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The use of ionising radiation (IR) for medical diagnosis and treatment procedures has had a major impact on the survival of paediatric patients. Although the benefits of these techniques lead to efficient health care, evaluation of potential associated long-term health effects is required. HARMONIC aims to better understand the increased risk of cancer and non-cancer effects after exposure to medical IR in children with cancer treated with modern external beam radiotherapy (EBRT) – radiation energy in MeV range – and in children with cardiac defects diagnosed and treated with cardiac fluoroscopy procedures (CFP) – radiation energy in keV range. The project investigates, among survivors of paediatric cancer, potential endocrine dysfunction, cardiovascular and neurovascular damage, health-related quality of life and second (and subsequent) primary cancer (SPC). The cardiac component builds a pooled cohort of approximately 90 000 paediatric patients who underwent CFP during childhood and adolescence to investigate cancer risk following exposure to IR and explore the potential effects of conditions predisposing to cancer. HARMONIC develops software tools to allow dose reconstruction in both EBRT and CFP to enable epidemiological investigations and future optimisation of treatments. With the creation of a biobank of blood and saliva samples, HARMONIC aims to provide a mechanistic understanding of radiation-induced adverse health effects and identify potential biomarkers that can predict these effects.

Objective Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD. Design This study is a cross-sectional study. Methods We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997–2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test. Results Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1–33.8 years) at follow-up and 14.8 years (range: 5.1–23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT). Conclusion This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1. Significance statement This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

Key Points Overall asparaginase-associated toxicity and relapse were not significantly associated with increased asparaginase enzyme activity levels.The risk of pancreatitis and osteonecrosis were significantly associated with increasing asparaginase enzyme activity., Visual Abstract, Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1155 children aged 1.0 to 17.9 years, diagnosed with ALL between July 2008 and March 2016, and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with ≥2 blood samples for AEA measurement drawn 14 ± 2 days after asparaginase administration were included (6944 trough values). AEA was measurable (or >0 IU/L) in 955 patients, whereas 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% confidence interval [CI], 0.98-1.41; P = .09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; P = .002), 0.99 (95% CI, 0.70-1.40; P = .96), and 1.36 (95% CI, 1.04-1.77; P = .02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66-1.16; P = .35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels.

Background Incidence rates in Denmark of central nervous system (CNS) tumors remain among the highest in the world. Survival rates, however, have improved in the past decades in high‐income countries. Methods We analyzed incidence and survival of childhood CNS tumors in Denmark diagnosed from 1997 to 2019 based on data from the Danish Childhood Cancer Registry and information on histological types, tumor localization, and treatment from medical records. Results From 1997 to 2019, 949 children, Incidence of childhood central nervous system (CNS) tumors in Denmark from 1997 to 2019 was 42.1 per million person‐years and did not increase from 1997 to 2019. Survival has improved especially among younger children with CNS tumors. Still, some subgroups in particular have a poor prognosis.

To ensure external validation of a study population in clinical late-effect studies of childhood cancer, the participation rate must be high. This study investigated demographic data in Nordic late-effect studies and potential factors impacting participation rates such as cancer type, time since diagnosis, and duration of clinical examinations. We found 80 published studies originating from 16 cohorts, with median follow-up of 6.0 years (range 3-14). The overall participation rates ranged from 27% to 100%. The highest participation rates were seen in studies of survivors with solid tumors (92%) and the lowest in hematologic malignancies (67%) and central nervous system tumors (73%). The clinical examination in 10 studies (62.5%) lasted for more than 3 hours. Neither duration of the clinical examination nor time since diagnosis seemed to affect the participation rate. We encourage future studies to describe the recruitment process more thoroughly to improve understanding of the factors influencing participation rates.

BACKGROUND: Brain tumours are the most common solid tumours in childhood. Half of these tumours occur in the posterior fossa, where surgical removal is complicated by the risk of cerebellar mutism syndrome, of which postoperative speech impairment (POSI) is a cardinal symptom, in up to 25% of patients. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We aimed to investigate the risk of developing POSI, the time course of its resolution, and its association with surgical approach and other clinical factors. METHODS: In this observational prospective multicentre cohort study, we included children (aged

Introduction: Several studies on late effects of childhood cancer have been conducted during the past decades. To ensure external validation of a study population, the participation rate must be high. This study investigated demographic data in late effect studies and potential factors impacting on participation rates such as cancer type, time since diagnosis and duration of clinical examinations. Procedure: By searching the databases PubMed, Embase and Web of Science and by contacting researchers and clinicians, we identified studies including an invitation to a clinical examination for late effects after childhood cancer. Studies conducted from January 2010 - March 2020 in the Nordic countries were included. Results: We found 80 published studies originating from 16 cohorts. The overall participation rates ranged between 27 and 100%. The majority of studies (eleven studies) were conducted more than ten years after the cancer diagnosis and primarily on hematologic malignancies (seven studies). The highest participation rates were seen in studies of survivors with solid tumors (92%) and the lowest in survivors with hematologic malignancies (67%) and central nervous system tumors (73%). Neither duration of the clinical examination nor time since diagnosis seemed to affect the participation rate. Conclusion: A trend of lower participation rates when recruiting survivors of hematologic malignancies and central nervous system tumors was found. We encourage future studies to describe the recruitment process more thouroughly to improve understanding of the factors influencing participation rates.

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.

INTRODUCTION High grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR) is a recently described tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. We report the outcome of two cases after 1st line multimodality therapy. MATERIAL AND METHOD A 7 year old girl with a ventricular tumour and a 6 year old boy with a tumour in the occipital region with infiltration of the transverse and sigmoid sinus were both diagnosed based on histology and methylation with HGNET-BCOR. No spinal or liquor dissemination were found at diagnosis in both cases. Treatment consisted of radical resection of the tumour. In the case of the lesion with sinus infiltration residual tumour in the vessel could not be removed. Both children were postoperatively treated with radiotherapy (craniospinal 36 Gy and boost to 54 Gy), concomitant Vincristin and adjuvant Cisplatin, Lomustine and Vincristine. RESULTS The girl developed a local recurrence at the primary tumour site 18 months after diagnosis. Reoperation showed the same histology. Start of 2nd line chemotherapy with Temozolomid and Irinotecan is being discussed. The boy with sinus infiltration developed seven months after diagnosis multiple liver, lung and bone metastasis. Biopsy of a liver lesion showed HGNET-BCOR. He was treated with Temozolomid, Irinotecan and died nine months after diagnosis. CONCLUSION We report two cases with failure after 1st line treatment for HGNET-BCOR. To our knowledge HGNET-BCOR with development of hematological disease dissemination is a rare finding.

INTRODUCTION Intracranial malignant germ cell tumours (iGCT) are rare brain tumours mainly diagnosed in children and younger adults. MATERIAL AND METHODS A retrospective analysis was performed by chart review of patients treated for iGCT in the northern and central region of Denmark. Teratoma only patients were not included in the study. RESULTS 20 patients with iGCT were diagnosed from 2008–2019 in Western Denmark. The cumulative incidence was 1.05 per 100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients had received radiotherapy and 18 patients were treated with multidrug chemotherapy including platinum and etoposide before irradiation. Two patients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem cell transplantation and reirradiation. Two NGGCT patients died, one patient after development of an anaplastic astrocytoma in the radiation field five years after radiotherapy and one patient after intracranial hemorraghe 18 months after salvage treatment for recurrent disease. Overall survival was 90%, 100% for GCT and 71% for NGGCT. CONCLUSION The outcome of patients with iGCT in Western Denmark was comparable to the literature. A nationwide study of epidemiology and outcome of iGCT in Denmark is planned.

Introduction: Asparaginase is a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), but the treatment is jeopardized by 20% or more developing asparaginase-associated toxicities (asp-tox), mostly hypersensitivity, osteonecrosis, pancreatitis and thromboembolism (Albertsen et al 2019). Therapeutic drug monitoring (TDM) of asparaginase enzyme activity (AEA) levels is widely used to identify patients with no AEA and to ensure sufficient treatment (Sluis et al 2016), but is not commonly used to identify patients with high levels. In this study, we investigate AEA-levels and the association with risk and severity of asp-tox. Methods: Children aged 1-17.9 years with non high-risk ALL treated according to the NOPHO ALL2008 protocol from July 2008 to March 2016 in the Nordic and Baltic countries were included in the study. Based on median AEA-level measured 14 days (+/-2 days) after administration, patients were grouped into four groups; 'no enzyme activity' (0 IU/L, n=201), 'fast clearance' (1-99 IU/L, n=82), 'therapeutic levels' (100-249 IU/L, n=543), and 'high levels' (≥250 IU/L, n=330). Furthermore, groups with AEA-levels Results: We included 1,156 patients and 6,929 samples for AEA-measurements in the study. The median number of samples for each patient was 5 [IQR: 3;9]. A total of 328 asp-tox events were registered in 311 patients (27.5%). The median age for patients with asp-tox was 5 years [Interquartile range (IQR): 2;9] compared with 4 years [IQR: 2;6] for patients without asp-tox (p Conclusion: We found no difference in the incidence of toxicities between AEA in ´therapeutic levels´ and ´high levels´ group, and there will be no clinical advantage in using TDM to identify patients with high AEA-levels for dose adjustment. The significantly lower incidence of asp-tox in patients without AEA and AEA-levels Disclosures Ranta: Roche: Other: Amember of Steering committee for a Roche study on Hemlibra (the contract is between Karolinska University Hospital and Roche). No financial benefits.. Wolthers:Novo Nordisk: Current Employment. Heyman:Servier: Other: Research funding in ALLTogether (research protocol). Schmiegelow:Jazz Pharmaceuticals: Other: Speaker and/or Advisory Board Honoraria ; Medscape: Other: Speaker fee; Servier: Other: Educational grant. Speaker and/or Advisory Board Honoraria ; Amgen: Other: Speaker fee. Albertsen:Erytech Pharma: Other: Sponsor of the investigator initiated study: NOR-GRASPALL 2016. No financial benefits..

Background L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG-asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol. Procedure Children (1–17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG-asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar®) 1,000 IU/m2/dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351). Results Of 615 evaluable patients, 79 patients developed clinical PEG-asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG-asparaginase therapy for that reason. PEG-asparaginase allergy occurred after a median of two doses (75% range 2–4, max 14). In 58% of PEG-asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG-asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase. Conclusion Clinical allergy to PEG-asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG-asparaginase administration. The risk of subsequent Erwinase allergic reactions was low. Pediatr Blood Cancer 2015;62:427–433. © 2014 Wiley Periodicals, Inc.

BACKGROUND: As pegylated asparaginase is becoming the preferred first-line asparaginase preparation in the chemotherapy regimens of childhood acute lymphoblastic leukemia (ALL), there is a need to evaluate this treatment.METHODS: The aim of this study was to evaluate the pharmacokinetics of prolonged upfront biweekly PEG-asparaginase (where PEG is polyethylene glycol) treatment by measuring serum l-asparaginase activity and formation of anti-PEG-asparaginase antibodies. A total of 97 evaluable patients (1-17 years), diagnosed with ALL, and treated according to the NOPHO ALL2008 protocol (where NOPHO is Nordic Society of Paediatric Haematology and Oncology) were included. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar(®) ) 1,000 IU/m²/dose, at 2-week or 6-week intervals with a total of 30-week treatment (Clinical trials.gov. no.: NCT00819351).RESULTS: The pharmacological target of treatment (l-asparaginase activity above 100 IU/l) was reached in 612 of 652 (94%) samples obtained 14 ± 2 days after PEG-asparaginase administration. Mean l-asparaginase activity was 338 IU/l. Six patients had l-asparaginase activity below 50 IU/l in all samples. A total of 25 patients (26%) developed Immunoglobulin G (IgG) anti-PEG-asparaginase antibodies, but there was no correlation between anti-PEG-asparaginase antibodies and low levels of asparaginase activity.CONCLUSION: We conclude that prolonged first-line biweekly PEG-asparaginase therapy, 1,000 IU/m²/dose was above the pharmacological target in the vast majority of patients. Presence of anti-PEG-asparaginase antibodies was not a predictor of l-asparaginase activity.

L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG-asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol.Children (1-17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG-asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar®) 1,000 IU/m(2) /dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351).Of 615 evaluable patients, 79 patients developed clinical PEG-asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG-asparaginase therapy for that reason. PEG-asparaginase allergy occurred after a median of two doses (75% range 2-4, max 14). In 58% of PEG-asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG-asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase.Clinical allergy to PEG-asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG-asparaginase administration. The risk of subsequent Erwinase allergic reactions was low.