Association between CEP72 genotype and persistent neuropathy in survivors of childhood acute lymphoblastic leukemia.
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ABSTRACT:
SUBMITTER: Goodenough CG
PROVIDER: S-EPMC8983435 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
Publications
Association between CEP72 genotype and persistent neuropathy in survivors of childhood acute lymphoblastic leukemia.
Goodenough Chelsea G CG Diouf Barthelemy B Yang Wenjian W Sapkota Yadav Y Finch Emily R ER Lu Lu L Partin Robyn E RE Wogksch Matthew D MD Hudson Melissa M MM Robison Leslie L LL Wang Zhaoming Z Jeha Sima S Evans William E WE Ness Kirsten K KK
Leukemia 20220104 4
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Project description:Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR)-based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy.
| S-EPMC5320866 | biostudies-literature
Project description:Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2-39.7)], insulin resistance [20.6 (5.2-82.1)] and the metabolic syndrome [11.2 (2.6-48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6-7.1) and 2.34 (1.3-4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6-6.8)], dyslipidemia [2.6 (1.4-4.9)] and MetS [6.5 (2.4-17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.
| S-EPMC7726154 | biostudies-literature
Project description:We investigated the effects of demographic, lifestyle (self-reported smoking status and physical activity levels), cancer-related treatment factors (radiation and chemotherapy), and diet (calcium and vitamin D intake) on bone turnover and the relationship of bone turnover to lumbar spine bone mineral density (BMD) Z-scores (LS-BMD Z-scores) determined by quantitative computed tomography (QCT) in 418 ?5-year survivors of childhood acute lymphoblastic leukemia (ALL).Bone turnover was assessed by biomarkers including serum bone-specific alkaline phosphatase (BALP), osteocalcin (OC), and urinary N-telopeptide of type I collagen indexed to creatinine (NTX/Cr). The 215 males ranged in age from 9 to 36 years (median age 17 years).Age and tanner score were inversely associated with all biomarkers (BALP, OC, NTX/Cr) (P?<?0.001). Males had higher BALP and OC than females (P?<?0.001). Body mass index (BMI) was inversely associated with OC and NTX/Cr (P?<?0.001). There was no significant association of biomarkers with lifestyle related factors, ALL treatment-related factors, dietary calcium, vitamin D, or LS-BMD Z-score.In this population of long-term survivors of ALL, bone turnover was significantly associated with age, gender, tanner stage, and BMI. ALL-related treatments did not influence bone turnover and bone turnover was not predictive of volumetric LS-BMD Z-score.
| S-EPMC4625912 | biostudies-literature
Project description:PurposeTo investigate the association of environmental factors, rehabilitation services during therapy and socioeconomic status (SES - insurance type), with neurocognitive outcomes at the end of therapy for survivors of childhood acute lymphoblastic leukemia (ALL).MethodsSurvivors (n = 236) treated on the St. Jude Total Therapy Study 16 completed end of therapy testing with performance measures (IQ, attention, processing speed, fine motor skills, academics) and caregiver ratings (attention, executive function, adaptive skills). Environmental factors were abstracted from the medical record.ResultsDistribution of sex (47.3% female, p = 0.399), treatment arm (45.5% low risk, 54.5% standard/high risk p = 0.929), insurance type (47.7% private, 52.3% public/none, p = 0.117), and mean age at diagnosis (7.7 vs. 6.8 years, p = 0.143) were similar for groups with (n = 110; 46.6%) and without (n = 126; 53.6%) rehabilitation services during therapy. Compared to those without rehabilitation, the rehabilitation group (n = 110; 46.4%) had more caregiver reported problems with attention (Z = -0.28 vs. 0.43, p = 0.022), executive function (Z = -0.50 vs. -0.08, p = 0.003), and adaptive skills (Z = -0.41 vs.-0.13, p = 0.031). Among the rehabilitation group, there was no difference in outcomes by insurance status. Among those without rehabilitation, those with public insurance had worse neurocognitive outcomes than those with private insurance in IQ (Z = -0.04 vs. -0.45, p = 0.0115), processing speed (Z = -0.10 vs. -0.75, p = 0.0030), reading (Z = 0.18 vs. -0.59, p < 0.0001), and math (Z = -0.04 vs. -0.50, p = 0.0021).ConclusionParticipation in rehabilitation services during early intensive therapy is associated with end of therapy caregiver-reported neurocognitive outcomes in daily life.
| S-EPMC10762952 | biostudies-literature
Project description:This study intended to explore the neuropsychological ramifications in childhood acute lymphoblastic leukemia (ALL) survivors in Malaysia and to examine treatment-related sequelae. A case-control study was conducted over a 2-year period. Seventy-one survivors of childhood ALL who had completed treatment for a minimum of 1 year and were in remission, and 71 healthy volunteers were enlisted. To assess alertness (processing speed) and essential executive functioning skills such as working memory capacity, inhibition, cognitive flexibility, and sustained attention, seven measures from the Amsterdam Neuropsychological Tasks (ANT) program were chosen. Main outcome measures were speed, stability and accuracy of responses. Mean age at diagnosis was 4.50 years (SD ± 2.40) while mean age at study entry was 12.18 years (SD ± 3.14). Survivors of childhood ALL underperformed on 6 out of 7 ANT tasks, indicating poorer sustained attention, working memory capacity, executive visuomotor control, and cognitive flexibility. Duration of treatment, age at diagnosis, gender, and cumulative doses of chemotherapy were not found to correlate with any of the neuropsychological outcome measures. Childhood ALL survivors in our center demonstrated significantly poorer neuropsychological status compared to healthy controls.
| S-EPMC10995164 | biostudies-literature
Project description:There is limited information on body composition, energy balance, and fitness among survivors of childhood acute lymphoblastic leukemia (ALL), especially those treated without cranial radiation therapy (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6 ± 5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared with peers (% body fat, 26.2 ± 8.2 vs 22.7 ± 7.1). Survivors without CRT had similar energy balance but had significantly impaired quadriceps strength (-21.9 ± 6.0 Newton-meters [Nm]/kg, 60°/s) and endurance (-11.4 ± 4.6 Nm/kg, 300°/s), exercise capacity (-2.0 ± 2.1 ml/kg per minute), low-back and hamstring flexibility (-4.7 ± 1.6 cm), and dorsiflexion range of motion (-3.1 ± 0.9°) and higher modified total neuropathy scores (+1.6 ± 1.1) than peers. Cumulative asparaginase dose ≥120,000 IU/m(2) was associated with impaired flexibility, vincristine dose ≥39 mg/m(2) with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose ≥8000 mg/m(2) with hand weakness, and intrathecal methotrexate dose ≥225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body-composition outcomes. Survivors remain at risk for impaired fitness.
| S-EPMC4447859 | biostudies-literature
Project description:Cancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosis-inducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1 (LAP TGF-β1). The ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors' 16-week exercise intervention led to significant reduction in inflammatory protein levels. Physical exercise should be promoted for survivors of childhood cancer.
| S-EPMC9713025 | biostudies-literature
Project description:PurposeThe aim was to provide evidence about the prevalence, incidence, and risk factors of cardiac electrical abnormalities in childhood acute lymphoblastic leukemia (ALL) survivors.MethodsWe included all original studies reporting the incidence and/or prevalence of cardiac electrical abnormalities and/or risk factors associated with cardiac electrical abnormalities in childhood ALL survivors (< 21 years old at the time of their initial cancer diagnosis) who were post-treatment. Searches of the databases PubMed, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R), Ovid All EBM Reviews, Ovid Embase, and ISI Web of Science were completed in May 2023. The risk of bias was assessed using the standard JBI critical appraisal checklists.ResultsThe 11 studies included in this review (N = 1,264 participants) evaluated various parameters, including different cardiac electrical abnormalities. Five studies reported heart rate abnormalities (0-68%), six reported repolarization disorders (0-30%), two reported depolarization disorders (0-1%), seven reported rhythm disturbances or abnormalities (0-100%), four reported conduction disorders (0-10%), and three reported unclassified abnormalities (1-38%). No risk factors were reported.ConclusionsElectrical heart problems have been observed in childhood ALL survivors after completion of treatment. Large prospective studies in childhood ALL survivors, clear definitions of cardiac electrical abnormalities, and comparison with a control group are warranted.Implications for cancer survivorsCardiac electrical abnormalities induced by chemotherapy-related cardiotoxicity in the growing population of childhood ALL survivors need to be better characterized to ensure better long-term follow-up and improve overall survival rate.
| S-EPMC10638753 | biostudies-literature
Project description:BackgroundThe progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors.MethodsWe performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness.ResultsOur results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the "high risk" prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females.ConclusionsFor the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects' trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.
| S-EPMC6515640 | biostudies-literature
Project description:BackgroundSurvivors of childhood acute lymphoblastic leukemia (ALL) are at-risk of developing cognitive impairment and neurobehavioral symptoms. Inflammation induced by a compromised health status during cancer survivorship is proposed as a pathophysiological mechanism underlying cognitive impairment in cancer survivors.ObjectivesTo evaluate the associations of biomarkers of inflammation with attention and neurobehavioral outcomes in survivors of childhood ALL, and to identify clinical factors associated with biomarkers of inflammation in this cohort.MethodsWe recruited patients who were diagnosed with ALL at ≤ 18 years old and were currently ≥5 years post-cancer diagnosis. The study outcomes were attention (Conners Continuous Performance Test) and self-reported behavioral symptoms (Adult Self-Report [ASR] checklist). Using a commercial screening kit, survivors' plasma (5ml) was assayed for 17 cytokines/chemokine cell-signaling molecules that are associated with neurodegenerative diseases. The final panel of the targeted markers included interleukin (IL)-8, IL-13, interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1β, and tumor necrosis factor-α. Biomarker levels were rank-ordered into tertiles based on the sample distribution. Multivariable general linear modeling was used to test for associations between biomarkers and study outcomes in the overall cohort and stratified by gender.ResultsThis study included 102 survivors (55.9% males, mean[SD] age 26.2[5.9] years; 19.3[7.1] years post-diagnosis). Survivors within top tertiles of IFN-γ (Estimate =6.74, SE=2.26; P=0.0037) and IL-13 (Estimate =5.10, SE=2.27; P=0.027) demonstrated more inattentiveness. Adjusting for age, gender and treatment, more self-reported thought (Estimate=3.53, SE=1.78; P=0.050) and internalizing problems (Estimate =6.52, SE=2.91; P=0.027) correlated with higher IL-8. Higher levels of IL-13 (RR = 4.58, 95% CI: 1.01-11.10) and TNF-α (RR = 1.44, 95% CI: 1.03-4.07) were observed in survivors had developed chronic health conditions (n=26, 25.5%). The stratified analysis showed that association of IFN-γ with attention was stronger in male survivors than in female survivors.ConclusionInflammation due to cancer-related late effects may potentially be mechanistic mediators of neurobehavioral problems in pediatric ALL survivors. Markers of inflammation can potentially be applied to assess or monitor the effectiveness of interventions, particularly behavioral interventions, in improving cognitive outcomes in survivors. Future work includes understanding the underlying gender-specific pathophysiology behind functional outcomes in the population.
| S-EPMC10320851 | biostudies-literature