Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020.

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Effects on Pediatric Cancer Survivors: The FAMily-Oriented Support (FAMOS) Randomized Controlled Trial.

OBJECTIVE: To examine as secondary analyses the effect the FAMily-Oriented Support (FAMOS) family therapy program on reducing parent-reported medical traumatic stress in the sub-sample of pediatric cancer survivors, age 2-5 years. METHODS: The FAMOS study was a national multicenter randomized controlled trial with all four pediatric oncology departments in Denmark (Clinicaltrials.gov [NCT02200731]). Families were randomized in parallel design (1:1) to intervention or usual care. The FAMOS program includes seven home-based psychotherapeutic sessions and is based on family systems therapy to address the individuals in the family system using cognitive behavioral, problem-solving and goal-setting techniques. Questionnaires were completed by parents at baseline, 6, and 12 months. In linear mixed-effects models, the effect of FAMOS on reducing children's trauma-related behavior after 6 and 12 months was examined in 62 children (31 in the intervention and 29 in the control group, respectively). It was also examined if a trauma-related behavior effect was mediated through reduced symptoms of depression in mothers and fathers, respectively. RESULTS: On average, children in the intervention group experienced significantly larger decreases in trauma-related behaviors at 6 and 12 months than the control group (predicted mean difference -3.89, p = .02 and -6.24, p = .003, respectively). The effect on trauma-related behavior was partly mediated through reduced symptoms of depression in mothers, but not fathers. CONCLUSIONS: Adding to previously reported positive effects of the FAMOS intervention on parents' symptoms of post-traumatic stress and depression, significant improvements were found in young children's trauma related-behavior. Further research is needed to develop therapy for children with cancer.

High CD34 surface expression in BCP-ALL predicts poor induction therapy response and is associated with altered expression of genes related to cell migration and adhesion.

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.

Health care utilisation following childhood acute lymphoblastic leukaemia: a population-based matched cohort study.

OBJECTIVES: Survival 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 SETTING: A Danish population-based matched cohort study linking multiple nationwide registries. PARTICIPANTS: 675 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 MEASURES: Repeated 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. RESULTS: Survivors 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. CONCLUSIONS: ALL 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 NUMBER: NCT03985826.

Health care utilisation preceding relapse or second malignant neoplasm after childhood acute lymphoblastic leukaemia: a population-based matched cohort study.

OBJECTIVES: To 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 SETTING: A Danish population-based matched cohort study linking multiple nationwide registries. PARTICIPANTS: Participants 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 MEASURES: Consultations 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. RESULTS: Of 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. CONCLUSIONS: Survivors 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.

The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark.

BACKGROUND: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT. OBJECTIVE: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients. PATIENTS/METHODS: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA. RESULTS: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P > .05) were identified. CONCLUSION: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant.

Home-based cognitive behavioural therapy for families of young children with cancer (FAMOS): A nationwide randomised controlled trial.

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).

A clinical prediction score for transient versus persistent childhood immune thrombocytopenia.

Essentials There is a need for improved tools to predict persistent and chronic immune thrombocytopenia (ITP). We developed and validated a clinical prediction model for recovery from newly diagnosed ITP. The Childhood ITP Recovery Score predicts transient vs. persistent ITP and response to intravenous immunoglobulins. The score may serve as a useful tool for clinicians to individualize patient care. ABSTRACT: Background Childhood immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The prognosis (transient, persistent, or chronic ITP) remains difficult to predict. The morbidity is most pronounced in children with persistent and chronic ITP. Clinical characteristics are associated with ITP outcomes, but there are no validated multivariate prediction models. Objective Development and external validatation of the Childhood ITP Recovery Score to predict transient versus persistent ITP in children with newly diagnosed ITP. Methods Patients with a diagnosis platelet count ≤ 20 × 109 /L and age below 16 years were included from two prospective multicenter studies (NOPHO ITP study, N = 377 [development cohort]; TIKI trial, N = 194 [external validation]). The primary outcome was transient ITP (complete recovery with platelets ≥100 × 109 /L 3 months after diagnosis) versus persistent ITP. Age, sex, mucosal bleeding, preceding infection/vaccination, insidious onset, and diagnosis platelet count were used as predictors. Results In external validation, the score predicted transient versus persistent ITP at 3 months follow-up with an area under the receiver operating characteristic curve of 0.71. In patients predicted to have a high chance of recovery, we observed 85%, 90%, and 95% recovered 3, 6, and 12 months after the diagnosis. For patients predicted to have a low chance of recovery, this was 32%, 46%, and 71%. The score also predicted cessation of bleeding symptoms and the response to intravenous immunoglobulins (IVIg). Conclusion The Childhood ITP Recovery Score predicts prognosis and may be useful to individualize clinical management. In future research, the additional predictive value of biomarkers can be compared to this score. A risk calculator is available (http://www.itprecoveryscore.org).

Identifying acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis in children.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) may present with arthritis implying the risk of being misdiagnosed as juvenile idiopathic arthritis (JIA). The aim of this study was to identify predictors for ALL based on clinical and laboratory information. METHODS: This cross-sectional, retrospective study compared clinical presentation and laboratory results of 26 children with ALL and arthritis versus 485 children with JIA (433 non-systemic, 52 systemic JIA). Using a Bayesian score approach the findings were evaluated by calculating odds ratios (OR) and lnOR as a measure of diagnostic weight. RESULTS: Distinction on clinical grounds was difficult, as even a high number of joints involved did not exclude ALL. One or more hematologic cell counts were low (Hb <10 g/dL, platelet count <100 x 109/L, neutrophil count < 1.0 x 109/L) in 92% with ALL, 25% with systemic JIA and 10% with non-systemic JIA. Neutropenia and thrombocytopenia had the highest ORs of 128 (95% CI 43-387) and 129 (95% CI 26-638), each giving a diagnostic weight of 4. The estimated risks of ALL were 0.2% with normal cell counts and 9%, 67% and 100% when one, two or three cell lines were affected. CONCLUSION: A simple count of cell lines with low counts can serve as a basic diagnostic strategy. Children with tri- or bilinear involvement should be referred to a bone marrow, and those with unilinear involvement a thorough screen for further evidence of ALL (organomegaly, ESR, LDH, uric acid, and blood smear).

Meropenem to Children With Febrile Neutropenia Induces Monoresistant Pseudomonas aeruginosa.

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

Time course of peripheral blood count recovery during induction chemotherapy for childhood acute lymphoblastic leukemia.

Introduction: Children with newly diagnosed acute lymphoblastic leukemia (ALL) present with low peripheral blood counts caused by bone marrow replacement. The recovery of counts during induction chemotherapy is not well described. Material and methods: Records for 63 children with ALL were reviewed. Peripheral hematology blood counts during five weeks of induction chemotherapy were extracted, and the time to partial recovery with safe counts and complete recovery with normal counts in the three cell lines determined. The number of red cell and platelet transfusions, the number of febrile episodes, and the number of days on intravenous antibiotics were counted. Results: Platelet recovery occurred early: median time to achieving counts >50/nL 14 days, to counts >100/nL 16 days. Neutrophil recovery was relatively slow: median time to counts >0.5/nL 18 days, to counts >1.0/nL 26 days. The time to partial recovery was shorter in high risk than in lower-risk treatment groups. Partial platelet recovery by day 15 indicated early recovery and lower morbidity. Complete platelet recovery day 15 was significantly associated with residual disease <0.1% after four weeks. Lymphocyte counts showed a marked decrease in first two weeks followed by a rise in the next three weeks; a count <0.35/nL on day 15 was associated with poor response. Conclusion: After starting chemotherapy for ALL, platelet recovery can be expected after two to three weeks while neutrophil recovery lasts three to five weeks. Platelet and lymphocyte counts after two weeks treatment may give an indication of residual disease after four weeks.

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study.

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/m2 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/m2 (n = 140 patients) or 8 g/m2 (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.

Pediatric Candidemia Epidemiology and Morbidities: A Nationwide Cohort.

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.

Characteristics of children with acute lymphoblastic leukemia presenting with arthropathy.

Acute lymphoblastic leukemia (ALL) is the most common childhood neoplasia and may present with arthralgia and arthritis, with the risk of misdiagnosis and diagnostic delay. We describe in detail arthropathy (arthritis/arthralgia) among children with leukemia as the children's laboratory results, misdiagnosis, and treatment before the diagnosis of ALL and the diagnostic delay. In this retrospective cohort study, we reviewed records of 286 children aged 1-15 years diagnosed with ALL from January 1992 to March 2013. We identified 26 children with arthralgia and 27 children with arthritis. The majority of the children had one or two joints involved (arthralgia 72%, arthritis 42%), and most often hips and knees. Morning stiffness was not reported. Imaging of affected joints was included in the initial workup of 77% of children with ALL and arthropathy, and 66% was abnormal. Misdiagnosis as JIA occurred in 26% and 71% of these children received treatment with intraarticular corticosteroids. The diagnostic delay was 3 weeks longer for the children with arthritis than those with arthralgia (median 54 vs 36 days), primarily as a consequence of a longer first doctor's delay. Compared to the children with arthralgia, the children with arthritis were more often misdiagnosed and treated with intraarticular steroid before the diagnosis of ALL. They also had longer diagnostic delay, primarily as a consequence of a longer first doctor's delay.

A Bayesian CUSUM plot: Diagnosing quality of treatment.

OBJECTIVES: To present a CUSUM plot based on Bayesian diagnostic reasoning displaying evidence in favour of "healthy" rather than "sick" quality of treatment (QOT), and to demonstrate a technique using Kaplan-Meier survival curves permitting application to case series with ongoing follow-up. METHODS: For a case series with known final outcomes: Consider each case a diagnostic test of good versus poor QOT (expected vs. increased failure rates), determine the likelihood ratio (LR) of the observed outcome, convert LR to weight taking log to base 2, and add up weights sequentially in a plot showing how many times odds in favour of good QOT have been doubled. For a series with observed survival times and an expected survival curve: Divide the curve into time intervals, determine "healthy" and specify "sick" risks of failure in each interval, construct a "sick" survival curve, determine the LR of survival or failure at the given observation times, convert to weights, and add up. RESULTS: The Bayesian plot was applied retrospectively to 39 children with acute lymphoblastic leukaemia with completed follow-up, using Nordic collaborative results as reference, showing equal odds between good and poor QOT. In the ongoing treatment trial, with 22 of 37 children still at risk for event, QOT has been monitored with average survival curves as reference, odds so far favoring good QOT 2:1. CONCLUSION: QOT in small patient series can be assessed with a Bayesian CUSUM plot, retrospectively when all treatment outcomes are known, but also in ongoing series with unfinished follow-up.

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

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 × 109 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.

FAMily-Oriented Support (FAMOS): development and feasibility of a psychosocial intervention for families of childhood cancer survivors.

BACKGROUND: We developed and tested the feasibility of a manualized psychosocial intervention, FAMily-Oriented Support (FAMOS), a home-based psychosocial intervention for families of childhood cancer survivors. The aim of the intervention is to support families in adopting healthy strategies to cope with the psychological consequences of childhood cancer. The intervention is now being evaluated in a nationwide randomized controlled trial (RCT). METHODS AND DESIGN: FAMOS is based on principles of family systems therapy and cognitive behavioral therapy, and is delivered in six sessions at home. Families were recruited from all four pediatric oncology departments in Denmark after the end of intensive cancer treatment. We evaluated the feasibility of the intervention and of a RCT design for comparing the intervention with usual care. The evaluation was conducted among families enrolled in the study by tracking procedures and parents' evaluations. RESULTS: A total of 68 families (68 mothers, 60 fathers, 68 children with cancer and 73 siblings) were enrolled, with a participation rate of 62% of families. Fathers were highly represented (88% of families); also families with single parents (12%) and parents with basic education (7-12 years of primary, secondary, and grammar school education) were represented (12%). The dropout rate was 12% of families (all in the control group), and two families did not complete the intervention because of relapse. Evaluation by parents in the intervention group showed overall satisfaction with the format, timing, and content of the intervention. CONCLUSION: The results indicate that the FAMOS intervention is feasible in terms of recruitment, retention, and acceptability. The effects of the intervention on post-traumatic stress, depression, anxiety, family functioning, and quality of life will be reported after the nationwide RCT has been completed.

Danish Childhood Cancer Registry.

AIM OF DATABASE: 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. STUDY POPULATION: 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. MAIN VARIABLES: 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. DESCRIPTIVE DATA: 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. CONCLUSION: 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.

Central Venous Catheters and Bloodstream Infection During Induction Therapy in Children With Acute Lymphoblastic Leukemia.

The purpose of the study was to assess the risk of first-time bloodstream infection (BSI) according to type of central venous catheter (CVC) during induction therapy in children with acute lymphoblastic leukemia (ALL). Patients eligible for our analysis were all newly diagnosed children with ALL treated at 3 pediatric centers in Denmark between 2008 and 2014. A total of 136 patients were followed from initial CVC placement until first BSI, CVC removal, death, or day 28, whichever occurred first. Thirty-nine BSIs were detected, of which 67% were gram-positive infections, and 59% met the criteria for being CVC associated. The 28-day cumulative incidence of BSI was similar in 77 patients with a nontunneled CVC (28%; 95% confidence interval, 19%-40%) and in 59 patients with a tunneled CVC with external lines (TE) (33%; 95% confidence interval, 23%-47%). Subgroup analyses showed that gram-negative blood isolates occurred more frequently in patients with a TE, and that lower incidences of BSI were detected in patients older than 9 years with a TE, and in patients with T-ALL. It is concluded that the type of CVC inserted at diagnosis has no impact upon the risk of BSI in patients with ALL undergoing induction therapy.

Flow cytometric measurement of platelet-associated immunoglobulin in children with newly diagnosed Immune Thrombocytopenia.

OBJECTIVE: To explore the clinical utility of measuring platelet-associated immunoglobulin (PAIG) at the time of diagnosis in children with immune thrombocytopenia (ITP). METHODS: PAIG was measured by flow cytometry using fluorescent murine anti-IgG and anti-IgM. In a cohort of 88 children with ITP, the assay was performed within 15 days of diagnosis and before any treatment in 68 cases. We reviewed the results and examined the relation of isotype profile and degree of elevation to clinical manifestations and course of disease. RESULTS: PAIG was elevated in 74%, with raised IgM being more frequent than IgG (63% vs. 44%, P = 0.04) and with isotype profile depending on symptom onset. Platelet counts at presentation were similar in all subgroups, but mucosal bleeding was less frequent in PAIG-negative patients compared to the positive groups (5.5% vs. 34%, P = 0.03). Duration of thrombocytopenia was similar in negative and positive cases, but during follow-up, significant bleeding events occurred less frequently in PAIG-negative patients (0% vs. 14%, P = 0.18). CONCLUSION: Approximately one-quarter of children are PAIG-negative, and these children have milder bleeding tendency at diagnosis and lower morbidity during follow-up. Raised PAIG possibly may cause some degree of platelet dysfunction.