Publications by authors named "Johanna Schrum"

15 Publications

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Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

Mol Genet Metab Rep 2021 Mar 14;26:100704. Epub 2021 Jan 14.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce.

Methods: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor.

Results: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia.

Conclusions: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815485PMC
March 2021

Irradiation-free re-conditioning in children following graft failure of a T cell-depleted graft from a haploidentical parent.

Bone Marrow Transplant 2021 Jan 8. Epub 2021 Jan 8.

Division for Pediatric Stem Cell Transplantation and Immunology, Clinic for Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1038/s41409-020-01196-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792555PMC
January 2021

Hematopoietic stem cell transplantation for children with acute myeloid leukemia-results of the AML SCT-BFM 2007 trial.

Leukemia 2020 02 2;34(2):613-624. Epub 2019 Oct 2.

Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Düsseldorf, Düsseldorf, Germany.

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).
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http://dx.doi.org/10.1038/s41375-019-0584-8DOI Listing
February 2020

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia-A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP.

Am J Hematol 2019 08 29;94(8):880-890. Epub 2019 May 29.

St. Anna Kinderspital and Children's Cancer Research Institute (CCRI), Department of Paediatrics, Medical University of Vienna, Vienna, Austria.

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.
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http://dx.doi.org/10.1002/ajh.25511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772138PMC
August 2019

Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial.

Br J Haematol 2018 10 20;183(1):104-109. Epub 2018 Jul 20.

Department of Paediatrics, Medical University of Vienna, Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna, Austria.

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.
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http://dx.doi.org/10.1111/bjh.15511DOI Listing
October 2018

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients.

JAMA Neurol 2016 09;73(9):1133-40

Department of Pediatric Hematology and Oncology, University Children's Hospital of Tübingen, Tübingen, Germany6Department of Pediatric Hematology and Oncology, University Children's Hospital Hamburg-Eppendorf, Hamburg, Germany.

Importance: Allogeneic hematopoietic stem cell transplantation (HSCT) has been the only treatment option clinically available during the last 20 years for juvenile metachromatic leukodystrophy (MLD), reported with variable outcome and without comparison with the natural course of the disease.

Objective: To compare the long-term outcome of patients who underwent allogeneic HSCT with control patients who did not among a cohort with juvenile MLD.

Design, Setting, And Participants: Patients with juvenile MLD born between 1975 and 2009 and who received HSCT at a median age of 7 years (age range, 1.5-18.2 years) and nontransplanted patients with juvenile MLD born between 1967 and 2007 were included in this case-control study. The median follow-up after HSCT was 7.5 years (range, 3.0-19.7 years). Patients underwent HSCT at 3 German centers between 1991 and 2012. The analysis was done between July 2014 and August 2015.

Main Outcomes And Measures: Survival and transplantation-related mortality, loss of gross motor function (Gross Motor Function Classification in MLD), loss of any language function, and magnetic resonance imaging (MRI) severity score for cerebral changes. To explore prognostic factors at baseline, patients who underwent HSCT (hereafter, transplanted patients) were a priori divided into stable vs progressive disease, according to gross motor and cognitive function.

Results: Participants were 24 transplanted patients (11 boys, 13 girls) and 41 control patients (22 boys, 19 girls) who did not receive transplantation (hereafter, nontransplanted patients) with juvenile MLD. Among the transplanted patients, 4 children died of transplantation-related mortality, and 2 additional children died of rapid MLD progression 1.5 and 8.6 years after HSCT, resulting in a 5-year survival of 79% (19 of 24). Among the nontransplanted patients, 5-year survival after disease onset was 100% (41 of 41). However, 11 died of MLD progression, resulting in similar overall survival within the observation period. Nine of the long-term survivors after HSCT had disease progression, while 11 showed stable disease. Compared with the nontransplanted patients, the transplanted patients were less likely to lose their gross motor or language function and demonstrated significantly lower MRI severity scores at the latest examination. Patients after HSCT were more likely to have a stable disease course when undergoing HSCT at an early stage with no or only mild gross motor deficits (Gross Motor Function Classification in MLD level 0 or 1) and an IQ of at least 85, when age at disease onset was older than 4 years, or when MRI severity scores were low (preferably ≤17).

Conclusions And Relevance: Among patients with juvenile MLD, patients who underwent HSCT had a better gross motor and language outcome and lower MRI severity scores compared with nontransplanted patients. Transplantation at a presymptomatic or early symptomatic stage of juvenile MLD is associated with a reasonable chance for disease stabilization.
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http://dx.doi.org/10.1001/jamaneurol.2016.2067DOI Listing
September 2016

Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia.

Haematologica 2016 06 11;101(6):741-6. Epub 2016 Feb 11.

Children's Cancer Research Institute, Vienna, Austria Department of Pediatrics, Medical University Vienna, Austria

Unlabelled: Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.

Trials: gov with the number NC01423747.
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http://dx.doi.org/10.3324/haematol.2015.135137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013947PMC
June 2016

A Case of a Bilateral Cicatricial Upper Eyelid Entropion After Hematopoietic Stem Cell Transplantation in Mucopolysaccharidosis Type I.

Ophthalmic Plast Reconstr Surg 2017 May/Jun;33(3S Suppl 1):S75-S77

*Department of Ophthalmology, and †University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Minor eyelid abnormalities are commonly encountered in mucopolysaccharidosis, but only rarely leading to a clinically relevant situation. The authors report a clinical case of severe bilateral cicatricial entropion of the upper eyelids, leading to recurrent conjunctival infections, corneal erosion, persistent epiphora, and a major decline in life quality in a 7-year-old boy with mucopolysaccharidosis type I who underwent hematopoietic stem cell transplantation at 1.6 years old. A bilateral anterior lamellar repositioning including eyelid split and cryoepilation was performed to correct bilateral upper eyelid entropium and trichiasis. Three months after the surgical intervention, the patient showed a persistent regular eyelid position with only mild recurrent right-sided lateral upper eyelid entropion. A significant reduction in conjunctival infections and epiphora with complete discontinuation of topical therapy was achieved. Although mucopolysaccaridosis is associated with eyelid abnormalities, the authors conclude that the described case is most likely due to chronic graft versus host disease.
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http://dx.doi.org/10.1097/IOP.0000000000000592DOI Listing
June 2017

Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial.

J Clin Oncol 2015 Apr 9;33(11):1265-74. Epub 2015 Mar 9.

Christina Peters, Susanne Matthes-Martin, and Ulrike Poetschger, St Anna Children's Hospital, Vienna, Austria; Martin Schrappe, University Medical Center Schleswig-Holstein and Christian-Albrechts-University Kiel; André Schrauder, Kinderarztpraxis am Aalborgring, Kiel; Arend von Stackelberg and Wolfram Ebell, Charité-Children's Hospital Berlin, Berlin; Peter Bader and Thomas Klingebiel, Johann Wolfgang Goethe University, Frankfurt; Peter Lang, University Hospital Tübingen, Tübingen; Karl-Walter Sykora and Martin Zimmerman, Hannover Medical School, Hannover; Johanna Schrum, University Medical Center Hamburg-Eppendorf, Hamburg; Bernhard Kremens, University Hospital Essen, Essen; Karoline Ehlert, University Clinic Greifswald, Greifswald; Michael H. Albert, Dr. von Hauner University Children's Hospital, München; Roland Meisel, University Hospital Düsseldorf, Düsseldorf; Wolfgang Holter, Children's University Hospital Erlangen, Erlangen; Brigitte Strahm, University Hospital Freiburg, Freiburg; Bernd Gruhn, University Hospital Jena, Jena; Ansgar Schulz, University Hospital Ulm, Ulm; Wilhelm Woessmann, University Clinic Giessen, Giessen, Germany; and Tayfun Gungor, University Children's Hospital Zürich, Zürich, Switzerland.

Purpose: Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia).

Patients And Methods: After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci.

Results: Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications.

Conclusion: Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.
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http://dx.doi.org/10.1200/JCO.2014.58.9747DOI Listing
April 2015

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.

Lancet 2012 Apr 23;379(9823):1301-9. Epub 2012 Feb 23.

University of Regensburg, Regensburg, Germany.

Background: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.

Methods: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948.

Findings: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.

Interpretation: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.

Funding: Gentium SpA, European Group for Blood and Marrow Transplantation.
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http://dx.doi.org/10.1016/S0140-6736(11)61938-7DOI Listing
April 2012

Severe phototoxicity associated with long-term voriconazole treatment.

J Dtsch Dermatol Ges 2011 Apr 3;9(4):274-6. Epub 2010 Nov 3.

Department of Pediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Hamburg, Germany.

Voriconazole is a second-generation triazole antifungal approved for the treatment of invasive fungal infections, particularly with Aspergillus, Candida, Fusarium, and Scedosporium spp. Frequently reported adverse effects of voriconazole include visual disturbance (21 %), elevated liver enzymes (15.6 %) and rashes (7 %), which are largely attributable to drug-induced photosensitivity. We report a case of serious phototoxicity in a 8 year old boy who underwent chemotherapy for AML. He received voriconazole for the treatment and subsequent re-infection prophylaxis after pulmonary aspergillosis. One year after the start of therapy he developed blistering eruptions on his face after minimal sunlight exposure. Recent reports about the development of squamous cell carcinoma and melanoma, respectively, in children during and after oral therapy with voriconazole seem to warrant systematic follow-up investigations of all voriconazole-treated patients.
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http://dx.doi.org/10.1111/j.1610-0387.2010.07563.xDOI Listing
April 2011

Ongoing remission after intensive ALL-type chemotherapy in pediatric intestinal T-cell lymphoma.

Pediatr Blood Cancer 2010 Apr;54(4):610-2

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

A rare case of primary intestinal T-cell lymphoma (ITL) of an 8-year-old boy is reported. Medium- to large-sized tumor cells were betaF1+, CD3+, CD8+. TIA-1+, but CD4-, CD5-, CD30-, CD56-, CD20-, CD79a-, TdT-, consistent with an intraepithelial lymphocyte (IEL) origin. They showed monoclonal rearrangement of the T-cell receptor gamma-chain and no evidence of EBV infection. No clinical, histologic, laboratory, or genetic evidence of celiac disease was detected. In adults, ITL is often associated with enteropathy and has a very poor outcome. Our patient remains in first remission 30 months after finishing the acute lymphoblastic leukemia protocol COALL-07-03 high risk standard.
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http://dx.doi.org/10.1002/pbc.22330DOI Listing
April 2010

HLA-mismatched unrelated donors as an alternative graft source for allogeneic stem cell transplantation after antithymocyte globulin-containing conditioning regimen.

Biol Blood Marrow Transplant 2009 Apr;15(4):454-62

Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Between August 1996 and December 2004, 369 patients with a median age of 41 years (range: 1-68 years) received stem cell transplantation (SCT) from unrelated donors after an antithymocyte-globulin (ATG)-containing conditioning regimen. In 268 patients, complete molecular typing (4-digit) of HLA-A, -B, -C, -DRB1, and -DQB1 was available: 110 patients were completely matched for 10 alleles, 91 patients had 1 allele-mismatch (9/10), and 67 patients were mismatched for 2-4 alleles (6-8/10). The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 33% in the 10/10, 41% in the 9/10, and 40% in the 6-8/10 group, respectively (P = .1). The cumulative incidence of treatment-related mortality (TRM) and relapse among the groups were similar (27%, 31%, and 32%, P = .2; and 28%, 27%, and 26%, P = .9. After a median follow-up of 35 months (range: 3-120 months), the estimated 5-year disease-free survival (DFS) was 42% and did not differ among the 10/10, the 9/10, and the 6-8/10-mismatched groups (45% versus 42% versus 39%) (P = .5). In multivariate analysis, only age (hazard ratio [HR] 1.013) (P = .004) and bad-risk disease (HR 1.975) (P < .001) were independent risk factors for DFS. In conclusion, pretransplant ATG allows allogeneic SCT from unrelated donors with HLA disparities.
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http://dx.doi.org/10.1016/j.bbmt.2009.01.002DOI Listing
April 2009

Non-surgical management of advanced cardiac lymphoma.

J Pediatr 2008 Mar;152(3):440

Department of Pediatric Cardiology, University Hospital, Hamburg, Germany.

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http://dx.doi.org/10.1016/j.jpeds.2007.10.051DOI Listing
March 2008