Liver In Children Research Articles

S1856 How Parental Exercise Habits Influence Their Children's Liver Health

S1856 How Parental Exercise Habits Influence Their Children's Liver Health

Progressive familial intrahepatic cholestasis type 4: a case report

BackgroundProgressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known.Case presentationA 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations.ConclusionOwing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.

Non Invasive Assessment of Pulmonary Artery Pressure in Children with Portal Hypertension

Abstract Background Pulmonary artery hypertension is a complication of liver cirrhosis with Portal Hypertension (PHT). It has been mentioned in case reports or small series of children. Fewinformation known on its prevalence and long-term survival in childhood liver disease. This study will assess the Pulmonary Atery Pressure (PAP) in children with PHT in Pediatric Hepatologyclinic, Ain Shams University Children Hospital in order to identify clinical characteristics of Porto PH and its prevalence among those children. Aim of the Work To assess the PAP using Echocardiography in children with PHT who attend Pediatric Hepatology clinic, Ain Shams University Children Hospital. Patients and Methods This case-control study was conducted on thirty patients enrolled from Pediatric Hepatology clinic, Ain Shams University Children Hospital in a period of one year from June 2021 to June 2022 according to inclusion criteria : history of hematemesis and melena, clinical examination: Splenomegaly, dilated anterior abdominal wall vessels, ascites ± firm hepatomegaly and imaging: Ultrasonography (US) /color Doppler-US (CDUS): Splenomegaly, presence of Porto collateral vessels and ascites. This information will be completed with data on liver size, echo texture, and margins which can suggest underlying cirrhosis, portal vein diameter, portal blood flow velocity, direction of blood flow in portal vein with age ranging from 1 to 16 years with median (IQR) of 8 (4.5-12) years; they were 11 females (36.7%) and 19 males (63.3%) and thirty healthy matched age and sex as a control group. Results In our study, MPAP was 9.79 ± 2.21 mmHg (7.2-18.2 mmHg). Statistically, there was statistically significant increase in the level of TR velocity, TR PG, RVSP and MPAP in patients with PHT than control group with p-value <0.001, 0.001; 0.001 and <0.001; respectively. Also, there was statistically significant increase in the percentage of patients with abnormal TR PG and patients with elevated systolic PAP in patients with PHT (20.0%) than control group (0.0%) with p-value = 0.010 and 0.010; respectively. Also, there was statistically significant decrease in the level of PA acceleration time (ms) in patients with PHT than control group with p-value <0.001. Also, there was statistically significant increase in the level of PAEDP (mmHg) and LA (cm) in patients with PHT than control group with p-value <0.001 and 0.014; respectively. In our studied group of patients we did not found any of them has PH despite the higher parameters of their Echo studies and that needs follow up of those patients. So the prevalence of PH in those patients is 0%. Conclusion PHT is an important risk factor of development of PH in children. Transthoracic echocardiography can be reliably used as an initial non-invasive, safe and reliable modality for the assessment of pulmonary artery hypertension in children, and can obviate the need of right heart catheterization in some patients, especially those with mild PHT.

Progress in Biomarkers Related to Biliary Atresia.

Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children's liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.

Study of Low kV, Low Contrast Agent Dosage, and Low Contrast Agent Flow Rate Scan in Computed Tomography Angiography of Children's Liver

Background: During computed tomography (CT) examinations, the presence of radiation material undoubtedly has a certain impact on patients, particularly children, who are more susceptible to radiation. Consequently, finding ways to minimize radiation dosage and mitigate radiation-related risks while enhancing the quality and accuracy of CT scans has become a crucial concern for medical professionals in CT equipment manufacturing companies and radiology departments to contemplate. Objectives: This study aimed to explore the feasibility of low dose and low contrast medium combined with low flow rate scanning in CT angiography (CTA) of children's liver. Patients and Methods: A total of 59 children who visited our department for liver vascular CT scans between April 2021 and December 2022 were prospectively selected and randomly divided into 2 groups: the experimental group and the control group. The experimental group consisted of 28 children who received an injection of 80 kV, automatic tube current, low contrast dose (1.5 mL/kg), and low flow rate of 20 s. The control group included 31 children who were injected with 100 kV, automatic tube current, contrast agent dose (2 mL/kg), and flow rate of 16 s. The objective and subjective image quality, radiation dose, and iodine intake in the arterial, portal, and venous phases were compared between the 2 groups. Results: During the arterial, portal, and venous phases, the experimental group exhibited lower signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) compared to the control group (P < 0.05). However, there was no significant difference in subjective quality scores between the 2 groups (P > 0.05). The effective dose (ED), volume CT dose index (CTDIvol), and dose-length product (DLP) of the experimental group were lower than those of the control group (P < 0.05). Additionally, the iodine intake in the experimental group was lower than that in the control group (P < 0.05). Conclusion: In the examination of hepatic vascular CTA in children, the use of a 3-low scanning technique can effectively decrease radiation and contrast agents while ensuring sufficient image quality for accurate clinical diagnosis.

Exploring the Role of Serum Osteonectin and Hsp27 in Pediatric MAFLD Diagnosis and Cardiometabolic Health.

Childhood obesity is one of the major challenges of public health policies. The problem of fatty liver in childhood, known as MAFLD (metabolic dysfunction-associated fatty liver disease), is of particular interest as the gold standard diagnosis technique is invasive (liver biopsy). Hence, efforts are made to discover more specific biomarkers for the MAFLD signature. Therefore, the aim of the study was to evaluate Osteonectin and Hsp27 as biomarkers for MAFLD diagnosis and to assess their links with auxological and biochemical profiles of overweight and obese pediatric subjects. A cross-sectional study in which we (re)analyzed data from the MR PONy cohort comprising 71 pediatric subjects. Auxological data, liver ultrasonography and biochemical serum profile were recorded. Lipid-derived indices and body composition indices were calculated. Nevertheless, serum Osteonectin and Hsp27 levels were assessed using an ELISA approach. MAFLD prevalence was 40.8%. Higher Osteonectin levels were noted in MAFLD subjects versus non-MAFLD subjects and in dyslipidemic children regardless of their liver function status. Lipid-derived indices had good diagnostic capacity for MAFLD. We confirm Osteonectin as a MAFLD diagnosis biomarker in children. Also, lipid-derived indices are useful as metabolic-associated organ impairment markers in children even before the onset of obesity.

Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.

High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort. MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87-0.94). At cutoff 52.8ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77-0.86), stool color = 0.68 (CI: 0.63-0.73), and pathology = 0.84 (CI: 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88-0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2ng/mL. Results were consistent within each assay technology and generated similar AUROCs. Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy.

Treatment of Undifferentiated Embryonal Sarcoma of the Liver in Children.

Undifferentiated embryonal sarcoma of the liver is a rare mesenchymal tumor with a highly malignant potential. It occurs almost exclusively in the pediatric population and typically has a poor outcome. Although previous studies have reported dismal prognoses, recent advances in combined treatment modalities, e.g., surgery and chemotherapy, have given cause for optimism. Even in those diseases not amenable to complete surgical resection or refractory diseases, other treatment modalities, such as liver transplant, have yielded promising results. This paper provides a review of the current treatment modalities for hepatic undifferentiated embryonal sarcoma in children.

UK guideline on the transition and management of childhood liver diseases in adulthood.

Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.

Wnt/β-catenin signaling pathway in liver biology and tumorigenesis.

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.

Biomarkers Associated With Future Severe Liver Disease in Children With Alpha-1-Antitrypsin Deficiency

Background and AimsChildren with Alpha-1-antitrypsin deficiency (AATD) exhibit a wide range of liver disease outcomes from portal hypertension and transplant, to asymptomatic without fibrosis. Individual outcomes cannot be predicted. Liver injury in AATD is caused by accumulation in hepatocytes of the mutant Z AAT protein, especially the toxic, intracellular polymerized conformation. AATD patients have trace Z polymer detectable in serum with unknown significance. Methods: The Childhood Liver Disease Research Network (ChiLDReN) is an NIH consortium for the study of pediatric liver diseases, including AATD. We obtained data and samples with the aim of identifying biomarkers predictive of severe AATD liver disease. Results: We analyzed prospective AATD ChiLDReN data and serum samples in 251 subjects from 2007-2015 for outcomes and Z polymer levels. 58 of 251 had clinically evident portal hypertension (CEPH) at enrollment and 10 developed CEPH during follow up. Higher Z AAT polymer levels were associated with existing CEPH (p=0.01). In infants without CEPH, higher polymer levels were associated with future CEPH later in childhood, but total AAT was not predictive. Higher GGT in the first few months of life was also significantly associated with future CEPH, and risk threshold GGT levels can be identified. A model was constructed identifying subjects at high risk of future CEPH by combining clinical GGT and polymer levels (area under the curve (AUC) 0.83; 95% CI: 0.656 – 1.00, p = 0.019). Conclusions: High circulating Z polymer levels and high GGT early in life are associated with future CEPH in AATD, and use of predictive cutoffs may assist in future clinical trial design.

Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.

Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children. Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls. GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01). GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.

Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance.

Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood. The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119). We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not. Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes. Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed. eSMM was calculated in 127 participants (5-18y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd. Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

Non-alcoholic Fatty Liver in Children and Adolescents in Saudi Arabia.

Objectives This study aims to describe the disease parameters of children and adolescents diagnosed with non-alcoholic fatty liver disease (NAFLD) in Saudi Arabia. It also investigates the disease's progression and compares clinical, biochemical, and radiological parameters at baseline and follow-up of patients with NAFLD. This study was done between two groups of patients: obese and those of average body weight. Methods A retrospective cohort study was conducted between 2014 and 2018 through retrieved data from medical records. It included all children aged between six to 18 years diagnosed with NAFLD. Medical history was taken from each medical record, liver function test results, cholesterol, blood pressure readings, and body weight. Data have been restored from King Abdullah Specialist Children's Hospital (KASCH)​, Security Forces Hospital (SFH), and King Khalid University Hospital (KKUH). Results A total of 116 subjects met the inclusion criteria; 65 (56%) were male, and 81 (70%) were obese. The majority of subjects (n=112) had mild NAFLD, with (71%) obese and(29%) non-obese, followed by moderate NAFLD with 50% among obese and non-obese (N=2), and non-alcoholic steatohepatitis (NASH) with 100% non-obese (N=2). Data showed that patients' proportion of obese to non-obese is 70% (N=81) to 30%(N=35), respectively. Conclusion NAFLDwas found to affect obese children and adolescents more than non-obese, and male patients had a higher proportion of NAFLD than females. Also, obese patients had more advanced stages of NAFLD than non-obese patients. Finally, most subjects had been diagnosed with mild stage while a few had developed NASH.

Mesoportal bypass surgery with congenital portocaval shunt in a child aged 1 year and 3 months

Introduction. Abernethy malformation (CEPS) is a rare condition in which portomesenteric blood bypasses the liver through a partial or complete shunt into the inferior vena cava. This pathology is extremely rare in children. Clinically, it can occur almost asymptomatically or under the guise of other diseases. It is manifested by signs of hepatic encephalopathy, pulmonary hypertension or hepatopulmonary syndrome. Mesoportal bypass surgery is an option for correcting portocaval shunts with the restoration of physiological blood flow in the liver.Since 2016, a center for treating developmental anomalies in the hepato-pancreato-biliary system in children has been operating in Filatov Municipal Children's Hospital (Moscow). To date, the center has performed more than 1,500 surgical interventions on the organs of biliopancreato-duodenal zone. For the period from 2016 to 2022, an endovascular occluder was used in 13 children with congenital portocaval shunts; surgical dressing – in 6 children.Description of clinical observation. This article describes a clinical case of a child with a congenital portocaval shunt. A comprehensive instrumental examination revealed a complete absence of portal blood flow in the liver of a newborn baby . The spleen vein and superior mesenteric vein flowed into the inferior vena cava as a single trunk. It is believed that liver transplantation is the only effective treatment for this type of pathology. Despite the ambiguous anatomy of liver vessels, the child was operated on for the mesoportal bypass. The architectonics of child's liver was restored, and he returned to an absolutely normal life without any life-threatening factors.Conclusion. This clinical case demonstrates the only described case of complete surgical cure of a complex liver vascular defect.

Cytomegalovirus in biliary atresia is associated with increased pretransplant death, but not decreased native liver survival.

Biliary atresia (BA) is likely caused by a common phenotypic response to various triggers; one proposed trigger, cytomegalovirus (CMV), may lead to worse outcomes. The aim of this study was to determine the severity of disease and pretransplant outcomes of infants with BA, who have evidence of CMV (CMV+) at diagnosis compared with CMV-negative (CMV-) infants. The study used data and biospecimens from the Childhood Liver Disease Research Network PROBE study of cholestatic infants. Plasma obtained at the time of hepatic portoenterostomy (HPE) of 249 infants with BA was tested for CMV by DNA-PCR and CMV-IgM. Comparisons between CMV+ and CMV- infants were made using Wilcoxon rank sum, Student t test, chi-square, or Fisher exact test. Native liver survival (NLS) outcomes were analyzed using Kaplan-Meier and Cox regression adjusting for age at HPE; pretransplant patient survival outcomes were analyzed using a competing risk model and adjusting for age at HPE. CMV+ infants (n = 29, 12%) underwent HPE later (67.8±13.6d vs. 55.1±18.5d, p = 0.0005) and had higher baseline alkaline phosphatase and aminotransferases. There was no difference between groups in jaundice clearance or NLS. The subdistribution HR of pretransplant death for CMV+ infants adjusted for age at HPE was 3.8 (p = 0.034). CMV infection at the time of HPE in infants with BA is not associated with worse NLS despite the association with worse liver injury, older age at HPE, and increased risk of pretransplant death adjusted for age at HPE. Continued evaluation of the consequences of CMV infection and the effects of antiviral treatment should be explored.

Reevaluation of sodium thiosulfate otoprotection using the consensus International Society of Paediatric Oncology Ototoxicity Scale: A report from the Children's Oncology Group study ACCL0431.

In two randomized trials (Children's Oncology Group ACCL0431 and International Childhood Liver Tumour Strategy Group SIOPEL-6), sodium thiosulfate (STS) demonstrated efficacy in preventing cisplatin-induced hearing loss (CIHL). However, the measures used in those trials have been superseded by the consensus International Society of Paediatric Oncology (SIOP) Ototoxicity Scale. To provide benchmark data for STS efficacy when using this contemporary scale, we reanalyzed ACCL0431 hearing outcomes with the SIOP scale and using multiple timepoints. Compared to the control arm, STS significantly reduced CIHL when assessed by the SIOP scale across these different approaches. These results provide critical data to inform treatment discussions and support future potential trial designs comparing otoprotectants.

Identification and experimental validation of druggable epigenetic targets in hepatoblastoma

Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n= 72) and tumoral (n= 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of β-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients. In spite of recent advances in the management of hepatoblastoma (HB), treatment resistance and drug toxicity are still major concerns. This systematic study reveals the remarkable dysregulation in the expression of epigenetic genes in HB tissues. Through pharmacological and genetic experimental approaches, we demonstrate that the histone-lysine-methyltransferase G9a is an excellent drug target in HB, which can also be harnessed to enhance the efficacy of chemotherapy. Furthermore, our study highlights the profound pro-tumorigenic metabolic rewiring of HB cells orchestrated by G9a in coordination with the c-MYC oncogene. From a broader perspective, our findings suggest that anti-G9a therapies may also be effective in other c-MYC-dependent tumors.

A great pediatrician and scholar devoting his whole life to pediatric infectious and digestive diseases—In memoriam of Professor Yongsui Dong

A great pediatrician and scholar devoting his whole life to pediatric infectious and digestive diseases—In memoriam of Professor Yongsui Dong