Publications by authors named "Steen Rosthøj"

51 Publications

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

Pediatr Blood Cancer 2021 Mar 27;68(3):e28853. Epub 2020 Dec 27.

Psychological Aspects of Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.

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).
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http://dx.doi.org/10.1002/pbc.28853DOI Listing
March 2021

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

J Thromb Haemost 2021 01 27;19(1):121-130. Epub 2020 Nov 27.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

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 × 10 /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 × 10 /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).
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http://dx.doi.org/10.1111/jth.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839442PMC
January 2021

Identifying acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis in children.

PLoS One 2020 11;15(8):e0237530. Epub 2020 Aug 11.

Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

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).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418991PMC
October 2020

Meropenem to Children With Febrile Neutropenia Induces Monoresistant Pseudomonas aeruginosa.

J Pediatr Hematol Oncol 2020 11;42(8):e783-e787

Departments of Pediatrics and Adolescent Medicine.

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.
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http://dx.doi.org/10.1097/MPH.0000000000001713DOI Listing
November 2020

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

Hematology 2019 Dec;24(1):467-472

a Pediatric Oncology Section, Pediatric Department , Aalborg University Hospital , Aalborg , Denmark.

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. 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. 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. 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.
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http://dx.doi.org/10.1080/16078454.2019.1621019DOI Listing
December 2019

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

Pediatr Blood Cancer 2019 06 5;66(6):e27637. Epub 2019 Mar 5.

Department of Pediatric Oncology, Aarhus University Hospital, Aarhus, Denmark.

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 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 (n = 140 patients) or 8 g/m (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.
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http://dx.doi.org/10.1002/pbc.27637DOI Listing
June 2019

Pediatric Candidemia Epidemiology and Morbidities: A Nationwide Cohort.

Pediatr Infect Dis J 2019 05;38(5):464-469

Department of Clinical Microbiology, Rigshospitalet, Copenhagen University Hospital.

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.
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http://dx.doi.org/10.1097/INF.0000000000002207DOI Listing
May 2019

Characteristics of children with acute lymphoblastic leukemia presenting with arthropathy.

Clin Rheumatol 2018 Sep 21;37(9):2455-2463. Epub 2018 Feb 21.

Department of Pediatrics, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1007/s10067-018-4034-1DOI Listing
September 2018

A Bayesian CUSUM plot: Diagnosing quality of treatment.

J Eval Clin Pract 2017 Dec 7;23(6):1415-1421. Epub 2017 Sep 7.

Pediatric Department, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1111/jep.12815DOI Listing
December 2017

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

Pediatr Blood Cancer 2017 Sep 19;64(9). Epub 2017 Apr 19.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

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 l ) 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.
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http://dx.doi.org/10.1002/pbc.26519DOI Listing
September 2017

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

Acta Oncol 2017 Feb 12;56(2):367-374. Epub 2017 Jan 12.

a Danish Cancer Society Research Center , Copenhagen , Denmark.

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.
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http://dx.doi.org/10.1080/0284186X.2016.1269194DOI Listing
February 2017

Danish Childhood Cancer Registry.

Clin Epidemiol 2016 25;8:461-464. Epub 2016 Oct 25.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

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.
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http://dx.doi.org/10.2147/CLEP.S99508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094529PMC
October 2016

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

J Pediatr Hematol Oncol 2016 Apr;38(3):e82-7

*Department of Pediatrics, Aarhus University Hospital, Aarhus †Department of Pediatrics, Odense University Hospital, Odense ‡Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1097/MPH.0000000000000519DOI Listing
April 2016

Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children.

Arch Dis Child 2015 Sep 27;100(9):821-5. Epub 2015 Jul 27.

Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.

Background: At disease onset, children with acute lymphoblastic leukaemia (ALL) may present with arthralgia or even signs of arthritis. This might cause misdiagnosis and thereby lead to prolonged diagnostic delay. The present study aimed to identify children with ALL with joint involvement and to compare their characteristics and outcome with children with ALL without joint involvement.

Methods: Case records of 286 children diagnosed with ALL between 1992 and 2013 were reviewed and analysed in this retrospective, descriptive study.

Results: Fifty-three (18.5%) children with ALL presented with localised joint pain, and half of them had objective signs of arthritis. The mean number of joints involved was 2.5, most frequently presenting as asymmetric oligoarthritis. The suspected misdiagnosis were reactive arthritis (19/53), osteomyelitis (9/53) and juvenile idiopathic arthritis (8/53). Children with joint involvement had less objective signs of haematological disease. Cytopenia was absent in 24% in children with joint involvement (vs 8% without, p=0.001), 50% had only one cell line affected (vs 21%, p=0.0005) and 44% had no organomegaly (vs 29%, p=0.05). Median diagnostic delay was 4 vs 2 weeks. The 5-year event-free and overall survival was superior for children with joint involvement: 94% vs 87% (p=0.049), and 96% vs 83% (p=0.044).

Conclusions: ALL with joint involvement is a frequent finding (18.5%). The clinical signs of leukaemia are less prominent, but non-articular pain should alert the clinician of a possible diagnosis of leukaemia. The overall and event-free survivals were superior compared with the children without joint involvement.
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http://dx.doi.org/10.1136/archdischild-2014-307751DOI Listing
September 2015

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

Eur J Haematol 2016 Apr 30;96(4):397-403. Epub 2015 Jun 30.

Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1111/ejh.12605DOI Listing
April 2016

A novel chemosensitivity profiling platform for small acute lymphoblastic leukemia cell populations.

Leuk Lymphoma 2015 Jul 21;56(7):2208-11. Epub 2015 Jan 21.

Department of Pediatric and Adolescent Medicine, University Hospital Rigshospitalet , Copenhagen , Denmark.

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http://dx.doi.org/10.3109/10428194.2014.996851DOI Listing
July 2015

[In Process Citation].

Authors:
Steen Rosthøj

Ugeskr Laeger 2014 Oct;176(44)

Børneonkologisk Afsnit, Børneafdelingen, Klinik Kvinde-Barn & Urinvejskirurgi, Aalborg Universitetshospital, Hobrovej 18-22, 9100 Aalborg.

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October 2014

Most central nervous system tumours in children are diagnosed with little delay after admission.

Dan Med J 2014 Aug;61(8):A4886

Børneafdelingen, Aarhus Universitetshospital, Brendstrupgårdsvej 100, 8200 Aarhus N, Denmark.

Introduction: Children with central nervous system (CNS) tumours often have a long symptom interval before diagnosis. We investigated delays in diagnosis and surgical management after the first admission with tumour-related symptoms.

Material And Methods: This study reviewed the medical records of 46 consecutive children with a CNS tumour admitted to a paediatric department. Clinical findings at the time of the first admission, duration of symptoms, time to radiological diagnosis and time to initial surgical procedures were recorded.

Results: The series comprised 26 supratentorial, 19 fossa posterior and one spinal tumour with equal numbers of high-grade and low-grade tumours. Headache, vomiting and lethargy were the most frequent symptoms, and pre-admission delay depended on tumour grade as well as location. Six cases had been diagnosed prior to admission; of the 40 undiagnosed cases, 32 (80%) were scanned within four days, but in four cases (10%) diagnosis was delayed for more than a week. Resection was performed within four days of diagnosis in 68% of children with resectable tumours (21/31). Initial surgical management of tumours causing hydrocephalus was completed within four days of diagnosis in 83% (20/24).

Conclusion: Delay in diagnosis and surgical management after the primary admission with symptoms caused by a tumour may influence the outcome negatively. In this review from a small centre, the majority of the cases were diagnosed and managed surgically within four days of admission and diagnosis, respectively. Criteria for good performance, i.e. accepted standards for time to diagnosis and intervention, need to be specified.

Funding: Not relevant.

Trial Registration: Not relevant.
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August 2014

Bone marrow involvement is not manifest in the early stages of childhood acute lymphoblastic leukaemia.

Dan Med J 2014 Aug;61(8):A4883

Jens Baggesens vej 33, 1.-6., 8200 Aarhus N, Denmark.

Introduction: Acute lymphoblastic leukaemia (ALL) in children may have atypical presentations causing diagnostic delay. Guidelines for prompt referral have been published. The utility of the specified criteria is unknown.

Material And Methods: Symptoms, signs and laboratory findings at the time of diagnosis were reviewed in a consecutive series of 100 children with ALL in order to determine the frequency of atypical features and to evaluate the Danish referral guideline.

Results: Only 36% had involvement of all three haematopoietic cell lines, and 23% presented with the classic clinical triad of pallor, fever and purpura. Symptoms of bone marrow insufficiency had been present in 77% for an average of two weeks as a late occurrence following musculoskeletal pains (in 49%, duration eight weeks) and constitutional symptoms (in 82%, duration four weeks). Organ infiltration was manifest in 71%. In 22%, only one or no cell count was abnormal; in this group, musculoskeletal symptoms were more frequent and symptom duration longer (two months versus one month). In 15%, lymphoblasts could not be detected in the blood. At the time of diagnosis, the Danish criteria for accelerated investigation were fulfilled in 98% of cases.

Conclusion: The clinical presentation of ALL is variable, and full-blown bone marrow insufficiency is a late occurrence as the disease progresses. Reduction of the diagnostic interval requires meticulous examination for organomegaly and attention to subtle haematologic changes.

Funding: Not relevant.

Trial Registration: Not relevant.
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August 2014

Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia.

Br J Haematol 2014 Jul 5;166(2):213-20. Epub 2014 Apr 5.

Department of Paediatrics, Aarhus University Hospital, Aarhus N, Denmark.

L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L-asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre-treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m(2) i.m. every second week effectively reduced CSF asparagine levels.
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http://dx.doi.org/10.1111/bjh.12865DOI Listing
July 2014

[About fishing trips and picnics].

Authors:
Steen Rosthøj

Ugeskr Laeger 2014 Feb;176(3):272

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February 2014

[Half of the new cancer treatments are better than the old treatments!].

Authors:
Steen Rosthøj

Ugeskr Laeger 2013 Nov;175(46):2811-2

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November 2013

Very late relapse of PTLD 10 yr after allogeneic HSCT and nine yr after stopping immunosuppressive therapy.

Pediatr Transplant 2014 Feb 29;18(1):E35-9. Epub 2013 Oct 29.

Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.

We present a very late onset relapse of PTLD 10 yr after allogeneic HSCT in a patient in third remission for ALL, nine yr after the first episode of PTLD. The recipient was conditioned with fractionated TBI 12 Gy, cyclophosphamide, and horse ATG. The first episode of PTLD with a large retroperitoneal tumor occurred one yr after transplantation; a residual tumor infiltrating spleen and colon was resected one yr later. Due to continual pathological signals in liver and lungs, persistent fever, and an M-component in peripheral blood, a new course of four rituximab doses was given, after which the fever settled, the PET scan normalized, and the M-component disappeared. Without any ongoing immunosuppressive therapy, PTLD relapsed nine yr later with large intra-abdominal lymph node masses causing ureteric obstruction with bilateral hydronephrosis. Pathological features were identical to the primary PTLD tumor: EBV related, of donor origin, positive for CD138 and CD79 alpha, but negative for CD20 and CD19. The transcription factor PAX5 was negative but BOB1 and OCT2 were positive, consistent with plasmablastic lymphoma. The relapse was successfully treated with a combination of low dose chemotherapy and rituximab. Five yr after end of treatment, the girl has moderately reduced renal function but otherwise remains well without evidence of disease.
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http://dx.doi.org/10.1111/petr.12180DOI Listing
February 2014

Acute favism: methemoglobinemia may cause cyanosis and low pulse oximetry readings.

Pediatr Hematol Oncol 2014 Feb 22;31(1):104-6. Epub 2013 May 22.

Pediatric Department, Aalborg University Hospital , Aalborg , Denmark.

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http://dx.doi.org/10.3109/08880018.2012.760022DOI Listing
February 2014

Prediction of bacteremia in children with febrile episodes during chemotherapy for acute lymphoblastic leukemia.

Pediatr Hematol Oncol 2013 Mar 2;30(2):131-40. Epub 2013 Jan 2.

Department of Pediatrics, Aarhus University Hospital, Aalborg, Denmark.

The purpose was to identify risk factors for bacteremia in febrile episodes occurring during chemotherapy for acute lymphoblastic leukemia (ALL) in children, and to develop a risk score permitting risk-adapted antibiotic therapy. We reviewed a total of 172 febrile episodes occurring during chemotherapy in 31 children and adolescents with ALL. Temperature, hematological parameters, culture findings, and antibiotic therapy were recorded. Bacteremias were classified as transmucosal or CVC-dependent. Blood cultures were positive with mucosal pathogens in 15 cases (9%) and with skin/environmental bacteria in 34 (20%). CVC-dependent infections occurred throughout the treatment phases, while transmucosal primarily during induction therapy. Transmucosal bacteremia was associated with induction therapy, leukocyte count ≤0.5 × 10(9)/L, neutrophil count ≤0.1 × 10(9)/L, monocyte count ≤0.01 × 10(9)/L, and platelet count ≤50 × 10(9)/L. Based on logistic conversion of the odds ratios for the five factors, a weight of 2 was assigned to induction therapy and leukocyte count ≤0.5 × 10(9)/L, and a weight of 1 to the remaining three parameters. The weights were included in a simple additive score ranging from 0 to 7, which defined groups with 4%, 6%, 24%, and 40% risk of transmucosal bacteremia. CVC-dependent bacteremia was not associated with markers of poor bone marrow function. In conclusion, transmucosal bacteremia in children with ALL is related to infiltration or suppression of the bone marrow. A score reflecting the condition of the marrow can define low-risk and high-risk groups and may prove clinically useful.
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http://dx.doi.org/10.3109/08880018.2012.748111DOI Listing
March 2013

[The Danish Registry of Childhood Cancer].

Ugeskr Laeger 2012 Oct;174(42):2542

Børneafdelingen, Aarhus Universitetshospital, Brendstrupgårdsvej 100, Aarhus.

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October 2012

Impact of hydrochloric acid instillation on salvage of infected central venous catheters in children with acute lymphoblastic leukaemia.

Scand J Infect Dis 2013 Jan 19;45(1):38-44. Epub 2012 Sep 19.

Department of Paediatrics, Aarhus University Hospital, Aalborg Hospital, Denmark.

Background: Bacteraemia associated with indwelling central venous catheters (CVC) causes significant morbidity in children with cancer. Hydrochloric acid (HCl) instillations have been reported to salvage CVCs with antibiotic-refractory infection. We implemented this treatment in 2002. The impact on the survival of CVCs has been evaluated in a retrospective cohort study of children with acute lymphoblastic leukaemia (ALL).

Methods: Children with newly diagnosed ALL during 1999-2005 having their first CVC inserted before (n = 16) and after (n = 24) the introduction of the procedure were studied. All bacteraemic episodes were reviewed, recording bacteriological findings and treatment, and the time to premature or planned removal of the CVC was determined.

Results: In the comparison cohort, 31.0% (9/29) of bacteraemic episodes led to removal of the CVC, compared to 5.5% (2/36) in the intervention cohort (p = 0.01). Thus, the rate of catheter loss due to infection fell from 56.3% (9/16) to 8.3% (2/24) after introducing HCl treatment (p = 0.0025). Overall, the premature catheter removal rate fell from 75.0% (12/16) to 45.8% (11/24) (p = 0.10). Analysed in a CUSUM plot the reduced frequency of premature CVC removal evidently coincided with the introduction of the procedure. In a subgroup analysis of 21 monobacterial infections with coagulase-negative staphylococci, a decrease in systemic and lock antibiotic therapy was found. No adverse events were noted.

Conclusions: HCl instillations significantly reduced the need to remove and replace CVCs. The procedure is practical, appears to be safe, and may reduce the consumption of antibiotics.
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http://dx.doi.org/10.3109/00365548.2012.708941DOI Listing
January 2013

Duration and morbidity of chronic immune thrombocytopenic purpura in children: five-year follow-up of a Nordic cohort.

Acta Paediatr 2012 Jul 4;101(7):761-6. Epub 2012 May 4.

Pediatric Department, Aarhus University Hospital, Aalborg Hospital, Denmark.

Aim: To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP).

Methods: Prospective 5-year follow-up of 96 children with ITP lasting more than 6 months, with reporting of hospital admissions, severity of bleeding episodes and stabilization of platelet counts above 20, 50 and 150 × 10(9) /L.

Results: The estimated 5-year recovery rate was 52%; exclusion of 12 splenectomized children did not change the estimate. Events eliciting admission to hospital occurred in 39 (41%). Major haemorrhages occurred in eight children (8%), including a nonfatal intracranial haemorrhage in one child (1%). The overall admission rate was 0.4/year of thrombocytopenia, decreasing during follow-up as thrombocytopenia converted to milder degrees. Early recovery within 2 years of diagnosis occurred in 35%, was associated with low morbidity and was more likely in young children with abrupt onset of symptoms.

Conclusion: In a Nordic cohort of children with chronic ITP, one half had recovered 5 years after diagnosis, more than half never required hospitalization and <10% experienced serious bleeding episodes, always with a platelet count <20 × 10(9) /L. Aggressive management can be restricted to the minority of children with continuing severe thrombocytopenia and frequent, clinically significant bleeding events.
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http://dx.doi.org/10.1111/j.1651-2227.2012.02671.xDOI Listing
July 2012

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D.

Blood 2011 Nov 19;118(22):5783-93. Epub 2011 Sep 19.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
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http://dx.doi.org/10.1182/blood-2011-07-369090DOI Listing
November 2011

Developmental problems in very prematurely born children.

Dan Med Bull 2011 Jun;58(6):A4283

Occupational Therapy and Physiotherapy Department, Aarhus University Hospital, Aalborg Hospital.

Introduction: The aim of the present study was to describe the developmental outcome of routine follow-up assessments at the age of five years in a regional cohort of children born at a gestational age < 32 weeks and to investigate neonatal risk factors associated with developmental problems.

Material And Methods: The cohort consisted of 237 infants with a gestational age ≥ 24 and < 32 weeks born in the 1996-2000 period. The children were assessed using the Movement Assessment Battery for Children and Miller Assessment for Preschoolers. The presenting clinical and demographic features were investigated for their association with developmental problems at five years of age by determining odds ratios in univariate analysis. The results are given with 95% confidence intervals.

Results: 14% died. 86% of the surviving children were routinely assessed at five years of age. 40% of the children had a normal developmental outcome, 41% were to be observed for developmental deficiencies and 19% had developmental deficiencies. Male gender, low social group, a gestational age < 28 weeks, sepsis, persistent ductus arteriosus, bronchopulmonary dysplasia and abnormal cerebral ultrasound were significantly associated with an unfavourable developmental outcome.

Conclusion: More than half of the assessed very prematurely born children had developmental problems at five years of age. Children who were to be observed for developmental deficiencies outnumbered children with deficiencies at a two to one ratio. Follow-up assessments of very prematurely born children are still needed to evaluate changes in neonatal practise and developmental outcome in the future.

Funding: not relevant.

Trial Registration: not relevant.
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June 2011