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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.

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P 30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P

Based on developing, implementing, and evaluating postgraduate interprofessional case-based learning, we have written these twelve tips for health education planners who wish to apply case-based learning in the clinical setting. Interprofessional case-based learning engages participants in a structured manner towards uncovering decisions processes and patterns of action that resemble the clinical reality in which various healthcare professionals handle multifaceted tasks related to the optimal patient treatment. Postgraduate interprofessional case-based learning has the potential to break down traditional hierarchical structures as interactions generate respectful behaviour. We present two models of case-based learning to assist in standardising, structuring, and systematising postgraduate interprofessional case-based learning. We have created 12 practical tips for the design, implementation, and evaluation of successful postgraduate interprofessional case-based learning integrated into the existing clinical setting.

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.

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.

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02‒1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.

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.

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.

Simple Summary In childhood cancer healthcare, interprofessional education involves multiple healthcare professionals with general and specific knowledge and skills. However, few interprofessional education programs exist in childhood cancer. This feasibility study assesses the acceptability, demand, practicality, and implementation of postgraduate interprofessional case-based learning for healthcare professionals from 13 different occupational groups working with children and adolescents with cancer. The study design is interventional, with subjective and objective assessment measures. Outcome measures provide sufficient information to inform a randomized controlled trial. Results from this feasibility study could be useful in the planning, design, and evaluation of postgraduate interprofessional education in other settings. Abstract This paper presents a feasibility study assessing the acceptability, demand, implementation, and practicality of postgraduate interprofessional case-based learning in childhood cancer at Copenhagen University Hospital—Rigshospitalet. Healthcare professionals included nurses, doctors, social workers, physiotherapists, occupational therapists, pharmacists, pharmacologists, dieticians, nursing assistants, and professionals with a supportive function (teachers, secretaries, priests, and daycare workers). All participated in a postgraduate interprofessional case-based learning session. Feasibility was assessed using Bowen’s focus areas of acceptability, demand, implementation, and practicality. Before and after the intervention session, three measurement tools were used 2–3 weeks before participation and 3–4 weeks after participation to collect data: Assessment of Interprofessional Team Collaboration Scale, Readiness for Interprofessional Learning Scale, and Safety Attitudes Questionnaire. Representing 13 occupational groups, 49 participants completed the case-based learning sessions, indicating acceptability and practicality. The pre- and post-intervention questionnaires were completed by 79% of the participants, 88% of whom rated the professional content as good or very good. A change over time was detected on all three scales measuring mean difference post-intervention scores. The outcome measures can be used to assess the effect of the intervention. Postgraduate interprofessional case-based learning in childhood cancer is feasible in terms of acceptability, demand, implementation, and practicality. Implementation requires leadership commitment at all levels.

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. This article is protected by copyright. All rights reserved.

ObjectiveAntenatal ultrasound diagnosed anomalies of the kidney and urinary tract (AUDAKUT) are reported in 0.3%–5% on prenatal ultrasound (US) and 0.3%–4.5% on postnatal US. The anterior-posterior diameter of the renal pelvis (APD) is an essential measurement. Series with low threshold values of APD prenatally and postnatally will include healthy infants. It is important to avoid follow-up of such infants.InterventionsIn 2006, new Danish guidelines for AUDAKUT were introduced.Aim of studyInvestigations of incidences and type of AUDAKUT based on Danish guidelines, including long-term follow-up.DesignCohort study.SettingCopenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet, Denmark.PatientsConsecutive cases with AUDAKUT in the second and third trimesters, which were either terminated before 22 completed weeks of gestation or born in the 8-year period January 2006–December 2013. Patients were followed until June 2014.Results50 193 live born children and 24 terminated fetuses (0.05%) were included. The prevalence of AUDAKUT was only 0.39% prenatally, 0.29% at first postnatal US and 0.22% at the end of follow-up, including terminated cases. The greater the prenatal and postnatal APD, the higher risk of febrile urinary tract infection (fUTI) and surgical intervention, and lower probability of resolution. 25% of the identified patients had fUTI and/or surgery.ConclusionsWe recommend threshold values of APD at least 10 mm in the third trimester and in general at least 12 mm at first postnatal US for intensive follow-up. In this largest to date unselected birth cohort of AUDAKUT, the incidences of clinically significant AUDAKUT were in the lowest range of those previously published.