ([TP] positive BDG with IFI), true negative ([TN] negative BDG without IFI), false positive ([FP] positive BDG without IFI), false negative ([FN] negative BDG with IFI), and nonevaluable.
RESULTS A total of 203 episodes were analyzed: 101 episodes (49.8%) were from stem cell transplants, 89 (43.8%) were from induction chemotherapy, and 13 (6.4%) were from graft-versus-host disease treatment. There were 62 nonevaluable episodes. Among 141 evaluable ones, there were 8 (5.7%) episodes of probable/proven IFI. True positive, TN, FP, and FN cases were 4 (2.8%), 112 (79.4%), 21 (14.9%), and 4 (2.8%) episodes, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value were 50.0%, 84.2%, 16.1%, and 96.5%, respectively. Positive predictive value was 26.7% and 0.0% in diagnostic and surveillance episodes, respectively.
CONCLUSIONS β-d-glucan test should be used to exclude IFI rather than for diagnosis in these patients.
PubMed IF 3.8 감염내과
472020

제1저자 기유정, 강지훈 · 교신저자 박경우

, , , , , , , ,
Efficacy and Safety of Long-Term and Short-Term Dual Antiplatelet Therapy: A Meta-Analysis of Comparison between Asians and Non-Asians.
J Clin Med. 2020;9(3):jcm9030652.

Abstract
While dual antiplatelet therapy (DAPT) is essential after percutaneous coronary intervention (PCI), the optimal duration is affected by various factors. However, the effect of ethnicity on DAPT duration has not been fully evaluated. In this study, we evaluated the different effect of DAPT duration by ethnicity. We searched Pubmed, Embase, Cochrane library, and relevant websites to search for randomized clinical trials (RCT) assessing the clinical impact of long term DAPT (L-DAPT) and short term DAPT (S-DAPT). Studies were divided by ethnicity, and we compared the efficacy and safety of DAPT duration in each ethnic group. Thirteen RCTs including 38,255 patients (five East Asian studies and eight non-East Asian studies) were eligible for analysis. For the primary outcome, L-DAPT showed a significantly lower rate of primary outcome only in non-East Asians (S-DAPT vs. L-DAPT, odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.02-1.32, p = 0.02), while in East Asians, the effect of S-DAPT and L-DAPT were comparable. S-DAPT significantly increased ischemic events only in non-East Asians (S-DAPT vs. L-DAPT, OR = 1.24, 95% CI: 1.09-1.42, p <0.01), while bleeding events were decreased by S-DAPT in both ethnicities. These results demonstrate that the adequate DAPT duration after PCI may be different in East Asians.
PubMed IF 3.3 순환기내과
462020

제1저자 기유정 · 교신저자 박경우

, , , , , , , ,
Safety and Efficacy of Second-Generation Drug-Eluting Stents in Real-World Practice: Insights from the Multicenter Grand-DES Registry.
J Interv Cardiol. 2020;2020:3872704.

Abstract
OBJECTIVE In this study, we sought to compare the efficacy and safety of the Xience Prime/Xience V/Promus EES and Biomatrix/Biomatrix Flex/Nobori BES with resolute integrity/resolute ZES using the grand drug-eluting stent (Grand-DES) registry.
BACKGROUND Currently, new-generation drug-eluting stents (DESs) are used as the standard of care in patients undergoing percutaneous coronary intervention. No study has simultaneously compared everolimus-eluting stent (EES), biolimus-eluting stent (BES), and zotarolimus-eluting stent (ZES).
METHODS Stent-related composite outcomes (target lesion failure) and patient-related composite outcomes were compared in crude and propensity score-matched analysis.
RESULTS Of the 17,286 patients in the Grand-DES group, 5,137, 2,970, and 4,990 patients in the EES, BES, and ZES groups completed a three-year follow-up. In the propensity score-matched cohort, the stent-related outcome (EES vs. BES vs. ZES; 5.9% vs. 6.7% vs. 7.1%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%, P = 0.226) and patient-related outcomes (12.7% vs. 13.5% vs. 14.3%.
CONCLUSIONS In this robust real-world registry with unrestricted use of EES, BES, and ZES, the three stent groups showed comparable safety and efficacy at the 3-year follow-up.
PubMed IF 1.4 순환기내과
452020

제1저자 조준환 · 교신저자 조현재

, , , , , , , , , , , , ,
Neutrophil-Lymphocyte Ratio in Patients with Acute Heart Failure Predicts In-Hospital and Long-Term Mortality.
J Clin Med. 2020;9(2):jcm9020557.

Abstract
The application of a simple blood test to predict prognosis in acute heart failure (AHF) patients is not well established. Neutrophil-lymphocyte ratio (NLR) is inexpensive and easy to obtain in hospitalized patients using a routine blood test. We evaluate the prognostic implications of NLR as an independent predictor of in-hospital and long-term mortality in AHF patients. Among 5625 patients enrolled in the Korean Acute Heart Failure registry, 5580 patients were classified into quartiles by their NLR level, and analyzed for in-hospital and post-discharge three-year mortality. Patients in the highest NLR quartile had the highest in-hospital and post-discharge three-year mortality. The same results were seen by dividing the aggravating factor into the infection or ischemia group and the non-infection or non-ischemia group. For patients aggravated from infection or ischemia, a cut-off NLR value was 7.0 that increase the risk of in-hospital and post-discharge three-year mortality. In subgroups of patients not aggravated from infection or ischemia, a cut-off NLR value was 5.0 that increase the risk of in-hospital and post discharge three-year mortality. Elevated NLR in AHF patients at the index hospitalization is an independent predictor for in-hospital and post-discharge three-year mortality. Taken together, NLR is a marker for risk assessment of AHF patients.
PubMed IF 3.3 순환기내과
442020

제1저자 오규철 · 교신저자 이해영

, , , , , , , , , , , , , , , , ,
Management and Prognosis of Heart Failure in Octogenarians: Final Report from the KorAHF Registry.
J Clin Med. 2020;9(2):jcm9020501.

Abstract
Treatment of heart failure (HF) in the elderly face many difficulties due to lack of robust evidence. We analyzed the outcome of HF in octogenarians using a nationwide HF registry. Among 5625 patients from the Korean Acute Heart Failure (KorAHF) registry, prognosis of octogenarian HF and the association of guideline-directed medical therapy (GDMT) with mortality and readmissions were analyzed. Octogenarian patients (1185, 22.4%) showed a higher mortality, and males were especially at increased risk (HR (hazard ratio) 1.19, 95% CI 1.01-1.40). A J-curve association between blood pressure (BP) and mortality was observed regardless of age, but the nadir value was lower in octogenarians (123.8 vs. 127.9 mmHg for systolic blood pressure (SBP); 67.1 vs. 73.9 mmHg for diastolic blood pressure (DBP), p < 0.001). Use of GDMT in octogenarian patients with HF and reduced ejection fraction (EF) were inadequate (74.3%, 47.1%, and 46.1% in octogenarians vs. 78.4%, 59.8%, and 55.2% in non-elderly for renin-angiotensin system inhibitors, beta-blockers, and aldosterone antagonists, respectively; all p < 0.05). However, those on medications had a significant reduction in 6 month mortality. For octogenarians with HF and preserved EF, angiotensin receptor blocker use reduced hospitalizations for HF in men (HR 0.19, 95% CI 0.04-0.87), but not in women (p-interaction = 0.037). HF in octogenarians were found to have different characteristics compared with the non-elderly. However, adequate use of GDMT was still associated with improved survival, and more attention should be given to prescribing medications with clinical benefits.
PubMed IF 3.3 순환기내과
432020

제1저자 박찬순, 박준빈 · 교신저자 조구영

, , , ,
Impact of sex and myocardial function on association of obesity with mortality in Asian patients with acute heart failure: a retrospective analysis from the STRATS-AHF registry.
BMJ Open. 2020;10(2):e031608.

Abstract
OBJECTIVES Impact of sex and myocardial function on the obesity paradox in heart failure (HF) is unknown. We explored whether sex, myocardial function, and left ventricular (LV) geometry explains the protective association of body mass index (BMI) with mortality, and investigated whether metabolic health status affects this association.
DESIGN A multicentre cohort study with patients with acute HF admitted from January 2009 to December 2016 with a median follow-up of 33.7 months.
SETTING Three tertiary hospitals.
PARTICIPANTS A total of 2021 overweight-to-obese (OW) and 1543 normal-weight (NW) patients with acute HF.
MEASUREMENTS The primary outcome was all-cause mortality. Patients were categorised as either OW (BMI≥23kg/m²) or NW (BMI<23kg/m²). BMI was used as both categorical and continuous variables. Clinical, laboratory and echocardiographic measures, including LV global longitudinal strain (LV-GLS), LV-ejection fraction, LV geometry, were obtained.
RESULTS During the follow-up period, 1392 patients died (685 OW and 707 NW). BMI was significantly associated with mortality in univariate (HR=0.929 per kg/m², p<0.001) and multivariate analyses (HR=0.954 per kg/m², p<0.001). In multivariable fractional polynomials, higher BMIs were associated with lower mortality overall and in subgroups by sex, LV-GLS and LV geometry, with a steeper association in men (p-interaction <0.001). In women, there were significant interactions of BMI with LV-GLS (p-interaction=0.044) and age (p-interaction=0.040) for mortality; the protective association of BMI with mortality was confined to subgroups with high LV-GLS (>10.1%) or elderly patients (≥75 years). In men, this association was found in all subgroups without significant interaction. Metabolically healthy obese patients had better survival than metabolically unhealthy obese patients (log-rank p<0.001).
CONCLUSIONS In women, a significant interaction was observed between BMI and age or LV-GLS in association with mortality, suggesting that sex, ageing and myocardial dysfunction can affect the magnitude of the obesity paradox in HF. Metabolic health status provides prognostic information beyond obesity status.
TRIAL REGISTRATION NUMBER Registry: ClinicalTrials.gov Number: NCT03513653 (https://clinicaltrials.gov/ct2/show/NCT03513653).
PubMed IF 2.5 순환기내과
422020

제1저자 서원우, 박진주 · 교신저자 최동주

, , , , , , , , , , , , , ,
Guideline-directed medical therapy in elderly patients with heart failure with reduced ejection fraction: a cohort study.
BMJ Open. 2020;10(2):e030514.

Abstract
OBJECTIVES AND DESIGN Guideline-directed medical therapy (GDMT) with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved survival in patients with heart failure with reduced ejection fraction (HFrEF). As clinical trials usually do not include very old patients, it is unknown whether the results from clinical trials are applicable to elderly patients with HF. This study was performed to investigate the clinical characteristics and treatment strategies for elderly patients with HFrEF in a large prospective cohort.
SETTING The Korean Acute Heart Failure (KorAHF) registry consecutively enrolled 5625 patients hospitalised for acute HF from 10 tertiary university hospitals in Korea.
PARTICIPANTS In this study, 2045 patients with HFrEF who were aged 65 years or older were included from the KorAHF registry.
PRIMARY OUTCOME MEASUREMENT All-cause mortality data were obtained from medical records, national insurance data or national death records.
RESULTS Both beta-blockers and RAS inhibitors were used in 892 (43.8%) patients (GDMT group), beta-blockers only in 228 (11.1%) patients, RAS inhibitors only in 642 (31.5%) patients and neither beta-blockers nor RAS inhibitors in 283 (13.6%) patients (no GDMT group). With increasing age, the GDMT rate decreased, which was mainly attributed to the decreased prescription of beta-blockers. In multivariate analysis, GDMT was associated with a 53% reduced risk of all-cause mortality (HR 0.47, 95% CI 0.39 to 0.57) compared with no GDMT. Use of beta-blockers only (HR 0.57, 95% CI 0.45 to 0.73) and RAS inhibitors only (HR 0.58, 95% CI 0.48 to 0.71) was also associated with reduced risk. In a subgroup of very elderly patients (aged ≥80 years), the GDMT group had the lowest mortality.
CONCLUSIONS GDMT was associated with reduced 3-year all-cause mortality in elderly and very elderly HFrEF patients.
TRIAL REGISTRATION NUMBER NCT01389843.
PubMed IF 2.5 순환기내과
412020

제1저자 강민우 · 교신저자 한승석

, , , , , ,
Machine learning algorithm to predict mortality in patients undergoing continuous renal replacement therapy.
Crit Care. 2020;24(1):42.

Abstract
BACKGROUND Previous scoring models such as the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scoring systems do not adequately predict mortality of patients undergoing continuous renal replacement therapy (CRRT) for severe acute kidney injury. Accordingly, the present study applies machine learning algorithms to improve prediction accuracy for this patient subset.
METHODS We randomly divided a total of 1571 adult patients who started CRRT for acute kidney injury into training (70%, n = 1094) and test (30%, n = 477) sets. The primary output consisted of the probability of mortality during admission to the intensive care unit (ICU) or hospital. We compared the area under the receiver operating characteristic curves (AUCs) of several machine learning algorithms with that of the APACHE II, SOFA, and the new abbreviated mortality scoring system for acute kidney injury with CRRT (MOSAIC model) results.
RESULTS For the ICU mortality, the random forest model showed the highest AUC (0.784 [0.744-0.825]), and the artificial neural network and extreme gradient boost models demonstrated the next best results (0.776 [0.735-0.818]). The AUC of the random forest model was higher than 0.611 (0.583-0.640), 0.677 (0.651-0.703), and 0.722 (0.677-0.767), as achieved by APACHE II, SOFA, and MOSAIC, respectively. The machine learning models also predicted in-hospital mortality better than APACHE II, SOFA, and MOSAIC.
CONCLUSION Machine learning algorithms increase the accuracy of mortality prediction for patients undergoing CRRT for acute kidney injury compared with previous scoring models.
PubMed IF 11.4 신장내과
402020

제1저자 이승표 · 교신저자 손대원

, , , , , , , , , , , , , , ,
Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.
J Am Coll Cardiol. 2020;75(4):380-390.

Abstract
BACKGROUND It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.
OBJECTIVES The purpose of this study was to demonstrate that ¹¹C-Pittsburgh B compound positron emission tomography (¹¹C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.
METHODS This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial ¹¹C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.
RESULTS The degree of myocardial ¹¹C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R² = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial ¹¹C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).
CONCLUSIONS These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by ¹¹C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.
PubMed IF 22.3 순환기내과
392020

제1저자 김진원, 민아름 · 교신저자 임석아

, , , , , , , , , , ,
TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy.
Cancers (Basel). 2020;12(2):cancers12020334.

Abstract
The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.
PubMed IF 4.8 혈액종양내과
382020

제1저자 방영주 · 교신저자 방영주

, , , , , , , , , , , , , ,
Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts.
Cancer Sci. 2020;111(2):536-547.

Abstract
Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C_trough >EC₉₀ (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).
PubMed IF 4.9 혈액종양내과
372020

제1저자 방영주 · 교신저자 Chen Li-Tzong

, , , , , , , , , , , , ,
Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.
Cancer Sci. 2020;111(2):513-527.

Abstract
The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).
PubMed IF 4.9 혈액종양내과
362020

제1저자 Hidenori Kato · 교신저자 방영주

, , , , , , , ,
Safety, Pharmacokinetics, and Clinical Activity of Adavosertib in Combination with Chemotherapy in Asian Patients with Advanced Solid Tumors: Phase Ib Study.
Target Oncol. 2020;15(1):75-84.

Abstract
BACKGROUND The WEE1 inhibitor adavosertib (AZD1775) has been investigated in Western patients.
OBJECTIVE This open-label Phase Ib study (NCT02341456) investigated the safety, pharmacokinetics, and clinical activity of adavosertib in combination with carboplatin alone or paclitaxel plus carboplatin in Asian patients with advanced solid tumors and defined the recommended Phase II dose.
PATIENTS AND METHODS Nineteen patients received adavosertib 175 mg twice daily (bid) for 2.5 days (five doses) in combination with carboplatin (AUC 5) alone or paclitaxel (175 mg/m²) plus carboplatin, or adavosertib 225 mg bid for 2.5 days in combination with paclitaxel plus carboplatin in 21-day cycles. Preliminary safety and dose-limiting toxicity analyses were performed and dose escalation/de-escalation conducted as appropriate.
RESULTS Adavosertib 175 mg bid for 2.5 days with carboplatin alone or paclitaxel plus carboplatin was considered tolerable. Two patients receiving adavosertib 225 mg bid in combination with paclitaxel plus carboplatin experienced dose-limiting toxicities (grade 4 sepsis; grade 5 acute respiratory distress syndrome); this regimen was not considered tolerable. Grade ≥ 3 adverse events reported most commonly in any cohort included: anemia; decreased white blood cell count; decreased neutrophil count; neutropenia; decreased platelet count; thrombocytopenia; and febrile neutropenia. Exposure to adavosertib, as determined by pharmacokinetic analysis, in Asian patients was higher than that previously seen in Western patients. A partial response occurred in 2/12 evaluable patients (16.7%) at the recommended Phase II dose.
CONCLUSIONS Adavosertib 175 mg bid for 2.5 days was chosen as the recommended Phase II dose in combination with paclitaxel and carboplatin in Asian patients.
PubMed IF 5.1 혈액종양내과

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