TGFß and IL10 have an impact on risk group and prognosis in childhood ALL.

BACKGROUND: Cytokines and their genes have been described to have an influence on incidence and prognosis in malignant, infectious and autoimmune disease. We previously described the impact of cytokine production on prognosis in paediatric standard-risk acute lymphoblastic leukaemia (ALL). PROCEDURE: In this study, we investigated the influence of cytokine gene polymorphisms (TNFα, TGFß, IL10 and IFNγ) on frequency, risk group and prognosis in 95 paediatric ALL-patients. We further report on intracellular production of these cytokines in T-cells. RESULTS: IL10 high-producer-haplotypes were reduced in ALL-patients compared with healthy controls and resulted in a reduced relapse rate compared with low-producer haplotypes. TGFß high-producer-haplotypes were correlated with a high initial blast-count (codon 25: G/G) and were elevated in high-risk ALL-patients (codon 10: T/T). IL10 was positively and IFNγ-production was negatively correlated with initial blast-count. At diagnosis the expression of TNFα and IFNγ was reduced in patients compared with healthy controls. This was more pronounced in high-risk and in T-ALL-patients. CONCLUSION: We conclude that gene-polymorphisms of the regulatory/anti-inflammatory cytokines, TGFß and IL10, but not of the pro-inflammatory cytokines, IFNγ and TNFα, have an impact on prognosis and risk-group of ALL. However, the reduced capacity to produce pro-inflammatory cytokines at diagnosis may serve as another important, functional risk factor. These data may help in further risk stratification and adaptation of therapy-intensity in paediatric patients with ALL.

[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Therapie hereditärer Thrombozytopathien. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

Successful treatment of an infant with CDA type II by intrauterine transfusions and postnatal stem cell transplantation.

Congenital dyserythropoietic anemias are rare hematological disorders leading to ineffective erythropoiesis with chronic anemia, complicated by iron overload. Here we present a remarkable clinical course of an infant with CDA type II who first presented as a severe fetal hydrops, requiring serial intrauterine red cell transfusions. While postnatal transfusion dependency persisted, the patient was successfully transplanted with a myeloablative conditioning regimen and peripheral blood stem cells of a matched donor. We believe that allogeneic HSCT is a reasonable therapeutic approach for patients with very severe CDA, even if only a matched unrelated donor is available.

Indication for allogeneic stem cell transplantation in Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia (GT) is an autosomal recessive disorder characterized by a lack of thrombocyte aggregation due to the absence of thrombocyte glycoproteins IIb and αIIbß3. The role of haematopoietic stem cell transplantation (HSCT) in GT remains controversial. However, HSCT offers the only curative approach for patients with a severe clinical phenotype. In this review, we will discuss the limitation of current status evidence and the specific risk of GT, in particular the alloimmunization and refractoriness to thrombocyte infusions. 19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients showed alloimmunization of thrombocytes. Median follow up is 25 months.

Homozygous point mutations in platelet glycoprotein ITGA2B gene as cause of Glanzmann thrombasthenia in 2 families.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex. Physiologically, the integrin GPIIb/IIIa binds Von Willebrand factor and fibrinogen on activated platelets. GT is caused by genetic alterations in ITGA2B or ITGB3 (genes encoding GPIIb and GPIIIa).This study describes 2 siblings diagnosed with GT type I associated with homozygous point mutations in ITGA2B. All patients presented with typical bleeding disorder including moderate hematomas, petechiae, and mucocutaneous bleedings.Both siblings showed severely reduced platelet aggregation especially after stimulation with collagen and adenosine diphosphate. Absence of platelet GPIIb/GPIIIa complex was determined using flow cytometry. Molecular genetic analysis revealed 2 distinct homozygous point mutations in exon 18 of ITGA2B. Family 1 was identified with c.1878G>C and family 2 with c.1787T>C substitution. While the c.1787T>C mutation causes a single amino acid substitution p.I565T, the c.1878G>C mutation (p.Q595H) is predicted to induce a mRNA splicing anomaly.These mutations were identified as cause of GT type I in the described patients. Patients with GT should be documented in a prospective register to verify the correlation between the severity of bleeding symptoms and the pathogenic mutation. This can have effects on therapeutic decisions.

Allogeneic hematopoietic stem cell transplantation in Glanzmann thrombasthenia complicated by platelet alloimmunization.

BACKGROUND: For Thrombasthenia Glanzmann (GT) patients presenting with a severe clinical phenotype due to complete lack of thrombocyte function or increased titres of anti-platelet antibodies hematopoietic stem cell transplantation (SCT) is the only curative therapy. CASE REPORT: We report the case of a 13-month-old boy, presenting with a severe course of GT, who was successfully treated with an HLA-identical sibling bone marrow transplant. SCT was complicated by anti-platelet alloimmunization after platelet transfusion successfully treated with high dosage immunoglobulins (2 g/kg) and partial plasma exchange. CONCLUSION: SCT may be a viable option for selected patients with GT. However, SCT in GT carries its own significant risks, resulting from the development of anti-platelet antibodies. A critical risk-benefit analysis is mandatory prior to SCT.

B-cell pathology in juvenile idiopathic arthritis.

Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of different diseases. Due to the promising results of B-cell depleting therapies in rheumatoid arthritis the role of B-cells in autoimmune diseases has to be discussed in a new context. Additionally, experiments in mouse models have shed new light on the antibody-independent role of B-cells in the development of autoimmune diseases. In this review we will discuss the importance of B-cells in the pathogenesis of JIA appraising the question for an immunological basis of B-cell targeted therapy in JIA.

Crohn's disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature.

Tumor necrosis factor alpha (TNFalpha) has broad effects on the immune system including lymphoid organ development as well as growth, survival und function of immune cells. TNFalpha has two main functions: regulatory effects and proinflammatory activities. In several diseases such as juvenile and adult "rheumatoid" arthritis, psoriasis and chronic inflammatory bowel disease, the application of TNFalpha-blocking medications has been beneficial. However, induction of inflammation in several organs including the eye, CNS, skin and gastrointestinal tract has been reported. We report on an 11-year-old girl with juvenile idiopathic arthritis, who developed Crohn's disease (CD) while taking etanercept for her arthritis. Etanercept was discontinued and an antibody-based anti-TNF treatment using adalimumab was started, which induced remission of the gastrointestinal symptoms promptly. This case indicates that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in the clinical practice. Furthermore, TNFalpha as a part of its function seems to downregulate mucosal inflammation in CD.