Publications by authors named "Marrie C A Bruin"

25 Publications

  • Page 1 of 1

Biological stratification of clinical disease courses in childhood immune thrombocytopenia.

J Thromb Haemost 2021 Jan 1. Epub 2021 Jan 1.

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

Background: In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes.

Objective: To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers.

Methods: Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies.

Results: In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10 /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses.

Conclusions: The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15232DOI Listing
January 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).
View Article and Find Full Text PDF

Download full-text PDF

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

Whole-body MRI versus an FDG-PET/CT-based reference standard for staging of paediatric Hodgkin lymphoma: a prospective multicentre study.

Eur Radiol 2021 Mar 3;31(3):1494-1504. Epub 2020 Sep 3.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Objectives: To assess the concordance of whole-body MRI (WB-MRI) and an FDG-PET/CT-based reference standard for the initial staging in children with Hodgkin lymphoma (HL) METHODS: Children with newly diagnosed HL were included in this prospective, multicentre, international study and underwent WB-MRI and FDG-PET/CT at staging. Two radiologists and a nuclear medicine physician independently evaluated all images. Discrepancies between WB-MRI and FDG-PET/CT were assessed by an expert panel. All FDG-PET/CT errors were corrected to derive the FDG-PET/CT-based reference standard. The expert panel corrected all reader errors in the WB-MRI DWI dataset to form the intrinsic MRI data. Inter-observer agreement for WB-MRI DWI was calculated using overall agreement, specific agreements and kappa statistics. Concordance for correct classification of all disease sites and disease stage between WB-MRI (without DWI, with DWI and intrinsic WB-MRI DWI) and the reference standard was calculated as primary outcome. Secondary outcomes included positive predictive value, negative predictive value and kappa statistics. Clustering within patients was accounted for using a mixed-effect logistic regression model with random intercepts and a multilevel kappa analysis.

Results: Sixty-eight children were included. Inter-observer agreement between WB-MRI DWI readers was good for disease stage (κ = 0.74). WB-MRI DWI agreed with the FDG-PET/CT-based reference standard for determining disease stage in 96% of the patients versus 88% for WB-MRI without DWI. Agreement between WB-MRI DWI and the reference standard was excellent for both nodal (98%) and extra-nodal (100%) staging.

Conclusions: WB-MRI DWI showed excellent agreement with the FDG-PET/CT-based reference standard. The addition of DWI to the WB-MRI protocol improved the staging agreement.

Key Points: • This study showed excellent agreement between WB-MRI DWI and an FDG-PET/CT-based reference standard for staging paediatric HL. • Diffusion-weighted imaging is a useful addition to WB-MRI in staging paediatric HL. • Inter-observer agreement for WB-MRI DWI was good for both nodal and extra-nodal staging and determining disease stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-020-07182-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880958PMC
March 2021

Anti-platelet antibody immunoassays in childhood immune thrombocytopenia: a systematic review.

Vox Sang 2020 May 20;115(4):323-333. Epub 2020 Feb 20.

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

Background: In adult immune thrombocytopenia (ITP), an acquired autoimmune bleeding disorder, anti-platelet autoantibody testing may be useful as a rule-in test. Childhood ITP has different disease characteristics, and the diagnostic and prognostic value of anti-platelet antibody testing remains uncertain.

Objective: To systematically review the diagnostic accuracy of anti-platelet autoantibody testing in childhood ITP.

Methods: PubMed and EMBASE were searched for studies evaluating immunoassays in childhood ITP. Study quality was assessed (QUADAS2), and evidence was synthesized descriptively.

Results: In total, 40 studies (1606 patients) were identified. Nine studies reported sufficient data to determine diagnostic accuracy measures. Anti-platelet IgG antibody testing showed a moderate sensitivity (0·36-0·80 platelet-associated IgG [direct test]; 0·19-0·39 circulating IgG [indirect test]). In studies that reported control data, including patients with non-immune thrombocytopenia, specificity was very good (0·80-1·00). Glycoprotein-specific immunoassays showed comparable sensitivity (three studies) and predominantly identified IgG anti-GP IIb/IIIa antibodies, with few IgG anti-GP Ib/IX antibodies. Anti-platelet IgM antibodies were identified in a substantial proportion of children (sensitivity 0·62-0·64 for direct and indirect tests).

Conclusion: The diagnostic evaluation of IgG and IgM anti-platelet antibodies may be useful as a rule-in test for ITP. In children with insufficient platelets for a direct test, indirect tests may be performed instead. A negative test does not rule out the diagnosis of ITP. Future studies should evaluate the value of anti-platelet antibody tests in thrombocytopenic children with suspected ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317748PMC
May 2020

Anti-platelet antibodies in childhood immune thrombocytopenia: Prevalence and prognostic implications.

J Thromb Haemost 2020 05 12;18(5):1210-1220. Epub 2020 Apr 12.

Laboratory for Platelet and Leukocyte Serology, Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Background: Anti-platelet antibody testing may be useful for the diagnosis and management of childhood immune thrombocytopenia (ITP).

Objectives: Here we aimed to assess the prevalence and prognostic significance of anti-platelet glycoprotein-specific IgM and IgG antibodies.

Methods: Children with newly diagnosed ITP were included at diagnosis and randomized to an intravenous immunoglobulins (IVIg) or careful observation group (TIKI trial). In this well-defined and longitudinally followed cohort (N = 179), anti-platelet glycoprotein-specific IgM and IgG antibodies were determined by monoclonal antibody-immobilization of platelet antigens.

Results: The dominant circulating anti-platelet antibody class in childhood ITP was IgM (62% of patients); but IgG antibodies were also found (10%). Children without IgM platelet antibodies were older and more often female. There was weak evidence for an association between IgM anti-GP IIb/IIIa antibodies and an increased bleeding severity (P = .03). The IgM and IgG anti-platelet responses partially overlapped, and reactivity was frequently directed against multiple glycoproteins. During 1-year follow-up, children with IgM antibodies in the observation group displayed a faster platelet recovery compared to children without, also after adjustment for age and preceding infections (P = 7.1 × 10 ). The small group of patients with detectable IgG anti-platelet antibodies exhibited an almost complete response to IVIg treatment (N = 12; P = .02), suggesting that IVIg was particularly efficacious in these children.

Conclusions: Testing for circulating anti-platelet antibodies may be helpful for the clinical prognostication and the guidance of treatment decisions in newly diagnosed childhood ITP. Our data suggest that the development of even more sensitive tests may further improve the clinical value of antibody testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318215PMC
May 2020

Fused high b-value diffusion weighted and T2-weighted MR images in staging of pediatric Hodgkin's lymphoma: A pilot study.

Eur J Radiol 2019 Dec 6;121:108737. Epub 2019 Nov 6.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, Utrecht University, the Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Purpose: To evaluate the value of fused high b-value diffusion weighted and T2-weighted MRI compared to T1-weighted imaging, T2-weighted imaging and DWI for staging pediatric Hodgkin's lymphoma.

Method: 21 consecutive pediatric patients who underwent whole-body MRI at Hodgkin's lymphoma staging were included. Fused, colorized DWI/T2-weighted images were created. Image sets consisting of (a) T1-weighted, T2-weighted and DWI images and (b) T1-weighted, T2-weighted, DWI and DWI/T2-weighted fused images were reviewed by a radiologist using a cross-over design with blinding and randomization. Scoring was performed using a standardized form, based on detection, characterization and reading time, using a FDG-PET/CT based reference standard. Test characteristics, test agreement to a FDG-PET/CT based reference standard and reading times were calculated.

Results: Agreement for whole-body MRI without fused images and FDG-PET/CT was very good for nodal staging (κ = 0.86, 95% CI 0.78-0.93) and extra-nodal staging (κ = 0.90, 95% CI 0.71-1.09). Agreement improved with the addition of the fused DWI/T2-weighted images (κ = 0.92 95% CI 0.87-0.97 (nodal staging), κ = 0.92 95% CI 0.76-1.08 (extra-nodal staging). Sensitivity and specificity for staging nodal disease were 99 % and 95% respectively for whole-body MRI including DWI/T2-weighted fused images (versus 88 % and 97 % without fused images) and 100 % and 99 % for extra-nodal disease (83 % and 100 % without fused images). Disease stage for MRI including fused DWI/T2-weighted images agreed with the reference standard in 18 out of 21 patients.

Conclusions: The addition of DWI/T2-weighted fusion images to T1-weighted, T2-weighted and DWI whole-body MRI might shorten reading times and might improve the diagnostic performance of whole-body MRI in staging pediatric Hodgkin's lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejrad.2019.108737DOI Listing
December 2019

Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms.

Blood Adv 2019 07;3(13):2003-2012

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

In childhood immune thrombocytopenia (ITP), anti-platelet autoantibodies mediate platelet clearance through Fc-γ receptor (FcγR)-bearing phagocytes. In 75% to 90% of patients, the disease has a transient, self-limiting character. Here we characterized how polymorphisms of FcγR genes affect disease susceptibility, response to intravenous immunoglobulin (IVIg) treatment, and long-term recovery from childhood ITP. Genotyping of the locus was performed in 180 children with newly diagnosed ITP, 22 children with chronic ITP, and 180 healthy control children by multiplex ligation-dependent probe amplification. Children with newly diagnosed ITP were randomly assigned to a single administration of IVIg or observation, and followed for 1 year (Treatment With or Without IVIg for Kids With ITP [TIKI] trial). We defined transient ITP as a complete recovery (≥100 × 10/L) 3 months after diagnosis, including both self-limiting disease/IVIg responders and chronic ITP as absence of a complete recovery at 12 months. ITP susceptibility, as well as spontaneous recovery and response to IVIg, was associated with the genetic variants *ORF and *27W and the promoter variant 2B.4. These variants were overrepresented in patients with transient (N = 131), but not chronic (N = 43), disease. The presence of *ORF predisposed to transient ITP with an odds ratio of 4.7 (95% confidence interval, 1.9-14.3). Chronic ITP was associated with a deletion of (copy number region 1) with an odds ratio of 6.2 (95% confidence interval, 1.8-24.7). Taken together, susceptibility to transient and chronic ITP is distinctly affected by polymorphic variants of genes. Our data suggest that genotyping of the locus may be useful for prognosis and guidance of treatment decisions in newly diagnosed childhood ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616256PMC
July 2019

Fatal Carbapenem Resistance Development in Pseudomonas Aeruginosa Under Meropenem Monotherapy, Caused by Mutations in the OprD Outer Membrane Porin.

Pediatr Infect Dis J 2019 04;38(4):398-399

Department of Pediatrics, Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

A 13-year old neutropenic boy succumbed to bacteremia and sepsis with a Pseudomonas aeruginosa strain that rapidly developed resistance to carbapenems during meropenem monotherapy. Whole genome sequencing of the susceptible and resistant blood culture isolates revealed the meropenem-resistant phenotype to be caused by truncation of the OprD gene, which added to a preexisting inactivated mexR gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/INF.0000000000002244DOI Listing
April 2019

Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial.

Blood 2018 08 26;132(9):883-891. Epub 2018 Jun 26.

Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 10/L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 10/L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 10/L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-02-830844DOI Listing
August 2018

Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma.

Br J Haematol 2017 02 28;176(4):637-642. Epub 2016 Nov 28.

Department of Radiology, University Medical Centre Utrecht-Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands.

Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14452DOI Listing
February 2017

Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

Haematologica 2015 Dec 24;100(12):1564-70. Epub 2015 Sep 24.

Dutch Childhood Oncology Group, The Hague, The Netherlands Princess Maxima Center, Utrecht, The Netherlands

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2015.125583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666332PMC
December 2015

Whole-body MRI-DWI for assessment of residual disease after completion of therapy in lymphoma: A prospective multicenter study.

J Magn Reson Imaging 2015 Dec 8;42(6):1646-55. Epub 2015 May 8.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: To assess the performance of whole-body MRI including diffusion-weighted imaging (whole-body MRI-DWI) for the detection of residual disease after completion of treatment in lymphoma patients.

Methods: Twenty-six patients with lymphoma prospectively underwent whole-body MRI-DWI (1.5 Tesla MR) and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for posttreatment evaluation which were visually assessed. Apparent diffusion coefficient (ADC) and FDG-PET/CT standardized uptake value measurements were performed in all residual lesions. An unblinded expert panel reviewed all cases and determined the presence or absence of posttreatment residual disease using all available imaging (except for whole-body MRI-DWI), clinical, and histopathological information with a follow-up of at least 6 months. The performance of whole-body MRI-DWI was compared with this panel reference standard.

Results: Five of 26 patients were diagnosed with residual disease. Sensitivity and specificity for detection of residual disease with whole-body MRI-DWI were 100% and 62%, respectively. By ROC analysis, the optimal threshold of ADC was 1.21 × 10(-3) mm(2) /s with sensitivity and specificity of 100% and 91.7%, respectively.

Conclusion: Our initial results suggest that visual whole-body MRI-DWI analysis has a very good sensitivity for detecting viable residual lesions after completion of therapy but lacks specificity. ADC measurements could potentially increase the specificity of whole-body MRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.24938DOI Listing
December 2015

C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia.

Blood 2015 Mar 29;125(11):1793-802. Epub 2014 Dec 29.

Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;

Immune-mediated platelet destruction is most frequently caused by allo- or autoantibodies via Fcγ receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a ligand for Fc receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro and in vivo in mice. Without antiplatelet antibodies, CRP was found to be inert toward platelets, but it bound to phosphorylcholine exposed after oxidation triggered by antiplatelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo- and autoantibody-mediated thrombocytopenias compared with healthy controls. Within a week, intravenous immunoglobulin treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers, and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest that CRP amplifies antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia on infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2014-05-579110DOI Listing
March 2015

Clinical and laboratory predictors of chronic immune thrombocytopenia in children: a systematic review and meta-analysis.

Blood 2014 Nov 10;124(22):3295-307. Epub 2014 Oct 10.

Department of Pediatric Hematology and Oncology, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands;

Childhood immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder. Most children recover within 6 to 12 months, but individual course is difficult to predict. We performed a systematic review and meta-analysis to identify predictors of chronic ITP. We found 1399 articles; after critical appraisal, 54 studies were included. The following predictors of chronic ITP in children, assessed in at least 3 studies, have been identified: female gender (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.04-1.31), older age at presentation (age ≥11 years; OR 2.47, 95% CI 1.94-3.15), no preceding infection or vaccination (OR 3.08, 95 CI 2.19-4.32), insidious onset (OR 11.27, 95% CI 6.27-20.27), higher platelet counts at presentation (≥20 × 10(9)/L: OR 2.15, 95% CI 1.63-2.83), presence of antinuclear antibodies (OR 2.87, 95% 1.57-5.24), and treatment with a combination of methylprednisolone and intravenous immunoglobulin (OR 2.67, 95% CI 1.44-4.96). Children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone developed chronic ITP less often (OR 0.39, 95% CI 0.28-0.54 and OR 0.71, 95% CI 0.52-0.97, respectively). The protective effect of intravenous immunoglobulin is remarkable and needs confirmation in prospective randomized trials as well as future laboratory studies to elucidate the mechanism of this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2014-04-570127DOI Listing
November 2014

The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.

Haematologica 2015 Jan 10;100(1):62-9. Epub 2014 Oct 10.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam Dutch Childhood Oncology Group, The Hague

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age- and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2014.110668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281314PMC
January 2015

Health-related quality of life in children with newly diagnosed immune thrombocytopenia.

Haematologica 2014 Sep 20;99(9):1525-31. Epub 2014 Jun 20.

Department of Pediatric Hematology and Oncology, University Medical Center/Wilhelmina's Children Hospital, Utrecht, the Netherlands.

Despite its generally transient and benign course, childhood immune thrombocytopenia has a large impact on health-related quality of life. Recently published guidelines state that quality of life should be taken into account while making decisions on management in childhood immune thrombocytopenia. We, therefore, assessed health-related quality of life in children with newly diagnosed immune thrombocytopenia in a prospective multicenter study. One hundred and seven children aged 6 months-16 years (mean age 5.57 years) were included. We used Pediatric Quality of Life Inventory™ and Kids' ITP Tools questionnaires at diagnosis and during standardized follow-up. Scores on the Pediatric Quality of Life Inventory™ Core Scales were compared with those of healthy children. Relationships between health-related quality of life scores and treatment modality, bleeding tendency and course of the disease were examined. Kids' ITP Tools proxy reports and parent self-reports showed significant higher health-related quality of life scores in children who recovered than in children with persistent immune thrombocytopenia (at 3 months: Kids' ITP Tools parent self-report score 80.85 for recovered patients (n=69) versus 58.98 for patients with persistent disease (n=21), P<0.001). No significant differences in health-related quality of life were found between children with mild or moderate bleeding or between children who received intravenous immunoglobulin or children who were carefully observed. In conclusion, health-related quality of life of children with newly diagnosed immune thrombocytopenia is not influenced by treatment modality or bleeding severity, but only by clinical course of the disease. (Dutch Trial Register identifier: NTR TC1563).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2014.106963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562543PMC
September 2014

Functional platelet defects in children with severe chronic ITP as tested with 2 novel assays applicable for low platelet counts.

Blood 2014 Mar 2;123(10):1556-63. Epub 2014 Jan 2.

Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;

Immune thrombocytopenia (ITP) is an autoimmune disease with a complex heterogeneous pathogenesis and a bleeding phenotype that is not necessarily correlated to platelet count. In this study, the platelet function was assessed in a well-defined cohort of 33 pediatric chronic ITP patients. Because regular platelet function test cannot be performed in patients with low platelet counts, 2 new assays were developed to determine platelet function: first, the microaggregation test, measuring in platelets isolated from 10 mL of whole blood the platelet potential to form microaggregates in response to an agonist; second, the platelet reactivity assay, measuring platelet reactivity to adenosine diphosphate (ADP), convulxin (CVX), and thrombin receptor activator peptide in only 150 μL of unprocessed whole blood. Patients with a severe bleeding phenotype demonstrated a decreased aggregation potential upon phorbol myristate acetate stimulation, decreased platelet degranulation following ADP stimulation, and a higher concentration of ADP and CVX needed to activate the glycoprotein IIbIIIa complex compared with patients with a mild bleeding phenotype. In conclusion, here we have established 2 functional tests that allow for evaluation of platelet function in patients with extremely low platelet counts (<10(9)). These tests show that platelet function is related to bleeding phenotype in chronic ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-08-519686DOI Listing
March 2014

Whole-body MRI, including diffusion-weighted imaging, for staging lymphoma: comparison with CT in a prospective multicenter study.

J Magn Reson Imaging 2014 Jul 31;40(1):26-36. Epub 2013 Oct 31.

Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: To compare whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), to computed tomography (CT) for staging newly diagnosed lymphoma.

Materials And Methods: In all, 108 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI (T1-weighted and T2-weighted short inversion time inversion recovery [n = 108], and DWI [n = 104]) and CT. Ann Arbor stages were assigned according to whole-body MRI and CT findings. Staging disagreements were resolved using bone marrow biopsy, FDG-PET, and follow-up studies. The results were descriptively analyzed.

Results: Staging results of whole-body MRI without DWI were equal to those of CT in 66.6%, higher in 24.1%, and lower in 9.3%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 15/7/4 and 9/1 patient(s), respectively. Staging results of whole-body MRI with DWI were equal to those of CT in 65.4%, higher in 27.9%, and lower in 6.7%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 18/6/5 and 6/1 patient(s), respectively.

Conclusion: The results of this study suggest that whole-body MRI staging equals CT staging in the majority of patients with newly diagnosed lymphoma. No advantage of additional DWI was demonstrated. Whole-body MRI can be a good alternative to CT if radiation exposure should be avoided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.24356DOI Listing
July 2014

Bone mineral density at diagnosis determines fracture rate in children with acute lymphoblastic leukemia treated according to the DCOG-ALL9 protocol.

Bone 2014 Feb 25;59:223-8. Epub 2013 Nov 25.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands; Dutch Childhood Oncology Group, The Hague, The Netherlands. Electronic address:

Purpose: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL).

Methods: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS≤-2 SDS combined with clinical significant fractures.

Results: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS=-1.10 SDS, P<0.001), and remained lower during/after treatment (8months: BMDLS=-1.10 SDS, P<0.001; 24months: BMDLS=-1.27 SDS, P<0.001; 36months: BMDLS=-0.95 SDS, P<0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: β=-0.52, P<0.01; age: β=-0.16, P<0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS=-0.36 SDS and ΔBMDLS=-0.12 SDS; interaction group time, P=0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis.

Conclusion: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2013.11.017DOI Listing
February 2014

Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia.

J Clin Oncol 2011 Nov 26;29(31):4143-50. Epub 2011 Sep 26.

Erasmus MC-Sophia Children's Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.

Purpose: We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL).

Patients And Methods: Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis.

Results: Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions.

Conclusion: Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2011.37.3217DOI Listing
November 2011

Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004).

Lancet Oncol 2009 Oct 9;10(10):957-66. Epub 2009 Sep 9.

Dutch Childhood Oncology Group, the Hague, Netherlands.

Background: A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting.

Methods: From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50,000 cells per microL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9.

Findings: 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1.16 vs >or=1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >or=10 years; 2.23, 1.60-3.11) and white-blood-cell count (<50,000 vs >or=50,000 cells per microL; 1.60, 1.13-2.26).

Interpretation: The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects.

Funding: Dutch Health Insurers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(09)70228-1DOI Listing
October 2009

p38 MAP kinase inhibits neutrophil development through phosphorylation of C/EBPalpha on serine 21.

Stem Cells 2009 Sep;27(9):2271-82

Molecular Immunology Lab, Department of Immunology, University Medical Center, Utrecht, The Netherlands.

Many extracellular stimuli regulate growth, survival, and differentiation responses through activation of the dual specificity mitogen activated protein kinase (MAPK) kinase three (MKK3) and its downstream effector p38 MAPK. Using CD34+ hematopoietic progenitor cells, here we describe a novel role for MKK3-p38MAPK in the regulation of myelopoiesis. Inhibition of p38MAPK utilizing the pharmacological inhibitor SB203580, enhanced neutrophil development ex vivo, but conversely reduced eosinophil differentiation. In contrast, constitutive activation of MKK3 dramatically inhibited neutrophil differentiation. Transplantation of beta2-microglobulin(-/-) nonobese diabetic/severe combined immune deficient (NOD/SCID) mice with CD34+ cells ectopically expressing constitutively active MKK3 resulted in reduced neutrophil differentiation in vivo, whereas eosinophil development was enhanced. Inhibitory phosphorylation of CCAAT/enhancer binding protein alpha (C/EBPalpha) on serine 21 was induced upon activation of p38MAPK. Moreover, ectopic expression of a non-phosphorylatable C/EBPalpha mutant was sufficient to abrogate MKK3-induced inhibition of neutrophil development. Furthermore, treatment of CD34+ progenitors from patients with severe congenital neutropenia with SB203580 restored neutrophil development. These results establish a novel role for MKK3-p38MAPK in the regulation of lineage choices during myelopoiesis through modulation of C/EBPalpha activity. This signaling module may thus provide an important therapeutic target in the treatment of bone marrow failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.152DOI Listing
September 2009

Granulocyte concentrates: prolonged functional capacity during storage in the presence of phenotypic changes.

Haematologica 2008 Jul 27;93(7):1058-67. Epub 2008 May 27.

Sanquin, Research Institute, Academic Medical Centre, University of Amsterdam, Plesmanlaan, 125, 1066 CX Amsterdam, The Netherlands.

Background: Granulocyte transfusion has been proposed as a bridging therapy for patients with prolonged periods of chemotherapy-induced neutropenia, who suffer from severe fungal and bacterial infections. To recover, adequate numbers of granulocytes are required when the patients are refractory to standard treatment. The aim of this study was to assess the functional characteristics and efficacy of granulocyte colony-stimulating factor/dexamethasone-mobilized granulocytes used for transfusions.

Design And Methods: Granulocytes from the leukapheresis products were tested for the expression of cell-surface antigens, interactions with endothelial cells, motility, killing of microbes and survival. The granulocytes were used in vivo for transfusion in 16 severely ill children, who were--apart from a patient with a granulocyte dysfunction--all suffering from prolonged neutropenia.

Results: Mobilization of granulocytes with granulocyte colony-stimulating factor and dexamethasone caused phenotypic changes (decreased CD62L expression and increased levels of CD66b and CD177). The ability of the granulocytes to interact with endothelial cells (rolling, adhesion, transmigration) and to kill various types of pathogens was not affected by the mobilization, leukapheresis and irradiation procedures. The granulocytes were functionally indistinguishable from those isolated from untreated donors, even after 24 hours of storage. Granulocyte transfusion seemed to benefit 70% of patients, as 11 out of the 16 children showed clinical recovery within 1-2 weeks after beginning the transfusions.

Conclusions: Although CD62L expression is downregulated on granulocytes used for granulocyte transfusions, concomitant CD177 upregulation may explain the intact interactions with endothelial cells. All other granulocyte functions tested were intact, including the ability to kill fungi. Granulocyte concentrates can be stored without loss of in vitro viability and functionality for at least 24 hours. As demonstrated in vivo, granulocyte transfusions may be an effective therapy for neutropenic pediatric patients suffering from life-threatening infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.12489DOI Listing
July 2008

Rituximab treatment for symptomatic chronic ITP.

Pediatr Blood Cancer 2006 Oct;47(5 Suppl):714-6

Beatrix Children's Hospital, University Medical Center Groningen, The Netherlands.

About 20% of the children diagnosed with acute idiopathic thrombocytopenic purpura (ITP) will run a chronic course. Only in a minority of these, platelet-count-enhancing treatments are indicated. Most treatment options are directed at decreasing platelet destruction including corticosteroids, intravenous immunoglobulins, splenectomy, and other immunosuppressive or immune modulating drugs. In children, rituximab seems to have similar efficacy as in adults with a lasting continuous remission rate of 30-35%. Toxicity includes fever, pruritus, throat tightness, and serum sickness that may be reason to discontinue rituximab treatment. No increased frequency of infections is noted. We conclude that rituximab should be given to those symptomatic ITP patients who would otherwise be referred for splenectomy; only those who fail rituximab treatment should proceed to surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.20967DOI Listing
October 2006