Children's Oncology Group's 2023 blueprint for research: Liver tumors.

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 Children's 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.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Dose modifications and pharmacokinetics of adjuvant cisplatin monotherapy while on hemodialysis for patients with hepatoblastoma.

Hepatoblastoma can be associated with chronic kidney disease and genitourinary anomalies. Cisplatin is a key agent for treating hepatoblastoma but renal clearance and toxicity can limit its use in end-stage renal disease. We present pharmacokinetic data and clinical outcomes using cisplatin on hemodialysis for three patients with hepatoblastoma. All patients were initially treated with surgery and adjuvant cisplatin [1.67 mg/kg (2 patients) or 50 mg/m2 (1 patient)]. The patient treated with body surface area-based dosing had higher exposures and ototoxicity. Treating hepatoblastoma with cisplatin on hemodialysis using 1.67 mg/kg achieved clinical efficacy with minimal morbidity.

Fractures in children with newly diagnosed hepatoblastoma.

BACKGROUND: Hepatoblastoma is the most common primary hepatic malignancy in children. We have recently noticed an increased incidence of unsuspected fractures in children with newly diagnosed hepatoblastoma. This association has been suggested in the past, but the incidence and pathophysiology remain uncertain. OBJECTIVE: To define the incidence and imaging features of fractures in children with newly diagnosed hepatoblastoma. MATERIALS AND METHODS: We searched the oncology database and the radiology picture archiving and communication system of our large tertiary care children's hospital between January 2000 and August 2013 for all patients who presented to our institution with newly diagnosed hepatoblastoma. We reviewed all available imaging exams (radiographs, CT scans, MRIs, and nuclear medicine studies) to identify children who had radiologically apparent fractures on exams during the 50 days prior to diagnosis or up to 2 weeks after the date of hepatoblastoma diagnosis. RESULTS: Forty-five children were included in this retrospective study. Eight children (17.8%) had fractures within 50 days prior to diagnosis or up to 2 weeks after the date of diagnosis, with a mean number of 4.9 fractures per patient (range 1-13). Only 21 of the 39 fractures (54%) were diagnosed during the initial image interpretation. Fractures most commonly occurred in the ribs (n=21) and vertebral bodies (n=10). The presence of a fracture was not associated with an identified demographic, tumor or laboratory finding. CONCLUSION: Unsuspected fractures are relatively common in children with newly diagnosed hepatoblastoma.

2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT).

Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system is made of two components: the PRETEXT group and the annotation factors. The PRETEXT group describes the extent of tumor within the liver while the annotation factors help to describe associated features such as vascular involvement (either portal vein or hepatic vein/inferior vena cava), extrahepatic disease, multifocality, tumor rupture and metastatic disease (to both the lungs and lymph nodes). This manuscript is written by members of the Children's Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric Liver Tumor (JPLT; now part of the Japan Children's Cancer Group) and represents an international consensus update to the 2005 PRETEXT definitions. These definitions will be used in the forthcoming Trial to Pediatric Hepatic International Tumor Trial (PHITT).

Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee.

BACKGROUND: The 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. METHODS: Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level <100 ng/mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m2 /day intravenously on days 1 and 8 and I at a dose of 50 mg/m2 /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% (>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. RESULTS: A 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. CONCLUSIONS: The 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.

Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes.

Kidney transplantation is the optimal treatment of ESRD in children. Some studies have reported inferior outcomes in recipients of LDN allografts who are ≤ 5 yr of age. We performed a retrospective review of pediatric recipient outcomes of 110 LDN allografts at our institution and examined predictors of adverse outcomes. Subgroup analysis was performed by dividing recipients into three age categories: 0-5 yr, 6-17 yr, and ≥ 18 yr. There was no significant difference between incidences of DGF or ARE between groups. Kaplan-Meier analysis demonstrated 100% allograft survival in 0- to 5-yr-old recipients, nearly reaching statistical significance (p = 0.07) for outcome superior to that of the two older age groups. Pretransplant HD was associated with increased risk of DGF (p = 0.05). Significant risk factors for ARE were recipient weight >15 kg (p = 0.033) and multiple renal arteries (p = 0.047). Previous ARE was associated with an increased risk of allograft failure (p = 0.02). LDN is not associated with increased risk of DGF, ARE, or allograft failure in the youngest recipients. These findings support an aggressive pursuit of preemptive transplantation even in the youngest pediatric allograft recipients.

Management and long-term consequences of portal vein thrombosis after liver transplantation in children.

Portal vein thrombosis (PVT) occurs in ≤12% of pediatric recipients of liver transplantation (LT). Known complications of PVT include portal hypertension, allograft loss, and mortality. The management of PVT is varied. A single-center, case-control study of pediatric LT recipients with portal vein (PV) changes after LT was performed. Cases were categorized as early PVT (if PVT was detected within 30 days of transplantation) or late PVT (if PVT was detected more than 30 days after transplantation or if early PVT persisted beyond 30 days). Two non-PVT control patients were matched on the basis of the recipient weight, transplant indication, and allograft type to each patient with PVT. Thirty-two of the 415 LT recipients (7.7%) received 37 allografts and developed PVT. In comparison with control patients, a higher proportion of patients with PVT had PVT present before LT (13.3% versus 0%, P = 0.01). Patients with early PVT usually returned to the operating room, and 9 of 15 patients (60%) had PV flow restored. Patients with late PVT had lower white blood cell (4.9 [1000/µL] versus 6.8 [1000/µL], P < 0.01) and platelet counts (140 [1000/µL] versus 259 [1000/µL], P < 0.01), an elevated international normalized ratio (1.2 versus 1.0, P < 0.001), and more gastrointestinal bleeding (25% versus 8.3%, P = 0.03) compared to controls. Patients with PVT were also less frequently at the expected grade level (52% versus 88%, P < 0.001). The patient survival rates were 84%, 78%, and 78% and 91%, 84%, and 79% for cases and controls at 1, 5, and 10 years, respectively. The allograft survival rates were 90%, 80%, and 80% for cases and 94%, 89%, and 87% for controls at 1, 5, and 10 years, respectively. In conclusion, patients with early and late PVT had preserved allograft function, and there was no impact on mortality. Patients diagnosed with early PVT often underwent operative interventions with successful restoration of flow. Patients diagnosed with late PVT experienced variceal bleeding, and some required portosystemic shunting procedures. Academic delays were also more common. In late PVT, the clinical presentation dictates care because the optimal management algorithm has not yet been determined. Multi-institutional studies are needed to confirm these findings and improve patient outcomes.

Micronutrient deficiencies in pediatric and young adult intestinal transplant patients.

Intestinal transplant recipients are at risk of micronutrient deficiency due to the slow process of post-transplant adaptation. Another contributing factor is calcineurin inhibitor-induced renal tubular dysfunction. Patients are typically supplemented with micronutrients during PN; however, the risk of deficiency may persist even after a successful transition to FEN. The goal was to determine the prevalence of, and associated risk factors for, iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12 deficiency in pediatric intestinal transplant recipients after successful transition to FEN. A retrospective review of prospectively collected data from children who underwent intestinal transplantation at Cincinnati Children's Hospital Medical Center was done. Deficiencies of various micronutrients were defined using the hospital reference values. Twenty-one intestinal transplant recipients, aged one to 23 yr, who were successfully transitioned to FEN were included in the study. The prevalence of micronutrient deficiency was 95.2%. The common deficient micronutrients were iron (94.7%) and magnesium (90.5%). Age ≤ 10 yr (p = 0.002) and tube feeding (p = 0.02) were significant risk factors for micronutrient deficiencies. Pediatric intestinal transplant recipients have a high risk of micronutrient and mineral deficiencies. These deficiencies were more common among younger patients and those who received jejunal feeding.

Deletion of Interferon Lambda Receptor Elucidates Susceptibility to the Murine Model of Biliary Atresia.

Biliary atresia (BA) is a life-threatening cholangiopathy occurring in infancy, the most common indication for pediatric liver transplantation. The etiology of BA remains unknown; however, a viral etiology has been proposed as multiple viruses have been detected in explants of infants afflicted with BA. In the murine model of BA, Rhesus rotavirus (RRV) infection of newborn BALB/c pups results in a cholangiopathy that mirrors human BA. Infected BALB/c pups experience 100% symptomatology and mortality, while C57BL/6 mice are asymptomatic. Interferon-λ (IFN-λ) is an epithelial cytokine that provides protection against viral infection. We demonstrated that IFN-λ is highly expressed in C57BL/6, leading to reduced RRV replication. RRV-infection of C57BL/6 IFN-λ receptor knockout (C57BL/6 IFN-λR KO) pups resulted in 90% developing obstructive symptoms and 45% mortality with a higher viral titer in bile ducts and profound periportal inflammation compared to C57BL/6. Histology revealed complete biliary obstruction in symptomatic C57BL/6 IFN-λR KO pups, while C57BL/6 ducts were patent. These findings suggest that IFN-λ is critical in preventing RRV replication. Deficiency in IFN-λ permits RRV infection, which triggers the inflammatory cascade causing biliary obstruction. Further IFN-λ study is warranted as it may play an important role in infant susceptibility to BA.

Critical elements of pediatric liver cancer surgery.

The appropriate management of pediatric liver malignancies, primarily hepatoblastoma and hepatocellular carcinoma, requires an in depth understanding of contemporary preoperative risk stratification, experience with advanced hepatobiliary surgery, and a good relationship with one's local or regional liver transplant center. While chemotherapy regimens have become more effective, operative indications more well-defined, and overall survival improved, the complexity of liver surgery in small children provides ample opportunity for protocol violation, inadequate resection, and iatrogenic morbidity. These guidelines represent the distillation of contemporary literature and expert opinion as a means to provide a framework for preoperative planning and intraoperative decision-making for the pediatric surgeon.

Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's 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.

Outcomes of children with well-differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731.

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 Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's 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.

Liver Tumors in Pediatric Patients.

The most recent advance in the care of children diagnosed with hepatoblastoma and hepatocellular carcinoma is the Pediatric Hepatic International Tumor Trial, which opened to international enrollment in 2018. It is being conducted as a collaborative effort by the pediatric multicenter trial groups in North America, Europe, and the Far East. This international effort was catalyzed by a new unified global risk stratification system for hepatoblastoma, an international histopathologic consensus classification for pediatric liver tumors, and a revised 2017 collaborative update of the PRE-Treatment EXTent of disease radiographic based staging system.

Variability in age at Kasai portoenterostomy for biliary atresia across US children's hospitals.

BACKGROUND/PURPOSE: The purpose of this study was to assess variability in age at Kasai portoenterostomy (KP) in infants with biliary atresia (BA) across children's hospitals in the United States. STUDY DESIGN: A multi-institutional retrospective study was performed examining infants with BA undergoing KP within 6 months of birth from 2016-2019, utilizing the Pediatric Health Information System (PHIS). Multivariable negative binomial mixed effects regression was performed for age at KP, and inter-hospital variability was examined. RESULTS: Across 46 hospitals, 470 infants with BA underwent KP at a median age of 57 days (IQR 42-72), with 212 (45.1%) undergoing KP at ≥60 days of age. There was significant inter-hospital variability in age at KP ranging from 38 days (95% CI: 31d, 47d) to 76 days (95% CI: 63d, 91d) (p<0.0001). Factors associated with later KP were black or African-American race, urgent/emergent admission, and treatment at a hospital in the Pacific-West region. Predictors of earlier KP included later year, history of neonatal comorbidity, and admission to an intensive care service (all p<0.05). CONCLUSION: There is significant variability in the age at KP in infants with BA across children's hospitals in the United States. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: III.

The role of surgical shunts in the treatment of pediatric portal hypertension.

BACKGROUND: Portal diversion by surgical shunt plays a major role in the treatment of medically refractory portal hypertension. We evaluate our center's experience with surgical shunts for the treatment of pediatric portal hypertension. METHODS: All patients who underwent surgical shunt at a single institution from 2008 to 2017 were reviewed. The primary outcome was intervention-free shunt patency. RESULTS: In this study, 34 pediatric patients underwent portal shunt creation. The median age was 7.7 years (interquartile range 4.3-12.0). Twenty-nine patients (85%) had prehepatic portal hypertension and 5 patients (15%) had intrahepatic portal hypertension. The primary manifestations of portal hypertension were esophageal varices (97%) and gastrointestinal bleeding (77%). Eighteen patients (53%) underwent meso-Rex bypass, 10 patients (29%) underwent splenorenal shunt, and 6 patients (18%) underwent mesocaval shunt. Outcomes were notable for minimal wound complications (9%), rebleeding events (12%), and mortality (3%). In the postoperative setting, 10 patients (29%) experienced a shunt complication (occlusion or stenosis), 4 of which occurred in the early postoperative period and required urgent intervention. The 1-year and 5-year "primary patency" patency rates were 71% and 66%, respectively. CONCLUSION: Children suffer significant morbidity from the sequelae of portal hypertension. Our experience reinforces the feasibility of surgical shunts as an effective treatment option associated with low rates of morbidity and mortality.

The management of pediatric renovascular hypertension: a single center experience and review of the literature.

INTRODUCTION: Renal artery occlusive disease is poorly characterized in children; treatments include medications, endovascular techniques, and surgery. We aimed to describe the course of renovascular hypertension (RVH), its treatments and outcomes. METHODS: We performed literature review and retrospective review (1993-2014) of children with renovascular hypertension at our institution. Response to treatment was defined by National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents at most-recent follow-up. RESULTS: We identified 39 patients with RVH. 54% (n=21) were male, with mean age of 6.93 ± 5.27 years. Most underwent endovascular treatment (n=17), with medication alone (n=12) and surgery (n=10) less commonly utilized. Endovascular treatment resulted in 18% cure, 65% improvement and 18% failure; surgery resulted in 30% cure, 50% improvement and 20% failure. Medication alone resulted in 0% cure, 75% improvement and 25% failure. 24% with endovascular treatment required secondary endovascular intervention; 18% required secondary surgery. 20% of patients who underwent initial surgery required reoperation for re-stenosis. Mean follow-up was 52.2 ± 58.4 months. CONCLUSIONS: RVH treatment in children includes medications, surgical or endovascular approaches, with all resulting in combined 79% improvement in or cure rates. A multidisciplinary approach and individualized patient management are critical to optimize outcomes. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: Level III.

Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data.

Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.

Beyond the Milan criteria for liver transplantation in children with hepatic tumours.

The Milan criteria were originally defined in the context of adult liver transplantation for patients with hepatocellular carcinoma and cirrhotic livers. The aim of the criteria was to select patients with small tumours and no disease spread who had a good chance of success, thus avoiding futile transplants. This objective was reached successfully. For the management of selected children with unresectable hepatoblastoma, an almost opposite strategy was proposed and has been implemented in the past two decades, in which transplantation is indicated on the basis of large tumour size and anatomy that precludes the possibility of safe and radical resection. This approach has also had great success. Although both strategies are well established for these two different age groups and diseases, a grey area exists with regard to hepatocellular carcinoma or other tumour types in children. In this Viewpoint, we aim to review the existing literature about the indications, selection process, and results of liver transplantation for liver tumours in children, and discuss evidence that supports the implementation of either of the two strategies in the context of managing selected children with liver tumours using transplantation.