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Background: Children and adolescents have the right to participate in decisions concerning their health and express their views, also regarding hospital experiences. Patient-reported experience measures (PREMs) are valuable tools for systematically incorporating patient voices into healthcare systems. New developments have focused on PREMs for children and adolescents, though they are more commonly used in adults. A recent systematic review mapping their use for children and adolescents indicates a growing interest in this area. However, most PREMs are completed by proxy, in this case parents, so they do not necessarily reflect children’s experiences or align with their rights. Innovation is required to support and engage children and adolescents in responding to these types of questionnaires. Methods: Collaborating with children and adolescents (4–17 years), the primary aim of this study is to develop and validate the tool MyHospitalVoice containing digital and developmentally appropriate PREMs. The secondary aim is to document and evaluate the approaches used to involve children and adolescents and to assess the impact of their involvement. Based on the European Organisation for Research and Treatment of Cancer framework, we will divide its development and validation into four phases. First, we will discuss PREM items with children and adolescents, who will select and prioritise what they perceive as most important. Second, we will create items targeting different age groups (4–7, 8–12, and 13–17 years) and design a responsive digital interface with child and youth friendly ways of responding to the questionnaires. Third, we will explore how children and adolescents perceive MyHospitalVoice using cognitive interviewing techniques and other age-appropriate methods. Last, we will pilot test MyHospitalVoice to explore patient experiences and response rates. In each phase, children and adolescents will play an active role. We will involve young adults as peer resea

Objectives Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. Methods We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1–45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. Results We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14–32] and 18 U/L [IQR 10–25] versus 29 [IQR 24–35] and 22 [17–28], p < .001 and p = .002) and community controls (28 U/L [IQR 22–33] and 21 U/L [IQR 17–26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. Conclusions ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up., Objectives: Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. Methods: We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1–45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. Results: We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14–32] and 18 U/L [IQR 10–25] versus 29 [IQR 24–35] and 22 [17–28], p <.001 and p =.002) and community controls (28 U/L [IQR 22–33] and 21 U/L [IQR 17–26], both p <.006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p =.001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p <.001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. Conclusions: ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.

Although play has existed in paediatric hospitals for decades, a shared understanding of why and how healthcare professionals use play in clinical practice is lacking. This study aims to reach consensus on a common set of principles and competencies for play interventions and practices in hospitals. We conducted a three-round Delphi study that included healthcare professionals selected by hospital management. The first round comprised open-ended questions on the use of play in clinical practice. Principles and competencies, including learning objectives, were established using content analysis through an iterative process. Participants rated the importance of each principle and learning objective in the second and third rounds. Among the 66 participants, 45 (68%) responded in round 1 and 41 (62%) in rounds 2 and 3. The participants represented ten countries and nine different health professions. After the three rounds, we identified 33 principles and six overall competencies: building trusting relationships; delivering information and increasing understanding; promoting cooperation and participation; reducing procedure-related anxiety and pain; supporting coping and development; and ensuring a professional approach to play, which comprised 20 learning objectives. Conclusion: According to healthcare professionals, play in clinical practice can be used to communicate and build relationships with paediatric patients and thus potentially help provide patient-centred care. Our findings may help guide and prioritize future research initiatives and operationalize play interventions and practices in hospitals, Although play has existed in paediatric hospitals for decades, a shared understanding of why and how healthcare professionals use play in clinical practice is lacking. This study aims to reach consensus on a common set of principles and competencies for play interventions and practices in hospitals. We conducted a three-round Delphi study that included healthcare professionals selected by hospital management. The first round comprised open-ended questions on the use of play in clinical practice. Principles and competencies, including learning objectives, were established using content analysis through an iterative process. Participants rated the importance of each principle and learning objective in the second and third rounds. Among the 66 participants, 45 (68%) responded in round 1 and 41 (62%) in rounds 2 and 3. The participants represented ten countries and nine different health professions. After the three rounds, we identified 33 principles and six overall competencies: building trusting relationships; delivering information and increasing understanding; promoting cooperation and participation; reducing procedure-related anxiety and pain; supporting coping and development; and ensuring a professional approach to play, which comprised 20 learning objectives. Conclusion: According to healthcare professionals, play in clinical practice can be used to communicate and build relationships with paediatric patients and thus potentially help provide patient-centred care. Our findings may help guide and prioritize future research initiatives and operationalize play interventions and practices in hospitals. What is Known: • Evidence suggests that using play in clinical practice can help paediatric patients during hospitals stays. • Despite the evidence supporting the use of play, a shared understanding of why and how paediatric healthcare professionals use play is needed. What is New: • This international Delphi study contributes to a shared interprofessional understa

Chemotherapy-induced mucositis increases the risk of blood stream infections (BSI) due to translocation of bacteria across the intestinal epithelium. Our study investigated if quantitative measures of intestinal mucositis severity, including plasma citrulline (a marker of functional enterocytes) and CCL20 (an intestinal immune homeostatic chemokine), could identify patients at risk of BSI. A total of 106 children with ALL undergoing induction treatment (NOPHO ALL 2008) were included and information regarding BSI episodes was collected from the patients' medical records. Twenty-seven patients (25%) developed BSI during induction. Patients with BSI had a larger decrease in citrulline after chemotherapy than patients without BSI, and nearly all BSI episodes (25/27) occurred in the group of patients exhibiting a drop in citrulline (OR = 6.4 [95% CI: 1.4-29.3], P =.008). Patients who developed BSI had higher plasma CCL20 levels on days 8, 15 and 22 than patients without BSI (all P <.05), and elevated CCL20 levels on day 8 increased the risk of subsequent BSI (OR = 1.57 [1.11-2.22] per doubling of CCL20 level, P =.01) in a multivariable logistic regression analysis. These findings suggest that children with ALL who develop BSI during chemotherapy are characterised by more severe intestinal mucositis, as measured by plasma citrulline and CCL20. These markers may be useful in early risk stratification to guide treatment decisions.

Background: Although neutropenic fever is frequently observed during chemotherapy, only a minor proportion is caused by blood stream infections (BSI). This study investigated measurements of neutrophil chemotaxis as risk markers for BSI in children with acute lymphoblastic leukemia (ALL). Methods: The chemokines CXCL1 and CXCL8 were measured weekly in 106 children with ALL during induction treatment. Information regarding BSI episodes was collected from the patients' medical records. Results: During induction treatment, 102 (96%) patients developed profound neutropenia and 27 (25%) were diagnosed with BSI, debuting on median day 12 (range: 4–29). Patients developing BSI had increased levels of CXCL1 on days 8 and 15 as well as increased CXCL8 on days 8, 15, 22, and 29 compared to patients without BSI (all p < 0.05). Patients with BSI < day 12 exhibited increased CXCL1 and CXCL8 levels as early as day 8 (81 vs. 4 pg/mL, p = 0.031 and 35 vs. 10 pg/mL, p < 0.0001, respectively), while CXCL1 and CXCL8 were increased on day 15 (215 vs. 57 pg/mL, p = 0.022 and 68 vs. 17 pg/mL, p = 0.0002) and after (all p < 0.01) in patients with BSI ≥ day 12. Conclusion: The markers of neutrophil chemotaxis, CXCL1, and CXCL8 may help to identify patients at increased risk of BSI during chemotherapy-induced neutropenia.

Play is a non-invasive, safe, and inexpensive intervention that can help children and adolescents better manage difficult aspects of hospitalisation. Play has existed in hospitals for decades but is emerging as an interdisciplinary scientific field. The field concerns all medical specialties and healthcare professionals working with children. In this review, we describe play within different clinical contexts and recommend that directed and non-directed play activities should be prioritised in future paediatric departments. We also emphasise the need for professionalisation and research in the area.

Background: The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis, thrombosis, and osteonecrosis. However, a systematic review investigating the incidence, management, and clinical implications of hyperlipidemia during childhood ALL treatment is lacking. Objectives: Systematically assess the incidence of hyperlipidemia during ALL treatment, explore associations with risk factors and severe toxicities (osteonecrosis, thrombosis, and pancreatitis), and review prevalent management strategies. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data synthesis was descriptive, and a meta-analysis of hypertriglyceridemia and risk of severe toxicities was performed. Results: We included 13 studies with 3,425 patients. Hyperlipidemia incidence varied widely (6.7%-85%) but with inconsistent definitions and screening strategies across studies. Evidence regarding risk factors was conflicting, but age (> 10 years) and treatment with asparaginase and glucocorticosteroids seem to be associated with hyperlipidemia. Hypertriglyceridemia (grade 3/4) increased the risk for osteonecrosis (odds ratio (OR): 4.27, 95% confidence interval (CI): 2.77-6.61). No association could be established for pancreatitis (OR: 1.60, 95% CI: 0.53-4.82) or thrombosis (OR: 2.45, 95% CI: 0.86-7.01), but larger studies are needed to confirm this. Conclusion: The overall evidence of this systematic review is limited by the small number of studies and risk of bias. Our review suggests that hypertriglyceridemia increases the risk for osteonecrosis. However, larger studies are needed to explore the clinical implications of hyperlipidemia and randomized trials investigating hyperlipidemia management and its impact on severe toxicities.

Background: Children diagnosed with cancer experience muscle weakness and impaired physical function caused by treatment and related immobility. The situation forces them into a negative cycle of diminished participation in physical and leisure activities and isolation from peers; inhibiting the natural development of social and gross motor skills. This manuscript presents a protocol for a study that explores the effects of using structured active play to maintain preschoolers' age specific gross motor function and social and personal skills while undertaking intensive cancer treatment. Methods: The study is a two-arm, superiority randomized controlled trial with an intervention and a control group designed to evaluate the effects of a structured active play intervention on gross motor function. Gross motor subtests of the Peabody Developmental Motor Scales, Second Edition (PDMS-2) are used for measurement; with the primary end-point at 6 months post-treatment initiation. Eighty-four preschool children (aged 1–5 years), newly diagnosed with cancer at the Copenhagen University Hospital are randomly assigned to either an intervention or control group, using a 1:1 allocation. The intervention group receives a combined in-hospital and home-based program that includes structured active play activities, while the control group receives standard care, including physiotherapy. During hospital admission, the intervention group undertakes 45-min structured active play group sessions three times weekly, conducted by exercise professionals. Parents receive training and supervision to facilitate daily individual sessions outside of group sessions. Secondary study outcomes target the children's overall function level in everyday life, general physical performance, and health-related quality of life. As well, children's and parents' experiences within the intervention are explored and the children's social and personal development is observed. Di

Long-chain n-3 fatty acids (n-3 LCPUFA) may prevent chemotherapy-induced hyperlipidemia in children with acute lymphoblastic leukemia (ALL). However, compliance could be a problem and intake-biomarker correlations may be affected by bodyweight and blood transfusions. We assessed whole blood n-3 LCPUFA three times during the first 83 days of treatment in six 1-17-year-old children with ALL, who received 2.4-4.9 g/d n-3 LCPUFA depending on bodyweight. Mean compliance was 73%, which resulted in a 2.5-fold increase in blood n-3 LCPUFA irrespective of blood transfusions. The correlation between relative blood content of n-3 LCPUFA and intake in g/d across the study period was strong (r=0.76, p=0.001). When n-3 LCPUFA was expressed in absolute concentrations and intake per kg bodyweight the correlation decreased (r=0.39, p=0.164) and was driven by baseline values. Thus, relative content of n-3 LCPUFA in blood reflects fish oil compliance in children with ALL despite blood transfusions and differences in bodyweight.

Truncation of asparaginase treatment due to asparaginase related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1-17 years, diagnosed with ALL between July 2008 and February 2016, and treated according to the NOPHO ALL2008 protocol including extended asparaginase exposure (1,000 IU/m2 intramuscularly weeks 5 to 33). Patients were included with delayed entry at their last administered asparaginase treatment or detection of SI and followed until relapse, death, secondary malignancy, or end of follow-up (median: 5.71 years, interquartile range: 4.02-7.64). In a multiple Cox model comparing patients with (n=358) and without (n=1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (aHR) was 1.33 (95% confidence interval [CI]: 0.86-2.06, P=0.20). In a substudy including only patients with information on enzyme activity (n=1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI: 6.9-15.4) versus 6.7% (95% CI: 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI: 1.05-2.74, P=0.03). The unadjusted bone-marrow relapse-specific HR was 1.83 (95% CI: 1.07-3.14, P=0.03) and 1.86 (95% CI: 0.90- 3.87, P=0.095) for any CNS relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.

BACKGROUND: Systemic infections are a major cause of morbidity in children with acute lymphoblastic leukaemia (ALL). However, identification of patients at increased risk is still a challenge. Knowing that both neutropaenia and gastrointestinal toxicity are risk factors for bacteraemia, we aimed at comparing absolute neutrophil counts (ANC) and plasma citrulline levels (indicating enterocyte loss) in children with ALL with and without bacteraemia during induction treatment.PROCEDURE: We prospectively included 61 children with ALL treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol. ANC and plasma C-reactive protein (CRP) were measured on treatment days 1, 8, 15, 22 and 29. Plasma citrulline was measured on days 1, 8, 15 and 29. Bacteraemia episodes during induction treatment were recorded retrospectively.RESULTS: Nineteen of sixty-one (31%) patients experienced bacteraemia occurring on median day 13 (range 5-20). Patients with bacteraemia during induction treatment had lower citrulline level on day 15 (P < .01) compared to patients without bacteraemia, indicating more severe enterocyte loss. Nevertheless, ANC was similar in the two patient groups on days 8 and 15. CRP was negatively correlated with same-day citrulline (P < .03 for all) and ANC (P < .04 for all).CONCLUSIONS: During chemotherapy-induced neutropaenia, plasma citrulline may help identify patients at increased risk of bacteraemia.

OBJECTIVE: Play is a non-invasive, safe and inexpensive intervention that can help paediatric patients and their families manage difficult aspects of being ill or hospitalised. Although play has existed in hospitals for decades, research on hospital play interventions is scarce. This review aimed to categorise and synthesise the last 20 years of research on hospital play interventions.DESIGN: Scoping review.DATA SOURCES: PubMed, CINAHL, CENTRAL, ERIC and PsycINFO (1 January 2000- 9 September 2020).STUDY SELECTION AND DATA EXTRACTION: We systematically searched for original peer-reviewed articles, written in English, on hospital play interventions in paediatric patients (0-18 years) in non-psychiatric settings. Two reviewers independently screened titles and abstracts, reviewed full text of relevant articles and extracted data. We thematically synthesised the data from the included studies, and a descriptive analysis, based on a developed framework, is presented.RESULTS: Of the 297 included articles, 78% came from high-income countries and 56% were published within the last 5 years. Play interventions were carried out across all ages by various healthcare professionals. Play interventions served different roles within four clinical contexts: A) procedures and diagnostic tests, B) patient education, C) treatment and recovery and D) adaptation. Across these contexts, play interventions were generally facilitated and purpose-oriented and had positive reported effects on pain, stress, and anxiety.CONCLUSIONS: Play in hospitals is an emerging interdisciplinary research area with a significant potential benefit for child and family health. Future research should further describe principles for play in hospitals. High-quality studies investigating short-term and long-term effects are needed to guide when and how to best integrate play in hospitals.

Purpose 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. Methods 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. Results 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. Conclusion Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Introduction More 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 analysis This 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 dissemination The 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.

Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual variation in disposition and is strongly influenced by polymorphisms in the thiopurine methyltransferase (TPMT) gene. In 952 patients treated according to the NOPHO ALL2008 protocol, we explored the association between thiopurine disposition, TPMT genotypes and MRD levels after consolidation therapy with 6MP, high-dose methotrexate (HD-MTX), asparaginase, and vincristine. The levels of the cytotoxic DNA-incorporated thioguanine were significantly higher on day 70-79 in G460A/A719G TPMT heterozygous (TPMT HZ) compared to TPMT wild type (TPMT WT) patients (mean: 230.7 vs. 149.7 fmol/µg DNA, p = 0.002). In contrast, TPMT genotype did not associate with the end of consolidation MRD levels irrespective of randomization of the patients to fixed dose (25 mg/m2/day) or 6MP escalation (up to 50 or 75 mg/m2/day) during consolidation therapy.

Hyperlipidemia is common during contemporary treatment of childhood acute lymphoblastic leukemia and may increase risk of osteonecrosis, thrombosis, and possibly acute pancreatitis. Marine fatty acids found in fish oil decrease levels of triglycerides and possibly total cholesterol in hyperlipidemic patients. This prospective pilot study provided fish oil for 83 days to seven children undergoing acute lymphoblastic leukemia treatment. On average fish oil was consumed 74% of the intervention period. Further, we found significant lower levels of triglycerides (P = 0.016) and total cholesterol (P = 0.027) compared to 22 historical controls, although correction for one extra PEG-asparaginase dose reduced the level of significance. However, the findings indicate that fish oil may alleviate development of hyperlipidemia during acute lymphoblastic leukemia treatment. Randomized controlled trials are warranted to confirm these findings and to investigate the potential effect of fish oil supplements on development of severe adverse events, including osteonecrosis, thrombosis, and acute pancreatitis.

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 (R), 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., Correction in: Leukemia (epub 2020). DOI: https://doi.org/10.1038/s41375-020-0821-1

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.

Background: The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain. Objectives: The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis. The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution). Search methods: We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematolog

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 interventi

Objective As survival rates increase, growing numbers of childhood acute lymphoblastic leukemia (ALL) survivors are at risk for somatic and psychosocial late effects. Adolescent and young adult (AYA) survivors represent a distinct and vulnerable group. This study aimed to explore how AYA survivors of childhood ALL experience everyday life after cancer while adjusting to the potential impact of prior disease and treatment. Methods Semi‐structured interviews were performed with survivors aged 15‐22 years. Criterion‐based homogenous purposive sampling was used to identify similarities within the group. Data were analyzed using an inductive, thematic approach. Results Data saturation occurred after 18 interviews. Identified themes included the post‐chemo body, negotiating identities, and disruption. More than 80% reported physical or cognitive late effects, but survivors adapted to these and had a positive view on own health. However, a co‐existing experience of frailty persisted. Social disruption during treatment had a negative impact on social relations even years following cure. Identity issues revolved around the paradox of seeking recognition for their cancer‐related experiences, while also wanting to be treated like everyone else. Some participants aged 18‐22 experienced delayed reactions and a new, but unmet, need to process the past. Conclusions AYA survivors of childhood ALL adapt well to their new life situations, but many experience ongoing cancer‐related disruptions and experience not being fully understood. We suggest exploration and verbalization of these issues alongside somatic follow‐up around the age of 16‐18 years to support the AYA survivors during their transition into adulthood.

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.

BACKGROUND: The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL).METHODS: Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration: www.clinicaltrials.gov NCT01766804).RESULTS: Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (7/29 patients, 24% mild; 6/29, 21% moderate; 1/29, 3% severe) compared with placebo (12/31, 39% mild; 1/31, 3% moderate; 7/31, 23% severe) (P = 0.02). Among patients receiving at least 1 dose of supplement (colostrum: n = 22; placebo: n = 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P = 0.009).CONCLUSION: The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.