Introduction The Children’s Hepatic Tumors International Collaboration (CHIC) previously developed the CHIC hepatoblastoma risk stratification (CHIC-HS) model by analyzing the original CHIC dataset (development set). A validation of the results was planned with data from contemporary trials that were ongoing at the time of the initial analysis. Material and Methods Subsequent analysis was performed on the contemporary trials (validation set) SIOPEL 4, SIOPEL 6, COG AHEP0731, and JPLT 2 (2011-2013 cohort) utilizing the same methodology as in the CHIC-HS development. Results 403 patients were available for analysis for validation of the CHIC-HS model. Clinical characteristics were comparable between the validation and development sets. Event free survival (EFS) was similar in the very low and low-risk CHIC-HS strata in both the development and validation sets. EFS was higher in the intermediate and high-risk strata in the validation set as compared with the development set consistent with improved survival of intermediate-risk patients on AHEP0731 and high-risk patients on SIOPEL 4. Conclusions The four risk groups in the CHIC-HS retain their relevance for risk stratification in this analysis, notwithstanding improved outcomes in patients with higher risk hepatoblastoma; therefore, the CHIC-HS remains a valid model which differentiates patients into statistically distinct risk strata. The model will be further evaluated with data from the current pediatric international hepatic tumors trial (PHITT).

Background In the treatment of resectable hepatoblastoma (HB), it has not been established whether upfront surgery (UF) at diagnosis or neoadjuvant chemotherapy and delayed surgery (DL) is preferred. We compared patients with localized HB who underwent either UF, or DL after neoadjuvant chemotherapy in the Children's Hepatic tumors International Collaboration (CHIC) database of 1605 cases enrolled in eight multicenter hepatoblastoma trials between 1988 and 2010. Methods Among the 512 resectable HB patients who had PRETEXT (PRETreament EXTent of disease) I or II unruptured tumors at diagnosis without extrahepatic invasion, distant metastases, or massive vascular invasion, 172 underwent UF and 340 underwent DL. The primary outcomes were event-free and overall survivals after start of treatment in these two groups. Survival analysis was performed using the Kaplan-Maier analysis with long-rank tests and multivariable Cox regression models. Findings Complete resection rates were comparable (93.6% in UF and 89.7% in DL). The total cycles of chemotherapy of DL (median:6) were significantly more than those of UF (median:4) (P < 0.01). The 5-year event-free survival (EFS) was 90.6% and 86.6% (P = 0.89) in the UF and DL cohorts, respectively. The surgical complications, recurrence rates, and late complications were not significantly different between the cohorts but the EFS rates of DL patients with a low alpha-fetoprotein (AFP) level (100-999 ng/mL) or older age at diagnosis (>= 3 years old) were significantly worse than others. Interpretation The outcomes, surgical resectability, and complications were not significantly different between the UF and DL groups. Eligible patients with a low AFP level (<1000 ng/mL) or older age (>= 3 years old) showed better outcomes in the UF group and might be considered for initial resection.

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.

IntroductionWilms tumor therapy in low- and middle-income countries (LMICs) relies on treatment protocols adapted to resource limitations, but these protocols have rarely been evaluated in real-world settings. Such evaluations are necessary to identify high-impact research priorities for clinical and implementation trials in LMICs. The purpose of this study was to identify highest priority targets for future clinical and implementation trials in sub-Saharan Africa by assessing outcomes of a resource-adapted treatment protocol in Malawi. MethodsWe conducted a retrospective cohort study of children treated for Wilms tumor with an adapted SIOP-backbone protocol in Lilongwe, Malawi between 2016 and 2021. Survival analysis assessed variables associated with poor outcome with high potential for future research and intervention. ResultsWe identified 136 patients, most commonly with stage III (n = 35; 25.7%) or IV disease (n = 35; 25.7%). Two-year event-free survival (EFS) was 54% for stage I/II, 51% for stage III, and 13% for stage IV. A single patient with stage V disease survived to 1 year. Treatment abandonment occurred in 36 (26.5%) patients. Radiotherapy was indicated for 55 (40.4%), among whom three received it. Of these 55 patients, 2-year EFS was 31%. Of 14 patients with persistent metastatic pulmonary disease at the time of nephrectomy, none survived to 2 years. Notable variables independently associated with survival were severe acute malnutrition (hazard ratio [HR]: 1.9), increasing tumor stage (HR: 1.5), and vena cava involvement (HR: 3.1). ConclusionHigh-impact targets for clinical and implementation trials in low-resource settings include treatment abandonment, late presentation, and approaches optimized for healthcare systems with persistently unavailable radiotherapy.

PURPOSE:A comprehensive operative report for cancer surgery is crucial for accurate disease staging, risk stratification, and therapy escalation/de-escalation, which affects the outcome. Narrative operative reports may fail to include some critical findings. Furthermore, standardized operative reports can form the basis of a local registry, which is often lacking in limited-resource settings (LRSs). In adult literature, synoptic operative reports (SOR) contain more key findings than narrative operative reports. In the LRSs, where the capacity of diagnostic pathology services is typically suboptimal, the value of a thorough operative report is even greater. The aim of this study was to develop a SOR template to help standardize childhood cancer surgery reporting in LRSs.METHODS:Twenty-three experts in pediatric cancer with extensive experience practicing in LRSs were invited to participate in a modified Delphi procedure. SOR domains for pediatric oncology surgery were drafted based on a literature search and then modified based on experts' opinions. The experts anonymously answered multiple rounds of online questionnaires until all domains and subdomains reached a consensus, which was predefined as 70% agreement.RESULTS:Sixteen experts participated in the study, and two rounds of the survey were completed. Twenty-one domains were considered relevant, including demographics, diagnosis, primary site, preoperative disease stage, previous tumor biopsy or surgery, preoperative tumor rupture, neoadjuvant therapy, surgical access, type of resection, completeness of resection, tumor margin assessment, locoregional tumor extension, organ resection, intraoperative tumor spillage, vascular involvement, lymph node sampling, estimated blood loss, intraoperative complications and interventions to address them, specimen names, and specimen orientation.CONCLUSION:We developed a SOR template for pediatric oncology surgery in LRSs. Consensus for all 21 domains and associated subdomains was achieved using a modified Delphi procedure.

This issue of Hepatoma Research is dedicated to liver tumors in Children, which is a quite rare group of tumors. Although the majority of pediatric liver tumors are malignant (57％), its main contributors, hepatoblastoma (HB) and hepatocellular carcinoma (HCC), only have an incidence of 1.6 per 1 million children, thus comprising 5％-8％ of all pediatric solid tumors.

This overview of pediatric liver tumors is presented with an emphasis on the two most common tumors, hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Other major benign and malignant liver tumors of childhood are summarized. The most exciting recent advances in HB and HCC is the Pediatric Hepatic International Tumor Trial (PHITT study), which opened to international enrollment in 2018. This study is being conducted as an international collaborative trial with the International Liver Tumors Strategy Group (SIOPEL), Children's Oncology Group (COG), and Japanese Children's Cancer Group (JCCG). This global effort has been catalyzed over the last 10 years by the Children's Hepatic tumor International Collaboration (CHIC). For HB CHIC was able to construct a large database comprised of eight multicenter trials from around the world, which was used to develop a new unified global risk stratification system. At the same time our pathology colleagues established a new international histopathological consensus classification for pediatric liver tumors and our radiology colleagues established a new 2017 international collaborative update of the PRE-Treatment EXTent of disease (PRETEXT) radiographic-based staging system. Concomitantly there have been advances in HB chemotherapy options, in the sophistication of our radiographic imaging, in percutaneous and endovascular treatment approaches, in surgical technique, and in our understanding of the role of liver transplantation for unresectable tumors. These achievements, along with identification of new biologic markers, treatment intensification for poor risk tumors, and chemotherapy reduction for low-risk tumors, are being tested and validated in the PHITT trial. Although chemotherapy advances have been more modest in HCC, effective vaccination programs for hepatitis B have shown a decreasing HCC incidence in areas of endemic hepatitis B virus. Complete resection is the strongest predictor of good outcome, and liver transplantation has increasingly become a viable option for selected children with HCC without extrahepatic disease. The role of new drugs targeting genomic pathways in pediatric HCC may become clear in future collaborative studies.

Purpose Wilms tumor is a common renal cancer of childhood with long-term survival rates exceeding 80% in high-resource countries, yet survival remains below 50% in the low-resource settings of Africa. We assessed outcomes of a resource-adapted treatment protocol at a Malawian hospital to identify actionable factors affecting survival. Methods We assessed clinical outcomes with a single-center retrospective cohort study of children diagnosed between 2016 and 2021 in Lilongwe, Malawi. Findings We identified 136 patients with Wilms tumor, most commonly with stage III (25.7%) or IV disease (25.7%). Two-year overall survival (OS) was: Stage I, 78%; Stage II, 27%; Stage III, 62%; Stage IV, 23%, Stage V, 0%. Event-free survival (EFS) was: Stage I, 60%; Stage II, 0%; Stage III, 51%; Stage IV, 13%; Stage V, 0%. After death, treatment abandonment was the most common event comprising EFS, occurring in 26.5% of patients. Among 43% of patients who completed therapy, 2-year OS was 80% and EFS was 69%. Relapse was documented in 9.6% of patients. Radiotherapy was indicated for 40.4% patients, among whom only three received it due to regional unavailability. Factors associated with OS were severe acute malnutrition (Hazard ratio, HR, 1.9), increasing tumor stage (HR, 1.5), and inferior vena cava involvement (HR, 2.7). On multivariable analysis, only tumor stage remained associated with outcome. Interpretation Implementing a curative resource-adapted treatment protocol in an extremely resourced-constrained environment was feasible in Malawi and resulted in relatively favorable outcomes in low-stage disease, particularly among those who completed therapy. However, factors such as late-stage disease, frequent abandonment, and absent radiotherapy represent ongoing implementation barriers that should be the focus of continued research funding and intervention in Africa.

Primary tumours of the liver are rare in childhood and comprise 0.8–1% of all pediatric tumours. Malignant tumours are more common (65% of primary liver tumours). An overview of both malignant and benign liver tumours will be given with a focus on clinical presentation and treatment options in the African setting.

PURPOSE:Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS:We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS:Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION:Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Pediatric Blood & CancerVolume 67, Issue 11 e28550 OBITUARY In memory of Jack Plaschkes (1932-2019) Giorgio Perilongo, Giorgio Perilongo orcid.org/0000-0002-3712-0386 Department of Woman's and Child's Health, Division of Pediatrics, University Hospital of Padua, Padua, ItalySearch for more papers by this authorAnton Vos, Anton Vos Retired, Amsterdam, the NetherlandsSearch for more papers by this authorDaniel C. Aronson, Daniel C. Aronson orcid.org/0000-0001-5139-7552 Department of Paediatric Surgery, University Children's Hospital Zürich, Zürich, SwitzerlandSearch for more papers by this authorChan Hon Chui, Corresponding Author Chan Hon Chui chchui@surgeryforchildren.com orcid.org/0000-0002-2514-9771 Surgery Centre for Children Pte Ltd., Mount Elizabeth Medical Centre, Singapore Correspondence Chan Hon Chui, Surgery Centre for Children Ptd Ltd, Unit 10-08 Mount Elizabeth Medical Centre, 3 Mount Elizabeth, Singapore 228510. Email: chchui@surgeryforchildren.comSearch for more papers by this author Giorgio Perilongo, Giorgio Perilongo orcid.org/0000-0002-3712-0386 Department of Woman's and Child's Health, Division of Pediatrics, University Hospital of Padua, Padua, ItalySearch for more papers by this authorAnton Vos, Anton Vos Retired, Amsterdam, the NetherlandsSearch for more papers by this authorDaniel C. Aronson, Daniel C. Aronson orcid.org/0000-0001-5139-7552 Department of Paediatric Surgery, University Children's Hospital Zürich, Zürich, SwitzerlandSearch for more papers by this authorChan Hon Chui, Corresponding Author Chan Hon Chui chchui@surgeryforchildren.com orcid.org/0000-0002-2514-9771 Surgery Centre for Children Pte Ltd., Mount Elizabeth Medical Centre, Singapore Correspondence Chan Hon Chui, Surgery Centre for Children Ptd Ltd, Unit 10-08 Mount Elizabeth Medical Centre, 3 Mount Elizabeth, Singapore 228510. Email: chchui@surgeryforchildren.comSearch for more papers by this author First published: 25 July 2020 https://doi.org/10.1002/pbc.28550Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume67, Issue11November 2020e28550 RelatedInformation

Background: Ectopic pancreatic tissue (EPT) in a Meckel diverticulum is a well-known anomaly. Other locations are rare, especially in pediatric patients. We report on three children with incidental findings of EPT and reviewed the literature. Patients and methods: Three children with incidental findings of EPT treated in our department, and 62 patients found in the literature were analyzed. The literature search was performed excluding EPT in Meckel's diverticulum and in tumors, i.e. teratomas. Results: Two of our patients presented with an umbilical mass. The third patient presented with a gastric outlet obstruction due to an antral/pyloric mass. Histopathology showed EPT in all three of our patients without any signs of malignancy. In the literature, patients with EPT often appear to be asymptomatic. Symptomatic patients may present with bowel obstruction or intussusception. EPT in the umbilicus frequently seems to cause umbilical discharge. Our analysis supported the leading opinion in the literature that the upper gastrointestinal tract and especially the gastric antrum must be considered the most common location of EPT. Conclusion: Although unusual in children, awareness of EPT may help to obtain the proper diagnosis faster and to plan accurate surgical therapy.

Background: To evaluate the impact of a microscopically positive resection margin (microPRM) on the outcome of hepatoblastoma patients pretreated with chemotherapy. Methods: Local recurrence and survival rates of 431 children treated in the SIOPEL 2 and 3 trials were analysed comparing 58 patients with microPRM with 371 who had a complete resection (CR) and who were then stratified by risk category. The tumour was standard-risk in 312 patients and high-risk (PRETEXT IV and/or extrahepatic disease and/or alpha-fetoprotein [AFP]<100 ng/ml) in 117 patients. All received cisplatinum-based neoadjuvant and postoperative chemotherapy as per protocol. Apart from one microPRM patient who went on to transplant, none received any additional local treatment. Results: With a median follow-up of 67 months, local relapse occurred in 3/58 patients with microPRM (5%) and in 23/371 (6%) patients with CR. The 5-year overall survival (OS) was 91% (95% confidence interval [CI] 80%-96%) for the microPRM and 92% (95% CI 89%-95%) for the CR group. The 5-year event-free survival (EFS) was 86% (95% CI 74%-93%) for the microPRM and 86% (95% CI 82%-89%) for the CR group. Neither OS nor EFS was statistically significantly different between the two groups, neither overall nor when risk group stratified. Conclusions: In the context of cisplatin-based chemotherapy, the presence of microPRM did not influence the outcome even without additional local treatment. Although CR remains the aim, microPRM does not necessitate mandatory second look surgery. A 'wait and see policy' is warranted if postoperative chemotherapy is administered and AFP levels and imaging become normal. (C) 2018 Elsevier Ltd. All rights reserved.

Pediatric hepatocellular carcinoma (HCC) is rare, resulting in scattered knowledge of tumor biology and molecular background. Thus far, the variant in children has been treated as a different entity from adult HCC. We weigh the hypothesis that HCC in the pediatric and adult groups may be the same entity and may benefit from the same treatment. Although certain differences between adult and pediatric HCC are obvious and certain types of HCC may ask for a customized approach, in conventional HCC, similarities predominate, warranting treatment aiming at common molecular targets in adult and pediatric HCC patients.

BackgroundThe purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols. MethodsSeventy-nine patients, treated between 1994 and 2006, were analyzed after stratification into three age groups:<1 month, between 1 and 3 months, and between 3 and 6 months. All received preoperative chemotherapy. ResultsClinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had -fetoprotein<100ng/ml, 68 were operated by partial hepatectomy, and 7 received liver transplant. Chemotherapy courses were delayed in 8.5%, 8.4%, and 11.8% of cycles in the three groups. Doses were calculated according to weight for children<5 and 5-10kg, and further reduced in 18.1%, 6.8%, and 5.9% of cycles. Acute toxicity was manageable. Long-term hearing loss was the major problem at follow-up occurring in two-thirds of children. Ten patients experienced progression or relapse, and 5 of 10 died. After a median follow-up of 5.6 years, the 5-year overall survival (OS) and event-free survival (EFS) were 91% (95% confidence interval [CI]: 84-96%) and 87% (95% CI: 78-92%), respectively. ConclusionsThe 5-year OS and EFS of children<6 months of age affected by HB seem to be similar to those documented in the elder children. Dose reduction does not seem to jeopardize the long-term outcome and may explain the lower toxicity profile. Ototoxicity though appears as high as in the whole population of SIOPEL 2 and 3. The treatment for these children should be further explored in international studies, particularly focusing on prevention of hearing loss.

INTRODUCTION:The aim of this article is to present an experience of two prospective studies from the International Childhood Liver Tumor Strategy Group (SIOPEL 2 [S2] and SIOPEL [S3]) trials and to evaluate whether modified platinum- and doxorubicin-based chemotherapy is capable of increasing tumor resectability and changing patient outcomes.METHODS:Between 1995 and 2006, 20 patients with hepatocellular carcinoma (HCC) were included in the S2 trial and 70 were included in the S3 trial. Eighty-five patients remained evaluable.RESULTS:Response to preoperative chemotherapy was observed in 29 of 72 patients (40%) who did not have primary surgery, whereas 13 patients underwent upfront surgery. Thirty-three patients had a delayed resection. Thirty-nine tumors never became resectable. Complete tumor resection was achieved in 34 patients (40%), including seven of those treated with liver transplantation (LTX). After a median follow-up period of 75 months, 63 patients (74%) had an event (a progression during treatment, a relapse after treatment, or death from any cause). Sixty patients died. Twenty-three of 46 patients (50%) who underwent tumor resection died. Eighteen of 27 patients (63%) with complete tumor resection (without LTX) and 20 of 34 patients (59%) with LTX survived. Only one of seven patients (14%) with microscopically involved margins survived. Overall survival at 5 years was 22%.CONCLUSION:Survival in pediatric HCC is more likely when complete tumor resection can be achieved. Intensification of platinum agents in the S2 and S3 trials has not resulted in improved survival. New treatment approaches in pediatric HCC should be postulated.

Ectopic adrenocorticotropic hormone-producing primary liver tumors are rare, especially in children. We report the case of an adolescent boy of mixed Dutch and Moroccan descent with an adrenocorticotropic hormone-producing calcifying nested stromal–epithelial tumor with long-term follow-up. Thus far, only two such cases have been reported.

Background Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. Methods The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; a fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. Findings Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. Interpretation We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic Inter national Tumour Trial (PHITT).