Biomedical subjects
T Büchner
Publications and source records attributed to T Büchner.
[Acute lymphatic leukemia of the adult. Diagnosis, risk groups and therapy].
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[Quality of life and coping with illness in patients with acute myeloid leukemia].
Advances in chemotherapy significantly prolong survival of patients with acute myeloid leukemia (AML) and may cure a significant percentage of patients. Therefore, the assessment of quality of life (QL) of patients undergoing chemotherapy is of growing interest. This study was designed to evaluate QL in patients with AML treated according to the protocol of the German AML-Cooperative Group (Münster, FRG). Based on conceptual, methodological and practical criteria, the EORTC-QLQ C 30 questionnaire was used. In addition, patients' coping strategies were assessed by the FQCI. Patients' individual perception of their disease and therapy was evaluated by a semi-structured interview. Currently, 61 patients are enrolled in the protocol. For those patients having completed the course of inpatient treatment, individual assessment of Global Health Status and Subjective QL improves significantly. The content analysis of the interviews shows to what extent aspects of the inpatient setting influence patients' QL. Although only a minority of patients with AML remain in continuous complete remission, the evaluation of QL in patients undergoing treatment shows that subjective benefit outweighs the effects of antileukemic therapy.
Pulmonary infiltrates in patients with haematologic malignancies: clinical usefulness of non-invasive bronchoscopic procedures.
In a prospective study 90 patients with haematologic malignancies (57 acute leukaemias, 6 Hodgkin's Diseases, 15 Non-Hodgkin Lymphomas, 12 other diseases), with fever exceeding 38.4 degrees C and newly developed pulmonary infiltrates underwent bronchoscopy obtaining bronchoalveolar lavage, bronchial washings and protected brush specimen (n = 71). Pneumonias due to gram-negative bacteria (n = 38) and fungi (n = 34) were most frequent. Bronchoscopic specimens yielded 226 isolates (2 different organisms/bronchoscopy on average). 112 organisms were finally regarded as causing pneumonia. Sensitivity of bronchoscopy in diagnosing infectious episodes was 66%, but only 4 out of 13 non-infectious pulmonary infiltrates could be identified. Bronchoscopy was most effective in the diagnosis of pneumocystis carinii and herpes virus pneumonia, whereas sensitivity and specificity of detecting fungal and bacterial pneumonia were low. Empirical antimicrobial therapy was verified by evaluation of bronchoscopic samples in 25 out of 90 cases. Empirical therapy was successfully changed according to the results of invasive samplings in 34 out of 90 cases. Early identification of causative pathogens had a significant impact on survival.
Clinical, morphologic, cytogenetic and prognostic implications of CD34 expression in childhood and adult de novo AML.
Expression of CD34 by leukemic blasts was analyzed in 230 pediatric and 251 adult patients with de novo AML enrolled in two large multicenter trials (AML-BFM-87 and AMLCG respectively). The association between CD34 positivity and morphological classification according to FAB criteria, cytogenetic aberrations, immunophenotypic features and clinical characteristics was investigated. CD34 was expressed (> or = 20%) by leukemic cells from 45% of childhood and 43% of adult AML patients. CD34+ AML was often associated with M1/M2 morphology as well as the coexpression of CD7 and TdT. Translocation t(8;21), inv(16) and chromosome 5 and 7 aberrations were more frequently observed in CD34+ AML. There was a low frequency of CD34 expression in infant AML but no age dependency was evident in adult patients. CD34 expression exerted no influence on the rate of complete remissions (CR) after intensive multidrug induction therapy. In adults, 56% of the CD34-positive and 64% of CD34-negative cases achieved CR (P = 0.29), and the childhood trial even revealed a slight advantage for CD34+ AML with a CR rate of 80% vs. 71% for CD34-negative cases (P = 0.068). Long-term follow-up disclosed no significant differences in remission duration or event-free survival between the CD34-positive and CD34-negative groups. In conclusion, CD34+ AML patients comprise a heterogeneous group with good as well as poor risk factors. Though characterized by some distinct features, CD34 lacks prognostic significance in de novo AML patients submitted to intensive polychemotherapy.
Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia.
The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)
[Comparison of 3 decubitus prevention measures stemming from the same principle--with reference to cost-benefit analysis].
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Hematopoietic growth factors in cancer treatment.
The introduction of hematopoietic growth factors during the past five years has changed the scenery of antitumor treatment. Growth factors following high-dose chemotherapy or bone marrow transplantation have become established as part of many treatment protocols. The main benefits are earlier recovery of neutrophils resulting in fewer days with fever, antibiotics and hospitalization. Growth factors were found to reduce the treatment-related morbidity and to improve the practicability of therapeutic regimens. First studies on a prospective chemotherapy dose intensification supported by growth factors are underway. As a further effect of growth factors, an attempted enhancement of antitumor cytotoxicity by recruitment of tumor cells to chemosensitivity or by modulation of antitumor drug metabolism appears realistic based on first data on growth factor priming in AML. New ways to support high-intensity and myeloablative antitumor strategies are opened by the autologous transplantation of peripheral blood progenitor cells mobilized by growth factors and also by the use of new factors like SCF and the synergistic combination of growth factors as part of future strategies against malignant disorders.
New perspectives in the treatment of acute myeloid leukemia by hematopoietic growth factors.
The application of hematopoietic growth factors in the treatment on acute myeloid leukemia (AML) may principally aim at shortening the period of treatment associated neutropenia and reducing the rate of infectious complications by their post-therapeutic administration but may also be used to increase the sensitivity of leukemic blasts to antileukemic therapy by pretherapeutic growth stimulation. Both aspects were addressed in subsequent clinical phase II studies and preclinical investigations. In a first clinical trial, 36 patients with high-risk AML received granulocyte-macrophage colony-stimulating factor (GM-CSF) after successful cytoreductive chemotherapy and experienced a shortening of the period of post-therapeutic neutropenia by 6 to 9 days, leading to a significant reduction of treatment-associated deaths from 39% to 14%. In preclinical studies an enhancement of the cytotoxicity of cytosine arabinoside (AraC) on leukemic blasts could be shown by pretreatment with GM-CSF or IL-3. Investigations on the impact of hematopoietic growth factors on the intracellular metabolism of AraC indicated that this effect was primarily mediated by an increase in the activity of DNA-polymerase-alpha. The evaluation of different doses of AraC showed the most marked increase after the combination of GM-CSF with conventional rather than high doses of AraC. Based on these preclinical experiments, a prospective randomized trial was subsequently initiated investigating the effect of GM-CSF before and during induction, consolidation, and the first two cycles of maintenance chemotherapy in newly diagnosed AML. This ongoing trial has enrolled 67 patients at the current time. An early interim analysis showed no differences in remission rates but a tendency toward a longer remission duration in patients receiving GM-CSF. These data indicate that hematopoietic growth factors like GM-CSF in particular may provide a new perspective in the treatment of acute myeloid leukemia with the possibility of reducing treatment associated mortality and perhaps of increasing the efficacy of antileukemic treatment.
Experimental basis for the use of recombinant human granulocyte-macrophage colony-stimulating factor in patients with acute myeloid leukemia.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only stimulates hematopoiesis, but also induces the proliferation and differentiation of leukemic myeloid cells. The observation that clonogenic growth of malignant cells can be induced in vitro has led to the development of therapeutic concepts that aim to increase the sensitivity of cells to cytostatic and cytotoxic agents by priming them with GM-CSF. In in vitro experiments, preincubating leukemic cells with recombinant cytokines including GM-CSF led to a consistent, dose-dependent increase in the cytotoxicity of cytosine arabinoside (Ara-C). This effect has since been observed in patients with acute myeloid leukemia (AML) although its mechanism is not yet entirely clear. It seems that GM-CSF increases the relative number of cells in the S phase of the cell cycle and enhances the activity of DNA polymerases, enzymes that are essential to nucleotide incorporation into DNA. Based on these experimental results, numerous clinical trials have investigated the role of GM-CSF in priming leukemic blasts before chemotherapy. These studies will allow us to determine whether our in vitro observations of increased cytotoxicity translate into higher remission rates and durations, and will help us to identify the patient subgroups most likely to benefit from this therapeutic approach.
The role of hematopoietic growth factors in the treatment of cancer and leukemias.
The introduction of hematopoietic growth factors during the last 5 years has changed the scenery of anti-tumor treatment. Growth factors following high dose chemotherapy or bone marrow transplantation have become established as part of many treatment protocols. Main benefits are earlier recovery of neutrophils resulting in fewer days with fever, antibiotics and hospitalization. Growth factors were found to reduce the treatment related morbidity and improve the practicability of therapeutic regimens. First studies on a prospective chemotherapy dose intensification supported by growth factors are underway. As a further effect of growth factors an attempted enhancement of anti-tumor cytotoxicity by recruitment of tumor cells to chemosensitivity or by modulation of anti-tumor drug metabolism appears realistic as from first data of growth factor priming in acute myeloid leukemia. New ways to support high intensity and myelo-ablative anti-tumor strategies are opened by the autologous transplantation of peripheral blood progenitor cells mobilized by growth factors and also by the use of new factors like stem cell factor and the synergistic combination of growth factors as part of future strategies against malignant disorders.
Modulation of intracellular metabolism of cytosine arabinoside in acute myeloid leukemia by granulocyte-macrophage colony-stimulating factor.
The current study investigated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine (araC) in leukemic cells of 45 patients with acute myeloid leukemia (AML). AML blasts from bone marrow (BM) (n = 39) and peripheral blood (PB) (n = 17) were incubated for 48 h with or without GM-CSF (100 U/ml) followed by a concurrent treatment with increasing concentrations of araC (0.06-100 microM) for an additional 24 h. After GM-CSF a 1.5-8.4-fold (median 2.3) increase in 3H-araC incorporation into the DNA was observed in ten of 14 peripheral blast specimens and in 23 of 28 bone marrow samples, 18 of whom also showed an enhanced 3H-TdR incorporation (1.5-8.5-fold, median 2.0-fold). Four different types of response were identified when analyzing 3H-araC incorporation into the DNA of bone marrow samples in relation to the applied araC dose: (i) 8/28 cases had increases of the araC incorporation at all araC dose levels applied (0.06-100 microM), (ii) 12/28 at low araC concentrations only (0.06-1.0 microM), (iii) 3/28 at high araC concentrations only (10-100 microM), and (iv) 5/28 showed no increase at any dose level given. Hence, 20 of the 23 responding patients revealed a GM-CSF induced enhancement of araC incorporation at low or conventional doses of araC (0.06-1.0 microM). Fourteen of the 18 cases with concomitant rises of 3H-TdR and 3H-araC incorporation into the DNA after GM-CSF had elevated DNA polymerase alpha activity (16-531%, median 72%) and in ten cases overall DNA polymerase activity was enhanced (10-70%, median 22.5%). In contrast, thymidine kinase (TK) and deoxycytidine kinase (dCK) activity were elevated after GM-CSF in only ten and five patients, respectively. An increase in the fraction of cells in S phase was found in 11/21 bone marrow specimens and in 5/9 peripheral blast samples. However, no correlation was observed between increases in the proportion of cells in S phase and enhancements in enzyme activities. In 13 cases the cytotoxicity of araC with and without GM-CSF was assessed by means of a blast cell colony assay. Preincubation with GM-CSF increased the araC mediated cytotoxicity in ten of 13 patients by a median of 3.2-fold (range 2.2-229-fold). The respective LD50 values for araC were reduced from 0.45 to 0.19 microM on average.(ABSTRACT TRUNCATED AT 400 WORDS)
Detection of aberrant antigen expression in acute myeloid leukemia by multiparameter flow cytometry.
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Immunophenotype of acute myeloid leukemia: correlation with morphological characteristics and therapy response.
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CD34 expression in de novo acute myeloid leukaemia.
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The role of GM-CSF in the treatment of acute myeloid leukemia.
After a first study showed that GM-CSF following chemotherapy effectively accelerated neutrophil recovery and reduced early mortality in high risk patients with AML, a second study was begun in which GM-CSF was applied preceding chemotherapy and continuing until neutrophil recovery in the initial 5 chemotherapy courses for patients with newly diagnosed AML. The CR rate in patients of 16-75 (median 50) years was 75% in GM-CSF patients and 84% in controls. GM-CSF patients showed a trend to more frequent rapid blast clearance and fewer persistent leukemias and a significantly superior remission duration as of this update two-and-a-half years after the study started. It should be shown later by this study whether GM-CSF multiple course priming and longterm administration adds to the cure rate of patients with AML.
[Acute myeloid leukemia].
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