Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background and Objectives: The Fractional Flow Reserve and Intravascular UltrasoundGuided Intervention Strategy for Clinical Outcomes in Patients with Intermediate Stenosis (FLAVOUR) trial demonstrated non-inferiority of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) compared with intravascular ultrasound (IVUS)-guided PCI. We sought to investigate the cost-effectiveness of FFR-guided PCI compared to IVUS-guided PCI in Korea. Methods: A 2-part cost-effectiveness model, composed of a short-term decision tree model and a long-term Markov model, was developed for patients who underwent PCI to treat intermediate stenosis (40% to 70% stenosis by visual estimation on coronary angiography).The lifetime healthcare costs and quality-adjusted life-years (QALYs) were estimated from the healthcare system perspective. Transition probabilities were mainly referred from the FLAVOUR trial, and healthcare costs were mainly obtained through analysis of Korean National Health Insurance claims data. Health utilities were mainly obtained from the Seattle Angina Questionnaire responses of FLAVOUR trial participants mapped to EQ-5D. Results: From the Korean healthcare system perspective, the base-case analysis showed that FFR-guided PCI was 2,451 U.S. dollar lower in lifetime healthcare costs and 0.178 higher in QALYs compared to IVUS-guided PCI. FFR-guided PCI remained more likely to be cost-effective over a wide range of willingness-to-pay thresholds in the probabilistic sensitivity analysis. Conclusions Based on the results from the FLAVOUR trial, FFR-guided PCI is projected to decrease lifetime healthcare costs and increase QALYs compared with IVUS-guided PCI in intermediate coronary lesion, and it is a dominant strategy in Korea.

Background: The stimulatory effects of caffeine contribute to poor sleep quality. However, the relationship between caffeinated beverages and sleep quality, considering frequency or types of caffeinated beverages, were not extensively studied. Methods: Data were collected from 160 urban workers (75 men [46.9%] aged 20–69 years; with an average age of 41.8±12.3 years) using a structured, self-administered online questionnaire. Sleep quality, time, satisfaction; types and frequency of caffeinated beverages (number of cups per week; Q1: 0 cup, Q4: 14 or more cups per week), demographics, and health behaviors were asked. Sleep quality were evaluated using the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). Multiple regression analysis was conducted on the association between the frequency of caffeinated beverages consumption and sleep quality. Results: The most frequently consumed beverages were unsweetened coffee (22.8%) and the most common time for caffeine was between 12 pm to 5 pm (58.2%). The average sleep quality score based on the PSQI-K was 6.0±2.0 overall, 5.3±1.6 in Q1, and 6.6±2.2 in Q4 (frequent caffeinated beverage drinkers), indicating poorer sleep quality in Q4 (P=0.022). In Q1, 13.3% rated their sleep quality as ‘very good,’ while in Q4, only 2.5% gave the same rating. Poor sleep quality was significantly associated with the frequency of caffeinated beverages per week (β=0.232, P=0.004) and self-reported stress level (β=0.256, P=0.002). Conclusions Frequent consumption of caffeinated beverages appears to be associated with poor sleep quality among urban workers. While reducing caffeine intake may contribute to improvements in sleep quality as a health promoting behavior, this hypothesis requires validation through future studies employing personalized intervention approaches.

Background: and Purpose: This clinical practice guideline provides evidence-based recommendations for treatment of dementia, focusing on cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists for Alzheimer’s disease (AD) and other types of dementia. Methods: Using the Population, Intervention, Comparison, Outcomes (PICO) framework, we developed key clinical questions and conducted systematic literature reviews. A multidisciplinary panel of experts, organized by the Korean Dementia Association, evaluated randomized controlled trials and observational studies. Recommendations were graded for evidence quality and strength using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Three main recommendations are presented: (1) For AD, cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are strongly recommended for improving cognition and daily function based on moderate evidence; (2) Cholinesterase inhibitors are conditionally recommended for vascular dementia and Parkinson’s disease dementia, with a strong recommendation for Lewy body dementia; (3) For moderate to severe AD, NMDA receptor antagonist (memantine) is strongly recommended, demonstrating significant cognitive and functional improvements. Both drug classes showed favorable safety profiles with manageable side effects. Conclusions This guideline offers standardized, evidence-based pharmacologic recommendations for dementia management, with specific guidance on cholinesterase inhibitors and NMDA receptor antagonists. It aims to support clinical decision-making and improve patient outcomes in dementia care. Further updates will address emerging treatments, including amyloid-targeting therapies, to reflect advances in dementia management.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

OBJECTIVES: Humidifier disinfectants (HDs) were sold in Korea from 1994 until their recall in 2011. We examined the incidence patterns of 8 respiratory diseases before and after the HD recall and estimated the attributable risk in the Korean population. METHODS: Using National Health Insurance data from 2002 to 2019, we performed age–cohort–period and differences-in-diffference analyses (comparing periods before vs. after the recall) to estimate the population-attributable fraction and the excess number of episodes. The database comprised 51 million individuals (99% of the Korean population). The incidence of 8 diseases—acute upper respiratory infection (AURI), acute lower respiratory infection (ALRI), asthma, pneumonia, chronic sinusitis (CS), interstitial lung disease (ILD), bronchiectasis, and chronic obstructive pulmonary disease (COPD)—was defined by constructing episodes of care based on patterns of medical care and the clinical characteristics of each disease. RESULTS: The relative risks (RRs) for AURI, ALRI, asthma, pneumonia, CS, and ILD were elevated among younger individuals (with an RR as high as 82.18 for AURI in males), whereas chronic conditions such as bronchiectasis, COPD, and ILD showed higher RRs in older individuals. During the HD exposure period, the population-attributable risk percentage ranged from 4.6% for bronchiectasis to 25.1% for pneumonia, with the excess number of episodes ranging from 6,218 for ILD to 3,058,861 for CS. Notably, females of reproductive age (19-44 years) experienced 1.1-9.2 times more excess episodes than males. CONCLUSIONS This study provides epidemiological evidence that inhalation exposure to HDs affects the entire respiratory tract and identifies vulnerable groups.

Background/Aims: Early diagnosis of esophageal cancer (EC) remains challenging despite the increasing frequency of endoscopic screenings globally. The rapidly increasing number of endoscopic screenings performed over a certain period might influence diagnostic performance. This study evaluated the association between the number of endoscopic screenings and EC detection rates in a nationwide cohort. Methods: This retrospective population-based study used the Korean National Cancer Screening Program database, comprising 32,774,742 males and females aged ≥40 years between 2015and 2019. Negative binomial regression model and least-squares mean evaluation were used to assess the association between month of the year and EC detection rates. Results: This study enrolled 28,032,590 participants who underwent upper endoscopy. The number of participants in the fourth quarter (October to December: 10,923,142 [39.0%]) was 2.1 times higher than that in the first quarter (January to March: 5,085,087 [18.1%]); this trend continued for all 5 years. Contrarily, detection rates for EC in the fourth quarter (0.08/1,000 person) were half that in the first quarter (0.15/1,000 person). The odds of detecting EC were lowest in November; in 2015 the odds were 0.57 (95% confidence interval, 0.41 to 0.79; p=0.001) times lower and in 2016, they were 0.51 (95% confidence interval, 0.37 to 0.68; p<0.001) times lower compared to January. The predicted detection rates showed a decreasing trend toward the end of the year (p>0.05 for all). Conclusions The workload of endoscopists increased excessively with the rising number of endoscopies toward the end of the year, which was reflected by the decreased EC detection rates during this period.

Background/Aims: The Korean guidelines for Helicobacter pylori treatment were revised in 2020, however, the extent of adherence to these guidelines in clinical practice remains unclear. Herein, we initiated a prospective, nationwide, multicenter registry study in 2021 to evaluate the current management of H.pylori infection in Korea. Methods: This interim report describes the adherence to the revised guidelines and their impact on firstline eradication rates. Data on patient demographics, diagnoses, treatments, and eradication outcomes were collected using a web-based electronic case report form. Results: A total of 7,261 patients from 66 hospitals who received first-line treatment were analyzed.The modified intention-to-treat eradication rate for first-line treatment was 81.0%, with 80.4% of the prescriptions adhering to the revised guidelines. The most commonly prescribed regimen was the 14-day clarithromycin-based triple therapy (CTT; 42.0%), followed by tailored therapy (TT; 21.2%), 7-day CTT (14.1%), and 10-day concomitant therapy (CT; 10.1%). Time-trend analysis demonstrated significant increases in guideline adherence and the use of 10-day CT and TT, along with a decrease in the use of 7-day CTT (all p<0.001). Multivariate logistic regression analysis revealed that guideline adherence was significantly associated with first-line eradication success (odds ratio, 2.03; 95% confidence interval, 1.61 to 2.56; p<0.001). Conclusions The revised guidelines for the treatment of H. pylori infection have been increasingly adopted in routine clinical practice in Korea, which may have contributed to improved first-line eradication rates. Notably, the 14-day CTT, 10-day CT, and TT regimens are emerging as the preferred first-line treatment options among Korean physicians.

Background/Aims: Although the urea breath test (UBT) is widely used as a representative monitoring test after Helicobacter pylori eradication, false-negative results can occur because of the gray zone related to its cutoff value. This study aimed to compare the diagnostic performances of the rapid urease test (RUT), the RUT with sweeping method, and the UBT, and to investigate the role of the sweeping method in the gray zone of UBT values. Methods: We retrospectively reviewed 216 patients who received standard first-line H. pylori eradication treatments (n=216). All participants underwent to testing using the sweeping method and UBT on the same day. The sensitivity, specificity, and accuracy were analyzed to compare the two methods. Results: The sensitivity (0.537 vs 0.806, p=0.002) and accuracy (0.843 vs 0.870, p=0.026) of the UBT were inferior to those of the sweeping method. A total of 31 individuals tested positive for H. pylori according to the UBT, whereas 54 individuals tested positive according to the sweeping method. In the group for which the gold standard definition indicated H. pylori positivity but UBT results were negative (n=31), all individuals had a UBT value under 2.5‰. In the multivariate logistic regression model, a UBT value of 1.4‰ to 2.5‰ increased the risk of false-negative results by 6.5 times (odds ratio, 6.5; 95% confidence interval, 2.077 to 20.288; p=0.001). Conclusions After H. pylori eradication, false-negative results can occur for individuals undergoing the UBT, primarily for values below the UBT cutoff. The RUT with the sweeping method can potentially help detect H. pylori in the gray zone of the UBT, improving diagnostic accuracy.

Purpose: Potassium voltage-gated channel subfamily Q member 2 (KCNQ2)-related epilepsy, caused by mutations in the KCNQ2 gene, encompasses a spectrum of epileptic phenotypes, ranging from self-limited epilepsy to severe developmental and epileptic encephalopathy (DEE). Although the mutational background of these disorders has been characterized, predicting outcomes based solely on genetic variants remains challenging. Methods: This multicenter observational study investigated the clinical features, genotype-phenotype correlations, and comorbidities in pediatric patients with KCNQ2-related epilepsy in Korea. Conducted across three tertiary hospitals, the study enrolled 20 pediatric patients with genetically confirmed KCNQ2-related epilepsy. Data were collected from medical records, including demographic information, age at seizure onset, types of seizures, comorbidities, and treatment history. Results: Of the 20 patients enrolled, nine had self-limited epilepsy, while 11 had DEE. Missense mutations were more prevalent in the DEE group, whereas truncation mutations were associated with milder forms of epilepsy. Although 75% of cases achieved effective seizure control, 55% of patients exhibited comorbidities such as intellectual disability and neuropsychiatric disorders. Genotype-phenotype correlations revealed variability in clinical outcomes, with specific mutations in similar regions resulting in different phenotypes. Conclusion This study highlights the complexity of KCNQ2-related epilepsy, demonstrating that genotype-phenotype correlations are not straightforward and may be influenced by genetic modifiers, environmental factors, or dominant negative effects. While seizure control often improves, neurodevelopmental challenges may persist, underscoring the need for therapeutic approaches that address both seizure management and developmental support. Further research into the relevant non-genetic factors is essential to enhance the understanding and treatment of KCNQ2-related epilepsy.