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IntroductionMore than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers.Methods and analysisThis population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008–2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors.Ethics and disseminationThe study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018–519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure.

Background Children with cancer experience impaired cardiorespiratory fitness and physical function during and after treatment restricting their possibilities to engage in social activities including sport, leisure activities, and school. The objectives were to determine the effects of classmate-supported, controlled, supervised, in-hospital, physical activity program to preserve cardiorespiratory fitness and physical function from time of diagnosis in children with cancer. Methods National non-randomized controlled trial including schoolchildren aged 6–18 years at diagnosis treated with chemo-/radiotherapy. We included 120 of 128 eligible patients (94%) in the intervention group (62.5% boys, 11.2 ± 3.1 years) from East Denmark and 58 patients in the control group (57% boys, 11.0 ± 3.2 years) from West Denmark. Eight children from the control group withdrew from participation. The groups were comparable in anthropometrics and cancer diagnoses ( p  > 0.05). The intervention consisted of (i) supervised in-hospital physical activity from diagnosis and throughout intensive treatment, (ii) 90-min general educational session on cancer and therapy in the child’s school class, and (iii) selection of two classmates as ambassadors who took turns to support the child’s physical training during the daytime. The primary outcome was cardiorespiratory fitness (VO 2 peak, mL/min/kg) at 6 months after diagnosis (sex, age, diagnosis adjusted). Secondary outcomes were sit-to-stand, timed-up-and-go, handgrip strength, and balance test scores. Results Ambassadors were identified for all, and 2542 individual and 621 group training sessions were held. VO 2 peak deteriorated over time in the control group (− 0.17 [95% CI − 0.32 to − 0.02] per week, p  = 0.02), but not in the intervention group ( p  = 0.14). At 6 months from diagnosis, VO 2 peak was higher in the intervention group (29.6 ± 5.6 mL/kg/min) than in the control group (22.1 ± 5.6 mL/kg/min) ( p  = 0.01), and the intervention group had a better physical function at 3 and 6 months ( p  < 0.0001). Conclusions Peer-supported, supervised, in-hospital, physical activity is safe and feasible in children with cancer during treatment. Further, the results suggest that the intervention might mitigate impairments in cardiorespiratory fitness during treatment in children with cancer. Trial registration The study was prospectively registered on the 11 January 2013. Clinicaltrial.gov NCT01772849 and NCT01772862 .

To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX). Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6. We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment. In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.

Minimal residual disease (MRD) constitutes the most important prognostic factor in B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP‐ALL patients, we found that a CD34‐positive, CD38 dim‐positive, nTdT dim‐positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥ 0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34‐negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness‐associated cell‐surface molecule, possibly involved in cell adhesion/migration or survival. Accordingly, genes associated with stemness were overrepresented among the most upregulated genes in CD34‐positive leukemias, and protein–protein interaction networks showed an overrepresentation of genes associated with cell migration, cell adhesion, and negative regulation of apoptosis. The present work is the first to demonstrate a CD34‐negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression is associated with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem‐like cells. This study reports that a leukemic cell immunophenotype with high CD34 surface expression predicts poor induction therapy response in B‐cell precursor acute lymphoblastic leukemia. Moreover, blast CD34 expression increases from diagnosis to relapse. Protein–protein interaction network analysis and gene set enrichment analysis show increased expression of genes associated with stemness, cell adhesion, cell migration, and cell survival in CD34‐positive cases.

Background Prevention of illness due to infection by influenza viruses is important for children with rheumatic diseases. Biological disease modifying antirheumatic drugs have become increasingly important in the treatment of juvenile idiopathic arthritis, and combinations of immunosuppressive drugs are used for the treatment of systemic disorders, which increase the risk of secondary immunodeficiency. Therefore, we investigated whether children with rheumatic disease can mount a protective antibody response after influenza immunization. Methods The prospective multicentre cohort study was conducted in Denmark during the influenza season 2015–2016. Children with rheumatic disease aged six months to 19 years were eligible. Controls were immunologically healthy children. A blood sample was collected before and after vaccination and analysed by haemagglutination inhibition (HI) assay for the 2015–2016 influenza vaccine-strains. In case of flu-like symptoms the child was tested for influenza. For statistical analyses the patients were grouped according to medical treatment or disease. Results A total of 226 patients and 15 controls were enrolled. No differences were found for the increase of antibodies from pre-vaccine to post-vaccine between the groups in our primary analyses: A/Cal H1N1pdm09 ( p  = 0.28), A/Swi H3N2 ( p  = 0.15) and B/Phu Yamagata ( p  = 0.08). Only when combining patients across groups a lower increase in antibodies was found compared to controls. Among all patients the pre-vaccine rates for seroprotection using the HI-titer cut-off ≥ 40 were 93.1–97.0 % for all three strains. For seroprotection using the HI-titer cut-off ≥ 110 the pre-vaccine rates for all patients were 14.9–43.6 % for all three strains and an increase in the proportions of patients being seroprotected after vaccination was found for A/Cal H1N1pdm09 and A/Swi H3N2. None of the children with flu-like symptoms tested positive for the vaccine strains. Conclusions Children with rheumatic diseases increase in antibody titres after influenza immunization, however, it remains uncertain whether a protective level is achieved.

Purpose We aimed to determine the effects of a classmate-supported, supervised, in-hospital physical activity program during treatment primarily on cardiorespiratory fitness and secondarily on physical function. Methods A multicenter non-randomized controlled intervention study including children diagnosed with cancer, 6–18 years at diagnosis treated with chemo-/radiotherapy. The intervention comprised (i) an educational session on cancer in the child’s school class; (ii) selection of two “ambassadors”—classmates who were co-admitted, supporting the child’s everyday hospital life; and (iii) supervised in-hospital physical activity from diagnosis and throughout intensive treatment. One-year post-treatment, physical testing included cardiorespiratory fitness (primary outcome), Sit-to-Stand test, Timed-Up-and-Go, and Handgrip Strength. Results The intervention group included 75 of 120 children (61% boys, 13.4 ± 3.1 years); the control groups included 33 of 58 children with cancer (58% boys, 13.5 ± 2.5 years), and 94 age- and sex-matched children without a cancer history. One-year post-treatment, cardiorespiratory fitness tended to be higher in the intervention group (37.0 ± 6.0 mL/kg/min) than in the patient control group with cancer (32.3 ± 9.7 mL/kg/min) (mean difference 4.7 [0.4 to 9.1], p = 0.034). The intervention group performed better in the secondary outcomes. Compared with community controls, both patient groups had lower cardiorespiratory fitness. The patient control group had lower Sit-to-Stand, Timed Up and Go, and Handgrip Strength, while the intervention group had strength comparable to that of the community controls. Conclusions Peer-supported, supervised, in-hospital physical activity during treatment may improve cardiorespiratory fitness and muscle strength 1-year post-treatment in children with cancer; however, survivors continue to have lower cardiorespiratory fitness than community controls. Implications for Cancer Survivors Children with cancer may benefit from in-hospital physical activity in improving long-term cardiorespiratory fitness and muscle strength.

The overall aim is to monitor the quality of childhood cancer care in Denmark; to register late effects of treatment; to analyze complications of permanent central venous catheters (CVCs); to study blood stream infections in children with cancer; and to study acute toxicity of high-dose methotrexate infusions in children with leukemia. All children below 15 years of age at diagnosis living in Denmark diagnosed after January 1, 1985 according to the International Classification of Diseases 10, including diagnoses DC00-DD48. Cancer type, extent of disease, treatment, participation in international studies, recurrence of malignant disease, survival, yearly follow-up status, causes of death, and development of secondary malignancies. Type of CVC, causes for removal of the CVC, type of blood stream infection, pathogens isolated, antimicrobial sensitivity, and outcome of antimicrobial chemotherapy. Since 1985, 4,944 children below 15 years of age have been registered in the database. There has been no significant change in the incidence of childhood cancer in Denmark since 1985. The 5-year survival has increased significantly since 1985 and is now 86%. The median number of days from diagnosis to initiation of therapy is 7 days and in 80% of the children less than 14 days. Clinical data of 95% of the patients are reported to open international studies. The survival of Danish children with cancer since 2003 compares favorably with other international population-based studies. The annual reports support the collaboration within pediatric oncology in Denmark.

Background During cancer treatment children have reduced contact with their social network of friends, and have limited participation in education, sports, and leisure activities. During and following cancer treatment, children describe school related problems, reduced physical fitness, and problems related to interaction with peers. Methods/design The RESPECT study is a nationwide population-based prospective, controlled, mixed-methods intervention study looking at children aged 6-18 years newly diagnosed with cancer in eastern Denmark (n = 120) and a matched control group in western Denmark (n = 120). RESPECT includes Danish-speaking children diagnosed with cancer and treated at pediatric oncology units in Denmark. Primary endpoints are the level of educational achievement one year after the cessation of first-line cancer therapy, and the value of VO 2max one year after the cessation of first-line cancer therapy. Secondary endpoints are quality of life measured by validated questionnaires and interviews, and physical performance. RESPECT includes a multimodal intervention program, including ambassador-facilitated educational, physical, and social interventions. The educational intervention includes an educational program aimed at the child with cancer, the child’s schoolteachers and classmates, and the child’s parents. Children with cancer will each have two ambassadors assigned from their class. The ambassadors visit the child with cancer at the hospital at alternating 2-week intervals and participate in the intervention program. The physical and social intervention examines the effect of early, structured, individualized, and continuous physical activity from diagnosis throughout the treatment period. The patients are tested at diagnosis, at 3 and 6 months after diagnosis, and one year after the cessation of treatment. The study is powered to quantify the impact of the combined educational, physical, and social intervention programs. Discussion RESPECT is the first population-based study to examine the effect of early rehabilitation for children with cancer, and to use healthy classmates as ambassadors to facilitate the normalization of social life in the hospital. For children with cancer, RESPECT contributes to expanding knowledge on rehabilitation that can also facilitate rehabilitation of other children undergoing hospitalization for long-term illness. Trial registration Clinical Trials.gov: file. NCT01772849 and NCT01772862