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Introduction: Evidence-based knowledge is needed to reduce psychological symptoms in families of young children with cancer after treatment ends., Objective: To evaluate the effect of a psychotherapeutic intervention, FAMily-Oriented Support (FAMOS) on parents of young children after cancer treatment., Methods: All families of children aged 0-6 years who had been treated for cancer at one of the four paediatric oncology departments in Denmark were invited to participate after ending intensive medical treatment. The families were randomly assigned 1:1 to up to seven sessions of FAMOS, a cognitive-behavioural manualised home intervention, for 6 months or to usual psychosocial care. The primary outcome was parents' symptoms of posttraumatic stress disorder (PTSD) at 6 and 12 months after enrolment. The secondary outcomes were parents' symptoms of depression and anxiety., Results: We enrolled 109 families (204 parents). Parents in the intervention group did not show a statistically significant decrease in symptoms of PTSD as compared with the control group at 6 months (predicted mean difference, -0.10; 95% confidence interval [CI] -0.19, 0.01), but a statistically significant decrease was seen at 12 months (predicted mean difference, -0.15; 95% CI -0.28, -0.02), and they had significantly lower symptoms of depression at both 6 and 12 months. Differences in reductions in symptoms of anxiety were not statistically significant., Conclusions: The FAMOS intervention reduced parents' symptoms of PTSD and depression. Next step is to also report on psychological effects in the children and siblings (clinicaltrials.gov: NCT02200731)., (© 2020 Wiley Periodicals LLC.)

Background: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity., Methods: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m 2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0-9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM., Results: Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4-1.06 μM). Of 1295 MTX infusions with 5 g/m 2 (n = 140 patients) or 8 g/m 2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX ≥4.0 μM., Conclusions: A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX., (© 2019 Wiley Periodicals, Inc.)

Background: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy., Procedure: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks., Results: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 10 9 l -1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01)., Conclusions: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses., (© 2017 Wiley Periodicals, Inc.)

Background: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol., Procedure: We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype., Results: The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03)., Conclusion: This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT)., (© 2014 Wiley Periodicals, Inc.)

Background: The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning., Procedure: In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening., Results: Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0-99.9% of the time, and 101 in the evening <50% of the time, six did not have any registrations. The circadian schedule did not differ significantly by age, sex, MTX/6MP doses, and average absolute neutrophil counts. The circadian schedule groups did differ on risk groups (P = 0.003) with fewer HR patients in the 50-99.9% group, and there was a negative correlation between percentage of time on evening schedule and average WBC (Spearman's rho -0.15; P = 0.0004). Average WBC was not associated with relapse on ALL92. In a Cox multivariate model the circadian schedule of MTX/6MP was not of prognostic significance for the risk of relapse, and the 10-year cumulative relapse risk was below 20% in all groups., Conclusion: An evening schedule may still be recommended based on the previous publications, but in this study morning administration of MTX and 6MP does not seem to impact EFS., (© 2013 Wiley Periodicals, Inc.)

Background: Herpes zoster (HZ) is rare in healthy children, but may occur frequently and take a complicated course in children receiving chemotherapy. We determined the morbidity related to HZ in children with acute lymphoblastic leukaemia (ALL)., Procedure: Medical records of 226 children diagnosed with ALL were reviewed. Of these, 160 were seropositive at the time of diagnosis. HZ eruptions during primary chemotherapy, during therapy for relapse and following bone marrow transplantation (BMT) were registered., Results: A total of 90 eruptions were recorded: 63 first-time attacks and 27 recurrent episodes among 14 children. All eruptions were treated with acyclovir (ACV) and in 60% it was given intravenously. Cutaneous dissemination occurred in 11 cases, post herpetic neuralgia in five, visceral dissemination in none. During primary chemotherapy 47 children (29%) had HZ. The eruption rate was significantly higher in children on high risk protocols compared to children on standard/intermediate risk protocols (0.36 vs. 0.07/0.09 per year) and was related to intensity of chemotherapy. During therapy for relapse 7 of 29 (24%) had a total of 13 eruptions. Following BMT 9 of 26 (35%) had a total of 10 eruptions., Conclusion: Almost one third of the seropositive children had HZ during primary chemotherapy. Of those treated on high risk protocols more than half had one or more eruptions during the course of treatment. The risk of complicated HZ is small, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions. Attempts to improve immunity by vaccination after attaining remission seem warranted., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Morphological evaluation of early response to chemotherapy and measurement of minimal residual disease by flow cytometry or PCR are being used for evaluation of prognosis and treatment stratification in children with acute lymphoblastic leukaemia (ALL)., Procedure: In a series of 14 consecutive bone marrow investigations from children with precursor B-cell ALL, morphological evaluations of smears and flow cytometric measurements of minimal residual disease in sequentially aspirated small (2 ml) and large (5-10 ml) volumes of bone marrow were compared, at various time points during therapy., Results: The density of nucleated cells was markedly reduced in the large volume aspirate. The percentage of erythroblasts measured by flow cytometry was smaller, indicating dilution with peripheral cells. Similarly, the blast percentage was reduced with 54% in large aspirates, and in four instances with minimal residual disease of >0.1% in the small volume, the level of blasts in the large aspirate was below this limit., Conclusions: The amount of minimal residual disease should be measured in the first 2.5 ml of bone marrow aspirated from one puncture site. The procedure should be performed by experienced and carefully instructed doctors. In large aspirates, minimal residual disease will be underestimated, which may lead to failure to undertake a required intensification of therapy and a lower fraction of high risk patients in the trial., (Copyright © 2011 Wiley-Liss, Inc.)

Background: The few published studies on caries among childhood cancer survivors are small and their results are conflicting. The study aim was to examine the risk of dental caries among children who have survived cancer., Procedure: We included 299,426 7-year-old, 313,461 12-year-old, and 301,930 15-year-old children born between 1984 and 1988 in a nationwide population-based study linking records from Danish Cancer Registry with records from the national database on oral health. Children whose dental examinations had been preceded by a cancer diagnosis (288 7-year-old, 459 12-year-old, and 526 15-year-old) were compared with children without cancer according to presence of caries: caries-free children; children with any caries experience; and children with severe caries experience (i.e., caries in one or more smooth tooth surface)., Results: Children diagnosed with cancer before the age of 5 years did not have increased caries prevalence in permanent teeth at ages 12; and 15. Children diagnosed with cancer between 5 and 6 years of age had an increased prevalence of severe caries at age 12 years (prevalence ratio (PR) = 1.59 (95% CI: 1.09-2.31; P = 0.02)), but this difference disappeared by age 15. For children diagnosed with cancer at 5 or 6 years of age and who received radiation therapy the PR of severe caries was 1.52 (95% CI: 0.97-2.37; P = 0.07), 2.13 (95% CI: 0.89-5.10; P = 0.09), and 0.31 (95% CI: 0.07-1.45; P = 0.13) at ages seven, 12 and 15 years respectively., Conclusion: Cancer and cancer treatment during childhood are risk factors for caries., ((c) 2007 Wiley-Liss, Inc.)