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: Pediatric patients sometimes develop graft fibrosis after living donor liver transplant (LDLT). Autotaxin is a recently developed serum marker for hepatic fibrosis. We studied the relationship between serum autotaxin levels and histological findings in patients after LDLT for biliary atresia (BA). Methods: Information on patients aged <19 years who received LDLT for BA and were followed for at least 1 year after LDLT was gathered. Autotaxin levels were compared with pathological fibrosis scores. Results: The study included 52 patients, of whom 4 patients had no fibrosis (F0), 36 patients had F1 fibrosis, and 12 patients had F2. The median serum autotaxin level was 0.89 mg/L. In patients with portal vein (PV) complications such as stenosis or thrombosis (n = 7), the mean autotoxin level was 1.25 mg/L compared with 0.95 mg/L in patients without PV complications (p = 0.004). Among patients without PV complications, the mean autotaxin level was 0.90, 0.88, and 1.18 mg/L in F0, F1, and F2 fibrosis, respectively. The mean autotaxin was higher in F2 fibrosis than in F0 or F1 fibrosis (p <0.05). Autotoxin had a high area under the curve (0.86) with the cut-off level of 0.897 mg/L. Conclusion: Serum autotaxin is a novel marker for liver fibrosis in patients after pediatric LDLT for BA. : Study of Diagnostic Test. : Level II. [ABSTRACT FROM AUTHOR]

Portoenterostomy is the standard treatment for biliary atresia (BA) that reduces jaundice in two thirds of cases. However, progressive liver fibrosis is common, leading to cirrhosis in most patients. Autotaxin is a new marker for the progression of hepatic fibrosis. We examined the relationship between serum autotaxin levels and liver histological findings in patients with BA. BA patients with native livers were identified in our hospital. Patients underwent protocol liver biopsies every 1 to 5 years, and liver fibrosis was evaluated based on the METAVIR score. Serum autotaxin levels were compared with the last available pathological findings. Thirty-five patients were included and the median age was 10.6 years. Serum autotaxin levels was median 1.6 mg/L. The mean autotaxin level was 1.08 mg/L in F0, 1.07 mg/L in F1, 0.95 mg/L in F2, 2.17 mg/L in F3, and 2.50 mg/L in F4; it was significantly higher in F4 than in F0–F2 (P <0.0024). For predicting cirrhosis (F4) and advanced liver fibrosis (≥F3), autotaxin had the almost same areas under the curve (AUCs 0.78 and 0.90, respectively) as well as M2BPGi. Autotaxin levels could be used to evaluate the status of native liver fibrosis. [ABSTRACT FROM AUTHOR]

Aim To characterize cholesterol regulation in the liver of patients with Alagille syndrome (AGS). Methods Serum total cholesterol (TC) and total bile acid (TBA) levels were measured in 23 AGS patients. The expressions of genes involved in cholesterol regulation, including low-density lipoprotein receptor ( LDLR ), scavenger receptor class B type I ( SR-BI ), 3-hydroxy-3-methylglutaryl coenzyme A reductase ( HMGCR ), cholesterol 7α-hydroxylase ( CYP7A1 ), ATP-binding cassette transporter ( ABC) A1 , and ABCG1/5/8 , were measured in liver tissues from five of these patients. Expression of regulators for these genes, including farnesoid X receptor/small heterodimer partner ( SHP ), liver X receptor α ( LXRα ) and mature Sterol regulatory element-binding protein 2 (SREBP2) was measured. The expression of mature SREBP2 protein was also examined. Results Serum TC and TBA levels were correlated in the AGS patients. Liver cholesterol was also increased compared with controls, and correlated with bile acid contents. LDLR , SR-BI , HMGCR , and ABCGs mRNA expression were upregulated, while CYP7A1 mRNA expression was downregulated in AGS livers. SHP and LXRα mRNA expression was also increased, but maturation of SREBP2 was not suppressed in the patients. Conclusions The major upregulators of liver cholesterol might be increased in AGS patients, indicating an impaired negative feedback mechanism and accelerated liver cholesterol accumulation. [ABSTRACT FROM AUTHOR]

• Everolimus could be used safely and effectively after intestinal transplant. • Early use of everolimus after intestinal transplant did not affect wound healing. • Renal function after intestinal transplant was well maintained with everolimus. 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. 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. 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. Everolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing. [ABSTRACT FROM AUTHOR]

• It is rare for hepatopulmonary syndrome (HPS) to occur without cirrhosis/liver disease or portosystemic shunting. • It is also rare for HPS to occur in liver transplant recipients. • HPS should be considered in a patient with hypoxemia with hepatic or biliary abnormalities who does not have cardiopulmonary disease even if there are no apparent causes of HPS. Hepatopulmonary syndrome (HPS) is a disease of gas exchange caused by intrapulmonary shunting secondary to liver disease-associated intrapulmonary vascular dilation. HPS is characterized by the triad of cirrhosis, chronic liver disease, or portosystemic shunting (PSS); arterial hypoxemia; and intrapulmonary arteriovenous shunting in the absence of a primary cardiopulmonary anomaly. We encountered a rare case of HPS without liver disease or PSS. The patient was an 8-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 11 months of her age. Eight years after LDLT, hypoxemia and shortness of breath developed. The shunt ratio on 99mTc-macroaggregated albumin (MAA) lung perfusion scintigraphy (99mTc-MAA lung scan) was 32%. The patient had no cardiopulmonary disease, so we diagnosed her illness as HPS. We did not find cirrhosis, chronic liver disease, or PSS as a cause of HPS. We thought the graft was the cause of HPS. A second transplantation was planned. One year after the diagnosis of HPS, the shunt ratio on 99mTc-MAA lung scan worsened to 42%, digital clubbing appeared, and hypoxemia was worsening. Thus, we performed a second LDLT. After LDLT the shunt ratio on 99mTc-MAA lung scan normalized (6%) and cyanosis resolved. We determined that the graft was the cause of HPS; the typical causes of HPS were not clearly revealed in the histologic examination of the second liver explant. Acute rejection occurred twice after LDLT, so we speculated that HPS occurred because the graft became stressed over the long term. [ABSTRACT FROM AUTHOR]

• Here we present a rare case report of a successful case of hepatoblastoma with pulmonary metastases in which recurrences were treated with repeated lung resection, chemotherapy, and living donor liver transplantation. • Liver transplantation following resection of pulmonary metastases was a feasible option. • Resection of recurrent pulmonary lesions after liver transplantation was a feasible option when lesions were located only in the lung. Liver transplantation (LTx) is indicated for unresectable hepatoblastoma (HB) without distal metastasis. However, to our knowledge, there is no consensus on the management of unresectable HB with pulmonary metastases, or on the treatment of recurrent HB. We report a successful case of metastatic HB treated with repeated lung resection, chemotherapy, and LTx. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source. Our case was a 1-year-old boy who developed pre-treatment extent of disease (PRETEXT) Ⅲ HB with multiple pulmonary metastases. The liver tumor was unresectable because it involved all hepatic veins. After 3 cycles of chemotherapy (cisplatin/carboplatin plus doxorubicin), the remaining 2 pulmonary metastases were resected and living donor liver transplantation (LDLT) was performed. Five months after LDLT, a tumor recurrence was detected in the right lung. Repeat lung resection was performed followed by 1 cycle of chemotherapy (carboplatin plus doxorubicin). There has been no recurrence for 18 months since the last lung resection. Previous reports revealed that 14 patients, including the present case, underwent LTx after resection of metastatic HB pulmonary lesions. Of these patients, the 2-year survival rate after LTx was 91%. Recurrence was reported in 5 patients, 2 of whom were successfully treated with repeated resection of the metastatic lesions. LTx after resection of lung recurrence may be a potential treatment for unresectable HB with pulmonary metastases. [ABSTRACT FROM AUTHOR]

• Estimated graft volume in infants varies widely. • Grafts were functioning well with the exception of one graft loss due to antibody-mediated rejection. • Monosegment grafting can be useful for infants as well as newborns. Left lateral segment grafts are generally used for very young pediatric patients undergoing living donor liver transplantation (LDLT). Recently, graft reduction techniques were developed for LDLT. Monosegment grafting has been used in newborns. The aim of this study was to determine the usefulness of monosegment grafting for infants. Recipients <2 years of age who underwent LDLT with a monosegment graft between 2010 and 2020 were gathered. Parents comprised all LDLT donors. A segment 2 monosegment graft was resected as a graft from the donor. Standard liver volume (SLV) was estimated using Urata's equation. Graft type, graft weight (GW), and native liver weight were assessed. Eight patients were included in the study. Original diseases consisted of biliary atresia (n = 6) and fulminant hepatitis (n = 2). Final graft type included monosegment (n = 5) and reduced monosegment (n = 3). Median final GW/body weight after reduction was 3% (range, 2%-3.4%). Median native liver weight/SLV was 134% except in patients with fulminant hepatitis. Median pre-reduction graft volume (GV)/estimated GV was 113% (range, 60%-208%). Median pre-reduction GV/SLV of monosegment grafts that required reduction (n = 3) was 109% (range, 106%-121%). Median final reduced graft GV/SLV was 80% (range, 74%-91%). Complications due to large-for-size grafts were not observed. One case of bile leakage due to graft reduction occurred as a complication. Grafts were functioning well with the exception of one graft loss due to antibody-mediated rejection. Estimated GV in infants varies widely. Monosegment grafting can be useful for infants as well as newborns. [ABSTRACT FROM AUTHOR]

• Tacrolimus-induced encephalopathy was observed in 5% of patients after pediatric living donor liver transplantation. • White blood cell count elevation was observed in all patients at the time of onset. • Patients can resume tacrolimus safely without further neurologic symptoms. Tacrolimus-related neurotoxicity is a serious complication. Posterior reversible encephalopathy syndrome, which is severe neurotoxicity after pediatric living donor liver transplantation (LDLT), is a medication-induced complication related to calcineurin inhibitors. The purpose of this study was to evaluate the long-term outcome of tacrolimus-related neurotoxicity after pediatric LDLT. Pediatric patients who underwent LDLT between 2007 and 2020 at our institution and developed neurologic symptoms with tacrolimus were included in the study. Tacrolimus-related encephalopathy was defined as encephalopathy that resolved after tacrolimus was discontinued. All patients received tacrolimus and a steroid for immunosuppression starting just after LDLT. During the study period, 128 patients underwent LDLT. All patients received tacrolimus and a steroid. Six patients (5%) developed tacrolimus-related encephalopathy. The median age at transplant was 1.6 years. The original diseases were biliary atresia (n = 5) and progressive familial intrahepatic cholangiopathy type 2 (n = 1). Patients developed encephalopathy at a median of 9 days after LDLT. All patients recovered with conversion to cyclosporine. Posterior reversible encephalopathy syndrome was confirmed by magnetic resonance imaging in 3 patients. The mean tacrolimus level at encephalopathy was 11 ng/dL (range, 5.6-14.6 ng/dL). White blood cell count elevation was observed in all patients. One patient died of pancreatitis. Surviving patients (n = 5) were followed for a median of 9 years. All patients resumed tacrolimus a median of 8 months from onset. No neurologic complications were observed after resuming tacrolimus. We observed tacrolimus-induced encephalopathy in 5% of patients after pediatric LDLT. Patients can resume tacrolimus safely without further neurologic symptoms. [ABSTRACT FROM AUTHOR]

• Portal vein stents were successfully placed in children as young as 3 years old. • Portal vein stents are effective for intractable portal vein stenosis in children. • A stent placed in young children does not cause portal hypertension as patients grow. Portal vein (PV) stenosis is sometimes seen in pediatric living donor liver transplantation (LDLT). PV stents have been attempted in adults with persistent stenosis. However, long-term usefulness of PV stenting is unknown because stents do not expand with growth. We investigated the effect and long-term outcome of PV stenting for stenosis after pediatric LDLT. We included patients aged <18 years who underwent LDLT from 1998 to 2020 and who underwent PV stenting for stenosis. We assessed age at procedure, stent complications, and long-term outcomes. Five patients underwent PV stent placement. The median age at LDLT was 10 years (range, 0.8-18.1 years). The median interval between LDLT and stent placement was 25 months. The median age at stent placement was 16 years (range, 3-20 years). The median body weight was 38 kg (range, 13-63 kg). The median stent diameter was 8 mm. The median observation period after stent placement was 8 years. On average, body weight increased 1.6 times. One complication associated with stent placement was PV thrombosis, which resulted in stent failure, but we observed no portal hypertension. In the other 4 patients, the stent has remained functioning, and there was no clinical evidence of portal hypertension. PV stents are effective for intractable PV stenosis in children. PV stents were successfully placed in children as young as 3 years old and weighing 13 kg. Our data suggests that a stent placed in young children does not cause portal hypertension as patients grow. [ABSTRACT FROM AUTHOR]

Everolimus (EVR) is a derivative of sirolimus with a similar mechanism of action. The safety and efficacy of EVR after pediatric living donor liver transplantation (LDLT) are currently unknown. The purpose of this study was to examine the safety and efficacy of EVR as rescue therapy after pediatric LDLT. This study included patients younger than 19 years of age who received EVR after LDLT at our institution. EVR was administered as rescue treatment in addition to tacrolimus. In 21 patients, EVR dose, trough level, outcomes, and adverse effects were assessed. Original diseases of patients consisted of biliary atresia (n = 11), Alagille syndrome (n = 3), fulminant hepatitis (n = 3), hepatoblastoma (n = 2), and other (n = 2). Mean age at transplant was 2.0 years (range 0.6-6.2 years). Mean age at initial EVR administration was 8.0 years (range 0.9-18.9 years). Indications for EVR use were graft fibrosis (n = 8), refractory acute cellular rejection (n = 5), renal sparing (n = 4), hepatoblastoma (n = 2), and chronic rejection (CR) (n = 2). Mean duration of administration was 17.1 months (range 2.1-60.4 months). Mean dose was 0.5 mg/m2 twice daily. Mean EVR trough level was 2.5 ng/mL (range 1.5-5.0 ng/mL). Liver function improved and fibrosis did not progress in all patients with CR. However, 14 patients (67%) experienced adverse effects that required EVR dose reduction or discontinuation. EVR is tolerable for pediatric patients after LDLT with dose adjustment. EVR had a certain effect to relieve progression on CR. Further follow-up is required. • Everolimus can be used after pediatric living donor liver transplantation. • Everolimus is an effective treatment for chronic rejection. • Everolimus had adverse effects that required dose adjustment. [ABSTRACT FROM AUTHOR]

Serum beta-D-glucan (BDG) levels may increase with anti-adhesion barrier film (ABF) use during pediatric living donor liver transplantation (LDLT). It may affect detection of fungal infections after LDLT. We evaluate BDG levels after pediatric LDLT. Pediatric patients who received an ABF during LDLT were included. Patients who may have had fungal infections prior to LDLT were excluded. One sheet of ABF was placed in the peritoneum during abdominal closure. Serum BDG levels before transplantation and on postoperative days (PODs) 1, 4, 7, 14, 21, and 28 and peritoneal fluid BDG levels on PODs 1 and 7 were measured. Sixteen patients received an ABF during LDLT. Median age at transplant was 1.9 years (range, 6-11 years). Median body weight was 12.6 kg (range, 6.8-39 kg). Indications for LDLT were biliary atresia (n = 10) and other (n = 5). Prior to transplantation, the mean serum BDG level was 3.8 pg/mL. Mean Serum BDG levels were 18.1, 38.3, 5.3, 3.8, 3.3, and 3.3 pg/mL on PODs 1, 4, 7, 14, 21, and 28, respectively. Mean peritoneal fluid BDG levels were 485.9 and 240.4 pg/mL on PODs 1 and 7, respectively. No clinical fungal infections were observed. BDG levels were high in serum and peritoneal fluid after pediatric LDLT. Serum BDG levels normalized after POD 7. Careful interpretation of BDG levels until POD 7 is needed when an ABF has been used. • B-D-Glucan levels were high in serum and peritoneal fluid after pediatric LDLT. • Serum B-D-Glucan levels normalized after POD 7. • Careful interpretation of BDG levels until POD 7 is needed when an ABF has been used. [ABSTRACT FROM AUTHOR]

Valganciclovir (VGCV) is used as prophylaxis against cytomegalovirus (CMV) infection after pediatric living donor liver transplantation (LDLT). The purpose of this study was to examine the efficacy of 1 year of preemptive VGCV administration compared with a shorter administration after pediatric LDLT. VGCV was administered to 56 children who underwent LDLT. CMV and Epstein-Barr virus (EBV) antibody status, pp65 antigenemia, and other laboratory data were assessed at 1 year after LDLT. Patients were divided into the 1-year group (n = 32) (patients who had 1 year of VGCV administration) and the <1-year group (n = 24) (patients who had less than 1 year of VGCV administration). Study participants consisted of 34 females and 22 males, with a mean age of 4.2 years at transplant. Regarding pretransplant donor (D)/recipient (R) CMV antibody status, 13 were D positive (+)/R negative (-), 27 were D+/R+, 8 were D-/R+, and 8 were D-/R-. For EBV, 22 were D+/R+, 32 were D+/R-, and 2 were D-/R-. In the 1-year group, only 2 patients (6.5%) developed CMV infection, whereas 8 patients (33.3%) developed CMV infection in the <1-year group. The CMV pp65 antigenemia assay was positive in 2 patients. CMV IgM was positive in 7 patients. One year of preemptive VGCV administration was associated with a lower incidence of CMV infection (P =. 008), but not EBV infection. No adverse effects were observed. One year of preemptive VGCV administration after LDLT is safe and suppresses CMV infection. It was useful after pediatric LDLT. • The study showed that 1 year of preemptive valganciclovir (VGCV) administration after pediatric living donor liver transplantation (LDLT) was safe. • One year of preemptive VGCV administration suppressed cytomegalovirus infection after pediatric LDLT. • One year of preemptive VGCV administration tended to suppress Epstein-Barr virus seroconversion after pediatric LDLT. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. This study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. Patients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3 x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. After LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress. • Infants require a higher mycophenolate mofetil (MMF) dose than older patients based on trough levels. • MMF stopped recurrent acute cellular rejection and recurrent fulminant hepatitis. • MMF cannot prevent allograft fibrosis progression. [ABSTRACT FROM AUTHOR]