Overview of the etiology of childhood cancer and future directions.

Purpose Of Review: We provide an overview of the etiology of childhood cancer, the state of the literature, and highlight some opportunities for future research, including technological advancements that could be applied to etiologic studies of childhood cancer to accelerate our understanding.

Recent Findings: Risk factors of childhood cancer were summarized based on demographics and perinatal factors, environmental risk factors, and genetic risk factors. Overall, demographics and perinatal factors are the most well studied in relation to childhood cancer.

Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

Background: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

EBV and post-transplant lymphoproliferative disorder: a complex relationship.

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous category of disease entities occurring in the context of iatrogenic immune suppression. Epstein-Barr virus (EBV)-driven B-cell lymphoproliferation represents the prototype of quintessential PTLD, which includes a range of histologies named nondestructive, polymorphic, and monomorphic EBV+ diffuse large B-cell lymphoma (DLBCL) PTLD. While EBV is associated with the majority of PTLD cases, other drivers of lymphoid neoplasia and lymphoma transformation can occur-with or without EBV as a codriver-thus underlining its vast heterogeneity.

Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I).

Purpose: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib.

Methods: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years.

Management of neonatal and infant aortic thrombosis: A single-center case series.

Neonatal and infant aortic thrombosis is a rare albeit life-threatening thrombotic event, particularly seen in premature infants with an arterial catheter in place. We describe our institutional experience and approach to the management of 11 infants with occlusive or nearly occlusive aortic thrombosis. We observed at least partial thrombus resolution in all patients.

Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience.

Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease.

A single-cell transcriptomic map of the developing Atoh1 lineage identifies neural fate decisions and neuronal diversity in the hindbrain.

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown.

Standardizing the evaluation and management of iron deficiency anemia secondary to heavy menstrual bleeding in the emergency department.

Background: Comprehensive guidelines for the management of iron deficiency anemia (IDA) in adolescents with heavy menstrual bleeding (HMB) presenting to the emergency department (ED) are lacking, leading to variability in care. We aimed to standardize the evaluation and management of these patients through the development and implementation of an evidence-based algorithm using quality improvement methodology.

Methods: Baseline data of the target population identified variability across four key measures of clinical management: therapy choice and administration, laboratory evaluation, hematology service consultation, and patient disposition.

Toxicity profile of high-dose methotrexate in young children with central nervous system tumors.

High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.

Update on Genetic Counselor Practice and Recommendations for Pediatric Cancer Predisposition Evaluation and Surveillance.

In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in patients with pediatric cancer have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals.

A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program.

Early rhombic lip Protogenin stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG) MYC NESTIN stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL). Oncogenic transformation of early Prtg rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG stem cells grow adjacent to a human-specific interposed vascular plexus in the RL, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma.

Optimizing early phase clinical trial washout periods: a report from the Therapeutic Advances in Childhood Leukemia and Lymphoma consortium.

Background: The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required to utilize evidence- and/or rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance.

Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity.

Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3β inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers.