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Prior to the introduction of chemotherapy and radiation in the 1940s, a cancer diagnosis meant certain death for the overwhelming majority of children. The implementation of cytotoxic therapy revolutionized childhood cancer care, drastically prolonging survival in various blood, brain, and bone cancers. Leukemia, which was the leading cause of cancer-related deaths in children in the 1970s, miraculously became a survivable disease. Osteosarcomas such as Ewing sarcoma saw drastic increases in survival rates. Pediatric brain tumors that were previously universally fatal saw remissions and even cures with radiotherapy.

By the 1990s, clinical progress in pediatric cancers plateaued and the darker side of cytotoxic cancer therapy began to emerge. Children that had been treated with chemotherapy and radiation started to exhibit a broad array of therapy-associated toxicities, including delayed or diminished neurocognitive function, cardiovascular diseases, metabolic diseases, pulmonary fibrosis, dental diseases, various infections, reproductive issues and infertility, and secondary malignancies. While adults treated with chemotherapy and radiation endure similar therapy-related toxicities, these toxicities are more pronounced in the pediatric population as they affect many aspects of growth and development. Likewise, surgery, bone marrow transplant, targeted therapy, and immune-based therapy have various short- and long-term side effects that can significantly reduce the quality of life for childhood cancer survivors.

Present day research focuses not only on novel therapy development but also on reducing the unnecessary use of toxic therapies. In the age of personalized medicine, clinical oncology is moving away from cytotoxic therapies in favor of more targeted, immune-centric therapeutic approaches with less associated toxicities. The first installation in this special two-issue series highlighted new frontiers in the diagnosis, treatment, and biological characterization of pediatric cancers; the second installation presented here includes 20 comprehensive review articles authored by leaders in pediatric oncology research that further discuss these frontiers with an emphasis on the short- and long-term management of treatment-associated toxicities.

Approximately one quarter of pediatric cancers originate in the brain or spinal cord and typically require some form of cytotoxic cancer therapy to be administered to the central nervous system (CNS). Thus, CNS therapy-associated toxicity presents a major clinical challenge in the management of pediatric cancers. Dr. Caren Armstrong and Dr. Lisa Sun from Johns Hopkins Department of Neurology provide a detailed overview of neurologic complications arising with tumor progression, paraneoplastic syndromes, or paradigm therapies in pediatric cancers. Dr. Yin Ting Cheung and his colleagues from the Chinese University of Hong Kong further detail neurocognitive impairment in Asian childhood cancer survivors, underlining its functional and psychosocial implications. Other therapy-associated toxicities discussed in this issue include oral and dental complications (Ritwik et al.), cardiovascular disease secondary to anthracyclines or radiotherapy (Bansal et al.), endocrine complications following hematopoietic stem cell transplant (Paetow et. al), and the role of bariatric surgery in treating therapy-induced obesity and metabolic disease in acute lymphoblastic leukemia (ALL) survivors.

In addition to medical management, therapy-associated obesity and cardiometabolic disease can be managed with exercise. Dr. Alejandro Lucia and his colleagues from Universidad de Europea de Madrid provide new insights into the effects of physical exercise interventions in childhood cancer survivors treated with cytotoxic therapy (Morales et al.). This group further explores the impact of exercise on metastasis in animal models (Rincón Castanedo et al.), providing two unique comprehensive reviews on the effects of exercise in both the pathogenesis and long-term management of cancer.

In addition to side effects, a major issue with cytotoxic therapy is therapy resistance and subsequent cancer relapse. Therapy resistance is believed to be due to cancer stem cells (CSCs), which are able to survive therapy and reestablish the tumor cell population following therapy cessation. One budding therapeutic approach to this issue is the repurposing of medications as anticancer agents. In this issue, Bahmad et al. elegantly characterize the anti-CSC activity of antidepressants, anti-inflammatories, antihypertensives, and other widely used drugs, and their potential roles as novel anticancer agents in pediatric brain tumors.

This issue explores a broad array of therapy-induced complications, highlighting the need for novel, non-toxic pediatric cancer treatments. However, many therapeutic advances are initially studied in adult clinical trials, and the results are difficult to adapt to the pediatric population. Thus, data on efficacy, toxicity, and impact on quality of life for the pediatric population are absent for many novel cancer drugs. In this issue, Dr. Teresa de Rojas and her colleagues from the Medical Department at the EORTC Headquarters in Belgium emphasize the importance of improving adaptation of clinical research tools from adult to pediatric populations. Given the debilitating short- and long-term effects of current cancer therapies, adapting clinical research tools and thereby opening avenues for novel drug use in younger patients are paramount to advancing pediatric cancer care.

While the first half of this issue focuses on the management of therapy-associated toxicity, alternative therapeutic strategies, and how to translate these from adult to pediatric populations, the second half sheds a spotlight on ongoing efforts to characterize and treat a broad array of pediatric malignancies. Blood and bone marrow cancers, especially leukemias, are the most common types of pediatric cancers worldwide. Of these, acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) are the most common. This issue explores both the prenatal origin of genomic aberrations in ALL (Hein et al.) and the molecular mechanisms and clinical implications of CNS involvement in ALL (Lenk et al.). Conneely et al. rounds out this issue’s exploration of leukemias with an insightful discussion of the genomic landscape of AML and its implications for therapeutic selection and patient outcomes.

CNS cancers, the vast majority originating in the brain, compromise the second most common type of pediatric malignancies worldwide. Medulloblastomas (MBs) account for the majority of these brain tumors and are thus the focus of many pediatric cancer researchers. This issue highlights the way in which scientific discovery informs clinical care, from an elegant review on how our increasing understanding of genetic heterogeneity in MB facilitates risk stratification and therapy selection (Menyhárt et al.) to Dr. Michelle M Kameda-Smith’s expert insights on how molecular data and radiogenomics have led to changes in the medical, but not neurosurgical, treatment of pediatric brain tumors. The critical role of scientific discovery in clinical advancement is not limited to MB, as emphasized by Dr. Sabine Mueller and her colleagues from the departments of neurology, neurosurgery, and hematology/oncology at the University of California San Francisco. In their review, Coleman et al. meticulously investigate how large-scale genomic analyses contribute to pediatric high-grade glioma (pHGG) classification and therapy selection while reviewing past, present, and future therapeutic strategies.

After blood and brain cancers, neuroblastoma (NB) is the most common pediatric malignancy. NBs overwhelmingly originate in the kidneys of infants, but can also be found in the chest, abdomen, or spinal cord. Like MB, NB is at the heart of pediatric oncology research due to its high incidence. In this issue, Dr. Jamie Fletcher and his colleagues from the Children’s Cancer Institute Australia and the Lowy Cancer Research Centre thoroughly characterize existing genetically engineered mouse models for high-risk subsets of NB, patient-derived xenograft models, and models of primary and metastatic disease. Preclinical research tools such as these are critical to furthering our understanding of the genetic origins of NB and their implications on therapeutic strategy and development. This topic is emphasized further in Tonini and Capasso’s comprehensive review, which expertly discusses the relationship between genomic predisposition and chromosome instability in NB.

This issue concludes with a discussion of rarer pediatric tumors. Unlike NB and other common pediatric tumors, many uncommon tumors remain poorly characterized in the pediatric population. While rare, tumors originating in soft tissue and bone, called sarcomas, disproportionately affect the pediatric population. This issue features an intricate discussion of rhabdomyosarcoma (RMS) invasion and metastasis (Ramadan et al.) as well as a unique discourse on melatonin’s apoptotic, antiangiogenic, and antiproliferative effects on sarcoma cells and potential use as an adjuvant cancer therapy (Lu et al.). Together, these reviews emphasize the exciting new therapeutic targets and strategies that have begun to emerge in pediatric sarcoma treatment.

Unlike sarcomas, ovarian teratomas are rare in both the general population and the pediatric population, as they primarily occur in reproductive-age females. Importantly, limited research on these tumors severely limits the possibility of therapeutic advancement and improved outcomes in these patients. This issue features a scoping review by Łuczak et al. that excellently summarizes the existing preclinical and clinical data ovarian teratomas, one of these aforementioned rare tumor types, and highlights the extensive knowledge gaps in our understanding of this tumor.

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Correspondence to Dipak Panigrahy.

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Panigrahy, D., Gilligan, M. Preface. Cancer Metastasis Rev (2020).

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