Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.
Neuroblastoma is a common pediatric tumor characterized by clinical heterogeneity. Because it is derived from sympathetic neuroblasts, the NTRK family of neurotrophin receptors plays an integral role in neuroblastoma cell survival, growth, and differentiation. Indeed, high expression of NTRK1 is associated with favorable clinical features and outcome, whereas expression of NTRK2 and its ligand, brain-derived neurotrophic factor (BDNF), are associated with unfavorable features and outcome. AZ64 (Astra Zeneca) is a potent and selective inhibitor of the NTRK tyrosine kinases that blocks phosphorylation at nanomolar concentrations. To determine the preclinical activity of AZ64, we performed intervention trials in a xenograft model with NTRK2-overexpressing neuroblastomas. AZ64 alone significantly inhibited tumor growth compared to vehicle-treated animals (p = 0.0006 for tumor size). Furthermore, the combination of AZ64 with conventional chemotherapeutic agents, irinotecan and temozolomide (irino–temo), showed significantly enhanced anti-tumor efficacy compared to irino–temo alone [(p < 0.0001 for tumor size, p < 0.0005 for event-free survival (EFS)]. We also assessed the combination of AZ64 and local radiation therapy (RT) on a neuroblastoma hindlimb xenograft model, and the efficacy of local RT was significantly increased when animals were treated simultaneously with AZ64 (p < 0.0001 for tumor size, p = 0.0006 for EFS). We conclude that AZ64 can inhibit growth of NTRK-expressing neuroblastomas both in vitro and in vivo. More importantly, it can significantly enhance the efficacy of conventional chemotherapy as well as local RT, presumably by inhibition of the NTRK2/BDNF autocrine survival pathway.
Acral erythema is a rare cutaneous reaction that has been associated with various chemotherapy regimens. Most occurrences have been described in adult patients. Recently, methotrexate has been implicated in the development of acral erythema; however, pediatric reports are few. All of the reports in the pediatric and adult literature have described patients receiving moderate to high-dose intravenous methotrexate. Here, we describe an instance of standard-dose oral methotrexate-associated acral erythema in a young girl with acute lymphoblastic leukemia, and review the recent literature as it relates to pediatric patients.
Symptomatic venous thromboembolism (VTE) in the general hospitalized pediatric population is increasing and is the second most common serious hospital-acquired condition for patients in children' s hospitals, causing significant harm and expense. 1-3 Unlike other hospital-acquired conditions in children and adult VTE, 4 however, there are no broadly accepted recommendations for the implementation of a standardized process of detection, prophylaxis, and treatment of VTE in hospitalized children. 5 In this issue of Hospital Pediatrics, Shaughnessy and colleagues report both on variable quality-improvement (QI) success in decreasing variability in risk screening 6 and in the detection of VTE events among hospitalized pediatric patients. 7 We comment below first on the improvement lessons from a comparative intervention around VTE and current algorithms and then discuss the active surveillance approach for quickly identifying VTEs in hospitalized patients. Finally, we discuss how these 2 studies, taken together, can help us develop robust, population-based pediatric algorithms for preventing and addressing healthcare-acquired pediatric VTE. INCREASING THE RELIABILITY OF VTE SCREENING: ARE SOME SURGICAL MICROSYSTEMS BETTER THAN OTHERS? In their first article in this issue, Shaughnessy et al 6 report on their variable success in significantly improving and sustaining the reliability of a VTE prophylaxis screening process 8 to 86% and 46% in hospitalized pediatric surgery and orthopedic patients, respectively. The authors found that in addition to leadership and engagement, linking to a computerized provider order entry system postoperatively was the most impactful approach to ensuring high reliability for completing VTE screening. At first glance, this tale of variable success in these 2 surgical specialties seems to be a culture or ownership issue, with general surgery outperforming orthopedics in screening reliability. Setting aside the question of different populations and risk patterns, the lack of success in the orthopedics unit is a true QI opportunity to re-evaluate through plan-do-study-act cycles and choosing to adapt, adopt, or abandon a given intervention. 9 Because neither initiative achieved sustainable .90% reliability, despite extensive engagement and computerized provider order entry, and some 38% of orthopedic patients were over-or undertreated, it may be worth abandoning the laborintensive interventions and instead revisiting the workflow for orthopedics by further engaging the frontline staff,
ImportanceLittle is known about the risk of post–COVID-19 multisystem inflammatory syndrome in children (MIS-C) in the setting of childhood cancer.ObjectiveTo evaluate factors associated with MIS-C and describe the clinical course of COVID-19 in the setting of MIS-C.Design, Setting, and ParticipantsMultisite observational cohort study of a registry representing more than 100 US pediatric oncology sites. All included patients were registered between April 1, 2020, and May 18, 2022. Sites submitted deidentified data surrounding sociodemographics, cancer diagnosis and treatment, and COVID-19 course (symptoms, maximum support required, outcome). Patients with MIS-C (n = 24) were compared with matched controls (n = 96). Children (&lt;21 years) with cancer who developed COVID-19 while receiving cancer treatment or within 1 year of completing treatment were characterized based on their development of MIS-C.Exposures(1) Clinical and sociodemographic characteristics of children with cancer and COVID-19; and (2) MIS-C.Main Outcomes and Measures(1) Development of MIS-C among children with cancer and COVID-19; and (2) symptoms and disease severity associated with MIS-C.ResultsAmong 2035 children with cancer and COVID-19, 24 (1.2%) developed MIS-C. COVID-19 occurred at a median (IQR) age of 12.5 (5.5-17.1) years in those with MIS-C and 11 (6-16) years among matched controls (P = .86). The majority of children with MIS-C had a hematologic cancer (83.3% [n = 20]), were publicly insured (66.7% [n = 16]), and were Hispanic (54.2% [n = 13]). Half (n = 12) had 1 or more noncancer comorbidity. Those with comorbidities were more likely to develop MIS-C than those without (odds ratio [OR], 2.5 [95% CI, 1.1-5.7]). Among children with MIS-C, 100% (n = 24) were admitted to the hospital and 54.2% (n = 13) to the intensive care unit (ICU), while COVID-19 contributed to the death of 20.1% (n = 5); cancer therapy was changed in 62.5% (n = 15). Compared with matched controls, those with MIS-C had higher odds of symptoms classified as systemic (OR, 4.7 [95% CI, 1.4-15.8]) or gastrointestinal (OR, 5.0 [95% CI, 1.7-14.6]) along with higher odds of hospitalization (OR, 42.9 [95% CI, 7.1-258]), ICU admission (OR, 11.4 [95% CI, 3.6-36.4]), and changes to cancer therapy (OR, 24.9 [95% CI, 6.5-94.8]).Conclusions and RelevanceIn this cohort study among children with cancer and COVID-19, those with MIS-C had a more severe clinical course than those without MIS-C. The risk of MIS-C and its severity are important to consider as clinicians monitor patients with COVID-19. These findings can inform their conversations with families regarding COVID-19 risks and the benefits of prevention strategies that are pharmacologic (vaccination) and nonpharmacologic (masking), as well as treatment (antivirals, monoclonal antibodies).
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