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Biomedical subjects

K Geissler

Publications and source records attributed to K Geissler.

At least 91 records · Page 5Linked to original sources
PubMed1996

Interleukin 10 inhibits growth and granulocyte/macrophage colony-stimulating factor production in chronic myelomonocytic leukemia cells.

Autonomous release of hematopoietic growth factors may play a crucial role in the pathogenesis of certain hematological malignancies. Because of its cytokine synthesis-inhibiting action, interleukin 10 (IL-10) could be a potentially useful molecule to affect leukemic cell growth in such disorders. Chronic myelomonocytic leukemia (CMML) cells spontaneously form myeloid colonies (colony-forming units-granulocyte/macrophage) in methylcellulose, suggesting an autocrine growth factor-mediated mechanism. We studied the effect of recombinant human IL-10 (rhIL-10) on the in vitro growth of mononuclear cells obtained from peripheral blood or bone marrow of patients with CMML. IL-10 specifically binding to leukemic cells had a profound and dose-dependent inhibitory effect on autonomous in vitro growth of CMML cells. IL-10 significantly inhibited the spontaneous growth of myeloid colonies in methylcellulose in 10/11 patients, and autonomous CMML cell growth in suspension in 5/5 patients tested. Spontaneous colony growth from CMML cells was also markedly reduced by addition of antigranulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies, but not by addition of antibodies against G-CSF, IL-3, or IL-6, IL-10-induced suppression of CMML cell growth was reversed by the addition of exogenous GM-CSF and correlated with a substantial decrease in GM-CSF production by leukemic cells, both at the mRNA and protein levels. Our data indicate that IL-10 profoundly inhibits the autonomous growth of CMML cells in vitro most likely through suppression of endogenous GM-CSF release. This observation suggests therapeutic evaluation of rhIL-10 in patients with CMML.

Aged↗
PubMed1996

Potentiation of granulocyte colony-stimulating factor-induced mobilization of circulating progenitor cells by seven-day pretreatment with interleukin-3.

Granulocyte colony-stimulating factor (G-CSF) as a single agent is increasingly used for the mobilization of peripheral blood progenitor cells (PBPCs) for stem cell transplantation. In patients with perturbed hematopoiesis the mobilizing capacity of G-CSF alone may be inadequate. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers by subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on G-CSF-induced mobilization of PBPCs in 6 patients with Hodgkin's disease (n = 5) or non-Hodgkin's lymphoma (n = 1) who had low progenitor cell numbers because of previous chemotherapy. Patients were treated in cycle 1 with G-CSF at a dose of 5 microgram/kg/d for 5 days and, after a treatment-free interval, received cycle 2 consisting of 5 microgram/kg/d of IL-3 for 7 days followed by G-CSF again at a dose of 5 microgram/kg/d for 5 days. G-CSF alone increased the mean number of circulating colony-forming units-GM (CFU-GM) by 21-fold, the number of burst-forming units-erythroid (BFU-E) by 9-fold, and the number of CFU-mix by 24-fold over pretreatment values. Treatment with 5 microgram/kg/d of IL-3 for 7 days did not mobilize by itself but significantly potentiated G-CSF-induced mobilization of all progenitor cell types leading to a 56-, 15-, and 46-fold increase over baseline of CFU-GM, BFU-E, and CFU-mix numbers, respectively. In 2 patients in whom leukapheresis was performed after G-CSF alone the target number of 2 x 10(6)/kg CD34+ cells was not reached. However, leukapheresis after the IL-3/G-CSF combination obtained > or =2 x 10(6)/kg CD34+ cells in 3 of 6 patients, including both patients who had inadequate collection after G-CSF alone. In one patient adequate function of mobilized progenitors could be shown by the demonstration of rapid trilineage engraftment after infusion of progenitors after myeloablative chemotherapy. Seven-day pretreatment with IL-3 may be a useful mean to augment mobilization of circulating progenitors by G-CSF. The combination of IL-3 and G-CSF seems to allow the procurement of sufficient numbers of PBPCs in some patients who cannot be mobilized adequately by G-CSF alone.

Adult↗
PubMed1996

Long-term leukemia-free survival after allogeneic marrow transplantation in patients with acute myelogenous leukemia.

Between February 1982 and April 1995, 62 patients (37 male, 25 female) with acute myelogenous leukemia (AML) with a median age of 32 years (19-51 years) received allogeneic marrow grafts from an HLA-identical sibling (n=60) or an HLA-mismatched family member (n=2). At the time of transplant, 35 patients were in first complete remission (CR), five in second CR, eight were primary refractory, eight were in untreated relapse and six in refractory relapse. The FAB subtypes were as follows: M1 (n=17), M2 (n=13), M3 (n=6), M4 (n=19), M5 (n=6), M6 (n=1). For conditioning most patients were given total body irradiation combined with cyclophosphamide (CY, n=50) or CY and busulfan (n=9). For graft-versus-host disease prophylaxis patients received cyclosporin A (CSA) and methotrexate (MTX) (n=32), MTX alone (n=12), CSA and methylprednisone (n=5), or CSA alone (n=13). As of April 1995, probability of leukemia-free survival projected at 10 years after BMT was 60% for patients transplanted in first CR compared with 10% for patients transplanted beyond first CR. Transplant-related mortality was 11% after BMT in first CR and 39% after BMT beyond first CR. Probability of relapse projected at 10 years after BMT is 32% for patients who received transplants in first CR and 81% for patients who received transplants beyond first CR. Thus, high-dose chemo/radiotherapy followed by allogeneic marrow infusion has a high curative potential for patients with AML who receive transplants in first CR and offers the chance of long-term disease-free survival for some patients with advanced disease.

Acute Disease↗
PubMed1996

Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study.

A total of 168 patients with de novo AML were retreated with chemotherapy at relapse following first CR; 66 patients (39%) achieved a second complete remission (CR). The probability of achieving a second CR was highly dependent on the duration of the first remission. Patients who received no or conventional postremission chemotherapy after second CR had a median remission duration of 7.5 months, and the probability of remaining in remission at 3 years was 24%. Patients with a first CR of more than 12 months had a median second remission duration of 18 months. The probability of a second CCR was 35% at 3 years and 24% at 5 years, whereas none of the patients with a first CR of less than 12 months was in remission at 3 years. Only a poor correlation (p = 0.31) was found when the durations of the first and second CR were compared in patients with a second relapse. Patients with long-lasting remissions and long-term survivors after second CR are characterized by a first CR duration of > 12 months and favorable or normal cytogenetics. The type of salvage treatment seems to be less important for achievement of long-term remission, but it is probably important to administer consolidation chemotherapy after second CR. Other so-far ill-defined factors may be responsible for the suppression of the leukemic clone in patients with long-lasting remissions following chemotherapy for relapse after second CR.

Adolescent↗
PubMed1996

FLAG (fludarabine, cytosine arabinoside, G-CSF) for refractory and relapsed acute myeloid leukemia.

Twenty-two patients with refractory or relapsed AML were treated with FLAG [25 mg/m2 fludarabine daily (days 1-5), 2 g/m2 daily Ara-C (days 1-5) and 400 micrograms/m2 daily G-CSF (day -1 till the absolute neutrophil count was > 500/microliter)]. Median age was 46 years (range 24-63). Eight patients had leukemia which was primarily refractory to conventional regimens, six were in first, seven were in second, and one was in third relapse. Overall, 11 of 22 (50%) patients achieved complete remission (CR), three had a partial response (PR), and seven did not respond (NR). One patient died of an early cerebral hemorrhage. The median remission duration from achievement of CR after FLAG was 9.9 months and median survival was 13.0 months. One patient is alive in CR at 31.9 months. Hematological toxicity of the regimen was severe. The median time to neutrophil recovery (ANC > 500/microliter) was 21 days (range 18-33). A median of seven red cell units (range 0-22) and of six platelet concentrate units (range 3-28) had to be given. Median duration of febrile neutropenia was 2 days (range 0-20 days) and patients were on i.v. antibiotics for a median of 16 days (range 0-51). There was no death from infection. Nonhematological toxicity was remarkably low, with almost no neurotoxicity and no major hepatotoxicity. In conclusion, FLAG seems to be an efficient and well tolerated regimen. It may be particularly useful for patients who have a sibling or unrelated donor for subsequent allogeneic bone marrow transplantation.

Acute Disease↗
PubMed1996

Current status of clinical development of interleukin-10.

Communication between cells in the lymphohematopoietic system is mediated by soluble molecules called cytokines. Lymphoid and myeloid cells are the cellular targets and source of these regulatory molecules. Interleukin-10 seems to be a main factor of a negative feedback system that inhibits synthesis of proinflammatory cytokines and of colony-stimulating factors in a variety of cells. Considering the cytokine synthesis-inhibiting action of interleukin-10 in activated macrophages, T cells, neutrophils, and eosinophils, many of the biologic effects of interleukin-10 may result in immunosuppression. Recently, the interleukin-10 receptor and some signal transduction events following interleukin-10 binding have been characterized. Substantial progress has also been made in providing the experimental basis for interleukin-10 therapy in various diseases. In vitro and preclinical studies suggest that interleukin-10 may prove quite useful in clinical settings in which overexpression of cytokines is likely to play an important role in pathogenesis, including inflammatory bowel disease, acute pancreatitis, septic shock, and certain malignancies.

Animals↗
PubMed1995

Anemia and erythropoietin levels in lung transplant recipients.

An evaluation of 26 surviving outpatient lung transplant recipients at one center showed that 65% (17/26) had significant anemia (hemoglobin < 11 g/L for women, < 14 g/dl for men) at a median follow-up of 13.5 months after transplantation (range, 1-41 months). There were 14 men and 12 women with a mean age of 45.1 years (range, 23.1-66.7 years). Fifteen had a double allograft and 11 had a single allograft. Anemia was normochromic and normocytic/macrocytic with a tendency to anisocytosis, with normal reticulocyte counts. Iron deficiency (transferrin saturation < 20%) was found in 35% (6/17) of anemic patients, and two of them also had ferritin levels < 15 micrograms/L. In addition, vitamin B12 was decreased in 1 patient. Folate levels were all normal. Erythropoietin levels were significantly decreased in anemic lung transplant recipients as compared with nontransplanted iron-deficient anemic patients (median, 1 mU/ml, range 1-41 mU/ml, vs. 53 mU/ml, 15-88 mU/ml; P < 0.05). In nonanemic lung transplant recipients, erythropoietin levels were decreased too, as compared with normal controls (median, 2 mU/ml, range 1-21 mU/ml, vs. 5 mU/ml, 3-32 mU/ml; P < 0.05). Investigation of peripheral stem cells in 9 patients showed normal stimulation of erythroids (burst-forming unit, erythroid; median, 573 cells/ml; range, 128-1898 cells/ml) independent of erythropoietin concentrations. Analysis of putative prognostic factors, such as age, surgical procedure (double vs. single lung allograft), indication for transplantation, time after transplantation, infection status, presence of bronchiolitis obliterans, immunosuppression (+/- azathioprine), serum creatinine, creatinine clearance, hypertension, and arterial partial pressure of oxygen, did not demonstrate any difference in erythropoietin concentrations. Only the sex variable revealed a trend to higher levels in women than in men (median, 4 mU/ml, range 1-41 mU/ml, vs. 1 mU/ml, 1-16 mU/ml; P > 0.05). The causes for low erythropoietin levels are not quite understood yet; however, they offer a rationale for the treatment of chronic anemia with recombinant human erythropoietin.

Adult↗
PubMed1995

Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance.

Karyotypic studies in patients with monoclonal gammopathy of undetermined significance (MGUS) have been hampered by a low percentage of bone marrow plasma cells (BMPC), which are predominantly nonproliferating. By combining cytomorphology and interphase fluorescence in situ hybridization (FISH) we investigated whether or not chromosomal abnormalities occur in BMPC from patients with MGUS. Studying chromosomes 3, 7, 11, and 18, which we found to be frequently aneuploid by FISH in multiple myeloma (MM), we observed three hybridization signals for one of these chromosomes 3 were most common, occurring in 38.9% of patients, followed by gains of chromosomes 11 (25%), 7 (16.7%), and 18 (5.6%) Among BMPC, the frequency of aneuploid cells was 18.9% +/- 13.9% (mean +/- SD) for chromosome 3, 22.3% +/- 9.2% for chromosome 11, 23.2% +/- 22.0% for chromosome 7, and 6.1% +/- 2.3% for chromosome 18. In five patients, chromosomal abnormalities were shown to be restricted to BMPC expressing cytoplasmic immunoglobulins corresponding to the serum paraprotein. No gain of hybridization signals was observed in normal and reactive plasma cells. In one patient with MGUS, metaphase cytogenetics revealed one abnormal metaphase with 47, XY, +4, and trisomy 4 was also demonstrated in a subpopulation of BMPC by interphase FISH. FISH results from patients with MGUS and newly diagnosed MM at stage IA (n = 14) indicated that aberrations involving > or = 2 chromosomes occurred significantly more often in early stage MM (P < .01). With respect to clinical and laboratory features, MGUS patients with and without chromosomal abnormalities were indistinguishable. Our results indicate that MGUS already has the chromosomal characteristics of a plasma cell malignancy.

Adult↗
PubMed1995

Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression.

The translocation t(9;22) in chronic myeloid leukemia (CML) generates a bcr-abl fusion gene that codes for an aberrant chimeric mRNA. Cell lines established from CML patients in blast crisis show higher expression of this aberrant bcr-abl transcript than cells from patients in chronic phase of the disease. This observation provided the stimulus to investigate whether increased expression of the aberrant bcr-abl fusion transcript is critical to the progression of CML from chronic phase to blast crisis. We have monitored the bcr-abl mRNA expression in 25 patients by serial quantitative polymerase chain reaction analyses during a follow-up period of 12 to 156 months after diagnosis, with a median observation time of 28 months. In all patients who have shown disease progression to accelerated phase (n = 4) or blast crisis (n = 7), an increase in bcr-abl mRNA expression was detected up to 16 months before laboratory or clinical parameters showed phenotypic transformation of the malignant clone. To investigate whether the elevated levels of bcr-abl mRNA reflected an increase in the proportion of leukemic cells in the samples analyzed or primarily enhanced transcriptional activity of the bcr-abl fusion gene, we performed quantitative analyses of the bcr-abl gene at the DNA level and of the Ph chromosome at the cytogenetic level and compared these data with steady-state bcr-abl mRNA levels. We show that increased levels of the bcr-abl transcript did not reflect increased proportions of leukemic cells but elevated steady-state levels of the chimeric mRNA in the malignant cells before disease progression. Therefore, our data strongly suggest that an increase of the chimeric mRNA expression in the leukemic cells precedes the phenotypic transformation of the malignant clone.

Adult↗
PubMed1995

Effect of interleukin-3 pretreatment on granulocyte/macrophage colony-stimulating factor induced mobilization of circulating haemopoietic progenitor cells.

Recombinant human colony stimulating factors (CSFs) as single agents are increasingly used for mobilizing peripheral blood progenitor cells (PBPCs) for stem cell transplantation. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers of subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on GM-CSF-induced mobilization of PB progenitors in patients who were potential candidates for autologous stem cell transplantation (n = 16). Patients were treated with GM-CSF at a dose of 5 micrograms/kg/d for 5 d and after a treatment free interval received another cycle of GM-CSF immediately following pretreatment with IL-3 at different doses and duration: 2.5 micrograms/kg/d (n = 4), 5 micrograms/kg/d (n = 3) and 10 micrograms/kg/d (n = 3) for 3 d, 5 micrograms/kg/d for 7 d (n = 4) and 5 micrograms/kg/d for 14 d (n = 2), respectively. Only 7 d pretreatment with IL-3 showed consistent effects. Although IL-3 did not mobilize by itself, pretreatment with 5 micrograms/kg/d of IL-3 for 7 d significantly potentiated GM-CSF-induced mobilization of PB CFU-GM numbers, leading to a mean increase in PB CFU-GM numbers over baseline by 18.5 +/- 5.2 (SEM) fold by IL-3/GM-CSF as compared to a 4.7 +/- 1.7-fold increase by GM-CSF alone. A significant enhancement by the 7 d IL-3 pretreatment was also observed for erythroid (BFU-E) and multipotential progenitor cells (CFU-mix) which were 3.3 +/- 1.3- and 3.4 +/- 0.9-fold, respectively, mobilized by GM-CSF alone, as compared to 8.5 +/- 2.3- and 19.2 +/- 3.4-fold, respectively, by the IL-3/GM-CSF combination. Our results suggest that 7 d pretreatment with IL-3 may be a useful mean to augment mobilization of circulating progenitors by more lineage-restricted CSFs. These findings may be important for the design of mobilization strategies that use growth factors without preceding chemotherapy.

Adolescent↗
PubMed1995

PCR-monitoring of minimal residual leukaemia after conventional chemotherapy and bone marrow transplantation in BCR-ABL-positive acute lymphoblastic leukaemia.

We report the results of consecutive tests in nine BCR-ABL-positive ALL patients by one-step and two-step (nested primer) reverse transcriptase-polymerase chain reaction (RT-PCR). Six patients could be tested in complete haematological remission (CHR). One patient remained one-step positive; four patients became one-step negative, but remained two-step positive; only one patient became two-step negative. In five patients the haematological relapse was preceded by one-step positivity by 1.5-5 weeks. In two patients who received autologous BMT in CHR, BCR-ABL was still detectable by two-step PCR, whereas allogeneic BMT was able to transiently reduce BCR-ABL below the two-step detection level. Our results show that one-step combined with two-step RT-PCR analysis gives valuable information about the efficacy of treatment and the dynamics of the leukaemic clone.

Adult↗
PubMed1995

Use of quantitative polymerase chain reaction to monitor residual disease in chronic myelogenous leukemia during treatment with interferon.

Interferon-alpha (IFN-alpha) has become a widely used treatment modality in chronic myelogenous leukemia (CML) and was shown to induce complete hematologic responses in about 70% of the patients. In a minority of cases, complete suppression of the Philadelphia (Ph)-positive clone has been observed by cytogenetic investigation or by Southern blot analysis. In most instances, however, analyses by the highly sensitive two-step polymerase chain reaction (PCR) reveal the presence of residual leukemic cells despite continuous treatment. Since PCR positivity has not been associated with an increased risk of disease recurrence, the monitoring of cells carrying the characteristic BCR/ABL rearrangement by qualitative PCR may not facilitate early identification of patients who are likely to relapse. We have therefore employed a quantitative PCR technique to monitor the BCR/ABL mRNA expression levels during the course of treatment in an attempt to assess the response to IFN-alpha at the molecular level and to provide a basis for early detection of progressive disease. Twenty CML patients who received therapy with IFN-alpha in first chronic phase of the disease were enrolled in the study. In addition, we have monitored two CML patients treated with IFN-alpha for relapse after bone marrow transplantation. Thirteen patients who displayed decreasing, constant or fluctuating levels of BCR/ABL expression during an observation period of up to 4 years (mean 25 months) have remained in hematologic remission. Two patients showed an elevation in the marker gene expression upon discontinuation of treatment, but no further increase in BCR/ABL mRNA has been observed after reinitiation of therapy with IFN, and the patients have remained in hematologic remission. In seven patients, quantitative PCR (Q-PCR) analyses revealed increasing expression of the chimeric gene during treatment with IFN-alpha. In all seven cases, the detection of elevated BCR/ABL transcripts by quantitative PCR preceded signs of hematologic or cytogenetic disease progression by up to 8 months (median 6 months). Our data show that quantitative PCR analysis facilitates the monitoring of the response to IFN-alpha therapy and provides an effective diagnostic tool for the timely detection of recurrent disease. The employment of this technique greatly enhances the diagnostic possibilities in the management of chronic myelogenous leukemia.

Adult↗
PubMed1995

The use of recombinant human erythropoietin in lung transplantation.

Recombinant human erythropoietin (r-HuEPO) was administered in 4 lung transplant recipients to treat chronic anemia beyond the immediate postoperative period. There were 2 males and 2 females with a mean age of 38 years (range 22-49). None of the patients had major infection or rejection problems, and no blood products were used. Because of different individual responses duration of therapy was 1 to 17 weeks (median 5) with a total dosage ranging from 8 to 36 x 10(3) IU (mean 21 x 10(3)). The median single dose was 58 IU/kg (range 36-100). Hemoglobin levels increased significantly from 9.1 +/- 0.2 to 12.7 +/- 0.3 g/dl (mean +/- SE; p < 0.01). There were no side effects. r-HuEPO is recommended in treatment of chronic anemia in lung transplant patients to save blood products and to exclude the potential risk of transfusion-transmitted viral infections.

Adult↗
PubMed1995

[Collection and long-term preservation of peripheral stem cells].

The methods of collection and storage of peripheral blood stem cells are described, and the harvesting after conditioning with cytokines and/or myelosuppressive therapy is discussed. It could be demonstrated that the combination of cytostatics and cytokines gives the best yield and enables to collect a sufficient amount of peripheral bloodstem cells for a successful engraftment after myeloablative therapy with only few aphereses.

Antineoplastic Agents↗
PubMed1994

Autoimmune-thrombocytopenia and SLE in a patient with 5q-anomaly and deletion of the c-fms oncogene.

Autoimmune-thrombocytopenia was the striking feature in a patient with typical clinical symptoms of systemic lupus erythematosus (SLE), complement C4 deficiency, and positive lupus serology. However, myelodysplasia was found in the bone marrow and chromosome analysis revealed a deletion of the long arm of chromosome 5 (5q-anomaly), which was confirmed by a hemizygosity for the c-fms oncogene (CSF-1-receptor) on Southern blot. Autoimmune phenomena reported in conjunction with myelodysplastic syndromes (MDS), e.g., an elevation of antinuclear antibodies, are usually regarded as nonspecific. This case report suggests that SLE can occur in patients with MDS and that a concomitant autoimmune-thrombocytopenia may mask the typical signs of the 5q- syndrome.

Adult↗
PubMed1994

Effective stimulation of neutropoiesis with rh G-CSF in dyskeratosis congenita: a case report.

Dyskeratosis congenita (DC) is a rare congenital X-linked disorder. The major clinical manifestations are abnormal skin pigmentation, nail dystrophy, and leukoplakia of mucosal membranes. About 50% of the patients develop bone marrow failure, which is partly responsible for the poor prognosis. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been administered to some neutropenic patients with DC, but only a moderate stimulation of neutropoiesis has been observed. We report on a patient with DC treated with recombinant human granulocyte-colony-stimulating factor (rhG-CSF). This treatment resulted in a substantial dose-dependent increase in the neutrophil count.

Adult↗