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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 415 records · Page 23Linked to original sources
PubMed1985

Differential pattern of DNA-aneuploidy in human malignancies.

The differential pattern of DNA-aneuploidy, detected by flow cytometry (FCM) regarding its frequency, grade and multiclonality, was investigated and correlated to tumor type, malignancy grade, tumor stage and prognosis in a multi-institutional study at the University of Münster. High resolution measurements using admixed normal blood reference cells were undertaken in 2413 cases of 13 different malignant diseases and in 776 benign lesions or samples. The incidence of DNA-aneuploidy was highest in melanomas, carcinomas, testicular tumors, sarcomas (75%-95%) and myelomas (65%). Acute leukemias showed an intermediate DNA-aneuploidy rate of 40% with special subgroups represented by common ALL (44%), p less than 0.05) and myelomonocytic/monocytic AML (47%, p less than 0.01). The lowest DNA-aneuploidy-rate was found in basal cell skin carcinomas (19%) and congenital melanocytic nevi (9%). No case of DNA-aneuploidy was observed in the 776 benign lesions or samples.--DNA-indices giving the grade of DNA-aneuploidy with 1.0 for normal diploid G1/0 cells were found distributed predominantly between 1.0 and 2.0 in the solid tumors, except testicular tumors, clustering around a triploid maximum at 1.5. DNA-indices of myelomas and acute leukemias generally ranged below 1.25 with lower DNA-aneuploidy grades in AML than in ALL (p less than 0.01).--In melanomas the aneuploidy rate was higher (86%) in metastases than in the primary tumors (54%, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Immunotherapy with allogeneic neuraminidase-treated blasts for maintenance in acute myelogenous leukemia (AML). Significant prolongation of remission duration in patients receiving at least 3 cycles of therapy.

102 patients with AML (leukemia after preleukemia, 2nd neoplasia included) were treated for remission induction by a modified TAD regimen in Munster; 55 patients (54%) achieved a complete remission (CR). For CR maintenance 40 patients were eligible for randomization according to the study protocol: cyclic chemotherapy (CT) alone vs. chemoimmunotherapy (CIT: plus allogeneic Neuraminidase-treated blasts in high dosage). 5 CR patients, induced identically in Essen, were randomized additionally. Evaluating all patients randomized there is only a marginally beneficial effect of CIT (21 patients) compared to CT (24 patients) concerning median survival (1020+ vs. 612 days) and relapse-free survival (494 vs. 380 days) until now. For patients receiving more than 2 cycles of maintenance therapy, however, CIT prolongs relapse-free survival significantly (930+ vs. 409 days; p = 0,02); that is also true for remission duration. This suggests that only repeated application of blasts may induce an immune response leading to a biologically relevant antileukemic effect.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

[AMSA/etoposide (VP 16-213). A phase I/II study in refractory acute myeloid leukemia].

In a phase I/II study the tolerable doses and antileukemic efficacy of the combination AMSA and etoposide (VP 16-213) was assessed in 20 patients with refractory acute myeloid leukemia. The following 5 day treatment course was found tolerable and effective: AMSA 210 mg/m2/die on days 2, 3 and 4, and etoposide on days 1 and 5 as a 1 h infusion of 100 mg/m2 followed by a 23-h continuous infusion of 230 mg/m2. In 5 of 20 patients partial remissions were achieved; 4 of these patients were primarily resistant against two TAD induction cycles. Bone marrow aplasia without a residual blast population was achieved in 7 of the 8 patients with primary TAD resistance. AMSA/etoposide thus seems to express an antileukemic efficacy without cross-resistance against TAD.

Aminoacridines↗
PubMed1985

Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group.

In two multicenter trials, a total of 576 patients with acute myeloid leukemia (AML) were treated and found to be evaluable. Two hundred forty-two patients were in a 1978 pilot study and 334 patients were in a 1982 randomized study. Ages were between 15 and 78 years (median, 48). The uniform remission induction therapy in both studies consisted of one to two courses of a 9-day combination of 6-thioguanine (TG) with cytosine arabinoside (ARA-C) and daunorubicin (DNR) [TAD9]. The timing and sequencing of TAD9 was designed according to cell kinetic effects of ARA-C. A complete remission (CR) was achieved in 65% (70% and 61%, respectively) of patients within a median of 33 days, and in 68% of responders after only one course. The CR rate in patients 60 to 78 years of age was 51% (66% and 39%, respectively). In the 1978 pilot study, different protocols of post-remission treatment were applied at the different centers: monthly 5-day maintenance, TAD9 consolidation, both consolidation and maintenance, or no further therapy. The group receiving treatment during CR showed 24% probability of remissions at 4 years v 0% probability of remissions in the untreated group. Between the different post-remission protocols, no significant differences were observed. Remission duration was not influenced by age, WBC, or morphologic cell type, but was longer in patients achieving CR within 30 days (P = .017). In the subsequent 1982 study, 145 patients in CR were randomized for TAD9 consolidation with or without monthly maintenance. The updated life-table analysis revealed a predicted rate of continuous remission at 2 1/2 years of 30% for the maintenance and 17% for the nonmaintenance arm (P = .003). These results of response and remission duration in adult patients of all ages support the validity of intensified induction therapy and of consequent myelosuppressive treatment in remission.

Actuarial Analysis↗
PubMed1984

Convention on nomenclature for DNA cytometry. Committee on Nomenclature, Society for Analytical Cytology.

Analysis of cellular DNA content by cytometry is important in clinical and biological research. Measurements are used widely to assess the relative DNA content of tumor stemlines and to assist in the detection and evaluation of malignant diseases. A review of the literature on DNA measurements in solid tumor and leukemias reveals a confusing variety of terms applied for the description of similar results. In order to facilitate the understanding of data and to standardize the terminology for DNA analyses, a questionnaire was distributed to more than 500 investigators. Subsequently, a workshop on terminology was held at the Combined Conference on Analytical Cytology and Cytometry IX and VIth International Symposium on Flow Cytometry, Schloss Elmau, West Germany, 18-23 October, 1982. The workshop nominated a nine-member committee to develop guidelines for nomenclature to be used in reporting results from analyses by DNA cytometry. The committee was charged by the Council of the Society for Analytical Cytology to complete this task and to publish its recommendations in Cytometry and in Cancer Genetics and Cytogenetics. The following guidelines are based on the questionnaires returned and the discussion at the workshop; they represent the unanimous recommendations of the committee. The five guidelines given herein apply to measurements of relative DNA content of cells that have been stained appropriately and analyzed by cytometry.

Animals↗
PubMed1984

[Combined therapy with AMSA and etoposide (VP 16-213) in refractory acute myeloid leukemia. A phase I study].

In a phase I study the combination of AMSA and etoposide was applied to 12 patients with intensively pretreated, refractory AML to evaluate the basis for a subsequent phase II study in terms of drug dosage and timing. Each treatment cycle consisted in a 5-day regimen of AMSA 210 mg/m2/d days 2, 3 and 4. Etoposide was administered on days 1 and 5 with a constant loading dose of 100 mg/m2 by an 1-h infusion followed by a 23-h infusion, the dose of which was escalated in 3 steps from 110 mg/m2 to 200 mg/m2 and 230 mg/m2. In 18 treatment cycles the recommended dosage for a subsequent phase II study was found to be 660 mg/m2 etoposide per cycle together with 630 mg/m2 AMSA per course. Main side effects were nausea and vomiting as well as mucositis; 1 patient developed a severe intrahepatic cholestasis. In 11 from 16 evaluable treatment cycles a significant reduction of bone marrow blasts was observed with a mean cytoreduction rate of 0,26 log10/d. 4 patients, 3 of whom were primarily resistent to 2 TAD induction courses, achieved a partial remission.

Aminoacridines↗
PubMed1984

New cytomorphologic methods in the diagnosis of bone tumors: possibilities and limitations.

The value of new morphologic methods in the diagnosis of bone tumors is demonstrated in a number of cases. In round cell malignancies (Ewing's sarcoma, malignant lymphoma, neuroblastoma, and anaplastic plasmacytoma) diagnostic accuracy can be improved by electron microscopic and immunohistochemical techniques. New methods are also of value in differentiating the metastatic carcinoma from malignant bone primaries. Electron microscopy may show epithelial cell features (ie, gland structures, desmosomes, and tonofilaments), while immunohistologic investigation of the cytoskeleton may facilitate differentiation of epithelial cells (positive for prekeratin) from mesenchymal cells (positive for vimentin). In the differential diagnosis of typical bone tumors, however, such as osteosarcoma, chondrosarcoma, and malignant fibrous histiocytoma, the value of enzyme histochemical, electron microscopic, and immunohistochemical methods appears somewhat restricted: alkaline phosphatase activity may be increased in both chondrosarcoma and osteosarcoma; collagen type II, the cartilage-specific collagen, is found not only in chondrosarcoma but in osteosarcoma as well. Moreover, osteosarcomas may contain a considerable number of macrophages and histiocytes, and so this feature is worthless in distinguishing osteosarcoma from malignant fibrous histiocytoma. A new approach for appraising the malignancy of bone tumors may be through flow cytometric investigation of nuclear DNA content. Osteosarcomas reveal DNA aneuploidies in more than 80% of cases, with a large proportion of cells in the S phase. These features may prove valuable for discerning osteosarcoma from myositis ossificans. In contrast to typical giant cell tumor of bone, a rare case of malignant giant cell tumor showed aneuploid cell lines indicating the malignant nature of the tumor.

Bone Neoplasms↗
PubMed1984

Effect of very high-dose thymidine infusions on leukemia and lymphoma patients.

The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.

Adult↗
PubMed1983

[The Münster study of intensive induction and consolidation therapy without maintenance therapy of acute myeloid leukemia. Results of 93 patients--cellular determinants for response and length of remission].

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.

Adolescent↗
PubMed1983

[Comparison of the therapeutic efficacity of 2 induction protocols in acute myeloid leukemia using exact quantification of bone marrow cellularity].

Using a recently developed technique for the determination of the pure bone marrow cell count per mm3 bone marrow, two different induction regimens for AML were compared for their efficacy, i.e. the therapy induced cytoreduction. In both protocols cytosine arabinoside, daunorubicin and 6-thioguanine were applied at comparable doses but different schedules. In both regimens a blast cell reduction of more than 2.0 log10 within the first 5 to 6 days of therapy strongly correlated (p less than 0.001) with the achievement of an adequate blast clearance in the marrow and complete remission (n = 18), while an inadequate blast cell reduction was revealed in all patients with a cell kill of less than 2.0 log10 (n = 9). Total cytoreduction on day 5 or 6 of therapy was comparable for both protocols. However, on one protocol a continuous logarithmic blast cell reduction was found while the cell kill followed a biphasic function on the other regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1982

Cell kinetics in acute leukemia: a critical reevaluation based on new data.

The current study was undertaken to compare biopsy and aspiration sampling techniques for reliable cell kinetic analysis in acute leukemia and to reevaluate the clinical significance of cell kinetic data in this disease. Ad 1: One hundred forty-three paired simultaneously taken marrow aspirates and Jamshidi biopsies from 61 patients with acute nonlymphocytic leukemia (ANLL) were compared by means of flow cytometry (FCM) for cellular DNA and RNA measurements, autoradiography for 3H-TdR labeling index and liquid scintillation counting for 3H-TdR uptake. Aspirates were found unreliable for pretreatment evaluation and for monitoring of drug induced cell kinetic perturbations due to contamination with peripheral blood. Aspiration should, therefore, be replaced by marrow biopsy which provides reliable sampling of bone marrow for cell kinetic studies. Ad 2: FCM S-phase index determined from biopsy material was not found predictive for therapeutic response in 43 patients with ANLL treated with two different induction regimens. In one of the two protocols, changes in FCM S-phase index after 48 hours continuous infusion of cytosine arabinoside correlated significantly with clinical response and nonresponse, respectively.

Biopsy↗
PubMed1982

Bone marrow biopsy instead of 'marrow juice' for cell kinetic analysis. Comparison of bone marrow biopsy and aspiration material.

Since cell kinetic bone marrow studies have so far exclusively been carried out on aspiration material and have yielded inconsistent or even contradictory results, we investigated the adequacy and reliability of aspirates for cell kinetic analyses in comparison to biopsies. Paired samples of bone marrow (133) were taken simultaneously by aspiration and Jamshidi biopsy from 48 patients with acute leukemias and 67 patients with non-leukemic disorders. Cell kinetic analysis by (1) flow cytometry (FCM) of cellular DNA and RNA content, (2) autoradiography for [3H]TdR pulse labelling indices and (3) liquid scintillation counting of [3H]TdR uptake revealed significantly higher values in biopsies (p less than 0.001) exceeding the corresponding results from aspirates on average by factors of 1.65 for FCM S-phase index, 1.90 for G0/1 cells with high RNA content, 1.82 for [3H]TdR LI and 1.90 for [3H]TdR uptake. In more than 70% of all samples results from biopsies were 1.1-11.4 times higher, indicating that aspirates were equivalent to biopsies in fewer tan 30% of cases. Cell kinetic analysis in vitro blood/biopsy mixtures and measurements of DNA synthesis rate in corresponding aspirates and biopsies revealed that these discrepancies are due to the contamination of aspirates with non-proliferating nucleated blood cells. Biopsy, however, was found to provide representative and reproducible sampling of marrow for cell kinetic studies and should replace the presently used aspirate already characterized as "unreliable marrow juice" by Dameshek et al. in 1937 [18].

Acute Disease↗
PubMed1982

Bone marrow cell count per cubic millimeter bone marrow: a new parameter for quantitating therapy-induced cytoreduction in acute leukemia.

A new technique is introduced for determining the number of bone marrow cells per cubic millimeter marrow, providing an accurate and objective means for quantitating therapy-induced cytoreduction. The method requires a correction for admixed peripheral blood in bone marrow aspirates to measure the fraction of remaining pure marrow. While cell kinetic differences between blood, aspirates, and biopsies identify the proportion of contaminating blood cells, the ratio of red cell hematocrits in blood and aspirate gives the volume of trapped blood. By combining both procedures, bone marrow cell counts per unit volume pure marrow result (BMC/cu mm BM), which were found highly reproducible. Blast cell counts (BMBC/cu mm BM) were obtained by additional morphological differentiation. BMC and BMBC/cu mm BM were monitored in 16 patients with acute nonlymphoblastic leukemia treated with daunorubicin, cytosine arabinoside, and 6-thioguanine in combination and in 4 patients with end-stage acute leukemias and non-Hodgkin's lymphomas during high-dose thymidine therapy. Total and daily therapy-induced cytoreduction rates were significantly greater (P less than 0.01) in responders than nonresponders to either regimen. Changes in BMC/cu mm BM were also found representative for changes in BMBC/cu mm BM, since the majority of bone marrow cells were blasts. In acute leukemia. BMC/cu mm BM thus provides accurate and objective measurements of treatment efficacy in vivo and after short periods of drug exposure. Differences in cytoreduction rates within the group of responders also suggest possible prognostic implications.

Acute Disease↗
PubMed1981

Intensified remission induction therapy for acute nonlymphocytic leukemia (ANLL). Treatment report on 60 patients.

Sixty patients with ANLL were given intensified remission induction therapy consisting of thioguanine, cytosine arabinoside and daunorubicin (TAD). The mean age of patients was 47.6 years (range 18 to 74 years). Basing on leukemic cell kinetic data time sequencing of drugs was different from the original TAD protocol. Complete remission (CR) waa achieved in 43/60 patients (72%) with 10 CR in 15 patients over 60 years of age. Seventy-nine percent of the CR were induced by one cycle vs thirty percent reported from the original TAD regimen. The major cause of induction failure--in ten of the 60 patients--was thrombocytopenia refractory to platelet transfusions. Persisting leukemia after two induction cycles was documented in only two patients. Median remission duration by life table analysis is 10 months with 17 patients in continuous CR for 1+ to 22+ months.

Acute Disease↗