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Biomedical subjects

L Stenke

Publications and source records attributed to L Stenke.

At least 19 recordsLinked to original sources
PubMed2002

Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.

Aclarubicin↗
PubMed2001

Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment.

The outcome of continued EPO therapy was studied in 18 responding MDS patients. The EPO dose was reduced in a stepwise fashion to find the lowest possible maintenance dose. Relapses of anemia were associated with either progressive disease or reduction of the administered EPO dose. In the latter group second responses to renewed EPO therapy were readily achieved. Long-term responses were seen in about a third of the patients. Thus, it seems safe to reduce the EPO dose among responding patients. This approach may have advantages both from a medical and a socio-economic perspective.

Aged↗
PubMed2000

Aberrant expression of active leukotriene C(4) synthase in CD16(+) neutrophils from patients with chronic myeloid leukemia.

Elevated leukotriene (LT)C(4) synthase activity was observed in peripheral blood granulocyte suspensions from patients with chronic myeloid leukemia (CML). Magnetic cell sorting (MACS) with CD16 monoclonal antibodies (mAbs), which were used to fractionate granulocytes from CML patients and healthy individuals, yielded highly purified suspensions of CD16(+) neutrophils. The purity of these cell fractions was verified by extensive morphologic examination. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses, demonstrating the absence of interleukin-4 messenger RNA (IL-4 mRNA), further confirmed the negligible contamination of eosinophils in these fractions. Notably, purified CML CD16(+) neutrophils from all tested patients transformed exogenous LTA(4) to LTC(4). These cells also produced LTC(4 )after activation with ionophore A23187 or the chemotactic peptide fMet-LeuPhe (N-formylmethionyl-leucyl-phenylalanine). Subcellular fractionation revealed that the enzyme activity was exclusively distributed to the microsomal fraction. Expression of LTC(4) synthase mRNA in CML CD16(+) neutrophils was confirmed by RT-PCR. Furthermore, Western blot analyses consistently demonstrated expression of LTC(4) synthase at the protein level in CML CD16(+) neutrophils, whereas expression of microsomal glutathione S-transferase 2 occurred occasionally. Expectedly, LTC(4) synthase activity or expression of the protein could not be demonstrated in CD16(+) neutrophil suspensions from any of the healthy individuals. Instead, these cells, as well as CML CD16(+) neutrophils, transformed LTA(4) to LTB(4). The results indicate that aberrant expression of LTC(4) synthase is a regular feature of morphologically mature CML CD16(+) neutrophils. This abnormality, possibly associated with malignant transformation, can lead to increased LTC(4) synthesis in vivo. Such overproduction may be of pathophysiological relevance because LTC(4 )has been demonstrated to stimulate proliferation of human bone marrow-derived myeloid progenitor cells. (Blood. 2000;95:1456-1464)

Antigens, CD↗
PubMed2000

[Radioimmunotherapy is rapidly developing to clinically efficient therapy].

The use of monoclonal antibodies (mabs) in cancer therapy has gained renewed interest, due to recent reports of remarkable clinical response, particularly in patients with low-grade non-Hodgkin lymphoma. Better defined and more appropriate target antigens and "humanized" mabs, reducing the risk of inducing neutralising human anti-mouse antibodies, have contributed to the improvement in results. Conjugation of mabs with various radionuclides is now being explored as a means of further enhancing clinical efficacy, the idea being to allow systemic delivery of targeted radiation to areas of disease while sparing normal tissue. Radioimmunotherapy may be administered as a single large dose of radiolabelled mabs, usually requiring haematological stem cell support, or as multiple, smaller fractions. The criteria for the selection of mabs and radionuclides are discussed in the article, as are recent clinical data and the problems and prospects of future developments in radioimmunotherapy.

Clinical Trials as Topic↗
PubMed2000

P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia.

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment. PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed. CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells--enhanced neurotrophin-4 expression induced by LTB4.

The expression of neurotrophin and neurotrophin receptor mRNAs in human granulocytes and bone marrow cells was examined using ribonuclease protection assay and reverse transcription-polymerase chain reaction. The granulocytes expressed mRNA coding for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3). Moreover, the inflammatory mediator leukotriene B4 (LTB4) up-regulated the expression of NT-4 mRNA in granulocytes, but did not affect the expression of other neurotrophin mRNAs. Granulocytes generally lacked expression of mRNA coding for neurotrophin receptors. In contrast, human bone marrow cells consistently expressed mRNA for trkB (the BDNF and NT-4 receptor) and displayed variable expression of mRNA coding for trkA (the tyrosine kinase NGF receptor) and LNGFR (the low-affinity NGF receptor), whereas mRNA for trkC (the NT-3 receptor) was not expressed. Contrary to granulocytes, normal bone marrow cells generally expressed only low levels of mRNA encoding BDNF and NT-4. Expression of mRNA encoding NGF and NT-3 was not detected. However, significantly increased expression of BDNF mRNA was observed when bone marrow cells from patients with chronic myeloproliferative disorders (MPD) were analyzed. The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4.

Bone Marrow Cells↗
PubMed1998

Novel enzymatic abnormalities in AML and CML in blast crisis: elevated leucocyte leukotriene C4 synthase activity paralleled by deficient leukotriene biosynthesis from endogenous substrate.

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory effects on human myelopoiesis. We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.

Acute Disease↗
PubMed1997

Differences in cell lineage involvement between MDS-AML and de novo AML studied by fluorescence in situ hybridization in combination with morphology.

We have employed fluorescence in situ hybridization (FISH) in combination with standard morphology (MGG/FISH) to identify the clonal involvement of different bone marrow cell lineages in 20 AML patients (14 MDS-AML, 6 de novo AML). Even though the number of cells belonging to the abnormal clone varied between individual cases, the percentage of clonal blasts was similar in MDS-AML and de novo AML patients. The erythropoietic cells appeared to be part of the abnormal clone in 13 of 14 patients with MDS-AML, but only in 1 of 6 with de novo AML. Similarly, clonal granulocytes were detected in 13 of 14 patients with MDS-AML, compared to 2 of 6 with de novo AML. Lymphocytes consistently displayed normal, diploid karyotype. The results suggest that it is possible to distinguish between MDS-AML and de novo AML by the use of MGG/FISH; in de novo AML the abnormal chromosomal clone is generally confined to the immature myeloid cells, while in MDS-AML mature granulocytes and erythroid cells are of clonal origin. It is, however, not possible to conclude that MDS-AML is a "multipotent" type of leukaemia, since it cannot be ruled out that the chromosomally aberrant erythroid cells and granulocytes represent surviving cells from the original MDS clone.

Adult↗
PubMed1996

A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes.

In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

Aged↗
PubMed1994

Leukotrienes and lipoxins--new potential performers in the regulation of human myelopoiesis.

Leukotrienes and lipoxins are bioactive lipoxygenase products formed by leukocytes alone or in collaboration with other cells. While the physiological role of lipoxins remains to be clarified, accumulating evidence shows that leukotrienes are important mediators in asthma and inflammation. Consequently, recent clinical trials with leukotriene D4 receptor antagonists and 5-lipoxygenase inhibitors have demonstrated marked reduction of airway symptoms in asthmatic patients. In addition, both leukotrienes and lipoxins have been indicated as modulators of cell proliferation. This article reviews recent findings suggesting that these compounds may also participate in the regulation of human myelopoiesis. Such a role is conceivable since leukotrienes and lipoxins can be produced by bone marrow cells and potently modulate GM-CSF-induced myeloid stem cell proliferation.

Bone Marrow↗
PubMed1993

Stimulation of human myelopoiesis by leukotrienes B4 and C4: interactions with granulocyte-macrophage colony-stimulating factor.

The regulatory role of leukotrienes (LT) on human myelopoiesis was investigated. Mononuclear bone marrow cells from 31 healthy donors were cultivated in the presence of suboptimal concentrations of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10 days in semisolid agar. The addition of LTC4 or LTB4 to the cultures dose-dependently stimulated myeloid stem cell proliferation. Maximal effects were observed at 10(-8) mol/L, at which LTC4 induced a 91% +/- 23% (mean +/- SEM; P = .004) and LTB4 a 73% +/- 22% (P = .008) increase in colony formation. In contrast, addition of the LTB4 isomer 5(S), 12(S)-diHETE did not affect the growth. LTD4 exerted a weak potentiating effect on progenitor proliferation (17% +/- 7% growth stimulation at 10(-10) mol/L; P = .034), whereas LTE4 was without consistent effect. Furthermore, LTC4-induced stimulation of colony formation was insensitive to the LTD4 antagonist ICI 198615. The dual lipoxygenase and prostaglandin endoperoxide synthase inhibitor CL42A potently suppressed the proliferation of myeloid colonies, a suppression that could be reversed by parallel addition of LTB4 or LTC4. The results suggest that both LTB4 and LTC4 possess strong and specific synergistic stimulatory effects on GM-CSF-induced human myeloid progenitor cell growth.

Bone Marrow↗
PubMed1993

Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes.

The effect of human recombinant erythropoietin (rhEPO) was investigated in 29 anemic patients with myelodysplastic syndromes (MDS). A rhEPO dosage of 150 U/kg was administered subcutaneously three times weekly for a minimum of 6 weeks. Seven out of 27 evaluable patients (26%) had an effective clinical response to therapy by increasing hemoglobin concentrations by more than 15 g/l (reaching at least 105 g/l) or by eliminating transfusion requirements. Six out of the seven patients responded within four weeks. Three of the responders successfully continued rhEPO treatment 15 months or more. To determine whether it may be possible to predict response to rhEPO, various clinical parameters were examined. Responders were found to be significantly different from non-responders in five aspects: They had less elevated baseline serum EPO levels (92 +/- 33 versus 515 +/- 108 U/l, mean +/- SEM; p = 0.023) and were more often transfusion-independent (71% versus 20% of non-responders; p = 0.022). Furthermore, responders were more often females (71% versus 40% in the non-responding group; p = 0.025), of subtype RA rather than RAEB (four patients and one patient, respectively, compared to seven and nine patients in the non-responding group; p = 0.025), and they predominantly displayed normal karyotypes or a 5q- aberration (86% versus 47%; p = 0.005). We conclude, that rhEPO treatment can reduce anemia in MDS and that certain pre-treatment clinical parameters may be used to predict response.

Aged↗