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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.

ObjectiveIn 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.MethodsEight 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.ResultsOverall, 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)) (pConclusionsIn 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.

Contains fulltext : 225882.pdf (Publisher’s version ) (Closed access) Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged

Contains fulltext : 245660.pdf (Publisher’s version ) (Closed access) 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 [β-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 β-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).

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, WFSI, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting metaanalyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment. (C) 2020 The Authors. Published by Elsevier Inc.

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., Central Illustration, Highlights • The main risk factors for cardiac disease in childhood cancer survivors are anthracyclines, mitoxantrone, and chest-directed radiotherapy dose. • Primary prevention strategies may reduce the risk of anthracycline-induced cardiomyopathy. • There is an increased prevalence of traditional cardiovascular risk factors in childhood cancer survivors; screening and early management are important to modify risk. • Multivariable risk prediction models may help to individualize prevention and surveillance strategies.

ObjectiveTo 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.MethodsWe 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 ResultsOf 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.ConclusionsIn 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.

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.

Item does not contain fulltext INTRODUCTION: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands. PATIENTS AND METHODS: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis

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 35 years at follow-up, a follow-up period 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.

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 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.

Introduction Plasma biomarkers may aid in the early diagnosis of anthracycline-induced cardiomyopathy in long-term childhood cancer survivors (CCS) and may provide insights into the underlying mechanisms involved. Natriuretic peptides and troponins are of limited value to diagnose left ventricular dysfunction in CCS >1 year after anthracycline treatment. To improve cardiomyopathy surveillance in long-term CCS, we aim to identify new plasma biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy. Methods Five-year CCS treated with anthracyclines and ≥18 years at time of the study were identified from the ongoing Dutch Childhood Oncology Late Effects After Childhood Cancer (DCOG-LATER) study. Genetic cardiomyopathy cases were identified from a dilated cardiomyopathy cohort in the Amsterdam UMC (figure 1). Levels of 184 plasma proteins (from 32 different biological processes) were compared between three groups of 30 patients: anthracycline-induced cardiomyopathy cases (left ventricular ejection fraction (LVEF) Results The results will be available in August 2019 and will be presented during the congress. Conclusion Targeted proteomics in CCS treated with anthracyclines may identify new biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy in CCS and may provide additional insights into the pathophysiology of anthracycline cardiomyopathy.

Introduction Long-term childhood cancer survivors (CCS) treated with cardiotoxic cancer therapies (CTCT) are screened for LV dysfunction (LVD). The intervals of 2 to 5 years in the Dutch Childhood Oncology Group guideline (Annals of Oncology 2012) depend on anthracycline (300 mg/m2) and radiotherapy dose (30 Gy). There is a gap between detection of LVD, defined as an ejection fraction (EF) Methods Patient and treatment characteristics were collected from a CCS cohort diagnosed with cancer between 1966 and 1997 who received anthracyclines and/or chest radiotherapy. Patients with congenital heart disease and heart failure before baseline echocardiogram were excluded. The first available echocardiogram at >5 years since cancer diagnosis was the baseline echocardiogram. All subsequent echocardiograms were collected. FS was measured by M-mode echocardiography. EF was calculated from two apical chamber views by the Simpson formula. If no EF was available, EF was calculated using the Teicholz formula. Patients with an available baseline echocardiogram were stratified into three subgroups: Reduced (EF Results Of 671 CCS eligible, 448 had a baseline echocardiogram at a median of 17years since cancer diagnosis and 381 had at least one follow-up echocardiogram. At baseline, 6, 41, and 334 CCS were in the reduced, grey zone and preserved EF group respectively. CCS in the grey zone received higher anthracycline dose (median 350 mg/m2) compared to the preserved group (median 200 mg/m2), and more CCS with anthracycline dose >300 mg/m2 were present in the grey zone (51.2% vs 26.6%). In the grey zone group 4.9% and 7.3% developed an EF Conclusion Long-term CCS treated with CTCT with an EF in the grey zone are at an increased risk of developing an EF

Background: The aim of this study was to investigate the long-term side effects of treatment for childhood Hodgkin's lymphoma with chemotherapy only on growth, bone mineral density (BMD), body composition, and thyroid function. Procedure: A total of 88 patients (56 male, 32 female; 17.6-42.6 yr), treated for childhood Hodgkin's lymphoma from 1974-1998 with combination chemotherapy adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine or epirubicin, bleomycin, vinblastine, dacarbazine with or without mechlorethamine, oncovin (vincristine), procarbazine, and prednisone (MOPP) with the intention to avoid radiotherapy, participated in this study. Median follow-up was 15.5 yr (range 5.6-30.2). BMD of lumbar spine and total body (BMD-TB), and body composition were measured using dual-energy x-ray absorptiometry. Bone mineral apparent density of the lumbar spine was calculated to correct for bone size. Free T-4 and TSH were measured. Results: Men treated with MOPP had a significantly reduced height with normal body proportions. Women treated with MOPP had decreased BMD-TB and bone mineral apparent density of the lumbar spine as compared with healthy controls. Percent body fat was significantly increased in female patients treated without MOPP. Body mass index was significantly increased in male patients treated without MOPP, whereas lean body mass was normal in all patients. All patients, except one, treated with chemotherapy only had normal thyroid function. However, five patients who received additional radiation to the thyroid either had abnormal levels of TSH or free T-4, or used thyroid hormones. Conclusions: Lean body mass was normal in all patients; thyroid function was normal in all but one patient. The use of MOPP leads to decreased height and increased body mass index in men and decreased BMD-TB in women. (J Clin Endocrinol Metab 94: 1904-1909, 2009)

Asymptomatic anthracycline-induced cardiac damage (A-CD) is a serious problem among young childhood cancer survivors. The aim of this survey was to assess the current treatment policy in these patients in the Netherlands. A questionnaire was sent to all 136 departments of adult or pediatric cardiology in the Netherlands. It was returned by 61% of the departments. Sixty-six percent of the respondents started medical treatment (ie, an ACE inhibitor and/or a beta-blocker) in childhood cancer survivors with asymptomatic A-CD. Fifty-eight percent of the respondents indicated that their treatment decision was based on published findings in the literature, but none of them referred to studies evaluating the treatment of asymptomatic A-CD. A majority of adult and pediatric cardiologists started medical treatment in childhood cancer survivors with asymptomatic A-CD without knowledge of the benefits and risks of treatment in this patient group. Before ACE inhibitors and/or beta-blockers can be recommended as routine practice in childhood cancer survivors with asymptomatic A-CD, randomized controlled trials should be performed. Until then, the authors recommend centralizing the treatment of childhood cancer survivors with asymptomatic A-CD in a specialized center to cluster the available knowledge and experience. Copyright

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.

Survival of childhood cancer has improved resulting in an increasing number of survivors who are at high risk of developing treatment-related health problems. The authors emphasize the need for specialized care for survivors of childhood cancer by describing three patients who all developed late effects of treatment. The first patient, a 32-year-old female, who had several late effects caused by treatment for nephroblastoma; the second a 39-year-old female, who developed breast cancer after thoracic irradiation for metastatic nephroblastoma; the third a 45-year-old female diagnosed with a meningioma caused by cranial irradiation for acute lymphoblastic leukaemia. In the Netherlands medical care for survivors is clustered at special outpatient clinics (in Dutch: Langetermijneffecten na kinderkanker (Long-term effects after childhood cancer; LATER)-outpatient clinics). In 2010 a guideline was published with recommendations for optimal follow-up and care for survivors of childhood cancer.

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.

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

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 ( 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 Δ 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.