Intellectual development of childhood ALL patients: a multicenter longitudinal study

Sleurs, Charlotte; Lemiere, Jurgen; Vercruysse, Trui; Nolf, Nathalie; Calster, Ben Van; Deprez, Sabine; Renard, Marleen; Vandecruys, Els; Benoît, Yves; Uyttebroeck, Anne

doi:10.1002/pon.4186

Cited by 20 publications

(31 citation statements)

References 40 publications

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“…Although a positive trend with age at diagnosis was expected as well, this correlation was not significant. Still, other pediatric oncology (i.e., brain tumor and leukemia) studies also evidenced higher neurotoxic vulnerability of the younger patients at diagnosis (Buizer et al, 2005;Caron et al, 2009;Sleurs et al, 2016b;von der Weid et al, 2003). Patients in our study were on average 13 years old at diagnosis.…”

Section: Microstructural Differences Intelligence Scores Chemothesupporting

confidence: 49%

“…Hence, it becomes essential to trace potential neurotoxic mechanisms. For pediatric oncology, it is well‐known that cranial irradiation leads to cognitive deficits in brain tumor patients (Chang et al, ; McDuff et al, ) and leukemia patients (Buizer Buizer, De Sonneville, Van Den Heuvel‐Eibrink, & Veerman, ; Giralt et al, ; Krull et al, ; Sleurs et al, ). Consequently, treatment for leukemia patients was replaced by CNS‐directed chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Advanced MR diffusion imaging and chemotherapy‐related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

Sleurs

Lemiere

Christiaens

et al. 2018

Human Brain Mapping

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With the increase of survival rates of pediatric cancer patients, the number of children facing potential cognitive sequelae has grown. Previous adult studies suggest that white matter (WM) microstructural changes may contribute to cognitive impairment. This study aims to investigate WM microstructure in childhood bone and soft tissue sarcoma. Differences in (micro-)structure can be investigated using diffusion MRI (dMRI). The typically used diffusion tensor model (DTI) assumes Gaussian diffusion, and lacks information about fiber populations. In this study, we compare WM structure of childhood bone and soft tissue sarcoma survivors (n = 34) and matched controls (n = 34), combining typical and advanced voxel-based models (DTI and NODDI model, respectively), as well as recently developed fixel-based models (for estimations of intra-voxel differences, apparent fiber density [AFD] and fiber cross-section [FC]). Parameters with significant findings were compared between treatments, and correlated with subscales of the WAIS-IV intelligence test, age at diagnosis, age at assessment and time since diagnosis. We encountered extensive regions showing lower fractional anisotropy, overlapping with both significant NODDI parameters and fixel-based parameters. In contrast to these diffuse differences, the fixel-based measure of AFD was reduced in the cingulum and corpus callosum only. Furthermore, AFD of the corpus callosum was significantly predicted by chemotherapy treatment and correlated positively with time since diagnosis, visual puzzles and similarities task scores. This study suggests altered WM structure of childhood bone and soft tissue sarcoma survivors. We conclude global chemotherapy-related changes, with particular vulnerability of centrally located WM bundles. Finally, such differences could potentially recover after treatment.

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Section: Microstructural Differences Intelligence Scores Chemothesupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Advanced MR diffusion imaging and chemotherapy‐related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

Sleurs

Lemiere

Christiaens

et al. 2018

Human Brain Mapping

Self Cite

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“…In many cases, especially those from the late 1900s, neurocognitive toxicity is the result of combined polychemotherapy and radiation treatments. However, recent systematic multicenter longitudinal studies of intellectual development of childhood acute lymphoblastic leukemia (ALL) patients treated solely with polychemotherapy also document lower performance IQ (intelligence quotient) scores and worse intellectual outcomes in patients diagnosed and treated prior to the 6th year of life [ 5 ]. Given that the tumor burden reflected by low versus increased risk did not affect IQ scores, the investigators attributed this adverse effect to treatment rather than to the disease burden.…”

Section: Introductionmentioning

confidence: 99%

“…Many studies have been performed in children with brain tumors and leukemia to explore chemotherapy impact on the developing CNS [ 14 – 16 ]. Studies of intellectual development of childhood acute lymphoblastic leukemia (ALL) patients treated solely with polychemotherapy document worse intellectual outcomes in patients diagnosed and treated prior to the 6th year of life [ 5 ]. Our understanding of how chemotherapy injures the pediatric brain, what the pathomechanisms of this injury are and what accounts for the higher vulnerability of children under 6 years of age remains limited.…”

Section: Introductionmentioning

confidence: 99%

“…The studies have focused on methotrexate, alkylating agents (ifosfamide, cyclophosphamide, cisplatin), and vincristine (see reviews [ 5 , 39 ]). Neuropathological and neurophysiological correlates of CNS toxicity in infant, young, and adult rodents have included marked increase of apoptosis, decline in neurogenesis, impairment of long-term potentiation (LTP), synaptic remodeling, increased blood–brain barrier permeability, impaired cell division and migration, and increased markers for oxidative stress [ 5 , 39 ]. Table 1 summarizes the types of CNS toxicity described in rodent models at different ages.…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy and the pediatric brain

Ikonomidou

2018

Mol Cell Pediatr

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Survival rates of children with cancer are steadily increasing. This urges our attention to neurocognitive and psychiatric outcomes, as these can markedly influence the quality of life of these children. Neurobehavioral morbidity in childhood cancer survivors affects diverse aspects of cognitive function, which can include attention, memory, processing speed, intellect, academic achievement, and emotional health. Reasons for neurobehavioral morbidity are multiple with one major contributor being chemotherapy-induced central nervous system (CNS) toxicity. Clinical studies investigating the effects of chemotherapy on the CNS in children with cancer have reported causative associations with the development of leukoencephalopathies as well as smaller regional grey and white matter volumes, which have been found to correlate with neurocognitive deficits.Preclinical work has provided compelling evidence that chemotherapy drugs are potent neuro- and gliotoxins in vitro and in vivo and can cause brain injury via excitotoxic and apoptotic mechanisms. Furthermore, chemotherapy triggers DNA (deoxyribonucleic acid) damage directly or through increased oxidative stress. It can shorten telomeres and accelerate cell aging, cause cytokine deregulation, inhibit hippocampal neurogenesis, and reduce brain vascularization and blood flow. These mechanisms, when allowed to operate on the developing brain of a child, have high potential to not only cause brain injury, but also alter crucial developmental events, such as myelination, synaptogenesis, neurogenesis, cortical thinning, and formation of neuronal networks.This short review summarizes key publications describing neurotoxicity of chemotherapy in pediatric cancers and potential underlying pathomechanisms.

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Long‐term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high‐dose intravenous chemotherapy

Sleurs

Lemiere

Radwan

et al. 2019

Pediatric Blood & Cancer

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Purpose: Knowledge is limited regarding the prevalence and persistence of chemotherapyinduced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. Methods:We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apo and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. Results:At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelinsensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. Conclusion and implication:This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

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Intellectual development of childhood ALL patients: a multicenter longitudinal study

Cited by 20 publications

References 40 publications

Advanced MR diffusion imaging and chemotherapy‐related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

Advanced MR diffusion imaging and chemotherapy‐related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

Chemotherapy and the pediatric brain

Long‐term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high‐dose intravenous chemotherapy

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