Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

Purpose: The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation.

Methods: All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1.

Toll-like 4 receptor variant, Asp299Gly, and reduced risk of hemorrhagic cystitis after hematopoietic stem cell transplantation.

Hemorrhagic cystitis (HC) is a major cause of morbidity after hematopoietic stem cell transplantation. Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system and induces inflammation. Individuals with the single nucleotide polymorphisms Thr399Ile (rs4986791) or Asp299Gly (rs4986790) of TLR4 show diminished inflammatory responsiveness to endotoxins.

Polymorphism of interleukin-23 receptor gene but not of NOD2/CARD15 is associated with graft-versus-host disease after hematopoietic stem cell transplantation in children.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The selection of a suitable donor is the most critical issue in preventing severe GVHD. Recent data suggest that the risk of GVHD does not only depend on human leukocyte antigens (HLA) but also on polymorphisms of genes that influence immune responses.

Cardiac and pulmonary late effects do not negatively influence performance status and non-relapse mortality of children surviving five yr after autologous hematopoietic cell transplantation: report from the EBMT Paediatric Diseases and Late Effects Working Parties.

The current prospective study dealt with clinical outcome associated with pulmonary and cardiac late effects of AuHCT in children with malignancies. We prospectively evaluated 58 children, utilizing pulmonary function tests and cardiac shortening fraction, performed in pre-AuHCT phase and then annually. The overall five-yr survival was 68%.

Cross-sectional study on bone density-related sonographic parameters in children with asthma: correlation to therapy with inhaled corticosteroids and disease severity.

The aim of this study was to screen asthmatic children for bone density-related sonographic parameters on the calcaneal bone. Findings were correlated to therapy with inhaled corticosteroids (ICS) as well as with asthma severity (AS), concomitance and severity of atopic dermatitis (AD), and rhinitis (AR). We enrolled 173 children with AS1-3 consecutively; 44% (AS1) had not received any ICS medication; 56% (AS2 and -3) received ICS therapy for > or =6 months (medium daily dose, 286 microg fluticasone-proprionate-equivalent/maximum 500 microg); and in addition 38% (n = 65) presented with AD and 66% (n = 115) with AR.

Prediction of broad spectrum resistance of tumors towards anticancer drugs.

Purpose: Drug resistance is a major obstacle in cancer chemotherapy. Although the statistical probability of therapeutic success is known for larger patient groups from clinical therapy trials, it is difficult to predict the individual response of tumors. The concept of individualized therapy aims to determine in vitro the drug response of tumors beforehand to choose effective treatment options for each individual patient.

Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95.

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.

Monitoring of Epstein-Barr virus load after hematopoietic stem cell transplantation for early intervention in post-transplant lymphoproliferative disease.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease is a life-threatening complication following hematopoietic stem cell transplantation. A quantitative polymerase chain reaction to evaluate EBV-genome copy numbers based on a nested polymerase chain reaction and an end-point dilution was used. Applying this assay EBV load was prospectively screened weekly in 123 patients after transplantation.

Effect of dexamethasone on the IGFBP-1 regulation in premature infants during the first weeks of life.

Background: Early glucosteroid treatment in preterm infants has a negative impact on physical growth and development. So far, data on dexamethasone effect on the GH/IGF axis and the clinical outcome are conflicting.

Objective: Therefore, we studied the effect of dexamethasone treatment on parameters of somatic growth and on the secretion of insulin like growth factors (IGFs) and insulin like growth factors binding proteins (IGFBPs) in preterm infants.

Expression of components of the IGF axis in childhood acute myelogenous leukemia.

Background: Insulin-like growth factor (IGF) system as regulator for cellular proliferation is of particular interest in search for new prognostic approaches in cancer treatment.

Procedure: We analyzed the mRNA expression profile of IGF-I, -II, and IGFBP-2, -3 in 50 children with previously untreated AML (mean age 10.8 +/- 4.

Potential role of the cellular allergen stimulation test (CAST) in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a severe complication in cystic fibrosis (CF), which is difficult to identify because of overlapping unspecific diagnostic features with common CF-manifestations. The cellular allergen stimulation test (CAST) is used in diagnosis of allergic and pseudoallergic reactions. This assay is based on the determination of sulfidoleukotrienes, which are produced by allergen-stimulated basophils in vitro.

Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure.

Background: DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4). The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion.

Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid.

The case of a 12-year-old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was undertaken with an oncolytic virus, MTH-68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far-reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention.

Childhood acute myelogenous leukaemia: association between PRAME, apoptosis- and MDR-related gene expression.

The gene PRAME (preferentially expressed antigen of melanoma) encodes an antigen recognised by autologous cytolytic T lymphocytes. The mRNA level of PRAME is used as a tumour marker due to its overexpression in various malignancies. Furthermore, it is known that the overexpression of genes encoding antiapoptotic proteins leads to the survival of leukaemic cells via exclusion of apoptosis.

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia.

A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL.

ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia.

Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases.

Identification of a set of seven genes for the monitoring of minimal residual disease in pediatric acute myeloid leukemia.

Background: Monitoring of minimal residual disease (MRD) has become a strong diagnostic tool in acute lymphoblastic leukemia. It is used for risk-adapted therapy and for the recognition of pending relapses. In acute myeloid leukemia (AML), there is still a need for more suitable MRD markers.

von Willebrand factor-cleaving protease (ADAMTS13) in the course of stem cell transplantation.

Transplantation-associated microangiopathy (TAM) is a severe complication of stem cell transplantation. Although TAM shares many features with idiopathic thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, the prognosis of TAM is worse. Clinical similarities and the observation that uncleaved ultralarge von Willebrand factor (ULVWF) multimers are found in the circulation of patients suffering from TAM suggest a defect in VWF proteolysis that may be due to a deficiency in ADAMTS13 activity.

Polyunsaturated but not conjugated linoleic acid supplementation of leukemic U937 cells can act as an amplification factor for photofrin-mediated photodynamic therapy.

Polyunsaturated fatty acids located in leukemia cell membranes are excellent targets for peroxidation. They can significantly enhance the effectiveness of Photofrin-mediated photodynamic therapy (PDT)-induced cell killing. In this study, the peroxidizability of conjugated fatty acid isomers (9c,11t-linoleic acid and 9c,11c-linoleic acid) and polyunsaturated fatty acids (PUFAs; linoleic acid, gamma-linolenic acid and arachidonic acid) with 2,2'-azo-bis(2-amidinpropane)dihydrochloride, soybean lipoxygenase and photomediated peroxidation are compared with each other.

Are MTT assays the right tool to analyze drug resistance caused by ABC-transporters in patient samples?

Drug resistance can be caused by ATP-binding-cassette (ABC)-transporters which function as outward pumps for chemotherapeutic drugs. The aim of the present study was to analyze the association between eight ABC-transporters (BCRP, MDR1, SMRP, MRP1, MRP2, MRP3, MRP4, and MRP5) and in vitro drug resistance. Leukemic cells from 52 children with previously untreated acute leukemia (ALL: n=37; AML: n=15) were analysed.

Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia.

Chimaerism analysis was performed by polymerase chain reaction amplification of short-tandem repeat markers in 30 children following haematopoietic stem cell transplantation for juvenile myelomonocytic leukaemia (JMML). Fourteen patients always had complete chimaerism (CC); one of them relapsed after the discontinuation of the study and 13 continued in complete remission (CR). Mixed chimaerism (MC) was noted in 16 patients.

Pediatric brain MRI in neurofibromatosis type I.

Neurofibromatosis (NF) is the most common of the phakomatoses, with a prevalence of 1 in 3-4,000. Many organ systems can be affected. In addition to multiple peripheral neurofibromas, NF I predisposed to CNS tumors including optic glioma, astrocytoma and plexiform neurofibroma.

High-flow priapism in acute lymphatic leukaemia.

Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. It is associated with excessive hyperleukocytosis (e.g.

Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT).

Acute megakaryoblastic leukemia (M7 AML) is a highly aggressive disease. We evaluated outcomes in 57 children (11 with Down syndrome) and 69 adults with M7 AML after first complete remission (CR1) following autologous or HLA-identical allogeneic transplantation. Characteristics of the recipients of autologous transplants (38 children, 37 adults) were, respectively: median age, 1.