[Accumulation of German bone marrow donor data].
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Adult↗
Biomedical subjects
D Hoelzer
Publications and source records attributed to D Hoelzer.
Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia.
The introduction of immunosuppressive therapy for treatment of aplastic anemia has led to a considerable improvement in the prognosis of this disease. However, long-term follow-up of these patients showed a high incidence of "late" hematologic complications such as myelodysplasia and paroxysmal nocturnal hemoglobinuria (PNH). The detection of the glycosylphosphatitylinositol (GPI)-anchoring defect on peripheral blood cells of patients with aplastic anemia is now available as a new tool for early specific detection of PNH and is more sensitive than the Ham-test. Granulocytes appear to be the first cells affected in 11 patients with a GPI-anchoring defect of 29 suffering from aplastic anemia investigated in the present study. The later involvement of erythrocytes and a positive Ham test was observed in 1 patient. From our data it can be concluded that the rate of PNH resulting from aplastic anemia might be higher than reported in the literature when the Ham test alone was used for follow-up. Furthermore, our results suggest the clinical response to immunosuppressive therapy appears to be worse in the group developing the GPI-anchoring defect than in the group without this deficiency.
Adolescent↗
Acute promyelocytic leukemia.
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Acute Disease↗
In patients with BCR-ABL-positive ALL in CR peripheral blood contains less residual disease than bone marrow: implications for autologous BMT.
Residual leukemic cells are detectable at frequencies as low as 1 in 10(6) normal cells in patients with Philadelphia chromosome/BCR-ABL-positive leukemias in complete remission (CR) using reverse-transcriptase polymerase chain reaction (RT-PCR) with specific nested primers. The level of minimal residual disease (MRD) in the bone marrow (BM) and the peripheral blood (PB) may favor one of the two as the source for an autologous graft. In order to quantify MRD with RT-PCR we analyzed patients ficolled cells after limiting logarithmic dilutions in normal ficolled buffy-coat cells. In six patients with BCR-ABL-pos ALL who were in CR by conventional criteria (5 in CR1 and 1 in CR2), we studied a total of nine paired BM and PB samples prior to scheduled ABMT. A positive RT-PCR signals was detectable in all samples up to dilutions ranging from 1:10(1) to 1:10(3) in PB, and at higher titers ranging from 1:10(3) to 1:10(5) in the BM. The BM titers exceeded the corresponding PB titers in all nine sample pairs by at least 1 log. The mean difference was 1.55 log (geometric mean, n = 9) and is statistically significant (p < 0.03). We conclude that residual leukemia in BCR-ABL-positive ALL preferentially locates in the BM compartment, and we assume that PB may yield autologous grafts with significantly less leukemic contamination.
Adult↗
Induction of soluble IL-2 receptor in patients with myelodysplastic syndromes undergoing high-dose interleukin-3 treatment.
Sera of ten healthy controls and of 15 patients with myelodysplastic syndromes (MDS) were investigated for soluble interleukin-2 receptor (sIL-2R) with a cell-free enzyme-linked immunosorbent assay (ELISA). The patients with MDS underwent treatment with IL-3: eight patients at dose levels of 250 and 500 micrograms/m2 s.c. daily for 15 days, and seven patients at the dose levels of 60 and 125 micrograms/m2 s.c. three times per week for 12 weeks. None of the patients had reported infectious episodes or been under treatment with cytotoxic drugs and/or cytokines within the preceding 2 months. sIL-2R levels were elevated in MDS patients compared with healthy controls (p < 0.001). sIL-2R increased in the high-dose treatment group from 504 +/- 68 U/ml to 731 +/- 199 U/ml (p < 0.025). The increased sIL-2R expression in MDS could be a primary event due to involvement of lymphocytes in the malignant clone or due to a secondary alteration of the cytokine network caused by chronic neutropenia. A down-regulation of the immune response caused by neutralization of free IL-2 by sIL-2R during IL-3 therapy seems possible.
Adult↗
Comparison of chemotherapy and bone marrow transplants using two independent clinical databases.
Comparing the outcome of chemotherapy and bone marrow transplants in the absence of a randomized trial is difficult but necessary for diseases where small numbers of patients make such trials difficult if not impossible. To address this issue for adults with acute lymphoblastic leukemia in first remission, we created an empirical database using two separate datasets, one from the International Bone Marrow Transplant Registry and the other from two multicenter chemotherapy studies. Prior to combining the datasets, a study protocol was developed to define inclusion criteria, outcomes to be compared and statistical methods. The main problems of a non-randomized comparison are biases potentially introduced by differences in baseline composition of the two cohorts and differences in time-to-treatment. The source of the latter bias is different distributions of waiting times between achieving complete remission and receiving post-remission therapy. Several techniques to control these biases were evaluated; each gave qualitatively similar results. These methods can easily be applied to other clinical situations where randomized trials are not available.
Adolescent↗
Acute lymphoblastic leukemia. Introduction.
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Adult↗
Therapy and prognostic factors in adult acute lymphoblastic leukaemia.
In acute lymphoblastic leukaemia (ALL) substantial progress has been achieved within the last few years. Complete remission rates up to 95% can now be achieved in children and 70-85% in adults; disease free survival rates are 70 and 30% respectively. To improve results further high dose treatment has been included, particularly to overcome drug resistance and to reach cytostatic levels in the sanctuary sites, such as the central nervous system. High dose cytarabine in combination with other cytostatic drugs, preferentially anthracyclines, seems to be of benefit for high risk adult ALL patients. High dose methotrexate, mostly explored in childhood ALL, is now also included in a variety of combinations in the treatment of adult ALL, but its effectiveness remains to be established. Substantial progress has been achieved in adult T-ALL and B-ALL with survival rates of 40-50%. The optimal form and duration of maintenance therapy in adult ALL is not yet clear but general omission of maintenance leaves patients with an inferior outcome. Which subgroups of adult ALL require maintenance and in what form still requires investigation. In recent adult ALL trials with intensive chemotherapy similar prognostic factors for disease free survival have emerged. Of adverse influence are delayed time to reach CR (more than 4/5 weeks), a high initial white blood cell count, higher age (above 50 or 60 years), and probably the immunological subtypes pre-T-ALL, pre-B-ALL, My(+)-ALL; of very adverse influence in elderly patients is the karyotype t(9;22) or the corresponding BCR/ABL gene rearrangement. High risk adult ALL patients with one or more of these adverse factors are candidates for allogeneic or autologous bone marrow transplantation in first remission. Whether all adult ALL patients are candidates for BMT in first CR is currently being explored in large prospective randomized trials.
Adult↗
In vitro improvement of bone marrow-derived hematopoietic colony formation in HIV-positive patients by alpha-D-tocopherol and erythropoietin.
The majority of patients with progressive HIV infection develop a severe hematopoietic failure which is aggravated by the hematotoxic effect of azidothymidine (AZT) treatment. Since it was shown in a mouse model that alpha-D-tocopherol (vitamin E derivative) antagonizes the inhibitory influence of AZT on the growth of burst-forming units-erythrocyte (BFU-E), it was the aim of this study to investigate whether alpha-D-tocopherol and high dosages of erythropoietin (EPO) increase the hematopoietic colony-forming capacity of bone marrow cells from patients with progressive HIV disease and especially if they reverse the inhibitory effects of AZT. The data demonstrate that tocopherol (1-100 mumol/l) significantly increases the growth of BFU-E and colony-forming units granulocyte-monocyte (CFU-GM) from HIV-infected patients. This stimulatory effect is dose-dependent (maximum at 30-100 mumol/l) and only occurs when the agent is present from the beginning of the cultures. EPO (5-10 U/ml) also augments the numbers of BFU-E from HIV-infected patients. Tocopherol equally ameliorates the growth of BFU-E and CFU-GM from the HIV-positive cohort in the presence of AZT (10-100 mumol/l). For healthy controls, no such increase was observed, either with tocopherol or with higher dosages of EPO. In conclusion, both tocopherol and EPO partially reverse the myelosuppressive action of AZT in HIV-positive patients.
Adult↗
Peroxidase expression in acute unclassified leukemias: ultrastructural studies in combination with immunophenotyping.
The lineage affinity of 61 cases of acute unclassified leukemias (AUL) was reevaluated by ultrastructural analysis of peroxidase expression (POEM) in combination with immunophenotyping. In 24 cases a significant proportion of the blasts displayed ultrastructural myeloperoxidase (UMPO) and in another 3 cases platelet peroxidase (UPPO) suggesting the allocation of these leukemias to the myeloid or megakaryoblastic lineage. No significant correlation between myeloid surface marker expression and POEM positivity could be detected, while the presence of the CD 19 or CD 24 antigen significantly correlated with POEM negativity. The detection of lymphoid markers on POEM+ blasts indicates, that these leukemias might be derived from bipotential progenitors, which have retained their lymphoid antigens during myeloid differentiation. In one case a bilineage leukemia with a POEM+/CD 19- and a POEM-/CD 19+ population could be identified by immunoelectron microscopical studies (IEM). The remaining 34 AUL cases were POEM negative. Combined data suggest that these cases probably derive from early lymphoid progenitors. Taken together, AUL are heterogenous in presentation and in their cellular origin including a major portion of cases with an unequivocal myeloid differentiation detectable by ultrastructural analysis of myeloperoxidase expression.
Acute Disease↗
Immunophenotypic features of childhood and adult acute lymphoblastic leukemia (ALL): experience of the German Multicentre Trials ALL-BFM and GMALL.
Immunophenotyping prospectively performed in about 2800 children and adults within the framework of the German multicentre ALL trials revealed marked differences in frequency distribution of immunologic subgroups with a higher incidence of immature B-cell precursor and pre-T/T phenotypic features in adults. Detailed immunophenotypic characterization by applying monoclonal antibodies to lymphoid- and myeloid-associated antigens as well as non-lineage-restricted molecules underlined the diagnostic value of pan-B and pan-T antigens that were expressed in virtually all cases of B-cell precursor (CD19, CD24) or T-cell ALL (cytoplasmic CD3, CD7) for lineage affiliation of leukemic blasts. About 10% of children and 20% of adults disclosed simultaneous expression of lymphoid markers and at least one myeloid-lineage-associated antigen. Our data confirm that immunophenotyping in ALL provides a solid basis for a biologically oriented and reliable classification of this heterogeneous disease.
Adult↗
The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells.
The Wilms' tumor gene (wt-1) is expressed in the developing fetal kidney, gonads and in Wilms' tumors. Recently, the expression of wt-1 in leukemia-derived cell lines and cases of acute leukemias (AL) was reported. The present study was designed to investigate the potential of wt-1 as genetic marker for acute myelocytic leukemias (AML). Blast cells from 52 patients with AML, 14 patients in complete remission (CR) and four leukemic cell lines were examined for expression of wt-1 mRNA. Peripheral blood mononuclear cells (PBMNC) and bone marrow (BM) from 13 healthy persons were used as negative controls. RNA of the wt-1 gene was expressed in 41/52 (79%) patients with previously untreated AML. The majority of the 14 patients studied in CR lost wt-1 expression. In three out of the four patients in CR reappearance of wt-1 expression preceded relapse of the disease. In three of the four tested cell lines wt-1 specific transcription was demonstrated. No correlation to FAB classification, immunophenotype or response to treatment was found. Our experiments indicate wt-1 expression in the majority of AML, but not in bone marrow or PBMNC of healthy controls. Therefore, wt-1 expression may be associated with the presence of malignant blast cells and the analysis of wt-1 gene expression via PCR may be a sensitive method for the detection of leukemic blast cells.
Adult↗
The study and treatment of the myelodysplastic patient.
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Bone Marrow↗
Microangiopathic hemolytic anemia and renal impairment following autologous bone marrow transplantation: a case of hemolytic uremic syndrome?
Thrombotic microangiopathy, which encompasses both thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), is a severe and life-threatening complication following bone marrow transplantation (BMT). It has been reported after allogeneic BMT but may also occur after autologous BMT. Here we describe a case of microangiopathic hemolytic anemia and progressive renal failure subsequent to autologous BMT.
Anemia, Hemolytic↗
Detection of HRX-FEL fusion transcripts in pre-pre-B-ALL with and without cytogenetic demonstration of t(4;11).
The t(4;11)(q21;q23) characterizes a distinct clinical entity of childhood and adult acute lymphoblastic leukemia (ALL) with a pre-pre-B-phenotype, monocytoid features, coexpression of CD15 and/or CDw65 and a dismal prognosis. The molecular correlate of the t(4;11) has been identified as a fusion transcript of HRX, a gene on 11q23 with homology to drosophila trithorax gene, and FEL, a serine-proline-rich gene on 4q21 of unknown function. The aim of the current study was to establish a reverse transcription-polymerase chain reaction (RT-PCR) approach for the rapid and sensitive detection of the HRX-FEL fusion transcript associated with the t(4;11). For this purpose, two groups of patients were studied: group A comprised cases with cytogenetically proven t(4;11) including three infant and four adult pre-pre-B-ALL, as well as the two cell lines RS4;11 and MV4;11. Group B consisted of ten adult pre-pre-B-ALL with the identical phenotype, but without cytogenetic confirmation of t(4;11). Using primers complementary to HRX and FEL cDNA sequences 300 to 500 bp 5' and 3' of published breakpoints, respectively, specific amplification products were obtained in all nine cases of group A and in nine of the ten cases of group B. Three different types of fusion transcripts were identified by sequence analysis with HRX breakpoints at nucleotides 4086 and 4218 and FEL breakpoints at nucleotides 1413, 1416, and 1458. These data indicate that RT-PCR allows the detection of HRX-FEL fusion transcripts in the vast majority of cytogenetically proven and immunophenotypically suspected t(4;11) ALL. Hence, this technique may allow identification of a further subset of high risk ALL and may also be useful for the monitoring of minimal residual disease in t(4;11) ALL.
Adult↗
Essential role of c-myc in ara-C-induced differentiation of human erythroleukemia cells.
The mode of action of the differentiation inducer 1-beta-D-arabinofuranosylcytosine (ara-C) is as yet unknown. We have analyzed the role of c-myc expression in ara-C-induced differentiation of K562 human erythroleukemia cells. Six hours after differentiation induction, c-myc expression is down-regulated transiently. This was followed by the onset of cell differentiation together with a final c-myc 'down-regulation' at 24 h after treatment. This regulation of expression may be caused by hypermethylation of c-myc DNA sequences, which we find to follow a similar pattern. We propose that the loss of c-myc expression might be a necessary prerequisite for ara-C-induced differentiation. This hypothesis was tested by transfecting a constitutive c-myc expression construct into K562 cells prior to ara-C treatment. By following the differentiation parameters cell morphology, benzidine staining (hemoglobin monitored), and alkaline phosphatase activity (presence of mature red blood cell antigen monitored) in cells expressing cotransfected LacZ marker gene, it was demonstrated that the introduction of the c-myc expression plasmid blocked ara-C-induced differentiation. We conclude that loss of c-myc expression mediated the differentiation found in ara-C-treated K562 cells.
Blotting, Northern↗
Application of hemopoietic growth factors in MDS.
Growth factors offer a new strategy in the treatment of MDS. Their favorable effect in the treatment of diseases related to previous therapy is well known. The evaluation of the influence of these factors on the total survival time requires further controlled investigations. Longer observation of a more numerous group of patients will enable us to show whether growth factors therapy significantly decreases the number of infections and letters the quality of life. To sum up, growth factors markedly improve the result of treatment of neoplasms.
Hematopoietic Cell Growth Factors↗