Charlotte Sleurs

Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: An update on current state of research and recommended future directions.

Neurocognitive sequelae are known to be induced by cranial radiotherapy and central-nervous-system-directed chemotherapy in childhood Acute Lymphoblastic Leukemia (ALL) and brain tumor patients. However, less evidence exists for solid non-CNS-tumor patients. To get a better understanding of the potential neurotoxic mechanisms of non-CNS-directed chemotherapy during childhood, we performed a comprehensive literature review of this topic. Here, we provide an overview of preclinical and clinical studies investigating neurotoxicity associated with chemotherapy in the treatment of pediatric solid non-CNS tumors. Research to date suggests that chemotherapy has deleterious biological and psychological effects, with animal studies demonstrating histological evidence for neurotoxic effects of specific agents and human studies demonstrating acute neurotoxicity. Although the existing literature suggests potential neurotoxicity throughout neurodevelopment, research into the long-term neurocognitive sequelae in survivors of non-CNS cancers remains limited. Therefore, we stress the critical need for neurodevelopmental focused research in children who are treated for solid non-CNS tumors, since they are at risk for potential neurocognitive impairment.

Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia

Background This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearmans rank and Pearsons correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.

The role of the MTHFR C677T polymorphism in methotrexate-induced toxicity in pediatric osteosarcoma patients

AIM Osteosarcoma patients receive high doses of methotrexate (MTX). However, pharmacogenetic information remains limited and has mainly been investigated in leukemia so far. PATIENTS & METHODS We investigated the link between the MTHFR C677T genotype, toxicity levels (mucositis, MTX plasma level, hematological toxicity and hepatotoxicity) and survival of 48 pediatric osteosarcoma patients. RESULTS The TT genotype did not show more toxicity compared with the CC/CT genotype. However, plasma MTX levels were related with mucositis, but not with hematological toxicity, nor hepatotoxicity. Survival rates did not differ between homozygous and non-homozygous patients. Yet, homozygous patients had higher relapse risk. CONCLUSION The MTHFR C667T polymorphism is not predictive for toxicity or overall survival, but could be used for relapse risk stratification.

Intellectual development of childhood ALL patients: a multicenter longitudinal study

In childhood acute lymphoblastic leukemia (ALL), radiotherapy for CNS prophylaxis is not used in frontline therapy anymore. Standard treatment for ALL nowadays consists of polychemotherapy. Therefore, assessment of potential chemotherapy‐induced cognitive side effects becomes important. Although neurotoxicity was demonstrated in cross‐sectional studies, longitudinal studies remain scarce.

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

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.

Sensitivity to Nonaccidental Configurations of Two-Line Stimuli:

According to Recognition-By-Components theory, object recognition relies on a specific subset of three-dimensional shapes called geons. In particular, these configurations constitute a powerful cue to three-dimensional object reconstruction because their two-dimensional projection remains viewpoint-invariant. While a large body of literature has demonstrated sensitivity to changes in these so-called nonaccidental configurations, it remains unclear what information is used in establishing such sensitivity. In this study, we explored the possibility that nonaccidental configurations can already be inferred from the basic constituents of objects, namely, their edges. We constructed a set of stimuli composed of two lines corresponding to various nonaccidental properties and configurations underlying the distinction between geons, including collinearity, alignment, curvature of contours, curvature of configuration axis, expansion, cotermination, and junction type. Using a simple visual search paradigm, we demonstrated that participants were faster at detecting targets that differed from distractors in a nonaccidental property than in a metric property. We also found that only some but not all of the observed sensitivity could have resulted from simple low-level properties of our stimuli. Given that such sensitivity emerged from a configuration of only two lines, our results support the view that nonaccidental configurations could be encoded throughout the visual processing hierarchy even in the absence of object context.