Search PubMed⌕ Search

Biomedical subjects

A Ganser

Publications and source records attributed to A Ganser.

At least 163 records · Page 9Linked to original sources
PubMed1995

Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial.

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Adolescent↗
PubMed1995

Comparative genomic hybridization in the investigation of myeloid leukemias.

Comparative genomic hybridization (CGH) was used for the examination of ten cases of myeloid leukemia (eight acute myeloid leukemias and two myelodysplastic syndromes). In five cases, genomic gains or losses were identified, which mapped to chromosomal regions known to be involved in this group of malignancies. In comparison to the results obtained by banding analysis, discrepancies were found in three of the ten cases; in two cases, chromosomal imbalances were not identified by CGH because they were present only in small subclones. In the other case, there were no evaluable metaphase cells for banding analysis; CGH revealed an overrepresentation of chromosome 8, which was confirmed by interphase cytogenetics with a chromosome 8-specific alphoid probe. All abnormalities revealed by CGH were confirmed by G-banding or subsequent interphase cytogenetic analysis, which demonstrates the high specificity of the method. Furthermore, in all cases, CGH identified the chromosomal imbalances present in the major clone as detected by banding analysis. The good correlation between CGH and chromosome banding results in myeloid leukemias makes this tumor a good model for the assessment of tools that are developed for automated and quantitative CGH analysis.

Aneuploidy↗
PubMed1995

Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL.

In four of 14 patients with acute lymphoblastic leukemia (ALL) who received induction chemotherapy containing weekly injections of vincristine and simultaneous antifungal prophylaxis with itraconazole, unusually severe and early vincristine-induced neurotoxicity was observed. In these patients (three female, one male) paresthesia and muscle weakness of the upper/lower extremities and paralytic ileus occurred after the first or second vincristine injection. In one patient a laryngeal nerve paresis required mechanical ventilation. The neurotoxic complications were more serious than those seen in a previous series of 460 ALL patients under the identical cytostatic regimen but without itraconazole prophylaxis. The underlying mechanism is unclear. Interaction with the cytochrome P-450 system, reversal of multidrug resistance, and influence of estrogens are to be considered.

Adolescent↗
PubMed1995

Modified antisense oligodeoxynucleotides against the splice acceptor site of tat do not inhibit in vitro hematopoietic colony growth in HIV-positive patients.

The hematopoietic failure in the majority of patients with progressive HIV infection is further aggravated by virustatic agents like azidothymidine. As an alternative therapeutic attempt, three derivatives of an antisense oligodeoxynucleotide (ODN) against the splice acceptor site of the tat gene have been shown to inhibit HIV replication in vitro. This study was aimed at examining whether these agents are toxic to the hematopoietic progenitor cells. To this end, bone marrow cells from HIV-positive and healthy persons were depleted from adherent cells to eliminate fibroblasts. In further experiments, the cells were additionally enriched for CD34-positive hematopoietic progenitor cells or were depleted from delta TCS-1-positive T lymphocytes. At concentrations of 1.25-10 microM, the three antisense ODN did not inhibit any erythrocyte or granulocyte-monocyte colony growth from CD34-positive cells, either from the HIV-positive or from the HIV-negative cohort. In contrast to azidothymidine, which served as inhibitory control, a significant increase of colony growth was seen after depletion of fibroblasts, of delta TCS-1-positive cells, or without cell separation. In conclusion, the three oligodeoxynucleotides do not exert any hematotoxic effect but do increase colony formation from low-density bone marrow cells in vitro and could therefore be useful in future clinical studies.

Antigens, CD↗
PubMed1995

In vivo distribution of integrins in renal cell carcinoma: integrin-phenotype alteration in different degrees of tumor differentiation and VLA-2 involvement in tumor metastasis.

We studied 23 renal cell carcinomas and two normal kidney tissues by immunohistochemistry using monoclonal antibodies against subunits of the VLA integrins (VLA-1 to VLA-6) and CD51. All integrins investigated in our study, except VLA-4 (ubiquitous negative), were distributed in different patterns in tumors assayed. We found a correlation between VLA-2 expression and site of tissue; primary tumor cells expressed no VLA-2 integrin, whereas tumor cells from metastatic tissues exhibited VLA-2 positivity (P < .009). Additionally, the expression of VLA-3 and VLA-5 correlated with tumor grading; both integrins were undetectable in G1 tumors but widely expressed in G2 and G3 tumors (VLA-3, p < .000; VLA-5, p < .005). Our results suggest that VLA-2 integrin is involved in metastasis of RCC and that poorly differentiated tumor cells have a different integrin phenotype when compared to normal or highly differentiated tumor cells.

Adult↗
PubMed1995

Hematopoietic growth factors in the treatment of the myelodysplastic syndromes.

Clinical trials with hematopoietic growth factors (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and erythropoietin) have been performed in patients with myelodysplastic syndromes. Absolute neutrophil counts can be readily raised to within the normal range by treatment with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Moderate increases in platelet counts have been reported for approximately 20% of patients during treatment with interleukin-3. Treatment with high-dose erythropoietin leads to an increase in hematocrit or decrease in transfusion needs in 15% to 20% of patients, but an improved response rate of approximately 40% has been reported for the combined treatment of erythropoietin with either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Although meta-analyses of published phase I/II trials allow a rough estimation of response rates and an improved selection of patients who are most likely to respond, phase III trials have not yet been published.

Clinical Trials as Topic↗
PubMed1995

Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors.

Differentiation induction therapy is used in myelodysplastic syndromes (MDS) to improve maturation defects and to restore impaired function of malignant cells. To this end, 18 patients with MDS received either a combination therapy consisting in study 1 of all-trans retinoic acid (ATRA) and granulocyte-colony stimulating factor (G-CSF), or in study 2 of a combination with ATRA, G-CSF, erythropoietin (Epo) and tocopherol. The ANC increased in 19/20 patients in both studies, whereas an increase in haemoglobin concentration, platelet counts or reduction of transfusion requirement was seen in only 8/20 patients, correlating strongly with good BFU-E growth (P < 0.001). To assess the role of accessory cells in the modulation of the haemopoietic response to treatment, we analysed the capacity of peripheral blood monocytes to secrete cytokines (IL-1 beta, IL-6, IL-8, TNF alpha). Secretion of all cytokines was significantly reduced before therapy when compared with healthy controls, but increased during therapy, reaching normal levels for IL-8. These data indicate that a combination therapy with ATRA and cytokines improves impaired cytokine secretion from monocytes and induces a multilineage clinical response in a subgroup of MDS patients characterized by an almost intact erythroid compartment. In contrast, induction of TNF alpha might be responsible for treatment failure.

Adult↗
PubMed1994

A low affinity chimeric human alpha/beta-granulocyte-macrophage colony-stimulating factor receptor induces ligand-dependent proliferation in a murine cell line.

The high affinity receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) is composed of at least two subunits, an 85-kDa low affinity GM-CSF-binding protein (alpha-GMR) and a 120-kDa beta-subunit (beta-GMR) necessary for high affinity binding and signal transduction. Previous studies have shown that deletion of the intracellular domain of alpha-GMR inactivates the receptor's ability to support proliferation, but has no effect on GM-CSF binding. Using anti-alpha-GMR- and anti-beta-GMR-specific antibodies, we show that alpha-GMR and beta-GMR coprecipitate only after GM-CSF binding, suggesting that binding of GM-CSF induces stabilization or assembly of an activated receptor complex involving recruitment of beta-GMR chains. To understand the contribution of each subunit of this receptor to the generation of an activated receptor complex, we attempted to construct minimal receptors with some or all of the functions of the wild-type heterodimer. We found that a hybrid human alpha/beta-GMR molecule in which the extracellular and transmembrane segments are composed of alpha-GMR sequences and the intracellular segment is composed of beta-GMR bound GM-CSF with low affinity, but activated tyrosine kinase activity, induced receptor internalization, and supported short- and long-term proliferation of transfected Ba/F3 cells. At least 1 ng/ml human GM-CSF was required for growth stimulation, and maximal proliferation occurred at a concentration of 10 ng/ml. This was 10-100-fold more than needed to stimulate growth of Ba/F3 cells expressing both full-length human alpha-GMR and beta-GMR and 1000-fold less than needed to stimulate growth of Ba/F3 cells expressing only human alpha-GMR. These results indicate that the cytoplasmic domain of alpha-GMR is not required to initiate a unique signaling event for proliferation in Ba/F3 cells, but can be functionally replaced by the cytoplasmic domain of beta-GMR.

3T3 Cells↗
PubMed1994

Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukemia by in situ hybridization.

The presence of BCR-ABL fusion genes has important diagnostic and prognostic implications in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The CML-specific chimeric BCR-ABL gene with a break involving the major breakpoint cluster region (M-bcr) of the BCR-gene has been detected by means of fluorescence in situ hybridization (FISH). In this study, we present a FISH protocol that allows the detection of breaks in both the major and the minor breakpoint cluster region (m-bcr). Three hybridization signals of D107F9, a yeast artificial chromosome (YAC)-derived probe spanning the breakpoint regions of the BCR gene, were indicative of the translocation events. To increase the specificity further, this probe was combined with cos-abl 8, a cosmid probe flanking the breakpoint within the ABL gene for dual-color hybridization. Samples of 21 patients with CML, the ALL-derived cell line SUP-B15, and of seven patients with Philadelphia chromosome (Ph1)-positive ALL (three of them with breakpoints within m-bcr) were examined. BCR-ABL fusion was detected in all cases with high specificity (false-positive nuclei: mean, 0.1%). On cytogenetic preparations, the percentages of BCR-ABL-positive interphase cells ranged from 53% to 91%. Comparable efficiencies were achieved on blood smears. In conclusion, hybridization with D107F9 and cos-abl 8 allows unambiguous diagnosis of BCR-ABL genes and is likely to become an important tool for the monitoring of therapies in patients with CML and ALL.

Adult↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

Effect of combination therapy with all-trans-retinoic acid and recombinant human granulocyte colony-stimulating factor in patients with myelodysplastic syndromes.

Since all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) not only enhance proliferation and differentiation of normal myeloid cells but also synergistically promote the differentiation of myeloid leukemic blast cells in vitro, we have started a pilot study of combined treatment with ATRA and G-CSF in patients with myelodysplastic syndrome, to analyze the effect of these drugs on hematopoietic differentiation. ATRA was given at 45 mg/m2/day p.o. from week 1-12 and G-CSF at 5 micrograms/kg/day s.c. from week 5-12 with dose modifications according to the absolute neutrophil counts (ANC). A total of 15 patients, predominantly with refractory anemia, were treated. During initial ATRA therapy, a bilineage response with increases of both ANC and platelet counts occurred in three patients. During combined ATRA/G-CSF therapy, ANC increased in all patients, and platelets increased in three out of 14 evaluable patients. An increase in hemoglobin concentration and a decrease in transfusion requirements occurred in one patient each. In the bone marrow, the myeloid-to-erythroid ratio increased during ATRA treatment and remained increased during concomitant G-CSF administration, while the maturation index of myeloid cells increased only in response to ATRA therapy, but returned to baseline during ATRA/G-CSF treatment. Cytogenetic analysis demonstrated persistence of the abnormal clones in all patients. The number of circulating progenitor cells CFU-GM increased in all patients studied. Serum concentrations of the soluble TNF receptor and IL-2 receptor both increased, while TNF-alpha--already elevated prior to therapy--and soluble ICAM-1 concentrations did not significantly change. Adverse effects included dermatitis and cheilosis in most patients, and a drop in platelet counts related to G-CSF in one patient. The pilot study demonstrates that the combination treatment with ATRA/G-CSF is well tolerated, leading to normalization of ANC in most, and improvement of platelets and red blood cells in a subgroup of patients.

Adult↗