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.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform—FiRST Cancer Panel (FCP)—over 7 years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. Ninety-seven point six percentage of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53 (56.2%), PIK3CA (31.2%), GATA3 (13.8%), BRCA2 (10.2%), and amplifications of CCND1 (10.8%), FGF19 (10.0%), and ERBB2 (9.5%). NGS analysis of ERBB2 amplification correlated well with human epidermal growth factor receptor 2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. Ten point three percent of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. Conclusion Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

Purpose: This study analyzed the pathological complete response (pCR) rates, long-term outcomes, and biological features of human epidermal growth factor receptor 2 (HER2)-zero, HER2-low, and HER2-positive breast cancer patients undergoing neoadjuvant treatment. Methods: This single-center study included 1,667 patients who underwent neoadjuvant chemotherapy from 2008 to 2014. Patients were categorized by HER2 status, and their clinicopathological characteristics, chemotherapy responses, and recurrence-free survival (RFS) rates were analyzed. Results: Patients with HER2-low tumors were more likely to be older (p = 0.081), have a lower histological grade (p < 0.001), and have hormone receptor (HorR)-positive tumors (p < 0.001). The HER2-positive group exhibited the highest pCR rate (23.3%), followed by the HER2-zero (15.5%) and HER2-low (10.9%) groups. However, the pCR rate did not differ between HER2-low and HER2-zero tumors in the HorR-positive or HorR-negative subgroups.The 5-year RFS rates increased in the following order: HER2-low, HER2-positive, and HER2-zero (80.0%, 77.5%, and 74.5%, respectively) (log-rank test p = 0.017). A significant survival difference between patients with HER2-low and HER2-zero tumors was only identified in HorR-negative tumors (5-year RFS for HER2-low, 74.5% vs. HER2-zero, 66.0%; log-rank test p-value = 0.04). Multivariate survival analysis revealed that achieving a pCR was the most significant factor associated with improved survival (hazard ratio [HR], 4.279; p < 0.001).Compared with HER2-zero, the HRs for HER2-low and HER2-positive tumors were 0.787 (p = 0.042) and 0.728 (p = 0.005), respectively. After excluding patients who received HER2-targeted therapy, patients with HER2-low tumors exhibited better RFS than those with HER2-zero (HR 0.784, p = 0.04), whereas those with HER2-positive tumors exhibited no significant difference compared with those with HER2-low tumors (HR, 0.975; p = 0.953). Conclusion Patients with HER2-low tumors had no significant difference in pCR rate compared to HER2-zero but showed better survival, especially in HorR-negative tumors.Further investigation into biological differences is warranted.

Purpose: This study evaluated the postoperative quality of life (QoL) after various types of gastrectomy for gastric cancer. Materials and Methods: A multicenter prospective observational study was conducted in Korea using the Korean Quality of Life in Stomach Cancer Patients Study (KOQUSS)-40, a new QoL assessment tool focusing on postgastrectomy syndrome. Overall, 496 patients with gastric cancer were enrolled, and QoL was assessed at 5 time points: preoperatively and at 1, 3, 6, and 12 months after surgery. Results: Distal gastrectomy (DG) and pylorus-preserving gastrectomy (PPG) showed significantly better outcomes than total gastrectomy (TG) and proximal gastrectomy (PG) with regard to total score, indigestion, and dysphagia. DG, PPG, and TG also showed significantly better outcomes than PG in terms of dumping syndrome and worry about cancer. Postoperative QoL did not differ significantly according to anastomosis type in DG, except for Billroth I anastomosis, which achieved better bowel habit change scores than the others. No domains differed significantly when comparing double tract reconstruction and esophagogastrostomy after PG. The total QoL score correlated significantly with postoperative body weight loss (more than 10%) and extent of resection (P<0.05 for both).Reflux as assessed by KOQUSS-40 did not correlate significantly with reflux observed on gastroscopy 1 year postoperatively (P=0.064). Conclusions Our prospective observation using KOQUSS-40 revealed that DG and PPG lead to better QoL than TG and PG. Further study is needed to compare postoperative QoL according to anastomosis type in DG and PG.

Purpose: The novel curability criteria for elderly (EL) patients have been proposed to stratify their risk of lymph node metastasis (LNM), following non-curative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Hence, this study aimed to evaluate the effectiveness of the EL criteria and compare them with those of the well-known eCura system. Materials and Methods: A retrospective analysis was performed on 143 patients who did not meet the curative ESD criteria at a tertiary hospital in Korea between 2011 and 2022. Of these, 102 underwent additional surgery, while 41 were followed up without further treatment. The LNM rates based on the EL and eCura systems were stratified and compared. Results: In the surgery group, 29.4% (30/102) patients were classified as EL-low (EL-L) and 70.2% (72/102) as EL-high (EL-H). The LNM rates (95% confidence interval) were 0.0% (0.0–11.6) and 9.7% (4.0–19.0) for EL-L and EL-H, respectively (P=0.102). EL-L was closely aligned with the eCura low-risk category, with a similar patient proportion (32.4%) and an LNM rate of 0.0% (0.0–10.6). The eCura system classified 94.1% (48/51) of the EL-L patients as lowrisk, with an 86% concordance rate (123/143). Discordant cases included patients with positive vertical margins, but without other risk factors, who were classified as EL-H without LNM. Conclusions Patients with EL-L showed no LNM, and the EL criteria demonstrated high concordance with the eCura system. The EL criteria may be as effective as the eCura system in identifying low-risk patients after non-curative ESD for EGC.

Gastric cancer is one of the most common cancers in both Korea and worldwide. Since 2004, the Korean Practice Guidelines for Gastric Cancer have been regularly updated, with the 4th edition published in 2022. The 4th edition was the result of a collaborative work by an interdisciplinary team, including experts in gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology, and guideline development methodology. The current guideline is the 5th version, an updated version of the 4th edition. In this guideline, 6 key questions (KQs) were updated or proposed after a collaborative review by the working group, and 7 statements were developed, or revised, or discussed based on a systematic review using the MEDLINE, Embase, Cochrane Library, and KoreaMed database. Over the past 2 years, there have been significant changes in systemic treatment, leading to major updates and revisions focused on this area.Additionally, minor modifications have been made in other sections, incorporating recent research findings. The level of evidence and grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation system. Key factors for recommendation included the level of evidence, benefit, harm, and clinical applicability. The working group reviewed and discussed the recommendations to reach a consensus. The structure of this guideline remains similar to the 2022 version.Earlier sections cover general considerations, such as screening, diagnosis, and staging of endoscopy, pathology, radiology, and nuclear medicine. In the latter sections, statements are provided for each KQ based on clinical evidence, with flowcharts supporting these statements through meta-analysis and references. This multidisciplinary, evidence-based gastric cancer guideline aims to support clinicians in providing optimal care for gastric cancer patients.

Background: Because of the low prevalence of inherited retinal diseases, reports on the distribution of retinitis pigmentosa (RP)-related genes in Korean patients are scarce. The aim of this study was to determine the mutation spectrum and allele frequency and observe the final diagnoses in a Korean cohort clinically diagnosed with RP. Methods: We used whole-exome sequencing (WES) to analyze a Korean cohort of 100 unrelated patients clinically diagnosed with RP. The possible pathogenicity of each variant was assessed based on the guidelines of the American College of Medical Genetics and Genomics and Association for Molecular Pathology, in-silico prediction tools, known clinical phenotypes, and inheritance patterns. Results: Definite causative genes were detected in 60/100 patients (60.0%). Of these 60 cases, USH2A was the most common causative gene (14/60, 23.3%), followed by EYS (13/60, 21.7%) and RP1 (6/60, 10.0%). The clinical diagnosis was redefined in 9 of the 60 probands (15.0%) with causative genes after WES. Five of the 60 patients (8.3%) carried a causative variant in CHM, and the clinical diagnosis was redefined as choroideremia. Leber congenital amaurosis was diagnosed in 2/60 probands (3.3%), and RDH12 and RPGRIP1 were the causative genes in each patient. One patient (1/60, 1.7%) was diagnosed with Bietti’s crystalline dystrophy, with CYP4V2 identified as the causative gene. In another patient (1/60, 1.7%), ABCA4 variants were detected with clinical findings suggestive of cone-rod dystrophy. Conclusion This study reports the mutational spectrum of a cohort of Korean patients with a clinical diagnosis of RP who were referred for genetic testing. This study adds valuable data regarding the frequency of genes as well as their relation to the age of symptom onset and relation to other inherited retinal degenerations.

Background: Maintenance of stable blood pressure (BP) during cerebrovascular bypass surgery is crucial to prevent cerebral ischemia. We compared the effect of remimazolam anesthesia with that of propofol-induced and desflurane-maintained anesthesia on intraoperative hemodynamic stability and the need for vasoactive agents in patients undergoing cerebrovascular bypass surgery. Methods: Sixty-five patients were randomized into remimazolam (n = 31, remimazolam-based intravenous anesthesia) and control groups (n = 34, propofol-induced and desflurane-maintained anesthesia). The primary outcome was the occurrence of intraoperative hypotension. The secondary outcomes included hypotension duration, lowest mean BP (MBP), generalized average real variability (ARV) of MBP, and consumption of phenylephrine, norepinephrine, or remifentanil. Results: Occurrence rate and duration of hypotension were significantly lower in the remimazolam group (38.7% vs. 73.5%, P = 0.005; 0 [0, 10] vs. 7.5 [1.25, 25] min, P = 0.008). Remimazolam also showed better outcomes for lowest MBP (78 [73, 84] vs. 69.5 [66.25, 75.8] mmHg, P < 0.001) and generalized ARV of MBP (1.42 ± 0.49 vs. 1.66 ± 0.52 mmHg/min, P = 0.036). The remimazolam group required less phenylephrine (20 [0, 65] vs. 100 [60, 130] μg, P < 0.001), less norepinephrine (162 [0, 365.5] vs. 1335 [998.5, 1637.5] μg, P < 0.001), and more remifentanil (1750 [1454.5, 2184.5] vs. 531 [431, 746.5] μg, P < 0.001) than the control group. Conclusions Remimazolam anesthesia may provide better hemodynamic stability during cerebrovascular bypass surgery than propofol-induced and desflurane-maintained anesthesia.

Objective: To prospectively evaluate the effect of accelerated deep learning-based reconstruction (Accel-DL) on improving brain magnetic resonance imaging (MRI) quality and reducing scan time compared to that in conventional MRI. Materials and Methods: This study included 150 participants (51 male; mean age 57.3 ± 16.2 years). Each group of 50 participants was scanned using one of three 3T scanners from three different vendors. Conventional and Accel-DL MRI images were obtained from each participant and compared using 2D T1- and T2-weighted and 3D gradient-echo sequences. Accel-DL acquisition was achieved using optimized scan parameters to reduce the scan time, with the acquired images reconstructed using U-Net-based software to transform low-quality, undersampled k-space data into high-quality images. The scan times of Accel-DL and conventional MRI methods were compared. Four neuroradiologists assessed the overall image quality, structural delineation, and artifacts using Likert scale (5- and 3-point scales). Inter-reader agreement was assessed using Fleiss’ kappa coefficient. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated, and volumetric quantification of regional structures and white matter hyperintensities (WMHs) was performed. Results: Accel-DL showed a mean scan time reduction of 39.4% (range, 24.2%–51.3%). Accel-DL improved overall image quality (3.78 ± 0.71 vs. 3.36 ± 0.61, P < 0.001), structure delineation (2.47 ± 0.61 vs. 2.35 ± 0.62, P < 0.001), and artifacts (3.73 ± 0.72 vs. 3.71 ± 0.69, P = 0.016). Inter-reader agreement was fair to substantial (κ = 0.34–0.50). SNR and CNR increased in Accel-DL (82.0 ± 23.1 vs. 31.4 ± 10.8, P = 0.02; 12.4 ± 4.1 vs. 4.4 ± 11.2, P = 0.02). Bland-Altman plots revealed no significant differences in the volumetric measurements of 98.2% of the relevant regions, except in the deep gray matter, including the thalamus. Five of the six lesion categories showed no significant differences in WMH segmentation, except for leukocortical lesions (r = 0.64 ± 0.29). Conclusion Accel-DL substantially reduced the scan time and improved the quality of brain MRI in both spin-echo and gradientecho sequences without compromising volumetry, including lesion quantification.