Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

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 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: 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.

Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review.

We performed a systematic review to define the long-term health problems and optimal treatment strategy for patients with neuroblastoma with intraspinal extension. Of 685 identified studies, 28 were included in this review. The burden of long-term health problems is high; a median of 50% of patients suffered from neurological motor deficit, 34% from sphincter dysfunction, and 30% from spinal deformity. The currently available literature remains suboptimal as a guide for treatment of NBL with intraspinal extension. More well-designed, prospective studies are needed to determine the optimal treatment strategy.

Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors.

AIM: To evaluate the prevalence of health problems in 5-year survivors treated for neuroblastoma (NBL) with intraspinal extension. PATIENTS AND METHODS: Retrospective, single center cohort study (using data from Childhood Cancer Registry and medical records) of patients treated for NBL with intraspinal extension (between 1980 and 2007) who survived ≥ 5 years after diagnosis. Health problems were graded according to the Common Terminology Criteria for Adverse Events (CTCAEv.3.0). RESULTS: All eligible patients (n = 19) were included (n = 7 no neurological symptoms at diagnosis), median age at diagnosis was 1.2 years (0.6-10.8 years), and median follow-up time was 15.6 years (6.3-29.5 years). Ninety-five percent of survivors had ≥1 health problem and 48% of survivors had ≥4 health problem with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (grade 3) or life-threatening/disabling (grade 4) health problem. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor neuropathy (32% of patients), and sensory neuropathy (26% of patients). Of the 13 patients who underwent a laminectomy, 54% (seven of 13) developed a grade 3 and 23% (three of 13) developed a grade 4 health problem. Among six patients, without laminectomy, 17% developed (one of six) a grade 3 and in 17% developed (one of six) a grade 4 health problem. CONCLUSIONS: Ninety-five percent of 5-year survivors treated for a childhood intraspinal NBL have health problems. The high prevalence of grade 3 and 4 health problems (especially in the laminectomy group) emphasizes the importance of specialized long-term multidisciplinary follow-up and identifies optimal treatment with limited morbidity and maximal efficacy.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Scaling up and implementing the digital Survivorship Passport tool in routine clinical care - The European multidisciplinary PanCareSurPass project.

BACKGROUND: Childhood cancer survivors (CCS), of whom there are about 500,000 living in Europe, are at an increased risk of developing health problems [1-6] and require lifelong Survivorship Care. There are information and knowledge gaps among CCS and healthcare providers (HCPs) about requirements for Survivorship Care [7-9] that can be addressed by the Survivorship Passport (SurPass), a digital tool providing CCS and HCPs with a comprehensive summary of past treatment and tailored recommendations for Survivorship Care. The potential of the SurPass to improve person-centred Survivorship Care has been demonstrated previously [10,11]. METHODS: The EU-funded PanCareSurPass project will develop an updated version (v2.0) of the SurPass allowing for semi-automated data entry and implement it in six European countries (Austria, Belgium, Germany, Italy, Lithuania and Spain), representative of three infrastructure healthcare scenarios typically found in Europe. The implementation study will investigate the impact on person-centred care, as well as costs and processes of scaling up the SurPass. Interoperability between electronic health record systems and SurPass v2.0 will be addressed using the Health Level Seven (HL7) International interoperability standards. RESULTS: PanCareSurPass will deliver an interoperable digital SurPass with comprehensive evidence on person-centred outcomes, technical feasibility and health economics impacts. An Implementation Toolkit will be developed and freely shared to promote and support the future implementation of SurPass across Europe. CONCLUSIONS: PanCareSurPass is a novel European collaboration that will improve person-centred Survivorship Care for CCS across Europe through a robust assessment of the implementation of SurPass v2.0 in different healthcare settings.

Evaluation of a patient information website for childhood cancer survivors.

PURPOSE: Childhood cancer survivors (CCS) are in need of specialized information about late effects of treatment. In the current study, we assessed the perceived usability and satisfaction with the content of a national website with information on late effects and analyzed possible determinants related to website usability and content satisfaction. METHODS: CCS and their parents were contacted through our local follow-up program and via online media to complete an online questionnaire regarding their baseline characteristics, medical decision style, and the usability and content of the website. Usability was evaluated using the System Usability Scale (SUS), a validated questionnaire resulting in a score from 0 to 100. For the content rating, we constructed a six-item scale resulting in a score from 1 to 5 (Cronbach's α, 0.83). Comments were analyzed qualitatively. RESULTS: Fifty-five survivors and forty-three parents of survivors completed the questionnaire. Median age of respondents was 41 years (range, 17-58). Respondents rated the website's usability with a mean SUS score of 72.5 (95 % CI, 69.2-74.9). The mean content rating was 3.7 (95 % CI, 3.5-3.8). No determinants were significantly related to the perceived usability or content satisfaction in multivariate analyses. Qualitative analysis revealed respondents' preference for more detailed and even scientific information on late effects. CONCLUSION: Respondents were satisfied with the usability and the contents of a website that targeted at their information needs. As knowledge about late effects is still limited among survivors, a website can be a valuable resource to improve their knowledge, promote healthy behavior, and in the end, improve their quality of life.

Prevalence, risk factors, and optimal way to determine overweight, obesity, and morbid obesity in the first Dutch cohort of 2338 long-term survivors of childhood cancer: a DCCSS-LATER study.

BACKGROUND: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA). We aimed to assess prevalence, identify determinants and biomarkers, and assess which method captures overweight best, in a nationwide cohort. METHODS: The prevalence of overweight and obesity, primarily defined by body mass index (BMI), was assessed in the DCCSS-LATER cohort of adult survivors treated from 1963-2002, with the LifeLines cohort as reference. The associations between risk factors and overweight metrics were investigated using logistic regression. Additional overweight metrics included DXA fat%, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and high-molecular-weight (HMW) adiponectin. RESULTS: A total of 2338 (mean age 35.5 years, follow-up 28.3 years) survivors participated. The overweight prevalence was 46.3% in men and 44.3% in women (obesity 11.2% and 15.9%, morbid obesity 2.4% and 5.4%), with highest rates among brain tumor survivors. Compared to controls, there was no overall increased overweight rate, but this was higher in women > 50 years, morbid obesity in men > 50 years. Overweight at cancer diagnosis (adjusted odds ratio [aOR] = 3.83, 95% CI 2.19-6.69), cranial radiotherapy (aOR = 3.21, 95% CI 1.99-5.18), and growth hormone deficiency (separate model, aOR = 1.61, 95% CI 1.00-2.59) were associated with overweight. Using BMI, WC, WHR, and WHtR, overweight prevalence was similar. Low HMW adiponectin, present in only 4.5% of survivors, was an insensitive overweight marker. Dual-energy X-ray absorptiometry-based classification identified overweight in an additional 30%, particularly after abdominal radiotherapy, total body irradiation, anthracyclines, and platinum. CONCLUSIONS: Overweight occurs in almost half of long-term survivors. There was no overall increased incidence of overweight compared to controls. We identified factors associated with overweight, as well as subgroups of survivors in whom DXA can more reliably assess overweight.

Effects of growth hormone therapy on bone mass, metabolic balance, and well-being in young adult survivors of childhood acute lymphoblastic leukemia.

Growth hormone deficiency (GHD), mostly after cranial radiotherapy (CRT), may lead to several negative effects. Young adult survivors of acute lymphoblastic leukemia (ALL) could benefit from GH therapy in different ways. Twenty ALL survivors (17.1 ± 4.3 y after diagnosis) with low bone mineral densities and/or low insulin-like growth factor-1 were included. Two of the 3 patients who only received chemotherapy had GHD. Of the 20 patients, 17 started with GH therapy and 14 completed the 2-year study period. At several time points, bone mineral density (BMD) was measured. Psychological functioning was assessed. At the start of the study, standard deviation scores of height, insulin-like growth factor-1, lumbar spine, and femoral neck BMD were all below -1. After 2 years of GH therapy, total body BMD and lean mass were significantly higher (P < 0.01 and P < 0.001, respectively), whereas the percentage fat was significantly lower (P < 0.02). Several psychological measures improved significantly after 2 years. In conclusion, GH therapy during 2 years in young adult survivors of childhood ALL did have a number of benefits, such as improvement of total body bone density and body composition. Results also suggest improvement of psychological well being. Furthermore, it also became clear that patients after chemotherapy alone should be tested for GHD.

Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study.

OBJECTIVE: In this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study. METHODS: Eight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3-5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors. RESULTS: Overall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14-30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)). CONCLUSIONS: In this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.

Bone Mineral Density in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma: A Longitudinal Follow-Up Study.

Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [ß-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers ß-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Cardiac Disease in Childhood Cancer Survivors: Risk Prediction, Prevention, and Surveillance: JACC CardioOncology State-of-the-Art Review.

Cardiac diseases in the growing population of childhood cancer survivors are of major concern. Cardiotoxicity as a consequence of anthracyclines and chest radiotherapy continues to be relevant in the modern treatment era. Mitoxantrone has emerged as an important treatment-related risk factor and evidence on traditional cardiovascular risk factors in childhood cancer survivors is accumulating. International surveillance guidelines have been developed with the aim to detect and manage cardiac diseases early and prevent symptomatic disease. There is growing interest in risk prediction models to individualize prevention and surveillance. This State-of-the-Art Review summarizes literature from a systematic PubMed search focused on cardiac diseases after treatment for childhood cancer. Here, we discuss the prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac diseases in survivors of childhood cancer.

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

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 PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, 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 genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Prevalence of congenital heart defects in neuroblastoma patients: a cohort study and systematic review of literature.

Data on the prevalence of congenital heart defects (CHD) in neuroblastoma patients are inconsistent. If CHD are more common in neuroblastoma patients than in the general population, cardiac screening might be warranted. In this study we used echocardiography to determine the prevalence of CHD in a single centre cohort of surviving neuroblastoma patients. In addition, we performed a systematic review of the literature. Echocardiography was performed in 119 of 133 patients (89.5%). Only two patients (1.7%) had CHD. The prevalence of CHD was not significantly different from a previously published control group of 192 leukaemia patients examined by echocardiography (P = 0.49). Literature search revealed 17 studies, showing prevalence rates of CHD in neuroblastoma patients ranging from 0 to 20%. Prevalence was less than 3.6% in the majority of studies. Most studies lacked information on validity. We conclude that current evidence does not support standard cardiac screening in all patients with neuroblastoma.

Extra-osseous Ewing sarcoma.

BACKGROUND: Clinical data and data on outcome of extra-osseous Ewing tumors are scarce. PROCEDURE: After a search for Ewing tumors in the database of a single institution over a period of 20 years, 16 out of 192 cases were found to have extra-osseous primary tumors. RESULTS: Ages at initial diagnosis ranged from 2.5 to 17 years. Follow-up period ranged from 4 months to 24.8 years (mean 8.4 years). Eleven patients were treated according to protocols for Ewing tumors, while in 4 cases soft tissue protocols were used. In a single patient only surgery was done. Two patients had progressive disease despite chemotherapy; a third patient had only tumor response on the initial 2 chemotherapy courses. All 3 patients with initially metastatic disease died. One patient developed a second malignancy. Overall survival at 5 years was 75%. Event-free survival (EFS) at 5 years was 68%; for nonmetastatic patients 5-year EFS was 83%. CONCLUSION: The authors conclude that nonmetastasized extra-osseous Ewing tumors have a prognosis at least similar to that of osseous Ewing tumors.

Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

OBJECTIVE: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines. METHODS: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction. RESULTS: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions. CONCLUSIONS: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study.

BACKGROUND: To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients. METHODS: Twenty young adult survivors of childhood ALL with reduced bone mineral density (<-1 SD) and/or low IGF-I SD-scores (<-1 SD) were included in the study. A final group of 13 patients (9 males and 4 females), mean age 23.7 +/- 2.9 years (range 20 - 29.7) completed a 2-year treatment with GH.IQ and neuropsychological performance were assessed at pre-treatment (T1) and after one (T2) and two (T3) years. ANOVA was performed with assessment at T1, T2 and T3 as repeated measurements factor. Relations between test score changes and changes of IGF-I levels were determined by calculating the Pearson correlation coefficient. RESULTS: Scores on the cognitive tests were in the normal range. Verbal short- and long-term memory performance decreased between T1 and T2, and increased between T2 and T3. Performance at T3 was not significantly different from that at T1. Performance for sustained attention improved from T1 to T2 and from T1 to T3. Visual-spatial memory was improved after one year of GH treatment. A significant positive correlation was found for Delta IGF-I (T2-T1) with difference scores of visual-spatial memory (T2-T1 and T3-T1), indicating that IGF-I increase after one year of GH treatment is associated with increase in cognitive-perceptual performance at month 12 and 24. CONCLUSION: Since the level of intellectual functioning of our patient cohort was in the normal range the present finding that GH treatment has negative effects on verbal memory and positive on attention and visual-spatial memory warrants similar studies in other groups of ALL survivors. Also, a lower dose of GH should be determined inducing as much IGF as needed to improve verbal as well as visual cognitive functions. The present findings indicate that more knowledge is needed before GH treatment may be recommended to enhance cognitive functions in ALL survivors.

Psychosocial development in survivors of childhood differentiated thyroid carcinoma: a cross-sectional study.

OBJECTIVE: The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC. DESIGN AND METHODS: Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used. RESULTS: We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales. CONCLUSIONS: Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.

Long-Term Quality of Life in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma.

Context: Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer-specific HRQoL in survivors only. Design: Survivors diagnosed between 1970 and 2013 at age ≤18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer-specific HRQoL questionnaire. Results: Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer-specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL. Conclusions: Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration.

Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study.

Platinum-containing chemotherapeutics are efficacious for a variety of pediatric malignancies, nevertheless these drugs can induce ototoxicity. However, ototoxicity data on large cohorts of childhood cancer survivors (CCSs) who received platinum agents, but not cranial irradiation are scarce. Therefore, we have studied the frequency and determinants of ototoxicity in a cross-sectional multicenter CCS cohort, including the role of co-medication since it has been suggested that these play a role in ototoxicity. We have collected treatment data and audiograms from the medical records of CCS treated in the seven pediatric oncology centres in The Netherlands. Ototoxicity was defined as Münster grade ≥2b (>20 dB at ≥4-8 kHz). Four-hundred-fifty-one CCS who received platinum agents, but not cranial irradiation (median age at diagnosis: 4.9 years, range: 0.01-19 years) were included. The overall frequency of ototoxicity was 42%. Ototoxicity was observed in 45% of the cisplatin-treated CCS, in 17% of the carboplatin-treated CCS and in 75% of the CCS that had received both agents. Multivariate analysis showed that younger age at diagnosis (odds ratio [OR]: 0.6, 95% confidence interval [CI]: 0.5-0.6 per 5 years increase); higher total cumulative dose cisplatin (OR: 1.2, 95% CI: 1.2-1.5 per 100 mg/m2 increase); and co-treatment with furosemide (OR: 2.3, 95% CI: 1.4-3.9) were associated with ototoxicity. We conclude that treatment with (higher total cumulative dose of) cisplatin, young age and furosemide co-medication independently are associated with an increased risk of ototoxicity in CCS. Future prospective studies are necessary to confirm the additive risk of co-medication on the development of ototoxicity.