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Background: Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure.Objective: To describe the methodology of the Dutch LATER cardiology study (LATER CARD).Methods: The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings.Conclusions: The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure. [ABSTRACT FROM AUTHOR]

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors. [ABSTRACT FROM AUTHOR]

Objective: To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer.Study Design: We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conversation regarding death occurred. The data were analyzed qualitatively using a framework approach.Results: Of the 86 parents of 56 children who answered the questions regarding discussing death with their child, 55 parents of 35 children did not discuss the impending death with their child. The following themes were identified: the parents' inability to discuss the impending death; the parents' desire to protect their child; views regarding talking with children; parents' views of child characteristics; the child's unwillingness to discuss the subject; lack of opportunity to talk; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they had brief, direct conversations regarding death. The majority of parents felt positive regarding their decision about whether to talk with their child about his/her impending death.Conclusion: Most parents in this study cited several reasons for not discussing death with their child. Our findings highlight the sensitive and complex issues surrounding these conversations, indicating that there may be a role for clinicians in supporting parents. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management. [Copyright &y& Elsevier]

Malignant rhabdoid tumors (MRTs) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is, therefore, dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient response to therapy. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single-agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as a therapeutic strategy in MRT. [Display omitted] • Patient-derived organoids can be used to identify tumor-specific drug vulnerabilities • Neddylation inhibitor MLN4924 is cytotoxic for malignant rhabdoid tumors (MRTs) • MLN4924 induces apoptosis in MRTs via activation of the unfolded protein response • Treatment with MLN4924 extends survival in vivo in an MRT PDX mouse model Calandrini et al. identify neddylation as a therapeutic vulnerability for malignant rhabdoid tumors (MRTs), an aggressive and deadly childhood cancer. The neddylation inhibitor MLN4924 specifically induces cell death in MRTs in vitro and extends overall survival in vivo. Neddylation inhibition may, therefore, be a promising therapeutic strategy for MRTs. [ABSTRACT FROM AUTHOR]

Abstract Background Observational studies have suggested that perinatal outcomes are worse in offspring of cancer survivors. We conducted a systematic review and meta-analysis to examine the risks of perinatal complications in female cancer survivors diagnosed before the age of 40 years. Methods All published articles on pregnancy, perinatal or congenital risks in female cancer survivors were screened for eligibility. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results Twenty-two studies met the inclusion criteria. Meta-analysis indicates that offspring of cancer survivors are at increased risk of prematurity (relative risk [RR]: 1.56; 95% confidence interval [CI] 1.37–1.77) and low birth weight (RR 1.47; 95% CI 1.24–1.73) but not of being small for gestational age (RR 0.99; 95% CI 0.81–1.22). Cancer survivors have higher rates of elective (RR: 1.38; 95% CI 1.13–1.70) and emergency caesarean section (RR: 1.22; 95% CI 1.15–1.30) as well as assisted vaginal delivery (RR: 1.10; 95% CI 1.02–1.18) and are at increased risk of postpartum haemorrhage (RR: 1.18; 95% CI 1.02–1.36). The risk of congenital abnormalities also appears increased (RR 1.10; 95% CI 1.02–1.20), but this is likely to be an artefact of analysis. Although meta-analysis of the effects of radiotherapy was not possible for all outcomes, there was an increased risk of prematurity (RR 2.27; 95% CI 1.34–3.82) and consistent findings of low birth weight (RR 1.38–2.31). Risk of being small for gestational age was increased only after high uterine radiotherapy dosage. Conclusion The increased perinatal risks warrant a proactive approach from healthcare providers in both counselling and management of perinatal care for cancer survivors. Highlights • Pregnancy in survivors of cancer can carry risk to both mother and foetus. • The offspring of survivors of cancer are at risk of prematurity and low birth weight. • Offspring are not at risk of being small for gestational age or congenital abnormalities. • Abdominal radiotherapy is associated with increased risk of postpartum haemorrhage. • Elective and emergency caesarean section rates are higher in cancer survivors. [ABSTRACT FROM AUTHOR]

Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding. Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3–18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect. The median age was 5.5 years (range 3.0–18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00–1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL. Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017–002738–22 (https://eudract.ema.europa.eu/). • 66% of paediatric ALL patients experience dexamethasone-induced behavioural problems. • Previous research showed that hydrocortisone may improve these problems. • Compared to placebo, hydrocortisone had no additional beneficial effect in this study. • Placebo and nocebo effects may play an important role in behavioural side-effects. [ABSTRACT FROM AUTHOR]

This population-based study is the first to provide a detailed analysis of trends in incidence and survival of children and adolescents diagnosed with renal malignancies in the Netherlands. Data on all renal malignancies diagnosed in paediatric patients (0–18 years) between 1990 and 2014 [N = 648, 92% Wilms tumour (WT)] were extracted from the Netherlands Cancer Registry. Five-year overall survival (OS) was estimated using the actuarial method. Time trends in incidence were assessed by calculating average annual percentage change. A parametric survival model was used to compare the multivariable-adjusted risk of dying from WT between two diagnostic periods. The incidence was 8 per million person-years and was constant over time (average annual percentage change -0.8%, p = 0.29). Patients with WT had a favourable outcome in both time periods; 5-year OS was 88% in 1990–2001 and 91% in 2002–2014. Multivariable analysis showed that the risk of dying from WT was not significantly decreased in the latest period (hazard ratio, 95% CI: 0.7, 0.4–1.3). Five-year OS decreased with increasing disease stage, ranging from 95 to 100% for stage I-II and about 80% for stage III–IV to 74% for bilateral disease. Five-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney. Incidence of paediatric renal malignancies in the Netherlands has been stable since the 1990s. Five-year OS of WT reached 91% and was similar to findings for other developed countries. Contrary to the excellent outcome for WT, the outcome of malignant rhabdoid tumour of the kidney remained inferior. • The incidence of paediatric renal tumours in the Netherlands was stable between 1990 and 2014. • 5-year OS of Wilms tumour reached 91% and was similar to rates in other developed countries. • 5-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney. • Particular attention should be paid to adverse prognostic subgroups, especially malignant rhabdoid tumour of the kidney. [ABSTRACT FROM AUTHOR]

Infertility is a serious early, as well as late, effect of childhood cancer treatment. If addressed in a timely manner at diagnosis, fertility preservation measures can be taken, preferably before the start of cancer treatment. However, pediatric oncologists might remain reluctant to offer counseling on fertility-preservation methods, although infrastructure to freeze ovarian tissue has become available and is currently considered standard care for pre- and postpubertal girls at high risk of gonadal damage. More importantly, risk factors have been identified for cancer treatment-related impairment of gonadal function, and the first successful pregnancies have been reported after autotransplanted ovarian tissue, which has been harvested from children. Additionally, great progress has been made in the field of ex vivo maturation of oocytes in frozen ovarian tissue, which provides opportunities for those at risk of ovarian micrometastasis. Hence, it is time to counsel girls at risk and make every effort to cryopreserve their ovarian tissue, now more than ever before. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Society of International Pediatric Oncology – Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93–01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0–81.6%) and 79.3% (95% CI: 71.5–88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228–1.638] [ p -value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126–1.700] [ p -value = 0.193]). Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies. • On behalf of the Society of International Pediatric Oncology- Renal Tumor Study Group. • Risk stratification of relapsed Wilms tumour is based on primary treatment intensity. • Patients treated with vincristine and actinomycin-D are advised a four-drug therapy at relapse. • A three-drug therapy is adequate relapse treatment in a subset of patients. • Identification of this subset requires large-scale epidemiological and molecular studies. [ABSTRACT FROM AUTHOR]

Since previous consensus-based Wilms tumour (WT) surveillance guidelines were published, novel genes and syndromes associated with WT risk have been identified, and diagnostic molecular tests for previously known syndromes have improved. In view of this, the International Society of Pediatric Oncology (SIOP)-Europe Host Genome Working Group and SIOP Renal Tumour Study Group hereby present updated WT surveillance guidelines after an extensive literature review and international consensus meetings. These guidelines are for use by clinical geneticists, pediatricians, pediatric oncologists and radiologists involved in the care of children at risk of WT. Additionally, we emphasise the need to register all patients with a cancer predisposition syndrome in national or international databases, to enable the development of better tumour risk estimates and tumour surveillance programs in the future. • Wilms tumour surveillance enables the detection of smaller and lower-stage tumours. • Guidelines are presented for all genes/syndromes associated with Wilms tumour risk. • Surveillance primarily recommended if >5% estimated childhood Wilms tumour risk. • Three-monthly renal ultrasonography until a child's 7th birthday. [ABSTRACT FROM AUTHOR]

• Postoperative flank irradiation is indicated in 20–25% of pediatric renal tumors. • For decades, two-opposing beams have been used to cover the flank target volume. • Target volumes adjusted for organ shift/motion combined with VMAT were introduced. • This new approach resulted in a 2-year loco-regional control rate of 94%. • Two locoregional relapses, unavoidable by two-opposing photon beams, were observed. In pediatric renal tumors, conventional two opposing photon beams have been used to cover the postoperative flank target volume for decades. This single center study describes the locoregional outcome using highly conformal flank target volumes adjusted for postoperative changes and intra-fraction motion combined with Volumetric-Modulated Arc Therapy (VMAT). Between 01-2015 and 12-2019, 36/161 newly diagnosed patients with renal tumors underwent flank only irradiation (n = 30) or flank + whole lung irradiation (n = 6) using highly conformal target volumes in line with the SIOP-RTSG consensus statement. VMAT consisted of full-arc 10MV photon beams optimized for constraints of the organs at risk. In case of locoregional relapses, image co-registration and dose reconstruction was performed. Each relapse was classified as either 'infield' (V95% relapse : ≥99.0%), ' marginal' (V95% relapse : 20.0–98.9%) or ' outfield' (V95% relapse : 0–19.9%). At a median follow-up from diagnosis of 3.1 years (range:0.4–5.7), the estimated 2-year Locoregional Control Rate, Disease-Free Interval and Overall Survival were 94%, 91% and 94%, respectively. Locoregional relapse was observed in two patients. One patient had a combined tumor bed and regional recurrence, classified as infield (V95% relapse : 100%) and outfield (V95% relapse : 1.2%). The second patient had a regional relapse in the inferior vena cava classified as marginal recurrence (V95% relapse : 93%). Relapses would not have been adequately covered by conventional beams. This single center analysis provides encouraging evidence that excellent locoregional control can be obtained by using highly conformal flank target volumes with VMAT in pediatric renal tumors. The safety of this approach will be validated in a prospective multicenter study. [ABSTRACT FROM AUTHOR]

Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands. In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer age <18 y (between 1963 and 2002) and are not subject to brain tumour screening. We identified histologically confirmed meningiomas by record linkage with the Dutch Pathology Registry (PALGA; 1991–2018), and in the Dutch LATER registry. We extracted details regarding diagnosis, treatment, and follow-up from medical records. We described 93 CCS with meningioma, of whom 89 (95.7%) were treated with CrRT (5.7% of 1551 with prior CrRT; OR = 68). Median age at diagnosis was 31.8 y (range: 13.2–50.5). Thirty survivors (32.3%) had synchronous meningiomas; 84 (90.3%) presented with symptoms. Only 16.1% of meningioma was detected at late effects clinics. Over time, all survivors had surgery; one-third also received radiotherapy. During follow-up 38 (40.9%), survivors developed new meningiomas, 22(23.7%) recurrences and at least four died due to the meningioma. Histologically confirmed meningiomas after childhood cancer are mostly diagnosed with symptoms and not during routine follow-up at late effects clinics. The meningiomas occur at a median of 20–25 y younger age than incidental meningiomas, are frequently multiple and recurrence after treatment is high. It is crucial to inform CCS and healthcare providers about risk and symptoms of subsequent meningiomas. • Histologically confirmed meningioma in childhood cancer survivors (CCS) are presented at young age with symptoms. • Synchronous and metachronous meningiomas and recurrences are common in CCS. • It is crucial to inform CCS and healthcare providers about risk and symptoms. [ABSTRACT FROM AUTHOR]

To describe experience with partial nephrectomy combined with brachytherapy as part of the local management of bilateral Wilms tumor (WT) including a review of the available literature. Between 2011 and 2014, three highly selected patients (age nine months, 16 months, and 4 years) with bilateral WT (two synchronous and one metachronous) underwent enucleation and perioperative brachytherapy to the tumor bed. With a minimum follow-up of 5 years, all three patients are in continuous complete remission with preserved kidney function. Although nephron sparing surgery aiming at tumor free-margins remains the gold standard for bilateral WT, tumor enucleation followed by brachytherapy may be considered in carefully selected patients at high risk for end-stage kidney failure. Given the rarity and complexity of the procedure, concentration of care of such patients is mandatory. [ABSTRACT FROM AUTHOR]

• Recently, SIOP-RTSG reached consensus on highly-conformal flank delineation applicable for IGRT. • A surgical clip is of benefit to mark the lateral GTV border in case of large preoperative tumors. • A superior surgical clip is used to estimate intrafraction tumor bed motion, registered by 4D-CT. • Both surgical clips significantly reduce highly-conformal flank target volumes. Two-opposing photon beams are considered standard of care for flank irradiation in pediatric patients with renal tumors. Nowadays, Image-Guided Radiotherapy (IGRT) techniques allow high-precision dose delivery to complex flank target volumes taking into account postoperative organ shifts and tumor bed motion. This study examines the contribution of a lateral and superior surgical clip on flank target volume delineation intended for IGRT. Between 01-2015 and 09-2019, 30/162 newly-diagnosed pediatric patients with renal tumors, lateral/superior surgical clips (n = 30/30) and available 4D-CT-scans (n = 27/30), underwent postoperative flank irradiation. The lateral and superior clip, as respective markers for the lateral tumor extension and intrafraction motion, were analyzed. The positive and negative values depict the lateral/dorsal/cranial or the medial/ventral/caudal direction, respectively. Planning target volumes (PTV) were generated based on lateral clips (PTV latclip), superior clips with 4D-CT technology (PTV supclip), and both clips combined (PTV combined), and compared to an approach without clips (PTV noclip). Indicated by clips, the mean lateral tumor bed extension along the posterior wall was 74° (range: 50°–93°), while mean intrafraction motion was +1.2 mm (range: −1.8/+4.8 mm), +0.6 mm (range: +0.6/+4.9 mm), −0.3 mm (range: −3.8/+0.7 mm) in craniocaudal, ventrodorsal, mediolateral direction, respectively. The median PTV noclip (556 mL) was statistically different from the median PTV latclip (454 mL, p = <0.01), median PTV supclip (373 mL, p = <0.01) and median PTV combined (348 mL p = <0.01). In pediatric patients with renal tumors, surgical clips at the lateral and superior border of the tumor bed can optimize flank target volume delineation and, consequently, reduce the normal tissue volume receiving high-dose irradiation when IGRT techniques are applied. [ABSTRACT FROM AUTHOR]

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration. [ABSTRACT FROM AUTHOR]

High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. These results call for new treatment approaches for patients with HR stage IV WT. • Fourteen percent of patients with metastatic Wilms tumours (WT) have high-risk (HR) histology. • Patients with metastatic WT with HR histology have a poor survival, despite intensive treatment. • Metastatic complete response after preoperative treatment is associated with outcome. [ABSTRACT FROM AUTHOR]

The impact of biopsying Wilms tumour (WT) at diagnosis on assigning the tumour stage and recommended treatment remains controversial. To address this important question, we analysed the potential association of all types of biopsy with local recurrence in patients treated in the SIOP WT 2001 trial, where needle biopsy was permitted without 'upstaging' the tumour to stage III. Only open biopsy required treatment as stage III. Among 2971 patients with unilateral WT (stages I-IV), 420 relapsed (139 local). Risk factors for recurrence were analysed by Cox proportional hazard methods. Biopsy was performed in 969 of 2971 (33%) patients (64% cutting needle, 30% fine needle aspiration [FNA] and 6% open biopsy). Biopsied patients were older, with larger tumours and a greater proportion with high-risk histology. In multivariate analysis that included all factors associated with local recurrence in univariate analysis, only high-risk histology (hazard ratio [HR] = 2.32; 95% confidence interval [CI]: 1.58–3.42, p=<0.0001), age≥2 years (HR = 2.24; 95% CI: 1.22–4.09, p = 0.01) and preoperative tumour volume (HR = 1.07 per 100 ml; 95% CI: 1.02–1.12, p = 0.01) were significant. The HR for the association of local recurrence and event-free and overall survival with biopsy was not significant (HR = 1.4; 95% CI: 0.9–2.17, p = 0.13; HR = 1.1; 95% CI: 0.85–1.42, p = 0.46 and HR = 1.13; 95% CI: 0.79–1.62, p = 0.51, respectively). These results were not materially different whether FNA or open biopsy were included in the biopsy group or not. This post hoc analysis provides some reassurance that needle biopsy is not an independent adverse factor for either local recurrence or survival after adjustment for all relevant risk factors. Needle biopsy should not be an automatic criterion to 'upstage' WT. • Biopsy is not associated with local relapse in multivariable analysis. • Results for local relapse are similar for fine needle or cutting needle biopsy. • Automatic 'upstaging' is unnecessary in needle biopsied Wilms tumour. • Open biopsy may carry greater risk and should not be used routinely. • Biopsy should be reserved for cases with atypical clinical or radiologic features. [ABSTRACT FROM AUTHOR]

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether abdominal-pelvic radiotherapy for childhood cancer impairs uterine function and increases the risk of pregnancy complications and adverse pregnancy outcomes.Design: Nested cohort study.Setting: Not applicable.Patient(s): Childhood cancer survivors previously exposed to abdominal-pelvic radiotherapy (RT-exposed CCSs) as part of their treatment for childhood cancer.Intervention(s): Radiotherapy-exposed CCSs (n = 55) were age- and parity-matched to nonirradiated CCSs (non-RT-exposed CCSs; n = 110) and general population controls (n = 110).Main Outcome Measures: Uterine volume, pregnancy complications, and pregnancy outcomes.Result(s): Among nulligravidous participants, median (interquartile range) uterine volume was 41.4 (18.6-52.8) mL for RT-exposed CCSs, 48.1 (35.7-61.8) mL for non-RT-exposed CCSs, and 61.3 (49.1-75.5) mL for general population controls. Radiotherapy-exposed CCSs were at increased risk of a reduced uterine volume (<44.3 mL) compared with population controls (odds ratio [OR] 5.31 [95% confidence interval 1.98-14.23]). Surprisingly, the same was true for non-RT-exposed CCSs (OR 2.61 [1.16-5.91]). Among gravidous participants, RT-exposed CCSs had increased risks of pregnancy complications, preterm delivery, and a low birth weight infant compared with population controls (OR 12.70 [2.55-63.40], OR 9.74 [1.49-63.60], and OR 15.66 [1.43-171.35], respectively). Compared with non-RT-exposed CCSs, RT-exposed CCSs were at increased risk of delivering a low birth weight infant (OR 6.86 [1.08-43.75]).Conclusion(s): Uterine exposure to radiotherapy during childhood reduces adult uterine volume and leads to an increased risk of pregnancy complications and adverse pregnancy outcomes. Preconceptional counseling and appropriate obstetric monitoring is warranted. [ABSTRACT FROM AUTHOR]

Abstract Aims Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. Methods PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. Results PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. Conclusions The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being. Highlights • PanCareLIFE is a large pan-European study on late effects after childhood cancer. • Studies of hearing loss, fertility impairment and quality of life are included. • Clinical and genetic methods with new guidelines will lead to improved health. [ABSTRACT FROM AUTHOR]

Background: Wilms' tumour is the most common renal cancer in childhood and about 15% of patients will relapse. There is scarce evidence about optimal surveillance schedules and methods for detection of tumour relapse after therapy.Methods: The Renal Tumour Study Group-International Society of Paediatric Oncology (RTSG-SIOP) Wilms' tumour 2001 trial and study is an international, multicentre, prospective registration, biological study with an embedded randomised clinical trial for children with renal tumours aged between 6 months and 18 years. The study covers 243 different centres in 27 countries grouped into five consortia. The current protocol of SIOP surveillance for Wilms' tumour recommends that abdominal ultrasound and chest x-ray should be done every 3 months for the first 2 years after treatment and be repeated every 4-6 months in the third and fourth year and annually in the fifth year. In this retrospective cohort study of the protocol database, we analysed data from participating institutions on timing, anatomical site, and mode of detection of all first relapses of Wilms' tumour. The primary outcomes were how relapse of Wilms' tumour was detected (ie, at or between scheduled surveillance and with or without clinical symptoms, scan modality, and physical examination) and to estimate the number of scans needed to capture one subclinical relapse. The RTSG-SIOP study is registered with Eudra-CT, number 2007-004591-39.Findings: Between June 26, 2001, and May 8, 2015, of 4271 eligible patients in the 2001 RTSG-SIOP Wilms' tumour database, 538 (13%) relapsed. Median follow-up from surgery was 62 months (IQR 32-93). The method used to detect relapse was registered for 410 (76%) of 538 relapses. Planned surveillance imaging captured 289 (70%) of these 410 relapses. The primary imaging modality used to detect relapse was reported for 251 patients, among which relapse was identified by abdominal ultrasound (80 [32%] patients), chest x-ray (78 [31%]), CT scan of the chest (64 [25%]) or abdomen (20 [8%]), and abdominal MRI (nine [4%]). 279 (68%) of 410 relapses were not detectable by physical examination and 261 (64%) patients did not have clinical symptoms at relapse. The estimated number of scans needed to detect one subclinical relapse during the first 2 years after nephrectomy was 112 (95% CI 106-119) and, for 2-5 years after nephrectomy, 500 (416-588).Interpretation: Planned surveillance imaging captured more than two-thirds of predominantly asymptomatic relapses of Wilms' tumours, with most detected by abdominal ultrasound, chest x-ray, or chest CT scan. Beyond 2 years post-nephrectomy, a substantial number of surveillance scans are needed to capture one relapse, which places a burden on families and health-care systems.Funding: Great Ormond Street Hospital Children's Charity, the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, The Danish Childhood Cancer Foundation, Cancer Research UK, the UK National Cancer Research Network and Children's Cancer and Leukaemia Group, Société Française des Cancers de l'Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé, Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP-Netherlands. [ABSTRACT FROM AUTHOR]

Context: Although a large percentage of children with advanced-stage cancer die at home, remarkably little information is available regarding the experience of general practitioners (GPs) with respect to providing home-based palliative care to children with incurable cancer.Objectives: The objective of this study was to explore the perspectives of GPs who care for children with advanced-stage cancer in a home-based setting.Methods: In this cross-sectional study, 144 GPs who provided home-based palliative care to 150 children with incurable cancer from 2001 through 2010 were invited to complete a questionnaire addressing their perspectives regarding: 1) symptom management, 2) collaboration with other health care professionals, 3) the child's death and care after death, and 4) impact of having provided palliative care, scored on distress thermometer (range 0-10).Results: A total of 112 GPs (78%) responded, and 91 GPs completed the questionnaire for 93 patients. The median interval between the child's death and completing the questionnaire was seven years. The most prevalent symptoms reported in the patients were fatigue (67%) and pain (61%). Difficulties with communicating with (14%), coordinating with (11%), collaborating with (11%), and contacting (2%) fellow members of the multidisciplinary treatment team were rare. Hectic (7%) and shocking (5%) situations and panic (2%) around the child's death were rare. GPs reported feelings of sadness (61%) and/or powerlessness (43%) around the time of the patient's death, and they rated their own distress level as relatively high during the terminal phase (median score 6, range 0-9.5). The majority of GPs (94%) reported that they ultimately came to terms with the child's death.Conclusion: In general, GPs appear to be satisfied with the quality of home-based palliative care that they provide pediatric patients with incurable cancer. Communication among health care professionals is generally positive and is considered important. Finally, although the death of a pediatric patient has a profound impact on the GP, the majority of GPs eventually come to terms with the child's death. [ABSTRACT FROM AUTHOR]

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/m 2 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. [ABSTRACT FROM AUTHOR]

In Europe, almost 1000 children are diagnosed with a malignant renal tumour each year. The vast majority of cases are nephroblastoma, also known as Wilms' tumour (WT). Most children are treated according to Société Internationale d’Oncologie Pédiatrique Renal Tumour Study Group (SIOP-RTSG) protocols with pre-operative chemotherapy, surgery, and post-operative treatment dependent on stage and histology. Overall survival approaches 90%, but a subgroup of WT, with high-risk histology and/or relapsed disease, still have a much poorer prognosis. Outcome is similarly poor for the rare non-WT, particularly for malignant rhabdoid tumour of the kidney, metastatic clear cell sarcoma of the kidney (CCSK), and metastatic renal cell carcinoma (RCC). Improving outcome and long-term quality of life requires more accurate risk stratification through biological insights. Biomarkers are also needed to signpost potential targeted therapies for high-risk subgroups. Our understanding of Wilms' tumourigenesis is evolving and several signalling pathways, microRNA processing and epigenetics are now known to play pivotal roles. Most rhabdoid tumours display somatic and/or germline mutations in the SMARCB1 gene, whereas CCSK and paediatric RCC reveal a more varied genetic basis, including characteristic translocations. Conducting early-phase trials of targeted therapies is challenging due to the scarcity of patients with refractory or relapsed disease, the rapid progression of relapse and the genetic heterogeneity of the tumours with a low prevalence of individual somatic mutations. A further consideration in improving population survival rates is the geographical variation in outcomes across Europe. This review provides a comprehensive overview of the current biological knowledge of childhood renal tumours alongside the progress achieved through international collaboration. Ongoing collaboration is needed to ensure consistency of outcomes through standardised diagnostics and treatment and incorporation of biomarker research. Together, these objectives constitute the rationale for the forthcoming SIOP-RTSG ‘UMBRELLA’ study. [ABSTRACT FROM AUTHOR]

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3–16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0 nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6 mg/m 2 ), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N = 11), sleeping problems, and/or somnolence (N = 12) ( P < 0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity. [ABSTRACT FROM AUTHOR]

Objective To evaluate the maternal and neonatal outcome of non-anonymous oocyte donation compared to in vitro fertilization. Study design We compared 84 oocyte donation pregnancies with a 251 matched in vitro fertilization cohort. Maternal and neonatal outcomes were retrieved from a nationwide perinatal registry. Oocyte donation and in vitro fertilization pregnancies were matched for maternal age, study center, ZIP code and embryo transfer date. Both maternal and neonatal complications and outcome were compared between oocyte donation and in vitro fertilization with univariate and multivariate logistic regression analyses, adjusting for maternal age, donor age, socio-economic status, ethnicity, and parity. Results In total, 277 women underwent 541 oocyte donation cycles. The median recipient age was 34.9 years (IQR: 31.5–38.5), while the median donor age was 34.4 years (IQR: 31.7–37.0). Clinical pregnancy rate was 26.6%, which is comparable to standard in vitro fertilization treatment. Donor age in years (OR 0.93, 95% CI 0.88–0.99) and a previous pregnancy of the recipient (OR 1.69, 95% CI 1.02–2.78) were significantly associated with clinical pregnancy rate. Both singleton and multiple oocyte donation pregnancies were associated with pregnancy-induced hypertension compared with in vitro fertilization singleton and multiple pregnancies (OR 1.99, 95%CI 1.02–3.89, OR 6.43, 95% CI 1.67–24.72, respectively). No significant differences in neonatal outcome were observed. Conclusion Oocyte donation pregnancies are associated with an increased incidence of pregnancy-induced hypertension compared with age-matched in vitro fertilization controls. However, no significant differences in neonatal outcome were observed between oocyte donation and in vitro fertilization. [ABSTRACT FROM AUTHOR]

Abstract: Context: Approximately 25% of children diagnosed with cancer eventually die. Losing a child puts parents at increased risk for developing psychological problems. Objectives: To explore parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement) and symptom management during the pediatric palliative phase, and to investigate the influence on long-term grief in parents who lost a child to cancer. Methods: A total of 89 parents of 57 children who died of cancer between 2000 and 2004 participated in this retrospective cross-sectional study by completing a set of questionnaires measuring grief (Inventory of Traumatic Grief), parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement), and symptom management during the palliative phase. Care was assessed on a five point Likert scale (1=disagree and 5=agree). Results: Parents highly rated communication (4.6±0.6), continuity of care (4.3±0.6), and parental involvement (4.6±0.7) during the palliative phase. Parents' most often reported physical and psychological symptoms of their child during the palliative phase were fatigue (75%), pain (74%), anxiety to be alone (52%), and anger (48%). Higher ratings of parents on communication (β=−9.08, P =0.03) and continuity of care (β=−11.74, P =0.01) were associated with lower levels of long-term parental grief. The severity of the child's dyspnea (β=2.96, P =0.05), anxiety to be alone (β=4.52, P <0.01), anxiety about the future (β=5.02, P <0.01), anger (β=4.90, P <0.01), and uncontrolled pain (β=6.60, P <0.01) were associated with higher levels of long-term parental grief. Multivariate models combining the interaction with health care professionals and symptom management showed a significant influence of both aspects on long-term parental grief. Conclusion: Both interaction with health care professionals, especially communication and continuity of care, and symptom management in children dying of cancer are associated with long-term parental grief levels. [Copyright &y& Elsevier]

Abstract: Purpose: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL). Methods: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS ≤−2 SDS combined with clinical significant fractures. Results: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS =−1.10 SDS, P <0.001), and remained lower during/after treatment (8months: BMDLS =−1.10 SDS, P <0.001; 24months: BMDLS =−1.27 SDS, P <0.001; 36months: BMDLS =−0.95 SDS, P <0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: β =−0.52, P <0.01; age: β =−0.16, P <0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS =−0.36 SDS and ΔBMDLS =−0.12 SDS; interaction group time, P =0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis. Conclusion: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL. [Copyright &y& Elsevier]

Abstract: Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n =201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9years (range 0.0–17.5) and discontinuation of treatment was reached at a median age of 8.2years (range 0.0–20.8). Inhibin B levels were first measured after a median follow-up time of 15.7years (range 3.0–37.0). Median interval between the first (T1) and second measurement (T2) was 3.3years (range 0.7–11.3). Median inhibin B level was 127ng/L (range 5–366) at T1 and 155ng/L (range 10–507) at T2. The prediction model suggests that inhibin B levels do not normalise in survivors with a very low Inhibin B level at T1. Conclusions: Our results suggest that recovery of gonadal function is possible even long after discontinuation of treatment. However, this recovery does not seem to occur in survivors who already reached critically low inhibin B levels after discontinuation of treatment. [Copyright &y& Elsevier]

Abstract: Background: Genetic variation that regulates insulin resistance, blood pressure and adiposity in the normal population might determine differential vulnerability for metabolic syndrome after treatment for childhood cancer. Objective: To evaluate the contribution of candidate single nucleotide polymorphisms (SNPs) relevant for metabolic syndrome in our single centre cohort of adult long-term childhood cancer survivors. Methods: In this retrospective study 532 survivors were analysed. Median age at diagnosis was 5.7years (range 0.0–17.8years), median follow-up time was 17.9years (range 5.0–48.8) and median age at follow-up was 25.6years (range 18.0–50.8). JAZF1 gene rs864745, THADA gene rs7578597, IRS1 gene rs2943641, TFAP2B gene rs987237, MSRA gene rs7826222, ATP2B1 gene rs2681472 and rs2681492 were genotyped. The association of genotypes with total cholesterol levels, blood pressure, body mass index, waist circumference and frequency of diabetes were assessed. Results: Metabolic syndrome was more frequent in cranially (23.3%, P =0.002) and abdominally (23.4%, P =0.009) irradiated survivors as compared with non-irradiated survivors (10.0%). Association of allelic variants in rs2681472 and rs2681492 with hypertension, rs987237 and rs7826222 with waist circumference and rs864745, rs7578597 and rs2943641 with diabetes were not significant. None of the SNPs was associated with the metabolic syndrome. Adjusting for age, sex, follow-up time, cranial irradiation and abdominal irradiation did not change these results. Conclusions: Treatment factors and not genetic variation determine hypertension, waist circumference, diabetes and metabolic syndrome in adult long-term survivors of childhood cancer. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. Patients and methods: Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6months and 18years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. Results: Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439ml at diagnosis and 163ml after preoperative chemotherapy. With a median follow-up of 8years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87–92%) and OS 95% (95% CI: 93–97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. Conclusion: Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors. [ABSTRACT FROM AUTHOR]

Abstract: Background: Adrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy. Objective: To assess adrenal function and its metabolic effects in survivors after adrenalectomy. Methods: In this cross-sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1μg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t =30) and 60min. Homoeostatic Model Assessment (HOMA) was calculated. Results: Adrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503nmol/l) (N =46) than in survivors with both adrenals intact (mean 393nmol/l, P =0.002) (N =52), and than in controls (mean 399nmol/l, P =0.013) (N =49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P <0.001), LDL-C (P =0.004), apolipoprotein-B (P <0.001) and HOMA (P =0.008). Conclusions: No adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma. [Copyright &y& Elsevier]