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  • 1
    ISSN: 1432-0584
    Keywords: Key words AML ; Idarubicin ; HDara-C/DNR consolidation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n=6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n=10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (〈500 neutrophils/μl) following HDara-C/DNR was 31.2 ± 16 days (mean ±SEM) in the IDA group compared with 18.7 ± 5 days in the DNR group (p〈.001 Mann-Whitney U-test). The duration of thrombocytopenia (platelets 〈25 000/μl) was 34.8 ± 20 days in the IDA group vs. 18.5 ± 6 days in the DNR group (p〈.005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 ± 24 vs. 6.9 ± 5.2 days). A greater incidence, length (11 ± 8 vs. 1.2 ± 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.
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  • 2
    ISSN: 1432-0584
    Keywords: Key words Myelodysplastic syndrome ; All-trans retinoic acid ; Interferon alpha ; Granulocyte colony-stimulating factor ; Differentiation therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Used as single agents, ATRA, G-CSF, and IFN-α have shown a moderate benefit in patients with low-risk MDS, with a response rate of 10%. The aim of the present study was to evaluate the efficacy of a combination of these agents. The effect on hemoglobin (Hb), platelets, and absolute neutrophil count (ANC), as well as on transfusion frequency, was examined in 25 patients with MDS (11 RA, four RARS, eight RAEB, two CMML). The median age was 61 years (range 44–81), and the male/female ratio was 14/11. Treatment consisted of ATRA at 25 mg/m2/day p.o. for months 1, 3, 5, 7, 9, and 11, IFN-α at 1.5 MIU twice a week s.c. for 52 weeks, and, in patients with initial ANC 〈500/μl, G-CSF at 100–480 μg daily s.c. according to the degree of ANC. The duration of therapy was scheduled for 12 months. Two patients achieved ongoing CR (+19 months; +16 months), one patient with RA after 3 months and one with CMML after 7 months of treatment. In all patients, the mean ANC increased significantly from 1400±200/μl before the start of therapy to 3500±600/μl at the end of treatment (p=0.025). In two patients an increase of Hb was observed, and one patient ceased to require transfusions. In an additional patient with RA and 5q-syndrome, the platelet count normalized following administration of ATRA/IFN-α, increasing from 89,000/μl to 293,000/μl. The eight RAEB patients were nonresponders. We conclude that therapy with ATRA, IFNα, and G-CSF is effective in approximately 35% of low-risk MDS patients (in this study: six of 17) and may induce complete remission in individual cases.
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  • 3
    ISSN: 1432-0584
    Keywords: HIV ; AIDS ; TGF-β ; TNF-α ; Hematopoietic progenitor cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF-β and TNF-α on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID50) of BFU-E by TGF-β occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID50 of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-α, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and 〉3,000 U/ml for CFU-GM, respectively. The ID50 of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF-β and TNF-α, thus confirming that the inhibitory activities were due to the cytokine preparation used.
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  • 4
    ISSN: 1432-0584
    Keywords: Key words All-trans-retinoic acid ; Granulocyte colony-stimulating factor ; Erythropoietin ; Myelodysplastic syndrome ; Tumor necrosis factor ; TNF receptor ; Soluble IL-2 receptor ; ICAM-1 ; Transferrin receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Differentiation induction therapy is being tested in myelodysplastic syndromes to ameliorate maturation defects and to restore normal hematopoietic function. To this end, 17 patients (eight with refractory anemia, two with refractory anemia and ring sideroblasts, and seven with refractory anemia and excess of blast cells) were treated with a combination of all-trans-retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and α-tocopherol for durations of 8–16 weeks. Absolute neutrophil counts increased in all patients; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients. Stimulation of erythropoiesis was seen in eight patients with an increase in hemoglobin concentration in three, a discontinuation of transfusion requirements in another three, and a significant increase in reticulocyte counts as the only parameter in two patients. Clinically important multilineage responses with increases of hemoglobin levels or discontinuation of transfusion needs were thus seen in six patients (35.3%) with three patients having a trilineage response. Serum erythropoietin concentrations did not differ significantly between responders and nonresponders, but the erythroid response was accompanied by a rise in the serum transferrin receptor levels. In the bone marrow, the myeloid-to-erythroid ratio and the maturation index of myeloid cells increased during therapy, while the percentage of blast cells did not change. Cytogenetic analysis demonstrated the persistence of the abnormal clones. Prior to therapy, nonresponders had a significantly higher serum TNF level than responders. Serum concentrations of TNF-α and soluble TNF-α receptor significantly increased during therapy, but mainly in the patients without an erythroid and platelet response. Soluble IL-2 receptor and soluble ICAM-1 concentrations both increased. This pilot study demonstrates that treatment with ATRA/G-CSF/EPO/tocopherol is well tolerated, leading to normalization of neutrophil counts in most, and to improvement of platelets and red blood cells in a significant subgroup of patients.
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  • 5
    ISSN: 1432-0584
    Keywords: Granulocyte colony-stimulating factor ; Acute lymphoblastic leukemia ; Chemotherapy ; Pilot study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present study was designed to determine whether Filgrastim, a neutrophil-specific hematopoietic growth factor, could be administered simultaneously with intensive induction chemotherapy for adult acute lymphoblastic leukemia (ALL). The effect of Filgrastim on the severity of chemotherapy-induced neutropenia, fever, and infections was assessed in 15 patients treated according to the protocol of the German multicenter ALL (GMALL) trial 04/89. Filgrastim (5μg/kg/day) was given concurrently with successive cycles of cyclophosphamide, cytosine-arabinoside (ara-C), 6-mercaptopurine (6MP), prednisone (PRD), intrathecal methotrexate, and prophylactic cranial irradiation. During the study period the median total duration of severe neutropenia (〈0.5×109/l) in 13 evaluable patients was 8 days, individual periods of neutropenia typically were short. Infections occurred in six patients; seven patients remained fever-free during treatment with Filgrastim. We conclude that simultaneous treatment with Filgrastim and chemotherapy in this specific setting is feasible and well tolerated. The efficacy of this treatment approach in terms of overall treatment results requires further testing in a randomized trial.
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  • 6
    ISSN: 1432-0584
    Keywords: sIL-2Receptor ; MDS ; Interleukin-3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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: eigth patients at dose levels of 250 and 500 Μg/m2 s.c. daily for 15 days, and seven patients at the dose levels of 60 and 125 Μg/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 sIL2R 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.
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  • 7
    ISSN: 1432-0584
    Keywords: Amifostine ; Myelodysplastic syndrome ; Refractory anemia ; Tumor necrosis factor alpha
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 2 /day three times per week followed by a 2-week interval. Since tumor necrosis factor (TNF)α is a main suppressive cytokine for hematopoiesis in RA patients, serum samples for analyzing endogenous levels of TNFα were collected prior to the study and after four treatment cycles. In three patients (21%), reduced transfusion requirement with prolongation of the transfusion interval from 4 weeks to 8 weeks (two patients) and 4 weeks to 6 weeks was seen. An increase in ANC from 400/μl to 2600/μl and 200/μl to 3400/μl was observed in two patients. Platelets increased from 129,000/μl to 277,000/μl in an additional patient. In one patient, disease progression from RA to RAEB was observed. Serum TNFα levels were increased in MDS patients compared with normal controls (18.8 pg/ml vs 9.1 pg/ml), and there was no change during the treatment with amifostine (17.5 pg/ml). In conclusion, treatment with amifostine as a single agent was of limited benefit in patients with RA. The serum TNFα levels were unchanged during treatment with amifostine in RA patients.
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  • 8
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aims:  To carry out an immunohistochemical study on bone marrow (BM) biopsy specimens in 75 patients with chronic myelogenous leukaemia (CML) on long-term STI571 therapy.Methods and results:  Sequential BM specimens taken at intervals of 21 ± 6 months were investigated by enzyme- and immunohistochemistry including proliferating cell nuclear antigen and apoptosis. Evaluation was performed either by semiquantitative scoring or by morphometry (CD61+ megakaryopoiesis). In 41 patients with chronic phase CML, treatment resulted in a significant decrease in cellularity and neutrophil granulopoiesis contrasting with an accumulation of erythroid precursor cells. Morphometry showed a reduction of abnormal micromegakaryocytes consistent with normalization. Regression of myelofibrosis was identified in eight of 15 patients, whereas progression occurred in 17 patients; mostly in those with acceleration and blastic crisis. The increased post-treatment incidence of reactive lymphoid nodules was remarkable. Myeloblasts, CD34+ progenitors and immature myelomonocytic cells initially decreased, but recurred in 14 patients who later developed a relapse. STI571 exerted an inhibitory effect on cell proliferation associated with enhanced apoptosis in responding patients.Conclusion:  Long-term treatment with STI571 exerts pronounced changes on BM histopathology that not only involve haematopoiesis and stromal constituents, but also proliferation and apoptosis.
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  • 9
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The human interleukin(IL)-18 is a key regulator of interferon(IFN)-γ production and T-cell differentiation. Here we report the complete genomic structure and characterization of the 5′untranslated promoter region of the human IL-18 gene. The gene is composed of six exons and five introns, spanning approximately 19.5kb. Promoter activity of the 5′-flanking region was investigated with a luciferase reporter gene assay. Transient transfection studies demonstrate a constitutive expression of the IL-18 gene in monocytic U937 and THP-1 cells. For this constitutive expression at least 92 base pairs of the promoter region are essential as shown by consecutive 5′ promoter deletions in both cell types. DNA protein binding experiments revealed specific binding of activated signal transducer and activator of transcription factor-5 (STAT5) but not of STAT3 to three consensus sequences upstream in the promoter region. Cotransfection of STAT5 resulted in increased induction of the IL-18 promoter in the U937 and THP-1 cells.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Der Internist 38 (1997), S. 1160-1167 
    ISSN: 1432-1289
    Keywords: Schlüsselwörter Zytokine ; Hämatopoetische Wachstumsfaktoren ; G-CSF ; GM-CSF ; Agranulozytose ; Therapie ; Leukopenie ; Therapie ; Leukämien ; Therapie
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zum Thema Die Therapie mit hämatopoetischen Wachstumsfaktoren hat in den letzten Jahren eine immer größere Bedeutung erlangt. Ganz im Vordergrund stehen dabei die 2 Zytokine Granulozyten Kolonien-stimulierender Faktor (G-CSF) und Granulozyten-Makrophagen-stimulierender Faktor (GM-CSF). Bei ermutigenden Therapieergebnissen besteht berechtigte Hoffnung, daß durch gezielten Einsatz dieser Zytokine die Mortalität, Morbidität und Lebensqualität bei Patienten mit darniederliegender Granulopoese günstig beeinflußt werden kann. Ein wichtiger Aspekt ist natürlich auch, daß die Stimulierung der Granulopoese eine höhere Dosierung von Chemo- und weiteren Therapien ermöglicht. Die Einsparung von Antibiotika und damit die Verminderung deren Nebenwirkungen, z.B. Pilzinfektionen, sollten dabei ebenso wie die Senkung von Hospitalisations- und Gesamttherapiekosten nicht außer Betracht gelassen werden. Über die eindeutigen, sinnvollen, nicht ausreichend untersuchten und derzeit (noch) nicht begründeten Indikationen für den Einsatz von G-CSF und GM-CSF sowie die Ergebnisse und Perspektiven dieser Behandlung wird in der vorliegenden Arbeit berichtet.
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