Efficacy of steroid therapy for improving native liver survival after pediatric acute liver failure with immune activation.

AIM: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment. METHODS: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed. RESULTS: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders. CONCLUSION: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis.

Deceased donor non-composite split liver and intestinal transplantation for children.

Children with intestinal failure suffer liver damage associated with parenteral nutrition: a condition known as intestinal failure-associated liver disease (IFALD), which requires transplantation of both liver and intestine. In many countries, simultaneous transplantation of these two organs is performed using grafts from a deceased donor, but there have been no such cases in Japan, and the details of the procedure are not clear. Recently, we performed simultaneous split liver and intestinal transplantation in two premature infants with IFALD, using organs from identical deceased donors and achieved good results. These are the first two cases of this procedure being performed in Japan. We report these cases and discuss the important aspects of the surgical and perioperative management.

The first successful case of ABO-incompatible living-donor lobar lung transplantation following desensitization therapy.

ABO-incompatible (ABO-I) living-donor lobar lung transplantation (LDLLT) was successfully performed in a 14-year-old girl who suffered from bronchiolitis obliterans due to graft-versus-host disease following hematopoietic stem cell transplantation. In the ABO-I LDLLT procedure, the blood type O patient received a right lower lobe donated from her blood type B father and a left lower lobe donated from her blood type O mother. Desensitization therapy, using rituximab, immunosuppressants, and plasmapheresis, was implemented for 3 weeks prior to transplantation to reduce the production of anti-B antibodies in the recipient and prevent acute antibody-mediated rejection after ABO-I LDLLT.

Outcome and growth of lobar graft after pediatric living-donor lobar lung transplantation.

BACKGROUND: Living-donor lobar lung transplantation (LDLLT) remains a life-saving option for pediatric patients with respiratory failure. However, the long-term survival and post-transplant quality of adult lobar grafts transplanted into children are unknown. Therefore, this study aimed to evaluate the outcomes of pediatric LDLLT and post-transplant graft growth. METHODS: We retrospectively reviewed the prospectively collected clinical data of 25 living-donor lung transplantations performed in 24 pediatric recipients aged ≤17 years. The annual pulmonary function test data and computed tomography scans of 12 recipients, followed up for >5 years without significant complications, were used to evaluate growth in height, graft function, and radiological changes. The Kaplan-Meier method and simple linear regression were performed for analysis. RESULTS: Bilateral lower lobe transplantation was performed in 12 patients, unilateral lower lobe transplantation in 12, and bilateral middle lobe transplantation in 1. The median volumetric size matching at transplantation was 142% (range, 54%-457%). The 5- and 10-year overall survival rates were 87.7% and 75.1༅, respectively. Chronic lung allograft dysfunction occurred in 2 patients. During a median follow-up of 6 years, the median increases in height and vital capacity were 14.4% (range, 0.80%-43.5%) and 58.5% (range, 6.7%-322%), respectively. Graft weight was positively correlated with graft volume (r2=0.622, p<0.001) after the graft volume exceeded the original lobar volume in the donor. CONCLUSIONS: This study shows that pediatric LDLLT offers satisfactory long-term survival, with the growth of mature adult lobes transplanted into growing children.

Living-donor segmental lung transplantation for pediatric patients.

OBJECTIVE: The preset study evaluated the outcome of living-donor segmental lung transplantation for pediatric patients. METHODS: Between August 2009 and May 2021, we performed living-donor segmental lung transplantation in 6 critically ill pediatric patients, including 1 patient on a ventilator alone and another patient on a ventilator and extracorporeal membrane oxygenation (ECMO). There were 4 male and 2 female patients, with a median age of 7 years (range, 4-15 years) and a median height of 112.7 cm (range, 95-125.2 cm). The diagnoses included complications of allogeneic hematopoietic stem cell transplantation (n = 4) and pulmonary fibrosis (n = 2). All patients received bilateral lung transplantation under cardiopulmonary bypass. A basal segment and a lower lobe were implanted in 3 patients, and a basal segment and an S6 segment were implanted in the other 3 patients. In 2 patients, the right S6 segmental graft was horizontally rotated 180° and implanted as the left lung. RESULTS: Among the 9 segmental grafts implanted, 7 functioned well after reperfusion. Two rotated S6 segmental grafts became congestive, with 1 requiring graft extraction and the other venous repair, which was successful. There was 1 hospital death (14 days) due to sepsis and 1 late death (9 years) due to leukoencephalopathy. The remaining 4 patients are currently alive at 9 months, 10 months, 1.3 years, and 1.9 years. CONCLUSIONS: Living-donor segmental lung transplantation was a technically difficult but feasible procedure with acceptable outcomes for small pediatric patients with chest cavities that were too small for adult lower lobe implantation.

Characterization and Study of Gene Expression Profiles of Human Periodontal Mesenchymal Stem Cells in Spheroid Cultures by Transcriptome Analysis.

A spheroid is known as a three-dimensional culture model, which better simulates the physiological conditions of stem cells. This study is aimed at identifying genes specifically expressed in spheroid-cultured human periodontal ligament mesenchymal stem cells (hPDLMSCs) using RNA-seq analysis to evaluate their functions. Transcriptome analysis was performed using spheroid and monolayer cultures of hPDLMSCs from four patients. Cluster and Gene Ontology analyses revealed that genes involved in cell-cell adhesion as well as the G2/M and G1/S transitions of mitotic cell cycles were strongly expressed in the monolayer culture group. However, genes involved in the negative regulation of cell proliferation, histone deacetylation, and bone morphogenetic protein signaling were strongly expressed in the spheroid culture group. We focused on the transcription factor nuclear receptor subfamily 4 group A member 2 (NR4A2) among the genes that were strongly expressed in the spheroid culture group and analyzed its function. To confirm the results of the transcriptome analysis, we performed real-time polymerase chain reaction and western blotting analyses. Interestingly, we found that the mRNA and protein expressions of NR4A2 were strongly expressed in the spheroid-cultured hPDLMSCs. Under osteogenic differentiation conditions, we used siRNA to knock down NR4A2 in spheroid-cultured hPDLMSCs to verify its role in osteogenesis. We found that NR4A2 knockdown significantly increased the levels of mRNA expression for osteogenesis-related genes alkaline phosphatase (ALP), Osteopontin (OPN), and type 1 collagen (COL1) (Student's paired t-test, p < 0.05). ALP activity was also significantly increased when compared to the negative control group (Student's paired t-test, p < 0.05). Additionally, spheroid-cultured hPDLMSCs transfected with siNR4A2 were cultured for 12 days, resulting in the formation of significantly larger calcified nodules compared to the negative control group (Student's paired t-test, p < 0.05). On the other hand, NR4A2 knockdown in hPDLMSC spheroid did not affect the levels of chondrogenesis and adipogenesis-related genes under chondrogenic and adipogenic conditions. These results suggest that NR4A2 negatively regulates osteogenesis in the spheroid culture of hPDLMSCs.

Retrospective evaluations revealed pre-symptomatic citrulline concentrations measured by newborn screening were significantly low in late-onset ornithine transcarbamylase deficiency patients.

INTRODUCTION: Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Late-onset OTCD manifests after the neonatal period; therefore, if pre-symptomatic diagnosis and treatment are performed, it can improve the prognosis by preventing hyperammonemia. However, pre-symptomatic diagnosis is unreliable as the specific screening marker of OTCD has not been established yet. This retrospective study aimed to evaluate the pre-symptomatic blood citrulline levels in patients with late-onset OTCD. METHODS: Patients with late-onset OTCD who were born after the newborn screening based on tandem mass spectrometry (MS/MS-NBS) was started and were referred to Hyogo College of Medicine Hospital between 2014 and 2018 were included. Pre-symptomatic blood citrulline levels measured by MS/MS-NBS were retrospectively evaluated. RESULTS: Four patients were included in this study. The pre-symptomatic blood citrulline levels were 2.02, 4.50, 4.97, and 3.75 µmol/l, respectively. Compared with the citrulline levels in all newborns in Hyogo prefecture, these values were significantly low. CONCLUSIONS: These results suggest the possibility that hypocitrullinemia detected by the MS/MS-NBS can be used as a screening marker for some patients with late-onset OTCD. Further retrospective evaluation of pre-symptomatic citrulline levels in patients with late-onset OTCD, as well as prospective monitoring of hypocitrullinemia on the MS/MS-NBS should be conducted.