Background: Alpha-fetoprotein (AFP) and its isoform AFP-L3 are well-established serum biomarkers for hepatocellular carcinoma (HCC), a common malignancy and a leading cause of cancer-related mortality worldwide. Current methods for measuring these biomarkers are primarily lectin-based assays including the liquid-phase binding assay (LiBA) and liquid chromatography–tandem mass spectrometry (LC-MS/MS), both of which have limitations in diagnostic sensitivity and clinical utility for samples with low AFP concentrations. We aimed to develop a lectin-independent LC-MS/MS method for quantifying fucosylated AFP proteins (AFP-Fuc%). Methods: We conducted analytical validation, including method comparisons, over 2 months. The analytical sensitivity and diagnostic performance of this method were evaluated using 525 human serum samples—235 from HCC patients and 290 from non-HCC individuals—and compared with those of LiBA, which measured AFP-L3 levels. Results: The LC-MS/MS method demonstrated acceptable within-laboratory imprecision (CVs < 17.1%) without detectable bias, carryover, or matrix effects. Our method exhibited a broader linear dynamic range (spanning five orders of magnitude) and 10-fold higher analytical sensitivity than LiBA. The diagnostic performance of our method was significantly superior to that of LiBA, particularly in patients with low AFP concentrations ( < 7 ng/mL, P < 0.001), with improved accuracy, sensitivity, and precision at a specificity of 96.2%. Conclusions The validated LC-MS/MS method demonstrated robust analytical performance and superior diagnostic accuracy over LiBA for HCC diagnosis while avoiding the inherent limitations of lectin-based assays. Our LC-MS/MS assay shows promise for early HCC detection and may contribute to enhanced patient care.

Background: In the era of nucleoside analogs (NA), we investigated the safety of using hepatitis B surface antigen (HBsAg)-positive grafts in liver transplantation (LT) using nationwide KOTRY data. Methods: Among 4,265 adult LTs in the KOTRY registry (April 2014–January 2020), 20 (0.5%) used HBsAg(+) grafts. The S(+) group was compared with HBsAg-nega-tive groups, both HBcAb(+) (C[+]) and HBcAb(−) (SC[−]), using 1:1 propensity scorematching. Patient and graft survival were evaluated using Kaplan–Meier analysis.Cox regression was used to identify prognostic factors. Results: No significant differences were observed in patient or graft survival be-tween S(+) and C(+) or SC(−) groups. Key prognostic factors for patient survivalincluded age, HCC, MELD score, ascites, and encephalopathy. For graft survival, HCC, preoperative HCC treatment, MELD score, ascites, and encephalopathy were significant. HBV recurrence occurred in the S(+) group, but did not compromise outcomes. Conclusion In HBV-endemic regions, HBsAg(+) liver grafts can be safely used to expand the donor pool without compromising LT outcomes when combined with appropriate prophylaxis.

Purpose: Chronic myeloid leukemia (CML) in children, adolescents, and young adults is rare and differs from older adults. This study evaluated the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in young Korean CML patients during the tyrosine kinase inhibitor (TKI) era. Materials and Methods: A retrospective analysis of 35 CML patients aged < 40 years who underwent allogeneic HSCT from 2009 to 2019 was conducted using Korean Blood and Marrow Transplantation Registry data. Patients were grouped by age < 20 years at HSCT (group 1, n=15) and 20-40 years at HSCT (group 2, n=20). Survival outcomes including overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were analyzed using the Kaplan-Meier method. Results: The median time between diagnosis and HSCT was 8.9 months. All the patients achieved engraftment but platelet recovery was significantly slower in group 1 (p=0.034). Acute and chronic graft-versus-host disease occurred in 54.3% and 34.3%, respectively. Five-year OS, RFS, and EFS rates of total patients were 66.8%, 50.8%, and 47.6%, with better OS was observed in group 1 by multivariable analysis (p=0.048). Disease status at HSCT was a significant predictor of OS (p=0.028), RFS (p=0.003), and EFS (p=0.004). Disease progression occurred in 13 out of 35 patients (37.1%); treatment-related mortality accounted for 63.6% of deaths (7 out of 11). Conclusion When performed at a younger age, allogeneic HSCT result in superior outcome in CML. Achieving remission before HSCT is critical for improved outcomes, highlighting the importance of pretransplant remission via optimal TKI strategies and minimal residual disease monitoring.

Hepatocellular carcinoma (HCC) is a highly invasive tumor with a strong tendency for metastasis. The most common sites of metastasis are the lungs, followed by lymph nodes, adrenal glands, and bones. However, metastasis of HCC to the small bowel is extremely rare. A 42-yearold female with HCC secondary to chronic hepatitis B and lung metastasis underwent a right hepatic lobectomy, followed by two wedge resections performed via video-assisted thoracic surgery, four sessions of transcatheter arterial chemoembolization, and stereotactic body radiation therapy. She was under regular follow-up for HCC, during which her alpha-fetoprotein level increased to 722.2 IU/ml. Abdominal computed tomography (CT) revealed segmental wall thickening and aneurysmal dilatation of the small bowel loops. An 18 F-fluorodeoxyglucose positron emission tomography/CT scan demonstrated a 3.3-cm hypermetabolic mass-like lesion (standardized uptake value: 11.3) in the small bowel. Surgical resection of the affected small bowel segment was performed. Histopathological examination of the specimen confirmed metastatic HCC, with immunohistochemical positivity for hepatocyte-specific antigen. The patient has remained cancer-free for 60 months post-operatively. Surgical intervention may offer favorable long-term outcomes in patients with small bowel metastasis from HCC.

Background: Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia. Methods: Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort. Results: An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027). Conclusion C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.

Background: Sepsis is a leading cause of intensive care unit (ICU) admission. However, few studies have evaluated how the ICU model affects the outcomes of patients with sepsis. Methods: This post hoc analysis of data from the Management of Severe Sepsis in Asia’s Intensive Care Units II study included 537 patients with sepsis admitted to 27 ICUs in Korea. The outcome measures of interest were compared between the closed ICU group, patients admitted under the full responsibility of an intensivist as the primary attending physician, and the open ICU group. The association between a closed ICU and ICU mortality was evaluated using a logistic regression analysis. Results: Altogether, 363 and 174 enrolled patients were treated in open and closed ICUs, respectively. Compliance with the sepsis bundles did not differ between the two groups; however, the closed ICU group had a higher rate of renal replacement therapy and shorter duration of ventilator support. The closed ICU group also had a lower ICU mortality rate than the open ICU group (24.7% vs. 33.1%). In a logistic regression analysis, management in the closed ICU was significantly associated with a decreased ICU mortality rate even after adjusting for potential confounding factors (adjusted odds ratio, 0.576; 95% CI, 0.342–0.970), and that association was observed for up to 90 days. Conclusions Sepsis management in closed ICUs was significantly associated with improved ICU survival and decreased length of ICU stay, even though the compliance rates for the sepsis bundles did not differ between open and closed ICUs.

Primary cilia function as critical sensory organelles that mediate multiple signaling pathways, including the Hedgehog (Hh) pathway, which is essential for organ patterning and morphogenesis. Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice. Cilk1, a highly conserved serine/threonine-protein kinase localized within primary cilia, plays a critical role in ciliary transport. Loss of Cilk1 results in severe ciliopathy phenotypes, including polydactyly, edema, and cleft palate. However, the role of Cilk1 in tooth development remains unexplored. In this study, we investigated the role of Cilk1 in tooth development. Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars. Cilk1 deficiency resulted in altered ciliary dynamics, characterized by reduced frequency and increased length, accompanied by downregulation of Hh target genes, such as Ptch1 and Sostdc1, leading to the formation of diastemal supernumerary teeth. Furthermore, in Cilk1^-/-;PCS1-MRCS1^△/△ mice, which exhibit a compounded suppression of Hh signaling, we uncovered a novel phenomenon: diastemal supernumerary teeth can be larger than first molars. Based on these findings, we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning: initially inducing diastemal supernumerary teeth, then enlarging them, and ultimately leading to molar fusion. This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.
Animals ; Hedgehog Proteins/physiology* ; Mice ; Signal Transduction/physiology* ; Tooth, Supernumerary ; Molar ; Cilia/physiology* ; Odontogenesis/physiology* ; Patched-1 Receptor ; Protein Serine-Threonine Kinases/physiology* ; Mice, Knockout ; Adaptor Proteins, Signal Transducing

Purpose: Extranodal natural killer/T-cell lymphoma (ENKTL) predominantly manifests in East Asia and Latin America. Despite shared intrinsic factors, such as ethnic and genetic backgrounds, the progression of ENKTL can be influenced by extrinsic factors related to changing lifestyle patterns. Materials and Methods: This study collected stool samples from newly diagnosed (ND)–ENKTL patients (n=40) and conducted whole genome shotgun sequencing. Results: ND-ENKTL revealed reduced alpha diversity in ND-ENKTL compared to healthy controls (HCs) (p=0.008), with Enterobacteriaceae abundance significantly contributing to the beta diversity difference between ENKTL and HCs (p < 0.001). Functional analysis indicated upregulated aerobic metabolism and degradation of aromatic compounds in ND-ENKTL. Enterobacteriaceae were associated not only with clinical data explaining disease status (serum C-reactive protein, stage, prognosis index of natural killer cell lymphoma [PINK], and PINK-E) but also with clinical outcomes (early relapse and short progression-free survival). The relative abundance of Enterobacteriaceae at the family level was similar between ENKTL and diffuse large B-cell lymphoma (DLBCL) (p=0.140). However, the ENKTL exhibited a higher abundance of Escherichia, in contrast to the prevalence of Enterobacter and Citrobacter in DLBCL. Linear regression analysis demonstrated a significant association between Escherichia abundance and programmed cell death-ligand-1 (PD-L1) levels in tissue samples (p=0.025), whereas no correlation with PD-L1 was observed for Enterobacteriaceae at the family level (p=0.571). Conclusion ND-ENKTL exhibited an abundance of Enterobacteriaceae and a dominant presence of Escherichia. These microbial characteristics correlated with disease status, treatment outcomes, and PD-L1 expression, suggesting the potential of the ENKTL microbiome as a biomarker and cause of lymphomagenesis, which warrants further exploration.

Background: Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia. Methods: Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort. Results: An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027). Conclusion C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.

Background: and Purpose We aimed to determine the proportion of Korean patients with early Alzheimer’s disease (AD) who are eligible to receive lecanemab based on the United States Appropriate Use Recommendations (US AUR), and also identify the barriers to this treatment. Methods: We retrospectively enrolled 6,132 patients with amnestic mild cognitive impairment or mild amnestic dementia at 13 hospitals from June 2023 to May 2024. Among them, 2,058 patients underwent amyloid positron emission tomography (PET) and 1,199 (58.3%) of these patients were amyloid-positive on PET. We excluded 732 patients who did not undergo brain magnetic resonance imaging between June 2023 and May 2024. Finally, 467 patients were included in the present study. Results: When applying the criteria of the US AUR, approximately 50% of patients with early AD were eligible to receive lecanemab treatment. Among the 467 included patients, 36.8% did not meet the inclusion criterion of a Mini-Mental State Examination (MMSE) score of ≥22. Conclusions Eligibility for lecanemab treatment was not restricted to Korean patients with early AD except for those with an MMSE score of ≥22. The MMSE criteria should therefore be reconsidered in areas with a higher proportion of older people, who tend to have lower levels of education.