Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately ...identifying cardiac injury and cardiomyopathy.
Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment.
cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables.
cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.
Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully ...understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL3. HDL2, especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders.
We sought to determine if neonatal phototherapy is associated with a greater risk of childhood cancer. We conducted a retrospective cohort study of 786,998 infants born in hospitals of Quebec, Canada ...between 2006 and 2016, with 4,660,868 person‐years of follow‐up over an 11‐year period. The exposures were neonatal phototherapy (32,314 or 4.1% of infants) and untreated jaundice (91,855 or 11.7% of infants). The outcome was hospitalization for solid or hematopoietic childhood tumours between 2 months and 11 years of age. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association of phototherapy with childhood cancer, adjusted for infant characteristics. The incidence of childhood cancer was higher for infants with phototherapy (25.1 per 100,000 person‐years) and untreated jaundice (23.0 per 100,000) compared to unexposed infants (21.6 per 100,000). Phototherapy appeared to be associated with late onset solid tumours, including brain/central nervous system cancers. Between age 4 and 11 years, children who received neonatal phototherapy had more than 2 times the risk of any solid tumour compared to unexposed children (HR 2.26, 95% CI 1.34–3.81). Results were similar for phototherapy compared against untreated jaundice. A similar trend was however less apparent for hematopoietic cancer. We conclude that neonatal phototherapy may be associated with a slightly increased risk of solid tumours in childhood, but cannot rule out an effect of bilirubin. Minimizing unnecessary exposure to phototherapy through adherence to recommended thresholds for treatment is encouraged.
What's new?
While phototherapy is widely used to treat neonatal jaundice, it can induce oxidative stress and DNA damage. Whether these factors raise the risk for subsequent development of childhood cancer remains uncertain. Here, associations between phototherapy and childhood cancer risk were investigated among infants born between 2006 and 2016 in Quebec, Canada. Childhood cancer incidence was found to be elevated among phototherapy‐treated infants and infants with untreated jaundice. Phototherapy appeared to be associated in particular with solid tumors that developed later, between ages 4 and 11. Closer study is needed to disentangle the potentially carcinogenic effects of phototherapy from hyperbilirubinemia.
We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic ...leukemia (ALL).
Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.
Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.
There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.
We aimed to identify contributors to cancer-related fatigue (CRF), explore non-pharmacological interventions addressing CRF, and highlight which contributors were targeted by these interventions in ...childhood cancer survivors.
We performed a search in various databases and used the PRISMA-ScR checklist. Findings were synthesized in various different tables and figures in accordance with our objectives.
We included 49 articles in this systematic scoping review. We identified 59 significant contributors. Depression and physical activity level were some of the most studied significant contributors. Ten interventional studies were identified (e.g., yoga, physical activity intervention) that addressed 6 contributors (e.g., physical activity level).
This review is the first to describe and relate contributors and non-pharmacological interventions targeting CRF in childhood cancer survivors. Important clinical implications could be derived from the variety of factors explaining CRF and how it is currently addressed.
Display omitted
•Identification of contributors, non-pharmacological interventions, and description of contributors targeted by interventions•Common candidate and significant contributors to CRF: depression, physical activity level, anxiety, pain, and sleep quality.•Interventions targeting contributors: exercise counseling, cognitive-behavior therapy, yoga, and physical activity
Context
There is no universal definition of cancer-related fatigue (CRF) specific to childhood cancer survivors, despite this population facing unique long-term side effects from their cancer. We ...aimed to synthesize and combine existing definitions of CRF specific to this context to inform on the necessity of a panel of experts to formulate a new definition of CRF for childhood cancer survivors.
Methods
The literature search was performed in various databases. Titles, abstracts, and keywords were screened by two researchers to confirm eligibility. The data extraction process was performed by two researchers. Our search was conducted in various databases.
Results
Thirty articles were included in the qualitative analysis. Two coders reached consensus on 14 codes. The thematization process produced 4 themes: frequency, context, attributes, and consequences of CRF. These themes were used to synthesize a definition of CRF, as follows: “In childhood cancer survivors, cancer-related fatigue is a common late effect of cancer and cancer treatments. It is characterized by a subjective, persistent, and multidimensional experience that differs from normal fatigue in the physical, emotional, and/or cognitive spheres. Cancer-related fatigue may have a variety of negative consequences including a reduced quality of life and level of functioning, a lack of vigor, work difficulties, relationship issues, and emotional distress.”
Conclusion
A definition of CRF applicable to childhood cancer survivors is timely to organize research efforts and design appropriate interventions. The proposed definition is a first step towards the formulation of a new definition of CRF specific to childhood cancer survivors by experts.
Background The 5-year survival rate for individuals with neuroblastoma is approaching 70%. Few data exist, however, on the long-term outcomes of these patients, who are often treated at a very young ...age. Methods Outcome data were obtained for 954 5-year neuroblastoma survivors who were diagnosed in 1970–1986 and enrolled in the Childhood Cancer Survivor Study (CCSS). Late mortality, second malignant neoplasms, and chronic health conditions were analyzed in relation to treatment factors using Poisson regression models and their modification with generalized estimating equations. Neuroblastoma survivors were compared with a cohort of 3899 siblings of CCSS participants for risk of chronic health conditions and selected sociodemographic outcomes. All statistical tests were two-sided. Results Six percent of patients died more than 5 years after their diagnosis (standardized mortality ratio = 5.6; 95% confidence interval CI = 4.4 to 6.9). The most common causes of death were disease recurrence (n = 43) and second malignant neoplasms (n = 13). The cumulative incidence of second malignant neoplasms was 3.5% at 25 years and 7.0% at 30 years after diagnosis. Compared with the sibling cohort, survivors had an increased risk of selected chronic health conditions (risk ratio RR = 8.3; 95% CI = 7.1 to 9.7) with a 20-year cumulative incidence of 41.1%. The most prevalent outcomes involved the neurological, sensory, endocrine, and musculoskeletal systems, with 20-year cumulative incidences of 29.8%, 8.6%, 8.3%, and 7.8%, respectively. Neuroblastoma survivors who were treated with multimodality therapy were more likely to develop a chronic health condition than survivors treated with surgery alone (RR = 2.2; 95% CI = 1.6 to 3.0). Neuroblastoma survivors were less likely than siblings to have ever been employed (P = .04) or to be married (P < .001) and had a lower personal income (P = .009). Conclusions Neuroblastoma survivors have an increased rate of mortality and second malignant neoplasms, relative to the age- and sex-comparable US population, and of chronic health conditions, relative to their siblings, which underscores the need for long-term medical surveillance.
Children with acute lymphoblastic leukemia (ALL) are treated with doxorubicin-based chemotherapy that can lead to cardiotoxicity which is a well-known cause of mortality. This study aims to ...characterize myocardial subtle changes induced by doxorubicin-related cardiotoxicity. We used the combination of cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing and the CircAdapt model to explore hemodynamics and intraventricular mechanisms at rest and during exercise in 53 childhood ALL survivors. A sensitivity analysis of the CircAdapt model identified the most influencing parameters on the left ventricle volume. ANOVA were performed to explore significant differences between left ventricle stiffness, contractility, and arteriovenous pressure drop, as well as survivors’ prognostic risk groups. No significant differences were observed between prognostic risk groups. The left ventricle stiffness and left ventricle contractility were non-significantly higher in survivors receiving cardioprotective agents (94.3 %), compared to those at standard and high prognostic risk (77 % and 86 %, respectively). In both left ventricle stiffness and left ventricle contractility, we observed that survivors receiving cardioprotective agents were close to the nominal value of CircAdapt (healthy reference group value is 100 %). This study allowed to improve our knowledge of potential subtle myocardial changes induced by doxorubicin-related cardiotoxicity in childhood ALL survivors. This study confirms that survivors exposed to a high cumulative dose of doxorubicin during treatments are at potential risk of myocardial changes many years after the end of their cancer, while cardio-protective agents may prevent changes in cardiac mechanical properties.
Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been ...reported.
We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures.
Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006).
Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.
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