Brain Development and Heart Function after Systemic Single-Agent Chemotherapy in a Mouse Model of Childhood Leukemia Treatment

Noakes, T. Leigh Spencer; Przybycien, Thomas S; Forwell, Amanda; Nicholls, Connor J; Zhou, Yuqing; Butcher, Darci T.; Weksberg, Rosanna; Guger, Sharon; Spiegler, Brenda J.; Schachar, Russell; Itô, Shinya; Plas, Ellen van der; Nieman, Brian J.

doi:10.1158/1078-0432.ccr-18-0551

Cited by 11 publications

(16 citation statements)

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“…The evidence regarding the impact of treatment burden on neurocognitive outcomes is conflicting, with some studies showing significant associations between exposure to MTX or corticosteroids, 28,29 while other studies did not 8,30 . The lack of association between cumulative treatment exposures and school performance observed in the present study may be due to difficulties detecting the individual contributions of agents that were administered in a combination and via various routes 8,28,31 …”

Section: Discussioncontrasting

confidence: 73%

“…8,30 The lack of association between cumulative treatment exposures and school performance observed in the present study may be due to difficulties detecting the individual contributions of agents that were administered in a combination and via various routes. 8,28,31 Younger age at diagnosis has commonly been found to be associated with poorer neurocognitive outcomes following childhood…”

Section: Discussionmentioning

confidence: 99%

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Characterizing academic performance in pediatric acute lymphoblastic leukemia with population‐based achievement tests

et al. 2021

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Background Recent shifts from radiation to chemotherapy‐based treatment for acute lymphoblastic leukemia (ALL) have contributed to reduced long‐term morbidity. Despite this, ALL survivors remain at increased risk for long‐term cognitive impairments. Aim To identify demographic and treatment factors associated with school performance in pediatric survivors of ALL. Methods We collected standardized test scores for reading, math, and science obtained in a school setting from grades 3–11 in 63 ALL survivors (46.0% boys). Most participants were assessed across multiple grades (median number of grades n = 5, range 1–7), and 269 observations were considered in the analyses. Treatment exposures were extracted from medical records. Socio‐economic status was estimated using participation in free/reduced lunch programs at school. Mixed effects linear regression models were conducted to determine factors associated with school performance. Results ALL survivors' scores were comparable to state norms on reading, math, and science performances. On multivariable analysis, participation in free/reduced lunch programs was significantly associated with lower reading scores ( β = −12.52; 95% CI −22.26:−2.77, p = .01). Exposure to radiation during treatment was also associated with lower reading test scores ( β = −30.81, 95% CI −52.00:−9.62, p = .01). No significant associations between demographics and treatment parameters were observed for math and science test scores. Conclusions We utilized population‐based achievement tests conducted from grades 3–11 to characterize school performance in ALL survivors. Our results imply that survivors with low socio‐economic status and those exposed to radiation during treatment could benefit from early monitoring and intervention to maximize academic success.

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Characterizing academic performance in pediatric acute lymphoblastic leukemia with population‐based achievement tests

et al. 2021

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“…Preclinical models may provide an important alternative approach to investigating these factors and candidate mechanisms. We have already employed this strategy to examine the influence of cranial radiation on brain development ( de Guzman et al, 2015 , de Guzman et al, 2019 , Beera et al, 2018 ), including detailed comparisons to human outcomes ( Nieman et al, 2015 ), and for systematic evaluation of ALL chemotherapy agents and their contribution to brain toxicity ( Spencer Noakes et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Quantitative MRI outcomes in child and adolescent leukemia survivors: Evidence for global alterations in gray and white matter

Plas

Noakes

Butcher

et al. 2020

NeuroImage: Clinical

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Highlights Studies of cognition in ALL survivors consistently show evidence of mild neurocognitive difficulties. Structural MRI showed widespread differences between survivors and controls. Gray and white matter volumes were respectively 5 and 6% smaller in survivors. Survivors also exhibited altered white matter diffusion overall.

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“…The delayed appearance of PRV‐ir cells in the neocortex compared to CR‐ir neurons (present on PN0, increase between PN5 and 10 and decline to adult levels by PN15) or SST‐ir interneurons (present at PN0 and drastically increase between PN3 and 21) may potentially render PRV interneuronal progenitors more vulnerable to the induction protocol. Systemic DOX administration in PN17 mice also causes brain volume reductions, as assessed by magnetic resonance imaging (MRI) studies, attributed to proinflammatory effects . Histopathologic findings in DLP rodent brains have shown that DOX, a cytotoxic chemotherapy drug, and LPS, a Toll‐like receptor 4 agonist, can cause prominent inflammation in the peri‐infusional cortical area .…”

Section: Discussionmentioning

confidence: 99%

“…Systemic DOX administration in PN17 mice also causes brain volume reductions, as assessed by magnetic resonance imaging (MRI) studies, attributed to proinflammatory effects. 53 Histopathologic findings in DLP rodent brains have shown that DOX, a cytotoxic chemotherapy drug, and LPS, a Toll-like receptor 4 agonist, can cause prominent inflammation in the peri-infusional cortical area. 16 Whether these inflammatory changes contribute to the bilateral reduction in PRV interneurons and cortical atrophy, for example, via leakage of cytokines in the cerebroventricular space, remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Acquired parvalbumin‐selective interneuronopathy in the multiple‐hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs?

Katsarou

Liu

et al. 2018

Epilepsia Open

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SummaryWest syndrome, an age‐specific epileptic encephalopathy, manifests with infantile spasms (IS) and impaired neurodevelopmental outcomes and epilepsy. The multiple‐hit rat model of IS is a chronic model of IS due to structural etiology, in which spasms respond partially to vigabatrin analogs. Using this model, we investigated whether IS due to structural etiology may have deficits in parvalbumin (PRV) and somatostatin (SST) immunoreactive (‐ir) interneurons, and calretinin‐ir (CR‐ir) neurons of the primary somatosensory cortex of postnatal day (PN) 20–24 rats, using specific immunohistochemical assays. PN3 Sprague‐Dawley male rats underwent the multiple‐hit induction protocol, were monitored until PN20–24, and were transcardially perfused to collect brains for histology. Age‐matched sham and naive control male rats were also used. Coronal brain cryosections were stained with anti‐PRV, anti‐CR, and anti‐SST antibodies, and regions of interest (ROIs) from the primary somatosensory cortices were selected to determine PRV‐, CR‐, and SST‐ir cell counts and cortical ROI volumes, with blinding to experimental group. Statistical analyses were done using a linear mixed model accounting for repeated measures. We found PRV‐ir interneuronal selective reduction, sparing of the CR‐ir and SST‐ir neurons, and bilateral cortical atrophy. Our findings provide evidence for acquired PRV‐selective interneuronopathy, possibly underlying the pathogenesis of IS, neurodevelopmental deficits, and epilepsy, and potentially contributing to the partial response to vigabatrin analogs in this model.

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Brain Development and Heart Function after Systemic Single-Agent Chemotherapy in a Mouse Model of Childhood Leukemia Treatment

Abstract: 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.

Cited by 11 publications

References 48 publications

Characterizing academic performance in pediatric acute lymphoblastic leukemia with population‐based achievement tests

Characterizing academic performance in pediatric acute lymphoblastic leukemia with population‐based achievement tests

Quantitative MRI outcomes in child and adolescent leukemia survivors: Evidence for global alterations in gray and white matter

Acquired parvalbumin‐selective interneuronopathy in the multiple‐hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs?

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