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Aim Risk of treatment-related life-threatening toxicity is high in childhood acute myeloid leukaemia (AML), and access to intensive care units (ICU) is crucial. We explored the ICU admission rate and outcome after intensive care in childhood AML in Sweden. Methods Patients diagnosed between 2008 and 2016 were identified from the Swedish Childhood Cancer Registry (SCCR), a national quality registry. Data from SCCR was cross-referenced with clinical questionnaire data from paediatric oncology centers and the Swedish Intensive Care Registry (SIR), another national quality registry. Results According to combined data, 46% of the children (58/126) were admitted to ICU, 17% (21/126) within 1 month from diagnosis. Overall, ICU mortality per admission was 12% and 6% during first-line treatment. There was a discrepancy between admission rate from the clinical questionnaires and SCCR (29%; 36/126 children) and SIR (44%; 55/126) All deaths during first-line treatment occurred at or after ICU care. Conclusion Although admission rate under AML treatment was high, the treatment-related mortality under first-line treatment was low. No child died under first-line treatment without admission to ICU, suggesting good availability. The discrepancy between the two registries, SCCR and SIR, highlights the need for future validation of registry data. Funding Agencies|Barncancerfonden [TJ2019-0048]; Swedish Childhood Cancer Foundation

The human cathelicidin hCAP-18 (pro-LL-37) is the pro-protein of the antimicrobial peptide LL-37. hCAP-18 can be produced by many different cell types; bone marrow neutrophil precursors are the main source of hCAP-18 in the circulation. Neutrophil count is used as a marker for myelopoiesis but does not always reflect neutrophil production in the bone marrow, and thus additional markers are needed. In this study, we established the reference interval of serum hCAP-18 level in healthy children and compared serum hCAP-18 levels between different diagnostic groups of children with haemato-oncological diseases, at diagnosis. We found that children with diseases that impair myelopoiesis, such as acute leukaemia, aplastic anaemia, or myelodysplastic syndrome, presented with low hCAP-18 levels, whereas patients with non-haematological malignancies displayed serum hCAP-18 levels in the same range as healthy children. Children with chronic myeloid leukaemia presented with high circulating levels of hCAP-18, probably reflecting the high number of all differentiation stages of myeloid cells. We suggest that analysis of serum hCAP-18 provides additional information regarding myelopoiesis in children with haemato-oncological diseases, which may have future implications in assessment of myelopoiesis in clinical management.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26,334 one-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127,531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared with the expected numbers derived from the comparison cohort. In total, 1,987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% CI, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors. This article is protected by copyright. All rights reserved.

OBJECTIVES The prevalence and significance of liver involvement at diagnosis was studied in pediatric acute lymphoblastic (ALL) and myeloid leukemia (AML). METHODS A population based cohort of 122 pre B-ALL, 22 T-ALL and 45 AML patients was formed from the Nordic Society of Pediatric Hematology and Oncology leukemia registries (years 2005-2017). Hepatomegaly, elevated alanine aminotransferase, high INR, hypoalbuminemia and conjugated hyperbilirubinemia at diagnosis were used as markers for liver involvement. Minimal residual disease (MRD), time to relapse and overall survival (OS) were correlated with liver involvements. RESULTS The pattern of liver involvement was significantly different between leukemia subtypes (P = 0.025). The proportion of patients without liver abnormalities was 50.0% in AML and 44.8% in pre B-ALL and 23.5% in T-ALL patients. Hepatomegaly characterized lymphatic leukemia being present in 41.8% and 58.8% of pre B- and T-ALL patients. Liver dysfunction was most common in AML (29.5%) and least frequent in pre B-ALL (7.4%,) (P = 0.001). Conjugated hyperbilirubinemia was present in less than 5% of patients. Hepatomegaly correlated positively with age in pre B-ALL (P = 0.036) and white blood cell count (WBC) in AML (P = 0.010). Hepatic dysfunction was related with high WBC in pre B-ALL (P = 0.037) and AML (P = 0.001). Liver involvement in patients with ALL was not associated with toxicity or outcome. Patients with AML without liver involvement demonstrated superior OS. CONCLUSIONS Liver involvement is frequent at diagnosis in pediatric leukemia and its prevalence is related with leukemia subtype, age and WBC. In AML, but not in ALL, it associates with suboptimal prognosis.

Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0–45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. After a median follow-up of 5.6 years [interquartile range (IQR) 3.6–7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6–3.8%] for patients aged 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Background To explore levels of inflammatory proteins (including cytokines) in plasma samples from children with juvenile idiopathic arthritis (JIA) and their relation to the degree of inflammation and pain. Methods A total of 69 plasma samples were collected from 51 children with JIA (51 at diagnosis in a higher disease activity state, 18 at follow-up in a lower disease activity state) and 18 healthy controls. Relative levels of 92 proteins related to a wide range of biological processes in inflammation were obtained using a proximity extension assay panel. Comparisons between children with and without JIA, in different JIA disease states, by juvenile disease activity score (JADAS 27), and by degree of pain on visual analogue scale (VAS), were performed using parametric and non-parametric statistical methods. Results Nineteen proteins involved in arthritic inflammation, such as interleukin 6 (IL-6) and S100 protein A12 (S100A12), were higher in patients with JIA than controls, seven decreased significantly during treatment, and 18 correlated significantly with JADAS27 score. Three proteins correlated with pain VAS scores in unadjusted analyses: the glial cell line-derived neurotrophic factor (GDNF), transforming growth factor beta (TGFβ), and IL-18R1. Levels of GDNF correlated significantly with pain VAS scores but not with JADAS 27. Conclusions Plasma levels of 18 of 92 tested proteins correlated with degree of disease activity. Levels of GDNF originating from neural cells correlated with pain without correlating to inflammatory degree, suggesting that it may play a role in pain in JIA. Further studies in larger cohorts are warranted.

Acute lymphoblastic leukaemia (ALL) has a high survival rate, but treatment is lengthy with risk of severe side-effects, which may also impact parents' health-related quality of life (HRQOL). We present data on 526 parents of 310 children treated for ALL according to the NOPHO ALL2008-protocol, in Sweden, Finland and Denmark. Parents were asked to complete the 36-Item Short Form Survey (SF-36) at least 6 months after end of treatment and data were compared with Norwegian reference data. Parental background factors were collected via a study-specific questionnaire. Participating parents scored significantly lower than the reference population on both physical and mental summary indexes, but only surpassed a minimal clinically important difference for the mental summary index (Mental Component Summary [MCS]). Mothers scored lower than fathers in the MCS and stopped working and took care of the affected child more often than the fathers. Higher mental HRQOL was associated with male gender and living in Finland or Denmark (compared to Sweden). Correlations within spouses in physical and mental scores were weak to moderate. In conclusion, ALL negatively affects parental HRQOL, especially the mental domains, even after treatment. Findings suggest that mothers are more affected than fathers and may require extra support.

Purpose This study aimed to explore educational outcomes in individuals diagnosed with lymphoma in childhood concerning school grade year 9 and attendance in high school and post-compulsory education. Whether sex or age at diagnosis affected the assessed variables was also explored. Methods Data from 174 children born 1988–1996 and diagnosed with lymphoma before age 15 were matched with approximately five controls per patient. The mean time since diagnosis to receiving school year 9 grades was 4.88 years for Hodgkin lymphoma (HL) cases (mean age at diagnosis 10.62, 11.76, and 10.05 years for all, girls, and boys, respectively) and 7.79 years for non-Hodgkin lymphoma (NHL) cases (mean age at diagnosis 7.85, 7.87, and 7.84 years for all, girls, and boys, respectively). Results We observed statistically significant differences between cases and controls in physical education, both for failing (p = 0.041) and the highest grade (p = 0.015). Compared with controls, HL cases were three times more likely to fail mathematics, and significantly fewer individuals in the whole lymphoma (p = 0.011) and NHL (p = 0.035) groups attended the third year of high school. Conclusions Educational outcomes are impacted for children treated for lymphoma, especially in physical education. Since patients with HL are treated without central nervous system-directed therapy, other factors, such as absence from school, may affect school results. Physical late complications in lymphoma survivors warrant special attention. Implications for Cancer Survivors The problems childhood lymphoma survivors face should be known by schools and parents, to enable their management. Children treated for lymphoma should be closely monitored and included in follow-up programs when needed, for example, to support physical activity.

Purpose Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT. Methods Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36. Results Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL. Conclusion Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Background Children develop symptomatic coronavirus disease 2019 (COVID-19) more rarely than adults upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pediatric oncology and hematology patients may be at increased risk of severe COVID-19 due to their underlying disease or treatment. We investigated COVID-19 and seroprevalence of anti-SARS-CoV-2 antibodies, respectively, in a Swedish cohort of pediatric oncology and hematology patients. Procedure Patients (n = 136) were recruited between June 2020 and September 2021 at Uppsala University Children's Hospital, Sweden. Up to six consecutive blood samples per patient were analyzed for wild-type anti-S1 IgM and IgG antibodies (including after vaccination, n = 4). Clinical data on COVID-19 (including polymerase chain reaction [PCR] test results) were collected from electronic medical records. A questionnaire was completed at recruitment. Results A cumulative seroprevalence (IgM and IgG) of 33% (45/136 patients, 95% confidence interval: 25%–41%) was observed in this patient cohort, of whom 66% (90/136 patients) were under severe immunosuppressive treatment during the study period. Increasing patient age (p = .037) and PCR test results (p < .002) were associated with seropositivity in nonvaccinated cases. Most seropositive, nonvaccinated cases (32/43, 74%) were never PCR-verified for SARS-CoV-2 infection. Of the 13 patients with PCR-verified infection, nine (69%) reported mild disease. A majority (63%) reported continued school attendance during the pandemic. Conclusions Swedish pediatric oncology and hematology patients developed antibodies against SARS-CoV-2, despite their diagnosis and/or treatment, and the observed seroprevalence was similar to that in national pediatric outpatients. PCR-verified cases underestimate the true incidence of COVID-19 in this patient cohort.

Late mortality of European five-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 to 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95%CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95%CI 6.32-6.62). At 60-68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95%CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95%CI 16.5-20.4) to 7.3% (95%CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960-69, the mortality hazard ratio declined for first neoplasms (p for trend

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.

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26–8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71–13.75; p = 0.003).

[EN] Background White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. Methods We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. Results We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (rho(BCP-ALL )= -.17, rho(T-ALL )= -.19; p < 3 x 10(-4)). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (rho = .43, p << 2 x 10(-6)). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. Conclusion These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC. Ingenior Otto Christensens Fond; Kirsten and Freddy Johansen Foundation; Kraeftens Bekaempelse, Grant/Award Number: R-257-A14720; Novo Nordisk Fonden; the Nordic Cancer Union; European Cooperation in Science and Technology, Grant/Award Number: Lekemia gene discovery by data sharing, mining and collaboration, CA16223; Barncancerfonden; Bornecancerfonden, Grant/Award Numbers: 2018-3755, 2019-5934; University Hospital Rigshospitalet; Interreg Oresund-Kattegat-Skagerak European Regional Development Fund, Grant: The interregional childhood oncology precision medicine exploration (iCOPE) project

Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment-related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2 center dot 0-17 center dot 9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non-high-risk protocol. Prospective treatment-related toxicities registered every three-month interval were used. Patients were classified according to sex- and age-adjusted international childhood cut-off values, corresponding to adult body mass index: underweight, = 30 kg/m(2). Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1 center dot 55 [95% confidence interval (CI) 1 center dot 07-2 center dot 50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy-weight children. Obese children aged >= 10 years had increased IRRs for asparaginase-related toxicities compared with healthy-weight older children: thromboses [IRR 2 center dot 87 (95% CI 1 center dot 00-8 center dot 21)] and anaphylactic reactions [IRR 7 center dot 95 (95% CI 2 center dot 15-29 center dot 37)] as well as higher risk for truncation of asparaginase [IRR 3 center dot 54 (95% CI 1 center dot 67-7 center dot 50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged >= 10 years with ALL.

BackgroundCancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. ProcedureSurvivors of ALL aged 16-30 years (n=21) with a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n=21), were studied. Stored plasma samples were analyzed with Olink’s 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a 16-week home-based exercise intervention (n=17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. ResultsInflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: TNFSF14, OSM, MCP-1, MCP-2, FGF-21, CCL4, TGF-alpha, TRAIL, ADA, CXCL6, and LAP TGF-beta-1. ConclusionsThe ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors’ 16-week physical exercise intervention led to significant beneficial change in inflammation protein levels. Physical exercise should be promoted for survivors of cancer.

Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT.Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36.Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL.Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Infants with acute lymphoblastic leukaemia (ALL) have a high frequency of central nervous system (CNS) involvement. Flow cytometric analysis of cerebrospinal fluid (CSF) was recently demonstrated to be a sensitive method for detecting CNS involvement in childhood ALL. In the present study, CSF from 14 infants was collected at routine lumbar punctures and analysed by multicolour flow cytometry. At initial diagnosis, leukaemic blasts were detected in CSF by flow cytometry in 11 patients (78·6%) compared to seven patients (50%) by cytospin. Larger studies are needed to determine if CSF flow cytometry has prognostic value in infant ALL.

Genetic analysis of leukemic clones in monozygotic twins with concordant acute lymphoblastic leukemia (ALL) has proved a unique opportunity to gain insight into the molecular phylogenetics of leukemogenesis. Using whole-genome sequencing, we characterized constitutional and somatic single nucleotide variants/insertion-deletions (indels) and structural variants in a monozygotic twin pair with concordant ETV6-RUNX1+ B-cell precursor ALL (BCP-ALL). In addition, digital PCR (dPCR) was applied to evaluate the presence of and quantify selected somatic variants at birth, diagnosis, and remission. A shared somatic complex rearrangement involving chromosomes 11, 12, and 21 with identical fusion sequences in leukemias of both twins offered direct proof of a common clonal origin. The ETV6-RUNX1 fusion detected at diagnosis was found to originate from this complex rearrangement. A shared somatic frameshift deletion in UBA2 was also identified in diagnostic samples. In addition, each leukemia independently acquired analogous deletions of 3 genes recurrently targeted in BCP-ALLs (ETV6, ATF7IP, and RAG1/RAG2), providing evidence of a convergent clonal evolution only explained by a strong concurrent selective pressure. Quantification of the UBA2 deletion by dPCR surprisingly indicated it persisted in remission. This, for the first time to our knowledge, provided evidence of a UBA2 variant preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.

IntroductionA subgroup of adolescent and young adult childhood cancer survivors (AYACCS) are at increased risk of psychological distress. Despite this, AYACCS experience difficulties accessing psychological support. E-mental health (e-MH) may offer a solution to reduce this treatment gap. However, research examining e-MH for AYACCS has experienced difficulties with recruitment, retention and adherence. Such difficulties may relate to: (1) help-seeking behaviour and/or (2) e-MH acceptability. The overall study aims are to: (1) examine potential associations between health service use factors, informed by Andersen’s behavioural model of health services use, and help-seeking behaviour; (2) examine attitudes towards e-MH interventions; and (3) explore perceived need for mental health support; past experience of receiving mental health support; preferences for support; and barriers and facilitators to help-seeking.Methods and analysisAn online and paper-based cross-sectional self-report survey (98 items) and embedded qualitative interview study across Sweden, with a target sample size of n=365. Participants are aged 16–39 years, diagnosed with cancer when 0–18 years and have completed successful cancer treatment. The survey examines sociodemographic and clinical characteristics, actual help-seeking behaviour, attitudes towards e-MH, stigma of mental illness, mental health literacy, social support and current symptoms of depression, anxiety, and stress. Survey respondents with past and/or current experience of mental health difficulties are invited into the qualitative interview study to explore: (1) perceived need for mental health support; (2) past experience of receiving mental health support; (3) preferences for support; and (4) barriers and facilitators to help-seeking. Potential associations between health service use factors and help-seeking behaviour are examined using univariable and multivariable logistic regressions. Qualitative interviews are analysed using content analysis.Ethics and disseminationEthical approval has been obtained from the Swedish Ethical Review Authority (Dnr: 2020-06271). Results will be disseminated in scientific publications and academic conference presentations.Trial registration numberISRCTN70570236.

Objectives Despite progress in the treatment of childhood acute lymphoblastic leukemia, severe complications are common, and the need of supportive care is high. We explored the cumulative prevalence, clinical risk factors, and outcomes of children with acute lymphoblastic leukemia, on first-line leukemia treatment in the ICUs in Sweden. Design A nationwide prospective register and retrospective chart review study. Setting Children with acute lymphoblastic leukemia were identified,and demographic and clinical data were obtained from the Swedish Childhood Cancer Registry. Data on intensive care were collected from the Swedish Intensive Care Registry. Data on patients with registered ICU admission in the Swedish Childhood Cancer Registry were supplemented through questionnaires to the pediatric oncology centers. Patients All 637 children 0-17.9 years old with acute lymphoblastic leukemia diagnosed between June 2008 and December 2016 in Sweden were included. Interventions None. Measurements and main results Twenty-eight percent of the children (178/637) were admitted to an ICU at least once. The Swedish Intensive Care Registry data were available for 96% of admissions (241/252). An ICU admission was associated with poor overall survival (hazard ratio, 3.25; 95% CI, 1.97-5.36; p ≤ 0.0001). ICU admissions occurred often during early treatment; 48% (85/178) were admitted to the ICU before the end of the first month of acute lymphoblastic leukemia treatment (induction therapy). Children with T-cell acute lymphoblastic leukemia or CNS leukemia had a higher risk of being admitted to the ICU in multivariable analyses, both for early admissions before the end of induction therapy and for all admissions during the study period. Conclusions The need for intensive care in children with acute lymphoblastic leukemia, especially for children with T cell acute lymphoblastic leukemia and CNS leukemia, is high with most admissions occurring during early treatment.

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.

Pathogenic germline variants in ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6. We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6. Whole-genome sequencing analysis of the affected female subjects’ leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.

Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac®) and PEG-asparaginase (Oncaspar®) as well as hypersensitivity reactions during treatment in Interfant-06 ( www.clinicaltrials.gov : NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs.We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study.After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex.Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.

Background Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. Methods Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. Results Survivors’ (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, −3.5 SD [range: −25.0 to 1.3 SD]), and processing speed and attention (median z score, −2.5 SD [range: −24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. Conclusions Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients. Funding Agencies|CancerfondenSwedish Cancer Society [CAN2018/623] Funding Source: Medline; Barncancerfonden [PR2017-0023, PR2019-0046] Funding Source: Medline

Aim To investigate the prevalence of vitamin D deficiency among children with non-haematological malignancies and to explore possible causes of low vitamin D levels among these patients. Methods We performed a cross-sectional study of 458 children diagnosed with solid tumours, brain tumours, non-Hodgkin lymphoma or Hodgkin disease at the University Childrens Hospital, Uppsala, Sweden. Serum 25-hydroxyvitamin D and parathyroid hormone levels were measured in samples taken at the time of cancer diagnosis and related to clinical data. Vitamin D deficiency was defined as a 25-hydroxyvitamin D level below 50 nmol/L. Results The prevalence rate of vitamin D deficiency among children with non-haematological malignancies was 41%. There was no association between sex or diagnosis and vitamin D status. Vitamin D deficiency was more common among school children than preschool children (51% vs. 24%). Older age, season outside summer, and a more recent calendar year were significant predictors of lower 25-hydroxyvitamin D. There was a significant, albeit weak, negative correlation between 25-hydroxyvitamin D and parathyroid hormone. Conclusion Vitamin D deficiency is common among children diagnosed with cancer, particularly among school-aged children diagnosed outside summer. The prevalence appears to be increasing, underlining the need for adequate replacement of vitamin D in these patients. Funding Agencies|Swedish Childhood Cancer FoundationEuropean Commission [PR2018-0101, ST2013-0008, TJ2014-0007]; Mary Beves Foundation

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. Methods Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients’ files. Results Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. Conclusions Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

Central nervous system (CNS) involvement by cytospin is associated with increased risk of relapse in childhood acute lymphoblastic leukemia. We investigated if flow cytometric analysis of cerebrospinal fluid (CSF) at diagnosis improves the prediction of relapse. This prospective cohort study included patients (1.0–17.9 years) treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. CSF flow cytometry samples were obtained at 17 centers, preserved with Transfix®, and analyzed at a central laboratory. One-hundred and seventy-one (25.4%) of 673 patients were positive by flow cytometry (CNSflow+). The 4-year cumulative incidence of relapse was higher for patients with cytospin positivity (CNScyto+) (17.1% vs. 7.5%), CNSflow+ (16.5% vs. 5.6%), and cytospin and/or flow positivity (CNScomb+) (16.7% vs. 5.1%). In Cox regression analysis stratified by immunophenotype and minimal residual disease day 29 and adjusted by sex, predictors of relapse were age (hazard ratio [HR] 1.1, 95% CI 1.1–1.2, P < 0.001), white blood cell count at diagnosis (HR 1.4, 95% CI 1.1–1.6, P < 0.001), and CNScomb+ (HR 2.2, 95% CI 1.0–4.7, P = 0.042). Flow cytometric analysis of CSF improves detection of CNS leukemia, distinguishes patients with high and low risk of relapse, and may improve future risk stratification and CNS-directed therapy.

Children and adolescents with leukemia are potentially at high risk of vitamin D inadequacy, which may have clinical relevance for skeletal morbidity, infections, and cancer outcome. This study aimed to evaluate vitamin D status at the time of diagnosis to investigate its predictors and association with overall survival in children with leukemia.We included all 295 children and adolescents diagnosed with leukemia at our institution between 1990 and 2016 who had available serum sample from the time of diagnosis. We analyzed serum 25-hydroxyvitamin D and parathyroid hormone levels and correlated them with clinical data.The 25-hydroxyvitamin D level was deficient ( 25 nmol/L), insufficient (25-50 nmol/L), sufficient (50-75 nmol/L), and optimal ( 75 nmol/L) in 6.4%, 26.8%, 39.7%, and 27.1% of the children, respectively. Older age and a more recent time of sampling (calendar year) predicted lower 25-hydroxyvitamin D level. In preschool children (age ≤6 years), lower 25-hydroxyvitamin D level was also associated with acute myeloid leukemia, and a 25-hydroxyvitamin D level 50 nmol/L was associated with inferior overall survival. In school-aged children (age 6 years), the 25-hydroxyvitamin D level showed significant seasonal variation.It remains unclear whether vitamin D supplementation in pediatric leukemia patients will improve outcome.

Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.

Objectives: High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method: In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0‐17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut‐offs: underweight