Severance Hospital

BackgroundDespite guideline recommendations, evidence from randomized trials evaluating the appropriate low-density lipoprotein (LDL) cholesterol target for secondary prevention in patients with atherosclerotic cardiovascular disease remains limited.MethodsIn this open-label superiority trial conducted in South Korea, we randomly assigned patients with atherosclerotic cardiovascular disease in a 1:1 ratio to a target LDL cholesterol level of less than 55 mg per deciliter (1.4 mmol per liter) (intensive-targeting group) or less than 70 mg per deciliter (1.8 mmol per liter) (conventional-targeting group). The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years. Safety was also assessed.ResultsOf 3048 patients who underwent randomization, 1526 were assigned to the intensive-targeting group and 1522 to the conventional-targeting group. The median follow-up was 3.0 years. The median LDL cholesterol level during the trial was 56 mg per deciliter (1.4 mmol per liter) in the intensive-targeting group and 66 mg per deciliter (1.7 mmol per liter) in the conventional-targeting group. A primary end-point event occurred in 100 patients (Kaplan–Meier estimate of cumulative incidence, 6.6%) in the intensive-targeting group and in 147 patients (Kaplan–Meier estimate of cumulative incidence, 9.7%) in the conventional-targeting group (hazard ratio, 0.67; 95% confidence interval, 0.52 to 0.86; P=0.002). The incidence of prespecified safety end points was similar in the two trial groups, except for a lower incidence of creatinine elevation in the intensive-targeting group.ConclusionsAmong patients with atherosclerotic cardiovascular disease, targeting an LDL cholesterol level of less than 55 mg per deciliter resulted in a lower risk of cardiovascular events at 3 years than targeting a level of less than 70 mg per deciliter. (Funded by the Cardiovascular Research Center and Yuhan; Ez-PAVE ClinicalTrials.gov number, NCT04626973.)

Radotinib is a second-generation tyrosine kinase inhibitor that selectively targets BCR-ABL1 and is used for the treatment of chronic myeloid leukemia (CML). This study aimed to evaluate the clinical pharmacokinetic characteristics and the food effect of radotinib. Healthy volunteers received a single oral dose of radotinib 400mg under fasted or fed conditions in a crossover manner, and CML patients received repeated oral doses of 300mg twice daily. The pharmacokinetic characteristics were evaluated by a noncompartmental method, using plasma concentration-time data following a single administration in healthy volunteers, and on Days 1 and 14 in CML patients. The food effect was assessed by comparing the pharmacokinetic parameters under fed and fasted conditions in healthy volunteers. The pharmacokinetic analyses of radotinib included data from 23 healthy male volunteers and 24 patients newly diagnosed with CML. In both populations, the plasma concentrations of radotinib peaked at approximately 3h. In healthy volunteers, the concentrations declined biexponentially with the terminal half-life (t1/2) of 17.5h under fasted conditions. In CML patients, radotinib was substantially accumulated with the accumulation ratio of 3.59 on Day 14. The effective t1/2 derived from the accumulation ratio was 25.5h. The systemic exposure to radotinib increased by 3.49-fold when administered after food intake, with time to maximum concentration delayed by 3h. The results of the study provide essential pharmacokinetic information for the clinical use of radotinib in the treatment of CML patients. ClinicalTrials.gov, Identifier NCT06461078, NCT03722420.

Intestinal Behçet's disease (BD) is a manifestation of BD involving the gastrointestinal tract. Although fecal calprotectin (FC) is a useful inflammatory marker, its role in intestinal BD is unclear. We retrospectively analyzed 78 patients with intestinal BD to evaluate correlations between FC levels and the Disease Activity Index for Intestinal Behçet's Disease (DAIBD), C-reactive protein (CRP), and erythrocyte sedimentation rate. FC and CRP levels were compared between patients in endoscopic remission and those with active disease. Receiver operating characteristic (ROC) curve analysis was used to evaluate FC's ability to predict endoscopic activity and ulcer size. FC levels significantly correlated with DAIBD scores (r= 0.253, P= 0.025) and CRP (r= 0.227, P= 0.046). Patients with endoscopically active disease had higher FC (1,124 ± 1,957 μg/g vs. 367 ± 1,208 μg/g; P< 0.001) and CRP levels (16.0 ± 23.7 mg/L vs. 14.4 ± 46.5 mg/L; P= 0.027) than those in remission. Patients with larger ulcers ( ≥ 30 mm) had higher FC levels than those with smaller ulcers (2,212 ± 2,609 μg/g vs. 962 ± 1,822 μg/g; P= 0.034). An FC cutoff level of 176 μg/g discriminated active endoscopic disease (sensitivity 59.3%, specificity 83.3%), with an area under the ROC curve (AUC) of 0.724 (95% confidence interval, 0.605-0.843; P= 0.002), outperforming CRP (AUC, 0.657). FC levels correlated with DAIBD scores and endoscopic inflammation in intestinal BD. FC outperformed CRP in detecting endoscopic activity, supporting its use in disease management.

Background: Ovarian cystectomy is standard treatment for endometrioma but is associated with decreased ovarian reserve. Catheter-directed sclerotherapy (CDS) is an ovary-sparing image-guided alternative; however, supporting evidence comprises retrospective comparative and prospective single-arm studies. Objective: To compare CDS and ovarian cystectomy in terms of therapeutic efficacy and effect on ovarian function in women with ovarian endometrioma through a randomized controlled trial. Methods: This prospective pilot study enrolled women evaluated for unilateral unilocular endometrioma measuring >3 cm from March 20221 to July 2024. Participants were randomized to treatment by fluoroscopic and ultrasound-guided CDS or laparoscopic cystectomy. The primary endpoint was percentage decline from baseline to 12 months in serum anti-Müllerian hormone (AMH) (an ovarian functional reserve marker). Additional procedural and 12-month outcomes were assessed including the Endometriosis Health Profile-30 (EHP-30) questionnaire addressing endometriosis-related symptoms and quality of life (lower score: better status). Results: The analysis included 40 participants: 20 randomized to CDS (mean age, 32.8 years), and 20 (mean age, 35.1.1 years) to cystectomy. Mean 12-month percentage decline in AMH (primary outcome) was smaller for CDS than cystectomy (14.9% vs 39.8%, P=.02). No complications occurred after CDS; one complication occurred after cystectomy. Hospital length of study was significantly shorter after CDS (2.3±0.5 days) than cystectomy (4.2±0.7 days) (P<.001). From baseline to 12 months, ultrasound-based cyst size significantly decreased for CDS (5.8±1.5 to 0.6±0.7 cm; P<.001) and cystectomy (5.3±1.4 to 0.0±0.0 cm; P<.001); mean AMH was not significantly different for CDS (3.1±2.2 to 2.7±1.7 ng/mL; P=.08) but decreased significantly for cystectomy (3.3±3.0 to 2.0±1.8 ng/mL; P<.001); mean CA-125 decreased significantly for CDS (69.2±61.7 to 17.3±14.2 U/mL; P<.001) and cystectomy (54.6±35.8 to 14.8±8.2 U/mL; P<.001); and mean EHP-30 score decreased significantly for CDS (31.3±12.8 to 6.3±6.9; P<.001) and cystectomy (34.5±18.0 to 8.1±4.3; P<.001). CA-125 and EHP-30 score were not significantly different between groups at 12 months (P>.05). No 12-month recurrence occurred in either group. Conclusion: CDS was associated with better preservation of ovarian reserve versus cystectomy, without significant difference for therapeutic efficacy measures. Clinical Impact: These results advance the level of evidence supporting CDS as an ovary-sparing cystectomy alternative for appropriately selected patients.

Abstract Brain tumors may start long before diagnosis, but the earliest genetic event and the first mutant “normal” cell remain unclear. We used multi-regional surgical sampling plus single-cell/spatial genomics and mouse models to map early initiation steps in glioblastoma (GBM), IDH-mutant glioma, and meningioma. We collected matched tumor and non-tumor tissues from patients. For GBM, we profiled tumors and matched non-tumor regions, including the tumor-free subventricular zone (SVZ) and peritumoral cortex, using single-nucleus RNA sequencing (snRNA-seq) with copy-number inference (13 tumors, 10 SVZ, 2 controls). For IDH-mutant glioma, we collected tumor, tumor-free SVZ, peritumoral cortex (n=18), and blood, and performed deep sequencing, droplet digital PCR (ddPCR), and spatial mapping. For meningioma, we analyzed paired meningioma tumors and pathologically tumor-free dura (n=22) using whole-exome sequencing (WES), amplicon sequencing, long-read sequencing, clonal and mutational-signature analyses, and single-nucleus DNA sequencing (snDNA-seq). In parallel, we tested SVZ-specific tumorigenicity in a mouse GBM model and built an oligodendrocyte progenitor cell (OPC)–targeted Idh1(R132H) CRISPR model with Trp53/Atrx/Nf1. GBM: Putative mouse originating cell candidate (mGBM-OCs) formed spheres, showed neuro/glial differentiation, and were highly invasive, but tumorigenicity was niche dependent: cortex implantation produced no tumors (0/20), whereas SVZ implantation produced tumors (11/29). In patients, SVZ neural stem cell–like, astrocyte-like, and OPC-like subsets showed low-level early copy-number signals consistent with chromosome 7 gain and/or chromosome 10 loss, suggesting these subsets as putative human GBM-OCs. IDH-mutant glioma: Tumor-free SVZ showed no shared mutations with tumor. Low-level IDH1(R132H) was detected in peritumoral normal cortex in 11/18 patients (61.1%) and localized mainly to OPC and astrocyte-precursor–like cells, supporting peritumoral cortical glial progenitor lineages as the first mutant cells. In mice, adding Idh1(R132H) increased tumor incidence (OPC-ITAN 18/29, 62.1% vs OPC-TAN 3/7, 42.9%) and worsened survival. Meningioma: Driver alterations were detected in tumor-free dura in 18/22 patients (82%) at very low variant allele fractions, including NF2 and non-NF2 drivers (TRAF7/KLF4/AKT1-related); remaining cases were supported by long-read detection of structural drivers. Dura patterns were inconsistent with tumor microinvasion and supported clonal evolution from dural developmental mosaicism. snDNA-seq identified NF2-mutant cells with chromosome 22q loss in both dura and tumor, indicating prenatal biallelic NF2 inactivation. Shared clonal mutations were enriched for SBS1/5, whereas tumor-private subclonal mutations were enriched for SBS15, consistent with later postnatal steps. These data reveal tumor-type–specific initiation programs and support origin-based therapeutic strategies targeting origin-like cells and their niches, beyond tumor-mass–focused treatment. Generative AI was used only for English-language editing. Citation Format: Hyeong-Chol Oh, Jung Won Park, Young-soo Chung, Ran Joo Choi, Hye Joung Cho, Se-Young Jo, Eunchae Yeo, Jihwan Yoo, Tae Hoon Roh, Jong Hee Chang, Joo Ho Lee, Hoon Kim, Jeong Ho Lee, Sangwoo Kim, Seok-Gu Kang. Multi-regional surgical sampling reveals tumor origins and early developmental pathways in glioblastoma, IDH-mutant glioma, and meningioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B039.

Isocitrate dehydrogenase (IDH)-mutant gliomas are primary malignant brain tumors defined by recurrent mutations in IDH1/2 genes and characterized by distinct molecular subtypes and relatively favorable clinical outcomes. Although these mutations represent early and defining events, recent data suggest that IDH1 mutant glial progenitor cells can reside within the histologically normal-appearing peritumoral cortex, indicating that cells harboring the founding driver mutation can persist beyond the tumor mass while retaining nonmalignant features. These observations challenge a purely gene-centric view of gliomagenesis. In this essay, we review emerging data supporting a multistep and context-dependent model in which the mutant IDH enzyme establishes an epigenetically altered cellular state, with subsequent genetic alterations and lineage-specific constraints that shape malignant progression. We further discuss the conceptual distinction between the "cell-of-mutation" and the "cell-of-origin" and consider how temporal stratification of tumor evolution may inform stage-specific therapeutic strategies along the transition from initiating clones beyond the tumor mass to overt tumors.

Spontaneous intracranial hypotension (SIH) is an underrecognized condition with rapidly evolving diagnostic and therapeutic strategies. This study investigated temporal and regional trends in diagnostic and therapeutic modalities for SIH in the published literature. We systematically reviewed SIH-related clinical studies in PubMed from inception through December 2024. Data on study site (continent/country/institute) and diagnostic and treatment modalities used in clinical settings were extracted. To assess temporal and regional trends, the reported use of each modality was analyzed over 5-year intervals and across regions, separately for case reports and original articles, which respectively reflect real-world and research settings. A total of 789 articles (529 case reports and 260 original articles) were included. In case reports, brain MRI (84.4%), lumbar puncture (84.4%), and RI cisternography (50%) were the most frequently used diagnostics in 1990–1999, while brain MRI (91.1%) and spine MRI (74.8%) became predominant in 2020–2024. The use of lumbar puncture and RI cisternography declined to 24.4% and 5.9%, respectively, while dynamic CT myelography (18.5%) and digital subtraction myelography (23.7%) became more common in 2020–2024. Conservative management (81.3%) was the most common treatment in 1990–1999, while surgical repair increased to 39.8% in 2020–2024. Similar trends were observed in original articles. These temporal trends were similar across regions; however, in 2020–2024, dynamic CT myelography, DSM, and surgical repair were reported more frequently in publications from North America and Europe than in those from Asia (dynamic CT myelography: 35.4% and 22.0% vs. 4.7%; DSM: 40.8% and 33.0% vs. 6.7%; surgical repair: 59.3% and 42.5% vs. 13.6%). Diagnostic and therapeutic modalities for SIH have markedly shifted over time, reflecting the actual changes both in real-world practice and academic settings. Standardized diagnostic and treatment guidelines and broader global awareness of evolving practice are warranted.

Hypertensive intracerebral hemorrhage (ICH) of the basal ganglia mostly occurs unilaterally. Therefore, we describe the differences between the morphological parameters of lesional and non-lesional carotid arteries using initial computed tomography angiography. A total of 284 patients were diagnosed with nontraumatic ICH between March 2020 and October 2024. Hypertensive basal ganglia hemorrhages were included with a total of 64 patients enrolled in this study. Using an IntelliSpace portal, morphological examination was conducted on both the intracranial and extracranial segments on each side of the carotid artery (intra- and extra group). The total length, short distance, maximal diameter, and minimal diameter of each segment was calculated. In both the intra- and extra-groups, the measured variables (Tortuosity, short distance, length, Dmin, Dmax) demonstrated no statistically significant differences between the ICH and non-ICH sides. There were no statistically significant differences in the five measured parameters after adjusting for the bleeding side to compensate for left/right (Lt/Rt) anatomical differences. To evaluate age-related alterations in blood vessels, we categorized individuals into 2 groups: those aged $$\ge$$65 and $$\le$$65 years, ensuring a comparable distribution across the groups. Subsequently, we analyzed morphological alterations in the blood vessels of both groups. Significant differences in tortuosity and short distances within the Intra group were observed using paired t-tests. (tortuosity- p = 0.011, short distance- p = 0.041) Morphological analysis revealed that the bilateral carotid arteries did not differ between the intracranial and extracranial segments. However, some parameters (tortuosity and short distance) exhibited morphological changes associated with aging.