Palliative care (PC) is an integral part of cancer treatment. However, data on service availability is limited in childhood cancers. To describe the availability of PC services in paediatric oncology centres across Europe, and to identify barriers and facilitators for implementing and providing paediatric palliative care (PPC). Paediatric oncology centres across Europe were invited to complete an online questionnaire. A total of 158 paediatric oncology centres from 27 European countries participated. More than half of the centres (n=102, 64.6%) reported offering specialised PPC (defined as 24/7 coverage services with specialized physician and a multidisciplinary team). Most centres included a multidisciplinary care team (n=123, 80.9%) and PC at home (n=105, 69.1%). In 38.7% centres, service capacity was reported to be lower than demand. In most centres, PC consultation was initiated for a refractory neoplasm (n=126, 81.2%). Few centres (n=11, 7.1%) offered PC consultation at the time of a new cancer diagnosis. Eighty-two centres (52.6%) reported having bereavement services. Negative parental perception (n=99, 64.7%) and late referrals (n=91, 59.5%) were major barriers to implementation perceived by health care providers. Our results suggest that specialised PPC is available in more than half of paediatric oncology settings across Europe. Although half have had PPC available for >10 years, many cannot fulfil the demand for service. Barriers to implementation (i.e., parental education, staff training) should be addressed, with resources and services further expanded to cover the demand for PPC, including bereavement care.
The Global Initiative for Childhood Cancer of the World Health Organisation emphasise the importance of registration, especially in low-and middle-income countries, where data are sparse. The Hospital-Based Cancer Registry (HBCR) established in the Paediatric Oncology Unit (POU) at Le Dantec Hospital in Dakar, Senegal, collects data about patients from the whole of Senegal. This study investigates the potential for establishing a Population-Based Childhood Cancer Registry (PBCR) in the region of Dakar in Senegal. In an attempt to cover the entire Dakar region in addition to those included in the HBCR, cases were also sought in other hospitals and departments susceptible to diagnose or treat cancer in children. Completeness was assessed and cancer patterns described. From 2017-2019, 568 cancers in children under 18 were recorded in the HBCR, including 133 residents of the Dakar region. An additional 283 cases were identified from other sources, 149 of them without information on their place of residence. Discrepancies in cancer type distribution were observed between the data sources. The overall incidence rate estimate was 33 per million person-years. The additional cases found outside the HBCR, the observed variability of cancer types, and the low incidence rates highlight the need for a PBCR to standardize the registration process and improve completeness of ascertainment. Given the few identified data sources, a PBCR in the Dakar region would provide accurate information about childhood cancer burden in the covered population. However, political and financial support is necessary to sustain the registry.
Response to induction chemotherapy has been shown to predict outcome in patients with high-risk neuroblastoma (HR-NB), with those achieving a complete response (CR) having superior outcomes. We evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. 1244 Patients from four COG high-risk trials were included. End-induction response was coded as CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Cox regression models were performed to calculate event-free and overall survival (EFS, OS) hazard ratios, including interaction terms between induction response and prognostic factors including sex, age, stage, primary tumor location, LDH, ferritin, ploidy, MYCN status, ALK status, histology, MKI, grade, and study era. Among patients who achieved a CR after induction, INSS stage 4 disease and trial era were the only factors that remained significantly associated with inferior OS. For those who achieved less than a PR, adrenal primary site, MYCN amplification, and 1p LOH were associated with inferior outcomes. Multivariable models showed that end-induction response remained prognostic of EFS and OS even after controlling for other factors. Multiple significant statistical interactions were observed between end-induction response and other prognostic factors. The impact of conventional prognostic factors is not static in patients with HR-NB. Instead, response to induction chemotherapy modifies the effect of conventional prognostic factors. These data can help to further refine prognosis for patients with variable responses to induction and help to identify candidates who might benefit from treatment other than standard post-induction therapy.
While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's Oncology Group Rare Tumor committee, divided into the Retinoblastoma and Infrequent Tumor subcommittees. The Infrequent Tumor subcommittee has traditionally included an emphasis on globally rare tumors such as adrenocortical carcinoma, nasopharyngeal carcinoma, or those tumors that are rare in young children, despite being common in adolescents and young adults, such as colorectal carcinoma, thyroid carcinoma, and melanoma. Pleuropulmonary blastoma, gonadal stromal tumors, pancreatic tumors including pancreatoblastoma, gastrointestinal stromal tumor, nonmelanoma skin cancers, neuroendocrine tumors, and desmoplastic small round cell tumors, as well as other carcinomas are also included under the heading of the Children's Oncology Group Rare Tumor committee. While substantial challenges exist in rare cancers, inclusion and global collaboration remain key priorities to ensure high quality research to advance care.
Despite their vulnerability to radiation-induced damage, the maxilla and dentition are not routinely contoured in head and neck (HN) radiotherapy (RT), preventing accurate dose assessment and establishment of dose-effect relationships. This literature review aimed to: (1) identify published dentofacial contouring approaches, (2) synthesise current methods, and (3) where feasible, compare practices in paediatric and adult RT. MEDLINE and Embase were searched for studies that contoured the maxilla, mandible, or teeth in HN RT. Reference lists were manually screened. Thirty-one (2003-2025) papers met inclusion criteria. Manual contouring predominated (77.4%), with substantial heterogeneity across all structures. Only seven studies (22.6%) contoured the maxilla. Tooth contouring varied from individual segmentation to variable groupings. Eight studies (25.8%) reported dental professional involvement. Dentofacial contouring lacks standardisation and predominantly relies on manual techniques. This variability impedes dose assessment and cross-study comparisons. Standardised international guidelines for the contouring of the maxilla, mandible and teeth are necessary to ensure uniformity and enable comparability between studies.
Children treated for a malignancy are at risk to develop serious illness from a COVID-19 infection. Pegylated E. coli asparaginase (PEG-asparaginase) is used in the treatment of acute lymphoblastic leukemia. Allergy to this drug is common and both asparaginase and polyethylene glycol (PEG) are identified as possible antigens. The mRNA-based vaccines against COVID-19 contain PEG as a stabilizing component. We developed a protocol to be able to safely vaccinate children with a PEG-asparaginase allergy. All patients with a history of allergy to PEG-asparaginase have been included and skin prick testing for various PEGs was performed before vaccination with the mRNA Pfizer-BioNTech COVID-19 vaccine. Twelve children between six and 16 years old were vaccinated, without allergic reaction. None of them got a positive skin prick test for PEG. Ten patients had pre-existing IgG or IgM antibodies against PEG. Children with a PEG-asparaginase allergy can be safely vaccinated against COVID-19 with mRNA vaccines containing PEG irrespective of IgG/IgM antibodies to PEG-asparaginase. Routine skin prick testing in patients with PEG-asparaginase allergy does not seem to be of added value.
This review aims to discuss similarities and dissimilarities between BCR::ABL1-rearranged (Philadelphia chromosome-positive [Ph+]) and ABL-class fusion-driven BCR::ABL1-like (Ph-like) acute lymphoblastic leukemia (ALL) in children and adolescents. Recent insights into the biology of these historically high-risk leukemias, modern laboratory diagnostics, current treatment approaches, potential causes of treatment failure, emerging new targeted therapies and immunotherapeutic approaches for patients will be discussed. While the primary focus of this review is upon children and adolescents with BCR::ABL1-positive and ABL-class ALL, extended knowledge from recent adult clinical trials will also be addressed.
Survival rates for childhood cancer reveal stark global disparities. While over 80 % of children survive in high-income countries (HICs), outcomes remain significantly lower in low- and middle-income countries (LMICs), where the burden is also higher. This study synthesizes observational data on survival outcomes for the six WHO Global Initiative for Childhood Cancer (GICC) index cancers in LMICs, aiming to establish survival estimates, identify key determinants, and assess data limitations. Following JBI and PRISMA-ScR guidelines, we conducted a scoping review searching MEDLINE, WHO Global Index Medicus, and EMBASE for observational studies published since 2013. Studies included children aged 0-19 diagnosed with acute lymphoblastic leukemia, Burkitt lymphoma, Hodgkin lymphoma, low-grade glioma, retinoblastoma, or Wilms tumor in LMICs. From 6358 records, 196 studies were included. Most (72.9 %) were retrospective cohorts; 71.9 % were single-institution studies. The most frequently reported cancers were acute lymphoblastic leukemia (35.2 %) and Wilms tumor (29.1 %). Mean reported overall survival varied widely, from 62.5 % for Burkitt lymphoma (range 20.0-92.0 %) to 78.6 % for Hodgkin lymphoma (range 40.0-96.6 %). Median follow-up was often poorly reported. Socioeconomic barriers, limited healthcare access, and diagnostic delays were common determinants of poor outcomes. Only 10 % of studies referenced hospital-based registries, and fewer than 5 % used population-based data, highlighting critical data gaps. This review underscores emerging evidence and persistent limitations in childhood cancer survival data from LMICs. The predominance of single-center, retrospective studies indicates a need for more standardized, collaborative research.
Evolving evidence indicates that tumor cells can transdifferentiate between distinct transcriptionally-determined cell states with changes in resultant phenotypes, a phenomenon known as cellular plasticity. These transitions are not driven by genetic mutations and typically in contrast to normal developmental processes, may proceed bidirectionally. Here, we review the role of cellular plasticity in the aggressive childhood solid tumor, neuroblastoma. We discuss the detection of two cell states, termed mesenchymal (MES) and adrenergic (ADRN), their properties and the transcriptional circuitries that control them, their relation to the normal embryogenesis of the sympathetic nervous system and their potential role in drug resistance, escape from therapy and development of relapse.
Wilms tumour (WT) is the fourth leading cause of cancer death in children. Elucidating modifiable risk factors is crucial in identifying venues for primary prevention of the disease. This study aimed to review literature and synthesize environmental risk factors for WT. We conducted a systematic review and meta-analysis of epidemiological studies using PubMed, Web of Science, and Embase databases. Studies were included if they were case-control or cohort studies of children under the age of 20 years at diagnosis and reported Relative Risks (RRs) with 95 % confidence intervals (CIs). Pooled effect sizes (ES) and 95 % CIs for risk factors associated with WT were estimated using random-effects models. We included 58 eligible studies from Asia, Europe, Latin and North America, and Oceania totalling approximately10000 cases of WT diagnosed between 1953 and 2019. We confirmed an association between high birthweight ((>4000 g) ES 1.54, CI 1.20-1.97) and WT. Similarly, consistent associations were suggested for Caesarean section (ES 1.23, CI 1.07-1.42), gestational age <37 weeks (ES 1.45, CI 1.21-1.74), and large-for-gestational age (ES 1.52, CI 1.09-2.12). Parental occupational exposure to pesticides during preconception / pregnancy also showed increased risks of WT (maternal ES 1.28, CI 1.02-1.60, paternal ES 1.48, CI 0.98-2.24). There were inverse associations for breastfeeding (ever breastfed = ES 0.71, CI 0.56-0.89; < 6 months ES 0.67, CI 0.49-0.91; and ≥6 months ES 0.75, CI 0.59-0.97), and maternal intake of vitamins (unspecified) and folic acid during pregnancy (ES 0.78, CI 0.69-0.89). Among factors showing no associations were low birthweight (<2500 g), small-for-gestational age, assisted reproductive technology, parental age, and smoking or alcohol consumption during preconception / pregnancy, paternal occupational extremely low frequency magnetic fields (ELF-MF) exposures, and maternal X-ray exposure during pregnancy. Our findings suggest that modifiable risk factors of WT are parental occupational exposure to pesticides, breastfeeding (beneficial), and intake of folic acid during preconception / pregnancy (beneficial), but all associations were rather modest in strength.
An integral part of understanding and then designing programs to reduce childhood cancer inequities includes adequate representation of people with cancer in research, including children. A scoping review was carried out to understand how cancer research is oriented toward inequities and to identify who has participated in childhood qualitative cancer research. A systematic search identified 119 qualitative studies that met inclusion criteria, with most studies taking place in high-income countries (n=84). Overall, data were lacking on social determinants of health at multiple levels-structural, household, child, and guardian. Only 29 studies reported on race and/or ethnicity, with the majority of those including predominantly or all white children. Six articles included socioeconomic information, and across most articles, attention was absent to the financial ramifications of cancer care. Limited reporting of sociodemographics highlights a broader issue of neglecting key demographics and social factors that contribute to inequities.
Childhood cancer survivors (CCS) require specialized follow-up throughout their lifespan to prevent or manage late effects of cancer treatment. Knowing the size and structure of the population of CCS is crucial to plan interventions. In this scoping review we reviewed studies that reported prevalence of CCS in Europe. We searched Medline, Web of Science, and Embase using permutations of terms referring to childhood, cancer, survivors, prevalence, registries, and Europe. We followed PRISMA-ScR guidelines to select studies and The Joanna Briggs Institute Prevalence Critical Appraisal Tool to evaluate their quality. From 979 unique studies published between 1989 and 2022, 12 were included. Limited-duration prevalence (LDP) for all childhood cancers, assessed in three studies using counting method, varied between 450 and 1240 persons per million. Complete prevalence (CP) of survivors of any childhood cancer except skin carcinomas, reported in three studies using observed data complemented with modelled data for the unobserved period, varied between 730 and 1110 persons per million. CP of survivors of an embryonal tumour was estimated by completeness index method in six studies. In four of them CP ranged from 48 to 95 persons per million for all embryonal tumours, while CP for those occurring in central nervous system was 43 per million in one study and CP for rhabdomyosarcoma was 17 per million in another. Information on prevalence of CCS in Europe is fragmented and inconsistent. The large variations in LDP and CP estimates were linked to differences in data availability, the selection of populations, prevalence measure, statistical method, incidence period, index date, age at diagnosis and prevalence, cancer types, sex, and, for LDP, also the length of follow-up. Standardisation of methodology and reporting are needed to systematically monitor and compare CCS prevalence in Europe and provide data to help address survivors' needs.
Autoimmune diseases have been linked to an increased risk of pregnancy-related complications. A family history of autoimmune diseases may be related to the risk of childhood cancer based on similar histocompatibility antigens. We utilized data from national registries in Denmark to examine associations between maternal autoimmune disease and cancer in their offspring. We linked data from several national registries in Denmark to identify childhood cancer cases in children <20 years diagnosed between 1977 to 2016. Controls were selected from the Central Population Register and matched to cases by birth year and sex (25:1). Mothers with autoimmune disease diagnosed in pregnancy or prior were identified from the National Patient Register. Multivariable conditional logistic regression analyses were used to estimate associations between maternal autoimmune diseases and childhood cancer in offspring. Autoimmune diseases (all types) were positively associated with all childhood cancers combined (Odds Ratio (OR) = 1.25, 95% CI 1.06, 1.47), acute lymphoblastic leukemia (OR =1.52, 95% CI 1.09, 2.13), Burkitt lymphoma (OR = 2.69, 95% CI 1.04, 6.97), and central nervous system tumors (OR = 1.45, 95% CI 1.06, 1.99), especially astrocytoma (OR = 2.27, 95% CI 1.36, 3.77) and glioma (OR = 1.75, 95% CI 1.13, 2.73). When we examined mothers with rheumatoid arthritis, we observed an increased association for all cancers (OR = 2.15, 95% CI 1.40, 3.30), acute lymphoblastic leukemia (OR = 3.55, 95% CI 1.69, 7.47), and central nervous system tumors (OR = 2.91, 95% CI 1.46, 5.82), especially glioma (OR = 3.58, 95% CI 1.40, 9.18) in offspring. There is a positive association between maternal autoimmune disease and childhood cancer. This association is especially prominent in the offspring of women with rheumatoid arthritis.
Neuroblastoma is a cancer of the sympathetic nervous system that develops in young children, either as low-risk or high-risk disease. The tumor microenvironment (TME) is now recognized as an important player of the tumor ecosystem that may promote drug resistance and immune escape. Targeting the TME in combination with therapies directly targeting tumor cells therefore represents an interesting strategy to prevent the emergence of resistance in cancer and improve patient's outcome. The development of such strategies however requires an in-depth understanding of the TME landscape, due to its high complexity and intra and inter-tumoral heterogeneity. Various approaches have been used in the last years to characterize the immune and non-immune cell populations present in tumors of neuroblastoma patients, both quantitatively and qualitatively, in particular with the use of single-cell transcriptomics. It is anticipated that in the near future, both genomic and TME information in tumors will contribute to a precise approach to therapy in neuroblastoma. Deciphering the mechanisms of interaction between neuroblastoma cells and stromal or immune cells in the TME is key to identify novel therapeutic combinations. Over the last decade, numerous in vitro studies and in vivo pre-clinical experiments in immune-competent and immune-deficient models have identified therapeutic approaches to circumvent drug resistance and immune escape. Some of these studies have formed the basis for early phase I and II clinical trials in children with recurrent and refractory high-risk neuroblastoma. This review summarizes recently published data on the characterization of the TME landscape in neuroblastoma and novel strategies targeting various TME cellular components, molecules and pathways activated as a result of the tumor-host interactions.
Despite intensive therapies, pediatric patients with relapsed or refractory solid tumors have poor outcomes and need novel treatments. Immune therapies offer an alternative to conventional treatment options but require the identification of differentially expressed antigens to direct antitumor activity to sites of disease. B7-H3 (CD276) is an immune regulatory protein that is expressed in a range of malignancies and has limited expression in normal tissues. B7-H3 is highly expressed in pediatric solid tumors including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, and many rare tumors. In this article we review B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell therapies for pediatric solid tumors, reporting preclinical development strategies and outlining the landscape of active pediatric clinical trials. We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.
Racial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current era therapy. Two patient cohorts were identified in the International Neuroblastoma Risk Group Data Commons (INRGdc) (Cohort 1: diagnosed 2001-2009, n=4359; Cohort 2: diagnosed 2010-2019, n=4891). Chi-squared tests were used to assess the relationship between race/ethnicity and clinical and biologic features. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to investigate the association between racial/ethnic groups and prognostic markers. Significantly higher 5-year event-free survival (EFS) and overall survival (OS) were observed for Cohort 2 compared to Cohort 1 (P<0.001 and P<0.001, respectively). Compared to White patients, Black patients in both cohorts had a higher proportion of high-risk disease (Cohort 1: P<0.001; Cohort 2: P<0.001) and worse EFS (Cohort 1: P<0.001; Cohort 2 P<0.001) and OS (Cohort 1: P<0.001; Cohort 2: P<0.001). In Cohort 1, Native Americans also had a higher proportion of high-risk disease (P=0.03) and inferior EFS/OS. No significant survival disparities were observed for low- or intermediate-risk patients in either cohort or high-risk patients in Cohort 1. Hispanic patients with high-risk disease in Cohort 2 had significantly inferior OS (P=0.047). Significantly worse OS, but not EFS, (P=0.006 and P=0.02, respectively) was also observed among Black and Hispanic patients assigned to receive post-Consolidation dinutuximab on clinical trials (n=885). Racial/ethnic survival disparities have persisted over time and were observed among high-risk patients assigned to receive post-Consolidation dinutuximab.
Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.
Advanced localized retinoblastoma can be cured by enucleation, but extraocular spread of retinoblastoma cells is associated with a high mortality. Risk-stratified adjuvant treatment with chemotherapy and radiotherapy has been shown to reduce the risk for extraocular relapse in children with histopathological risk factors. Data of 184 patients with retinoblastoma and primary enucleation were collected in a prospective, multicenter, observational study between 2013 and 2020. The clinical characteristics were evaluated as risk factors and progression-free and overall survival rates were compared. Seventy-one percent of 184 children with retinoblastoma treated with primary enucleation were diagnosed with low risk histopathological factors (pT1/pT2a) and received no adjuvant therapy. Children with intermediate risk (pT2b,pT3; 48 children, 26.0%) and high risk for metastasis (pT4; 5 children, 2.7%) received risk-stratified adjuvant treatment. None of the children with low risk or intermediate risk (pT1-pT3) relapsed, but two of five children with high-risk retinoblastoma (pT4) developed extraocular relapses and one deceased. The 2-year progression-free survival rate and 2-year overall survival rate was 100% for children with pT1-3 retinoblastoma. However, the 2-year progression-free survival rate and 2-year overall survival rate for children with pT4 was statistically notably reduced with 2 of 5 children developing progression and 1 death among the 5 children within 2 years after diagnosis. Primary enucleation alone and with additional risk-stratified adjuvant chemotherapy treatment provides high cure rates in patients with pT1-3 retinoblastoma, but children with pT4 retinoblastoma remain at high risk to develop extraocular retinoblastoma. International prospective clinical trials are required to evaluate reduction of intensity of adjuvant chemotherapy in some risk groups (pT2, pT3) and intensification for pT4 retinoblastoma.
Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways. Here, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls. We employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways. PLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism. Our findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.
Automated stuttering detection (ASD) systems struggle with paediatric speech due to high acoustic variability in developing voices and the subtle distinction between pathological stuttering and typical developmental disfluencies. We introduce Paediatric-HGNN, a framework using a Context-aware Part-whole Interaction Network (CaPIN) tailored for paediatric data. Instead of conventional 1D signal modelling, our approach builds a heterogeneous graph capturing hierarchical relationships between lexical units (word nodes) and fine-grained acoustic segments (frame nodes). Trained on curated paediatric corpora (UCLASS and FluencyBank), Paediatric-HGNN achieves 82.4% weighted accuracy and a Typical Disfluency F1-score of 0.386. Modelling hierarchical lexical-acoustic interactions captures developmental "searching" behaviour, offering a more robust and interpretable tool for early clinical intervention.