Search

Additional figures and tables

Purpose:Chemotherapy for childhood acute lymphoblastic leukemia (ALL) can cause late-appearing side effects in survivors that affect multiple organs, including the heart and brain. However, the complex ALL treatment regimen makes it difficult to isolate the causes of these side effects and impossible to separate the contributions of individual chemotherapy agents by clinical observation. Using a mouse model, we therefore assessed each of eight representative, systemically-administered ALL chemotherapy agents for their impact on postnatal brain development and heart function.Experimental Design:Mice were treated systemically with a single chemotherapy agent at an infant equivalent age, then allowed to age to early adulthood (9 weeks). Cardiac structure and function were assessed using in vivo high-frequency ultrasound, and brain anatomy was assessed using high-resolution volumetric ex vivo MRI. In addition, longitudinal in vivo MRI was used to determine the time course of developmental change after vincristine treatment.Results:Vincristine, doxorubicin, and methotrexate were observed to produce the greatest deficiencies in brain development as determined by volumes measured on MRI, whereas doxorubicin, methotrexate, and l-asparaginase altered heart structure or function. Longitudinal studies of vincristine revealed widespread volume loss immediately following treatment and impaired growth over time in several brain regions.Conclusions:Multiple ALL chemotherapy agents can affect postnatal brain development or heart function. This study provides a ranking of agents based on potential toxicity, and thus highlights a subset likely to cause side effects in early adulthood for further study.

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2(+) mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

A clinical decision report appraising: Schwartz CL, Wexler LH, Krailo MD, et al. Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer. 2016;63(1):54-615. https://doi.org/10.1002/pbc.25753 for a patient with osteosarcoma and concerns about the risk of secondary malignant neoplasms that attend use of dexarazoxane.