The Longitudinal Parallel Process Analysis of Biomarkers of Oxidative Stress, Symptom Clusters, and Cognitive Function in Children With Leukemia

Abstract

Background: During treatment for acute lymphoblastic leukemia (ALL), children report co-occurring symptoms of fatigue, sleep disturbance, pain, nausea, and depression as a symptom cluster. Central nervous system–directed ALL therapies also put children at risk for cognitive impairments. Cancer therapies can cause an increase in oxidative stress, which may contribute to treatment-related symptoms. This study examined the longitudinal relationships between biomarkers of oxidative stress in the cerebrospinal fluid, the Childhood Cancer Symptom Cluster–Leukemia (CCSC-L), and cognition, in children over the first year of ALL treatment. Methods: Glutathione (GSH) biomarkers of oxidative stress were measured in cerebrospinal fluid collected during treatment lumbar punctures. GSH biomarkers, symptoms, and cognitive function of 132 children aged 3 to 18 years were evaluated at four time points during the first year of leukemia treatment. Participants, 7 years and older, completed self-report measures, and parents reported for younger children. Cognitive function measurements for all participants were completed by parents. A longitudinal parallel-process model was used to explore the influence of the initial measurement and the subsequent change over four time points of the GSH biomarkers on the CCSC-L and cognition. Results: GSH biomarkers increased over the four time points indicating decreasing oxidative stress. When GSH biomarkers were higher (less oxidative stress) at the initial measurement, the CCSC-L severity was lower, cognition was better, and cognition improved over the four measurements. Screening children for high levels of oxidative stress would be a foundation for future intervention studies to address symptom distress and cognitive impairments.

Targeting Redox Regulation as a Therapeutic Opportunity against Acute Leukemia: Pro-Oxidant Strategy or Antioxidant Approach?

“…Moreover, many young patients suffer alteration in cognitive function. A study evaluated the relationships between markers of OS in the cerebrospinal fluid, the CCSC-L, and cognition in ALL patients before and after chemotherapy [ 139 ]. The results demonstrated that, when GSH markers were elevated (less OS) the CCSC-L severity was lower, and cognitive function tended to improve over time [ 139 ].…”

“…A study evaluated the relationships between markers of OS in the cerebrospinal fluid, the CCSC-L, and cognition in ALL patients before and after chemotherapy [ 139 ]. The results demonstrated that, when GSH markers were elevated (less OS) the CCSC-L severity was lower, and cognitive function tended to improve over time [ 139 ]. This fact is certainly interesting, as assessing ALL patients for elevated OS before stating chemotherapy would allow identification patients with elevated risk for cognitive impairments.…”

Biomarkers of Cognitive Impairment in Pediatric Cancer Survivors

“…Longitudinal studies of such biomarkers of oxidative stress in CSF collected from children treated for leukemia show consistent relationships with neurocognitive functioning and symptom clusters. [44][45][46] EPIGENETIC CHANGES Epigenetic modifications such as DNA methylation and histone modification influence gene control without changing the underlying DNA sequence and may help us understand how environmental exposures interact with genetic predisposition to cause disease. Global DNA methylation, methylation at specific cytosine-guanine (CpG) sites, and histone modification have been implicated in Alzheimer's, dementia, and mild neurocognitive impairment.…”

“…Longitudinal studies of such biomarkers of oxidative stress in CSF collected from children treated for leukemia show consistent relationships with neurocognitive functioning and symptom clusters. 44-46…”

Symptom Adverse Events and Quality of Life of Children With Advanced Cancer: Results From a Longitudinal Study Using the Pediatric Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events

“…Despite increases in survival rates, cancer remains the leading cause of disease-related death in children in the United States, with approximately 1,800 children and adolescents aged birth to 19 years dying a cancer-related death each year (SEER, 2018). The therapies used to treat various cancer types lead to poorly controlled physical and psychological symptoms that are often distressing and negatively impact health outcomes, including quality of life (QoL; Hooke et al, 2020; Linder & Hooke, 2019). Children with advanced cancer, defined as relapsed, refractory, or progressive disease, are especially vulnerable to treatment-related toxicities and symptoms, and poor health outcomes.…”