Liver transplantation for pediatric liver malignancies.

In the last few decades, collaboration between international pediatric oncology groups has resulted in significant improvement in survival after liver transplantation (LT) for pediatric liver tumors, and LT has become the accepted standard of care for unresectable pediatric liver tumors-either living donor liver transplantation or deceased donor liver transplantation. Hepatoblastoma and HCC are the common pediatric liver malignancies treated by LT, and LT is now the accepted treatment modality for unresectable nonmetastatic cases. The long-term survival rate is more than 80% in hepatoblastoma transplants. Furthermore, with the advent of living donor liver transplantation, the waitlist mortality, availability of a better graft quality with shorter ischemic times, and performance of LT with the appropriate timing between chemotherapy have all improved. Up to 80% of pediatric HCCs are unresectable, and studies have shown that LT for pediatric HCC has better outcomes than liver resection. Furthermore, LT has also shown better results than liver resection for cases of HCC not meeting Milan criteria. Given the rarity of pediatric liver malignancies and challenges in optimal management, a multidisciplinary treatment approach, research models building on what is already known, and consideration of newer treatment modalities are required for further improving the treatment of pediatric liver malignancies.

Impact of Portal Flow on the Prognosis of Children With Congenital Portosystemic Shunt: A Multicentric Observation Study in Japan.

BACKGROUND: Although congenital portosystemic shunts (CPSSs) are increasingly being recognized, the optimal treatment strategies and natural prognosis remain unclear, as individual CPSSs show different phenotypes. METHODS: The medical records of 122 patients who were diagnosed with CPSSs at 15 participating hospitals in Japan between 2000 and 2019 were collected for a retrospective analysis based on the state of portal vein (PV) visualization on imaging. RESULTS: Among the 122 patients, 75 (61.5%) showed PV on imaging. The median age at the diagnosis was 5 months. The main complications related to CPSS were hyperammonemia (85.2%), liver masses (25.4%), hepatopulmonary shunts (13.9%), and pulmonary hypertension (11.5%). The prevalence of complications was significantly higher in patients without PV visualization than in those with PV visualization (P < 0.001). Overall, 91 patients (74.6%) received treatment, including shunt closure by surgery or interventional radiology (n = 82) and liver transplantation (LT) or liver resection (n = 9). Over the past 20 years, there has been a decrease in the number of patients undergoing LT. Although most patients showed improvement or reduced progression of symptoms, liver masses and pulmonary hypertension were less likely to improve after shunt closure. Complications related to shunt closure were more likely to occur in patients without PV visualization (P = 0.001). In 25 patients (20.5%) without treatment, those without PV visualization were significantly more likely to develop complications related to CPSS than those with PV visualization (P = 0.011). CONCLUSION: Patients without PV visualization develop CPSS-related complications and, early treatment using prophylactic approaches should be considered, even if they are asymptomatic. LEVEL OF EVIDENCE: Level III.

Living-donor liver transplantation for methylmalonic acidemia patient with hepatocellular carcinoma: A case report and literature review.

BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl-CoA (P-CoA) catabolism; of note, liver neoplasms rarely occur as a long-term complication of the disorder. Herein, we report the case of a patient with MMA and hepatocellular carcinoma (HCC) who was successfully treated with a living-donor liver transplant (LDLT) following prior kidney transplantation. CASE REPORT: A 25-year-old male patient with MMA underwent LDLT with a left lobe graft because of metabolic instability and liver neoplasms. He had presented with chronic symptoms of MMA, which had been diagnosed by genetic testing. Additionally, he had undergone living-donor kidney transplantation with his father as the donor due to end-stage kidney disease 6 years before the LDLT. He had an episode of metabolic decompensation triggered by coronavirus disease in 2019. Imaging studies revealed an intrahepatic neoplasm in the right hepatic lobe. Due to concerns about metabolic decompensation after hepatectomy, LDLT was performed using a left lobe graft obtained from the patient's mother. Pathological findings were consistent with the characteristics of well-to-moderately differentiated HCC. The postoperative course was uneventful, and the patient was discharged 48 days after the LDLT without any complications. At the 9-month follow-up, the patient's condition was satisfactory, with sufficient liver graft function and without metabolic decompensation. CONCLUSION: This case indicates that although HCC is a rare complication in patients with MMA, clinicians should be aware of hepatic malignancies during long-term follow-up.

N-Desmethylmajusculamide B, a lipopeptide isolated from the Okinawan cyanobacterium Okeania hirsuta.

A new lipopeptide, N-desmethylmajusculamide B (1), was isolated from the Okinawan cyanobacterium Okeania hirsuta along with 2 known compounds majusculamide A (2) and majusculamide B (3). The planar structure of (1) was elucidated by a detailed analysis of mass spectrometry and nuclear magnetic resonance spectra. The absolute configurations of the amino acid residues were determined using Marfey's analysis. The configuration of C-16 in the α-methyl-ß-keto-decanoyl moiety was determined unambiguously to be S by conducting a semisynthesis of N-desmethylmajusculamide B from 3. The cytotoxicity against mouse L1210 leukemia cells was evaluated for majusculamides (1-3).

Expert management of congenital portosystemic shunts and their complications.

Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.

The role of liver transplantation in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis): A review of the literature.

BACKGROUND: COACH syndrome is a rare autosomal recessive genetic disease characterized by liver fibrosis, which leads to severe complications related to portal hypertension. However, only a few patients with COACH syndrome undergoing liver transplantation (LT) have been reported. MATERIALS AND METHODS: We herein report the outcomes of four children who underwent LT for COACH syndrome at our institute and review three previously reported cases to elucidate the role of LT in COACH syndrome. RESULTS: All four patients in our institute were female, and three received living donors LT. All patients were diagnosed with COACH syndrome by genetic testing. LT was performed in these patients at 3, 7, 9, and 14 years old. The indication for LT was varices related to portal hypertension in all patients. One showed an intrapulmonary shunt. Blood tests revealed renal impairment due to nephronophthisis in three patients, and one developed renal insufficiency after LT. The liver function was maintained in all patients. A literature review revealed detailed information for three more patients. The indication for LT in these three cases was portal hypertension, such as bleeding from esophageal varices. One patient had chronic renal failure on hemodialysis at LT and underwent combined liver and kidney transplantation. Of these three previous patients, one died from hepatic failure due to de novo HCV infection 3 years after LT. CONCLUSIONS: LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. However, a detailed follow-up of the renal function is necessary.

Aborted living-donor liver transplantation in the real-world setting, lessons from 13 937 cases of Vanguard Multi-center Study of International Living Donor Liver Transplantation Group.

There are exceedingly uncommon but clearly defined situations where intraoperative abortions are inevitable in living-donor liver transplantation (LDLT). This study aimed to summarize the cases of aborted LDLT and propose a strategy to prevent abortion or minimize donor damage from both recipient and donor sides. We collected data from a total of 43 cases of aborted LDLT out of 13 937 cases from 7 high-volume hospitals in the Vanguard Multi-center Study of the International Living Donor Liver Transplantation Group and reviewed it retrospectively. Of the 43 cases, there were 24 recipient-related abortion cases and 19 donor-related cases. Recipient-related abortions included pulmonary hypertension (n = 8), hemodynamic instability (n = 6), advanced hepatocellular carcinoma (n = 5), bowel necrosis (n = 4), and severe adhesion (n = 1). Donor-related abortions included graft steatosis (n = 7), graft fibrosis (n = 5), primary biliary cholangitis (n = 3), anaphylactic shock (n = 2), and hemodynamic instability (n = 2). Total incidence of aborted LDLT was 0.31%, and there was no remarkable difference between the centers. A strategy to minimize additional donor damage by delaying the donor's laparotomy or trying to open the recipient's abdomen with a small incision should be effective in preventing some causes of aborted LDLT, such as pulmonary hypertension, advanced cancer, and severe adhesions.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

BACKGROUND: Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. METHODS: This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. RESULTS: Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. CONCLUSIONS: In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Prevalence, management and efficacy of treatment in portal vein obstruction after paediatric liver transplantation: protocol of the retrospective international multicentre PORTAL registry.

INTRODUCTION: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO. METHODS AND ANALYSIS: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques. ETHICS AND DISSEMINATION: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL9261).

Optimal liver transplant procedure in progressive familial intrahepatic cholestasis type 1 treated with biliary diversion or intestinal transplantation: Lessons learned from three cases treated with different approaches.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an autosomal recessive cholestatic liver disorder caused by ATP8B1 gene mutations. Although liver transplantation (LT) is indicated for progressive liver disease, postoperative complications, including severe diarrhea and graft steatohepatitis leading to graft loss, have been reported. CASES: The first patient had jaundice, pruritus, diarrhea, and growth retardation (weight z-score: -2.5; height z-score: -3.7). She underwent LT with total internal biliary diversion (TIBD) to the colon at 2 years of age. Graft biopsy at the 7-year follow-up examination revealed microvesicular steatosis (60%). Her diarrhea improved, and her growth failure was recovering (weight z-score: -1.0; height z-score: -1.7). The second patient underwent sequential intestine-liver transplantation at 8 years of age due to end-stage liver disease (ESLD) and short bowel syndrome caused by massive bowel resection for internal hernia after partial external biliary diversion (PEBD) at 21 months of age. She developed severe pancreatitis induced by steroid-bolus therapy for rejection after transplantation. She died 1.7 years after intestinal transplantation due to an uncontrollable pancreatic abscess and acute respiratory distress syndrome. The third patient underwent PEBD at 15 months of age and received LT with TEBD at 15 years of age due to ESLD with hepatic encephalopathy. Throughout the perioperative period, she showed no abdominal symptoms, including diarrhea and pancreatitis. Graft biopsy at the 2-year follow-up examination revealed macrovesicular steatosis (60%) with inflammation. CONCLUSIONS: The patients showed different outcomes. Effective therapeutic options to mitigate post-LT complications in patients with PFIC1 must be considered individually.

Gallstone ileus at 17 years after living donor liver transplantation: A case report.

BACKGROUND: Gallstone ileus (GI) occurs in <0.1% of all cases of mechanical bowel obstruction. There have been a few reports of GI occurring after Kasai procedures or Roux-en-Y anastomosis for bariatric surgery. We herein report a case of GI that occurred over 17 years after liver transplantation (LT). CASE REPORT: A 33-year-old woman who had undergone living donor LT for biliary atresia at 16 years old and had been regularly followed on an outpatient basis in our hospital presented with the sudden onset of increased abdominal distension, pain, and nausea. Enhanced abdominal computed tomography showed dilatation of the intrahepatic bile duct and the whole intestinal tract of the Roux limb as well as ischemic changes near the jejuno-jejunal anastomosis. On laparotomy, a movable and hard foreign body was palpated in the intestinal tract close to the jejuno-jejunal anastomosis site. Enterotomy was performed, and a 4-cm gallstone was removed. The patient had a good postoperative course and was discharged on postoperative day 12. CONCLUSIONS: Although GI after LT is a rare complication, it may need to be differentiated as a cause of ileus. An accurate differential diagnosis and early reliable intervention for stone removal will help prevent serious bowel complication, which may lead to graft dysfunction.

Significance of a multidisciplinary approach to congenital extrahepatic portosystemic shunt: A changing paradigm for the treatment.

AIM: To review the current institutional practice to treat patients with congenital extrahepatic portosystemic shunt (CEPS) and to determine the optimal strategy. METHODS: We retrospectively reviewed the records of 55 patients diagnosed with CEPS at our center between December 2008 and March 2022. RESULTS: Among these 55 patients, 44 (80.0%) received treatment for CEPS at a median age of 4.7 years. The most common indication for treatment was cardiopulmonary complications (45.5%). Therapeutic intervention included shunt closure by endovascular techniques (50.0%) or surgery (40.9%), and liver transplantation (9.1%). A total of 11 were classified as short shunt types, and surgical ligation was performed in all to preserve the major vascular system and prevent complications (p < 0.001). Children who received a surgical ligation were more likely to develop complications after shunt closure (p = 0.02). Among seven patients with portopulmonary hypertension (POPH), one patient, who received a shunt ligation at <1 year-of-age, was only able to completely discontinue medication. Most other CEPS-related complications were completely resolved. Post-treatment complications, including thrombosis and symptoms of portal hypertension, were seen in 16 patients. After shunt closure, one patient was scheduled to undergo liver transplantation for progressive POPH and large residual hepatocellular adenoma. During follow-up, one patient without any treatment for CEPS developed POPH 16 years from the diagnosis. CONCLUSION: Earlier therapeutic interventions should be strongly considered for patients with POPH related to CEPS. However, in view of the invasiveness and treatment complications, special attention should be paid to the management of patients with short shunt types.

Early Detection of Epstein-Barr Virus as a Risk Factor for Chronic High Epstein-Barr Viral Load Carriage at a Living-donor-dominant Pediatric Liver Transplantation Center.

BACKGROUND: Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorders (PTLDs) after pediatric liver transplantation (LT) account for significant morbidity and mortality. Knowledge of EBV kinetics, epidemiology, and outcomes among pediatric living-donor LT cases is largely lacking. This study aims to provide clinical information related to EBV infection, chronic high EBV load (CHL) carriage, and PTLD at a living-donor-dominant pediatric LT center. METHODS: A total of 5827 EBV load measurements from 394 LT recipients fulfilling inclusion criteria and their clinical data were analyzed. EBV loads >1000 copies/µg DNA (742 IU/µg DNA) were considered "high," and CHL was defined by persistence >6 mo. RESULTS: The highlighted results were as follows: (1) 94% of recipients underwent living-donor LT; (2) 80% of EBV seronegative recipients developed first EBV infection <2 y post-LT, and their EBV loads were consistently higher than those of seropositive recipients within <3 y post-LT but did not differ thereafter; (3) 61 (15%) recipients met CHL criteria, but none developed PTLD; (4) age <5 y, cytomegalovirus seronegative donors, and early development of EBV DNAemia <6 mo post-LT were independent risk factors for CHL; (5) the incidence of rejections after 1-y post-LT was comparably low among CHL carriers whose immunosuppression was minimized. CONCLUSIONS: Early detection of EBV following LT and CMV seronegative donors would facilitate risk stratification to prevent PTLD while titrating immunosuppression among pediatric LT recipients.

Strategy for hepatoblastoma with major vascular involvement: A guide for surgical decision-making.

BACKGROUND: Surgical management of tumor thrombus extending to the major vascular system for children with hepatoblastoma is challenging and insufficiently discussed. METHODS: We conducted a retrospective review of hepatoblastoma with tumor thrombus extending to the major vascular system (inferior vena cava, 3 hepatic veins, and portal vein trunk) treated at our center between May 2010 and June 2021. We describe our preoperative assessment, surgical strategies, and outcomes. RESULTS: We identified 9 patients (median age at the diagnosis: 3.4 years). All patients received chemotherapy before liver surgery. At the time of the diagnosis, tumor thrombus extended to the portal vein trunk (n = 6), inferior vena cava (n = 3), and 3 hepatic veins (n = 2). Among the 9 patients, 4 underwent liver resection. Liver transplantation was performed in 5 patients. The inferior vena cava wall was circumferentially resected for tumor removal in 1 patient and partially resected in 2 patients. One patient underwent liver transplantation using veno-venous bypass. Patients with tumor thrombus extending to the portal vein trunk were more likely to be managed by liver transplantation in comparison to those with tumor thrombus spreading to the inferior vena cava. The median follow-up period was 5.5 years. One patient underwent transhepatic balloon dilatation for biliary stricture after liver resection. Tumor recurrence was seen in 3 patients (33.3%; lung, n = 2; lymph node and liver, n = 1). No patients died during the follow-up period. CONCLUSION: Surgical intervention for pediatric hepatoblastoma with tumor thrombus extending into the major vascular system is safe, feasible, and achieves excellent outcomes.

Hematological and biochemical characteristics and diagnostic imaging results in acute T cell-mediated rejection after pediatric liver transplantation.

BACKGROUND: Liver biopsy is the gold standard for diagnosing TCMR after LT. However, complications caused by liver biopsy may occur especially during the immediate post-transplantation period and other effective methods for predicting TCMR have not been established. Thus, we investigated whether hematological and biochemical characteristics and Doppler ultrasonography findings are associated with acute TCMR. METHODS: A multiple logistic regression analysis was performed to identify the prognostic factors of acute TCMR, defined as a RAI ≥4. Then, a ROC curve analysis was conducted to evaluate for diagnostic performance. The relationship between prognostic factors and each histological category of RAI was investigated. RESULTS: Eighty-nine liver biopsies were performed on 85 patients between January 2012 and December 2019. The RAI of 62 (69.7%) liver biopsies was ≥4. AEC (×104 /µl), direct bilirubin level (mg/dl), and MHVV (cm/s) were found to be associated with acute TCMR (OR: 4.96, 95% CI: 1.44-17.0, p = .011; OR: 1.41, 95% CI: 1.04-1.91, p = .025; OR: 1.05, 95% CI: 1.02-1.08, p < .001, respectively). The area under the ROC curves for predicting acute TCMR was 0.86 (95% CI: 0.78-0.94). There was a correlation between AEC, direct bilirubin level, and MHVV as well as the severity of RAI. CONCLUSIONS: AEC, direct bilirubin level, and MHVV were the independent risk factors for acute TCMR. This study could provide information regarding the identification of patients requiring liver biopsy.

Surgical technique and the long-term outcomes of pediatric living donor domino liver transplantation from patients with maple syrup urine disease.

BACKGROUND: The native liver of patients with maple syrup urine disease (MSUD) (1st recipients) can be used as a graft for non-MSUD patients with end-stage liver disease (2nd recipients). This study aimed to demonstrate the optimal operational procedures and the long-term outcomes of 2nd recipients. METHODS: Six 2nd recipients of living donor domino liver transplantation (LD-DLT) (age: 42.5 [22-169] months at DLT) received a native liver as a graft from an MSUD patient at our hospital between June 2014 and April 2020. We reviewed the operational procedures and outcomes of 2nd recipients after LD-DLT. RESULTS: The 2nd recipients' original diseases included biliary atresia, congenital hepatic fibrosis, congenital protein C deficiency, familial hypercholesterolemia, hepatoblastoma, and mitochondrial hepatopathy. Five of the six recipients had a whole liver and one had a right lobe graft. The site at which the vessels of the MSUD liver were dissected prioritized the safety of the 1st recipient. At the end of follow-up, all recipients were doing well without surgical complications. The mean serum amino acid values of the 2nd recipients did not exceed the upper limit of the reference values during the long-term observation period. All patients showed normal growth while maintaining the same z-score of height and weight after LD-DLT as the preoperative level. CONCLUSION: The liver of patients with MSUD can be used safely without concern regarding long-term complications or de novo MSUD development. LD-DLT using the MSUD liver can expand the donor pool as an alternative graft in pediatric LT.

Comparative study of open and laparoscopic Kasai portoenterostomy in children undergoing living donor liver transplantation for biliary atresia.

PURPOSE: The effectiveness of laparoscopic Kasai portoenterostomy (Laparoscopic-KPE) for biliary atresia (BA) has been reported but remains controversial. We reviewed our own cases and cases described in previous studies of liver transplantation (LT) for BA after Laparoscopic-KPE to investigate the efficacy of Laparoscopic-KPE. METHODS: Subjects were children of ≤ 2 years old with LT for BA after KPE who underwent Laparoscopic-KPE (n = 10) or Open-KPE (n = 115) between 2009 and 2020. Propensity score matching was performed to reduce the effect of treatment selection bias. The clinical data regarding the preoperative characteristics and surgical results were compared. RESULTS: The rates of hypoplastic portal vein and retrograde portal vein flow were lower in the Laparoscopic-KPE group than in the Open-KPE group (0 vs. 40.0%, p = 0.02 and 0 vs. 35.0%, p = 0.04). There was no marked difference in the operation time or duration of hepatectomy. For portal vein reconstruction, a vein graft was not required in the Laparoscopic-KPE group (0 vs. 35.0%, p = 0.03). No patients in the Laparoscopic-KPE group developed portal vein complications or required re-laparotomy for bowel perforation or re-bleeding, in contrast to the Open-KPE group (0 vs. 15.0% and 0 vs. 10.0%, respectively). CONCLUSION: Laparoscopic-KPE may reduce postoperative complications that necessitate re-laparotomy in LT.

The morphological and histopathological assessment of Alagille syndrome with extrahepatic bile duct obstruction: the importance of the differential diagnosis with subgroup "o" biliary atresia.

PURPOSE: The differential diagnosis between Alagille syndrome (AGS) with extrahepatic bile duct obstruction (EHBDO) and biliary atresia (BA) is difficult. We report a case series of AGS with EHBDO with detailed validation of the morphological and histopathological features for the differential diagnosis of BA. METHODS: Six liver transplantations (LTs) were performed for AGS with EHBDO. All patients were diagnosed with BA at the referring institution and the diagnosis of AGS was then confirmed based on a genetic analysis before LT. We verified the morphological and histopathological findings of the porta hepatis and liver at the diagnosis of BA and at LT. RESULTS: All patients had acholic stool in the neonatal period and were diagnosed with BA by cholangiography. The gross liver findings included a smooth and soft surface, without any cirrhosis. The gross findings of the porta hepatis included aplasia of the proximal hepatic duct, or subgroup "o", in five patients. The histopathological examination of the EHBD also revealed obstruction/absence of the hepatic duct. There were no patients with aplasia of the common bile duct. CONCLUSIONS: Aplasia of the hepatic duct and the macroscopic liver findings may help in to differentiate between AGS with EHBDO and BA.