Background
Fatigue is often reported by patients with childhood cancer both during and after cancer treatment. Several instruments to measure fatigue exist, although none are specifically validated ...for use in childhood cancer survivors (CCS). The aim of the current study was to present norm values and psychometric properties of the Checklist Individual Strength (CIS) and Short Fatigue Questionnaire (SFQ) in a nationwide cohort of CCS.
Methods
In total, 2073 participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Normative data, construct validity, structural validity, and internal consistency were calculated for the CIS and SFQ. In addition, reliability and a cutoff score to indicate severe fatigue were determined for the SFQ.
Results
Correlations between CIS/SFQ and vitality measures asking about fatigue were high (>0.8). Correlations between CIS/SFQ and measures of different constructs (sleep, depressive emotions, and role functioning emotional) were moderate (0.4–0.6). Confirmatory factor analysis resulted in a four‐factor solution for the CIS and a one‐factor solution for the SFQ with Cronbach's alpha for each (sub)scale showing good to excellent values (>0.8). Test–retest reliability of the SFQ was adequate (Pearson's correlation = 0.88; ICC = 0.946; weighted Cohen's kappa item scores ranged 0.31–0.50) and a cut‐off score of 18 showed good sensitivity and specificity scores (92.6% and 91.3%, respectively).
Conclusion
The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS. The CIS can be used as a tool to assess the multiple fatigue dimensions in CCS.
Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS and that the CIS can be used as a tool to assess the multiple fatigue dimensions in CCS.
To evaluate the prevalence of and risk factors for hypertension in childhood cancer survivors (CCSs) who were treated with potentially nephrotoxic therapies.
In the Dutch Childhood Cancer Survivor ...Study LATER cohort part 2 renal study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study participation, treated between 1963 and 2001 with nephrectomy, abdominal radiotherapy, total body irradiation (TBI), cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide (≥1 g/m2 per single dose or ≥10 g/m2 total) or haematopoietic stem cell transplantation participated and 500 controls from Lifelines. Hypertension was defined as blood pressure (BP) (mmHg) systolic ≥140 and/or diastolic ≥90 or receiving medication for diagnosed hypertension. At the study visit, the CKD-EPI 2012 equation including creatinine and cystatin C was used to estimate the glomerular filtration rate (GFR). Multivariable regression analyses were used.
For ambulatory BP monitoring (ABPM), hypertension was defined as BP daytime: systolic ≥135 and/or diastolic ≥85, night time: systolic ≥120 and/or diastolic ≥70, 24-h: systolic ≥130 and/or diastolic ≥80. Outcomes were masked hypertension (MH), white coat hypertension and abnormal nocturnal dipping (aND).
Median age at cancer diagnosis was 4.7 years (interquartile range, IQR 2.4–9.2), at study 32.5 years (IQR 27.7–38.0) and follow-up 25.5 years (IQR 21.4–30.3). The prevalence of hypertension was comparable in CCS (16.3%) and controls (18.2%). In 12% of CCS and 17.8% of controls, hypertension was undiagnosed. A decreased GFR (<60 ml/min/1.73 m2) was associated with hypertension in CCS (OR 3.4, 95% CI 1.4–8.5). Risk factors were abdominal radiotherapy ≥20 Gy and TBI. The ABPM-pilot study (n = 77) showed 7.8% MH, 2.6% white coat hypertension and 20.8% aND.
The prevalence of hypertension was comparable among CCS who were treated with potentially nephrotoxic therapies compared to controls, some of which were undiagnosed. Risk factors were abdominal radiotherapy ≥20 Gy and TBI. Hypertension and decreased GFR were associated with CCS. ABPM identified MH and a ND.
•Prevalence of hypertension is comparable in childhood cancer survivors and controls.•Risk factors for hypertension are abdominal radiotherapy and total body irradiation.•Hypertension is associated with decreased glomerular filtration rate in childhood cancer survivors.•Ambulatory blood pressure monitoring has added value for childhood cancer survivors.
Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood ...cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers.
Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined.
900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term platinum compound∗cumulative dose of cisplatin. The predictive performance of the genetic markers was poor compared with the clinical risk factors.
PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
•A coding polymorphism in SLC22A2 was associated with platinum induced ototoxicity.•Other genetic markers were not significantly associated with platinum ototoxicity.•Results do not support preemptive genetic testing as recommended in a guideline.•Identifying patients at high risk of platinum ototoxicity remains a challenge.•Compared to genetic markers, clinical factors have a much higher predictive value.
This investigation aimed to evaluate glomerular dysfunction among childhood cancer survivors in comparison with matched controls from the general population. In the Dutch Childhood Cancer Survivor ...Study (DCCSS)-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, 1024 survivors five or more years after diagnosis, aged 18 or more years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated. In addition, 500 age- and sex-matched controls from Lifelines, a prospective population-based cohort study in the Netherlands, participated. At a median age of 32.0 years (interquartile range 26.6-37.4), the glomerular filtration rate was under 60 ml/min/1.73m
in 3.7% of survivors and in none of the controls. Ten survivors had kidney failure. Chronic kidney disease according to age-thresholds (glomerular filtration rate respectively under 75 for age under 40, under 60 for ages 40-65, and under 40 for age over 65) was 6.6% in survivors vs. 0.2% in controls. Albuminuria (albumin-to-creatinine ratio over3 mg/mmol) was found in 16.2% of survivors and 1.2% of controls. Risk factors for chronic kidney disease, based on multivariable analyses, were nephrectomy (odds ratio 3.7 (95% Confidence interval 2.1-6.4)), abdominal radiotherapy (1.8 (1.1-2.9)), ifosfamide (2.9 (1.9-4.4)) and cisplatin over 500 mg/m
(7.2 (3.4-15.2)). For albuminuria, risk factors were total body irradiation (2.3 (1.2-4.4)), abdominal radiotherapy over 30 Gy (2.6 (1.4- 5.0)) and ifosfamide (1.6 (1.0-2.4)). Hypertension and follow-up 30 or more years increased the risk for glomerular dysfunction. Thus, lifetime monitoring of glomerular function in survivors exposed to these identified high risk factors is warranted.
Purpose
This study assessed cardiorespiratory fitness (CRF), physical activity (PA), and sedentary behavior (SB), as well as factors associated with these outcomes in children during or shortly after ...cancer treatment.
Methods
Cross-sectionally, CRF data, obtained by the cardiopulmonary exercise test, and PA and SB data, obtained by an accelerometer, were assessed in children with cancer (8–18 years old). Linear regression models were used to determine associations between CRF, PA, or SB and patient characteristics.
Results
Among 60 children with cancer, mean age 12.6 years, 35 boys, 28 % were during cancer treatment. CRF, reported as the
z
score of VO
2peak
, showed that 32 children had a VO
2peak
z
score which was −2 below the predicted value. CRF was significantly associated with PA and SB: each additional activity count per minute resulted in 0.05 ml/kg/min VO
2peak
increase and each additional minute sedentary reduced VO
2peak
by 0.06 ml/kg/min. Multiple linear regression models of PA and SB showed that decreased activity was significantly associated with higher age, being fatigued, being during childhood cancer treatment (
p
< 0.001), or having a higher percentage of fat mass. The multiple linear regression model showed that lower CRF was significantly associated with increased fatigue, being during cancer treatment, having a higher percentage of fat mass, and lower belief of own athletic competence (
p
< 0.001).
Conclusion
This study revealed that children during or shortly after cancer treatment have low CRF scores. The most inactive children had a higher fat mass, were fatigued, older, and during childhood cancer treatment. Unexpectedly, treatment-related factors showed no significant association with activity behavior.
Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated ...reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring.
Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood ...cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75;
=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50;
=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.
Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes ...related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10
) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m
: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
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