Outcomes of Wilms tumor therapy in Lilongwe, Malawi, 2016-2021: Successes and ongoing research priorities.

INTRODUCTION: Wilms 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. METHODS: We 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. RESULTS: We 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). CONCLUSION: High-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.

Development of a template for operative reporting of pediatric cancer surgery in limited-resource settings by using a modified Delphi method.

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.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

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.

Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group.

BACKGROUND: The 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. METHODS: Seventy-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. RESULTS: Clinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had α-fetoprotein <100 ng/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 5-10 kg, 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. CONCLUSIONS: The 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.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.

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; α 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. RESULTS: 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 International Tumour Trial (PHITT). FUNDING: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning.

UNLABELLED: Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1ß, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation. CONCLUSION: Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal-plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not.

Children With Anorectal Malformations, Hirschsprung Disease, and Their Siblings: Proxy Reports and Self-Reports.

OBJECTIVES: The aim of the present study was to compare parent proxy reports with that of self-reports of children with anorectal malformations (ARMs) or Hirschsprung disease (HD) and healthy siblings and thereafter was examine whether these comparisons differed between patients and their siblings. METHODS: Parents (n = 98) of either children with ARM (n = 44) or HD (n = 54) and a healthy sibling (n = 98) recruited from the 6 Dutch pediatric surgical centers and from the ARM and HD patient societies were included in this cross-sectional multilevel study. Agreement between child self-reports and parent proxy reports was compared through mean differences and through (intraclass) correlations. We conducted multilevel analyses to take dependencies between assessments within families into account. RESULTS: All of the children (children with ARM or HD and their siblings) reported more pain and symptoms than their parents reported. We also found that only children with ARM or HD reported less positive emotions than their parents. Furthermore, higher correlations were found between parent proxy reports and patient-self reports than between parent proxy reports and sibling self-reports on cognitive functioning and social interaction. CONCLUSIONS: Parents tend to overestimate the physical functioning of both their ill and healthy children, and overestimate the emotional functioning of only their children with ARM or HD. Furthermore, children with ARM or HD and parents agree more on health-related quality of life domains than healthy children and parents.

Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children.

BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Although the use of diagnostic MIS to obtain biopsy specimens for pathology is accepted in paediatric surgical oncology, there is limited evidence to support the use of MIS for the resection of malignancies. This review is the second update of a previously published Cochrane review. OBJECTIVES: To ascertain differences in outcome between the minimally invasive and open surgical approaches for the treatment of solid intra-abdominal or intra-thoracic neoplasms in children. The primary outcomes of interest are OS, EFS, port-site metastases and recurrence rate; the secondary outcome of interest is surgical morbidity. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE/PubMed (from 1966 to February 2014) and EMBASE/Ovid (from 1980 to February 2014) to identify relevant studies. In addition, we searched reference lists of relevant articles and reviews and the conference proceedings of the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2003 to 2013. On 1 May 2014 we scanned the ISRCTN Register (on www.controlled-trials.com), the National Institutes of Health register (on www.controlled-trials.com and www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (on www.apps.who.int/trialsearch) for ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS to open surgery for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children (aged 0 to 18 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: The literature search retrieved 542 references. After screening the titles and abstracts we excluded 534 references which clearly did not meet the inclusion criteria. We assessed eight full text studies for eligibility and all of these studies were excluded from the review because they were not RCTs or CCTs. These excluded studies included case series, retrospective chart reviews and retrospective cohort studies. The scanning of reference lists and conference proceedings did not identify any additional studies and no (ongoing trials) were identified by the searches of trial registries. No studies that met the inclusion criteria of this review were identified AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified. The current evidence base informing the use of MIS in children with solid abdominal and thoracic neoplasms is based on other study designs like case reports, retrospective chart reviews and cohort studies and should be interpreted with caution. Thus there is insufficient evidence to allow any definitive conclusions regarding the use of MIS in these patients. High quality RCTs comparing MIS to open surgery are required. To accomplish this, centres specialising in MIS in children should collaborate.

Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation.

PURPOSE OF REVIEW: This is part two of a two-part state of the art--hepatoblastoma. International hepatoblastoma specialists were brought together to highlight advances, controversies, and future challenges in the treatment of this rare pediatric tumor. RECENT FINDINGS: Pretreatment extent of disease (PRETEXT) is a grouping system introduced as part of the multicenter international childhood liver tumors strategy group, SIOPEL-1, study in 1990. The system has been refined over the ensuing years and has now come to be adopted for risk stratification by all of the major pediatric liver tumor multicenter trial groups. PRETEXT is being intensively studied in the current Children's Oncology Group (COG) AHEP-0731 trial in an attempt to validate interobserver reproducibility and ability to monitor response to neoadjuvant chemotherapy, and determine surgical resectability. PRETEXT is now used to identify those patients who are at risk for having an unresectable tumor and who should be referred to a liver specialty center with transplant capability early in their treatment schema. SUMMARY: International collaborative efforts in hepatoblastoma have led to increased refinements in the use of the PRETEXT and post-treatment extent to define prognosis and surgical resectability. PRETEXT criteria which suggest a possible need for liver transplantation are discussed in detail.

Nephron sparing surgery (NSS) for unilateral wilms tumor (UWT): the SIOP 2001 experience.

BACKGROUND: Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT-2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non-infiltrating tumors. AIM: Inventory of the current SIOP NSS-experience. PROCEDURES: 2,800 patients with a unilateral, localized or metastatic and an unequivocal surgical technique recorded were included. All had neo-adjuvant chemotherapy and delayed surgery. In 91 (3%) NSS was performed and in 2709 TN. Data was retrieved from the SIOP WT 2001 database. RESULTS: NSS group contained 65% stage I tumours and the TN group 48%. Tumor volume (at diagnosis and surgery) was significantly smaller in the NSS group. Within stage III, after NSS, 7/12 (58%) had positive margins (M +), 5 with tumor negative lymph nodes (LN-). After TN, 355/712 (55%) had M + , 182 were LN-. Treatment of M+ in the NSS group resulted in two conversions to TN (one combined with radiotherapy), three patients had radiotherapy only and in two patients local therapy, if given, was not recorded. After NSS, four recurrences occurred. For localized disease the 5-year overall (OS) and event free survival (EFS) in NSS group was 100 and 94.8 (95% CI:89.9-99.9), respectively, while OS and EFS in the TN group were 94.4 (95% CI: 93.2-95.5, log-rank test P = 0.06) and 86.5 (95% CI:85.0-88.1, log-rank test P = 0.06), respectively. CONCLUSIONS: NSS was only performed in 3% of patients with uWT. Despite excellent survival with few relapses, the gain of nephrons needs to be weighed against the risk to induce stage III with intensified therapy.

The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials.

AIM OF THE REVIEW: To describe the significant improvement in the diagnosis, treatment and outcome of children diagnosed with hepatoblastoma (HB) that has occurred in the past four decades. Recent findings are mainly focused on lessons learned from the experiences of the Childhood Liver Tumors Strategy Group (SIOPEL). Important milestones were the risk stratification of HB that allowed to tailor down therapy for standard-risk HB and intensify treatment for high-risk HB. The multi-institutional international cooperative SIOPEL trials are reviewed and current treatment guidelines are given. Intensified cooperation between the SIOPEL and the Children's Oncology Group (COG) and the national study groups from Germany (GPOH) and Japan (JPLT) led to the acceptance and use of one staging system (PRETEXT) and the formation of a single robust database containing data of 1605 HB patients. This will allow analysis with enough statistical power of treatment directing factors that will form one of the bases of the next-generation clinical trial that is currently designed by all four collaborating study groups. SUMMARY: Successive SIOPEL trials and increasing international collaboration have improved survival rates of patients with HB through risk stratification, advances in chemotherapy and increased complete resection rates including liver transplantation as a surgical option.

Upfront or delayed surgery in resectable hepatoblastoma: analysis from the children's hepatic tumors international collaboration database.

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. Funding: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission; Children's Oncology Group Cure Search grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; and Swiss Cancer Research grant.

Possible roles of DLK1 in the Notch pathway during development and disease.

The Delta-Notch pathway is an evolutionarily conserved signaling pathway which controls a broad range of developmental processes including cell fate determination, terminal differentiation and proliferation. In mammals, four Notch receptors (NOTCH1-4) and five activating canonical ligands (JAGGED1, JAGGED2, DLL1, DLL3 and DLL4) have been described. The precise function of noncanonical Notch ligands remains unclear. Delta-like 1 homolog (DLK1), the best studied noncanonical Notch ligand, has been shown to act as an inhibitor of Notch signaling in vitro, but its function in vivo is poorly understood. In this review we summarize Notch signaling during development and highlight recent studies in DLK1expression that reveal new insights into its function.

Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC).

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.

DLK1, a serum marker for hepatoblastoma in young infants.

Hepatoblastoma is a malignant pediatric liver tumor. The currently used diagnostic serum marker for hepatoblastoma, α-fetoprotein (AFP), is not always reliable in infants with hepatoblastoma, due to the physiologically elevated levels of AFP in this age group. In this report, we show that Delta-like 1 homolog (DLK1), a protein highly expressed during fetal development, but almost completely absent after birth, and an established liver-stem cell marker, is a new candidate serum marker of hepatoblastoma, especially in young infants.

The results of treatment of children with metastatic Wilms tumours (WT) in an African setting: do liver metastases have a negative impact on survival?

BACKGROUND: From Africa, where socio-economic circumstances differ from the developed world, there are no data regarding the influence of liver metastases on survival of children with Wilms tumour. PROCEDURE: One hundred fifty new patients with WT were seen between 2002 and 2010, 45 (30%) had metastases at diagnosis. Seven patients had bilateral disease with additional visceral metastases. Nine patients who developed liver metastases during treatment were excluded. The site of metastases and the results of pretreatment biopsies were retrieved. Neo-adjuvant chemotherapy was combined with nutritional resuscitation, and aggressive supportive care. Post-operative treatment was determined by stage and histology. RESULTS: Liver metastases were present in 19 (42%) patients but were the sole metastatic site in only 4 (9%). Overall survival at 5 years was 58.5%. Event Free Survival was 54%. Thirty-three (73%) had favourable histology, nine unfavourable and undetermined in three. No influence of histology on outcome was evident. Three patients had resection of persistent liver metastases. The pattern of metastatic disease had no influence on outcome. Despite aggressive supportive care two patients (4%) died within a week of presentation. Two patients died of chemotoxicity and two of complications following biopsy. Eight patients (17%) were lost to follow-up of whom five were on palliative treatment only. CONCLUSIONS: In Africa liver metastases do not appear to worsen the prognosis of children with Stage IV WT. Despite the poor socio-economic circumstances survival is comparable to other countries.

Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children.

BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Diagnostic MIS to obtain biopsy specimens for pathology has been accepted as a technique in paediatric surgical oncology, but there is limited experience with the use of MIS for the resection of malignancies. OBJECTIVES: To ascertain the differences in outcome between the minimally invasive and open approach in the treatment of solid intra-thoracic and intra-abdominal neoplasms in children, regarding overall survival, event-free survival, port-site metastases, recurrence rate and surgical morbidity. SEARCH METHODS: We searched the electronic databases of MEDLINE/PubMed (from 1966 to February 2011), EMBASE/Ovid (from 1980 to February 2011) and CENTRAL (The Cochrane Library 2011, Issue 1) with pre-specified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS and open surgery for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children (aged 0 to 18 years). DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: No studies that met the inclusion criteria of this review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified, therefore no definitive conclusions could be made about the effects of MIS in these patients. Based on the currently available evidence we are not able to give recommendations for the use of MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children. More high quality studies (RCTs and/or CCTs) are needed. To accomplish this, centres specialising in MIS in children should collaborate.

Long-term outcome of bilateral Wilms tumors (BWT).

BACKGROUND: Modern WT management consist of ample chemotherapy, nephron-sparing surgery, and, when indicated, radiotherapy. Survivors may develop renal failure or secondary tumors due to anticancer treatment. We analyzed long-term outcome (follow-up >5 years) after bilateral Wilms tumor (BWT) treatment with respect to survival, renal function, and secondary malignancies. METHODS: From 41 patients (23 females, 28 synchronous tumors) diagnosed with BWT between 1967 and 2007, 25 (18 females, 14 synchronous) with a follow-up >5 years could be included. Of this subgroup, median age at diagnosis was 1.64 years (range 0.27-5.35), and at maximum follow-up 14.99 years (range 5.40-33.99). Data were retrospectively collected and analyzed. RESULTS: One patient (4%) died 17.75 years after diagnosis, five (20%) had renal transplants: 3/5 after bilateral nephrectomy for Denys-Drash syndrome (DDS), and 2/5 for ESRD after an interval of 7 and 18 years, respectively. All transplanted patients remained in CR. Another three patients developed mild renal insufficiency (creatinine levels 1.3, 1.8, and 2.8 mg/100 ml, respectively; N = 0.5-1.2), combined with hypertension in 1; neither of them was transplanted. Sixteen (64%) had normal renal function and were in CR. Long-term renal function appeared significantly better after bilateral nephron sparing surgery (NSS) then after other surgical procedures (P < 0.0001). Seven secondary tumors were found in five (20%) patients, one of whom had a DDS. CONCLUSION: Long-term 10-year overall survival was 78%. There was significant morbidity (13/25, 52%), in terms of renal failure (8/25, 32%) including renal transplantation (5/25, 20%), and secondary tumors (5/25). These findings necessitate long-term follow-up beyond childhood. Future work should be directed at reducing the harmful effects of treatment, including the increased use of NSS.

Mortality of biliary atresia in children not undergoing liver transplantation in the Netherlands.

In order to further improve the outcome of BA, we characterized the mortality of BA patients who did not undergo OLT in the Netherlands, and compared our results with international data. For this purpose, we analyzed the causes of mortality of non-transplanted BA patients before the age of five yr, using the NeSBAR database. To evaluate trends in mortality, we compared the cohort 1987-1996 (n=99) with 1997-2008 (n=111). We compared clinical condition at OLT assessment with available international data, using the PELD-score. Mortality of non-transplanted BA children was 26% (26/99) in 1987-1996 and 16% (18/111) in 1997-2008 (p=0.09). Sepsis was the prevailing direct cause of death (30%; 13/44). PELD-scores at the time of assessment were higher in non-transplanted BA patients (median 20.5; range 13-40) compared with international data (mean/median between 11.7 and 13.3). Based on our national data, we conclude that pretransplant mortality of BA patients is still considerable, and that sepsis is a predominant contributor. Our results strongly indicate that the prognosis of patients with BA in the Netherlands can be improved by earlier listing of patients for OLT and by improving pretransplant care.

Commentary on bilateral Wilms' tumour: An international comparison of treatments and outcomes.

This is a commentary on the manuscript titled "Bilateral wilms' tumour: An international comparison of treatments and outcomes" by Drysdale H, Fawkner-Corbett D, Solomon Z, et al.