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M Schrappe

Publications and source records attributed to M Schrappe.

At least 19 recordsLinked to original sources
PubMed2006

Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study.

We genotyped six folate metabolic pathway genes for 11 polymorphisms in 460 cases of childhood acute lymphoblastic leukemia (ALL) and 552 ethnically matched controls. None of the polymorphisms except the 66A>G (I22M) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene showed any effect on disease risk. The carriers of the G-allele were associated with a marginal decreased risk of ALL (gender-adjusted global P=0.03; multiple-testing corrected P=0.25). Analysis of four polymorphisms in the MTRR gene showed statistically significant differences in haplotype distribution between cases and controls (global P<0.0001). The haplotypes GCAC (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4-0.6) and ATAC (OR 0.5, 95% CI 0.3-0.6) were associated with a reduced risk and the haplotypes ACAC (OR 2.3, 95% CI 1.8-2.9) and GTAC (OR 1.8, 95% CI 1.4-2.3) with an increased risk. The genotype-combination analyses indicated that the best model stratifies cases and controls based on the 66A>G and the 524C>T polymorphisms in the MTRR gene (global P=0.03). Our results suggest that, besides a weak association of childhood ALL with the 66A>G polymorphism, haplotypes within the MTRR gene may, in part, account for population-based differences in risk.

Adolescent↗
PubMed2006

Consensus guidelines for microarray gene expression analyses in leukemia from three European leukemia networks.

A plethora of studies have documented that gene expression profiling using DNA microarrays for various types of hematological malignancies provides novel information, which may have diagnostic and prognostic implications. However, to successfully use microarrays for this purpose, the quality and reproducibility of the whole procedure need to be guaranteed. Critical steps of the method are handling, processing and storage of the leukemic sample, purification of tumor cells (or lack thereof), RNA extraction methods, quality control of RNA, labeling techniques, hybridization, washing, scanning, spot filtering, normalization and initial interpretation, and finally the biostatistical analysis. These items have been extensively discussed and evaluated in different multi-center quality rounds within the three networks, that is, I-BFM-SG, the German Competence Network 'Acute and Chronic Leukemias' and the European LeukemiaNet. Based on the exchange of knowledge and experience between the three networks over the last few years, we have formulated guidelines for performing microarray experiments in leukemia. We confine ourselves to leukemias, but many of these requirements also apply to lymphomas or other clinical samples, including solid tumors.

Data Interpretation, Statistical↗
PubMed2006

[Patient safety in hospitals--a health services research issue].

Health services research as a multidisciplinary approach to transfer scientific results and clinical experience to health care includes quality research as one of its main topics. Quality research describes the total of conditions, which hinder or promote quality of care as one important output factor of health care. At present, patient safety research is one of the central issues of quality research, as preventable adverse events represent the most substantial consequences of problems in quality. Research issues start with epidemiological data, which are lacking in Germany, and the transfer of international data to the German health care system. Reporting instruments including critical incident reporting systems have to be validated, patient safety indicators should be developed, under consideration of the use of administrative data. Patient safety research addresses the effect of public disclosure of adverse events, errors and injury in respect to improvement of care and should analyse as well as elaborate prevention strategies for the most important adverse events and errors. Team factors such as communication and supervision and determinants of safety culture are issues, which illustrate the significant role of management theory and organisational research.

Germany↗
PubMed2006

The Eighth International Childhood Acute Lymphoblastic Leukemia Workshop ('Ponte di legno meeting') report: Vienna, Austria, April 27-28, 2005.

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27-28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation.

Austria↗
PubMed2006

Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients.

Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 19 age-matched healthy controls. Dendritic cells were identified by their expression of HLA-DR, lack of B, T, NK, and monocyte markers, and expression of CD11c (myeloid DC(mDC)) or BDCA-2 (plasmacytoid DC(pDC)) using flow cytometry. We found that in children with B-lineage ALL, numbers of both mDC and pDC were significantly reduced (P = 0.0001). In contrast, T-lineage ALL patients showed normal pDC and significantly elevated mDC (P = 0.003) levels, with normal expression of HLA-DR and co-stimulatory molecules. A decrease in DC could not be explained by general impairment of myelopoiesis, as we could not demonstrate a correlation of DC numbers with granulocyte/monocyte numbers in patients with B-lineage ALL. However, aberrant expression of myeloid surface markers on leukemic blasts was frequent in patients lacking myeloid DC indicating a potential block of DC differentiation. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses.

Adolescent↗
PubMed2006

The MLL recombinome of acute leukemias.

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

Acute Disease↗
PubMed2006

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance.

The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A case-control study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosin-containing protein was chosen for validation and quantification by Western blot analysis in a second case-control group of ALL patients. In this second independent cohort, median VCP expression (P25-P75) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P = 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.

Adenosine Triphosphatases↗
PubMed2006

Lack of expression of the chondroitin sulphate proteoglycan neuron-glial antigen 2 on candidate stem cell populations in paediatric acute myeloid leukaemia/abn(11q23) and acute lymphoblastic leukaemia/t(4;11).

It has increasingly been acknowledged that only a few leukaemic cells possess the capability to renew themselves and that only these self-renewing leukaemic stem cells are able to initiate relapses. Therefore, these leukaemic stem cells should be the target cells for therapy and for minimal residual disease (MRD) detection. Because of its presence on blasts of 11q23-rearranged high-risk leukaemic patients, neuron-glial antigen 2 (NG2) is thought to be a valuable marker for detecting leukaemic stem cells. Six acute myeloid leukaemia (AML)/abn(11q23) and three acute lymphoblastic leukaemia (ALL)/t(4;11) samples were analysed by four-colour flow cytometry for NG2 expression on primitive cell populations. Candidate leukaemic cell populations were defined by the antigen profiles CD34+CD38- in AML and CD34+CD19-CD117+ in ALL. Surprisingly, in all patients these candidate stem cell populations were shown to lack expression of NG2. Instead, a correlation between the expression of the myeloid differentiation marker CD33 and increasing levels of NG2 on maturing cells could be demonstrated. Similarly, in ALL patients CD34+CD19+ cells showed a higher expression of NG2 mRNA compared with CD34+CD19-. Thus, NG2 appears to be upregulated with differentiation and not to be expressed on primitive disease-maintaining cells. This hampers the clinical use of NG2 as a therapeutic target and as a sensitive marker for MRD detection.

Acute Disease↗
PubMed2005

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler).

Hurler syndrome (MPS1H) is a progressive inborn error of mucopolysaccharide metabolism leading to premature death. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and improve long-term survival. However, large studies have shown that preparative regimen-related toxicity (RRT) and graft failure rates have been relatively high. We transplanted five Hurler children with a fludarabine-based conditioning regimen, consisting of fludarabine/busulphan/ATG for matched family donor (MFD), with the addition of melphalan for mismatched family donor and matched unrelated donor (MUD) transplantations. Median age at HCT was 27 months (range 10-36). The source of stem cells was bone marrow in one MFD and CD34-selected PBSC in four patients. Median CD34+ cell dose was 25 x 10(6)/kg (range 11.5-54). No RRT > grade II was observed. All patients are surviving at a median of 32 months (range 14-41) and show sustained donor engraftment with 3/5 having full donor chimerism, and 2/5 mixed chimerism (> 85%). We conclude that this regimen is feasible and has low toxicity in Hurler children. In combination with high doses of CD34+ selected cells (> 10 x 10(6)/kg) and donor lymphocyte infusions, stable engraftment could be achieved in unrelated and mismatched related transplantations.

Antigens, CD34↗
PubMed2005

Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/EBMT concepts.

Children with high risk or relapsed acute lymphoblastic leukaemia (ALL) can benefit from allogeneic haematopoietic stem cell transplantation (SCT). To reduce transplantation-associated complications, the BFM study group, the IBFM study group and the PD-WP-EBMT initiated a prospective cooperative multicentre trail for paediatric ALL patients with an indication for allogeneic stem cell transplantation. Four-digit high-resolution HLA typing for all nonsibling donors, standardised GvHD prophylaxis and therapy, uniform conditioning regimen and minimum standards for supportive care should reduce not only treatment-related mortality but also ameliorate late effects for young patients. Furthermore, the prospective evaluation aims to assess the role of haematopoietic SCT in comparison to chemotherapy to enable valuable treatment recommendations for further decisions.

Child↗
PubMed2005

The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia.

Experimental and clinical data demonstrate an antileukemia effect of acute graft-versus-host disease (aGVHD). In all, 58 pediatric patients with acute lymphoblastic leukemia (ALL) who had received an allogeneic bone marrow transplant (BMT) at our institution were retrospectively analyzed for a correlation between the development of aGVHD and leukemic relapse. Probability of relapse after 5 (3) years was 13% (7%) in patients developing grade II-IV aGVHD vs 30% in patients with grade 0 or I aGVHD. There was a trend for a difference of the point estimates at 3 years, but no overall significance because of an unusual late relapse. Moreover, we analyzed the impact of cyclosporin A (CsA) on aGVHD in a subgroup of 22 children who had received a matched sibling donor (MSD) BMT. An increased dose of CsA within the first 2 weeks after BMT led to decreased occurrence and severity of aGVHD (P=0.035). The cumulative CsA dose appeared to have more impact than the average CsA whole-blood levels within the first 2 weeks and than the CsA dose given from day 15 to 40. In this subgroup, no life-threatening aGVHD or death from aGVHD occurred. In all cases (6/22), leukemic relapse was the cause of death. We therefore suggest that there is a relation between dose of CsA and relapse rate in childhood ALL transplanted from a MSD.

Adolescent↗
PubMed2005

Immunosurveillance of childhood ALL: polymorphic interferon-gamma alleles are associated with age at diagnosis and clinical risk groups.

Interferon-gamma (IFN-gamma) has been implicated as an important mediator of antitumor immunity in murine model systems. To determine whether a CA-repeat associated with differential NFkappaB-binding and IFN-gamma-expression levels may influence the incidence, manifestation and early clinical treatment response of childhood acute lymphoblastic leukemia, we performed PCR-based genotyping of 393 patients with ALL and 207 healthy controls. We could not find any differences in the allele distribution comparing patients and controls. However, when we further analyzed the allele frequencies with respect to age of clinical manifestation, we found that patients with B-lineage ALL showing the IFN-gamma high-expressing genotype presented at a more advanced age compared to those patients with intermediate and low-expressing genotypes (median 6 vs 4.4 years, P=0.01). Furthermore, we found a significantly higher number of low expressors in the group of high-risk patients (HR n=32 and MR/SR n=266, P=0.025, defined by prednisone response, cytological remission and minimal residual disease (MRD)) with B-lineage ALL. Thus, we provide evidence that polymorphic IFN-gamma alleles are associated with age at clinical presentation and risk groups such as prednisone response in B-lineage ALL, suggesting distinct effects of IFN-gamma in immunosurveillance and early response to steroid therapy.

Cell Lineage↗
PubMed2005

No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities.

This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

Child↗
PubMed2005

The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29--30, 2005.

Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.

Antineoplastic Agents↗
PubMed2004

[Quality management and strategic consequences of assessing documentation and coding under the German Diagnostic Related Groups system].

INTRODUCTION: The introduction of the German Diagnostic Related Groups (D-DRG) system requires redesigning administrative patient management strategies. Wrong coding leads to inaccurate grouping and endangers the reimbursement of treatment costs. This situation emphasizes the roles of documentation and coding as factors of economical success. PURPOSE: The aims of this study were to assess the quantity and quality of initial documentation and coding (ICD-10 and OPS-301) and find operative strategies to improve efficiency and strategic means to ensure optimal documentation and coding quality. METHODS: In a prospective study, documentation and coding quality were evaluated in a standardized way by weekly assessment. RESULTS: Clinical data from 1385 inpatients were processed for initial correctness and quality of documentation and coding. Principal diagnoses were found to be accurate in 82.7% of cases, inexact in 7.1%, and wrong in 10.1%. Effects on financial returns occurred in 16%. Based on these findings, an optimized, interdisciplinary, and multiprofessional workflow on medical documentation, coding, and data control was developed. CONCLUSIONS: Workflow incorporating regular assessment of documentation and coding quality is required by the DRG system to ensure efficient accounting of hospital services. Interdisciplinary and multiprofessional cooperation is recognized to be an important factor in establishing an efficient workflow in medical documentation and coding.

Diagnosis-Related Groups↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗