佐久間 康成

BACKGROUND: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling combined with machine learning. METHODS: Non-targeted metabolomics were performed on bile samples collected on post-operative day (POD) 1 (n = 38) and serum on POD 14 (n = 45) from liver transplant recipients. Partial least squares discriminant analysis-based variable selection was followed by logistic regression and least absolute shrinkage and selection operator models, which were evaluated via cross-validation in the discovery cohort to explore potential biomarkers for acute rejection. RESULTS: A three-variable, bile-based model for predicting acute rejection achieved a mean cross-validated AUC of 0.872 (95% confidence interval: 0.814-0.930). Glycohyocholic acid and sulfolithocholylglycine were the main contributors. A nine-variable serum model for the Rejection Activity Index, including the change in γ-glutamyl transferase, showed a mean cross-validated R2 of 0.728 (95% confidence interval: 0.609-0.846), with methionine, creatine, and oxidized fatty acids contributing prominently. CONCLUSIONS: These findings suggest that metabolomic profiling combined with machine learning may provide candidate biomarkers for acute rejection after liver transplantation. However, given the exploratory nature of the study and the lack of external validation, the clinical utility of these metabolite signatures remains to be determined. Therefore, external validation in larger, independent cohorts will be required.

Liver transplant (LT) recipients, particularly pediatric survivors, face an elevated lifetime risk of de novo malignancies due to prolonged immunosuppressive therapy. Alpha-fetoprotein (AFP) is widely used as a biomarker for hepatocellular carcinoma (HCC) in post-LT surveillance, but elevations may also reflect extrahepatic tumors. Here, we report a rare case of a testicular tumor incidentally detected through AFP monitoring in a pediatric LT survivor. A 20-year-old male with situs inversus totalis underwent living donor LT for biliary atresia at 1 year of age. Nineteen years post-transplant, AFP was elevated to 493 ng/mL during routine surveillance, raising suspicion for de novo HCC. Imaging studies revealed no liver lesions, but physical examination identified testicular swelling. Scrotal ultrasonography demonstrated a heterogeneous mass, and orchiectomy confirmed a mixed germ cell tumor composed of seminoma, yolk sac tumor, and embryonal carcinoma. AFP normalized postoperatively, and the patient is being carefully monitored during postoperative surveillance. This case highlights both the benefits and limitations of AFP-driven surveillance: while it facilitated early detection of a curable extrahepatic tumor, reliance on AFP alone may miss AFP-negative testicular cancers. Comprehensive surveillance strategies incorporating tumor markers, structured physical examinations, and patient education are warranted, with future emphasis on standardized guidelines for pediatric LT survivors.

Acute liver failure in the neonatal period is commonly caused by infections, metabolic disorders, immune disorders, or neonatal hepatitis-like diseases of unknown etiology; however, malignant diseases are rarely included in the differential diagnosis, and leukemia may be overlooked. We report a case of neonatal acute liver failure that required living-donor liver transplantation from the patient's father, which was later diagnosed as acute megakaryoblastic leukemia (AMKL) harboring an RBM15::MKL1 fusion transcript. After liver transplantation, leukemic blasts infiltrated the transplanted liver, necessitating the initiation of chemotherapy. The patient achieved remission and has survived for four years after completion of reduced-intensity AML-type chemotherapy. RBM15::MKL1-positive AMKL is characteristically associated with both myelofibrosis and hepatic fibrosis. Congenital cases have also been reported, suggesting that RBM15::MKL1 AMKL may originate in the intrauterine fetal liver. A literature search for "acute liver failure" and "acute megakaryoblastic leukemia" revealed five cases reported since 2000. All patients had an RBM15::MKL1 fusion transcript and all died. In contrast, survival has been reported in patients with RBM15::MKL1-AMKL who did not present with acute liver failure. We speculate that our patient survived because acute liver failure was successfully managed with living-donor liver transplantation.

BACKGROUND: Neoadjuvant therapy has been increasingly adopted for resectable pancreatic ductal adenocarcinoma (PDAC) in Japan following the Prep-02/JSAP-05 trial. However, real-world evidence regarding effectiveness and underlying pathological mechanisms remains limited. This retrospective study evaluated neoadjuvant chemotherapy with gemcitabine plus S-1 (NAC-GS) impacts on resectable PDAC patient oncological and pathological outcomes. METHODS: Consecutive resectable PDAC patients treated with NAC-GS (n = 60) or upfront surgery (UFS) (n = 101) between 2013 and 2023 were retrospectively analyzed (total diagnosed during the study period, n = 186). An intention-to-treat principle assessed overall survival (OS) and recurrence-free survival (RFS). Propensity score matching using six baseline variables (1:1) minimized selection bias. RESULTS: Fifty-four patients were included in each group. The NAC-GS group demonstrated significantly longer OS than the UFS group (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90; P = 0.023). Among resected cases, NAC-GS was associated with improved OS (HR, 0.42; 95% CI, 0.20-0.90; P = 0.026). Pathologically, the NAC-GS group showed significantly lower lymph node stage and less lymphatic invasion. Pathological complete response was observed in 4.0% of NAC-GS patients. DISCUSSION: Neoadjuvant chemotherapy with GS was associated with prolonged survival in resectable PDAC, potentially through lymphatic spread suppression. Pathological complete response was rare but may represent a clinically meaningful benefit of neoadjuvant treatment in selected patients.