Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into ...DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher 95% confidence interval: 160-341; P<0.0001), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher 95% confidence interval: 147-398; P<0.0001). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.
Abstract
Background
The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.
Methods
In this prospective, ...population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives.
Results
Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6–21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e−4) and all other genes (P = 5e−17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity—raising the question of the role of other highly constrained gene alterations detected.
Conclusions
Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.
ObjectivesSurvival among children diagnosed with acute lymphoblastic leukaemia (ALL) has increased considerably. However, morbidity in survivors constitutes a potential increasing burden not limited ...to secondary health care. Our objectives were to compare health care utilisation, including both primary and secondary health care, between childhood ALL survivors and matched references up to 15 years after curative treatment. Moreover, to increase knowledge on survivors’ health service seeking behaviour as time from treatment elapsed.Design and settingA Danish population-based matched cohort study linking multiple nationwide registries.Participants675 cases, diagnosed with childhood (1.0–17.9 years) ALL between 1994 and 2015, and 6750 matched references sampled randomly from the source population (matched on age, gender and geographical region).Primary outcome measuresRepeated consultations in general practice and hospital (outpatient and inpatient) estimated as yearly rates from 2.5 years after diagnosis and onwards. We compared cases and references with yearly incidence rate ratios (IRRs) from negative binomial regression models.ResultsSurvivors of childhood ALL had a mean number of yearly daytime contacts in general practice of 4.75 (95% CI 4.41 to 5.11) the first year, corresponding to an IRR of 1.85 (95% CI 1.71 to 2.00); decreasing to 1.16 (1.01 to 1.34) after 15 years, and without significant impact of gender (p=0.894) or age (p=0.399). For hospital contacts, ALL survivors had a mean number of yearly contacts of 14.21 (13.38–15.08) the first year, corresponding to an IRR of 31.50 (28.29–35.07); decreasing to 2.42 (1.59–3.68) after 15 years. No differences were found across calendar time.ConclusionsALL survivors used significantly more health care services across sectors than the reference population. Decreasing use over 15 years illustrated the dynamics of health care needs; this knowledge may inform the future organisation of integrated follow-up programmes.Trial registration numberNCT03985826.
ObjectivesTo investigate health care utilisation including both primary and secondary health care 6 months before the diagnosis of a relapse or a second malignant neoplasm (SMN) in survivors of ...childhood acute lymphoblastic leukaemia (ALL).Design and settingA Danish population-based matched cohort study linking multiple nationwide registries.ParticipantsParticipants were recruited from a total of 622 childhood ALL 2.5-year event-free survivors diagnosed between 1994 and 2015. Cases were survivors developing a relapse or an SMN and references were survivors still in first remission. Each case was matched with five references on age, sex, treatment protocol and risk group.Primary outcome measuresConsultations in general practice and hospital the last 6 months before relapse or SMN. Cases and references were compared with monthly incidence rate ratios (IRRs) from negative binomial regression models.ResultsOf the 622 childhood ALL survivors, 60 (9.6%) developed a relapse (49) or an SMN (11) and 295 matched references were identified. Health care utilisation in general practice increased among cases the last month before the event compared with references with an IRR of 2.71 (95% CI 1.71 to 4.28). Data showed a bimodal structure with a significantly increased number of visits 4, 5 and 6 months before the event. Hospital health care utilisation increased 2 months before the event in cases with an IRR of 5.01 (3.78 to 6.63) the last month before the event and an IRR of 1.94 (1.32 to 2.85) the second-last month comparing cases and references.ConclusionsSurvivors of childhood ALL developing a relapse or an SMN have a short period of increased health care utilisation before diagnosis. At hospital, this might be explained by pre-diagnostic examinations. In general practice, data suggest a bimodal structure with children later developing a relapse having more contacts also half a year before the relapse, suggesting that there could be early warnings.
Purpose
Cerebellar mutism syndrome (CMS) is a severe neurological complication of posterior fossa tumour surgery in children, and postoperative speech impairment (POSI) is the main component. ...Left-handedness was previously suggested as a strong risk factor for POSI. The aim of this study was to investigate the relationship between handedness and the risk of POSI.
Methods
We prospectively included children (aged < 18 years) undergoing surgery for posterior fossa tumours in 26 European centres. Handedness was assessed pre-operatively and postoperative speech status was categorised as either POSI (mutism or reduced speech) or habitual speech, based on the postoperative clinical assessment. Logistic regression was used in the risk factor analysis of POSI as a dichotomous outcome.
Results
Of the 500 children included, 37 (7%) were excluded from the present analysis due to enrolment at a reoperation; another 213 (43%) due to missing data about surgery (
n
= 37) and/or handedness (
n
= 146) and/or postoperative speech status (
n
= 53). Out of the remaining 250 (50%) patients, 20 (8%) were left-handed and 230 (92%) were right-handed. POSI was observed equally frequently regardless of handedness (5/20 25% in left-handed, 61/230 27% in right-handed, OR: 1.08 95% CI: 0.40–3.44,
p
= 0.882), also when adjusted for tumour histology, location and age.
Conclusion
We found no difference in the risk of POSI associated with handedness. Our data do not support the hypothesis that handedness should be of clinical relevance in the risk assessment of CMS.
Around the world humans use products that contain phthalates, and human exposure to certain of these phthalates has been associated with various adverse health effects. The aim of the present study ...has been to determine the concentrations of the metabolites of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(iso-butyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) in urine samples from 441 Danish children (3–6 years old). These children were subjects in the Danish Indoor Environment and Children's Health study. As part of each child's medical examination, a sample from his or her first morning urination was collected. These samples were subsequently analyzed for metabolites of the targeted phthalates. The measured concentrations of each metabolite were approximately log-normally distributed, and the metabolite concentrations significantly correlated with one another. Additionally, the mass fractions of DEP, DnBP, DiBP and BBzP in dust collected from the children's bedrooms and daycare centers significantly correlated with the concentrations of these phthalates’ metabolites (monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP) and monobenzyl phthalate (MBzP), respectively) in the children's urine. Such correlations indicate that indoor exposures meaningfully contributed to the Danish children's intake of DEP, DnBP, DiBP and BBzP. This was not the case for DEHP. The urine concentrations of the phthalate metabolites measured in the present study were remarkably similar to those measured in urine samples from children living in countries distributed over four continents. These similarities reflect the globalization of children's exposure to phthalate containing products.
Parents of children/adolescents with cancer are placed in a state of severe suffering due to serious concerns, fears, and radical daily life changes. Human support is an important source of support ...for successful coping. This study explored fundamental aspects of parents' daily, social, and personal life during their child's treatment to deepen our understanding of ‘who’ plays a significant role in supporting parents, and how, and to what extent this support is provided.
This qualitative study was undertaken in a compassion paradigm, designed and guided by Heidegger's and Gadamer's philosophy and compassionate methods. Data were generated through ethnographic observations (144 h), focus group interviews (n = 2), and individual/couple interviews (n = 16) at two Danish hospitals. Inductive content analysis was used to analyse data.
Overall, support from peers, health professionals, and social networks constituted significant sources of support. Especially peers and health professionals had a continuous support role, which was fundamental for establishing interpersonal closeness and relieving suffering. Sharing responsibilities between parents and among social networks seemed to ease the emotional and practical burden. However, to ensure effectiveness, social networks must be available, outreach, and responsive to needs. Moreover, parents disclosed little self-awareness and resources and options for self-care due to a combination of lack of awareness, time, and space in the hospitals.
Safeguarding interpersonal and interparental understanding and closeness in parental care is essential. One way is building resilience and a broader human-to-human-based safety net around the family, including social networks and professional psychosocial support, advantageously using compassion.
•A compassionate approach to qualitative research is applicable.•Professional and social networks are important and need to be present and active.•Providing support for parents at the hospital and those at home is necessary.•Shared responsibilities between parents and amongst relatives may ease the burden.•Creating a greater community sense using compassion may provide broader safety nets.
Objective
Childhood spinal tumors often present with musculoskeletal symptoms, potentially causing a misdiagnosis and delays in diagnosis and treatment. This study aims to identify, characterize, and ...compare children with spinal tumors who had prior musculoskeletal misdiagnoses to those without, analyzing clinical presentation, diagnostic interval, and outcome.
Study design
This retrospective cohort study evaluated all children aged 0–14 years diagnosed with a spinal tumor in Denmark from 1996 to 2018. The cohort was identified through the Danish Childhood Cancer Registry, and the registry data were supplemented with data from medical records. The survival was compared using the Kaplan–Meier method.
Results
Among 58 patients, 57% (33/58) received musculoskeletal misdiagnoses before the spinal tumor diagnosis. Misdiagnoses were mostly nonspecific (64%, 21/33), involving pain and accidental lesions, while 36% (12/33) were rheumatologic diagnoses. The patients with prior misdiagnosis had less aggressive tumors, fewer neurological/general symptoms, and 5.5 months median diagnostic interval versus 3 months for those without a misdiagnosis. Those with prior misdiagnoses tended to have a higher 5‐year survival of 83% (95% confidence interval CI: 63%–92%) compared to 66% (95% CI: 44%–82%) for those without (p = .15).
Conclusion
Less aggressive spinal tumors may manifest as gradual skeletal abnormalities and musculoskeletal symptoms without neurological/general symptoms, leading to misdiagnoses and delays.
BACKGROUND:Candidemia is the most frequent pediatric fungal infection, but incompletely elucidated in population-based settings. We performed a nationwide cohort study including all pediatric ...patients with candidemia in Denmark from 2004 to 2014 to determine age, incidence, species distribution, underlying diseases, patient management and outcomes.
METHODS:All candidemia episodes were identified through the active nationwide fungemia surveillance program. Susceptibility testing followed the EUCAST E.Def 7 (European Committee on Antifungal Susceptibility Testing, Edition Definitive) reference method. χ test, Fisher exact test and Venn diagrams were used for statistical analyses.
RESULTS:One hundred fifty-three pediatric patients (≤ 15 years) with 158 candidemia episodes were identified. The overall annual incidence rate was 1.3/100,000 population, higher for neonates (5.7/100,000 live births) and low birth weight neonates (103.8/100,000 live births). From 2004 to 2009 to 2010 to 2014, the proportion of Candida albicans decreased from 74.4% to 64.7%, whereas fluconazole resistance increased from 7.8% to 17.7%. Virtually all patients had at least 1 underlying disease (98.6%) and multimorbidity was common (43.5%, ≥2 underlying diseases). Underlying diseases differed by age with heart malformations and gastrointestinal disease prevalent in children younger than 3 years. The overall 30-days mortality was 10.2% and highest for neonates (17.1%). Mortality increased from 2004 to 2010 to 2014, driven by an increase among older children.
CONCLUSION:This first nationwide epidemiologic study of pediatric candidemia confirmed a high incidence among neonates and a substantial burden of comorbidities. Moreover, an increasing proportion of fluconazole resistant nonalbicans species was observed. Our findings underline the importance of choosing correct treatment and continuous surveillance of pediatric candidemia.
Background
Survival possibilities among children and adolescents (referred to as “children”) with cancer have increased, resulting in more children and parents living with sequelae and psychological ...distress, respectively. Childhood cancer treatment is intensive and long term and affects the everyday life and functioning of the whole family, including daily and social life restrictions and hospitalizations, which force the parents to split up between the hospital and home to care for both the ill child and siblings and manage their jobs and homelife routines. Adequate parental coping strategies are essential for family adjustment and the child’s coping ability. Parenting a child with cancer, however, is challenging and stressful.
Objective
This study aimed to identify parental needs when caring for a child with cancer.
Methods
Using a participatory design approach, we generated data through field studies and semistructured interviews with parents of children receiving treatment at Odense or Aarhus University Hospital and focus group interviews with parents of children who have completed treatment within the past 2 years.
Results
The parents felt trapped in an endless, emotional roller-coaster ride of fear, hope, grief, and mental and emotional exhaustion and had very limited resources for self-care. The presence of support from peers, health care providers, and relatives was a facilitator of successfully coping with the illness. In contrast, full-time isolation in the hospital, due to COVID-19 restrictions, was a barrier and linked with feelings of loneliness. Loneliness was also experienced as navigating difficult emotions when responding differently from the spouse or not feeling understood by relatives.
Conclusions
Parents of children with cancer face many stressors that may become a psychological burden. New innovative approaches to provide psychosocial support, taking into account that the families are periodically isolated, are needed. For this goal, technological solutions may be useful and should be the focal point of this study’s experimental design phase.
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