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Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Childrens Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.

Background and aimsDetailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.Approach and resultsA targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p

BACKGROUND: Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone. PATIENTS AND METHODS: Patients on the Childrens Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evans stage, tumor histology, and serum alpha-fetoprotein level at diagnosis. Patients were eligible for the very low risk stratum of surgery and observation if they had a complete resection at diagnosis and rapid central histologic review demonstrated HB with 100% WDF histology. RESULTS: A total of 8 eligible patients were enrolled on study between September 14, 2009 and May 28, 2014. Outcome current to 06/30/2020 was used in this analysis. The median age at enrollment was 22.5 months (range: 8-84 months) and the median AFP at enrollment was 714 ng/ml (range: 18-77,747 ng/mL). With a median follow-up of 6.6 years (range: 3.6-9.8 years), the 5-year event-free (EFS) and overall survival (OS) were both 100%. CONCLUSION: This report supports that HB with 100% WDF histology completely resected at diagnosis is curable with surgery only. The development of evidence-based surgical guidelines utilizing criteria based on PRETEXT group, vascular involvement (annotation factors), tumor-specific histology and corresponding biology will be crucial for optimizing which patients are candidates for resection at diagnosis followed by observation. LEVEL OF EVIDENCE: Prognosis study, Level I evidence.

Background & aimsHepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS.MethodsWe tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8).ResultsMolecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes.ConclusionsOur study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms.Lay summaryWe molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Childrens Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

ObjectivesTo identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere.Study designThe Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected.ResultsWe enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score.ConclusionsPortal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Childrens Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.

BackgroundThe identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma.MethodsPatients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone.ResultsA total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively.ConclusionsThe VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.

Simple Summary: Patients with pediatric liver cancers hepatoblastoma and hepatocellular carcinoma very often develop lung metastases. These cancers can present with lung metastases and are at higher risk of relapse. Although cisplatin is very effective at clearing lung metastases, they can still relapse. Therefore, there is an urgent need to develop therapeutic approaches to prevent the development of lung metastases in patients with pediatric liver cancers. In this paper, we show that the metastatic microenvironment of HBL and HCC patients contains a heterogeneous cell population that formed tumor clusters. We found that both fresh primary tumors and generated primary cell cultures had increased the expression of HDAC1, a histone deacetylase, and the transcription factor Sp5. Sp5 and HDAC1 work in tandem by transporting HDAC1 to the promoters of genes and changing their expression. We analyzed the effects of the HDAC inhibitor, SAHA, on the metastasis-initiating cells in combination with cisplatin. We found that HDAC inhibition increases the efficacy of cisplatin to eliminate these metastasis-initiating cells. The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. [ABSTRACT FROM AUTHOR]

ObjectivesIn a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy.Study designA multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months.ResultsA total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy.ConclusionsA substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.