Michael Deel

Hematologic homeostasis requires an intricate interaction of red blood cells, white blood cells, platelets, and coagulation factors. Normal parameters vary with age, sex, and race. Underlying causes for hematologic abnormalities in children may range from common benign phenomena such as self-limited cytopenias following viral infections, to rarer and more life-threatening entities like childhood acute lymphoblastic leukemia. Overlapping presenting features among these disorders demand thoughtful analysis and clinical acumen. Early recognition and intervention can often minimize complications and decrease long-term morbidity and mortality. In the majority of cases, diagnosis and management of these conditions will require consultation with a pediatric hematologist. Non-malignant quantitative and qualitative hematologic disorders are discussed in this section and have been curated with a general pediatric audience in mind. Given the relatively large number of disorders and the broad scope of the chapter, tables have been utilized to provide lists of disorders within categories, and not all disorders are discussed within the text.

Childhood and adolescent cancer are broadly categorized into leukemia, lymphoma, extracranial solid tumors, and central nervous system (CNS) tumors. Many of these cancers can present as oncologic emergencies, which are important to recognize. Supportive care for these patients is critical, including symptom management and blood product transfusions. Cancer predisposition syndromes can increase the risk of certain pediatric cancers. Prognosis depends on the pathology, anatomic location, age, and initial response to treatment. According to the National Cancer Institute, the 5-year survival rate for childhood cancer from 2010 to 2016 was 84.1% in children and 85.3% in adolescents. The duration of treatment is variable and dependent on several factors such as cancer type, age of patient, site of disease, molecular features, and staging. In this article, we will review different types of pediatric cancers, common cancer predisposition syndromes, oncologic emergencies, transfusion medicine, and chemotherapy related toxicities.

<jats:title>Abstract</jats:title> <jats:p>Although more than 20 years have passed since the discovery that fusion-positive rhabdomyosarcoma (FP-RMS) is driven by the chimeric fusion oncogene PAX3-FOXO1 (P3F), therapeutically tractable components of the P3F tumorigenic program have yet to be uncovered and survival rates remain dismal (5-yr overall survival &amp;lt;50%). YAP1 and TAZ, transcriptional co-activators of the Hippo pathway, are potent oncogenes known to mediate transcriptional addiction in malignancy. Here, we demonstrate that YAP1/TAZ complex with P3F and positively regulate P3F transcriptional activity in FP-RMS. Immunohistochemical (IHC) staining of human tissue microarrays were used to identify the relative abundance of YAP1 and TAZ in FP-RMS tumor samples. Functional interactions of YAP1/TAZ and P3F were investigated using P3F reporters, immunoblots, and co-immunoprecipitation (co-IP); while co-IP-coupled mass spectrometry (IP-MS) was used to identify the YAP1/TAZ/P3F interactome. Experiments utilized gain- and loss-of-function vectors expressing control, wild-type YAP1/TAZ, constitutively active YAP1/TAZ (S89A/S127A), or shRNA knockdown. To identify P3F-mediated genes and pathways that are YAP1/TAZ-dependent, we used RNA-Seq and quantitative proteomics via tandem mass tag labeling. We demonstrate via IHC that YAP1/TAZ are highly abundant in FP-RMS, and through functional assays that YAP1/TAZ regulate many FP-RMS cancer phenotypes. Mechanistically, an interaction between YAP/TAZ and P3F was demonstrated via co-IPs for endogenous as well as epitope-tagged proteins. This was confirmed with IP-MS, which also revealed that YAP/TAZ and P3F share an enrichment for co-immunoprecipitated proteins involved in DNA binding and transcriptional regulation. IP-MS also demonstrated that chromatin remodeling complex proteins were enriched with TAZ immunoprecipitation. YAP1/TAZ functionally augment P3F transcriptional activity in reporter assays as well as expression of candidate P3F target genes. An unbiased approach using RNA-Seq and quantitative proteomics demonstrate that YAP1/TAZ positively regulate differential expression of P3F target genes, as well as proteins involved in cell cycle progression and pan-cancer related proteins that are typically up- or down-regulated across multiple malignancy types.In conclusion, we identify a novel complex between YAP1/TAZ and P3F, show YAP1/TAZ are positive regulators of P3F transcriptional activity, and identify the YAP1/TAZ axis as a vulnerability for P3F-transcriptional reprogramming in FP-RMS.</jats:p> <jats:p>Citation Format: Tooba Rashid, Breanne A. Burgess, Corinne M. Linardic, Michael D. Deel. YAP1 and WWTR1 (TAZ) positively regulate PAX3-FOXO1 transcriptional programming in fusion-positive rhabdomyosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3882.</jats:p>

Malignant ectomesenchymoma (MEM) is a rare multiphenotypic tumor comprised of mesenchymal and neuroectodermal components. MEM is typically diagnosed in infants and younger children and outcomes are variable. The current approach for treating MEM includes targeting the more aggressive mesenchymal component of the tumor, which is often rhabdomyosarcoma. Here, we describe a case of an orbital tumor initially diagnosed and treated as low-risk rhabdomyosarcoma. Local failure prompting a second biopsy revealed neuronal differentiation consistent with a diagnosis of MEM. Intensifying therapy and local radiotherapy led to a long-term cure. This case offers a cautionary tale that while outcomes for MEM were similar to matched rhabdomyosarcoma cohorts when treated on conventional Intergroup Rhabdomyosarcoma Study Group (IRSG) III/IV protocols, treating MEM using a decreased intensity low-risk rhabdomyosarcoma regimen may not be sufficient.