Associations between cancer-related distress and fatigue in childhood cancer survivors: A longitudinal study.

BACKGROUND AND AIMS: A chronic feeling of fatigue occurs in up to 85% of childhood cancer survivors (CCS). This phenomenon has a detrimental effect on quality of life, reintegration in daily life activities and psychosocial functioning of the patient. Therefore, it is important to elucidate potential individual risk and protective factors. METHODS: CCS who were treated in the University Hospital of Leuven, completed two annual questionnaires on cancer-related distress (fear of cancer recurrence and post-traumatic stress, resilience and fatigue). Associations between distress and fatigue levels were examined by performing cross-lagged panel analyses. Resilience was included as a potential moderator. These models included all within-time associations, stability paths, and cross-lagged paths. Gender and time since diagnosis were included as covariates. RESULTS: In total, 110 CCS participated in this study, aged 14-25 years (average time since diagnosis 12.2 years; 41.8% boys; diagnosed with leukemia/lymphoma [49%], solid tumor [15%], brain tumor [16%] or other [20%]). Fear of cancer recurrence and post-traumatic stress at baseline positively predicted fatigue 1 year later. Cross-lagged panel analyses showed that resilience did not buffer the effect of fear of cancer recurrence on fatigue, in contrary to our expectations. Stability coefficients were high for all study variables. CONCLUSION: This study indicates associations between cancer-related distress (fear of cancer recurrence and post-traumatic stress), resilience and cancer-related fatigue over time in CCS. Interventions to improve fatigue levels could be focusing on both tackling cancer-related distress, while improving resilience levels as well.

Effect of chemotherapy (with and without radiotherapy) on the intelligence of children and adolescents treated for acute lymphoblastic leukemia; a meta-analysis.

OBJECTIVE: This meta-analysis assesses cognitive functioning in children with acute lymphoblastic leukemia post-treatment who were treated with either chemotherapy-only (CT-only) or in combination with radiation therapy (CTRT). METHODS: The databases Pubmed and PsychInfo were searched between 1-1-2000 and 31-12-2021. Data were analyzed using Comprehensive Meta-Analysis (version 2). RESULTS: Mean weighted intelligence after treatment was 100.2 (number of studies n = 51, 95% CI: 98.8-101.5). For CT-only, it was 100.8 (95% CI: 99.5-102.2) and for CTRT 97.8 (95% CI: 95.9-100.2). Compared to recruited healthy controls, treated children had on average lower IQ scores (n = 23, mean difference -7.8, 95% CI: -10.7 to -5.0, p < 0.001). When looking only at studies using controls recruited from the patient's family, results remained significant (n = 5, mean difference -6.0, 95% CI: -8.6 to -3.5, p = 0.001). Meta-regressions aimed at identifying predictors of IQ after treatment failed to find an effect for sex or age. We could demonstrate an effect of time between diagnosis and IQ measurement for the CTRT treated patient (B = -0.26, 95% CI: -0.40 to -0.1, p = 0.002). CONCLUSIONS: IQ scores of patients treated with CT-only or CTRT treatment regimens did not differ from the normative population. However, compared to recruited control groups, patients showed lower mean IQ scores. The Flynn effect and/or selection effects may play a role in this discrepancy. Considering time since diagnosis may have a significant impact on IQ, at least in CTRT treated patients, long-term clinical follow-up of neurocognitive development may be prudent to detect possible (late) neurocognitive effects.

Physical fitness throughout chemotherapy in children with acute lymphoblastic leukaemia and lymphoma.

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) and its treatment interfere with normal physical functioning. However, it remains unclear how physical fitness (PF) is affected throughout treatment for ALL/LBL. Sixty-two patients (2.1 to 18.3 years) treated for ALL/LBL underwent four physical tests at nine timepoints from baseline up to 6 months post-treatment. We assessed muscle strength of the quadriceps and tibialis anterior, standing broad jump test (SBJ) for functional mobility and six-minute walk test (6MWT) for endurance. One-sample t-tests were used to compare our results to the norm at each timepoint. Norm-referenced Z-scores were predicted based on time, risk group and age at diagnosis, using linear mixed models. Quadriceps strength, SBJ and 6MWT scores were significantly lower than norm values at all timepoints from diagnosis up to 6 months after maintenance therapy. Significant decreases over time were encountered for quadriceps strength and SBJ, mainly occurring after induction therapy (F = 3.568, p < 0.001 and F = 2.699, p = 0.008, respectively). Age at diagnosis was a significant predictor for tibialis anterior strength (F = 5.266, p = 0.025), SBJ (F = 70.422, p < 0.001) and 6MWT (F = 15.890, p < 0.001) performances, with lower results in adolescents at all timepoints. Six months after treatment, quadriceps strength, 6MWT and SBJ scores remained below expected levels. CONCLUSION: The decreased quadriceps strength, functional mobility and endurance at all timepoints, with a large deterioration following induction therapy, suggest the need for early interventions, specifically in the adolescent population. The continued low results 6 months after therapy emphasise the importance of long-term rehabilitation. WHAT IS KNOWN: •Acute lymphoblastic leukaemia is the most common type of cancer among children, with increasing survival rates due to therapeutic improvements. •Acute lymphoblastic leukaemia/lymphoma and its treatment can cause muscle weakness, neuromuscular toxicity and a decreased cardiopulmonary fitness. Together with physical inactivity, this can result in a decreased physical fitness. WHAT IS NEW: •Quadriceps strength, functional mobility and endurance are decreased during treatment for acute lymphoblastic leukaemia/lymphoma. The lowest measurements are observed after induction therapy, suggesting the need for early interventions. •We observed continued lower results for quadriceps strength, functional mobility and endurance at the end of treatment, up to 6 months after therapy, supporting the need for long-term rehabilitation.

Recommendations for the surveillance of education and employment outcomes in survivors of childhood, adolescent, and young adult cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Educational achievement and employment outcomes are critical indicators of quality of life in survivors of childhood, adolescent, and young adult (CAYA) cancer. This review is aimed at providing an evidence-based clinical practice guideline (CPG) with internationally harmonized recommendations for the surveillance of education and employment outcomes in survivors of CAYA cancer diagnosed before the age of 30 years. The CPG was developed by a multidisciplinary panel under the umbrella of the International Late Effects of Childhood Cancer Guideline Harmonization Group. After evaluating concordances and discordances of 4 existing CPGs, the authors performed a systematic literature search through February 2021. They screened articles for eligibility, assessed quality, and extracted and summarized the data from included articles. The authors formulated recommendations based on the evidence and clinical judgment. There were 3930 articles identified, and 83 of them, originating from 17 countries, were included. On a group level, survivors were more likely to have lower educational achievement and more likely to be unemployed than comparisons. Key risk factors for poor outcomes included receiving a primary diagnosis of a central nervous system tumor and experiencing late effects. The authors recommend that health care providers be aware of the risk of educational and employment problems, implement regular surveillance, and refer survivors to specialists if problems are identified. In conclusion, this review presents a harmonized CPG that aims to facilitate evidence-based care, positively influence education and employment outcomes, and ultimately minimize the burden of disease and treatment-related late adverse effects for survivors of CAYA cancers. LAY SUMMARY: A multidisciplinary panel has developed guidelines for the surveillance of education and employment outcomes among survivors of childhood, adolescent, and young adult cancer. On the basis of evidence showing that survivors are at risk for lower educational achievement and unemployment, it is recommended that all survivors receive regular screening for educational and employment outcomes.

Neurocognition in adults with intracranial tumors: does location really matter?

OBJECTIVE: As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. METHODS: This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p < .001 and p < .05 for voxel- and cluster-level, resp.). RESULTS: A cohort of 179 intracranial tumor patients was included [aged 19-85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20-30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. INTERPRETATION: Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

Quality of life of long-term childhood acute lymphoblastic leukemia survivors: Comparison with healthy controls.

OBJECTIVE: Improved treatment landscape has led to better outcomes for paediatric acute lymphoblastic leukemia (ALL) survivors. As the number of survivors increase, we need to elucidate the long-term quality of life (QoL) and domains of complaints in these patients. Furthermore, the main priorities of these patients need to be clarified. We assessed long-term QoL outcomes of survivors of childhood ALL compared to matched population controls. METHODS: QoL data were collected from survivors recruited in France and Belgium between 2012 and 2017, including the Short Form Health Survey (SF-12) and the Quality of Life Systemic Inventory (QLSI). The Wilcoxon test was used to compare SF-12 scale scores between survivors and matched population controls. For the QLSI, comparisons were mainly descriptive. RESULTS: One hundred and eighty-six survivors (mean age: 27.6 years; range: 18.1-52.8) at follow-up completed QoL measures, amongst whom 180 were matched to controls. Overall, survivors had higher QoL on all SF12 scale scores, indicating that they had better functioning compared to controls. Statistically significant differences on the SF12 were observed for Vitality, Social Functioning, Role Limitations due to Emotional Problems and Mental Health scales. QLSI outcomes suggested that survivors were happier than controls with Couple and Social Relations. Controls were unhappiest compared to survivors with Money, Love life, Self-esteem, Nutrition and Paid Work. CONCLUSIONS: Our findings suggest that survivors of childhood ALL have better QoL outcomes on some domains compared to the general population, specifically around social and emotional functioning, and that they tend to prioritize their relationships more. Interventions for improving QoL outcomes, might build on existing positive experiences with family, friends and partners.

Better detection of reduced motor functioning in brain tumor survivors based on objective motor assessments: an incentive for improved standardized follow-up.

Long-term sequelae are well-known in childhood brain tumor survivors, but motor functioning remains poorly described. This cross-sectional study aimed to assess objective motor functioning, patient-specific risk factors, and parental perceptions. Fifty-two childhood brain tumor patients (pilocytic astrocytoma, medulloblastoma, and other types) who were at least 6 months out of treatment were evaluated. Mean age at testing was 11.7 years. Objective motor functioning was assessed with the Movement Assessment Battery for Children (MABC-2-NL) and/or Bruininks-Oseretsky test of motor proficiency (BOT-2). Functional walking capacity was assessed with the 6-min walk test (6MWT). Parent-reported motor functioning was addressed using the ABILHAND-Kids, ABILOCO-Kids questionnaires, and a standardized anamnesis. Patients showed impaired motor functioning in all domains (p < 0.001). Regarding risk factors, younger age at diagnosis (< 5 year) was significantly associated with lower scores on body coordination (p = 0.006). Adjuvant treatment resulted in lower scores for fine manual control of the BOT-2 (p = 0.024) and balance of MABC-2-NL (p = 0.036). Finally, questionnaires revealed an underestimation of motor problems as perceived by the parents. In conclusion, many children who are in follow-up for a brain tumor show impaired motor functioning on multiple aspects, with younger age at diagnosis and adjuvant treatment as specific risk factors. Based on the questionnaires and anamnesis, motor problems appear to be underestimated by the parents.  Conclusion: These findings point to the need for timely prospective screening of motor functioning. Based on a screening assessment, adequate rehabilitation programs can be applied in childhood brain tumor survivors, aiming to reduce the adverse impact on their daily lives, both for functional activities and cardiovascular fitness. What is Known: • A pediatric brain tumor and its treatment are associated with potential long-term motor sequelae. • Test assessments could enable us to objectify motor functioning of these patients. What is New: • Pediatric brain tumors survivors show lower motor performance compared to the norm, which is often underestimated by parents. • Younger age at diagnosis and adjuvant treatment could be specific risk factors.

Neuroimaging Biomarkers and Neurocognitive Outcomes in Pediatric Medulloblastoma Patients: a Systematic Review.

Medulloblastoma is a malign posterior fossa brain tumor, mostly occurring in childhood. The CNS-directed chemoradiotherapy treatment can be very harmful to the developing brain and functional outcomes of these patients. However, what the underlying neurotoxic mechanisms are remain inconclusive. Hence, this review summarizes the existing literature on the association between advanced neuroimaging and neurocognitive changes in patients that were treated for pediatric medulloblastoma. The PubMed/Medline database was extensively screened for studies investigating the link between cognitive outcomes and multimodal magnetic resonance (MR) imaging in childhood medulloblastoma survivors. A behavioral meta-analysis was performed on the available IQ scores. A total of 649 studies were screened, of which 22 studies were included. Based on this literature review, we conclude medulloblastoma patients to be at risk for white matter volume loss, more frequent white matter lesions, and changes in white matter microstructure. Such microstructural alterations were associated with lower IQ, which reached the clinical cut-off in survivors across studies. Using functional MR scans, changes in activity were observed in cerebellar areas, associated with working memory and processing speed. Finally, cerebral microbleeds were encountered more often, but these were not associated with cognitive outcomes. Regarding intervention studies, computerized cognitive training was associated with changes in prefrontal and cerebellar activation and physical training might result in microstructural and cortical alterations. Hence, to better define the neural targets for interventions in pediatric medulloblastoma patients, this review suggests working towards neuroimaging-based predictions of cognitive outcomes. To reach this goal, large multimodal prospective imaging studies are highly recommended.

Effects of a mindfulness-based intervention on cancer-related cognitive impairment: Results of a randomized controlled functional magnetic resonance imaging pilot study.

BACKGROUND: Many breast cancer survivors suffer from cognitive complaints after cancer treatment, affecting their quality of life. The objective of this pilot study was to investigate the effect of a blended-care mindfulness-based intervention (MBI) on chemotherapy-related cognitive impairment and functional brain changes. Furthermore, correlations between changes in cognitive functioning and self-reported behavioral factors were investigated. METHODS: Breast cancer survivors (n = 33) who reported cognitive impairment were randomly allocated to a mindfulness condition (n = 18) or a waitlist control condition (n = 15). Patients completed questionnaires on cognitive impairment, emotional distress, and fatigue; neuropsychological tests; and resting-state functional magnetic resonance imaging before the start of MBI (time 1 [T1]), immediately after the completion of an 8-week MBI program (T2), and 3 months postintervention (T3). Resting-state functional connectivity was estimated in the default mode network, the dorsal and salience attention networks, and the frontoparietal network. Mixed model repeated-measures analysis was performed to test the intervention effect. RESULTS: Patients in the mindfulness condition exhibited significantly higher connectivity between the dorsal and salience attention networks after the mindfulness intervention compared with those in the control condition. MBI participants also had reduced subjective cognitive impairment, emotional distress, and fatigue. No intervention effect was observed on neurocognitive tests. CONCLUSIONS: MBI may induce functional brain changes in networks related to attention and may have a positive effect on subjective measures of cognitive impairment in breast cancer survivors. Therefore, MBI could be a suitable intervention to improve quality of life in this population and deserves further study in this context.

Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients.

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p < .05). In conclusion, we found age-dependent cognitive decline and white matter volume changes in patients with breast cancer after chemotherapy, which could possibly be linked to neuroinflammatory processes. White matter expansion after chemotherapy, more pronounced in premenopausal patients, correlated with less cognitive decline. This suggests such expansion to be age-dependent, possibly caused by a protective response in the younger brain to chemotherapy-induced neurotoxicity.

Genetic Modulation of Neurocognitive Development in Cancer Patients throughout the Lifespan: a Systematic Review.

The rise in cancer survival rates has raised concerns about the long-term adverse effects of cancer treatment, including neurocognitive impairment. Neurocognitive deficits such as attention and processing speed are frequently observed and can have a profound, lifelong impact in daily life of cancer patients. Interestingly, large interpatient variability exists in cognitive outcomes. Emerging evidence indicates that such differences may be related to genetic variation. The aim of our review was to systematically summarize the current literature on the modulatory effects of germline genetic polymorphisms on cancer treatment-induced cognitive changes and the potential age-dependent impact in cancer survivors. The PubMed/Medline database was screened using an extensive search string focusing on four components: "cancer", "cancer treatment", "neurocognitive outcome" and "germline genetic variation". Seventeen studies meeting predefined eligibility criteria were analyzed, including sixteen candidate gene studies and one genome-wide association study. 38 polymorphisms in 15 genes across proposed pathophysiological pathways, including (1) neural plasticity and repair, (2) neuroinflammation and defenses against oxidative stress, (3) neurotransmission, and (4) folate metabolism pathway, were reported to be significantly associated with treatment-related neurocognitive dysfunction or neuroimaging abnormalities. Still, some study results remained discordant, partly due to the methodological heterogeneity (i.e. in test assessments, age, cancer-type populations). Future large-scale, (epi-)genome studies integrating neurocognitive assessments and advanced neuroimaging techniques, are recommended in order to investigate neurotoxicity throughout the lifespan. Hence, adverse neurodevelopmental problems during childhood and neurodegenerative processes later in life could be minimized based on genetic risk classifications.

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

PURPOSE: Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced 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 Apoε 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 myelin-sensitive 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.

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.

Intellectual development of childhood ALL patients: a multicenter longitudinal study.

BACKGROUND: 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. PROCEDURE: We evaluated intellectual development of 94 pediatric ALL patients between 1990 and 1997, diagnosed before the age of 12 years, treated according to the European Organisation for Research and Treatment of Cancer Children's Leukemia Group 58881 protocol. Three assessments of the Wechsler Intelligence Scale for Children Revised were performed since diagnosis, according to age. Using repeated measures regression analysis, we investigated the effect of gender (low versus increased) risk group, parents' education, age at diagnosis, intelligence quotient (IQ) subscale (verbal (VIQ) versus performance (PIQ) intelligence), and test session. RESULTS: PIQ scores were lower than VIQ at baseline (-5.3 points on average, p = 0.0032), yet PIQ increased more strongly (PIQ: +3.9 points per test session; VIQ: +0.8, p = 0.0079), so this baseline difference disappeared (p = 0.0079). There were no clear effects of gender (girls: +0.6 points; p = 0.78) or risk group (low risk: +1.5 points; p = 0.49), but IQ scores were higher when one parent had followed higher education (+9.5 points, p < 0.0001). Finally, diagnosis at younger age predicted lower IQ scores (-1.3 points per year, p = 0.0009). CONCLUSION: Given that IQ scores did not decline, our findings demonstrate a stable pattern. However, the lower PIQ scores at baseline may indicate that performance functioning is vulnerable to acute neurotoxicity. Also, lower scores for younger patients highlight the stronger impact of the disease and/or treatment at younger age.Copyright © 2016 John Wiley & Sons, Ltd.

Biomarkers of fatigue in oncology: A systematic review.

Cancer-related fatigue (CRF) is a distressing side effect of cancer and treatment, affecting both patients during active treatment and survivors, negatively impacting quality of life. While its exact cause remains uncertain, various mechanisms such as immune dysfunction, HPA-axis dysfunction, and treatment toxicity are proposed. Inflammatory biomarkers of CRF have been explored in previous research, but non-inflammatory markers have not been comprehensively studied. This systematic review analysed 33 studies to identify non-inflammatory peripheral blood biomarkers associated with CRF. Promising markers included Hb, blood coagulation factors, BDNF, tryptophan, GAA, mtDNA, platinum, CA125, and cystatin-C. Inconsistent findings were observed for other markers like VEGF, leptin, and stress hormones. Most studies focused on adults. Research in pediatrics is limited. This review showed partial evidence for the inflammaging hypothesis (neurotoxicity due to neuro-inflammation) laying at the basis of CRF. Further research, especially in pediatrics, is needed to confirm this hypothesis and guide future biomarker studies.

Brain network topology and its cognitive impact in adult glioma survivors.

Structural brain network topology can be altered in case of a brain tumor, due to both the tumor itself and its treatment. In this study, we explored the role of structural whole-brain and nodal network metrics and their association with cognitive functioning. Fifty WHO grade 2-3 adult glioma survivors (> 1-year post-therapy) and 50 matched healthy controls underwent a cognitive assessment, covering six cognitive domains. Raw cognitive assessment scores were transformed into w-scores, corrected for age and education. Furthermore, based on multi-shell diffusion-weighted MRI, whole-brain tractography was performed to create weighted graphs and to estimate whole-brain and nodal graph metrics. Hubs were defined based on nodal strength, betweenness centrality, clustering coefficient and shortest path length in healthy controls. Significant differences in these metrics between patients and controls were tested for the hub nodes (i.e. n = 12) and non-hub nodes (i.e. n = 30) in two mixed-design ANOVAs. Group differences in whole-brain graph measures were explored using Mann-Whitney U tests. Graph metrics that significantly differed were ultimately correlated with the cognitive domain-specific w-scores. Bonferroni correction was applied to correct for multiple testing. In survivors, the bilateral putamen were significantly less frequently observed as a hub (pbonf < 0.001). These nodes' assortativity values were positively correlated with attention (r(90) > 0.573, pbonf < 0.001), and proxy IQ (r(90) > 0.794, pbonf < 0.001). Attention and proxy IQ were significantly more often correlated with assortativity of hubs compared to non-hubs (pbonf < 0.001). Finally, the whole-brain graph measures of clustering coefficient (r = 0.685), global (r = 0.570) and local efficiency (r = 0.500) only correlated with proxy IQ (pbonf < 0.001). This study demonstrated potential reorganization of hubs in glioma survivors. Assortativity of these hubs was specifically associated with cognitive functioning, which could be important to consider in future modeling of cognitive outcomes and risk classification in glioma survivors.

Neurocognitive Dysfunction After Treatment for Pediatric Brain Tumors: Subtype-Specific Findings and Proposal for Brain Network-Informed Evaluations.

The increasing number of long-term survivors of pediatric brain tumors requires us to incorporate the most recent knowledge derived from cognitive neuroscience into their oncological treatment. As the lesion itself, as well as each treatment, can cause specific neural damage, the long-term neurocognitive outcomes are highly complex and challenging to assess. The number of neurocognitive studies in this population grows exponentially worldwide, motivating modern neuroscience to provide guidance in follow-up before, during and after treatment. In this review, we provide an overview of structural and functional brain connectomes and their role in the neuropsychological outcomes of specific brain tumor types. Based on this information, we propose a theoretical neuroscientific framework to apply appropriate neuropsychological and imaging follow-up for future clinical care and rehabilitation trials.

A Systematic Review on the Potential Acceleration of Neurocognitive Aging in Older Cancer Survivors.

As survival rates increase, more emphasis has gone to possible cognitive sequelae in older cancer patients, which could be explained by accelerated brain aging. In this review, we provide a complete overview of studies investigating neuroimaging, neurocognitive, and neurodegenerative disorders in older cancer survivors (>65 years), based on three databases (Pubmed, Web of Science and Medline). Ninety-six studies were included. Evidence was found for functional and structural brain changes (frontal regions, basal ganglia, gray and white matter), compared to healthy controls. Cognitive decline was mainly found in memory functioning. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes with an increased risk of Alzheimer's disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in patients with non-central nervous system cancer but can play a role in patients with central nervous system cancer, while neurosurgery seemed to improve their cognition in the short-term. Individual risk factors included cancer subtypes (e.g., brain cancer, hormone-related cancers), treatment (e.g., anti-hormonal therapy, chemotherapy, cranial radiation), genetic predisposition (e.g., APOE, COMT, BDNF), age, comorbidities (e.g., frailty, cognitive reserve), and psychological (e.g., depression, (post-traumatic) distress, sleep, fatigue) and social factors (e.g., loneliness, limited caregiver support, low SES). More research on accelerated aging is required to guide intervention studies.

Changes in leukoencephalopathy and serum neurofilament after (neo)adjuvant chemotherapy for breast cancer.

BACKGROUND: Previous case studies have provided evidence for chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective research is lacking. Hence, we investigated leukoencephalopathy before and after chemotherapy and its association with a serum neuroaxonal damage marker. METHODS: This prospective cohort study included 40 patients receiving chemotherapy for breast cancer, and two age- and education-matched control groups, recruited between 2018 and 2021 (31-64 years of age). The latter control groups consisted of 39 chemotherapy-naïve patients and 40 healthy women. Fluid-attenuated inversion-recovery magnetic resonance imaging was used for lesion volumetry (total, juxtacortical, periventricular, infratentorial, and deep white matter) and blood serum to measure neurofilament light chain (NfL) levels. Acquisition took place pre-chemotherapy and three months and one-year post-chemotherapy, or at corresponding intervals. Within/between group differences were compared using robust mixed-effects modeling, and associations between total lesion volume and serum-NfL with linear regression. RESULTS: Stronger increases in deep white matter lesion volumes were observed shortly post-chemotherapy, compared with healthy women (ßstandardized=0.09, pFDR<0.001). Increases in total lesion volume could mainly be attributed to enlargement of existing lesions (mean±SD, 0.12±0.16 mL), rather than development of new lesions (0.02±0.02 mL). A stronger increase in serum-NfL concentration was observed shortly post-chemotherapy compared with both control groups (ß>0.70, p<0.004), neither of which showed any changes over time, whereas a decrease was observed compared with healthy women one-year post-chemotherapy (ß=-0.54, p = 0.002). Serum-NfL concentrations were associated with lesion volume one-year post-chemotherapy (or at matched timepoint; ß=0.36, p = 0.010), whereas baseline or short-term post-therapy levels or changes were not. CONCLUSION: These results underscore the possibility of chemotherapy-induced leukoencephalopathy months post-treatment, as well as the added value of serum-NfL as a prognostic marker for peripheral/central neurotoxicity. TRANSLATIONAL RELEVANCE: Previous case studies have provided evidence of chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective studies to estimate longitudinal changes are currently missing. In this study, we used longitudinal fluid-attenuated inversion-recovery magnetic resonance imaging to assess white matter lesion volumes in patients treated for non-metastatic breast cancer and healthy women. Our findings demonstrate that chemotherapy-treated patients exhibit stronger increases in lesion volumes compared with healthy women, specifically in deep white matter, at three months post-chemotherapy. Increases could mainly be attributed to enlargement of existing lesions, rather than development of new lesions. Last, serum concentrations of neurofilament light chain, a neuroaxonal damage marker, increased shortly after chemotherapy and long-term post-chemotherapy levels were associated with lesion volumes. These findings highlight the potential of this non-invasive serum marker as a prognostic marker for peripheral and/or central neurotoxicity. Implementation in clinical practice could aid in therapeutic decisions, assessing disease activity, or monitoring treatment response.