Adaptive, behavioral, and emotional outcomes following postoperative pediatric cerebellar mutism syndrome in survivors treated for medulloblastoma.

OBJECTIVE: Patients who experience postoperative pediatric cerebellar mutism syndrome (CMS) during treatment for medulloblastoma have long-term deficits in neurocognitive functioning; however, the consequences on functional or adaptive outcomes are unknown. The purpose of the present study was to compare adaptive, behavioral, and emotional functioning between survivors with and those without a history of CMS. METHODS: The authors examined outcomes in 45 survivors (15 with CMS and 30 without CMS). Comprehensive neuropsychological evaluations, which included parent-report measures of adaptive, behavioral, and emotional functioning, were completed at a median of 2.90 years following craniospinal irradiation. RESULTS: Adaptive functioning was significantly worse in the CMS group for practical and general adaptive skills compared with the group without CMS. Rates of impairment in practical, conceptual, and general adaptive skills in the CMS group exceeded expected rates in the general population. Despite having lower overall intellectual functioning, working memory, and processing speed, IQ and related cognitive processes were uncorrelated with adaptive outcomes in the CMS group. No significant group differences or increased rates of impairment were observed for behavioral and emotional outcomes. CONCLUSIONS: Survivors with CMS, compared with those without CMS, are rated as having significant deficits in overall or general adaptive functioning, with specific weakness in practical skills several years posttreatment. Findings from this study demonstrate the high risk for ongoing functional deficits despite acute recovery from symptoms of CMS, highlighting the need for intervention to mitigate such risk.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Children's Oncology Group's 2023 blueprint for research: Young investigators.

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list. The YI Committee has held virtual symposia designed to describe how COG operates and provide guidance on how YIs can reach their goals; over 300 YIs have attended these since 2021 and have consistently rated them as helpful. Through these and other elements of the program, the YI Committee remains committed to developing a future pipeline of new investigators.

Neurocognitive outcomes in pediatric brain tumors after treatment with proton versus photon radiation: a systematic review and meta-analysis.

BACKGROUND: Advances in cancer treatments, particularly the development of radiation therapy, have led to improvements in survival outcomes in children with brain tumors. However, radiation therapy is associated with significant long-term neurocognitive morbidity. The present systematic review and meta-analysis aimed to compare the neurocognitive outcomes of children and adolescents with brain tumors treated with photon radiation (XRT) or proton therapy (PBRT). METHODS: A systematic search was conducted (PubMed, Embase, Cochrane, and Web of Science from inception until 02/01/2022) for studies comparing the neurocognitive outcomes of children and adolescents with brain tumors treated with XRT vs. PBRT. The pooled mean differences (expressed as Z scores) were calculated using a random effects method for those endpoints analyzed by a minimum of three studies. RESULTS: Totally 10 studies (n = 630 patients, average age range: 1-20 years) met the inclusion criteria. Patients who had received PBRT achieved significantly higher scores (difference in Z scores ranging from 0.29-0.75, all P < 0.05 and significant in sensitivity analyses) after treatment than those who had received XRT for most analyzed neurocognitive outcomes (i.e., intelligence quotient, verbal comprehension and perceptual reasoning indices, visual motor integration, and verbal memory). No robust significant differences (P > 0.05 in main analyses or sensitivity analyses) were found for nonverbal memory, verbal working memory and working memory index, processing speed index, or focused attention. CONCLUSIONS: Pediatric brain tumor patients who receive PBRT achieve significantly higher scores on most neurocognitive outcomes than those who receive XRT. Larger studies with long-term follow-ups are needed to confirm these results.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.

Cognitive Sparing in Proton versus Photon Radiotherapy for Pediatric Brain Tumor Is Associated with White Matter Integrity: An Exploratory Study.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

Comparison of neurocognitive and quality-of-life outcomes in pediatric craniopharyngioma patients treated with partial resection and radiotherapy versus gross-total resection only.

OBJECTIVE: The optimal management of pediatric craniopharyngioma patients remains controversial, shifting from radical resection (gross-total resection [GTR]) to a more conservative approach with partial resection/biopsy followed by radiotherapy (PR+RT). To the authors' knowledge, no previous studies have compared neurocognitive and quality-of-life (QOL) outcomes between the two main treatments. In this study, the authors compared changes in intellectual, adaptive, and QOL scores in children treated for craniopharyngioma with GTR and those treated with PR+RT. METHODS: Patients underwent annual neurocognitive and QOL evaluations for up to 10 years posttreatment, including the Full-Scale IQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI). Child- and parent-reported QOL scores and adaptive behavior in different domains were assessed. General linear mixed models were used to examine change in scores over time by treatment group with adjustment for significant covariates. RESULTS: Scores from 43 patients treated between 2009 and 2019 (21 GTR, 22 PR+RT) were examined. Within the PR+RT group, 9 patients had intensity-modulated RT and 13 had proton beam therapy. The treatment groups were similar in sex (44% male) and age (median 7.3 years). There were no significant differences in the trajectory of intellectual functioning or QOL scale scores between the two groups. However, patients who underwent GTR exhibited significant improvement over time in overall adaptive behavior (p = 0.04) and conceptual skills (p = 0.01), which was not observed in patients treated with PR+RT. CONCLUSIONS: Long-term pediatric craniopharyngioma survivors treated with GTR and PR+RT have similar intellectual function and QOL. Larger studies are needed to explore small but clinically significant differences between the two groups.

Superior verbal learning and memory in pediatric brain tumor survivors treated with proton versus photon radiotherapy.

OBJECTIVE: Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers lower doses of radiation to healthy brain tissue. PRT has been associated with improved long-term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory. METHOD: Survivors of pediatric brain tumor treated with either XRT (n = 29) or PRT (n = 51) completed neuropsychological testing > 1 year following radiotherapy. Performance on neuropsychological measures was compared between treatment groups using analysis of covariance. Chi-squared tests of independence were used to compare the frequency of encoding, retrieval, and intact memory profiles between treatment groups. Associations between memory performance and other neurobehavioral measures were examined using Pearson correlation. RESULTS: Overall, patients receiving PRT demonstrated superior verbal learning and recall compared to those treated with XRT. Encoding and retrieval deficits were more common in the XRT group than the PRT group, with encoding problems being most prevalent. The PRT group was more likely to engage in semantic clustering strategies, which predicted better encoding and retrieval. Encoding ability was associated with higher intellectual and adaptive functioning, and fewer parent-reported concerns about day-to-day attention and cognitive regulation. CONCLUSION: Results suggest that PRT is associated with verbal memory sparing, driven by effective encoding and use of learning strategies. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline, which will better inform treatment approaches. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Prospective Evaluation of Fatigue in Pediatric Brain Tumor Patients Treated With Radiation Therapy.

Background: Fatigue is a well-established consequence of cranial radiotherapy in survivors of pediatric brain tumor, but less is known about acute fatigue during radiotherapy treatment. This study aimed to longitudinally evaluate fatigue in newly diagnosed pediatric patients with brain tumors during treatment. Methods: Primary caregivers of pediatric patients with brain tumors completed the proxy-reported Parent Fatigue Scale assessments prior to radiotherapy and weekly during radiotherapy treatment. The association between clinical factors and fatigue at each assessment was evaluated with multiple linear regressions. A comparison of fatigue between radiation modalities was also analyzed. Results: A total of 33 caregivers completed pre-radiation fatigue assessments, with 29 reporting fatigue during radiotherapy. Patients were aged 3 to 16 years (M = 8.32) at diagnosis and diagnosed with medulloblastoma (n = 23), primitive neuroectodermal tumor (n = 2), ependymoma (n = 1), germ cell tumor (n = 1), pineoblastoma (n = 1), atypical teratoid rhabdoid (n = 1), and other unspecific tumors (n = 3). Moderate-to-severe fatigue was reported for the majority of patients (31/33; 94%) during treatment. Craniospinal irradiation dose was the only significant predictor of fatigue (p < .05), but this association was restricted to the first week of therapy and was attenuated by therapy completion. Discussion: Although fatigue is often considered a long-term consequence of cranial radiotherapy, this pilot study demonstrates that moderate-to-severe fatigue is pervasive prior to radiotherapy and persists throughout treatment in pediatric patients with brain tumors, regardless of radiation modality or clinical factors. Additional research is warranted to establish a link between acute and long-term fatigue and develop interventions to mitigate this adverse outcome.

Predicting neurocognitive function in pediatric brain tumor early survivorship: The neurological predictor scale and the incremental validity of tumor size.

BACKGROUND: The Neurological Predictor Scale (NPS) quantifies cumulative exposure to conventional treatment-related neurological risks but does not capture potential risks posed by tumors themselves. This study evaluated the predictive validity of the NPS, and the incremental value of tumor location and size, for neurocognitive outcomes in early survivorship following contemporary therapies for pediatric brain tumors. PROCEDURE: Survivors (N = 69) diagnosed from 2010 to 2016 were administered age-appropriate versions of the Wechsler Intelligence Scales. Hierarchical multiple regressions examined the predictive and incremental validity of NPS score, tumor location, and tumor size. RESULTS: Participants (51% female) aged 6-20 years (M = 13.22, SD = 4.09) completed neurocognitive evaluations 5.16 years (SD = 1.29) postdiagnosis. The NPS significantly predicted Full-Scale Intelligence Quotient (FSIQ; ΔR2  = .079), Verbal Comprehension Index (VCI; ΔR2  = 0.051), Perceptual Reasoning Index (PRI; ΔR2  = 0.065), and Processing Speed Index (PSI; ΔR2  = 0.049) performance after controlling for sex, age at diagnosis, and maternal education. Tumor size alone accounted for a significant amount of unique variance in FSIQ (ΔR2  = 0.065), PRI (ΔR2  = 0.076), and PSI (ΔR2  = 0.080), beyond that captured by the NPS and relevant covariates. Within the full model, the NPS remained a significant independent predictor of FSIQ (ß = -0.249, P = 0.016), VCI (ß = -0.223, P = 0.048), and PRI (ß = -0.229, P = 0.037). CONCLUSIONS: Tumor size emerged as an independent predictor of neurocognitive functioning and added incrementally to the predictive utility of the NPS. Pretreatment disease burden may provide one of the earliest markers of neurocognitive risk following contemporary treatments. With perpetual treatment advances, measures quantifying treatment-related risk may need to be updated and revalidated to maintain their clinical utility.

Cerebellar Mutism Syndrome in Pediatric Neuro-oncology: A Multidisciplinary Perspective and Call for Research Priorities.

Cerebellar mutism syndrome (CMS), also known as posterior fossa syndrome, occurs in a subset of children after posterior fossa tumor resection, most commonly medulloblastoma. Patients with this syndrome exhibit often transient, although protracted, symptoms of language impairment, emotional lability, cerebellar, and brainstem dysfunction. However, many patients experience persistent neurological deficits and lasting neurocognitive impairment. Historically, research and clinical care were hindered by inconsistent nomenclature, poorly defined diagnostic criteria, and uncertainty surrounding risk factors and etiology. Proposed diagnostic criteria include two major symptoms, language impairment and emotional lability, as proposed by the international Board of the Posterior Fossa Society in their consensus statement as well as other experts in this field. Risk factors most commonly associated with development of CMS include midline tumor location, diagnosis of medulloblastoma and specific tumor subtype, younger age at diagnosis, and preoperative language impairment. A proposed etiology of CMS includes disruption of the cerebellar outflow tracts, the cerebellar nuclei, and their efferent projections through the superior cerebellar peduncle. Treatment for CMS remains supportive. Herein, we present a comprehensive overview of CMS etiology, diagnosis, risk factors, clinical presentation, and clinical management. In addition, we identify essential multidisciplinary research priorities to advance diagnostics, prevention, and intervention efforts for patients with, or at risk for, development of CMS.

Cognitive predictors of social adjustment in pediatric brain tumor survivors treated with photon versus proton radiation therapy.

BACKGROUND: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. PROCEDURE: Survivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills. RESULTS: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2 (1) = 38.67, p < .001; χ2 (1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = -1.99, p = .05). Tumor diameter predicted social skills (t = -2.07, p < .05). CONCLUSIONS: Regardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Association between fatigue and sleep disturbances during treatment for pediatric acute lymphoblastic leukemia and posttreatment neurocognitive performance.

BACKGROUND: Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of neurocognitive weakness in the areas of attention, executive function, and processing speed. Although fatigue and sleep disturbances are frequent complications of ALL therapy and associated with cognitive functions, the impact of fatigue and sleep profiles during active ALL treatment on posttreatment neurocognitive performance has received limited attention. METHODS: Pediatric patients (n = 120) with ALL (diagnosed 2011-2016) who completed fatigue and sleep questionnaires at four time points during active treatment were enrolled in a study of neurocognitive performance. Latent class growth analysis identified subgroups of patients with similar sleep and fatigue profiles during treatment. Neurocognitive performance collected >6 months post treatment on 40 participants was compared between latent classes using multivariable linear regression models. RESULTS: Participants (57.5% male and 79.1% Hispanic or non-Hispanic White) were classified into one of two fatigue and sleep profiles: Class 1 characterized by mild fatigue and sleep disturbances during treatment (50.8%), and Class 2 characterized by higher levels of fatigue and sleep disturbances (49.2%). Posttreatment cognitive performance was in the normal range for most measures, but significantly below normative means for executive function, verbal short-term memory, attention, and distractability measures. Compared to Class 1, Class 2 demonstrated significantly (p < .05) poorer posttreatment neurocognitive performance, particularly in measures of attention. CONCLUSIONS: Our findings indicate that fatigue and sleep disturbances during the first year of pediatric ALL therapy may impact long-term neurocognitive performance. Sleep and fatigue may be targets for intervention to preserve cognitive functioning in survivors.

Genetic modulation of longitudinal change in neurocognitive function among adult glioma patients.

PURPOSE: Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy. METHODS: Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). RESULTS: Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. CONCLUSION: Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.

Long-term cognitive and academic outcomes among pediatric brain tumor survivors treated with proton versus photon radiotherapy.

BACKGROUND: Proton radiotherapy (PRT) may be associated with less neurocognitive risk than photon RT (XRT) for pediatric brain tumor survivors. We compared neurocognitive and academic outcomes in long-term survivors treated with XRT versus PRT. METHODS: Survivors underwent neurocognitive evaluation >1 year after craniospinal (CSI) or focal PRT or XRT. Groups were compared using separate one-way analyses of covariance for the CSI and focal groups. RESULTS: PRT (n = 58) and XRT (n = 30) subgroups were similar on gender (66% male), age at RT (median = 6.5 years), age at follow-up (median = 14.6 years), and government assistance status (32%). PRT and XRT focal groups differed on follow-up interval, shunt history, and total RT dose (all p < .05), whereas PRT and XRT CSI groups differed on follow-up interval, baseline neurocognitive performance score, boost volume, and CSI dose (all p < .05). The PRT focal group outperformed the XRT focal group on inhibition/switching (p = .04). The PRT CSI group outperformed the XRT CSI group on inattention/impulsivity (both p < .05). Several clinical variables (i.e., RT dose, boost field, baseline performance) predicted neurocognitive outcomes (all p < .05). The PRT focal group performed comparably to population means on most neurocognitive measures, while both CSI groups performed below expectation on multiple measures. The XRT CSI group was most impaired. All groups fell below expectation on processing speed, fine motor, and academic fluency (most p < .01). CONCLUSIONS: Findings suggest generally favorable neurocognitive and academic long-term outcomes following focal PRT. Impairment was greatest following CSI regardless of modality. Dosimetry and baseline characteristics are important determinants of outcome alone or in combination with modality.

Treatment age and neurocognitive outcomes following proton beam radiotherapy for pediatric low- and intermediate-grade gliomas.

The relationship between age and neurocognitive functioning following proton beam radiotherapy (PRT) in low- and intermediate-grade gliomas (LIGG) has yet to be examined. Eighteen LIGG patients treated with PRT were prospectively enrolled and received annual neurocognitive evaluations of perceptual/verbal reasoning, working memory, and processing speed postradiotherapy. The median age at diagnosis was 8.2 years (range 1.0-14.7) and the median age at PRT was 9.9 years (range 4.2-17.0). Patients' neurocognitive performance did not change on any measure following PRT (p ≥ .142). We did not observe significant changes in cognitive function over time among a small group of LIGG patients treated with PRT.

Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.

CONTEXT: Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. OBJECTIVES: We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. METHODS: Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons. RESULTS: Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062). CONCLUSION: The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.

Prospective patient-reported symptom profiles associated with pediatric acute lymphoblastic leukemia relapse.

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. METHODS: Pediatric patients with ALL (age 2-18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms, and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. RESULTS: Eligible patients (n = 208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI 1.23-2.73) and MC1 (HR = 2.14, 95%CI 1.62-2.84), pain at DI (HR = 1.80, 95%CI 1.19-2.72), nausea at the end of induction (HR = 1.19, 95%CI 1.01-1.39), and sleep disturbances at the end of induction (HR = 2.00, 95%CI 1.11-3.62), DI (HR = 1.73, 95%CI 1.01-2.96), and MC1 (HR = 2.19, 95%CI 1.10-4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. CONCLUSION: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse.