Importance:Lymphatic malformations (LMs) are congenital vascular anomalies with limited treatment options. Eppikajutsuto, a traditional Japanese (Kampo) herbal medicine, is commonly used to treat inflammatory conditions and has been reported to reduce lesion volume in patients with LMs; however, data on its effectiveness in pediatric patients are needed. Objective:To evaluate the association of eppikajutsuto with reduced LM lesion volume in pediatric patients with LMs. Design, Setting, and Participants:This open-label nonrandomized clinical trial was conducted from April 14, 2021, to September 30, 2024, at multiple centers in Japan. Eligible participants were 18 years or younger with a confirmed diagnosis of LM by imaging. Data were analyzed from October 14, 2024, to March 4, 2025. Intervention:Participants received eppikajutsuto granules (0.6 g/kg/d to ≤7.5 g/d) orally for 6 months. Main Outcomes and Measures:The primary outcome was the proportion of patients achieving a 20% or greater reduction in lesion volume, measured with magnetic resonance imaging volumetry at baseline and 6 months. Secondary outcomes included a 50% or greater reduction in lesion volume, median shrinkage rate, improvement in quality of life, and safety. Results:A total of 19 patients (10 male [52.6%]; mean [SD] age, 24.1 [29.4] months) were enrolled. A total of 10 patients (52.6%; 90% CI, 32.0%-73.0%) achieved a 20% or greater reduction in lesion volume at 6 months. The median shrinkage rate was 22.9% (IQR, -142.3% to 96.0%). No serious adverse events occurred, and medication adherence of 70% or greater was observed in 17 of 19 patients (89.5%). Conclusions and Relevance:In this nonrandomized clinical trial of children with LMs, eppikajutsuto was associated with a reduction in lesion volume and was well tolerated. Further studies, including randomized clinical trials, are warranted to confirm these findings. Trial Registration:Japan Registry of Clinical Trials Identifier: jRCTs041210007.

To evaluate the impact of three-year Glucagon-like peptide 2 (GLP-2) analog therapy on parenteral nutrition (PN) dependency, intestinal rehabilitation, and quality of life in pediatric-onset short bowel syndrome (SBS). Between August 2021 and December 2024, 18 pediatric-onset SBS patients underwent GLP-2-based intestinal rehabilitation. The remaining length of the small intestine ranged from 20 to 50 cm in adults and averaged 20 cm in children. Clinical data were retrospectively analyzed over a three-year period. PN requirements in adults decreased by up to 54.6

Patients with biliary atresia (BA) suffer from progressive liver damage, even after successful Kasai portoenterostomy (KPE). The purpose of this study is to analyze the relevance of follow-up percutaneous liver biopsy (LBx) and long-term prognosis of patients with BA. This study included patients with BA who were born between 1983 and 2005 and survived with their native liver until 10 years of age. Patient characteristics, laboratory data and Child–Pugh score at the time of LBx, and native-liver survival (NLS) and complication-free survival (CFS) in patients with mild (F0-F2) or severe fibrosis (F3, F4) on follow-up LBx were retrospectively analyzed. Forty-three patients were gathered in this study and the most recent LBx was performed at age 21.1 ± 2.9 years. Thirty-three patients had mild fibrosis and ten patients had severe fibrosis on follow-up LBx. Long-term NLS and CFS were significantly worse in patients with severe fibrosis. Among those patients, 18 patients had follow-up LBx between the ages of 6 and 12 years, and CFS were significantly worse in patients with severe fibrosis. We found that patients with BA with severe liver fibrosis on follow-up LBx had worse long-term survival and a higher rate of progression of complications of BA.

QuestionIs eppikajutsuto, a traditional Japanese (Kampo) herbal medicine, associated with reduced lesion volume among children with lymphatic malformations (LMs)?FindingsIn this nonrandomized clinical trial of 19 children with LMs, 10 (53%) achieved a 20% or greater reduction in lesion volume at 6 months. No serious adverse events were reported.MeaningThese findings suggest that eppikajutsuto was associated with a reduction in lesion volume and was well tolerated in children with LMs. This nonrandomized clinical trial evaluates the association of eppikajutsuto, a traditional Japanese (Kampo) herbal medicine, with lesion size in pediatric patients with lymphatic malformations. ImportanceLymphatic malformations (LMs) are congenital vascular anomalies with limited treatment options. Eppikajutsuto, a traditional Japanese (Kampo) herbal medicine, is commonly used to treat inflammatory conditions and has been reported to reduce lesion volume in patients with LMs; however, data on its effectiveness in pediatric patients are needed.ObjectiveTo evaluate the association of eppikajutsuto with reduced LM lesion volume in pediatric patients with LMs.Design, Setting, and ParticipantsThis open-label nonrandomized clinical trial was conducted from April 14, 2021, to September 30, 2024, at multiple centers in Japan. Eligible participants were 18 years or younger with a confirmed diagnosis of LM by imaging. Data were analyzed from October 14, 2024, to March 4, 2025.InterventionParticipants received eppikajutsuto granules (0.6 g/kg/d to <= 7.5 g/d) orally for 6 months.Main Outcomes and MeasuresThe primary outcome was the proportion of patients achieving a 20% or greater reduction in lesion volume, measured with magnetic resonance imaging volumetry at baseline and 6 months. Secondary outcomes included a 50% or greater reduction in lesion volume, median shrinkage rate, improvement in quality of life, and safety.ResultsA total of 19 patients (10 male [52.6%]; mean [SD] age, 24.1 [29.4] months) were enrolled. A total of 10 patients (52.6%; 90% CI, 32.0%-73.0%) achieved a 20% or greater reduction in lesion volume at 6 months. The median shrinkage rate was 22.9% (IQR, -142.3% to 96.0%). No serious adverse events occurred, and medication adherence of 70% or greater was observed in 17 of 19 patients (89.5%).Conclusions and RelevanceIn this nonrandomized clinical trial of children with LMs, eppikajutsuto was associated with a reduction in lesion volume and was well tolerated. Further studies, including randomized clinical trials, are warranted to confirm these findings.Trial RegistrationJapan Registry of Clinical Trials Identifier: jRCTs041210007

Purpose: The Short Bowel Syndrome‐Quality of Life (SBS‐QoL) scale is a reliable and sensitive instrument developed to measure and evaluate the quality of life (QoL) in adult patients with short bowel syndrome (SBS). In Japan, increasing attention has been given to the assessment of QoL in patients with SBS; however, no Japanese‐language SBS‐specific scale is currently available. This study aimed to develop a Japanese version of the SBS‐QoL based on the original English version. Methods: A provisional Japanese version was created in accordance with the guidelines of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force, utilizing a process of forward translation, adjustment, and back translation. Results: Cognitive debriefing using the provisional Japanese version was conducted with six Japanese patients with SBS. Based on these results, the Japanese wording was evaluated and revised, leading to the creation of the final Japanese version. Conclusion: The Japanese SBS‐QoL, which has been confirmed to possess linguistic equivalence with the original English version, is expected to support the treatment of Japanese SBS patients, ultimately aiming to improve their QoL.

Short Bowel Syndrome‐Quality of Life(SBS‐QoL™)は, 成人短腸症候群 (short bowel syndrome, SBS) 患者のQuality of Life (QoL) 測定のために開発された信頼性・感度が高い評価尺度である. 日本でもSBS患者の治療でQoL評価が注目されているが, SBSに特化した日本語のQoL評価尺度は存在しないことから, 原版 (英語) SBS‐QoL™をもとに日本語版SBS‐QoL™ (©2023武田薬品工業) を作成した. International Society for Pharmacoeconomics and Outcomes Researchタスクフォースのガイドラインに準拠し, 順翻訳, 調整, 及び逆翻訳を経て日本語暫定版を作成した. この日本語暫定版を用いて日本人SBS患者6名を対象に認知デブリーフィングを実施し, その結果をもとに日本語表現の妥当性を評価・調整した上で, 日本語版を最終化した. 英語版と言語的妥当性のある日本語版SBS‐QoL™は, 日本人SBS患者のQoL改善を治療目標とした診療の一助となることが期待される.

BACKGROUND:Patients who undergo pediatric living donor liver transplantation (LDLT) sometimes develop graft fibrosis. Recently, Mac-2 binding protein glycosylation-modified isomer (M2BPGi) was developed as a new marker of hepatic fibrosis progression. We performed this study to examine the relationship between serum M2BPGi levels and liver histologic findings in patients after LDLT for biliary atresia.METHODS:Patients aged <19 years who underwent LDLT for biliary atresia at our institution and followed up for at least 1 year after LDLT were eligible. There were 56 patients in this study. Pathologic findings of the last available biopsy were assessed. Portal vein (PV) stenosis was confirmed with angiography. M2BPGi levels were compared with pathologic fibrosis scores and PV stenosis findings.RESULTS:The mean age at transplant was 4.3 years. The mean observation period was 8.6 years. In terms of the degree of liver fibrosis, F0 was observed in 7 patients, F1 in 36, and F2 in 13. The median serum M2BPGi value was 0.8 cut-off index (COI) overall and 0.60 COI for F0, 0.74 COI for F1, and 1.07 COI for F2. The mean M2BPGi value in F2 was higher than that in F0 (P = .016) and F1 (P = .012). Mean serum M2BPGi values were 1.57 COI (0.29 COI) in patients with PV complications (n = 5) and 0.72 COI in patients without PV complications (n = 51) (P = .0001).CONCLUSION:M2BPGi is a novel marker for liver fibrosis in patients after pediatric LDLT. It is especially useful for follow-up of pediatric patients after LDLT to support liver biopsy interpretation.

BACKGROUND:Liver failure and gastrointestinal bleeding occur in the end-stage of biliary atresia (BA). Living-donor liver transplantation (LDLT) is a standard treatment in Japan. Our program actively provides pre-transplant total parenteral nutrition (TPN) for such patients, and here we report its efficiency and safety.METHODS:Patients with BA for whom LDLT was indicated were identified. Those with a long-term external central venous catheter and TPN, longer than 4 weeks before LDLT, were analyzed. Ascites was controlled with diuretics. TPN indications, efficacy, and complications were assessed along with patient growth, biochemical markers, and gastrointestinal bleeding.RESULTS:Fourteen patients were included in the study, of whom 8 were girls and 6 were boys. The median age at LDLT was 0.9 years. Body weight (BW) at TPN initiation averaged 6799 g, and the median serum total bilirubin was 9.5 mg per dL. The median catheterization duration was 54 days, and 1 patient received home TPN. Indications for TPN were gastrointestinal bleeding and/or massive esophageal varices in 4 patients and poor nutritional status in 10 patients. No complications were observed except for 1 catheter infection and 1 catheter occlusion. The median final body weight before LDLT was 7906 g. The mean rate of BW gain was significantly higher after TPN than before (149 vs 32 g/wk, respectively, P = .0002). Mean prothrombin time and levels of albumin, cholinesterase, and total bilirubin were not significantly different at the start and end of TPN.CONCLUSIONS:Pre-transplant TPN was safe and effective for patients with end-stage BA.

BACKGROUND:Pediatric living-donor liver transplantation (LDLT) candidates often receive long-term antibiotic treatment. Micafungin has been used as an antifungal agent after LDLT, but the adequate dose after pediatric LDLT was unknown. Here, we report micafungin blood concentrations after pediatric LDLT and discuss its safety and adequate dosing.METHODS:Pediatric patients with data on micafungin concentrations after LDLT were identified. Those with surgical complications were excluded. All patients received standard tacrolimus-based immunosuppression. A micafungin dose of 1 mg/kg was administered once daily for 10 days starting on postoperative day (POD) 1. The trough and peak micafungin blood concentrations were evaluated on PODs 1, 4, 7, and 10. Beta D glucan levels and liver function tests were assessed to determine micafungin effectiveness and safety.RESULTS:Ten patients were enrolled, with a median age of 1.2 years. The median graft vs body weight ratio was 2.7%. The primary diseases were biliary atresia (n = 7), Alagille syndrome (n = 2), and progressive familial intrahepatic cholestasis type 2 (n = 1). Mean peak micafungin levels were 4.47, 6.27, 5.47, and 5.47 µg/mL on PODs 1, 4, 7, and 10, respectively. Mean trough levels were 2.03, 1.88, and 2.66 µg/mL on PODs 4, 7, and 10, respectively. The micafungin half-lives were 13.7, 14.7, and 14.0 hours on PODs 4, 7, and 10, respectively. Beta D glucan levels were 4.4 pg/mL and 3.7 pg/mL before and after transplantation, respectively, indicating no significant difference (P = .3). No clinical fungal infections were observed.CONCLUSION:Micafungin administration is safe and effective after pediatric LDLT.

Congenital esophageal stenosis (CES) associated with esophageal atresia (EA) is rare, and no standard treatment has been established. We reviewed cases of EA-associated CES to assess the clinical characteristics and treatment outcomes, especially the feasibility of endoscopic dilatation. We retrospectively examined patients with EA-associated CES. We also compared treatment outcomes of EA-associated CES with those of EA patients without CES who developed postoperative anastomotic stricture. Among 44 patients with EA, ten had CES (23

Background. The appropriate timing of liver transplantation (LT) in patients with biliary atre-sia (BA) who survived with their native livers until adolescence remains controversial. The liver -spleen volume ratio (LSR) has been reported to be efficacious in predicting the prognosis of chronic liver disease. We investigated whether LSR could predict long-term native liver progno-sis and serve as an indication for LT in patients with BA.Methods. Patients with BA who survived with their native liver until the age of 15 years were included. These patients were classified into 2 groups. The unfavorable prognosis group included patients who underwent or were awaiting LT or developed complications such as refractory chol-angitis or gastrointestinal bleeding due to esophagogastric or intestinal varices. The favorable prognosis group included patients who survived with their native liver without complications. We compared the 2 groups regarding LSR, hematological, and histologic data.Results. Of 19 patients, 8 were in the unfavorable prognosis group, and 11 were in the favor-able prognosis group. LSR was significantly lower in the unfavorable prognosis group (P = .009). Analysis of the receiver operating characteristic curve showed that the area under the curve of the LSR was 0.891, which was higher than the area under the curve of liver fibrosis markers. The optimal LSR cut-off value for predicting poor native liver prognosis was 1.97, with a sensitivity of 75.0% and a specificity of 87.5%.Conclusions. The LSR reflects splenomegaly and liver atrophy. The LSR might be a reliable predictor of native liver prognosis and could guide decisions about LT in patients with BA.

The COL4A1 (collagen Type 4 alpha1) pathogenic variant is associated with porencephaly and schizencephaly and accounts for approximately 20% of these patients. This gene variant leads to systemic microvasculopathy, which manifests as brain, ocular, renal, and muscular disorders. However, only a few patients with surgical interventions have been reported and the potential surgical risks are unknown. Here, we present the cases of two female patients between 7 and 8 years of age who were diagnosed with the COL4A1 variant and underwent laparoscopy-assisted percutaneous endoscopic gastrostomy (LAPEG) for oral dysphagia. Their primary brain lesions were caused by porencephaly and paralysis, which are caused by multiple cerebral hemorrhages and infarctions, and both patients had refractory epileptic complications. Although LAPEG was successfully performed in both patients without any intraoperative complications, one patient developed alveolar hemorrhage postoperatively and required mechanical ventilation. Thus, careful perioperative management of patients with the COL4A1 variant is important.

Introduction: Macrophage-mediated xenogeneic rejection is one of the important immunological obstructions that need to be overcome. Because macrophage is one of the main sources of proinflammatory cytokines and the fact that proinflammatory cytokines orchestrate a variety of inflammatory responses, the regulation of macrophages could result in solving the problem of xenogeneic rejection. We recently reported that membrane-type surfactant D (SP-D) on swine endothelial cells (SECs) suppresses macrophage-mediated rejection. Similar to SP-D, the carbohydrate recognition domain of surfactant protein-A (SP-A) induces inhibitory signals in effector cells. In this study, we examined the suppressive effect of SP-A on macrophage-mediated xenogeneic rejection. Methods: Naïve SEC and SP-A-transfected SEC (SEC/SP-A) were co-cultured with THP-1 cells and cytotoxicity was evaluated. To investigate the effect on phagocytosis, human macrophages were co-cultured with SEC or SEC/SP-A, and the extent of phagocytosis and production of reactive oxygen species (ROS) were assessed by flow cytometry. The mRNA expression of inflammatory cytokines in macrophages was determined using RT-PCR. In addition, THP-1 cell with a luciferase reporter gene driven by an NF-kB response element (THP-1 Luc NF-kB) cells was used to verify their effects on the NF-κB transcription factors. Results: The cytotoxicity of SEC/SP-A was significantly reduced compared to those of naïve SEC (40.7 vs 22.9%, p=0.025). The phagocytosis by macrophages against SEC was also significantly suppressed by SP-A on SEC (75.8 vs 33.0%, n=5, p=0.0010). Co-culture of human macrophages with SEC/SP-A decreased ROS production (%MFI: 99.9 vs 79.5, p=0.013). The mRNA expression of TNFα was reduced in macrophages (1.160 vs 0.009, p=0.0022), whereas that of IL-10 was increased (1.357 vs 10.20, p=0.0007). The balance between iNOS and Arg-1 was significantly suppressed by CL-SPA (1.002 vs 0.4792, p = 0.0027), indicating that CL-SPA on porcine cells inhibits the differentiation of peripheral blood monocytes into inflammatory M1 macrophages. The NF-κB transcription was decreased in THP-1 Luc NF-kB which was co-cultured with SEC/SP-A compared to that in THP-1 Luc NF-kB with SEC (RLU: 1160 vs 983.8, p=0.0258). Conclusion: The ectopic expression of human SP-A in porcine cells represents an attractive method for suppressing macrophage-mediated cytotoxicity. To further investigate the effects of SP-A on xenogeneic innate immune response in more detail, in vivo studies should be performed in the future.

The postoperative course after surgery for congenital biliary dilatation (CBD) has some complications. Intrahepatic bile duct (IHBD) stones were known as a late complication. We report on the treatment and long-term follow-up of postoperative IHBD stones in our department. Patients who underwent CBD surgery at age 15 years or younger in our department were identified. Those followed up for 5 years or more were enrolled. Annual blood chemistry tests and abdominal ultrasonography were performed. Each patient’s surgical procedure, IHBD stone diagnosis, treatments, and outcomes were retrospectively assessed. Fifty-one patients were analyzed. The median age at the last visit was 24 years (range 7–45 years), and the median age at CBD surgery was 3 years. Eight patients (16

BACKGROUND:In patients with intestinal transplantation (ITx), renal function is easily impaired because of long-term parenteral nutrition and side effects of tacrolimus. Everolimus was used in patients with renal insufficiency in our study.METHODS:We administered everolimus as a third immunosuppressive agent in addition to tacrolimus and steroids for renal sparing in patients who received ITx. We assessed everolimus levels, complications, and renal function.RESULTS:Two patients received everolimus after ITx. Patient 1 was a 13-year-old boy who underwent ITx for an allied disorder of Hirschsprung's disease. After induction therapy with rabbit antithymocyte globulin, maintenance therapy consisted of tacrolimus and steroids. Everolimus was introduced 3 months after ITx for renal sparing. Seven months later, the patient required partial intestinal graft resection owing to bowel obstruction. Everolimus was suspended for only 2 weeks. Four years after ITx, the trough level of tacrolimus was maintained at 3 to 5 ng/mL. The trough level of everolimus was maintained at 3 to 5 ng/mL. Patient 2 was a 32-year-old man who underwent deceased ITx for short gut syndrome. Induction and maintenance immunosuppression was the same as for patient 1. Everolimus was introduced 1 month after surgery. Two years after ITx, trough levels of tacrolimus and everolimus were the same as in patient 1. No rejection was observed in either patient, and renal function was well maintained. We observed no side effects caused by everolimus.CONCLUSIONS:Everolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing.