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Pediatric Cancer

Explore the latest in pediatric cancers, including advances in genetic sequencing and treatment of solid and liquid tumors in children.

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This cohort study examines racial disparities in stage at diagnosis and overall survival for the 10 deadliest cancers among adolescents and young adults.

In this narrative medicine essay, a pediatric neurology resident who survived childhood cancer reflects on her experience and later how it affected her mother and by extension how life-threatening diagnoses of children impact their parents, grandparents, and siblings.

This cross-sectional study analyzes whether associations of epigenetic age acceleration (EAA) with cancer treatment vary by race and ethnicity among survivors of childhood cancer and whether socioeconomic factors mediate the associations.

This Viewpoint explores the important role that patient advocates play in pediatric oncology as exemplified by ACCELERATE, a multiparty collaboration that centers advocate involvement in pediatric oncology research.

This cohort study evaluates surveillance outcomes across a wide spectrum of cancer predisposition syndromes in children and young adults.

This review describes the process of updating the global evidence-based consensus guideline on management of desmoid tumor.

In this narrative medicine essay, a pediatric oncologist gains new insight into the decision to transition from cancer-directed therapy to comfort-focused care when roles are reversed and she experiences end-of-life decision-making as a caregiver.

This prognostic study analyzes the accuracy of the Phoenix Sepsis Score for the classification of attributable mortality risk in children with cancer presenting to the intensive care.

This randomized clinical trial evaluates the Pediatric Cancer Resource Equity (PediCARE) intervention, which provided groceries and transportation, vs usual care, for poverty-exposed pediatric oncology families.

In this narrative medicine essay, a newly minted pediatric critical care physician learns firsthand what holistic medical care is from the love and attention she received during a hospitalization for mediastinal lymphoma.

This comparative effectiveness analysis examines the outcomes of pediatric patients with acute myeloid leukemia (AML) by race and cytarabine pharmacogenomics.

This cross-sectional study examines the factors associated with symptom burden and health-related quality of life in 5-year survivors of childhood cancer.

• Cancer Risk Among Children Born After Fertility Treatment JAMA Network Open Opinion May 2, 2024 Pediatrics Hematologic Cancer Leukemias Hematology Neonatology Full Text | pdf link PDF open access

This cohort study assesses the risk of cancer, overall and by cancer type, among children born after medically assisted reproduction compared with children conceived naturally.

• Use of Insecticide-Treated Bed Nets and Incidence of Burkitt Lymphoma JAMA Network Open Opinion April 18, 2024 Global Health Hematology Oncology Pediatrics Hematologic Cancer Full Text | pdf link PDF open access

This systematic review and meta-analysis investigates whether large-scale use of insecticide-treated bed nets is associated with reduced incidence of Burkitt lymphoma among children in sub-Saharan Africa.

This systematic review and meta-analysis investigates the association between childhood cancer and socioeconomic potential in survivors of childhood cancer.

This cross-sectional study uses US commercial health insurance claims data to assess mental health care utilization among parents of children with vs without cancer.

This cohort study assesses the association of germline cancer-predisposition variants with outcomes among children with rhabdomyosarcoma.

• Exploring Exclusive Breastfeeding and Childhood Cancer Using Linked Data JAMA Network Open Opinion March 26, 2024 Pediatrics Hematologic Cancer Leukemias Nutrition, Obesity, Exercise Hematology Full Text | pdf link PDF open access

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Cancer Research Catalyst The Official Blog of the American Association for Cancer Research

Home > Cancer Research Catalyst > Raising Awareness of Childhood Cancer

Raising Awareness of Childhood Cancer

September is Childhood Cancer Awareness Month. 

Childhood cancer is relatively rare, but it is a devastating diagnosis that can ravage a family and create lifelong health challenges. In the United States, approximately 15,590 children and adolescents under 20 were diagnosed with cancer in 2018, according to the latest data from the National Cancer Institute. Pediatric cancers are the leading cause of death from disease of children and adolescents.

Thanks to advances propelled by cancer research, pediatric cancer death rates have declined by nearly 70 percent over the past four decades. Survivors may face long-term health effects, but they often thrive, leading full lives and bringing immeasurable joy to their families and loved ones.

This month,  Cancer Research Catalyst introduced readers to Fernando Whitehead and Cami Green, two young cancer survivors whose families have graciously shared their stories with the American Association for Cancer Research (AACR). Fernando was featured In the AACR’s inaugural  Cancer Disparities Progress Report , released September 16, and Cami’s story appeared in the  AACR Cancer Progress Report 2020 , released September 23. Patients like them provide constant inspiration for the AACR’s mission to prevent and cure cancer. 

The AACR supports a wide range of research on childhood cancer. Recently, AACR journals featured  studies that examined how radiation treatment received as a pediatric cancer patient can adversely affect cardiovascular health, metabolism, and the chance of surviving adult breast cancer. The AACR’s Pediatric Cancer Working Group bridges the AACR with advocacy and legislative groups to promote the prevention and treatment of childhood cancers.  Also, the AACR is the Scientific Partner to Stand Up To Cancer, which conducts pioneering research on pediatric cancer through a  Dream Team collaboration with St. Baldrick’s Foundation. 

Here are some other AACR  resources on pediatric cancer.

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Introduction

Genomic and epigenomic profiling studies, breakthroughs in targeted therapies, epigenetic drivers of pediatric cancer, developmental and cellular origins of pediatric tumors, experimental model systems, immune microenvironment profiles of pediatric tumors, immunotherapeutic approaches for pediatric tumors, conclusions and outlook, authors' disclosures, acknowledgments, recent advances in pediatric cancer research.

Cancer Res 2021;81:5783–99

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• Version of Record December 1 2021
• Accepted Manuscript January 1 2021

Troy A. McEachron , Lee J. Helman; Recent Advances in Pediatric Cancer Research. Cancer Res 1 December 2021; 81 (23): 5783–5799. https://doi.org/10.1158/0008-5472.CAN-21-1191

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Over the past few years, the field of pediatric cancer has experienced a shift in momentum, and this has led to new and exciting findings that have relevance beyond pediatric malignancies. Here we present the current status of key aspects of pediatric cancer research. We have focused on genetic and epigenetic drivers of disease, cellular origins of different pediatric cancers, disease models, the tumor microenvironment, and cellular immunotherapies.

The treatment of pediatric cancers has been a success story, with current overall survival (OS) of ∼80% in the United States. It is estimated that there are currently >500,000 survivors of pediatric cancer in the United States. Nonetheless, this success has occurred at a significant price, as the prevalence of severe chronic health disorders among long-term survivors of pediatric cancer is 3-fold higher than in matched controls. In addition, there are still close to 13,000 pediatric cancer deaths per year in the United States, and there are several tumors for which long-term survival remains poor. Recently, the adult cancer research community has seen major advances in detailing the molecular and cellular mechanisms of disease that have resulted in the generation of novel targeted therapies and immunotherapies, some of which are applicable to pediatric tumors. Here, we have reviewed several major topics that we believe have had a major impact already on fundamental understanding of the biology of pediatric cancers and will continue to impact the field going forward. To maintain the current relevance of this review, we have restricted most of our literature search to the last 5 to 6 years and have included a few older references for context. The following sections focus on new insights into the genetic and epigenetic underpinnings of these cancers, therapeutic breakthroughs, developmental and cellular origins of these tumors, model systems that have provided new perspectives, microenvironmental influences on tumor biology, and immunotherapy approaches to treatment. Although a comprehensive review of the current status of pediatric cancer research is of course beyond the scope of this article, we believe that each of the areas discussed will continue to generate new ideas and hypotheses in the near future that hopefully will lead to new and improved therapies that ultimately improve both short-term and long-term outcomes of childhood cancer.

Pediatric pan-cancer profiling studies

Large-scale genomic profiling of various hematologic and nonhematologic tumors, so-called pan-cancer studies,” has been instrumental in revealing the overall landscape of adult malignancies allowing for the identification of genetic drivers of disease, discovery of mutational signatures and complex structural aberrations, and investigation of drug targets ( 1, 2 ). Recently, several pediatric pan-cancer genomic studies have been completed and have reported that pediatric tumors contain fewer coding mutations than adult tumors, that TP53 remains the most frequently recurring mutation, and that mutations in epigenetic-associated genes were common events ( 3–6 ). Profiling close to 1,700 pediatric leukemias and solid tumors revealed 142 somatic driver gene mutations and found that copy-number alterations and structural variants were the most prevalent types of alterations to impact these driver genes ( 3 ). Furthermore, this study discovered two new mutation signatures in addition to the existing signatures within the COSMIC (Catalogue Of Somatic Mutations In Cancer) database.

Analysis of DNA sequencing data obtained from 961 tumors across 24 different pediatric, adolescent, and young adult patient histologies identified 34 genomic loci recurrently affected by copy-number alterations ( 4 ). This study also demonstrated that of the 77 significantly mutated genes identified across the entire sample cohort, the majority of these mutations were exclusive to specific tumor types ( 4 ). Furthermore, the authors highlighted the differences between the genomic landscapes of adults and pediatrics, showing that only 30% of the significantly mutated genes identified in pediatric tumors were present in adults. Of the 24 tumor types profiled in this study, osteosarcomas and adrenocortical carcinomas were the most genomically complex, hallmarked by an increased rate of hyperdiploidy and chromothripsis, a catastrophic shattering of chromosomes with subsequent error-prone repair ( 4, 7 ). Whether the observed genomic complexity in adrenocortical carcinoma and osteosarcoma represents the culmination of persistent chromosomal instability or the product of a single early cataclysmic event is yet to be experimentally determined. Collectively, these pan-cancer studies further highlight the unique biology driving several pediatric cancers ( Fig. 1 ). Moreover, the data from these studies validate the seminal publication by Bert Vogelstein and colleagues illustrating the age-associated differences in the mutational landscapes across multiple cancer types ( 8 ).

Features of pediatric tumors. A, SVs are more common than SNVs. B, Somatic mutations in TP53 are frequently recurrent and mutations in epigenetic genes are also common. C, The mutation spectra between adult and pediatric tumors share little overlap. SNV, single-nucleotide variant; SV, structural variant; Epi; epigenetic-associated genes.

DNA methylation profiling of brain tumors

DNA methylation refers to the addition of methyl groups to chromosomal DNA to regulate gene transcription. Recently, numerous studies have emerged demonstrating the utility of DNA methylation analysis to subcategorize central nervous system (CNS) tumors. Genome-wide DNA methylation profiling of 3,093 meningiomas revealed that clear cell meningiomas, a histology predominantly observed in children and young adults, clustered independently of all other subtypes ( 9 ). DNA methylation arrays subdivided group 3 and 4 medulloblastomas into 8 different molecular subgroups ( 10 ). DNA methylation analysis of pilocytic astrocytoma specimens showed that tumors arising in the infratentorial, midline, and cortical regions of the brain had distinct methylation profiles ( 11 ). A separate study comparing diffuse astrocytoma and pilocytic astrocytoma specimens showed that the pilocytic specimens were hypomethylated and had a different methylation profile than the diffuse astrocytoma specimens ( 12 ). Integrated epigenetic profiling of CNS atypical teratoid/rhabdoid tumors (ATRT) identified three disease subgroups with distinct DNA methylation profiles and epigenetic landscapes ( 13, 14 ). Together, these data illustrate the power and applicability of DNA methylation to subcategorize CNS tumors, which has clinical implications pertaining to the refinement of ambiguous diagnoses ( 15, 16 ).

Mutational activation of RAS–MAPK pathway

Upstream and downstream components of the RAS and MAPK pathways are recurrently mutated in various pediatric CNS and solid tumors ( 4, 5, 17 ). Analysis of the Foundation Medicine sequencing data generated from 1,215 different pediatric tumors showed MAPK mutations were common in hypermutant tumors driven by replication repair deficiency and that the RAS/MAPK pathway was indeed active in these tumors ( 5 ). By performing functional experiments using pediatric hypermutant glioma and pediatric hypermutant colorectal cancer patient-derived xenograft (PDX) models, the authors showed that these RAS–MAPK-mutant replication repair-deficient tumors were susceptible to MEK inhibition, highlighting a potential context for synthetic lethality ( 5 ).

Whole-genome sequencing of matched primary-relapsed neuroblastoma specimens led to the discovery that 78% of relapsed specimens contained mutations in genes involved in RAS–MAPK signaling ( 18 ). Similarly, mutations in PHOX2B, CIC , and DMD activated RAS–MAPK signaling in neuroblastoma cell lines and tumor specimens ( 19 ). Importantly, both studies demonstrated that mutations in genes involved in RAS–MAPK signaling conferred increased sensitivity to pharmacologic MEK inhibition both in vitro and in vivo ( 5, 19 ).

In the largest study of its kind, mutational analysis of DNA from 641 rhabdomyosarcoma patients indicated that mutations in the RAS pathway occurred at a frequency of 56% in fusion-negative tumors that lack the pathogenomic FOXO1 fusion oncogenes ( 20 ). This study also showed that isoform-specific RAS mutations associated with age where HRAS mutations were enriched in infants, KRAS in toddlers, and NRAS in adolescents ( 20 ). This incredibly intriguing finding implies that the different RAS isoforms may impart specific age-restricted oncogenic programs.

Somatic mutations to the RAS–MAPK pathway have also been reported in aggressive pediatric hematologic malignancies. Survivors of pediatric cancer are at increased risk for subsequent malignancies due to the late effects of their highly cytotoxic chemotherapy treatments ( 21, 22 ). Genomic analysis revealed a high frequency of KRAS and NRAS mutations in pediatric cancer survivors who had developed therapy-related myeloid neoplasms ( 23 ). A combination of exome and whole-genome sequencing discovered that 44% of relapsed acute lymphoblastic leukemia (ALL) specimens had somatic mutations in NRAS , KRAS , or PTPN11 ( 24 ). Using isogeneic leukemia cell lines expressing either wild-type or the G12D KRAS mutant, this study showed that oncogenic KRAS conferred resistance to methotrexate and an unexpected sensitivity to vincristine. Although juvenile myelomonocytic leukemia has long been associated with oncogenic RAS signaling, integrated genomic and DNA methylation analysis revealed that mutations in NRAS , KRAS , and PTPN11 were differentially enriched in independent molecular subgroups ( 25 ). Although each of the subgroups was associated with different clinical and molecular features, the extent to which the respective somatic RAS pathway mutations contributed to these subgroup-specific features was not reported.

Germline variants associated with predisposition and increased disease risk

The importance of understanding the deleterious effects of germline mutations in pediatric cancer patients can be traced back to Knudson's original 1971 publication describing the two-hit hypothesis of tumorigenesis in patients with retinoblastoma ( 26 ). Five decades later, the prevalence and impact of germline variants in patients with pediatric tumors is still an active area of research due, in large part, to the advances in genome sequencing technology. A comprehensive summary of the various germline variants associated with pediatric cancers and cancer predisposition syndromes is beyond the scope of this article but have been thoroughly reviewed ( 27–31 ). Analysis of germline DNA sequencing data from 1,120 pediatric cancer patients diagnosed with leukemia, CNS tumors, neuroblastoma, retinoblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, adrenocortical carcinoma, and melanoma revealed that the overall rate of pathogenic or likely pathogenic germline variants was a striking 8.5% ( 32 ). Two additional studies estimated the frequency of causative germline variants in pediatric cancer patients to be slightly lower at 6% and 6.9%, respectively ( 4, 33 ). When hematologic malignancies were excluded, the percentage of pediatric patients diagnosed with solid tumors and CNS tumors that carried germline variants in known cancer predisposition genes increased to 12% ( 34 ). Strikingly, germline variants were frequently observed in the following DNA repair genes: TP53 , BRCA2 , PMS2 , CHECK2, MSH2 , and MSH6 ( 4, 32 ).

The frequency of germline variants in TP53 varies by tumor type. Germline variants in TP53 increased the risk of developing sonic hedgehog (SHH) medulloblastomas and were associated with an increased prevalence of chromothripsis in these patients ( 35 ). This is consistent with the finding that germline variants in TP53 were associated with a higher number of somatic chromosomal structural variations ( 4 ). In adrenocortical carcinoma, germline TP53 variants were observed in approximately 50% of patients, and rather than clustering in hotspots, these variants were distributed throughout the gene ( 36 ). Between 4% and 5.3% of patients with osteosarcoma harbored pathogenic or likely pathogenic germline TP53 variants, with almost half of these mutations occurring de novo ( 37, 38 ). These osteosarcoma patients tended to be younger, have disease within the axial skeleton, were more likely to present with metastatic disease upon diagnosis, and had an inferior prognosis ( 37 ). Germline TP53 variants were observed at a frequency of 2% in pediatric B-cell ALL ( 39 ). According to this study, pathogenic TP53 variants were enriched in older children and those diagnosed with hypodiploid ALL, a more aggressive form of this disease. Moreover, these patients experienced inferior outcomes and were at a higher risk of developing a secondary malignancy ( 39 ).

As stated above, there are several germline variants in genes other than TP53 that have also been documented in pediatric cancers. Patients with osteosarcoma were found to have pathogenic or likely pathogenic germline variants in CDKN2A, MEN1, VHL, POT1, APC, MSH2 , and ATRX ( 37 ). Amazingly, this study concluded that 28% of patients with osteosarcoma had a pathogenic or likely pathogenic germline variant in a cancer predisposition gene ( 37 ). Furthermore, the GLDC/IL33 locus has been identified as an osteosarcoma susceptibility locus, and two single-nucleotide polymorphisms (SNP), rs3765555 and rs55933544, were associated with significantly decreased survival and decreased IL33 expression ( 40, 41 ). Data from the Children's Oncology Group identified germline variants in 15 genes at a frequency of 7.3% in children with rhabdomyosarcoma ( 42 ). Similar results were obtained in a separate rhabdomyosarcoma study showing that approximately 7% of patients had a germline variant in a known cancer predisposition gene ( 43 ). Interestingly, in both studies, these germline variants were enriched in patients with FOXO1 fusion-negative disease. Separate genome-wide association studies (GWAS) have identified new SNPs associated with Ewing sarcoma risk at the 6p25.1, 20p11.22, and 20p11.23 loci ( 44, 45 ). In patients with Ewing sarcoma, pathogenic or likely pathogenic germline variants occurred at a frequency of 13% and were enriched in several genes associated with DNA damage repair ( 46 ). GWAS of 707 neuroblastoma patients revealed that the rs6720708 SNP at the BARD1 locus, a known high-risk neuroblastoma susceptibility locus, was significantly associated with the development of adrenal neuroblastoma versus developing thoracic disease ( 47 ).

A study consisting of 280 California patients with glioblastoma, anaplastic astrocytoma, and astrocytoma not otherwise specified reported that pathogenic germline variants were present in approximately 11% of the patients and that these variants were enriched in patients with glioblastoma ( 48 ). In medulloblastoma, germline variants were differentially enriched according to disease subgroups. The SHH subgroup of medulloblastoma had the highest rate of germline alterations affecting various genes including TP53 , SUFU , PTCH1 , PABL2 , BRCA2 , GPR161 , and ELP1 ( 35, 49, 50 ). Germline variants in APC were enriched in the WNT subgroup, whereas PALB2 and BRCA2 germline variants were observed in SHH, group 3, and group 4 medulloblastomas ( 35 ).

ETV6 germline variants were associated with increased risk of developing childhood ALL, and patients with these predisposing germline variants were more likely to be older at the time of diagnosis and have hyperdiploid ALL, a leukemia subtype with a favorable prognosis ( 51 ). The rs3824662 SNP in GATA3 was recently discovered to confer increased risk of relapse in patients with ALL ( 52 ). New ALL risk loci were also identified at 5q31.1, 6p21.31, 9q21.31, and 17q21.32 and associated with specific ALL subtypes ( 53 ). Two SNPs rs886285 (at 5q31.1) and rs210143 (at 6p21.31) were associated with high-hyperdiploidy ALL, rs10853104 (at 17q21.32) with the ETV6–RUNX1 subtype, and rs76925697 (at 9q21.31) with B-cell ALL ( 53 ). Patients with Down syndrome have an extraordinarily high risk for developing various leukemias during childhood, including acute myeloid leukemia (AML), ALL, and megakaryoblastic leukemia ( 54 ). ALL patients with Down syndrome exhibited an increased frequency of a risk allele in CDKN2A , a previously established susceptibility locus ( 55 ). The IKZF1 SNP rs58923657, which maps to an active B-cell enhancer, was also enriched in patients with Down syndrome, and the risk allele decreased the enhancer activity ( 55 ). Moreover, silencing IKZF1 preferentially increased the proliferation of lymphoblastoid cells from individuals with Down syndrome versus cells from those without Down syndrome ( 55 ). Together, these data suggest that presence of trisomy 21 modifies the phenotypic effect of the rs58923657 risk allele.

Telomeres are complexes of proteins bound to repetitive DNA sequences positioned at the end of each chromosome that shorten with each cell division, thus acting as a cellular clock recording each replicative event. Telomere length is disproportionately associated with cancer incidence where shorter telomeres seem to be protective while longer telomeres confer an increased risk ( 56–58 ). For instance, longer telomere length was associated with a higher risk of developing ependymoma with adolescent and adult onset ( 59 ). In osteosarcoma, a weighted polygenic risk score revealed that longer telomere length was a risk factor for developing disease in Hispanic, Asian/Pacific Islander, and African American children ( 60 ). The association between telomere length and osteosarcoma risk was recapitulated in a separate study where the data were not stratified by ethnicity ( 61 ). Additionally, this GWAS study also found that SNPs in known telomere maintenance genes increased the risk of developing neuroblastoma and ALL ( 61 ).

Given that pediatric tumors are rare, germline variants that moderately increase risk in adult disease may indeed have a larger affect size in certain pediatric tumors. That said, not all germline variants in known cancer predisposition genes are causative of disease but may impact disease severity and/or other phenotypic aspects of the tumor. Similarly, germline variants in genes not previously associated with adult diseases may have biological and/or clinical relevance in children and vice versa ( 62 ). However, the accessibility to large-scale genomic databases combined with growing institutional genomic profiling efforts affords researchers a collaborative opportunity to perform clinically annotated genotyping studies to further investigate the impact of germline variants in pediatric cancers. For example, the MSK-IMPACT study (NCT01775072) is performing prospective clinical germline sequencing on pediatric solid tumor patients and using the resultant data to identify actionable targeted therapeutics and prioritize patients and families that may benefit from further screening/surveillance ( 63 ). These types of clinical studies can also inform the surveillance protocols for these patients. In 2017, the Pediatric Cancer Working Group of the American Association for Cancer Research convened a Childhood Cancer Predisposition Workshop where a set of screening and surveillance recommendations were established. This meeting included the discussions on the use and interpretation of whole-body MRI, the need for registries to enable natural history studies, the consultancy role of syndrome-specific centralized centers of excellence, and modifications to existing surveillance protocols ( 64–70 ).

In summary, the widespread adoption of advanced genomic technologies in both the clinic and the research laboratory has led to the discovery of numerous germline variants. Experimental investigations aimed at determining the functional impact of these and other reported variants in racially and ethnically diverse cohorts will further our understanding of the biological and clinical significance of germline genetics in pediatric malignancies. Nonetheless, the current data clearly indicate that subsets of pediatric cancer patients are genetically predisposed to developing disease and support the observed inverse relationship between germline variants and age ( Fig. 2 ; refs. 36, 37, 71 ).

Comparison of germline and somatic mutations in pediatric versus adult cancers. Germline variants are more frequently observed in pediatric cancer patients than in adult cancer patients, whereas adult tumors have an increased somatic mutation burden than pediatric tumors.

Liquid biopsies

Disease monitoring is an important aspect to the management of both pediatric and adult disease. However, unlike the adult setting where repeated biopsies are more readily obtained, performing serial biopsies in pediatric patients has traditionally been discouraged unless deemed medically necessary. This “one and done” approach constrains the ability to identify and/or develop reliable biomarkers for the longitudinal study of CNS and solid tumors in children. Liquid biopsies are minimally invasive tests that utilize accessible body fluids (i.e., blood, urine, saliva, and/or cerebral spinal fluid) to detect cellular and/or molecular biomarkers of a given disease such as cell-free DNA (cfDNA), circulating tumor cells, microRNAs, proteins, and metabolites ( 72–74 ). Emerging data suggest that liquid biopsies may circumvent these sampling limitations and allow for longitudinal assessments of disease burden. Detection and quantification of cfDNA have been documented in various solid and CNS tumors of childhood, with the earlier studies largely relying on polymerase chain reaction–based approaches ( 75 ). These methods were reliable in detecting cfDNA from diseases in which known recurrent driver mutations existed, for example, histone mutations in high-grade glioma (HGG; refs. 76, 77 ).

More recently, next-generation sequencing (NGS)-based methods have been used and have the potential to identify mutations in tumors a priori . NGS profiling studies of cfDNA from patients with neuroblastoma, Ewing sarcoma, Wilms tumor, osteosarcoma, alveolar rhabdomyosarcoma, medulloblastoma, and HGG have consistently reported positive associations between cfDNA abundance and disease burden ( 77–86 ). The anatomical site from which cfDNA is obtained can impact the cfDNA yield for subsequent downstream analyses. Studies have shown improved detection of cfDNA isolated from cerebral spinal fluid versus that of plasma in patients with medulloblastoma and brain stem glioma ( 83, 87 ). For Wilms tumor, detecting mutations in cfDNA isolated from urine was not only achievable, but more mutations were detected in the urine versus plasma from these patients ( 82 ). Optimization of this urine-based Wilms tumor cfDNA profiling approach is particularly appealing as it presents zero risk to the patient, allows for serial collections in large quantities, and can be done at home. Moreover, this study provides a rationale to investigate the applicability of cfDNA profiling in other childhood kidney tumors such as renal cell carcinoma, malignant rhabdoid tumors, and clear cell sarcoma of the kidney.

cfDNA has also been used to gain important biological insight. Longitudinal profiling of cfDNA from patients with neuroblastoma demonstrated the ability to identify clonal populations with distinct mutational patterns, model clonal evolution throughout the treatment regimen, and identify relapse specific clones ( 78 ). Analysis of gene-specific 5-hydroxymethylcytosine–modified cfDNA from neuroblastoma patients identified unique profiles associated with disease burden ( 80 ). Further analysis revealed differentially enriched biological processes and pathways in patients with and without active disease. Methylation analysis of cfDNA isolated from the cerebral spinal fluid of patients with medulloblastoma was used to derive an epigenetic signature based on differentially methylated CpG sites that could specifically and sensitively identify medulloblastoma subtypes ( 84 ).

Several companies have gained, or are seeking, FDA approval for their respective adult oncology liquid biopsy assays, including Guardant, FoundationOne, Grail, and Thrive ( 88–94 ). Currently, liquid biopsies have not yet been approved for use with pediatric patients, but trials investigating the clinical utility of liquid biopsies to monitor disease burden and treatment response in various pediatric cancers are under way. It is likely that additional studies on the utility of liquid biopsies will increase in the coming years and ultimately integrate into standard of care for patients with certain tumor types.

Filling in the knowledge gaps

Despite the recent advances in exploring the genomic landscapes of various pediatric cancers, knowledge gaps remain. One such knowledge gap is that there are only a few studies that detail the genomic and transcriptomic profiles of specimens from patients with recurrent, refractory, and/or relapsed CNS and solid tumors as the majority of published genomic studies were performed using treatment-naïve specimens. The emerging data from the few studies performed on recurrent, refractory, and/or relapsed specimens from pediatric patients with CNS and solid tumors suggest a comparatively higher mutation burden compared with treatment-naïve patient specimens ( 4, 18, 95–97 ). Additional descriptive and functional studies are needed to uncover the mechanisms associated with disease progression in each of these tumors and tumor subtypes.

Another knowledge gap is that most of the genomic profiling data have been generated using short-read sequencing methods. Although the identification of single-nucleotide variants from these data is well established, many short-read sequencing analytical tools struggle to resolve complex genomic aberrations, necessitating the implementation of sophisticated algorithms, each with their own biases and limitations ( 98, 99 ). Long-read sequencing platforms routinely produce continuous sequencing read lengths of >10 kb and have been demonstrated to resolve complex genomic rearrangements, including chromothripsis ( 100, 101 ). As part of the Gabriella Miller Kids First (GMKF) Pediatric Research Program, long-read sequencing technologies will be used to uncover the genomic complexities associated with certain pediatric cancers and birth defects. It is anticipated that long-read sequencing technologies may supplement the existing data to better resolve the complex structural variants inherent to tumors such as osteosarcoma and adrenocortical carcinoma.

Unlike adults, few efficacious targeted therapies exist for childhood cancers. Recently, larotrectinib and selumetinib received FDA and European Medicines Agency (EMA) approval, a significant therapeutic advance for the treatment of pediatric cancer patients bearing driver mutations targeted by these kinase inhibitors. Larotrectinib targets TRK proteins and is indicated for cancers with oncogenic TRK fusions such as those found in 2.22% of pediatric patients ( 102, 103 ). The overall response rate for patients with TRK fusion–positive tumors treated with larotrectinib was 79%, with 16% having complete responses ( 104 ). In addition to its potent and durable antineoplastic effect, larotrectinib improved the quality of life for patients, the gold standard for any therapeutic agent ( 105 ).

Selumetinib is a MEK1/2 inhibitor indicated for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas ( 106–108 ). Of the patients treated with selumetinib, >70% exhibited a confirmed durable partial response of >20% reduction in tumor size ( 106, 107 ). Impressively, all the patients who had received selumetinib had experienced some degree of tumor shrinkage. Selumetinib is also currently under clinical investigation for pediatric patients with BRAF- mutant pilocytic astrocytoma and NF1- associated low-grade gliomas ( 109 ). The approval of selumetinib marks the first ever approved targeted therapy for patients with neurofibromatosis. Moreover, these two targeted agents validate the necessity of a pediatric drug development pipeline.

Histone H3K27

Since the first reports of somatic histone H3 mutations at lysine 27 (H3K27M) and glycine 34 (H3G34) in pediatric HGG in 2012, the interest in these “onco-histones” has sparked numerous investigations aimed at understanding their role in tumorigenesis ( 110, 111 ). Functional studies show that the H3K27M mutation increased the self-renewal capacity of neurospheres in vitro , whereas CRISPR-mediated correction of the H3K27M mutation in glioma cell lines decreased cell proliferation ( 112, 113 ). In genetically engineered murine HGG models, the presence of the H3K27M mutation decreased tumor latency ( 112, 114 ). Multiple studies have shown that the H3K27M mutation regulated genes involved in neurogenesis and differentiation ( 112, 113, 115–117 ). Bivalent promoters are chromatin domains that are marked by both repressive and activating histone modifications. Mutant H3K27M histones colocalized with the H3K27Ac mark at bivalent promoters and enhancers, diminished the deposition and spreading of H3K27me3 marks, and allowed for transcription of polycomb-repressed genes ( 112, 113, 116, 117 ). Interestingly, the H3K27M mutation did not sequester polycomb repressor complex 2 (PRC2; refs. 116, 117 ). Correction of the mutation restored the balance between H3K27me3 and H3K27Ac marked loci, reestablished polycomb-mediated repression of developmental genes, and promoted glial lineage commitment ( 113, 115 ). Therapeutically, H3K27M-mutant cell lines were sensitive to pharmacologic inhibition of EZH2, the PRC2 histone methyltransferase, and did so in a p16 INK4a -dependent manner, and such interventions prolonged the survival of tumor-bearing mice ( 114 ). Bromodomain and extraterminal (BET) proteins are “chromatin readers” that bind to acetylated lysines to recruit chromatin remodelers that subsequently regulate transcription. The BET inhibitor JQ1 forced the differentiation of H3K27M-mutant glioma cells in vitro and prolonged survival in vivo ( 117 ). Interestingly, an aggressive subset of pediatric posterior fossa ependymomas has been identified as having low levels of H3K27me3 and increased levels of H3K27Ac ( 118 ). These tumors exhibited DNA methylation profiles like that of H3K27M-mutant gliomas as well as overlapping H3K27me3 ChIP-seq peaks. This signifies that histone mutations are not the only means by which to achieve the molecular and phenotypic characteristics attributed to the H3K27M mutation.

Enhancer dysregulation

Enhancers are regulatory chromatin domains that recruit transcriptional machinery to promote or repress gene expression from a specific locus. The accessibility and activity of enhancers are developmentally regulated and associated with lineage commitment but can be dysregulated to aberrantly drive oncogenic transcriptional profiles. In pediatric HGG, the presence of the H3G34 mutation arrested the cells in a developmental state where the chromatin conformation juxtaposed the GSX2 enhancer and PDGFRA locus and allowed for PDGFR A to hijack the enhancer of this developmentally regulated transcription factor to drive pathologic PGDFRA expression ( 119 ). Enhancer hijacking has also been observed in MYCN -amplified neuroblastoma. An integrative genomic approach identified two classes of MYCN amplicons ( 120 ). Class I amplicons were simple amplification events that contained both MYCN and its local enhancer, whereas class II amplicons contained MYCN without the local enhancer. Further investigation revealed that these class II amplicons were double-minute chromosomes and circumvented the lack of the local MYCN enhancer by hijacking distal enhancers through complex chromosomal structural rearrangements ( 120 ).

Differential enhancer activity was observed in matched primary–metastatic osteosarcoma tumors and isogenic cell line pairs, revealing that these metastatic-specific enhancers promoted transcriptional programs necessary for metastatic seeding ( 121 ). Further analysis indicated that an enhancer regulating the expression of coagulation factor 3 was positively selected for in the metastatic cell lines and that perturbation of this enhancer reduced pulmonary metastasis in vivo ( 121 ). The EWS–FLI1 chimeric oncoprotein is the product of the EWSR1–FLI1 translocation that defines 85% of Ewing sarcoma tumors. GGAA repeats are the known EWS–FLI1 binding motif in Ewing sarcoma ( 122 ). Recent data demonstrated that these GGAA repeats are enriched at super-enhancers, were bound by EWS–FLI1, and identified MEIS1, a developmentally regulated homeobox protein, as a super-enhancer–driven oncogenic transcription factor ( 123 ). Additionally, MEIS1 and EWS–FLI1 colocalized at a subset of super-enhancers to further drive transcriptional dysregulation.

Recently, both mesenchymal stem-like and adrenergic-like cells were identified in primary and established neuroblastoma cell lines, and each subpopulation of cells had unique super-enhancer landscapes that were responsible for maintaining their respective lineage identities ( 124 ). Additional functional analysis showed that ectopic expression of the mesenchymal stem-like super-enhancer–associated transcription factor PRRX1 partially reprogramed the adrenergic-like neuroblastoma cells toward a more mesenchymal stem-like state as evidenced by global shifts in the super-enhancer landscape and transcriptional profiles ( 124 ).

The PAX3/7–FOXO1 translocations, the hallmark chromosomal aberrations in alveolar rhabdomyosarcoma, bring PAX3/7 gene transcription under the control of the FOXO1 super-enhancer ( 125 ). Mutations in the RAS–MAPK pathway drive a subset of fusion-negative rhabdomyosarcomas tumors ( 126 ). In this context, RAS-mutant cells were developmentally arrested due to oncogenic MAPK signaling, which imparted a RAS-dependent super-enhancer landscape ( 127 ). Inhibition of MAPK signaling by trametinib altered the chromatin accessibility and restored the myogenic super-enhancer landscape to drive differentiation of fusion-negative rhabdomyosarcoma cells ( 127 ). SNAI2 was shown to compete with MYOD1, a master myogenic transcription factor, and inactivate myogenic enhancers to halt differentiation in fusion-negative rhabdomyosarcoma ( 128 ). A separate study demonstrated that TWIST2 repressed myogenesis by both upregulating SNAI2 expression and competing with MYOD1 binding at target genes associated with muscle differentiation ( 129 ). The loss of H3K27Ac and deposition of H3K27me3 at TWIST2-bound myogenic loci indicated that TWIST is capable of recruiting PRC2 to inhibit differentiation in fusion-negative rhabdomyosarcoma cells.

Pioneer factors

Pioneer factors are the first transcription factors to bind specific heterochromatic loci and alter the local chromatin accessibility by recruiting additional chromatin remodelers. OTX2 is a developmentally regulated transcription factor that was found to occupy several active enhancers in group 3 medulloblastoma cells ( 130 ). Additionally, NEUROD1, an established neuronal pioneering factor, was shown to interact with OTX2 at enhancers ( 130, 131 ). Ectopic expression of OTX2 induced a group 3 medulloblastoma chromatin accessibility and enhancer signature in mesenchymal stem cells, suggesting that OTX2 functions as a pioneer factor ( 130 ). The EWS–FLI1 oncogenic fusion gene endowed Ewing sarcoma cells with a unique enhancer profile ( 132 ). Mechanistically, EWS–FLI1 bound to GGAA repeats to remodel chromatin and generate de novo enhancers and displaced ETS transcription factors to promote transcription of target genes ( 133 ). The PAX3–FOXO1 fusion was found to function as a pioneering factor in alveolar rhabdomyosarcoma and created de novo super-enhancers that drove oncogenic and myogenic transcription programs in a BRD4-dependent manner ( 134 ). BRD4 is a member of the BET family of “chromatin readers” and CHD4 is a chromatin remodeler. CHD4 interacted with BRD4 and colocalized with PAX3–FOXO1 at a subset of super-enhancers in alveolar rhabdomyosarcoma ( 135 ). These data also demonstrated that PAX3–FOXO1 binding was, at least in part, dependent on the presence of CHD4 chromatin remodeling ( 135 ).

Redirecting/hijacking of chromatin remodelers

BAF is the mammalian equivalent of the SWI/SNF chromatin remodeling complex, of which, SS18 is a member. The SS18–SSX chimeric oncoprotein, the gene product of the translocation that defines synovial sarcoma, competed with SS18 to hijack the BAF complex ( 136 ). The SS18–SSX fusion antagonized PRC2-mediated gene repression by directing the BAF complex away from enhancers and toward bivalent genes to promote aberrant gene transcription ( 137, 138 ). Additionally, the histone demethylase KDM2B, a member of the noncanonical PRC1.1 complex, has been shown to recruit BAF complexes containing the SS18–SSX fusion to repressed developmentally regulated genes, resulting in their transcription ( 139 ).

At active enhancers, the interaction between EWS–FLI1 and RING1B of the PRC1 complex was necessary for target gene expression ( 140 ). These data also showed that RING1B maintained its repressive function at non-EWS–FLI1 bound loci. Together, the data suggest that RING1B targets EWS–FLI1 to repressed enhancers to recruit additional chromatin modifiers and transcription factors to activate these enhancers and subsequent transcriptional programs ( 140 ). The prion domain present in wild-type EWS is retained in the EWS–FLI1 fusion, and this domain was deemed critical for recruiting the BAF complex to activate enhancers ( 141 ).

As previously mentioned, most pediatric tumors have a relatively low mutational burden. It is becoming clear that in contradistinction, many pediatric tumors have significantly reprogramed epigenomes, leading to widespread transcriptional dysregulation. Better mechanistic understanding of the means by which this epigenetic reprograming occurs may lead to new therapeutic “targeted” approaches in a variety of pediatric tumors.

Despite decades of research and various hypotheses, the question regarding the cell of origin of childhood tumors has plagued the field of pediatric cancer research. Recent advances in single-cell RNA-seq (scRNA-seq) technologies combined with powerful informatic analyses have allowed investigators to more deeply probe this question. Since many pediatric tumors are “embryonal” in appearance, an integrated approach utilized across various studies from multiple groups has involved comparing the single-cell transcriptional profiles of normal developing tissues with that of tumors derived from the same tissue. Comparative single-cell analysis of transcriptomes from normal human fetal adrenal glands and dissociated neuroblastoma tumors suggested that, of the cells profiled, neuroblastoma cells most closely resembled developmentally arrested sympathoblasts ( 142 ). Strikingly, this comparison was consistent across the different neuroblastoma risk groups. A separate study used scRNA-seq data from embryonic and post-natal murine adrenal glands to demonstrate that neuroblastoma cells significantly correlated with neuroblasts, a cell type whose signature partially overlapped with that of sympathoblasts ( 143 ). This study also highlighted a subset of neuroblastoma cells that closely resembled Schwann cell precursors that were hallmarked by decreased MYCN and ALK expression ( 143 ). Another study mapped neuroblastoma cells to cells isolated from early human embryos and fetal adrenal glands and showed that neuroblastoma cells most closely resembled undifferentiated chromaffin cells ( 144 ). In these studies, chromaffin cells clustered adjacently to sympathoblasts, thus approximating the potential cellular origins of neuroblastoma ( 142–144 ). The creation of a single-cell transcriptome atlas derived from healthy fetal, pediatric, adolescent, and adult kidneys and ureters identified ureteric bud cells and primitive vesicle cells of the developing nephron as the cells that most closely correlated with Wilms tumor cells ( 145 ).

Similar comparative scRNA-seq approaches have been used to identify the cellular origin in pediatric brain tumors. Comparing scRNA-seq data from human medulloblastoma cells to cells from the developing mouse brain revealed that WNT subgroup medulloblastoma cells were heterogeneous and did not explicitly correlate with any cell type in the murine cerebellum but, in fact, resembled lower rhombic lip mossy-fiber neurons of the pons ( 146, 147 ). Group 4 medulloblastoma cells mapped to unipolar brush cells and glutamatergic cerebellar nuclei ( 146, 147 ). The SHH subgroup were enriched in granule neuron progenitors that varied in their differentiation status in accordance with age, highlighting the differences between adult and pediatric disease ( 146 ). scRNA-seq on both the developing brain and tumor cells from a mouse model of SHH medulloblastoma revealed significant correlations between cerebellar granule neuron progenitor cells and the murine tumor cells, thereby independently validating the conclusions of similar studies ( 146–148 ). Projection of bulk RNA-seq data onto a single-cell atlas derived from scRNA-seq data of the developing human brain stem, murine pons, and murine forebrain identified neural progenitor cells as the potential cell of origin for H3K27M pontine gliomas ( 147 ). Similarly, the H3G34 mutation arrested HGG tumor cells in a developmental state most consistent with interneuron progenitor cells ( 119 ). Analysis of embryonal tumors with multilayered rosettes suggested that these tumors were likely derived from fetal radial glial cells ( 147 ). The cellular origins of ATRTs were more ambiguous and, although the precise cell of origin was not identified, the data suggested that these tumors likely arose from early progenitor cells of non-neuroectodermal origin ( 147 ).

Comprehensively profiled patient-derived xenografts

In comparison with adult diseases, the rate of progress in the field of pediatric cancer research has been somewhat constrained due to the relative rarity of these diseases, which ultimately equates to a paucity of reliable models for experimentation. PDX models help to circumvent this issue as the implanted tumor cells reflect the natural history of the disease. However, assessing the fidelity of these models is of paramount importance in interpreting the resultant data, thus necessitating comprehensive characterization of these models. Recently, different groups have established large banks of clinically annotated and genomically profiled pediatric PDX models ( 97, 149–153 ). Collectively, these PDX models comprised hematologic malignancies, solid tumors, CNS tumors, and rare histologies obtained from patients with primary, relapsed, and/or metastatic disease and have been made available to the research community ( Table 1 ). A combination of genomic, transcriptomic, and epigenomic profiling concluded that these PDX models closely resembled the original tumor tissues from which they were derived.

PDX repositories.

Genomic data derived from molecularly characterized osteosarcoma PDX models were used to identify druggable targets and demonstrated the efficacy of genome-informed therapeutic approaches ( 149 ). Genomically characterized PDX models of high-risk rhabdomyosarcoma were used to conduct phase II and III preclinical trials and identified that the addition of a WEE1 inhibitor improved the therapeutic response to irinotecan and vincristine ( 150 ). A separate Pediatric Preclinical Testing Consortium study evaluating the efficacy of WEE1 inhibition in combination with irinotecan in neuroblastoma, osteosarcoma, and Wilms tumor xenografts yielded similar results ( 154 ). Importantly, these two independent studies provided compelling preclinical data, resulting in the establishment of a phase I/II clinical trial to investigate the combination of WEE1 inhibition with irinotecan in pediatric patients with relapse or refractory solid tumors (NCT02095132).

Although these thoroughly characterized models are useful in facilitating the study of cell autonomous mechanisms of disease and preclinical identification/evaluation of therapeutic targets, they are not ideal for mechanistic immuno-oncology investigations, which require an intact immune system not present in PDX models. Expanding the use of these models into humanized mice can partially address this deficiency, albeit certain species incompatibility issues and other limitations remain ( 155 ). Furthermore, it is important to note that, although PDX models exhibit high fidelity with respect to the source material, sampling bias still exists, due to the variable extent of intratumoral heterogeneity present in CNS and solid tumors. Therefore, depending on the abundance and distribution of clonal and/or subclonal populations present in the tumor location from which the specimen was obtained, the PDX generated from this material may or may not be representative of the bulk tumor, but rather a regional subpopulation. Nonetheless, PDX models are incredibly valuable in advancing the field of pediatric cancer research.

Patient-derived organoids

Several factors impact the engraftment of tumor tissues, and thus the rate of successful PDX generation varies markedly. The patient-derived organoid is a newer model system that fills the gap between PDX models and patient-derived cancer cell lines ( 156 ). Recently, a pediatric renal tumor organoid biobank comprised of 54 organoids derived from tumors including Wilms tumor, metanephric adenoma, malignant rhabdoid tumors, renal cell carcinoma, congenital mesoblastic nephroma, and a hyperplastic intralobular nephrogenic rest was established ( 157 ). Corresponding normal tissue organoids were also developed. A hepatoblastoma tumor–normal organoid pair was also recently reported ( 158 ). In both studies, genomic and transcriptomic profiling revealed that the organoid models resembled the tumors from which they were derived and demonstrated the applicability of these tumor-derived organoids for in vitro drug screening ( 157, 158 ).

Somatic genome engineering of oncogenic translocations

Numerous pediatric solid tumors are defined by hallmark translocations that give rise to fusion oncoproteins that drive disease, most notably Ewing sarcoma ( EWSR1–FLI1 ), desmoplastic small round cell tumors ( EWSR1–WT1 ), and rhabdomyosarcoma ( PAX3/7–FOXO1 ). Somatic genome engineering via CRISPR-Cas9 has been used to successfully generate these translocations. Functional EWSR1–FLI1 translocations have been engineered into HEK293 cells ( 159, 160 ) as well as mesenchymal stem cells and induced pluripotent stem cells ( 161 ). Functional EWSR1–WT1 translocations have also been engineered using CRISPR-Cas9 ( 160, 162 ). The PAX3–FOXO1 translocation was engineered into mouse myoblasts using a Cre-Lox strategy to invert the FOXO1 locus followed by CRISPR-Cas9 to create intronic double strand breaks in PAX3 and FOXO1 ( 163 ). Here, the rate of successful translocation formation varied between forelimb and hindlimb myoblasts and was attributed to the differences in the 3D genome organization and physical proximity of the PAX3 and FOXO1 loci.

All experimental models have inherent flaws, and their utility is dependent upon the specific questions being interrogated. However, a thorough comprehension of the benefits and limitations of each model will allow for strategic utilization of the most appropriate model(s) to generate useful data that will drive the field forward. It is likely that integrated studies that utilize scRNA-seq of tumor tissues and/or organoids to map the cellular origins of disease will be critical in the development of new models where disease-specific mutations are engineered into the presumed permissive cells of origin. If successful, this approach could provide new insights into diseases such as Ewing sarcoma, where despite immense effort put forth by international groups of researchers, murine models have yet to be successfully engineered ( 164 ).

The tumor microenvironment is comprised of neoplastic cells, immune cells, fibroblasts, endothelial cells, pericytes, various extracellular matrix components, growth factors, soluble stimulatory and inhibitory molecules, nutrient gradients, and variable oxygen tension that work in concert to sustain tumor growth ( 165 ). Over the last decade, the number of tumor microenvironment studies in adult cancers has increased dramatically. Although still less studied, recent reports documenting the landscape of the tumor microenvironment in different pediatric cancers have increased. The use of computational tools to impute cell types from RNA-seq data has significantly contributed to this increase by allowing for data mining and retrospective inquiry of established data sets ( 166–168 ). Functional studies are also beginning to emerge, albeit at a reduced frequency that is likely attributable to a scarcity of robust immunocompetent tumor models to study. In reviewing the available literature, one more consistent finding is that the molecular and cellular microenvironmental profiles of pediatric CNS and solid tumors are incredibly heterogeneous and are thus deserving of their own discussion.

Osteosarcoma

scRNA-seq analysis of osteosarcoma specimens revealed marked cellular heterogeneity between primary, metastatic, and recurrent disease states ( 169 ). This study also reported a decreased abundance of CD4 + and CD8 + lymphocytes in the recurrent and metastatic specimens with CD8 + cells expressing markers of T-cell exhaustion ( 169 ). These data are consistent with reports that metastatic osteosarcoma specimens contained fewer CD8 + lymphocytes than nonmetastatic specimens, expressed low cytotoxicity scores, and exhibited lymphocyte exclusion ( 170–172 ). Additionally, an integrated multiomic analysis showed that osteosarcomas exhibited an ineffective immune response and low neoantigen expression ( 173 ). This study also showed that copy-number alterations inversely correlated with immune cell abundance. One of the most striking findings from this study was the data showing the correlation between patient age and tumor inflammation with tumor-infiltrating lymphocytes being more abundant in adult specimens versus pediatric specimens ( 173 ). These data further highlight the differences between pediatric and adult disease.

Myeloid cells are an important feature of the osteosarcoma microenvironment. Analysis of osteosarcoma specimens demonstrated that myeloid-lineage cells were the most abundant immune cells present in these tissues ( 169 ). Clustering analysis of these data identified 10 distinct subgroups of myeloid cells, highlighting the heterogeneity of myeloid-lineage cells in osteosarcoma. Experimental data showed that M2 tumor-associated macrophages (TAM) promoted osteosarcoma metastasis and that treatment with all-trans retinoic acid reduced TAM-dependent metastasis in vivo ( 174 ). Myeloid-derived suppressor cells (MDSC) are highly suppressive immature myeloid cells with demonstrated ability to limit the efficacy of chimeric antigen receptor (CAR) T cells in osteosarcoma models in vivo ( 175, 176 ). All-trans retinoic acid was sufficient to eliminate monocytic MDSCs and relieve the suppressive phenotype of granulocytic MDSCs ( 176 ). These studies highlight the biological significance, phenotypic plasticity, and functional heterogeneity of myeloid-lineage cells within the osteosarcoma microenvironment.

Ewing sarcoma

Ewing sarcoma specimens exhibited the lowest lymphocyte abundance when compared with other pediatric solid tumors and the presence of CD8 + T cells did not confer a survival benefit to patients ( 177, 178 ). Examination of pregnancy-associated plasma protein-A ( PAPPA ) expression across various pediatric solid tumors illustrated that Ewing sarcoma had the highest expression levels ( 179 ). Functional analysis demonstrated that inhibition of PAPPA expression upregulated the expression of numerous genes associated with an active immune response, suggesting that PAPPA is immunosuppressive. IHC revealed that suppressive HLA-G + lymphocytes outnumbered HLA-G − lymphocytes in Ewing sarcoma biopsy specimens and that HLA-G was upregulated on xenografted tumors cells in response to CAR T-cell treatment ( 180 ). Moreover, CCL21, an immunostimulatory cytokine, was shown to be downregulated in metastatic patient specimens, was inversely correlated with the CD4 + /CD8 + T-cell ratio and was associated with a better prognosis ( 181 ). Together, these data highlight the immunosuppressive nature intrinsic to Ewing sarcoma. Exactly how the EWS–FLI1 fusion oncoprotein contributes to the immunosuppressive phenotype of Ewing sarcoma is not yet known.

Neuroblastoma

Gene-expression and IHC analyses of neuroblastoma specimens revealed that T cells positively correlated with intratumoral dendritic cells (DC) and natural killer (NK) cells, both of which served as positive prognosticators of OS ( 182 ). When compared with other pediatric solid tumors, the gene-expression level of CD200 was significantly higher in neuroblastoma specimens than in any of the other tumor types ( 183 ). Moreover, CD200R-high neuroblastoma specimens contained fewer CD4 + and CD8 + T cells and expressed lower levels of IFNγ and TNFα, associating CD200 with a dampened T-cell response. MYCN -amplified neuroblastoma tumors were shown to be less immunogenic than nonamplified tumors as evidenced by lower immune scores and decreased MHC class I gene expression ( 184, 185 ). Interestingly, a separate study using RNA-seq data from the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) and GMKF cohorts demonstrated that the activation of downstream MYCN transcriptional programs, rather than amplification of MYCN itself, was inversely correlated with T-cell abundance and tumor inflammation ( 186 ). This study also showed that increased T-cell infiltration and a higher neoantigen load were independently associated with improved OS in these patients ( 186 ). For high-risk MYCN nonamplified neuroblastoma specimens with a high MYCN gene signature, T-cell clonal expansion was associated with improved outcomes while a subgroup of these specimens demonstrated T-cell exhaustion ( 184 ). Increased abundance of CSF1R + myeloid cells was associated with inferior relapse-free survival for patients with neuroblastoma, and therapeutically targeting these cells both decreased tumor burden and sensitized animals to PD-1 inhibition ( 187 ).

Wilms tumor

In Wilms tumor specimens, an inverse relationship between M1 macrophage abundance and tumor stage was observed, whereas the opposite was true for M2 macrophages ( 188 ). Functional studies show that loss of the tumor suppressor WT1 upregulated COX2 expression in normal kidneys, and that Wilms tumors derived from the WT1-IGF2 murine model demonstrated robust COX2 expression, elucidating one possible mechanism by which Wilms tumor cells promote a suppressive microenvironment ( 189 ). This study also highlighted the immunosuppressive microenvironment of Wilms tumors as indicated by increased abundance of regulatory T cells, the expression of suppressive cytokines, and a diminished Th1 response when compared with normal kidneys ( 189 ).

Rhabdomyosarcoma

Although the abundance of infiltrating immune cells did not dramatically differ between embryonal and alveolar rhabdomyosarcoma, their distribution throughout the tumor tissue did indeed vary. The vast majority of both CD3 + and CD163 + cells localized within 15 μm of tumor blood vessels in alveolar specimens, whereas the perivascular localization in embryonal specimens was more diffuse ( 190 ). Additionally, tertiary lymphoid structures were more frequently associated with the alveolar histology. Consistent across the histologies was that both embryonal and alveolar rhabdomyosarcoma contained higher numbers of TAMs than T cells ( 190, 191 ). Fibrocytes have been shown to promote an immunosuppressive microenvironment and undermine the efficacy of immune-checkpoint inhibition in a syngeneic embryonal rhabdomyosarcoma model ( 192 ).

Medulloblastoma

Analysis of immune infiltrates across multiple CNS tumors revealed a consistent inverse correlation between tumor grade and immune cell content ( 193 ). In comparison with the other major brain tumor histologies, medulloblastomas were characterized as being immunologically “cold” ( 194 ). However, within medulloblastomas, the relative abundance of immune cells varied by subgroup with SHH and WNT tumors having higher proportion of CD8 + T cells than group 3 and 4 tumors ( 193 ). In low-risk group 3 medulloblastoma, a decreased Treg abundance was associated with inferior progression-free survival ( 193 ). A murine model of SHH and group 3 medulloblastoma also revealed subtype-specific differences where SHH medulloblastoma tumors contained higher numbers of infiltrating lymphocytes and myeloid-lineage cells than group 3 tumors ( 195 ). Interestingly, a murine model of SHH medulloblastoma demonstrated that tumoricidal TAMs were recruited to the tumors in a CCL2/CCR2-dependent manner, suggesting a beneficial role of macrophages in the SHH medulloblastoma microenvironment ( 196 ). A separate study using a p53-mutant medulloblastoma model demonstrated that mutant p53 inhibited the presentation of MHC class I by negatively regulating the expression of TAP1 and ERAP1, molecules needed for successful antigen loading ( 197 ). Importantly, activation of TNFR2 and LTβR signaling was sufficient to restore MHC class I expression in the tumor cells in vitro .

The microenvironmental heterogeneity of pediatric gliomas varied in accordance with grade, subgroup, and histone mutation status ( 193, 198, 199 ). Multiplexed immunofluorescent imaging showed that low-grade gliomas (LGG) had a higher density of CD3 + cells than HGG and that, among the LGGs, pilocytic astrocytomas had the lowest T-cell density ( 199 ). This study also reported increased vascularity in recurrent versus primary pilocytic astrocytomas. IHC evaluation of infiltrating immune cells demonstrated that there were no statistically significant differences in the abundance of NK cells or CD163 + myeloid cells between LGG and HGG ( 200 ). In a separate study, diffuse intrinsic pontine gliomas were shown to be “immunologically cold” tumors with little immune infiltrate ( 201, 202 ). Proteomic and phospho-proteomic analysis revealed marked heterogeneity in the immune microenvironment of both LGG and HGG and showed that different subgroups of gliomas were classified as “hot” or “cold” irrespective of histology and/or diagnosis ( 194 ).

The pediatric tumor microenvironment field, although gaining interest, is still emerging, and additional studies are needed to comprehend the dynamic interaction between tumor cells and the various components of their microenvironment. Studies directed at answering important questions pertaining to the microenvironmental mechanisms that promote immunosuppression and drive resistance to current immunotherapies are of critical clinical importance and will contribute to shaping the therapeutic landscape.

The 2011 approval of ipilimumab by both FDA and EMA marked the start of the immunotherapy revolution ( 203, 204 ). This rapidly evolving therapeutic landscape has dramatically changed the treatment paradigm for adult and select pediatric malignancies ( Table 2 ). With the various late effects associated with certain prolonged cytotoxic chemotherapy and radiotherapy regimens, it is the hope that immunotherapy may increase the quality of life for pediatric and adolescent patients in addition to providing durable responses, but this will require long-term follow-up.

FDA-approved immunotherapies for pediatric oncology patients.

Note: Table contents obtained from NCI cancer.gov/about-cancer/treatment/drugs/childhood-cancer-fda-approved-drugs.

Immune-checkpoint inhibition in CNS and solid tumors

Data show that robust expression of PD-L1 is not a universally common finding in most pediatric tumors, although a subset of 11q-deleted neuroblastomas exhibited increased expression of PD-L1 ( 201, 205–207 ). Furthermore, somatic copy-number gains at loci encompassing genes that encode for PD-L1/PD-L2 have been shown in a subset of osteosarcoma specimens ( 208 ). Two patients with hypermutant glioblastoma driven by biallelic mismatch-repair deficiency syndrome were successfully treated with single-agent nivolumab and exhibited durable clinical and radiologic responses ( 209 ). In a separate study, a patient with a hypermutant glioma and constitutional mismatch-repair deficiency was treated with pembrolizumab yet succumbed to their disease ( 63 ). These two studies support the findings that mismatch-repair deficient tumors exhibit variable responses to checkpoint inhibition ( 210 ). Nonetheless, immune-checkpoint inhibition targeting PD-1 or CTLA4 has shown limited therapeutic efficacy for most pediatric patients with CNS and solid tumors with some notable exception ( 205, 211–213 ). Given the clinical inefficacy of currently available immune-checkpoint inhibition, adoptive cell therapies have played a much larger role to date in the immunotherapy of pediatric tumors.

CD19 CAR T-cell therapy in leukemia

One of the most remarkable advances in cancer research has been the development, clinical implementation, and efficacy of CAR T-cell therapy in high-risk pediatric B-cell ALL. Furthermore, the fact that the first FDA-approved use of CAR T-cell therapy, tisagenlecleucel, was for a pediatric and adolescent indication before being approved for adults was a ground-breaking milestone for the field of pediatric oncology. Infusion of these autologous CD19-directed CAR T cells into pediatric and young adult patients with relapsed/refractory B-cell ALL achieved a remission rate of >80% with no evidence of residual disease at 3 months post-infusion ( 214 ). Additionally, these patients demonstrated 1-year event-free survival (EFS) and OS rates of 50% and 76%, respectively. Nonetheless, this therapy is not without side effects as a high incidence of cytokine release syndrome was observed with 40% of these patients experiencing neurologic events ( 214 ). CD19 CAR T-cell therapy has also demonstrated efficacy in pediatric patients with CNS B-cell ALL ( 215, 216 ). In these patients, neurotoxicity was associated with an increased CNS disease burden prior to treatment ( 216 ). The acute effects of cytokine release syndrome can be managed, but late effects may exist in children and longitudinal monitoring is needed in these patients ( 217 ).

Leukemic B cells can escape killing by CAR T cells by using a variety of mechanisms, including downregulating the expression of CD19 ( 218 ). To address this, studies investigating sequential infusion of CD19 and CD22 CAR T cells and preclinical efficacy of CD19/CD22 bivalent CAR T cells are under way ( 219–221 ). Additionally, the use of low-affinity CD19 CAR T cells demonstrated superior in vitro and in vivo T-cell responses when compared with high-affinity CAR T-cells ( 222 ). In patients, these lower affinity CAR T cells were associated with increased persistence and expansion of the adoptively transferred cells, lower toxicity, a remission rate of 85%, a 1-year EFS rate of 64%, and a 1-year OS rate of 46% ( 222 ). With a median follow-up of 4.8 years, a recent study found that allogeneic hematopoietic stem cell transplant after CD19 CAR T-cell infusion significantly reduced the relapse rate in patients with recurrent B-ALL ( 223 ).

GD2-targeted CAR T-cell therapy

GD2 is a carbohydrate-containing sphingolipid that is expressed by many cell types throughout the body and highly expressed by neuroblastoma cells ( 224 ). GD2-targeted CAR T cells engineered to coexpress IL15 reduced T-cell exhaustion in vitro and enhanced the therapeutic efficacy in vivo ( 225, 226 ). Interestingly, GD2-targeted CAR T cells were effective at killing neuroblastoma xenografts but were ineffective in osteosarcoma and Ewing sarcoma xenografts, both of which expressed GD2 ( 176 ). Moreover, the expansion and immunosuppressive effects of MDSCs in the sarcoma microenvironment was responsible for the lack of therapeutic effect of the CAR T cells ( 176 ).

Tumor cells can evade GD2 CAR T cells. Upon encountering GD2-targeted CAR T cells, osteosarcoma cells upregulated PD-L1 to induce exhaustion and apoptosis of the CAR T cells ( 227 ). Systemic administration of GD2 CAR T cells in orthotopic DIPG xenografts resulted in a durable reduction in tumor burden and improved survival; however, a small subset of xenografted tumor cells lost antigen expression ( 228 ). Retinoblastoma cells that were initially responsive to GD2 CAR T-cell therapy escaped killing by downregulating GD2 expression and increasing the expression of PD-L1 and PD-1 on the surface of tumor cells and CAR T cells, respectively ( 229, 230 ). Sequential exposure of retinoblastoma cells to CAR T cells against different targets (GD2 and CD171) enhanced tumor cell killing in vivo ( 230 ).

In phase I studies of patients with relapsed/refractory neuroblastoma, lymphodepletion prior to infusion of GD2 CAR T-cells was deemed safe ( 231, 232 ). In one study, despite demonstrated evidence of transient tumor regression in 25% of patients, the investigators did not observe an objective clinical response ( 232 ). The second study showed a significant CAR T-cell expansion in the patients who received prior lymphodepleting therapy versus those who did not and that inhibition of PD1 did not improve the performance of the CAR T cells ( 231 ). This study also observed an expansion of CD11b + CD163 + myeloid cells after GD2 CAR T-cell infusion. Although the results are promising, comprehensive investigations of the tumor-specific microenvironments need to be performed in order to better understand the complexities of immune escape and optimize immunotherapeutic interventions.

NY-ESO-1 engineered T-cell receptors

NY-ESO-1 is a cancer testes antigen expressed in the majority of synovial sarcoma tumors and a subset of malignant peripheral nerve sheath tumors ( 233, 234 ). Synovial sarcoma patients treated with autologous T cells expressing an NY-ESO-1 engineered T-cell receptor (NY-ESO-1 c259 T cells) resulted in an overall response rate of 50% ( 235 ). After infusion, NY-ESO-1 c259 T cells generated a memory T-cell response, did not exhibit signs of T-cell exhaustion, were clonally expanded, and persisted in vivo . A second study revealed that increased expression of NY-ESO-1 was likely associated with more robust and durable therapeutic responses ( 236 ). These studies provide a degree of optimism for a difficult-to-manage adolescent/young adult tumor.

Despite some successes, immunotherapy for pediatric cancer patients is still in the early phase of development. To realize the full potential of immunotherapy to provide efficacious and durable responses for pediatric patients, especially those with CNS and solid tumors, a better understanding of the interaction between the tumor, the microenvironment, and the immune cells will be required to move this field forward. To address this, the Cancer Moonshot has created the Pediatric Immunotherapy Discovery and Development Network and the Cancer Immunotherapy Trials Network. The goal of these networks is to collaboratively advance the field of pediatric cancer immunotherapy by characterizing new targets, generating suitable experimental models for preclinical evaluation, and better understand pediatric tumor immunology.

The last 5 years have witnessed significant advances in our understanding of the genetic and epigenetic underpinning of pediatric cancers as well as the treatments of some pediatric tumors. At the genetic level, it is clear that many genetic changes identified are distinct from adult cancers and will require unique interventions ( Fig. 2 ). Furthermore, it is also clear that pediatric tumors appear to have a high degree of epigenetic changes that lead to widespread alterations in gene expression secondary to these changes. This, in turn may, ultimately lead to novel therapeutic approaches in the future. Germline genetic variations associated with predisposition to cancer appear to occur at a higher frequency in pediatric patients with cancer compared with adult cancer patients, and these findings may ultimately allow both earlier intervention in identified high-risk children and hopefully prevention in the future. Finally, adoptive immunotherapy, particularly CAR T cells, has had a major impact on the treatment of childhood ALL, but immune-checkpoint inhibitors have to date been of minimal use in pediatric tumors. Ongoing work identifying the impact of the tumor microenvironment on trafficking of immune cells necessary for immune checkpoint inhibition activity may help improve the effect of these agents in the future.

L.J. Helman reports AbbVie-CRADA ending 2019 for work on osteosarcoma models, is a OncoHeros Biosciences-compensated advisor, and is on the Medically Home-compensated advisory board. No disclosures were reported by the other author.

The authors are indebted to the patients and their families who have participated in the various studies, without which progress would not have been made. They are both grateful and thankful to our scientific and clinical colleagues around the world who have dedicated their careers to investigating pediatric malignancies. Given the numerous recent developments and achievements in pediatric cancer research, the authors regret that they were not able to encompass all these studies into this review. Nonetheless, your collective accomplishments and efforts are noted and appreciated. T.A. McEachron is supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The views and opinions contained within this article do not necessarily reflect those of the NIH or the US Department of Health and Human Services. The mention of trade names and/or commercialized products does not indicate endorsement by the US government.

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Childhood cancer survivors' and their parents' experiences with participation in a physical and social intervention during cancer treatment: A RESPECT study

Natasha nybro petersen.

1 Department of Pediatrics and Adolescent Medicine, University Hospital (Rigshospitalet), Copenhagen Denmark

Hanne Bækgaard Larsen

2 Faculty of Health Sciences, University of Copenhagen and The Pediatric Clinic, Juliane Marie Centre, University Hospital (Rigshospitalet), Copenhagen Denmark

Anna Pouplier

Peter schmidt‐andersen, troels thorsteinsson, kjeld schmiegelow, martin kaj fridh, associated data.

Research data is not shared.

This study explores experiences of childhood cancer survivors and their parents with a combined physical and social activity intervention during treatment, including how the survivors and their parents perceive physical activity post‐treatment.

A process evaluation using semi‐structured interviews.

Using a criterion‐sampling strategy, 18 Danish childhood cancer survivors (aged 11–18 years) and their parents were interviewed from September 2019 through May 2020. Data analysis used an inductive thematic approach focused on meaning.

Three themes emerged: (1) being physically active during hospitalization; (2) peers as motivators and (3) physical activity post‐treatment. During hospitalization, daily motivation to do physical activity was dependent on the daily well‐being, that is, presence of the side effects from the child's treatment. Healthy classmates provided distraction, reduced loneliness and promoted normality for those hospitalized. For most of the survivors, their healthy peers provided motivation for being physically active during treatment. When surplus energy was lacking, some survivors preferred doing physical activity alone with a professional. Those who were physically active in the hospital sustained being physically active post‐treatment while their parents continued seeking advice about appropriate activity levels.

Childhood cancer survivors and their parents benefited from the intervention which also provided guidance to remaining physically active post‐treatment. This was particularly true for the participants with leukaemia.

Healthcare professionals should support children with cancer to be physically active during hospitalization. Including social and physical components in their care plan and being aware of individual preferences is pivotal to improving the survivors' level of physical and social well‐being during and post‐treatment.

Patient or Public Contribution

The participants were involved in designing the interview guides to ensure that the interview guides were understandable for the participants to provide rich descriptions of their experiences with a physical and social activity intervention during hospitalization.

1. INTRODUCTION

The treatment for childhood cancer is often intense and can cause muscle strength loss, impaired physical function and behavioural problems (Braam et al.,  2016 ; Ness et al.,  2015 ; Nielsen et al.,  2020 ). Moreover, the treatment often requires long and recurring hospitalizations resulting in prolonged absences from school and a dramatic reduction in peer interactions (Helms et al.,  2016 ; Warner et al.,  2016 ). The combination of being physically impaired, school absence and lacking peer interactions can negatively impact quality of life for the child with cancer (Germain et al.,  2019 ). Identifying potential facilitators and barriers for physical activity during cancer treatment is pivotal to countering physical inactivity post‐treatment (Grimshaw et al.,  2020 ; Thorsteinsson et al.,  2017 ). According to the Medical Research Council's (MRC) guidance for complex interventions, process evaluation can be useful when investigating how the intended audience is impacted by the intervention (Moore et al.,  2015 ). In this study, process evaluation was conducted after the childhood cancer survivors had participated in the intervention to understand how they perceived and experienced the intervention.

1.1. Background

Refined treatment for childhood cancer has positively impacted the 5‐year cancer survival rates (Armstrong et al.,  2014 ). As survival rates improve, however, minimizing treatment late effects comes to the forefront of promoting long‐term health and development for these survivors (Barrett et al.,  2020 ; Schmiegelow & Frandsen,  2018 ). Regular physical activity is beneficial for children with cancer both physically and socially as it can ward off treatment‐related fatigue and depression by stimulating endorphins (Speyer et al.,  2010 ).

Research has shown that parents and peers are pivotal motivators for children and adolescents to undertake physical activity as they can offer emotional support and establish routines during cancer treatment (Thorsteinsson et al.,  2019 ; Zecevic et al.,  2010 ). However, various barriers to physical activity in childhood cancer exist. Parents of these survivors point to the following contributing barriers during treatment: treatment side effects, restricted movement, loss of independence, isolation and low motivation (Grimshaw et al.,  2020 ). Cancer treatment is often also described as stressful for both the child and his/her parents due to feeling overwhelmed by the cancer diagnosis, having to keep abreast of various medical appointments, and not least focusing on recovery (Beeler et al.,  2021 ; Götte et al.,  2014 ). All this may not allow parents to prioritize physical activity during treatment. The parents themselves can also be considered as potential barriers; for example, when they dismiss the importance of physical activity rehabilitation or when they fail to motivate their child to be physically active post‐treatment (Cheung et al.,  2021 ; Wakefield et al.,  2011 ). Parents may also be unaware of the importance of being physically active as a childhood cancer survivor (Cheung et al.,  2021 ; Mizrahi et al.,  2020 ). Earlier studies report that the combination of cancer treatment and reduced peer interaction during treatment affect the cancer survivors' ability and desire to be physically active and ultimately lowers the child's health‐related quality of life post‐treatment (Ness et al.,  2009 ; Vannatta et al.,  2007 ). Thus, to target and ameliorate their impaired physical, social and academic functioning, a multimodal intervention was designed for implementation during the children's cancer treatment. The intervention included in‐hospital supervised physical activity combined with co‐admission days by healthy classmates as the link between the hospital and the child's school peer group (Nielsen et al.,  2020 ; Thorsteinsson et al.,  2013 ).

2. THE STUDY

This study explores experiences of childhood cancer survivors and their parents with a physical and social activity intervention during cancer treatment, including how the survivors and their parents perceive physical activity post‐treatment.

2.2. Design

We designed a qualitative descriptive study using in‐depth semi‐structured interviews. Qualitative description research offers the opportunity to gather direct rich descriptions of the phenomena of interest from the people involved (Bradshaw et al.,  2017 ). In health care research, this methodology is often used to learn from the descriptions gained from the participants. The knowledge gained from the participants' descriptions can be used to influence interventions (Sullivan‐Bolyai et al.,  2005 ). The qualitative descriptive design offered detailed descriptions of the intervention during cancer treatment from the involved participants. The knowledge gained from the participants' descriptions can be used to design future physical and social activity interventions.

2.3. Setting

The study is embedded in the REhabilitation including Social and Physical Activity and Education in Children and Teenagers with Cancer (RESPECT) Study. RESPECT is a Danish nationwide, controlled rehabilitation study initiated in 2013, that includes children with cancer aged 6–18 years. Its purpose is to examine the academic, social and physical rehabilitation of children with cancer throughout the treatment trajectory and is embedded in the work structure of the Center for Integrated Rehabilitation of Cancer Patients (CIRE) programme (Adamsen et al.,  2020 ).

2.4. Intervention components

The intervention included three components; (1) an educational session on cancer and cancer treatment; (2) visits by classmates (“ambassadors”) during hospitalization and (3) supervised in‐hospital physical activity. A full description of the components is available in previous articles from the RESPECT study (Lindgren et al.,  2017 ; Nielsen et al.,  2020 ; Thorsteinsson et al.,  2013 ). The intensity of the programme has been published elsewhere (Thorsteinsson et al.,  2017 ).

When feasible, the child with cancer participated in a supervised in‐hospital physical activity intervention (the RESPECT physical activity programme) (Nielsen et al.,  2020 ). This programme consisted of various tailored physical activities, that is, game‐based activity, walking, running, endurance and strength building. The individual sessions were 5–30 min whereas the group sessions were 30–120 min. The group sessions included all admitted children and their ambassadors. Physical activity sessions were held either in the child's hospital room or at a nearby gym (Nielsen et al.,  2020 ). The sessions were led by two exercise professionals associated with the RESPECT Study. Each session was designed to consider the child's daily well‐being status (i.e. presence of nausea, pain, dizziness or other treatment side effects) and physical capability and as such the intensity of the sessions was individualized. See Table  1 for RESPECT activity programme details.

The in‐hospital RESPECT activity programme. From Nielsen et al. ( 2020 )

2.5. Sample/participants

A criterion‐based sampling strategy was used to select participants from the RESPECT cohort ( n  = 120). Participants were sampled in dyads (survivors with their parents) and as such selection was based on the dyads that matched the inclusion criteria. If matches were identified, parents of the matched children were contacted by the project nurse either by mail or telephone. Participants were found eligible if the cancer survivor: (1) was between the age of 9–18 years at the time of the interview; (2) was at least 1‐year post‐treatment and (3) had been enrolled in the RESPECT Study's intervention group during treatment. Exclusion criteria were the inability to speak Danish, presence of cognitive dysfunction or mental retardation. As we wanted to gain insight into the participants' descriptions of their participation in the RESPECT physical activity intervention, a conscious attempt was made to include childhood cancer survivors who had required long treatment episodes as they would have had more exposure to the physical and social impacts of treatment. The childhood cancer survivors included in the study were diagnosed with: tumours located in the central nervous system ( n  = 1); leukaemia ( n  = 11); extracranial solid tumour ( n  = 3); Hodgkin's lymphoma ( n  = 1) and non‐Hodgkin's lymphoma ( n  = 2). See Table  2 for participant characteristics. Twenty childhood cancer survivors were asked to participate in the interviews. As the sampling was done in dyads, two childhood cancer survivors declined as their parents' unwillingness to participate in the study. In total, 18 childhood cancer survivors (8 females; 10 males) aged 11–18 years (mean = 14) and 19 parents (14 mothers; 5 fathers) participated in the study. In one parent interview, two parents participated. In total, 36 interviews were conducted. All survivors participating in this study had been enrolled in the RESPECT physical activity programme during treatment. The recruitment process is described in Figure  1 .

Recruitment process

Participant demographics

Note : Age is presented in median and (range). Length of treatment is presented in (range). Years after ended treatment, in‐hospital stays, training sessions and ambassador co‐admissions are presented in median and (range).

2.6. Data collection

This study does not include data from the experiences of the classroom educational sessions on cancer as this aspect has been highlighted in earlier articles from the RESPECT Study (Ingersgaard et al.,  2021 ; Lindgren et al.,  2017 ; Thorsteinsson et al.,  2013 ). Rather, the current study focuses on the physical and social aspects of RESPECT.

Two semi‐structured interview guides were developed, that is, one for the childhood cancer survivors and another for the parents. The interview guides were designed to elicit participant experiences on the following themes: (1) overall perception of RESPECT; (2) physical activity a component of the hospitalization care plan; (3) physical activity in general; (4) knowledge gained from the intervention programme and (5) physical activity post‐treatment. Open‐ended questions were raised to encourage participants to reflect on their experiences (Bradshaw et al.,  2017 ). The interviewer (NNP) had not previously been involved with the RESPECT Study, thus ensuring that participants were able to express themselves freely. Participants were interviewed individually in person, once from September 2019 through May 2020. The childhood cancer survivors were interviewed separately from their parents. Interviewers were conducted: in the participant's home ( n  = 26) or in a private room at the hospital ( n  = 10), depending on the participant's preference. The duration of the interviews ranged from 13 to 65 min (mean: 32 min) and were audio‐recorded and transcribed ad verbatim.

2.7. Ethical considerations

The Regional Ethics Committee for the Capital Region (file. 3‐2012‐105) and the Danish Data Protection Agency (file. 2007‐58‐0015/nr.30‐0734) approved the RESPECT Study. RESPECT is registered at ClinicalTrials.gov (files: NCT01772849 and NCT01772862) and complies with the Helsinki II Declaration norms and subsequent amendments. Parents of children under the age of 16 gave verbal and written consent as did the adolescents aged 16 years and above. All participants were informed of their right to withdraw from the study at any time.

2.8. Data analysis

The transcripts were analysed and discussed by first authors NNP and HBL. An inductive thematic analysis focusing on meaning was used (Clarke et al.,  2015 ).

The data were organized and coded using NVivo 12 coding software. The thematic analysis included the following steps: (1) the transcripts were read repeatedly until NNP gained an in‐depth understanding of the content; (2) all transcripts data were initially coded and later assigned meaning units agreed upon between the first authors NNP and HBL; (3) the meaning units were then analysed and reassembled into themes; (4) the themes were reviewed to ensure that all the coded data was included, after which the themes were examined in relation to the entire dataset to ensure that the analysis represented the entire body of data and (5) the themes and names were finalized and all authors agreed on their ultimate selection. The authors experienced minor disagreements about wordings and how findings should be presented. However, these were resolved through compromise and agreement of highest credibility selections.

2.9. Rigour

To ensure trustworthiness of this study, we used Bradshaw et al. and their demonstration of four principles for trustworthiness in qualitative descriptive research (Bradshaw et al.,  2017 ). Their four principles stemmed from Lincoln and Guba's four principles (credibility; dependability; confirmability; and transferability) for trustworthiness in qualitative research (Lincoln & Guba,  1986 ). To ensure transferability, we purposefully sampled participants with mixed sex, varying ages of the survivors, and included their parents. Furthermore, sampling was done following in‐hospital‐based treatment days. All contributed to rich descriptions of the intervention. To strengthen the data credibility, we used an independent interviewer and semi‐structured interviews with open‐ended questions to offer the opportunity for participants to elaborate on issues vital to them within and beyond the pre‐determined themes. To ensure the confirmability of this study, the interviews were audio‐recorded and description of demographics of the participants were provided (Table  2 ). A native‐speaking medical writer compared the English version with the Danish version to ensure translation accuracy and that all concepts were captured correctly and were accurately interpreted across languages. All authors approved all translations.

3. FINDINGS

The study participants included 18 childhood cancer survivors (n = 56% males) aged 11–18 years (age median = 14) and their parents ( n  = 19). The survivors had completed their treatment between 1 and 5 years prior to being interviewed. Inductive analysis of the dyads' (survivors and their parents) experiences resulted in following themes: (1) being physically active during hospitalization; (2) peers as motivators and (3) physical activity post‐treatment. The themes captured insights into how the dyads experienced the RESPECT Study's physical activity programme and perceived physical activity post‐treatment.

3.1. Being physically active during hospitalization

Overall, the hospital‐based physical activity programme was found to be favourable to both the children and parents, who described it as a positive learning experience, a huge support during treatment and motivational for engaging in further physical activity during and post‐treatment. Most of the survivors ( n  = 15) stated that they had participated in the physical activity sessions whenever they were not significantly affected by treatment side effects. Some survivors ( n  = 4) found the sessions challenging and exhausting due to the treatment's impact on their body, that is, breathlessness when walking the hallway, feeling fatigued or nauseous.

In contrast, five survivors informed that they could have done more physical activity and that the sessions were not challenging enough. Although all the survivors ( n  = 18) had participated in the sessions during their hospitalization, three of them could only vaguely recall being physically active. These three survivors remembered walking the hallways or from their bed to their hospital room door, but they did not associate that with being physically active. The survivors agreed, however, that the sessions were a good diversion while in the hospital. One girl explained:

It [physical activity] was hard but it was very nice to get up and move around because, otherwise, you didn't get much of a chance (Female, aged 13 years)

Although most of the survivors ( n  = 16) and their parents ( n  = 16) had an overall positive view of the RESPECT physical activity programme, few of the survivors ( n  = 2) and their parents ( n  = 2) reported negative experiences. Three survivors described intermittently feeling too ill to participate, which proved demotivating for them. One boy explained:

I was in bad shape. I was sick even before he [the physical activity professional] came to ask me to participate, and I know that I'd be more ill if I went with him. So, there was no real bonus in it for me to go. (Male, aged 13 years)

From the parents' perspective, the RESPECT physical activity programme could have offered more individual sessions. As one mother explained:

I would have liked to have seen more individual training for him while we were there [in hospital]. Perhaps also because he [the child] became more withdrawn whenever other kid participated. (Mother to 16 years‐old male)

Few survivors ( n  = 3) described not wanting to participate in group sessions as they lacked the surplus energy. They would have preferred using the physical activity professionals as personal trainers at those times. Their parents ( n  = 3) felt that the professionals did not motivate their child enough during the sessions, which resulted in the child not fully benefiting from the programme. As one mother explained:

I think they [the physical activity professionals] could have pushed her more. They didn't need to leave it up to them [the children] to [decide to] participate. They could have just told her it was a part of being in RESPECT.” (Mother to 12‐year‐old female)

The parents ( n  = 3) were unsure whether their child's participation in the intervention had any impact on their child being physically active during treatment or during the first‐year post‐treatment. However, most of the survivors ( n  = 14) explained that they continued be physically active afterwards. Some survivors ( n  = 4) did not resume the same physical activities as prior to their diagnosis but instead found new ones, that is, horseback riding, badminton and swimming. Most of the survivors ( n  = 15) and their parents ( n  = 15) experienced that the survivors were unafraid of being physically active post‐treatment. The parents ( n  = 15) described the survivors as having developed a different perspective of physical activity because they were physically active during treatment.

3.2. Peers as motivators

Most of survivors ( n  = 16) and their parents ( n  = 16) agreed that using classmates as ambassadors offered emotional support during hospitalization. Ambassador actions during visits included combatting the child's feelings of isolation from school and their social networks as well as deviating their focus away from the cancer experience and towards a sense of normality. Most of the survivors ( n  = 15) were more motivated to get out of bed during ambassador visits. As one boy explained:

I liked it. Having your friends visit and staying in touch with your class. But it was more the fact that it was an escape from just being in the hospital. And the part about working outs was also nice because you could do it with those you knew. (Male, aged 18 years)

The dyads ( n  = 31) agreed that physical and social activities tended to merge as the ambassadors, who provided a social dimension, also participated in the physical activity sessions alongside the survivors. As one mother described:

[…] his ambassadors did the same exercises as he did, and he could see that he was lagging a bit behind them […], that they always did a bit more than he could. He was eager to come in first place every time, so he pushed himself to do the same exercises as they did. (Mother to 14‐year‐old male)

However, two survivors declined having ambassadors as their treatment occurred during the summer school break. Although the survivors ( n  = 15) and their parents ( n  = 16) agreed that the ambassadors were motivators for survivors' participation in the sessions, some survivors ( n  = 5) recalled a disparity between the two groups. As one girl explained:

They could do more stuff than me, and that was kind of annoying because they were better than me. But at the same time, it was nice not to have to do it alone (Female, aged 13 years)

Despite the differences between them and the ambassadors, most of the survivors ( n  = 15) experienced the sessions to be more fun when their classmates were there rather than having to do the sessions alone with the professionals. For some of the survivors ( n  = 8), these ambassadorships led to deeper friendships post‐treatment.

The survivors ( n  = 8) who remained connected with their ambassadors found that the latter continued to support them post‐treatment. One girl explained:

I appreciated them [the ambassador visits] very much. It's easier to speak with those who were there during my treatment than with friends I've known since I was ten years old. They understand things differently […]. They know what it's like to be sick and not be able to talk with your parents about not having hair or having a bloated face […] Those things that other people just don't get (Female, aged 17 years)

A few of the survivors ( n  = 3) lost contact with their ambassadors as they had to repeat a school year or change schools altogether. However, these survivors found new friends with whom they could exercise. Most survivors ( n  = 16) noticed that they did not lag far behind their healthy peers during physical activities post‐treatment.

3.3. Physical activity post‐treatment

The survivors ( n  = 18) and their parents ( n  = 19) were taught the importance of physical activity during the programme and how cancer and its treatment can impact the child's physical function. Most parents ( n  = 17) expressed an understanding of this importance and several of the parents stated that their child also benefited from receiving guidance from the professionals. As one father explained:

I really do think it [RESPECT] helped him. It made him more aware of how important it is to stay physically active. (Father to 13‐year‐old male)

Many parents ( n  = 15) felt supported during the treatment because the physical activity professionals guided them in their role as part‐time trainers, motivators and caregivers. This guidance provided parents with the tools needed to fulfil the expectation placed on them. As one mother explained:

I asked the physical activity professionals what she was capable of doing if he thought she could do this or the other. He told me that there were no limitations and that we should let her go as far as she felt she could. We kept using that physical activity professional [for guidance] even after we came home (Mother to 11‐year‐old female)

The dyads ( n  = 31) agreed that the survivors who were active during treatment experienced an easier transition post‐treatment. However, the view of the survivors differed from that of their parents about the motivation for being physically active post‐treatment. Some parents ( n  = 6) felt that their personal support to their child was the motivation. As one mother explained:

I think it's very demanding on parents. Being active can mean a lot of things. If parents don't feel like doing it then it doesn't amount to anything. In fact, it's up to the parents to figure out what triggers their child. Because if it interests them [the children] then it's easier to motivate them. (Mother to 11‐year‐old female)

In contrast with their parents, most of the survivors ( n  = 16) looked to peers for support in being physically active and doing physical activities with peers positively impacted their physical and emotional well‐being. As one girl explained:

I think you need to find something you're interested in. That'll quickly motivate you to keep going and you also find friends who are interested in the same things. I just think it's important to get back to it [physical activity] right away because it does something for your body (Female, aged 17 years)

The dyads' understanding of the importance of physical activity continued post‐treatment. Most parents ( n  = 14) felt that they succeeded in motivating their children to be physically active, but some parents ( n  = 5) felt that more guidance on structuring physical or school activities would have been useful to ease the transition post‐treatment.

4. DISCUSSION

Semi‐structured interviews were used to explore experiences of young cancer survivors (aged 11–18 years) and their parents with a combined physical and social activity intervention during cancer treatment; including the programme's impact on the survivors' ability to be physically active post‐treatment. This study showed that a physical activity programme during treatment can enhance the survivors' and their parents' (dyads) views of how important physical activity can be during rehabilitation. Additionally, the knowledge they gained from the intervention proved useful to them post‐treatment.

In this study, the survivors had different physical activity needs during treatment. For example, some survivors found the sessions to be challenging while other survivors did not. This suggests that it is important to consider individual needs when promoting physical activity during hospitalization. When children with cancer participate in physical activity during treatment, they are susceptible to side effects (Nielsen et al.,  2018 ). In the present study, survivors who experienced treatment side effects preferred doing sessions only with professionals. Some survivors found the presence of other children in the sessions to be generally demotivating. These findings suggest that while physical activity during hospitalization is feasible, professionals should adjust sessions to meet individual preferences. This finding is further supported by Lam et al. ( 2020 ) and shows that using a physical activity coach during treatment can increase the children with cancer's knowledge and confidence in doing physical activity.

Our findings show that most of the survivors found ambassador participation in the sessions to be motivating and as such ambassador support did reinforce survivor participation. This finding confirms previous research proposing that children and adolescents diagnosed with cancer are most likely to be motivated to engage in physical activity if they participate with their peers or receive positive feedback about their ability to be physically active (Mizrahi et al.,  2020 ). Similar findings from the RESPECT study show that being physically active in a social context, for example, with ambassadors was motivating (Thorsteinsson et al.,  2019 ). Our findings show that the social aspect of being physically active continued to motivate the survivors post‐treatment. This finding builds on previous research showing that adolescents with good peer support tend to participate in physical activity more than those who do not (Heitzler,  2010 ; Strauss et al.,  2001 ). Earlier findings from the RESPECT Study suggest that a mutual understanding between survivors and their healthy peers can be developed if interventions include healthy peers during the child with cancer's rehabilitation (Ingersgaard et al.,  2021 ). The present study also supports the recommendation that professionals working with children with cancer during hospitalization should facilitate contact between the child and their peers.

Research shows that children with cancer and their parents tend to believe that physical activity during treatment induces or worsens side effects, for example, fatigue (Cheung et al.,  2021 ; Lam et al.,  2017 ). A central finding of this study is that witnessing their child receiving professional guidance and observation during physical activities resulted in the parents developing a positive attitude towards physical activity and encouraging their child to be active post‐treatment. As such, the present study underscores the importance of professional guidance as a tool for challenging misconceptions about physical activity during cancer treatment. Previous research shows that parents with a positive attitude towards physical activity have a greater chance of motivating their children to engage regularly in physical activity (Brockman et al.,  2009 ; Zecevic et al.,  2010 ).

Our findings show that parents felt responsible for motivating their child to be physically active post‐treatment. Similar findings reported that childhood cancer survivors may be more influenced by parents to do physical activities than by their healthy peers, due to developmental disruption caused by having a cancer diagnosis and being hospitalized (Gilliam & Schwebel,  2013 ). In contrast, the present study shows that survivors consider their peers and their own understanding of the importance of physical activity to be the main motivators post‐treatment. These findings support Yao and Rhodes ( 2015 ) suggestion that when childhood cancer survivors go through puberty, modelling behaviours of peers over those of their parents motivates them more to doing physical activity. Healthcare professionals can benefit from this study's findings to better understand dyadic experiences with physical activity during and post‐treatment. Furthermore, healthcare professionals should motivate the child with cancer to be physically active during treatment by including peers and parents in sessions. As treatment is dynamic and the child with cancer's needs vary throughout the process, healthcare professionals should use an explorative approach when motivating the child with cancer. To ensure the possibility of being physically active, healthcare professionals should include physical activities within the care plan. Post‐treatment, healthcare professionals should be encouraged to explore facilitators and barriers to survivors doing physical activity and provide them with the necessary support.

4.1. Strength and limitations

In the RESPECT Study, authors MKF and TT assumed the role of physical activity professionals and worked with the survivors during their treatment. This is considered a potential bias as they may have assumed a more positive outlook when writing this article. However, to accommodate this potential bias and to strengthen this study's credibility, an independent interviewer was included, and the authors (MKF and TT) were excluded from any data analysis. An additional strength was the fact that the interviews were conducted in person. The face‐to‐face interaction helped the interviewer to establish a relationship with the participants, thus facilitating the discussion of sensitive topics. Our attempt to include childhood cancer survivors with long treatment episodes were successful which resulted in comprising mainly former leukaemia patients (61%). This is considered a limitation, as the study findings may not be representative of the overall diversity of childhood cancer. Furthermore, there may be differences in diagnoses and treatments and their impact on survivors' ability to be physically active post‐treatment. This aspect was not explored in this study.

Another limitation is that the parents' recall may have been influenced by the survivors' current physical and social activity level and as such may have affected their responses at the time of the interviews, for example, being selective by offering statements confined to things that impressed them most. The importance of physical activity is a widely accepted norm in the daily lives of children and adolescents in Denmark. Accordingly, the parents may have expressed their desire to promote physical activity in their daily lives because the interviewer may view this attitude as favourable. Consequently, this may have affected the trustworthiness of the study.

The study findings may be transferable to other paediatric oncology settings as the knowledge about professional guidance and the importance of peer support during and post‐treatment may be used across disease groups and cultures. We acknowledge that other frameworks may have been useful tools to discover other important dimensions of the participants' experiences. Future studies that focus on exercise may find these frameworks useful when conducting qualitative research.

5. CONCLUSION

Childhood cancer survivors and their parents benefited from participating in an intervention where physical and social activities were combined. The study findings indicate that the dyads understood the importance of being physically active during hospitalization and their appreciation of it continued post‐treatment. Physical activity support varied according to the daily health status of the survivors during treatment.

The importance of including peers in physical activities with survivors should not be underestimated, however, sensitivity of individual preferences should be considered. Differentiating between ages, needs and motivation would be valuable when designing future physical activity interventions during treatment for children with cancer.

AUTHOR CONTRIBUTIONS

All authors have agreed on the final version and made substantial contributions to the design of this study and the interpretation of data. Furthermore, all authors have revised the article critically to ensure intellectual content.

FUNDING INFORMATION

The Danish Childhood Cancer Foundation, The Danish Cancer Society; The Novo Nordisk Foundation; Lundbeck Foundation; Toyota Foundation; Familien Hede Nielsens Foundation; ML Jørgensen and Gunnar Hansens Foundation; Arvid Nilssons Foundation; Aase og Ejnar.

CONFLICT OF INTEREST

No conflict of interest has been declared by the authors.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1111/jan.15381 .

Supporting information

Appendix S1

ACKNOWLEDGEMENT

This work is part of Childhood Oncology Network Targeting Research, Organization & Life expectancy (CONTROL) and supported by Danish Cancer Society (R‐257‐A14720) and the Danish Childhood Cancer Foundation (2019‐5934).

Petersen, N. N. , Larsen, H. B. , Pouplier, A. , Schmidt‐Andersen, P. , Thorsteinsson, T. , Schmiegelow, K. , & Fridh, M. K. (2022). Childhood cancer survivors' and their parents' experiences with participation in a physical and social intervention during cancer treatment: A RESPECT study . Journal of Advanced Nursing , 78 (11), 3806–3816. 10.1111/jan.15381 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Natasha Nybro Petersen and Hanne Bækgaard Larsen shared first authorship.

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Research on Childhood Cancers

In 2013, Phineas Sandi received CAR T-cell therapy for acute lymphoblastic leukemia while participating in an NCI clinical trial. Phineas, holding the syringe that was used to infuse his CAR T cells, is cancer-free.

Why Research is Critical to Progress against Childhood Cancer

Cancer is the leading cause of death from disease among children in the United States. Although substantial progress has been made in the treatment of several types of childhood cancer over the past five decades, progress against other types has been limited. Even when long-term survival is achieved, many survivors of childhood cancer may experience long-term  adverse effects from the disease or its treatment.

Clearly, more research is needed to develop new, more-effective, and safer treatments for childhood cancer. And infrastructure and practices that allow researchers to learn from every child with cancer need to be put in place.

NCI has a number of programs that address childhood cancers specifically, and many of the institute’s other research programs are applicable to children with cancer even if they aren’t focused specifically on pediatric cancers. The institute supports a broad range of biomedical research that is relevant to this population, including:

• Basic research to enhance our understanding of the fundamental mechanisms of cancer
• Clinical research to test new treatments for safety and effectiveness
• Survivorship research to reduce the long-term adverse effects of cancer and its treatment

Dr. Brigitte Widemann Appointed as the Special Advisor to the NCI Director for Childhood Cancer

Brigitte Widemann, MD, Chief of the NCI Center for Cancer Research Pediatric Oncology Branch and practicing pediatric oncologist, has been appointed as Special Advisor to the NCI Director for Childhood Cancer.

Challenges in Childhood Cancer Research

One challenge in conducting research on childhood cancer is that cancers in children and adolescents are relatively uncommon. Childhood cancers represent less than 1% of all new cases of cancer diagnosed in the United States each year. Because the number of children with cancer is small and patients are treated at many different institutions, answering complex biological questions about childhood cancer requires collaboration.

As clinical trials are increasingly restricted to smaller numbers of patients who are defined by the molecular characteristics of their tumors rather than where the tumors originated in the body, collaboration among children’s cancer centers and a strong national clinical research program are essential to ensure that trials enroll sufficient numbers of participants to produce meaningful results.

In addition, more efficient ways to curate and share research knowledge—from genomic data to clinical outcomes—need to be developed to speed progress against childhood cancers.

NCI’s Rare Cancer Clinics Fostering Collaboration

Clinics bring together clinicians, patients, and advocates.

Another challenge is that, although most cancers in children (and adults) are thought to develop as a result of genetic changes that lead to uncontrolled cell growth and eventually cancer, the causes of most of these genetic changes in children are unknown. A small percentage of cancers in children can be linked to inherited genetic changes or to exposure to diagnostic or therapeutic radiation. But environmental causes have not been identified for most childhood cancers. As a result, identifying opportunities to prevent childhood cancer may be difficult.

In addition, the types of cancers children develop, and the biology of those cancers, generally differ from those of cancers diagnosed in adults. For example, tumors that originate in developing organs and tissues (such as retinoblastomas in the eye and osteosarcomas in bone) are more common in children.

Moreover, most childhood cancers have relatively few genetic alterations , and they often lack the genetic targets for treatments that have been developed and approved for cancers occurring in adults. And drugs that target signaling pathways that are active in some adult cancers might be difficult to use in children, given that many of these signaling pathways are essential for normal development.

Investigating Fusion Proteins in Childhood Cancers

The work of NCI’s FusOnc2 Consortium may one day lead to new treatments for children with cancer.

In fact, the genetic changes that drive childhood cancers are often distinct from those in adult cancers. For example, chromosomal translocations that fuse parts of different genes together to form fusion oncoproteins are common in childhood cancer. Although fusion oncoproteins are also found in some adult cancers, those found in children have proven particularly difficult to target. Another contributing factor to the small number of targeted therapies for childhood cancers is that the rarity of these diseases has been an impediment to commercial drug development.

Developing new treatments that are less toxic and cause fewer adverse effects (both acute and late) than current treatments and developing interventions to mitigate the adverse effects of both current and future treatments are additional challenges in childhood cancer research. The late effects of some childhood cancer therapies can have profound physical, emotional, and other consequences for survivors, including a shortened life expectancy. Finding ways to minimize and address these late effects to improve both the quality and the length of life of survivors is a research priority.

More information about cancer drug metabolism in children, which varies with developmental age, is also needed, as are better laboratory and animal models for screening and testing drugs for potential use in children and adolescents. The optimal use of radiation therapy in treating childhood cancers also needs to be defined so that efficacy is maintained or increased while long-term side effects are reduced.

Basic Research Drives Progress against Childhood Cancer

Virtually all progress against cancer in both children and adults has its origins in basic research, often in areas that are not directly related to the disease.

As an example, the discovery of CRISPR-Cas9 for gene editing has revolutionized the study of genes that control cancer cell growth and survival in both childhood and adult cancers. This discovery came from basic research in microbiology on how bacteria resist infections by viruses.

Another example had its origins in basic research on proteins called histones , which are DNA-binding proteins that provide structural support for chromosomes and help control the activity of genes. Scientists spent years investigating how these proteins are modified in the cell nucleus and the role of histone modifications in controlling when and to what extent genes are expressed.

The findings of this research became immediately relevant to a type of pediatric brain tumor called diffuse intrinsic pontine glioma (DIPG)  when it was discovered that most DIPG tumors have a mutation in the gene for the histone protein H3.3 that prevents a specific modification of the protein. This mutation in H3.3 is thought to be a driver mutation for DIPG and is associated with aggressive disease and shorter survival.

Promising Areas of Research on Childhood Cancers

Although our understanding of the biology underlying cancers that occur in children has increased tremendously in the past decade, there are still critical gaps in our knowledge. NCI has identified several areas in which more research is needed and has identified opportunities to use new approaches to gain additional insights into childhood cancers.

Immunotherapies for Childhood Cancers

Immunotherapy Drug Effective in Children with Relapsed Leukemia

In two studies, blinatumomab improved survival and was less toxic than chemotherapy.

Immunotherapies are treatments that restore or enhance the immune system’s ability to fight cancer. The field of cancer immunotherapy research has produced several new methods for treating cancer.

One example is chimeric antigen receptor (CAR) T-cell therapy , which is now used to treat some children with acute lymphoblastic leukemia . This therapeutic approach arose from decades of research on how the immune system works and how to manipulate it for clinical benefit.

The NCI Center for Cancer Research's Pediatric Oncology Branch (POB) conducts clinical trials of immunotherapy in pediatric and young adult patients, and the Children’s Oncology Group (COG) and the Pediatric Brain Tumor Consortium (PBTC) are evaluating immunotherapy treatments for selected childhood cancers. The Cancer Immunotherapy Trials Network (CITN) has a pediatric component that is developing clinical trials to test immunotherapies for children with cancer.

As part of the Cancer Moonshot, NCI has established the  Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium , Pediatric Immunotherapy Discovery and Development Network (PI-DDN) , and Childhood Cancer–Data Integration for Research, Education, Care, and Clinical Trials (CC-DIRECT).

Learn about POB, COG, and the other programs mentioned above in How NCI Programs Are Making a Difference in Childhood Cancer .

Molecularly Targeted Therapies for Childhood Cancers

NCI Research and the National Cancer Plan

The broad variety of research NCI supports on childhood cancers aligns with the goals of the National Cancer Plan. Read about the plan and explore each goal.

Molecularly targeted therapies are drugs or other substances that kill cancer cells by targeting specific molecules that are necessary for cancer cells to grow and survive. These therapies can be small-molecule inhibitors , monoclonal antibodies , or antibody–drug conjugates .

POB conducts clinical trials of targeted therapy in pediatric and young adult patients, and COG and the PBTC are evaluating targeted therapies for selected childhood cancers.

For example, results from an NCI-sponsored clinical trial, conducted by COG and led by Alice Yu, M.D., Ph.D., of the University of California, San Diego, led to the approval of the monoclonal antibody dinutuximab (Unituxin) to treat high-risk neuroblastoma .

Additionally, the PBTC studied the targeted agent selumetinib in children with relapsed or refractory low-grade gliomas . Reductions in tumor size were observed in most patients. Based on these results, COG researchers are studying selumetinib in phase 3 clinical trials for children with newly diagnosed low-grade glioma .

In 2017, NCI and COG launched the NCI–COG Pediatric Molecular Analysis for Therapy Choice (Pediatric MATCH) trial, which is testing molecularly targeted therapies in children with advanced solid tumors that are not responding to treatment. Tumor DNA sequencing is being used to identify those children whose cancers have a genetic abnormality that is targeted by a drug being studied in the trial.

How NCI Programs Are Making a Difference in Childhood Cancer

NCI FY26 Annual Plan & Professional Judgment Budget Proposal

Each year, NCI prepares a plan for advancing cancer research and proposes the budget required to fund a broad research portfolio.

NCI recognizes that children are not just small adults and that specialized treatments tailored to childhood cancers are needed. NCI engages with researchers, clinicians, policymakers, advocates, and other partners to address this critical area of research. NCI supports an array of programs specifically to advance childhood cancer care and has renewed these initiatives and programs over numerous funding periods. Some of these programs include:

• The Pediatric Oncology Branch (POB) in NCI’s Center for Cancer Research conducts high-risk, high-impact basic, translational, and clinical research on childhood cancers. For example, POB investigators helped lead a team of international researchers who analyzed data from many patients with rhabdomyosarcoma , a rare childhood cancer that affects the muscles and other soft tissues, and found mutations in several genes that are associated with a more aggressive form of the disease . Genetic clues from the study could lead to more widespread use of tumor genetic testing to predict how children with this cancer will respond to therapy, as well as to the development of targeted treatments for the disease.
• NCI's Division of Cancer Epidemiology and Genetics (DCEG) conducts clinical, genetic, molecular pathology, and epidemiological studies of children at high risk of cancer. For example, DCEG researchers are leading a genome-wide association study of Ewing sarcoma to better understand the genetic architecture of the disease and to identify regions of the genome that may increase risk. DCEG researchers are also studying osteosarcoma to better understand the role that genetic variation plays in risk and patient outcomes and identify genes or genomic regions that may be important in osteosarcoma . The division also studies familial cancer syndromes, including Li-Fraumeni Syndrome , DICER1 syndrome , NF1 , and inherited bone marrow failure syndromes (IBMFS) , to better understand these disorders and investigate possible genotype/phenotype relationships that will improve clinical management and aid in genetic counseling.
• The T herapeutically Applicable Research to Generate Effective Treatments (TARGET) program uses genomic approaches to catalog the molecular changes in several types of childhood cancer to increase our understanding of their pathogenesis, improve their diagnosis and classification, and identify new candidate molecular targets for better treatments. For example, TARGET researchers performed a pan-cancer study of somatic alterations in nearly 1,700 pediatric leukemias and solid tumors and found major genomic differences when compared with adult cancers. The related Cancer Genome Characterization Initiative (CGCI) includes genomic studies of various pediatric cancers that often do not respond well to treatment.

Tailored Radiation for Kids with Medulloblastoma?

Study suggests the volume and dose could be tailored to the genetics of the patient’s tumors.

• The NCI–COG Molecular Analysis for Therapy Choice (Pediatric MATCH) precision medicine trial is a nationwide trial to explore whether targeted therapies can be effective for children and adolescents with solid tumors that harbor specific genetic mutations and have progressed during or after standard therapy. The trial, which is funded by NCI and conducted by COG, opened to patient enrollment in 2017. Germline testing is performed on all enrolled patients to assess whether the genetic aberrations identified in their tumors are inherited. The genomic data captured in the trial will serve as an invaluable resource for researchers seeking to understand the genetic basis of pediatric cancer.
• The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to identifying better treatment strategies for children with primary brain tumors.
• NCI participates in the Gabriella Miller Kids First Pediatric Research Program , which is building a rich data resource (sponsored by the National Institutes of Health) to increase knowledge about the genetic changes associated with childhood cancers and structural birth defects. The program allows investigators from different research communities to share data and collaborate, and it encourages new ways of thinking about childhood diseases.
• NCI supports several research projects for children, adolescents, and young adults (AYAs) with cancer as authorized by the Childhood Cancer Survivorship, Treatment, Access, Research (STAR) Act . The act enables NCI to enhance biospecimen collection, biobanking, and related resources for childhood and AYA cancers, with an emphasis on those cancer types, subtypes, and their recurrences for which current treatments are least effective.

The CCDI Molecular Characterization Initiative (MCI)

Learn what MCI is and how it’s providing state-of-the-art testing at no cost.

• The Childhood Cancer Survivor Study (CCSS) is examining the long-term adverse effects of cancer and cancer therapy on approximately 35,000 survivors of childhood cancer who were diagnosed between 1970 and 1999. The study was created to gain new knowledge about the long-term effects of cancer and its treatment and to educate survivors and the medical community about the potential impacts of a cancer diagnosis and treatment. The results obtained from CCSS are used to help design treatment protocols and interventions that will improve survival, while minimizing harmful late effects. This research is also used to develop and expand programs for early detection and prevention of late effects in children and adolescent cancer survivors. For example, to better understand the genetic risk of second cancers, DCEG and CCSS researchers are collaborating on studies that aim to identify both common and rare genetic variants that may be associated with second cancers or other late adverse effects among survivors of childhood cancer. In a related study, DCEG scientists also are studying the long-term health of survivors of retinoblastoma , following a cohort of individuals with hereditary or nonhereditary disease to understand how retinoblastoma treatments impact risk for second cancers and long-term mortality.
• The New Approaches to Neuroblastoma Therapy (NANT) Consortium consists of a multidisciplinary team of laboratory and clinical scientists focused on improving outcomes for patients with high-risk neuroblastoma by discovering mechanisms of resistance to therapies, discovering targetable vulnerabilities driving resistance, and translating these insights into clinical trials. NANT works closely with COG to translate their experimental therapy findings into COG phase 3 clinical trials. Their findings on the tumor microenvironment , tumor response to therapy, and the application of cellular therapies to solid tumors have implications beyond neuroblastoma.
• The RACE for Children Act requires that all new adult cancer drugs also be tested in children when the molecular targets are relevant to a childhood cancer. NCI launched the Pediatric Preclinical in Vivo Testing (PIVOT) program to systematically evaluate new agents in genomically characterized models of childhood cancer. The primary goal of the PIVOT program is to develop high-quality preclinical data to help pediatric cancer researchers identify agents that are most likely to show significant anticancer activity when tested in the clinic against selected childhood cancers. NCI also plans to partner with the Food and Drug Administration, academia, and pharmaceutical companies in the Pediatric Preclinical Testing Public-Private Partnership (PPTP3) , which will be established by the Foundation for the National Institutes of Health to accelerate the pace and broaden the scope of pediatric preclinical testing of these agents.
• The Pediatric Genomic Data Inventory (PGDI) is an open-access resource to help researchers access data from genomic sequencing projects for pediatric cancer. The inventory lists ongoing and completed sequencing projects from the United States and other countries, the type of cancer studied, molecular characterization data available, and points of contact for each project.
• The Hyperactive RAS Specialized Programs of Research Excellence (SPOREs) focus on developing better treatments for neurofibromatosis type 1 and related cancers in children, adolescents, and young adults.
• The Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium is a multidisciplinary, collaborative network of investigators studying select fusion oncoproteins implicated in childhood cancers that have a high risk of treatment failure and for which there has been little progress in identifying targeted agents.
• The Pediatric Immunotherapy Discovery and Development Network (PI-DDN)  is a collaborative research network identifying and advancing research opportunities for translating immunotherapy concepts for children and adolescents with cancer toward clinical applications. Primary goals of the PI-DDN include the discovery and characterization of immunotherapy targets for childhood and adolescent cancers, the development of new immunotherapy treatment approaches, and an improved understanding of the immunosuppressive tumor microenvironment in order to advance new, more effective immune-based treatment regimens for high-risk pediatric cancers.

Mapping Tumors across Space and Time

A new NCI program will create maps of cancers with unprecedented detail.

• The Pediatric Cancer Immunotherapy Trials Network (CITN) is using the clinical trials infrastructure of the CITN to conduct clinical trials of immunotherapy agents of specific relevance to children and adolescents with cancer. Examples of the types of novel treatments to be investigated by the Pediatric CITN include cellular therapies (e.g., CAR T cells targeting pediatric cancer antigens) and antibody-based therapies, including antibody-drug conjugates, that target surface antigens preferentially expressed on childhood cancers.
• The My Pediatric and Adult Rare Tumor (MyPART) Network  of scientists, patients, family members, advocates, and health care providers is working together to help find new treatments for rare childhood, teen, and young adult solid tumors that have no cures. Working as a team, researchers share data and help design experiments and clinical trials, advocates discuss issues important to patients, and clinicians share their experiences treating rare cancers. MyPART is part of the larger NCI Rare Tumor Patient Engagement Network.
• DCEG researchers collaborate with the International Childhood Cancer Cohort Consortium (I4C) and the Childhood Leukemia International Consortium (CLIC) , collaborations that pool information from cohort studies from around the world to answer questions about childhood cancers. I4C brings together multidisciplinary teams of epidemiologists, basic scientists, and clinicians, to collaborate on investigations into the role of early-life exposures on cancer risk. CLIC includes more than 30 case–control studies and has identified associations between childhood leukemia and environmental risk factors.

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Paediatric cancer articles within Nature Medicine

Article 06 June 2024 | Open Access

Precision-guided treatment in high-risk pediatric cancers

In the observational ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial, children with high-risk cancer were treated with molecular tumor board-recommended therapies, resulting in overall clinical response rates that translated into survival benefit after long-term follow-up.

• Loretta M. S. Lau
• , Dong-Anh Khuong-Quang
•  &  David S. Ziegler

Article 11 April 2024 | Open Access

Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers

In an observational study evaluating functional precision medicine in children and adolescents with relapsed or refractory solid and hematologic malignancies, it was feasible to provide personalized treatment recommendations to treating physicians on the basis of genomic profiling and ex vivo drug sensitivity testing within 4 weeks.

• Arlet M. Acanda De La Rocha
• , Noah E. Berlow
•  &  Diana J. Azzam

Article | 07 March 2024

Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors

An observational study reports the joint effects of polygenic risk scores and radiation treatment exposure with a subsequent increased risk of multiple solid cancers in two large cohorts of survivors of childhood cancer.

• Todd M. Gibson
• , Danielle M. Karyadi
•  &  Lindsay M. Morton

Article 17 November 2023 | Open Access

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF -altered relapsed/refractory pediatric low-grade glioma.

• Lindsay B. Kilburn
•  &  Karsten Nysom

Article 11 September 2023 | Open Access

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

In a pooled analysis of six international studies involving about 17,900 female survivors of childhood cancer, the use of doxorubicin was associated with a dose-dependent risk of subsequent breast cancer, irrespective of prior chest radiotherapy exposure.

• Yuehan Wang
• , Cécile M. Ronckers
•  &  Jeanette F. Winther

Article 06 July 2023 | Open Access

Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia

In children with relapsed or refractory B cell acute lymphoblastic leukemia and in complete remission after CD19 CAR-T cell therapy, long-lived CAR-T cells express a persistence gene signature that is also present in persistent CD19 CAR-T cells from adults with chronic lymphocytic leukemia.

• Nathaniel D. Anderson
• , Jack Birch
•  &  Sara Ghorashian

Consensus Statement | 15 June 2023

A joint international consensus statement for measuring quality of survival for patients with childhood cancer

The International Childhood Cancer Outcome Project group, involving survivors and other relevant stakeholders, develop a set of core outcomes to measure the quality of care for 17 types of childhood cancers.

• Rebecca J. van Kalsbeek
• , Melissa M. Hudson
•  &  Lisa Zwiers

Article | 15 May 2023

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results

In updated results from a phase 1 trial of GD2-specific CAR-NKT cells in patients with neuroblastoma, no dose-limiting toxicities were observed across multiple dose levels; the maximum tolerated dose was not reached; and there was evidence of anti-tumor activity.

• Andras Heczey
•  &  Leonid S. Metelitsa

Article 03 April 2023 | Open Access

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results

In children, adolescents and adults with mutated ALK-driven relapsed or refractory neuroblastoma, a third-generation ALK inhibitor with or without chemotherapy was well tolerated, and recommended phase 2 doses were successfully identified in all patient groups.

• Kelly C. Goldsmith
• , Julie R. Park
•  &  Yael P. Mossé

News & Views | 17 March 2023

Accurate diagnosis of pediatric brain cancers

Integrative approaches continue to improve diagnostic accuracy for pediatric brain cancers, but much more is needed from researchers, governments and regulators if precision medicine with curative treatments are to become a reality.

• Pratiti Bandopadhayay
•  &  Elaine R. Mardis

Article 17 March 2023 | Open Access

Diagnostic classification of childhood cancer using multiscale transcriptomics

A new multilevel clustering approach applied retrospectively to 13,000 transcriptomes of different tumors reveals a new diagnostic classification of childhood cancers, in some cases allowing a better prediction of disease outcomes.

• Federico Comitani
• , Joshua O. Nash
•  &  Adam Shlien

Article 16 March 2023 | Open Access

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

The integration of DNA methylation profiling and targeted sequencing with neuropathology improves the diagnostic accuracy of central nervous system tumors in a population-based cohort of more than 1,200 newly diagnosed pediatric patients.

• Dominik Sturm
• , David Capper
•  &  David. T. W. Jones

Article 05 January 2023 | Open Access

Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

Pharmacotyping analyses of large cohorts of pediatric acute lymphoblastic leukemia identify correlations between drug sensitivities and clinical outcomes across different genomic subtypes.

• Shawn H. R. Lee
• , Wenjian Yang
•  &  Jun J. Yang

News & Views | 08 August 2022

Predicting chronic morbidity in childhood cancer survivors

Incorporating genetic factors into risk models improves the prediction of severe obesity for survivors of childhood cancer, which could promote early interventions and better long-term care.

• Lynda M. Vrooman
•  &  Lisa R. Diller

Article | 23 June 2022

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

An interim report from the GAIN/iCat2 study shows that molecular profiling of pediatric solid malignancies clarifies diagnostic classifications and provides opportunities for matched targeted therapy.

• Alanna J. Church
• , Laura B. Corson
•  &  Katherine A. Janeway

World View | 19 April 2022

How to correct the market for children’s cancer drugs

The development of pediatric cancer drugs is vastly underfunded compared with that for adults, but legislation can correct market failures.

• Nancy F. Goodman

Article | 13 January 2022

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication

The combination of anti-GD2 and CD47 blockade mediates robust anti-tumor activity in mouse models of neuroblastoma, osteosarcoma and small-cell lung cancer by reorienting macrophage activity toward tumor cell phagocytosis.

• Johanna Theruvath
• , Marie Menard
•  &  Robbie G. Majzner

Article 06 January 2022 | Open Access

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

• Anirban Das
• , Sumedha Sudhaman
•  &  Uri Tabori

Article 12 October 2021 | Open Access

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.

• Shaun Cordoba
• , Shimobi Onuoha
•  &  Persis J. Amrolia

Article | 12 July 2021

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis

In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.

• Nicholas A. Vitanza
• , Adam J. Johnson
•  &  Julie R. Park

Article | 13 January 2021

Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial

Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.

• Michael J. Fisher
• , Chie-Schin Shih
•  &  D. Wade Clapp

News & Views | 19 October 2020

Entering the era of precision medicine in pediatric oncology

The Zero Childhood Cancer Program’s multi-platform sequencing approach identified molecular alterations in 94% of a cohort of 247 pediatric patients with high-risk cancers, which has enabled more-precise diagnoses and alternative therapeutic recommendations.

• Djihad Hadjadj
• , Shriya Deshmukh
•  &  Nada Jabado

Brief Communication | 12 October 2020

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis

In an interim analysis of a first-in-human phase 1 trial of patients with neuroblastoma, highly pure GD2-specific CAR-NKT cells were well tolerated with no observed dose-limiting toxicities.

• , Amy N. Courtney

Article | 05 October 2020

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

The Zero Childhood Cancer pediatric precision medicine program informs treatment recommendations for children with high-risk cancers through comprehensive molecular profiling

• , Chelsea Mayoh
•  &  Mark J. Cowley

Article | 27 April 2020

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models.

• Laura K. Donovan
• , Alberto Delaidelli
•  &  Michael D. Taylor

Letter | 27 April 2020

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors

CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.

• , Elena Sotillo
•  &  Crystal L. Mackall

Review Article | 06 March 2019

Developmental origins and emerging therapeutic opportunities for childhood cancer

Childhood cancers are developmentally distinct from adult cancers and arise from cellular reprogramming as a result of epigenetic mutations or gene fusions, providing unique therapeutic opportunities.

• Mariella Filbin
•  &  Michelle Monje

Resource | 22 October 2018

A biobank of patient-derived pediatric brain tumor models

A resource of preclinical pediatric brain tumor models with detailed molecular characterization provides a platform for the community to test novel therapeutic approaches.

• Sebastian Brabetz
• , Sarah E. S. Leary
•  &  James M. Olson

Article | 02 July 2018

Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells

Genomic and functional analysis of intratumor heterogeneity in pediatric glioma uncovers early clonal divergence and stable spontaneous cooperation between subclonal populations throughout tumor evolution.

• , Anna Burford
•  &  Chris Jones

News & Views | 07 May 2018

CAR T cells for childhood diffuse midline gliomas

Anti-GD2 chimeric antigen receptor (CAR)-modified T cells may be a new and innovative approach for the treatment of pediatric H3-K27M-mutant diffuse midline gliomas.

• Vijay Ramaswamy
•  &  Michael D Taylor

News & Views | 01 January 2018

Genomics in childhood acute myeloid leukemia comes of age

A Children's Oncology Group study of nearly 1,000 pediatric acute myeloid leukemia (AML) cases reveals marked differences between the genomic landscapes of pediatric and adult AML and offers directions for future work.

• Andrew M Brunner
•  &  Timothy A Graubert

Resource | 11 December 2017

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

A comprehensive molecular analysis of almost 1,000 pediatric subjects with acute myeloid leukemia (AML) uncovers widespread differences in pediatric AML as compared to adult AML, including a higher frequency of structural variants and different mutational patterns and epigenetic signatures. Future studies are needed to characterize the functional relevance of these alterations and to explore age-tailored therapies to improve disease control in younger patients.

• Hamid Bolouri
• , Jason E Farrar
•  &  Soheil Meshinchi

Editorial | 01 September 2017

Children first

Drugs administered to children with cancer were typically developed under the assumption that childhood cancers are similar to their tissue-matched adult counterparts. Focusing on identifying and targeting alterations present specifically in childhood tumors will accelerate the development of tailored therapies and improve the prognosis of children with cancer.

Resource | 30 January 2017

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

DNA methylation sequencing and bioinformatic analyses uncover an epigenetic disease spectrum in Ewing sarcoma. These characteristic epigenome patterns correlate with state of differentiation and disease aggressiveness, and pave the way for the development of biomarkers.

• Nathan C Sheffield
• , Gaelle Pierron
•  &  Eleni M Tomazou

News & Views | 07 March 2011

Hunting ALK to feed targeted cancer therapy

Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.

• Anton Wellstein
•  &  Jeffrey A Toretsky

News | 07 March 2011

The search for child cancer drugs grows up

• Branwen Morgan

News & Views | 06 December 2010

Crippling SWI-SNF makes tumors GLI-ful

The chromatin remodeling complex SWI-SNF is altered in cancer. New findings now show that the core component SNF5 can block a Hedgehog (Hh) effector, which promotes malignant rhabdoid tumor growth when SNF5 is lost (pages 1429–1433 ). Targeting this Hh effector may be a way to combat these aggressive childhood tumors.

• Jeremy F Reiter

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8 Common Childhood Cancer Myths and Questions

Childhood cancer is rare, but when it happens, it usually brings up an endless stream of questions for parents. How did this happen? What will life be like for my child?

In this episode of Cancer Mythbusters from Dana-Farber Cancer Institute, we talk about some of the most common questions and myths about childhood cancer with Allison O’Neill, MD , Clinical Director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorder Center .

MEGAN RIESZ: Let’s start off with a big question: What do we know about what causes childhood cancer?

ALLISON O’NEILL, MD: That is a big question, and I think it’s one we wish we knew more about. In truth, there have been so many longitudinal epidemiologic studies trying to arrive at more definitive risks for pediatric cancer, and the bottom line is we still don’t know enough of what causes this variety of diseases across children in general.

I think that studies are ongoing, and I think, in some cases, we do know that there might be genetic risks, for instance — but in the adult population, where we know that smoking causes lung cancer, or significant exposure to the sun can lead to melanoma. There aren’t necessarily the same environmental risks per se that we can link to childhood cancer.

MEGAN: You kind-of alluded to this, but can cancer be inherited, and what would you have to say to parents who might think it’s their fault that their child got diagnosed with cancer?

O’NEILL: So, yes, it certainly can be inherited. We know of a number of genetic syndromes, I should say, or cancer predisposition syndromes that [are] essentially defined by a gene that is abnormal within a family that then is inherited in each generation that may lend to risk for cancer.

Now, that risk can vary substantially within generations. It can vary based on the genetic abnormality within families. The same abnormality might not be seen in two disparate families, and the risks might be very different, so just because a family has a particular gene abnormality doesn’t necessarily mean the risk between families is the same.

We actually have a cancer predisposition clinic now at the Jimmy Fund Clinic that sees all pediatric patients diagnosed with cancer… Cancer is so rare in pediatrics that I think, over time, we’re going to identify that there are more genetic causes than we previously realized.

That being said, it’s never the fault of the family. We can’t control our genetic makeup. Unfortunately, we can’t determine how these genes get passed on — by virtue of having children, genes are passed on — so really, families should never place blame on themselves. Parents should never place blame, and I think the goal of this cancer predisposition clinic, in particular, is to create surveillance programs such that we watch children with more frequency when we know they have a particular risk, such that we can, hopefully, diagnose cancer at an earlier stage, such that it’s curable.

MEGAN: One common question is whether children with cancer pose a health risk to other children. Can you talk about this?

O’NEILL: Of course. They pose absolutely no risk, but I can imagine that communities might be fearful of that. I think children with cancer probably still carry some stigma. I think it’s more a stigma of the unknown. I think a lot of other children in classrooms — you know, if a child shares a classroom with a patient that’s been recently diagnosed, or if communities and families share resources — they may not know enough to realize that cancer is not contagious.

In reality, patients who are diagnosed and families that have a child recently diagnosed need more support than ever before, so I think what we need to do is break that stigma and really bring communities together to support these families.

MEGAN: How is cancer treatment in kids different than cancer treatment in adults?

O’NEILL: That’s a tough question. I think the diseases are very different, so I think we need to start there. The diseases that affect adults are very different from what we see in children, with a few exceptions — there are some diseases that overlap. The disease is really what dictates the therapy. For many diseases, we still rely upon combination chemotherapy (more than one chemo therapeutic agent in different combinations delivered in a cyclical fashion).

I think our field is gradually moving more and more towards targeted therapies that are dictated by the genetic makeup of these tumors, but we haven’t yet evolved to a point where we utilize those therapies alone. What I will say is that we’re very fortunate that children are able to tolerate therapy much better than adults, in many circumstances. They are younger. Their organs are quite healthy. They’re unbelievably resilient both, I think, physically and mentally and emotionally.

So, I think many families will come into our clinic with expectations or prior experiences that lend fear to how well their child will cope with the diagnosis or the treatment, and I think what we often reassure families is that children do a remarkably excellent job of tolerating their therapies.

MEGAN: And yes, many parents, kind of along those lines, wonder if their children can live a “normal life” after treatment — so can they?

O’NEILL: That’s our absolute goal. We often set patients and families up for the expectation that they should lead as normal a life as possible during their treatment, and we have a number of resources to accommodate them in school and at home, [as well as] their siblings and their families, but the goal, really, is for them to lead as normal a life as possible after their treatment.

Now, of course, their treatment may come with certain toxicities that are lifelong medical problems. I think, as our cancer treatments evolve and become more targeted, less toxic, and/or as we’re able to deliver less intensive therapy over time, the longstanding consequences of treatment are going to become more tolerable.

We have a cancer survivorship clinic at Dana-Farber where all of our patients are followed not just in childhood but well into adulthood, such that they undergo surveillance for any possible risks after having received these drugs. Certainly, many of our children undergo life-altering surgeries as well for which they may have prostheses or require significant physical therapy or occupational therapy, but again, all of these things are put in place early such that these families — that these children — can have as normal a life as possible in the aftermath of treatment.

MEGAN: If a child goes through cancer treatment, can they still have kids some day?

DR. O’NEILL: That’s a very good question. It really depends on the treatment they’ve received. So, we have recently instituted in our pediatric program a fertility specialist…who works closely with…one of our pediatric oncologists, and has really established an information gathering session very early on in treatment and [a] plan going forward as it pertains to fertility preservation, if necessary.

So, what we review with families is the treatment that they will receive, the risks that that treatment might impart on fertility, and then we provide a number of options as it pertains to fertility preservation, if the family would like to preserve either sperm or egg and whether the child is even eligible for any of those procedures, and really, we try to counsel the family as to the risks of infertility to help them make that decision prior to initiation of therapy. So, it really is very treatment specific, but having put this program in place in the last few years, I think it has really helped families plan for the future after treatment.

MEGAN: A myth that we want to explore here is whether all cancer treatments are toxic — what do you have to say on this?

O’NEILL: Yeah, that’s an excellent question, and that’s very treatment specific. So, each of the drugs we use comes with obligatory side effects, but I can say the same thing for Tylenol. If you read the Tylenol insert, there are four thousand side effects, and that’s a very benign drug, so you can imagine the same holds true for each chemotherapeutic agent we use or each targeted agent — but our jobs at the end of the day are to balance the potential side effects with the benefit of cure and the benefit of treatment. So, we are able to really compile treatment regimens that cause the least amount of harm, that are the least toxic, if possible, but confer the greatest benefit for efficacy.

And in truth, we’re getting better and better at predicting toxicities and/or protecting patients from them, and as I mentioned previously, our goal is really to cut back on toxic therapies when possible such that we can provide children with normal lives in the aftermath of treatment.

MEGAN: Anything else? Any parting words? Anything you think a parent of a childhood cancer patient should know or keep in mind?

O’NEILL: That’s a good question. I think you brought this up earlier—parents of pediatric cancer patients always blame themselves in some way, and if I can leave you with one tidbit to these parents: Don’t blame yourselves. You did nothing to cause this, even in the context of a genetically inherited abnormality. It’s not your fault.

And I think parents often wonder whether they can be doing more, and I can tell you that you’re doing everything you can, and you’re doing your very best, and that’s what your child needs. Those are my parting words and the truth that this is difficult to go through, but the vast majority of patients and families do an unbelievable job in supporting their child.

Learn more about treatment and support for pediatric cancer from Dana-Farber/Boston Children’s.

Pediatric Oncology: Working Towards Better Treatment through Evidence-Based Research

Pediatric oncology is working towards better treatment. The most significant credit goes to the time and resources used to research the cancer-related ailments that affect children. Survival rates for pediatric cancer patients have increased, and their survival has triggered the need for more treatment methods and studies on the effects of cancer therapy. Research centers such as John Hopkins University have been on the front line in elaborating various ways of saving lives from the cancer menace. Another crucial institution for curing and fighting childhood cancer is St. Jude Children’s Research Hospital, which conducts different clinical trials and offers intense care for patients. Blood disorders and cancer have become rampant among children worldwide, and specialists in the medical department are to make sure that they give the right treatment and care to decrease mortality rates. Globally, there are unmeasurable efforts by the pathology departments, orthopedics, and therapeutic radiologists to secure that blood disorders and cancer in people under 18 years are neutralized. Through the research, it has been found that more than a hundred and seventy thousand children are diagnosed with cancer, and 96,000 kids succumb to different types of cancer. In developed countries, the mortality rate is low, accounting for less than 20%, whereas, in less developed states, the mortality rate of children who suffer from cancer-related diseases is more than 80%. Therefore, evidence-based research in pediatric oncology enhances the technology that aids in solving problems of diagnosing cancer in children.

Significance of the Evidence-Based Research

Nevertheless, there is a need for more extensive evidence-based research on childhood cancer; the main goal is saving lives. The types of cancer that are most common in the young ones are leukemia, which is the most rampant kind, then it is followed by brain tumors, as well as lymphomas, which are the least common. In the United States, 5 out of 100,000 children are diagnosed with leukemia before age 20. One out of those five kids dies from leukemia. Juniors between the ages of 1 and 4 were observed to have new cancer cases, whereas juveniles between the ages of 10 and 14 recorded the highest number of pediatric cancer deaths. Besides, there are other less common types of childhood cancer, such as retinoblastoma, Wilms’ tumor that affects the kidney, osteosarcoma, which affects the bones, and Non-Hodgkin lymphoma, which affects the blood.

Nevertheless, positive outcomes will be produced when more evidence-based research is undertaken on childhood cancer. The strides made by the research programs cannot distract from the fact that over 10,000 children in the United States 15 will be diagnosed with cancer this year. However, the significance of the research has been a reliable pillar in overcoming the cancer problem.

Literature Review

One of the evidence-based researches was conducted in 2014 when the experts investigated evidence-based recommendations regarding fertility preservation options and treatment procedures for adolescents diagnosed with cancer. The researchers noted that the long-term effects were not considered when chemotherapy was introduced to fight cancer cells. Moreover, it was proved that cancer therapies have negative sustainable implications on other body organs and adverse influence on the reproductive system. When chemotherapy was discovered to have saved many lives, the attention was diverted to the fact that it could cause more harm than good. That is why Alison and her team decided to elaborate on better ways to provide safer chemotherapy for teenagers. Family members have reported that patients that had cancer in their childhood are infertile in their old age. This is because when the gonads are exposed to radiation emitted during chemotherapy, the reproductive system becomes affected, thus leading to infertility. However, a big challenge is faced by the specialist when giving fertility preservation counseling to adolescents with cancer and determining the ones at risk of losing their fertility because of age, sex and available resources for treatment.

Prevention of Infertility among Cancer Teenagers Undergoing Chemotherapy

Alison and the team of researchers started their research with the stage of question development, where they reviewed the systematic procedures used during chemotherapy so that they would note down the loopholes where radiation can reach the reproductive organs. The scholars proceeded with the literature search, and they resorted to 1108 articles, but only 258 of them were relevant to the topic of pediatric cancer. Of the 258 relevant articles, 30 discussed fertility preservation in females, whereas 23 dealt with fertility preservation in males during chemotherapy. When the evidence was reviewed, it was observed that a few procedures are safe for female teenagers during chemotherapy. One of the methods is known as oophoropexy, a surgical procedure of relocating the ovaries of the female patient to safer areas of the reproductive organs to avoid any contact with the radiation. Besides, the two journals utilized in the research stated that out of 11 women who underwent oophoropexy after pelvic radiation, 14 pregnancies were reported. Ovarian tissue cryopreservation is another beneficial and safe method for girls in their pre-puberty stage. It entails removing the part or the entire ovarian tissue and preserving it in a special way for future use. In the case of male children who have not reached puberty, the research advocates for cryopreservation; hence, the services of a sperm bank are highly recommended to prevent infertility.

Integration of Psychological Care in the Treatment of Pediatric Oncology

Anne Kazak and Robert Noll from the University of Pittsburgh undertook a study in 2015 on how to improve the care for children with cancer and their families. Thus, this research aimed to integrate psychology with pediatric oncology after it was realized that childhood cancer patients faced severe trauma and became aggressive during treatment and the healing process generally. Kazak and Noll suggested seven contributions that psychologists can make to help cancer patients at a young age cope with the stigma that they encounter in their life since they have it in mind that they are not like the rest. When children with cancer got psychological counseling, they developed better than those who did not get counseling regarding personal relations.

Helping Cancer Patients to Cope with Pain through the Use of a Mobile Application

In 2014, Ellen Henderson and her colleague Passchier conducted thorough research on the kind of pain adolescents with cancer undergo after they finish the therapies. The two researchers wanted to devise a phone application that could predict the pain the cancer patients experienced and send signals for the patient to receive help immediately. Due to the comprehensive literature review and complex algorithm development, the two scholars applied the centered approach. The results showed that the pain management device was suitable for 7 out of 10 teenage cancer patients because of the different themes that the application had.

The evidence-based research done by specialists is quite considerate, and it is clear that cancer treatment imposes another burden, which is a follow-up of the side effects of the therapy. Cancer among children demands extra care since those youngsters need a favorable environment to feel loved and additional care during the therapies since those radiations have side effects on the heart and other organs, particularly the reproductive system. Therefore, evidence-based research seems to be well-balanced, and all the studies aim to reduce mortality rates.

Significant programs have been launched occasionally to help scholars get the correct information when answering their research questions. Good libraries and exemplary laboratories have been a pillar to the positive findings of many researchers who dared to reveal gaps in pediatric oncology. Some of the results obtained by different investigators have been considered during the treatment and care of patients with childhood cancer, whereas other discoveries are still under scrutiny so that the health board in charge of the young ones can approve them. Evidence-based research findings have improved the conditions of children with cancer by lowering the infertility risk during chemotherapy sessions.

Practice Implications

One of the implications of the research programs involved reaching a deeper understanding of how gene expression can serve as a critical factor in cancer development among children. The study of genes in kids with cancer is an issue in determining the type of drugs prescribed for treating these youngsters with cancer. The gene known as LIN28B was a major cause of cancer among children. Carpenter and Lo also identified that the gene contributed to the development of liver tumors in adolescents under the age of 16 years. When the gene LIN28B is produced exceedingly, it leads to hepatoblastoma, and the only way to stop the gene from spreading and multiplying is by blocking it. When the researchers discovered such news, they were confident to assert that liver cancer in children can be cured using methods other than chemotherapy.

Additionally, the research increases the safety of bone-marrow transplants. Numerous lives could have been saved due to the bone-marrow transplant. The latter is necessary to restore the blood-forming capacity of cancer children who have undergone cancer treatment, namely chemotherapy. Nevertheless, this type of transplant is not very safe for patients, as some develop complications, sometimes resulting in death. Evidence-based research has aided in identifying the best microenvironment for the cells that form blood during the transplant. Hence, Kasow and Stinson helped determine the environment for the cells responsible for blood formation. Moreover, they contributed to classifying the cells and establishing their growth factors. Consequently, such discoveries have decreased the number of deaths during bone marrow transplantation, and new therapeutic methods are being considered.

The elaboration of better control mechanisms of metabolism is another significant study point. Since cancer is the growth of malignant cells, there is a dire need to find ways to reduce the factors that lead to the abnormal development of cells. In the past, a type of glucose in medical institutions known as FDG-PET was used to identify lung cancer cells. The character of sugar uptake of lung cancer cells was the main reason for the utilization of this type of glucose. Through research, it was disclosed that the glucose used to identify lung cancer cells is responsible for their increased growth. The successful research led to the application of an alternative method, which implies the employment of magnetic resonance technology intended to monitor the behavior of tumors before a cancer patient undergoes surgery. Therefore, evidence-based research has promoted improved diagnosis and therapy for children with cancer, eventually resulting in fewer deaths among cancer patients.

Summary and Conclusion

Childhood cancer takes many lives every year, and researchers have to conduct tests to reduce the death rates. Therefore, evidence-based research programs need to be implemented in pediatric oncology to decrease youngsters’ mortality and mitigate the after-effects of cancer therapy. Moreover, the evidence-based research undertaken by various people has proved beneficial due to providing recommendations on preventing tampering with teenagers’ fertility and using psychology in cancer treatment to overcome stigmatization in cancer patients. Nevertheless, studies and investigations should be funded better to produce more effective outcomes in the fight against cancer. More research centers like John Hopkins University should be established for pediatric oncology research-related activities so that children can lead healthy lives even after being cured of cancer. The disease has put plenty of people to death; thus, it is high time that researchers burnt the midnight oil to find solutions that will enhance the neutralization of the effects of cancer on children.

📎 References:

1. Benjamin, D. I., Cravatt, B. F., & Nomura, D. K. (2012). Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metabolism, 16(5), 565-577. https://dx.doi.org/10.1016/j.cmet.2012.09.013 2. Bryant, R., Rodgers, C., & Stone, S. (2013). Enhancing pediatric oncology nursing care through research, quality improvement, and evidence-based practice. Journal of Pediatric Oncology Nursing, 30(3), 123-128. https://dx.doi.org/10.1177/1043454213478837 3. Carpenter, R. L., & Lo, H. W. (2014). STAT3 target genes relevant to human cancers. Cancers, 6(2), 97-925. https://dx.doi.org/10.3390/cancers6020897 4. El-Fattah, M. (2017). Survival pattern of chronic myeloid leukemia in a pediatric population in the United States. Journal of Pediatric Hematology/Oncology, 39(2), 159-160. https://dx.doi.org/10.1097/mph.0000000000000693 5. Fernbach, A., Lockart, B., Armus, C. L., Bashore, L. M., Levine, J., … Rodgers, C.(2014). Evidence-based recommendations for fertility preservation options for inclusion in treatment protocols for pediatric and adolescent patients diagnosed with cancer. Journal of Pediatric Oncology Nursing, 31(4), 211-222. https://dx.doi.org/10.1177/1043454214532025 6. Jibb, L. A., Stevens, B. J., Nathan, P. C., Seto, E., Cafazzo, J. A., & Stinson, J. N. (2014). A smartphone-based pain management app for adolescents with cancer: Establishing system requirements and a pain care algorithm based on literature review, interviews, and consensus. JMIR Research Protocols, 3(1), e15. https://dx.doi.org/10.2196/resprot.3041 7. Kasow, K. A., & Stinson, P. (2017). Ensuring donor safety in the operating room during a bone marrow harvest. Biology of Blood and Marrow Transplantation, 23(3), S421-S422. https://dx.doi.org/10.1016/j.bbmt.2016.12.511

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Holes – A Survivor’s College Essay

One year ago, Matthew Buff, a leukemia survivor, was fine-tuning his college applications. Today, he is a busy freshman at Emory University majoring in biology on a pre-med track. Matthew's personal goal is to become a pediatric oncologist focused on genetic research. The following is his college admissions essay. 

A round piece of silicone wrapped in a metal ring about the size of a quarter. If you tip it slightly, at just the right angle, where it catches the light, you would see hundreds of tiny holes covering the entirety of its surface. A miniature vacated battlefield of a war once won. It may not look like much to most people, but this tiny piece of plastic riddled with needle holes called a port or port-a-cath, helped to save my life and is now my visual inspiration to help others.

In the beginning, each hole could have easily represented another round of chemotherapy, spinal tap, blood transfusion, hospitalization, surgery or enrollment into a new study to treat my leukemia. They could also represent another day unable to attend school, each time being isolated from friends, and too many middle-of-the-night trips to the emergency room that would ultimately lead to another round of pokes, tests and abruptly waking to the beeping alarm of my IV pole early the next morning.

However, as my body has recuperated over the past five years since completing cancer treatment, the meaning of each hole has also transformed. Each hole now represents a lesson learned, a person met through my experience and the opportunity to make impactful change or people affected by catastrophic illness.

My parents and doctors have always encouraged me to not let my experience with cancer define me. I believe I have done a good job of incorporating that into my daily life, relationships and pursued interests. However, as I have matured and started to gain new experiences in life, I have chosen to reconnect with my past and allow it to acutely influence my perspective. I can’t help but to see the world from a slightly different angle than my peers after experiencing the delicateness and resiliency of life by age 12. I no longer view those years in and out of the hospital as negative, but a gift to help shape my abilities and sharpen my purpose.

From a very young age, I’ve learned to be an advocate for myself, to be an effective communicator, how to endure and thrive through challenges, become a capable and independent learner and find joy in contributing back to the community that surrounded me during my time of need. I want to now expand on those experiences and create new and meaningful relationships within the college environment that will continue to mold how I see the world and my future contributions within it.

I want to bravely explore other “holes” people have endured within their own lives, sit with them, and begin to find ways to alleviate their struggles through the commonalities of the human experience. If we can appreciate our differences, yet focus on what connects us, I believe there would be more peace in the world and fewer opportunities for any kind of pain and suffering. Empathy and compassion, in combination with technology and research, has the potential to redefine health and care. I intend for my experience and knowledge to be part of this progress.

My current objective is to build my college education with a concentration in biology and life sciences with the goal to become a research oncologist. Beyond my academic interest in those areas, I believe shifting my experiences from patient or receiver of care, to student of science with the intent to deliver care, will provide me the knowledge and holistic perspective to begin to develop the passion and endurance necessary to make a life-long commitment to healing through medicine.

We can’t always choose the experiences that shape us into who we are meant to be, but we can utilize them to empower ourselves, inspire each other and help others. Holes don’t have to be permanent; they can be the necessary foundation to begin to build something important and meaningful. We must be willing to excavate our own comfort, take risk, overcome challenges, plant new footings and create solutions to fill the gaps that are exposed in both our own lives, and in the lives of the people around us. Sometimes, if we look at things from a slightly different angle, like when the light reflects off my port, we can find new solutions to effectively and completely fill each new hole.

Written by Matthew Buff   Matthew was diagnosed with acute lymphoblastic leukemia in March 2009. Now six years beyond treatment, he is a college student working towards his goal of becoming a pediatric oncologist focused on genetic research. 

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Children With Cancer and Schooling Challenges

• To find inspiration for your paper and overcome writer’s block
• As a source of information (ensure proper referencing)
• As a template for you assignment

Introduction

Literature review, reference list.

Significant increase in the cases of childhood cancer has characterised the past five decades. Even though the survival rate of children has improved tremendously, it is imperative to appreciate that little has been done to understand the psychological and social implications of childhood cancer.

Additionally, little has been done to assist kids to cope with life after recovering from cancer (Donovan 2014). The medical advancement and increased rate of survival of children with cancer have called for society to look for ways to reintegrate the kids into school. Indeed, “there is an emergent trend that stresses the importance of incorporating the provision of comprehensive care for pediatric cancer patients that recognises the social and emotional needs of the children in addition to their clinical requirements” (Donovan 2014, p. 141).

The comprehensive treatment program seeks to enable children to go on with their academic and social life. According to Gorin and McAuliffe (2013), the education of kids who have recovered from cancer and those struggling with the health condition is a critical issue since it would help them to achieve healthy emotional and social growth. Education institutions should treat children with cancer like normal kids and allow them to engage in activities that they would do were they not suffering from the disease. This literature review will analyse the challenges that children with cancer face in their endeavour to pursue education and how to assist the kids.

Peers and Social Relationship

A study conducted by Fraser (2015) revealed that children with cancer find it difficult to cope with their peers when they return to school. The rationale for the study was to identify what society has done to meet the social needs of children with cancer. A qualitative study carried out on 12 families revealed that kids with cancer have unique social needs that surpass the effect of absence from school.

Fraser (2015) posits that cancer treatment results in changes in the physical appearance of a patient. Consequently, when kids with cancer go back to school, their colleagues see them differently. In some instances, it becomes hard for kids with cancer to re-establish a friendship with former members who find them different.

Studies indicate that many children who have cancer are reluctant to go back to school because they fear that their friends might not accept them back. Gorin and McAuliffe (2013) support this finding by alleging that kids with cancer occasionally experience seclusion and rebuff by peers, which border the isolation that children with disabilities encounter.

Lightfoot, Mukherjee and Sloper (2012, p. 61) posit, “The novelty of the child’s condition and possible shock that peers experience when a child who has had cancer returns to school can have a negative impact on how they react to that kid”. The study is helpful as it delves into changes in peer relationships and friendships, which arise after a child has cancer. It has explored ways that society can use to address the issues.

The study fails to appreciate that it is not only the physical appearance of the kid that determines how peers treat children with cancer. The research does not consider the impacts of misconceptions that children have regarding chronic diseases. Lightfoot, Mukherjee and Sloper (2012) argue that apart from physical appearance, contrary ideas regarding chronic illness may contribute to kids with cancer facing rejection from their colleagues. Most students believe that cancer is infectious, and are worried that they might contract the disease if they interact with the sick child. Fear of contamination contributes to children avoiding their peers who have cancer.

Social Inclusion

McLoone, Wakefield and Cohn (2013, p. 487) argue, “The study of the education of children with medical conditions has fallen into two opposing streams”. The first stream focuses is the medical model, and associates emotional and social challenges and education problems with the illness itself. The second stream is the social model, which associates the challenges that children with cancer experience with lack of knowledge on the part of the learning institutions and the public at large. A study by McLoone, Wakefield, and Cohn (2013), sought to determine how social inclusion helps children with cancer to return to school after being away for a long time.

The study analysed school reentry experience of kids who had just completed cancer treatment. It sought to determine the perceptions of forty-two parents whose children were undergoing cancer treatment. The researchers used semi-structured telephone interviews to gather information. The Miles and Huberman framework was used to analyse the interviews.

The study identified social inclusion as a major challenge that inhibits children’s ability to reintegrate into the school system. Ethically, the study raised concerns over parents’ emphasis on the academic success of their children at the expense of overall personal development. It recommends research on the role of continued peer socialisation in the success of school reentry process.

McLoone, Wakefield, and Cohn (2013) allege that educating kids with medical conditions should follow an individual and holistic approach, which acknowledges the unique needs of every child. Their study emphasises the significance of ensuring that academic and social settings consider the needs of kids with cancer as well as those of their peers.

According to McLoone, Wakefield, and Cohn (2013), educational institutions should not only offer quality education to children with cancer but also act as compensation or disruption from the ordeal that the kids have endured due to sickness. They allege that social elements and friendship, in conjunction with institutional factors, determine the success of the child’s reintegration into school.

Academic and Cognitive Impacts of Childhood Cancer

Childhood cancer does affect not only the social and psychological life of the kid but also cognitive functioning. Barrera et al. (2014) conducted a study to determine the academic and cognitive impacts of childhood cancer on kids aged below 17. The rationale for the study was to evaluate the educational and social development of survivors of childhood cancer. A total of 800 survivors were pooled together with 923 control participants.

Questionnaires were used to gather information about the academic performance of the kids. The study found that most cancer survivors performed poorly in academics and repeated some grades. Ethically, the study raised a question about the significance of using cranial radiation to treat cancer patients. The radiation was found to contribute to learning challenges as well as difficulties in making friendships.

According to Barrera et al. (2014), cancer survivors encounter challenges in scholastic performance due to the late effects of their treatment. The effects “are associated with brain damage as a result of radiation and chemotherapy, which are commonly used to treat childhood cancer” (Barrera et al. 2014, p. 1754). Studies indicate that administration of cranial radiation affects the cognitive functioning of a child.

Kids who undergo the treatment encounter challenges in Mathematics, English, and Science. Additionally, they have difficulties in visual-motor skills and verbal fluency. Other psychological challenges include problems with mental processing speed, attention, and intellectual deterioration.

Even though the mode of treatment of cancer can have impacts on the academic and cognitive functioning of a child, other factors such as the age of the patient also play a significant role. The study fails to consider the impact of the age of a child on cognitive functioning and academic performance. Children who undertake cancer treatment at an early age have a high risk of experiencing academic and cognitive challenges.

Shiu (2014, p. 273) argues, “Developing brains are sensitive to treatment and the damage that it may cause”. Provision of educational support can go a long way towards helping children with academic and cognitive challenges. According to Shiu (2014), survivors of childhood cancer require additional tutoring to enhance their academic potential.

Teachers play a significant role in assisting survivors of pediatric cancer to reintegrate into school. Bessell (2013) conducted a study to analyse school experience, quality of life, and psychosocial adjustments of survivors of childhood cancer. The researcher used a multimethod approach to evaluate how survivors coped with the disease and their opinion regarding psychological and educational changes as a result of cancer treatment. A total of 51 survivors aged between 8 and 17 participated in the study.

Quantitative analysis showed that the survivors suffered from anxiety and challenges in psychosocial changes in the fields of intellectual and social skill and emotional balance. The study found that educators require having specific skills and knowledge to deal with cancer students. It also brought out the significance of social inclusion in enhancing students’ performance. The study did not touch on ethical issues attributed to the teacher-student relationship.

A study by Donovan (2014) supports the significance of teachers in the creation of a healthy learning environment for kids with cancer. Many survivors of pediatric cancer argue that they prefer educators who understand them and their conditions. A healthy relationship amid teachers and childhood cancer survivors entails giving the kids adequate time to complete assignments and altering teaching methods to cater to their needs. Childhood cancer survivors require a lot of educational support. Unfortunately, most educators do not have knowledge on how to assist the survivors.

As a result, they become anxious and are unable to deal with children suffering from chronic diseases. In secondary schools, students deal with many teachers, thus the need to ensure that all instructors have adequate skills in how to handle cancer survivors and establish a supportive learning environment. The inability of the teachers to align instructions with the needs of individual students impedes the academic success of childhood cancer survivors.

Supporting Childhood Cancer Survivors

A’Bear (2014) conducted a study, which sought to determine methods that parents and teachers can use to assist childhood cancer survivors in continuing their education. The rationale for the study was to establish how technology may help to reduce the effects of nonattendance and enable learners to be at par with other students. The study contributed to the understanding of the role that school districts can play to ensure that kids with chronic diseases do not miss learning opportunities. It delved into the theory of inclusion. Teachers, parents, and childhood cancer survivors were among the participants in the study. The research considered confidentiality ethics. The names of the members were kept secret for privacy purpose.

A’Bear (2014) used focus group interviews to collect qualitative data. The data analysis entailed a detailed examination of information gathered from each focus group. The researcher used data triangulation technique to identify major themes and eliminate possible biases. The study found that technological instruments like Skype are critical in enhancing the learning environment for children with cancer, particularly those recuperating at home. The major limitation of the study is that it relied on descriptive and ethnographic data which is prone to bias.

Thies and McAllister (2012) underline the significance of hospital schools to children with cancer. However, such a strategy can only be useful to kids who are admitted to hospitals. Children who do not spend a lot of time in hospitals may not benefit from such learning arrangements. Advancement in treatment procedures has resulted in children spending limited time in hospitals.

Currently, some school districts organise for homebound programs where instructors visit learners at home. Unfortunately, the programs do not yield significant results as kids study in isolation. Suzuki and Kato (2014, p. 163) report, “patients in homebound schooling often feel unprepared to return to their community schools and report feeling lonely and isolated”.

According to Suzuki and Kato (2014), parents and teachers can use distributed learning to assist children with cancer. Suzuki and Kato (2014, p. 170) define distributed learning as “a system that responds to the unique learning needs of individual learners, and takes place outside the traditional classroom”. Literature review shows that few scholars have focused on the effectiveness of distributed learning in promoting education amid children with chronic illnesses. The learning method utilizes online technology, print-based materials, and Web 2.0 instruments to teach childhood cancer survivors who are recuperating at home. Even though distributed learning assists students to continue with their studies, it does not fulfill the socialisation needs.

Research conducted in Australia appreciates the significance of transforming the provision of educational assistance to children with cancer. The study champions the use of technology to deliver curriculum to students who are recuperating at home. The application of contemporary technology like Skype helps to establish an interactive learning environment, as the chronically ill student can connect with the classroom. Moreover, technology supports self-sufficiency and facilitates individualised learning, which is tailored to the needs of the student.

A study by Thies and McAllister (2012) reinforces the findings of the significance of technology in promoting learning amid cancer students. The research underlines that synchronous technology enables the student to stay in contact with classmates. Additionally, the chronically ill learner remains active both academically and socially.

According to Thies and McAllister (2012, p. 171), “shared online whiteboarding allows students to participate in tutoring sessions with the teacher during mathematics lessons”. The strategy is more helpful than telephone conversations as instructors can elaborate on areas that the learner does not understand. Additionally, children with cancer get an opportunity to interact with their classmates, albeit virtually, and share ideas on how to handle certain mathematical questions.

Lightfoot, Mukherjee and Sloper (2012) report that the use of synchronous technology to assist children with cancer to continue with their education helps the learners to establish a custom that links them to an essential nonmedical constituent of their lives. The classmates and teachers become more compassionate and understand the challenges that children with cancer endure, thus embracing them as members of the school community.

Nevertheless, Thies and McAllister (2012) raise the question about the number of interruptions that arise in the course of learning because of the continuing treatment. The study recommends research to determine the role that asynchronous communication tools can play to enhance schooling amid cancer children.

Significance of Communication

Thompson et al. (2015) conducted a study to investigate the importance of communication in providing school reentry support to children with cancer. The study relied on secondary information from peer-reviewed journals bearing literature on communication and school reentry support for children with cancer. A total of 17 scholarly journals were used. The study found that communication-enabled teachers and children to understand the needs of childhood cancer survivors.

Additionally, cooperation between parents and teachers enabled them to offer the necessary support to the children. The study did not touch on ethical issues that might inhibit school reentry of children with cancer. Communication between parents and teachers enable children to be at par with other students (Charlton, Pearson & Morris-Jones 2012). It allows a child to complete assignments and follow the established lesson plans. Moreover, some teachers provide academic assistance such as tutoring. It encourages a child to continue with its studies despite the health condition.

Charlton, Pearson and Morris-Jones (2012, p. 1339) argue, “Maintaining excellent communication with your child’s school will activate additional resources that may be available to help you and your child as they balance the awkward bridge between school and treatment”. Some schools provide emotional support to children with cancer. They offer counselling services to emotionally distressed kids and assure them that they will overcome their condition and go back to school.

Many schools facilitate social interaction between children with cancer and other students. They help students to understand the challenges that kids with cancer have to endure and their role in helping them to reintegrate into school. It contributes to minimising rejection and guarantees a smooth return to school.

Children with cancer encounter numerous challenges in their effort to continue with studies. Rejection from peers is a major problem that makes it difficult for children to reintegrate into school. Apart from changes in the physical appearance of a child due to treatment, misconceptions about cancer lead to students avoiding childhood cancer survivors when they return to school. Social inclusion is paramount in helping children with cancer return to school. Education institutions should ensure that they meet the social needs of children with cancer. Childhood cancer affects the academic and cognitive functioning of a child.

The affected child has problems in understanding Mathematics, English and Science subjects. The most affected children are those who undergo cancer treatment at an early age. Teachers have a role to play in helping children with cancer return to school. They require establishing a healthy relationship with childhood cancer survivors and giving them adequate time to complete assignments. Pediatric cancer survivors prefer teachers who understand their conditions.

The use of technology can help students to continue with studies as they recuperate at home. Synchronous technology can aid to establish an interactive learning environment and enable a child to stay in touch with classmates. Communication between parents and school administration can go a long way towards ensuring that a child is not left behind academically.

A’Bear, D 2014, ‘Supporting the learning of children with chronic illness’, Canadian Journal of Action Research , vol. 15, no. 1, pp. 22-39.

Barrera, M, Shaw, A, Speechley, K, Maunsell, E & Pogany, L 2014, ‘Educational and late social effects of childhood cancer and related clinical, personal, and familial characteristics’, Cancer , vol. 104, no. 8, pp. 1751-1760.

Bessell, A 2013, ‘Children surviving cancer: psychosocial adjustment, quality of life, and school experiences’, Exceptional Children , vol. 67, no. 3, pp. 345-359.

Charlton, A, Pearson, D & Morris-Jones, P 2012, ‘Children’s return to school after treatment for solid tumors’, Social Science and Medicine , vol. 22, no. 12, pp. 1337-1346.

Donovan, O 2014, ‘Building personal and social competence through cancer-related issues’, Journal of School Health , vol. 79, no. 3, pp. 138-143.

Fraser, D 2015, ‘Strangers in their own land: friendship issues when children have cancer’, Journal of Research in Special Education Needs , vol. 3, no. 3, pp. 147-153.

Gorin, S & McAuliffe, P 2013, ‘Implications of childhood cancer survivors in the classroom and the school. Health Education , vol. 109, no. 1, pp. 25-48.

Lightfoot, J, Mukherjee, S & Sloper, P 2012, ‘Supporting pupils with special health needs in mainstream schools: policy and practice’, Children and Society , vol. 15, no. 1, pp. 57-69.

McLoone, J, Wakefield, C & Cohn, R 2013, ‘Childhood cancer survivors’ school (re)entry: Australian parents’ perceptions’, European Journal of Cancer Care , vol. 22, no. 4, pp. 484-492.

Shiu, S 2014, ‘Issues in the education of students with chronic illness’, International Journal of Disability, Development and Education , vol. 48, no. 3, pp. 269-281.

Suzuki, L & Kato, P 2014, ‘Psychosocial support for patients in pediatric oncology: the influences of parents, schools, peers, and technology’, Journal of Pediatric Oncology Nursing , vol. 20, no. 4, pp. 159-174.

Thies, K & McAllister, J 2012, ‘The health and education leadership project: a school initiative for children and adolescents with chronic health conditions’, Journal of School Health , vol. 71, no. 5, pp. 167-172.

Thompson, A, Christiansen, H, Elam, M, Hoag, J, Irwin, M, Pao, M, Voll, M, Noll, R & Kelly, K 2015, ‘Academic continuity and school reentry support as a standard of care in pediatric oncology’, Pediatric Blood & Cancer , vol. 62, no. 1, pp. 805-817.

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The Latest Research on Why So Many Young Adults Are Getting Cancer

By Bill Piersol Tuesday, September 3, 2024

Charisma McDuffie, diagnosed with breast cancer at age 28, was treated by MSK's Dr. Shari Goldfarb in a program specifically tailored for young women with breast cancer.

It’s a disturbing mystery that has drawn the attention of investigators from across Memorial Sloan Kettering Cancer Center (MSK).

Why are a growing number of young people under 50 being diagnosed with over a dozen forms of cancer around the world?

Types of Cancers Becoming More Common in Young People

Men and women in the prime of their lives are increasingly being diagnosed with serious cancers, including  colorectal ,  breast ,  prostate ,  uterine ,  stomach (gastric) ,  pancreatic , and more. One  forecast predicts cancer for this age group will increase by 30% globally from 2019 to 2030.

“This is serious and worrisome,” says  Shari Goldfarb, MD, breast oncologist and Director of MSK’s  Young Women With Breast Cancer program.   

MSK breast oncologist Dr. Shari Goldfarb

“This is not a blip,” explains  Andrea Cercek, MD, gastrointestinal oncologist and Co-Director of  The Center for Young Onset Colorectal and Gastrointestinal Cancer . “The more data we gather, the clearer this becomes.”

MSK is a pioneer in caring for the specific needs of people facing what are often called early-onset cancers, who confront very different challenges than older adults. The coming surge in cases is a key reason MSK is building a new state-of-the-art hospital, called the MSK Pavilion.

Just as importantly, MSK experts are leading the investigation into why this is happening.

Is Obesity Causing More Young People to Get Cancer?

An obvious focus for rising cancer rates is the vicious circle of  obesity, highly processed foods, and sed­entary lifestyles , which are an epidemic in America and growing in many countries.

“We know obesity causes inflamma­tion, which can lead to cancer,” explains Dr. Goldfarb. “We believe that plays a role and needs to be addressed. But it doesn’t fully explain the growing rates of young women with breast cancer.”

MSK gastroenterologist Dr. Robin Mendelsohn

Nor does it explain the increase in cases seen by MSK’s Center for Young Onset Colorectal and Gastrointestinal Cancer, which is co-directed by  gastroenterologist Robin Mendelsohn, MD . The center has tracked more than 4,000 younger adults. “They are actually less likely to be obese than the general popu­lation,” says Dr. Mendelsohn. “They are also less likely to use tobacco or have other known risk factors.”

Promising Leads for the Mystery of Increasing Rates of Cancer in Young Adults

MSK experts agree there is not a single smoking gun. “If there was, researchers would have found it,” says Dr. Mendelsohn. “Instead, there are likely several causes.”

Dr. Cercek explains, “The working hypothesis is that there is an environmen­tal exposure — or multiple exposures — that people born starting in the 1950s came in contact with.” It’s possible, she says, that the “exposures began in the 1960s or ’70s and have been continuously present since then.”

While MSK researchers don’t yet know what that exposure might be, they have discovered promising leads.

How Microbiome Diversity Effects Cancer Rates

In May, Dr. Mendelsohn presented prelim­inary data at a medical conference about the microbiome of people with early-onset colorectal cancer. The microbiome, also known as the invisible organ, is the enormous community of bacteria and other microbes that live in our gut, which help regulate our digestive system.

“We found that younger people with colorectal cancer had less diversity in their microbiome than older patients,” says Dr. Mendelsohn. “And the makeup of the two groups’ microbiome is different too.” That’s important because more diversity generally means better health.

By scouring the vast amount of life­style data younger patients at MSK have provided, she says, MSK is “investigating factors we know affect the microbiome, including dietary changes, medications such as antibiotics, and even factors from childhood, such as breastfeeding and C-section patterns, age of parents at birth, and more.”

The goal, says Dr. Mendelsohn, is to “look for a possible trigger that would explain why the microbiomes of these patients are different.” 

MSK gastroenterologist Dr. Monika Laszkowska

Stomach cancer research by  gastro­enterologist Monika Laszkowska, MD, MS , focuses on another angle: how to identify younger people at high risk so they can be screened.

“We know that certain groups, such as people of East Asian ancestry, are at higher risk of stomach cancer, which is often trig­gered by a microbe called Helicobacter pylori ,” she explains. “Our research involv­ing patients at MSK also found other groups, such as younger Hispanic women, are more likely to develop early-onset stomach cancer.” That insight could lead to more awareness among Hispanic and Latina women and their doctors.

Dr. Laszkowska’s research also raises new questions. “Stomach cancer is slow-moving. So why is it developing more quickly in younger people?” she asks. “Could the malignancy be growing through a different pathway? Or could it be spurred by another condition, such as an autoimmune disease?”

Is Early-Onset Cancer Biologically Different?

These questions led to another: Is early-onset cancer biologically different and more aggressive than cancer in older people?

MSK gastrointestinal oncologist Dr. Andrea Cercek

A  study led by Dr. Cercek discovered an intriguing dynamic involving colorectal cancer. Her research found that colorectal patients treated at MSK responded the same way to chemotherapy “whether they were 17 or 70,” she says. “Those in the younger group were more likely to have rectal cancer. But the biology of the disease looked the same as in older patients.

More Dangerous Breast Cancer Subtypes Appearing in Younger Women

However, cancer is not a single disease. Instead, it is over 400 different diseases.

Dr. Goldfarb points out, “Breast cancer subtypes called  triple-negative and  HER2-positive are more common among young women — and have a worse prognosis.”

She explains that “some of the risk factors for breast cancer are increasingly found in younger women.” She adds, “For example, they are exposed to more years of unopposed reproductive hormones because they are experiencing menstru­ation earlier and having children later.”

However, she stresses that this — along with the rise of obesity — does not fully explain why more women under 50 are developing particularly aggressive forms of breast cancer.

MSK’s investigation into why includes every tool at researchers’ disposal, from surveys that reveal all aspects of lifestyle and personal history to next-generation genomic testing to determine what’s happening on the genetic level.

Dr. Goldfarb points to research by  breast oncologist Pedram Razavi, MD, PhD , to uncover minimal residual disease in patients. She also uses blood tests that look for mutations in tumors to help guide treatment decisions by predicting which treatments will be most effective.

Comprehensive Cancer Care for the Needs of Younger People

As the investigations continue, MSK specialists support the unique needs of younger adults. “Our program helps with the specific concerns of this stage of life, including  fertility preservation , talking with children , parents and colleagues about a cancer diagnosis, discussing impact on work , dating ,  sexual health and much more” says Dr. Goldfarb.

“When a person is diagnosed with cancer, it turns their world upside down. We’re there to help not just with their physical health, but their entire social and emotional well-being.”

Change lives with us.

Essay on Cancer for Students and Children

500+ words essay on cancer.

Cancer might just be one of the most feared and dreaded diseases. Globally, cancer is responsible for the death of nearly 9.5 million people in 2018. It is the second leading cause of death as per the world health organization. As per studies, in India, we see 1300 deaths due to cancer every day. These statistics are truly astonishing and scary. In the recent few decades, the number of cancer has been increasingly on the rise. So let us take a look at the meaning, causes, and types of cancer in this essay on cancer.

Cancer comes in many forms and types. Cancer is the collective name given to the disease where certain cells of the person’s body start dividing continuously, refusing to stop. These extra cells form when none are needed and they spread into the surrounding tissues and can even form malignant tumors. Cells may break away from such tumors and go and form tumors in other places of the patient’s body.

Types of Cancers

As we know, cancer can actually affect any part or organ of the human body. We all have come across various types of cancer – lung, blood, pancreas, stomach, skin, and so many others. Biologically, however, cancer can be divided into five types specifically – carcinoma, sarcoma, melanoma, lymphoma, leukemia.

Among these, carcinomas are the most diagnosed type. These cancers originate in organs or glands such as lungs, stomach, pancreas, breast, etc. Leukemia is the cancer of the blood, and this does not form any tumors. Sarcomas start in the muscles, bones, tissues or other connective tissues of the body. Lymphomas are the cancer of the white blood cells, i.e. the lymphocytes. And finally, melanoma is when cancer arises in the pigment of the skin.

Get the huge list of more than 500 Essay Topics and Ideas

Causes of Cancer

In most cases, we can never attribute the cause of any cancer to one single factor. The main thing that causes cancer is a substance we know as carcinogens. But how these develop or enters a person’s body will depend on many factors. We can divide the main factors into the following types – biological factors, physical factors, and lifestyle-related factors.

Biological factors involve internal factors such as age, gender, genes, hereditary factors, blood type, skin type, etc. Physical factors refer to environmental exposure of any king to say X-rays, gamma rays, etc. Ad finally lifestyle-related factors refer to substances that introduced carcinogens into our body. These include tobacco, UV radiation, alcohol. smoke, etc. Next, in this essay on cancer lets learn about how we can treat cancer.

Treatment of Cancer

Early diagnosis and immediate medical care in cancer are of utmost importance. When diagnosed in the early stages, then the treatment becomes easier and has more chances of success. The three most common treatment plans are either surgery, radiation therapy or chemotherapy.

If there is a benign tumor, then surgery is performed to remove the mass from the body, hence removing cancer from the body. In radiation therapy, we use radiation (rays) to specially target and kill the cancer cells. Chemotherapy is similar, where we inject the patient with drugs that target and kill the cancer cells. All treatment plans, however, have various side-effects. And aftercare is one of the most important aspects of cancer treatment.

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"My Friend Has Cancer:" Helping Adolescents and Young Adults Cope

Normally, adolescents and young adults first experience cancer from older relatives who have been diagnosed. But what happens when a peer gets diagnosed with cancer?

Mary Laliberte , Licensed Clinical Social Worker at Connecticut Children’s Center for Cancer and Blood Disorders specializes in supporting Adolescents and Young Adults (AYA) and their families through scenarios like these. She offers the following guidance to teens and young adults.   Read below or print out our downloadable guide, My Friend Has Cancer. How Do I Help? to share. 

When a friend has cancer, expect a mix of emotions.

If you are reading this, you probably have a friend who was just diagnosed with cancer. This may feel a bit overwhelming as you try to figure out how to help your friend navigate what is ahead. It’s ok to feel a mix of emotions…sad, angry or just disbelief this is happening  to someone you care about. We hope you find the information ahead helpful as you support your friend with cancer. They are going to need you! So let’s start at the beginning.

What is cancer?

To keep it simple, it is when cells in your body multiply too quickly. These can be cells in your blood, bones or really anywhere. We don’t know why cancer happens to some people but many doctors and researchers are working hard to figure it out.

>Related: Here’s how to talk to kids about a sibling’s cancer diagnosis .

How does a medical team help my friend with cancer?

The most common treatments for cancer involve surgery, chemotherapy and/or radiation. Surgery helps to remove the cancer and chemotherapy and radiation help destroy cancer cells in different ways. Your friend is on a treatment protocol for their specific type of cancer. Think of it as a recipe of different medicines (called chemotherapy) and/or radiation (beams of intense energy). Treatment may require frequent visits to the hospital’s outpatient clinic or ongoing inpatient admissions (where they have to stay in the hospital overnight) that can last a few days to a few weeks. Total treatment time may be a few months or a few years, depending on the type of cancer. In order to make treatment a little bit easier, your friend may get a “port”, which is a device surgically placed in their chest that is used to get chemotherapy or have blood drawn. It’s a lot…which is why your friend needs your support in the days, weeks and months ahead.  

Sometimes cancer can make things weird between friends.

You might be worried you are going to say or do the wrong thing. The one thing people with cancer want you to know is that they are still the same person, just with a new challenge before them. In fact, we know that the worst thing you can do is nothing! People with cancer want to feel supported and connected to their friends.  And while that may look a bit different now, it is more important than ever.  

There are many ways to be a good friend to someone with cancer.

The most important part of being a good friend is to keep showing up…not just in the beginning but throughout the entire course of their treatment… and you can do that in big and small ways. Even just sending a text on a regular basis lets them know you are thinking about them. You may ask them, “How can I help?” and they may or may not have an answer. So perhaps you can ask if they want a school/work update, offer to watch a movie, bring over some food, coffee or ice cream or just be there to listen. It’s important to keep checking in because how your friend is doing physically and emotionally can change frequently. It is also ok to admit to your friend that you just aren’t sure what to say or do. Sometimes just putting that out there allows everyone to take a breath and move forward.

It is helpful to keep in mind that some people are very public about their diagnosis and others only let their inner circle know what’s up. Always check in with your friend about what they want shared and what they want to be held in confidence.  If you have read this far, it is clear you care about your friend and want to help. Cancer does change many things but your friendship can remain one of the constants in your friend’s life >Attention, families: We know being an adolescent or young adult with cancer comes with its own set of challenges. That’s why Connecticut Children’s adolescent and young adult (AYA) cancer program offers specialized support and resources for the road ahead.   

Want more articles like this from pediatric experts you trust?

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Childhood Brain Tumor Survivors Can Lag in School -- Interventions Can Help

Key Takeaways

Very young children who survive a brain tumor often lag behind at school later

New research shows that families with the resources for early interventions can help kids catch up

Making such interventions available to all families could be a game-changer, researchers said

TUESDAY, Sept. 3, 2024 (HealthDay News) -- Brain tumors in young children are rare, but those who survive them can lag in school for years afterwards, new research shows.

For those families that can afford it, intervening when kids are still in the preschool years might help them perform better academically later on, researchers said.

“We now know that we don't need to wait until patients are struggling with math and reading; we can intervene earlier,” said study senior author Heather Conklin .

“We showed that the variability we're seeing early on predicts longer-term academic skills, which highly suggests earlier interventions will be beneficial and make a real difference," said Conklin, chief of neuropsychology at  St. Jude Children’s Research Hospital in Memphis, Tenn.

The new research focused on an understudied group: Children who had been treated and survived a brain tumor that occurred in infancy or before the age of 3.

Conklin and her colleagues followed the academic progress of 70 of these children every six months over the course of five years.

"We found an increasing gap between these young patients treated for brain tumors and their typically developing peers because their academic readiness skills were not developing as fast,” she noted in a St. Jude news release. "They were gradually falling behind their same-age peers in academic fundamentals, such as learning their letters, numbers and colors.”

The lag in development and academic skills was durable.

“Early academic readiness was predictive of long-term reading and math outcomes,” Conklin said. “The effect isn’t temporary. These children don’t just catch up naturally.”

A certain segment of children did tend to close the gap over time, however: Those from better-off families.

“The only clinical or demographic factor we found that predicted academic readiness was socioeconomic status,” Conklin said. “Being from a family of higher socioeconomic status had a protective effect on children’s academic readiness.” 

That's probably because parents have the money and time to invest in interventions that help toddlers catch up.

Finding ways to help the families of all childhood survivors of brain cancer access these resources is important, the researchers said, because cancer treatment keeps youngsters from developing as they naturally would.

“We know that being away from their home environment, caregivers, daycare, play dates, parks and early intervention services during these critical developmental years is probably having a negative impact on very young patients,” Conklin explained.

“Our results suggest that families can make play meaningful, and by making little changes in how they interact with their child, with the support of their medical team and receiving appropriate resources, they may be able to make a difference in their child’s cognitive and academic outcomes," she said.

The study was funded by St Jude and the National Cancer Institute, and published recently in the Journal of the National Cancer Institute .

More information

Find out more about the treatment of pediatric brain tumors at Johns Hopkins Medicine .

SOURCE: St. Jude Children's Research Hospital, news release, Aug. 20, 2024

What This Means For You

Very young kids who survive a brain tumor often lag in academics later, but early interventions can help.

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Meet Kid Captain Atlas Coleman

Call it a parent’s intuition. Call it knowing that expert health care happens at University of Iowa Health Care Stead Family Children’s Hospital. Whatever you call it, Atlas Coleman’s family is forever grateful that a second opinion meant an early diagnosis for their baby’s rare, aggressive cancer.

Stacy and Neal Coleman took their son to the emergency room after Atlas suddenly became inconsolable while eating a grilled burger when he was about 15 months old. An X-ray showed no foreign objects, but revealed a lung abnormality, and after a subsequent CT scan, doctors diagnosed Atlas with congenital pulmonary airway malformation, or CPAM, a non-cancerous lung lesion.

While that type of cyst is benign, it had the potential to turn malignant, so it would need to be removed. The couple decided to schedule an appointment at Stead Family Children's Hospital for another opinion.

“After meeting with the surgeon, we immediately knew we wanted to transfer Atlas’ care to the children’s hospital,” Stacy says. “They made us feel so comfortable about what was to come.”

How surgery found the ‘rare thing’

At about 18 months old, Atlas slept in his car seat as his parents drove from their central Iowa home to Iowa City for surgery to remove the lower lobe of his left lung.

“We had very good medical advice, but of course, it’s scary,” Stacy says. “I remember crying in the car on the way there.”

Neal notes that the surgeons at Stead Family Children's Hospital perform this type of operation once or twice per month, more than anywhere else in the state.

“Talking with a surgeon who does it routinely made us feel more comfortable,” he says. “There was some comfort knowing we were in good hands.”

Expecting a two-hour surgery, Atlas’ parents say the operation took twice as long, as Erica Carlisle, MD — sensing Atlas might have a rare cancer, as something did not look quite right — spent extra time to make sure his entire chest cavity was clear of abnormalities.

An analysis of the removed tissue would tell the couple if it was CPAM or something else.

“The other possibility was so rare that we did not expect anything out of the ordinary from the biopsy results,” Stacy remembers.

On the final day of their hospital stay, Carlisle came to the family’s room with the results of the biopsy.

“She said, ‘The really rare thing that we thought was unlikely to happen, happened,’” Stacy recalls.  

The couple learned their toddler had pleuropulmonary blastoma, a fast-growing cancer that forms in lung tissue.

“It’s very rare,” Stacy says. “It’s only diagnosed a few times a year.”

Designing a custom treatment plan

Through genetic testing, they also learned Atlas has a rare mutation of the DICER1 gene that puts him at high risk for other types of cancers.

Though shocked by the diagnosis, they were relieved the cancer was caught when it was, especially after being given advice elsewhere to monitor the cyst for six months.

“If we had waited another month, the cancer would have been in a more advanced stage,” Neal notes.

Because of its rarity, Stacy said there was no standard plan for treating it, but Atlas’ care team at Stead Family Children’s Hospital reached out to a partner program to design a treatment plan specific to his needs.

Atlas underwent six months of chemotherapy, an intense time for the family, filled with in-patient stays, weekly drives to Iowa City for infusions and clinic visits, regular scans, additional surgeries, and “the seismic shift that living our day-to-day with a child with cancer had on our lives,” Stacy says. 

“It can so easily feel overwhelming and insurmountable, but a constant source of comfort was the capable team supporting him,” she adds. “They were always patient, responsive, and caring.”

Here to stay

Scans showed no detectable cancer in his body throughout the course of Atlas’ treatment. “It was in remission for the entire time of his surveillance,” Stacy notes, but because Atlas was so young at the time, many of his blood draws and other procedures were difficult, resulting in medical anxiety.

“He didn't understand that these pokes were necessary to help him get better, so he resisted at every turn,” she says. “But even at his most challenging, we were never treated with anything except patience and kindness. The hospital’s Child Life team made an effort to learn what helped him get through the challenging moments, and his doctors and nurses partnered with us on ways to make each appointment as easy as possible on him.”

Neal noted that the couple has not considered going elsewhere for Atlas’ care.

“We had such a good experience and felt confident in the care team there,” he says.

While concern about his lungs has diminished, Neal says the DICER 1 mutation means cancer could appear in his kidneys, thyroid, or elsewhere, so Atlas will need to be continuously monitored, possibly for life.

Now 8 and in third grade, Atlas has tested cancer-free for six years. The West Des Moines boy enjoys drawing, sports, reading, and telling jokes.

“He likes all the things,” Stacy says. “He picks up an interest and he never puts it down.”

Atlas also loves going to local cancer walks to wear his survivor shirt, “letting others know that they can beat this, too,” she says.

“We tell people all the time: Stead Family Children's Hospital saved our son’s life,” Stacy adds. “He is alive today because of the knowledge and proactive care provided to him by an incredible team of doctors, nurses, and support staff. We are endlessly thankful to be from Iowa and have such close access to this amazing hospital.”

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Elle Macpherson reveals breast cancer diagnosis, why she rejected traditional treatment

Elle Macpherson has revealed she’s a breast cancer survivor, a diagnosis she kept secret for seven years.

The supermodel says she was diagnosed with HER2-positive estrogen receptive intraductal carcinoma — sometimes called stage 0 breast cancer — after undergoing a lumpectomy and finding out the results on a Friday the 13th.

“It was a shock, it was unexpected, it was confusing, it was daunting in so many ways,” Macpherson, 60, told The Australian Women’s Weekly in an interview published Monday, Sept. 2.

Her doctor advised a mastectomy with radiation, chemotherapy, hormone therapy and breast reconstruction. But Macpherson said that after consulting 32 doctors and experts, she decided not to undergo chemotherapy and focus on “an intuitive, heart-led, holistic approach” to treatment instead.

The decision was in line with her long-held belief in holistic medicine, noting she had to be “true to myself” and felt the chemo and surgery route "was extreme."

But she admitted people thought she was “crazy” to reject traditional treatment.

One of Macpherson's sons wasn’t comfortable with her choice, the other was fine with it, she noted.

“Saying no to standard medical solutions was the hardest thing I’ve ever done in my life. But saying no to my own inner sense would have been even harder,” she writes in her new book, “Elle.”

“I came to the understanding that there was no sure thing and absolutely no guarantees. There was no ‘right’ way, just the right way for me.”

Macpherson said her treatment involved spending eight months in Phoenix, Arizona, under the care of her primary doctor, who specializes in integrative medicine. This practice combines conventional and complementary approaches, with an emphasis on treating the whole person, according to the National Center for Complementary and Integrative Health .

She also saw a doctor of naturopathy, a holistic dentist, an osteopath, a chiropractor and two therapists, describing her time there as “focusing and devoting every single minute to healing myself.”

The supermodel said she’s now “in clinical remission,” with every test and scan coming back clear.

What is intraductal carcinoma?

Intraductal carcinoma, also called ductal carcinoma in situ, is a non-invasive or pre-invasive breast cancer, according to the American Cancer Society . It makes up about 20% of new diagnoses of breast cancer.

The condition means abnormal cells have been found in the lining of a breast duct, but haven’t spread, the National Cancer Institute notes.

Almost all women with this stage 0 breast cancer can be cured.

Macpherson’s cancer was HER2 positive , which means she had a higher level of a protein that helps breast cancer cells grow quickly, according to the American Cancer Society.

How is intraductal carcinoma treated?

DCIS can sometimes become invasive, but there’s currently no way to know which cases will progress so most patients are treated.

Women with DCIS usually undergo breast-conserving surgery — where the tumor and a small amount of normal breast tissue around it is removed — or a mastectomy, where the entire breast is removed, the American Cancer Society notes. That’s followed by radiation.

HER2-positive cancer is also usually treated with drugs that target the protein. If the cancer is hormone receptor-positive for estrogen or progesterone, hormone therapy is part of the treatment.

Left untreated, about 10% to 50% of DCIS cases may progress to invasive breast cancer, according to Susan G. Komen .

A 2019 study published in the Journal of the National Cancer Institute found DCIS patients who don’t undergo treatment have a limited risk of invasive progression.

A. Pawlowski is a TODAY health reporter focusing on health news and features. Previously, she was a writer, producer and editor at CNN.

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Childhood Cancer Awareness Month 2024

The International Agency for Research on Cancer (IARC) is highlighting some of the research areas that IARC scientists are working in, to mark Childhood Cancer Awareness Month 2024, and will post news items, infographics, and videos during the month of September to offer insights into how and why IARC focuses on these aspects of childhood cancer.

IARC scientists are engaged with partners at the international, regional, and relatively local levels in their studies on paediatric cancers. Locally, IARC is part of South-ROCK, an integrated centre of excellence in childhood cancer research based in Lyon and Marseille, France. Activities at the regional level include IARC’s recently released review of the prevalence of childhood cancer survivors in Europe. Internationally, IARC researchers are supporting global initiatives to standardize and improve registration of childhood cancers, research projects to define molecular profiles of childhood cancer cases, and the World Health Organization (WHO) Global Initiative for Childhood Cancer.

The cancer types that occur most often in children are very different from the cancer types that occur mainly in adults. Worldwide, more than 275 000 children and adolescents (aged 0–19 years) are estimated to be diagnosed with cancer per year. Leukaemia, brain cancers, and lymphomas are the most common types overall. Young children also develop tumours specific to their young age, such as neuroblastoma, retinoblastoma, or kidney tumours. Preventing these cancer types is difficult because the causes are not yet well understood.

Visit the IARC website and social media channels regularly throughout September to learn more about the above-mentioned projects and others.

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Read more about the IARC Global Initiative for Childhood Cancer (GICC) Team

Read more about IARC’s work on childhood cancer

Visit the IARC X page

Published in section: Featured News

Publication date: 2 September, 2024, 1:27

Direct link: https://www.iarc.who.int/featured-news/childhood-cancer-awareness-month-2024/

Mobile phone use doesn't increase brain cancer risk, says research review

The authors also found no increased risk of leukaemia or brain cancers in children from radio or TV transmitters or mobile phone base stations.

Tuesday 3 September 2024 16:29, UK

A review of 63 studies has found no link between mobile phone use and an increased risk of brain cancer.

Commissioned by the World Health Organization (WHO), it found no rise in cases despite a huge increase in wireless technology over the last 20 years.

The review was headed by experts from the Australian Radiation Protection and Nuclear Safety Agency, and included investigators from 10 countries.

It looked at research on radio frequencies in the wavelengths of 300 Hz to 300 GHz - used for mobile phones, wi-fi, radar, baby monitors and other applications.

Co-author of the review Professor Mark Elwood, an honorary professor of cancer epidemiology at University of Auckland, said the team looked at cancers of the brain, pituitary gland, salivary glands, and leukaemias.

"None of the major questions studied showed increased risks," he said.

"For the main issue, mobile phones and brain cancers, we found no increased risk, even with 10+ years exposure and the maximum categories of call time or number of calls."

During the pandemic, 5G mobile phone masts were attacked in the UK and elsewhere in the baseless belief they were contributing to the virus.

The research review looked at 63 relevant articles, published between 1994 and 2022, from 22 countries.

"For mobile phones and brain cancers, there were studies with 10 or more years' use, and quite extensive use," said Professor Elwood.

"Most phone use in these studies was from past years and 1G -2G networks; the newer 3G-4G networks have substantially lower RF emissions.

"There were several studies that reported some increased risks, but these were outweighed in considering all the available evidence."

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When it comes to 5G mobile networks, Professor Elwood said there were no major studies so far, but that studies of radar - which has similar high frequencies - did not show an increased brain cancer risk.

The review is published in the Environment International journal and took four years to complete.

The risk in relation to other cancer types is due to be reported separately.

Keep up with all the latest news from the UK and around the world by following Sky News

Read more from Sky News: Brazil's Supreme Court upholds X ban Strange noises from Boeing spacecraft aren't serious - NASA

Professor Alberto Najera, a physicist and expert on radio frequencies and health at the University of Castilla-La Mancha in Spain, praised the "exhaustive systematic review".

He said the conclusions were "robust" and "supported by quality studies".

"The main implications of this study are that, according to the best available evidence to date, exposure to radiofrequency electromagnetic fields, such as those produced by mobile phones or telephone antennas, does not appear to significantly increase the risk of developing cancer," said Professor Najera.