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Biomedical subjects

T Büchner

Publications and source records attributed to T Büchner.

At least 127 records · Page 7Linked to original sources
PubMed1990

Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial.

Previous investigations in animals and one retrospective study in man suggest that verapamil can prevent anthracycline-induced cardiomyopathy. In the following study, patients with acute myeloid leukemia (AML) treated with double induction and consolidation chemotherapy (AML COOP study 1986, [3]) were randomized in a group with and without accompanying low-dose oral verapamil treatment. Since July 1986, 64 patients have been included. Thirty patients have been evaluated for pre- and posttreatment cardiological investigations. So far, no significant difference in cardiotoxicity has been observed either between the verapamil and nonverapamil group or between the two induction chemotherapy regimens (TAD/TAD - TAD/HAM).

Adolescent↗
PubMed1990

Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy for acute leukemias at higher age or after relapse.

Chemotherapy (CT) induced critical cytopenia remains as the major dose limiting problem in the treatment of acute leukemias. This is especially true in patients at high risk of early death due to high intensity chemotherapy for relapse or to higher age. In an attempt to reduce the phase of risk we administered human recombinant GM-CSF to 23 patients at a median age of 65 (range 17-84) years including 8 acute myelogenous (AML) and 5 lymphoblastic (ALL) leukemias after early or second relapses and 10 patients of 65 years and older in primary induction treatment for AML. 3 patients with AML had prior bone marrow transplantation. 4 AML's were secondary to tumor chemotherapy (2) or myelodysplastic syndrome (2). The study was part of chemotherapeutic phase II and III studies using TAD9 for primary induction chemotherapy and S-HAM for relapses. Starting on day 4 after the end of intensive CT GM-CSF 250 micrograms/m2/day was given by continuous i.v. infusion and after recovery of neutrophils was deescalated in two 4 day steps and discontinued. 12/23 patients achieved a complete remission (CR) and median age of responders is 61 (range 17-84) years. In the group of the non-transplanted patients the median recovery time of neutrophils is reduced by one week when compared to controls receiving the same chemotherapy (p = 0.002). We observed a leukemic regrowth in 3 patients of 61, 70, and 78 years, 2 of whom having secondary AML. After discontinuation of GM-CSF the regrowth of blasts was reversible in 1 patient and continued unaffectedly in its kinetics in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1990

Synergistic cytotoxicity of cytosine arabinoside and mitoxantrone for K562 and CFU-GM.

High-dose cytosine arabinoside (Ara-C) plus mitoxantrone (MX) have proved to be effective in the treatment of refractory acute leukemia. The optimal sequence of drug administration was tested in a clonogenic assay with the leukemic myeloid cell line K562, and with CFU-GM of normal human bone marrow. The exposure times were 24 h for Ara-C and 1 h for MX with 1 h delay between incubations. Either order of the drugs and a wide range of drug concentrations were tested. Cytotoxicity was quantified by the survival fraction (fs) of colonies scored on day 7 (K562) or day 14 (CFU-GM). Drug synergism was evaluated by a cooperative index (CI). CI less than 1 indicates synergism, CI = 1 summation, and CI greater than 1 antagonism of the cytotoxic drugs. In K562 the sequence Ara-C much greater than MX was significantly more toxic (3.68 logs cell kill, CI = 0.02) than MX much greater than Ara-C (2.64 logs kill, CI = 0.31). The highest synergism was found by adding MX during the last hour of a 24 h Ara-C exposure. For CFU-GM, Ara-C much greater than MX showed higher synergistic toxicity (2.24 log cell kill, CI = 0.23) than MX much greater than Ara-C (1.44 logs, CI = 1.11). The clinical high dose Ara-C/MX protocol was transformed into an in vitro model and tested on K562. The highest synergism was found after the sequence of 3 h Ara-C followed by 0.5 h MX after 8.5 h delay (1.73 logs kill, whole sequence 2.01 logs kill), thus supporting the clinically applied sequence.

Cells, Cultured↗
PubMed1990

Predictive models for achievement of complete remission and duration of first remission in adult acute myeloid leukemia.

Achievement of CR. Using the data of 501 patients treated identically with the TAD9 regimen we could not find any factor of predictive value besides age and state of health. The effect of FAB-M seems to be spurious as it disappeared using prospective data. Duration of Relapse-Free Survival. In patients with monthly maintenance, the maintenance overrides the possible effects of the considered factors. In patients without monthly maintenance we only found a slight effect of WBC.

Aged↗
PubMed1990

Sequential decision strategy of the AML Cooperative Group studies.

The ongoing 1985 studies are showing at present no clear advantage for either therapy. In the 1981 study, randomization was terminated by the sequential procedure after 161 randomizations. A test with the same alpha and beta but fixed sample size would have required at least 200 patients, 100 for each therapy. So in this case the use of the sequential procedure saved about 40 randomizations.

Aged↗
PubMed1990

Analysis of the cellular DNA and RNA content in acute leukemias by flow cytometry.

In the present study bone marrow samples from 573 patients with newly diagnosed acute myeloid (AML) and lymphoblastic or undifferentiated leukemias (ALL/AUL), were analysed for their cellular DNA and DNA/RNA content, respectively, by means of flow cytometry. From 237 patients with AML 35.4% revealed aneuploid DNA stemlines. While no relation of DNA aneuploidy with other pretherapeutic parameters, including FAB subtype, white blood cell count, lactate dehydrogenase, S-phase index and percentage of blasts in the bone marrow, was observed, cases with aneuploid DNA stemlines revealed a tendency towards longer remission duration. In ALL/AUL 21.8% of 280 patients expressed DNA aneuploidies, which were less frequently found in T-cell ALL (11.1%) as compared to common(C)-ALL (21.4%) or null-cell(null)-ALL (23.5%). DNA aneuploidy was not related with other clinically defined risk factors such as age, white blood cell count, and rapid achievement of remission. Patients with DNA indices less than 1.0, however, tended to have shorter remissions. A significant difference in RNA indices was observed between AML and ALL/AUL with median values of 14.4 and 10.1, respectively (P less than 0.05). These data indicate the usefulness of flow cytometric analyses of cellular DNA and RNA content for the characterization and classification of acute leukemias, complementing the identification of clinical risk factors, immuno-phenotyping and cytogenetics.

Acute Disease↗
PubMed1990

Treatment strategies in acute myeloid leukemia (AML). B. Second line treatment.

The strategy for treatment of relapsed or refractory acute myeloid leukemia must primarily be based on the patient's age and clinical condition as well as on the stage of the disease. Accordingly, the general decision between an intensive approach including high-dose chemotherapy or possibly immediate allogeneic bone marrow transplantation versus less-aggressive palliative treatment will precede the selection of the most appropriate salvage regimen. In patients qualifying for intensive second-line chemotherapy the duration of the first remission and the number of relapses provide the means to discriminate between refractoriness or maintained responsiveness to conventional protocols. More than 50% of patients with first relapses after 6-12 months remission duration will respond to standard therapy again and should therefore not be entered on investigational agents with unproven antileukemic activity. The latter seems deeply warranted, on the other hand, for early relapses, second recurrences and resistant first relapses with a remission rate of less than 30% after conventional regimens. These guidelines not only provide an objective rationale for selecting the most appropriate strategy at relapse in individual patients. Furthermore, they facilitate interstudy comparisons and a better judgement of different treatment protocols.

Bone Marrow Transplantation↗
PubMed1990

Hepatosplenic candidiasis, a late manifestation of Candida septicaemia in neutropenic patients with haematologic malignancies.

Systemic candidiasis with Candida-induced abscesses, predominantly in the liver and the spleen, was diagnosed in 27 patients with haematologic malignancies after intensive cytostatic therapy. Specific features included septic fever unresponsive to antimicrobial therapy, hepatosplenomegaly with multiple lesions in the liver and spleen (diameter up to 2 cm) as detected by computed tomography (CT) or ultrasound, and an elevation in liver enzymes. During treatment, induced neutropenia, hepatic and splenic foci were poorly defined histologically and were not identified by imaging procedures. After granulocyte recovery these foci showed characteristic histological patterns. Ultrasound and/or CT investigations of the abdomen now revealed characteristic lesions in the liver and the spleen. Gamma-GT and alkaline phosphatase were early indicators of hepatic involvement in Candida septicaemia and were often already elevated in aplasia.

Abscess↗
PubMed1990

Changing response of clonogenic myeloid leukemia blasts to granulocyte-macrophage colony-stimulating factor (GM-CSF) during anti-leukemic therapy--a case report on the basis of a clinical phase II trial.

In a clinical phase II trial GM-CSF was applied to 23 patients with acute leukemias carrying a high risk of early death because of old age or advanced disease. Concomitant laboratory investigations included the analysis of colony assays for normal granulopoietic progenitors (CFU-GM) and leukemic CFU-L with and without the addition of GM-CSF, as well as DNA measurements by flow cytometry (FCM) for the detection of DNA-aneuploidies. The present analysis is focused on one particular patient with acute myeloid leukemia (AML) in whom the detection of a DNA aneuploidy provided the readily accessible means to monitor the response of leukemic blasts to induction chemotherapy and subsequent GM-CSF treatment in vivo complementing the colony assay analyses performed in vitro. Prior to therapy 60% of cells revealed a DNA aneuploidy with a DNA index of 1.26 and in-vitro exposure of leukemic bone marrow blasts to GM-CSF (100 U/ml) enhanced the growth of CFU-L and CFU-GM with a significantly higher stimulatory index for CFU-L (1:19 versus 1:5.5). Three days after the completion of two cycles of induction therapy with thioguanine, cytosine arabinoside and daunorubicin (TAD 9) a morphologic bone marrow evaluation revealed aplasia without leukemic blasts. By FCM DNA analysis, however, 8% residual aneuploid cells were found. No growth of CFU-L was observed at this time point neither spontaneously nor after the addition of GM-CSF which induced the growth of CFU-GM, only. In-vivo application of GM-CSF (250 micrograms/mg2/day by continuous 24-h infusion) led to the recovery of normal granulopoiesis without evidence of a concomitant stimulation of aneuploid leukemic cells. These data indicate a change in the susceptibility of leukemic blasts to GM-CSF before and after chemotherapy. A reduction of the leukemic cell burden below a critical level or a selection of GM-CSF non-responsive early leukemic precursor cells may account for these observations.

Aged↗
PubMed1990

High-dose versus intermediate-dose cytosine arabinoside in combination with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia--preliminary clinical and pharmacological data of a randomized comparison.

The present randomized trial addressed the pending question whether cytosine arabinoside (AraC) should be given at high or intermediate dose to patients with relapsed or refractory acute myeloid leukemia. Based upon the previously established regimen of the sequential administration of AraC and mitoxantrone (S-HAM) patients below 60 years of age were randomized to receive AraC at either 3.0 g/m2 vs. 1.0 g/m2 per dose while older patients were randomly assigned to either 1.0 g/m2 or 0.5 g/m2 AraC. Concurrent pharmacokinetic analyses were performed to determine the plasma AraC pharmacokinetics as well as the intracellular AraCTP peak concentrations and retention times. At the present stage 65 patients are evaluable for response and toxicity. Complete remissions were achieved at similar frequencies for patients treated with 3.0 g/m2 or 1.0 g/m2 AraC with 56% and 50%, respectively. Reasons for failure were different, however, with a higher incidence of resistant disease in patients treated with 1.0 g/m2 AraC and more early deaths in the higher dose treatment group. Pharmacokinetic studies indicated a homogeneous distribution of AraC plasma concentrations but a substantial interpatient variability for intracellular AraCTP peak concentrations and retention times.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: a proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy.

Response to salvage therapy at first and second relapse was analyzed in 150 patients with acute myeloid leukemia (AML) to improve the characterization of relapsed AML and to deduce from this analysis a proposal for the definition of refractoriness against conventional therapy. Salvage treatment consisted of a repetition of the TAD 9 regimen which was already applied as induction protocol at initial diagnosis. All patients were recruited from the multicenter 1982 trial of the German AML Cooperative Group and had thus received a standardized first line treatment. Response at first relapse was significantly related to the duration of the first remission. From 38 patients relapsing within 6 months after successful induction therapy, only 11 (28%) achieved a second complete remission as compared to 58 of 98 (59%) cases with later occurring relapses (p less than 0.01). This difference was due to a significantly higher incidence of persistent leukemia in the former group and not biased by differences in early death rates. No other variable was found predictive for the response to salvage treatment including age, WBC, serum LDH, morphologic subtype, presence or absence of DNA aneuploidy as detected by flow cytometry or maintenance chemotherapy. A low remission rate of 28% was also obtained in the 14 patients at second relapse. These data indicate that patients with a duration of their first remission of more than 6 months cannot be considered as being refractory against standard chemotherapy while patients with early relapses and second recurrences have a response rate of less than 30% due to refractory disease. Hence, the following criteria are proposed for the definition of refractoriness against standard chemotherapy in advanced AML: (a) nonresponse to first-line induction therapy, (b) early relapse within 6 to 12 months of first remission, (c) relapse after 6 to 12 months of first remission and failure on a reinduction attempt with established regimens, (d) second and subsequent relapses. These criteria may provide a useful rationale for the selection of the most appropriate treatment at relapse. They may also serve as eligibility criteria for clinical phase I/II studies and will facilitate interstudy comparisons.

Adult↗
PubMed1990

Treatment of refractory acute lymphoblastic leukemia in adults with high dose cytosine arabinoside and mitoxantrone (HAM).

In a clinical phase II study the combination of high dose cytosine arabinoside and mitoxantrone (HAM) was applied to 24 patients with refractory acute lymphoblastic leukemia (ALL). All patients had received a standardized first line treatment and were considered refractory against conventional chemotherapy as defined by nonresponse to induction treatment (n = 8), nonresponse to an alternative salvage regimen at first relapse (n = 9), second and third relapses (n = 5) and relapse after bone marrow transplantation (n = 2). Therapy consisted of HD-araC 3 g/m2 q 12 hr days 1-4 and mitoxantrone 10 mg/m2/d days 2-5 or 2-6. Twelve of the 24 patients (50%) achieved a complete remission (CR), one patient had a partial remission, and five patients were nonresponders. Five patients died in aplasia due to infections, one additional patient succumbed to HD-araC related CNS toxicity. Nonhematologic side effects consisted predominantly in infection, nausea and vomiting, mucositis and diarrhea. Recovery of blood counts occurred at a median of 28 days from the onset of treatment; the median time to CR was 33 days. Three of the 12 responders underwent subsequent bone marrow transplantations and one is alive disease free at 40+ months. The median remission duration for the remaining nine patients is 3.5 months, with one case in ongoing CCR at 36+ months; the median survival time is 5 months. Considering the selection of a highly unfavorable group of patients, these data demonstrate a significant antileukemic activity of HAM in refractory ALL and support its application as consolidation treatment during first line ALL therapy.

Adolescent↗