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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 145 records · Page 8Linked to original sources
PubMed1999

Transforming growth factor beta is a growth-inhibitory cytokine of B cell lymphoma in SIV-infected macaques.

Cytokine dysregulation is accepted as one of the pivotal factors in the pathogenesis of B cell lymphomas in HIV-positive patients. So far no data exist on inhibitory cytokines in the regulatory network of HIV-associated B-NHL. Simian immunodeficiency virus (SIV)-infected macaques are a well-established in vivo model of HIV infection in humans. We used this model for the identification of TGF-beta as a growth-inhibitory cytokine of SIV-associated B cell lymphomas. Fifty-seven rhesus macaques were infected with SIVmac. Nine animals developed B cell lymphomas: eight with high-grade lymphomas of the immunoblastic, centroblastic, and "Burkitt-like" type, and one with the centroblastic/centrocytic type according to the Kiel classification. Six of seven analyzed lymphomas were infected with the macaque EBV, herpes virus macaca mulatta (HVMM). The lymphomas and the SIV-associated B cell lymphoma cell line H50 were positive for transcription of the TGF-beta gene. Protein expression and secretion of the active cytokine were proved by immunohistochemistry and ELISA. H50 transcribed the TGF-beta type I and type II receptor (R I/II), betaglycan, and endoglin. Furthermore, all primary lymphoma samples tested were positive for receptor type I/II transcription and protein expression. TGF-beta induced reduction of cell viability by 67% (range, 50-84% and enhanced apoptosis by 69% (range, 33-111%) compared with the control. TGF-beta activity was blocked by a specific anti-TGF-beta antibody. Thus, TGF-beta fulfilled the criteria of a negative autocrine inhibitor in H50. These data identify TGF-beta as a promising candidate as an inhibitory factor in the regulatory network of HIV-associated lymphomagenesis.

Animals↗
PubMed1999

Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group.

Early intensification of chemotherapy with high-dose cytarabine either in the postremission or remission induction phase has recently been shown to improve long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induction strategy. The present trial evaluated the contribution of high-dose versus standard-dose cytarabine to this strategy. Between March 1985 and November 1992, 725 eligible patients 16 to 60 years of age with newly diagnosed primary AML entered the trial. Before treatment started, patients were randomized between two versions of double induction: 2 courses of standard-dose cytarabine (ara-C) with daunorubicin and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose cytarabine (3 g/m2 every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 21 before remission criteria were reached, regardless of the presence or absence of blast cells in the bone marrow. Patients in remission received consolidation by TAD and monthly maintenance with reduced TAD courses for 3 years. The complete remission (CR) rate in the TAD-TAD compared with the TAD-HAM arm was 65% versus 71% (not significant [NS]), and the early and hypoplastic death rate was 18% versus 14% (NS). The corresponding RFS after 5 years was 29% versus 35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire population; they included patients with more than 40% residual blasts in the day-16 bone marrow, patients with unfavorable karyotype, and those with high levels of serum lactate dehydrogenase. Their CR rate was 65% versus 49% (p =.004) in favor of TAD-HAM and was associated with a superior event-free survival (median, 7 v 3 months; 5 years, 17% v 12%; P =.012) and overall survival (median, 13 v 8 months; 5 years, 24% v 18%; P =.009). This suggests that the incorporation of high-dose cytarabine with mitoxantrone may contribute a specific benefit to poor-risk patients that, however, requires further substantiation. Double induction, followed by consolidation and maintenance, proved a safe and effective strategy and a new way of delivering early intensification treatment for AML.

Adolescent↗
PubMed1999

Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.

We performed a prospective, randomized, multicenter trial to evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in patients after chemotherapy or autologous bone marrow transplantation and an expected duration of neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis in an unblinded fashion. The incidence of proven, probable, or possible IA infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P =.37). Moreover, no differences in the overall mortality (13% v 10%; P =.37) or in the infection-related mortality (8% v 7%; P =.79) were found. In contrast to other nonrandomized trials, we observed no benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA infections was low.

Administration, Inhalation↗
PubMed1999

[Treatment of adult acute lymphoblastic leukemia].

In patients with adult ALL, substantial progress has been made in the past 20 years. At present a cure rate of 30-40% can be achieved and varies in defined subgroups between 10-51%. ALL does not represent an uniform disease but is formed by biologic subentities, which differ in their natural history, clinical presentation and prognosis. A comprehensive diagnostic examination, including morphology, cytochemistry, immunology, cytogenetic and molecular genetic analysis is a precondition for prognostic assessment and therapeutic stratification. The basic principle of ALL treatment is a combination chemotherapy with sequential administration of induction, consolidation and maintenance therapy. Bone marrow transplantation has become an important part of the treatment strategy and is performed in patients with high risk. In the subgroup of T-ALL a significant progress has been made in the last years with survival rates of 40-50%. In B-ALL the results have been greatly improved to 48-51% by introduction of a specific treatment strategy. However, the results (about 30%) stagnate for the total group of B-lineage-ALL (common ALL, pre-B-ALL, pro-B-ALL). Patients with B-lineage-ALL can be subdivided in a high and low risk group according to the presence of risk factors (age, white blood cell count, time to achieve a complete remission, pro-B-ALL and the translocations t[4;11], t[9;22]). The outcome of the subgroup of adult pro-B-ALL has been substantially improved (50%). An increase of treatment results (20%) appears in outlines for patients above 50 years. The Ph/bcr-abl positive ALL has in spite of improved complete remission rates (60-70%) consistently unfavourable survival rates (10%).

Adult↗
PubMed1999

[MRI-controlled regional hyperthermia].

PURPOSE: Regional hyperthermia in combination with chemotherapy or/and radiotherapy is a promising treatment concept for locally advanced, deep-seated tumors. The purpose of the project is the optimization of the therapy using non-invasive, three-dimensional imaging of tissue changes or of the temperature distribution during regional hyperthermia. METHODS: MRI offers methods suitable in principle for tissue characterization and MR thermometry. A new MRI-hyperthermia hybrid system has been developed based on an innovative hyperthermia applicator and an open MRI system. RESULTS: After successful testing of the new MRI-hyperthermia hybrid system simultaneous MRI and regional hyperthermia in patients could be accomplished for the first time. At present the T1 relaxation time seems to be a promising parameter for MR thermometry. CONCLUSION: The first clinical application of the MRI-hyperthermia hybrid system can be regarded as an important step towards the development of regional hyperthermia. This new hybrid system and the MR thermometry methods have to be investigated prospectively in clinical studies.

Equipment Design↗
PubMed1999

Cytidine deaminase - the methodological relevance of AraC deamination for ex vivo experiments using cultured cell lines, fresh leukemic blasts, and normal bone marrow cells.

The clinical effects of cytosine arabinoside (AraC) are highly dependent on schedule and dose. Many regimens administered to patients are derived from artificial model systems involving permanent leukemic cell lines. The differences in pharmacokinetics between the in vivo situation and such cell lines are largely neglected. However, cytidine deaminase activity in particular has a major impact on AraC pharmacokinetics by degrading AraC to its inactive metabolite AraU, and it has been shown to be of prognostic relevance in the treatment of acute myeloid leukemia. This study therefore investigated cytidine deaminase activities and AraC deamination in a variety of the most commonly used leukemic cell lines and fresh blasts and their impact on the results of an in vitro model system. It was found that cells from different cell lines (BLIN, CEM, HL60, K562, RAJI, REH, U937) vary greatly in cytidine deaminase activity (e.g., 1.89 nmol per min/mg in K562 versus 0.01 in BLIN cells) and degrade between 18.5 (BLIN) and 96.5% (REH) of AraC to AraU in the incubation medium. This degradation results in highly different AraC exposures for different cells (e.g., AUC of 960 ng per h/ml in REH versus 4048 ng per h/ml in BLIN cells) in spite of identical starting concentrations of the drug. Formation of AraCTP as the main cytotoxic metabolite of AraC is significantly influenced by the differences in cell type-dependent cytidine deaminase activity (e.g., 35.6 ng/10(7) cells in REH versus 180.2 ng/10(7) cells in BLIN cells). In contrast to permanent cell lines, fresh leukemic blasts and normal bone marrow mononuclear cells featured low AraC degradation in the model system.

Acute Disease↗
PubMed1999

Results of a randomized double-blind placebo-controlled trial evaluating sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy with or without granulocyte/macrophage-colony-stimulating factor in high-risk myelodysplastic syndromes.

A prospective, randomized, double-blind placebo-controlled trial was designed to evaluate the impact of granulocyte/macrophage-colony-stimulating factor (GM-CSF) on the efficacy of sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy (S-HAM) in adult patients with high-risk myelodysplastic syndromes (MDS). GM-CSF or placebo was given subcutaneously once daily at a dose of 250 microg/m2, starting 48 h prior to chemotherapy, and continued until neutrophil recovery. Owing to high toxicity and slow patient recruitement the study was closed and unblinded after 31 patients had been enrolled; 15 were randomized to receive placebo and 16 to receive GM-CSF. A total of 29 patients were evaluable for response; their median age was 57 years. Ten patients achieved a complete remission (34.5%), 9 patients had persistent MDS (31%), 10 patients died within 6 weeks after the onset of treatment (early death) (34.5%). The median remission duration was 190 days (range: 2.5-45 months). Among the 29 evaluable patients no significant differences could be found between the two study arms regarding complete remission rate [GM-CSF: 31% (5/16) versus placebo: 38% (5/13) P = 0.45], rate of persistent MDS [GM-CSF: 25% (4/16) versus 38% (5/13) P = 0.35), early death rate [44% (7/16) versus 23% (3/13) P = 0.22] and remission duration (GM-CSF: 87 days versus placebo 221 days). Duration of granulocytopenia (median: 33 days with GM-CSF) versus 35 days with placebo) and frequency of infectious episodes were not significantly influenced by GM-CSF. The small number of patients finally analyzed means that no definite conclusions about the effect of GM-CSF can be reached.

Adult↗
PubMed1999

Expression of granulocyte colony-stimulating factor- and granulocyte-macrophage colony-stimulating factor-associated signal transduction proteins of the JAK/STAT pathway in normal granulopoiesis and in blast cells of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is characterized by the malignant transformation of hematopoietic stem cells leading to dysregulated growth and differentiation of myeloid cells. Normally, proliferation and differentiation of myeloid cells are regulated by cytokines such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Abnormal signaling of the signal transduction pathway from the cytokine receptors via Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) might be involved in the pathogenesis of AML. We examined whether an abnormal expression of one of the four JAKs, STAT1, STAT3, STAT5, or the tyrosine phosphatase SHP-1, a negative regulator of this pathway, is associated with malignant transformation in AML. Analysis of the expression of proteins of the JAK/STAT pathway in normal myeloid cells at three stages of maturation revealed a strong expression of all proteins in CD34+ cells, whereas the level of the proteins was significantly lower in granulocytic precursors and mature neutrophils. Furthermore, during maturation the relation of the isoforms of STAT1 and STAT3 changed from predominantly alpha to predominantly beta. Leukemic blast cells from 25 patients and 12 cell lines showed a high level of STAT proteins and SHP-1, whereas a deficiency of at least one of the four JAKs was found in 10 of 25 patients. In primary AML blast cells a deficiency of three JAKs was more common in patients with an abnormal karyotype. In addition, a lack of JAK2 and Tyk2 protein was strongly associated with the FAB M2 phenotype. The proliferation rate in response to GM-CSF available in a small number of patients appears to be related to the JAK2 expression. Our data suggest that the degree of expression of G-CSF/GM-CSF receptor-associated proteins of the JAK/STAT pathway in normal myeloid cells is related with their clonogenic potential. STAT3 appears to be involved in early differentiation. Similar to CD34+ cells, it is likely that the high levels of STATs and SHP-1 found in leukemic cells reflects their proliferative activity, whereas a lack of members of the JAK family might lead to an inability to proliferate in response to G-CSF/GM-CSF described in a considerable percentage of AML blasts.

Antigens, CD34↗
PubMed1999

Monoclonal antibody therapy for B cell non-Hodgkin's lymphomas: emerging concepts of a tumour-targeted strategy.

Although much progress has been made in the understanding of the pathobiology of malignant lymphomas in recent years, progress in the treatment of patients with this diagnosis has been limited. Monoclonal antibody therapy is an innovative and promising concept in the treatment of malignant lymphoma, and the current status of this treatment is reviewed here. Phase I/II clinical trials have proven the high antilymphoma activity of antibody-based therapeutic strategies. Radioimmunoconjugates with myeloablative activity have induced response rates of between 80 and 100% in heavily pretreated patients. The chimeric monoclonal antibody IDEC-C2B8 has shown high antilymphoma activity in patients with relapsed follicular lymphoma with an overall response rate of up to 50%. The combination of the IDEC-C2B8 antibody with standard chemotherapy has shown encouraging results with no increase in toxicity compared with chemotherapy alone. The introduction of antibody therapy promises to open new perspectives in the treatment of patients with malignant lymphoma. Prospective randomised clinical trials will define the patient who will gain maximal benefit from antibody-based therapy.

Antibodies, Monoclonal↗
PubMed1999

Suppressive subtractive hybridisation reveals differential expression of serglycin, sorcin, bone marrow proteoglycan and prostate-tumour-inducing gene I (PTI-1) in drug-resistant and sensitive tumour cell lines of haematopoetic origin.

The development of therapy-induced drug resistance is still one of the most important therapeutic limitations. Nevertheless, an integrating view of the molecular mechanisms underlying resistance development in general is missing. In order to shed some light on the network of this resistance development, we established drug-resistant (doxorubicin (DX), methotrexate (MTX), cisplatin (cisPt), vincristine (Vin)) derivatives of six tumour cell lines (Jurkat, U937, HL60, DoHH-2, K562 and ARH77) of haematopoetic origin. Differential gene expression of drug-sensitive parental cell lines and the drug-resistant derivatives thereof was analysed by suppressive subtractive hybridisation. After dot blot screening for differential expression and sequencing of the cloned PCR fragments, differential expression was confirmed by Northern blot analysis. In an attempt to discriminate for differentially expressed genes only related to one or the other of the investigated drugs, the cDNAs of various resistant sublines (doxorubicin-, methotrexate-, cisplatin-resistant Jurkat cells) were pooled and compared with the sensitive parental cell line. In addition, cDNAs of the resistant derivatives of the different haematopoetic tumour cell lines were pooled and compared with the pooled cDNAs of the corresponding sensitive haematopoetic cell lines to eliminate cell line to cell line variations that were not related to drug resistance. As a result of this screening, the following genes showed a higher (at least 2-fold) or exclusive expression in the drug-resistant variants: serglycin, sorcin, BMPG (bone marrow proteoglycan gene) and PTI-1 (prostate-tumour-inducing gene 1). In addition, elevated expression of hsp90, previously found by our group to be upregulated in the drug-resistant colon carcinoma cell line LoVo H67P was found to be overexpressed in drug-resistant HL60 cells.

Antineoplastic Agents↗
PubMed1999

Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission.

Acute myeloid leukemia arises from the clonal expansion of a malignant transformed progenitor cell. Despite intensive chemotherapy, final disease eradication is achieved by a small proportion of cases only and 50-70% of adults with AML will ultimately relapse and die from their disease. Hence residual disease below the level of morphological detectability must be assumed in clinical and morphological complete remission. CD34+/CD38- and CD34+/CD38+ subpopulations of seven patients in morphological complete remission were isolated by FACS (purity >98%) and were analyzed by conventional cytogenetics or FISH for chromosomal aberrations. In five of seven patients, clonal chromosomal abnormalities were detected in the CD34+/CD38+ subpopulation and in one patient with AML M2 (add (2)(q37)) in the most immature CD34+/CD38- stem cell compartment. One patient with AML M4Eo (inv(16),+8), showed a normal karyotype by conventional cytogenetic analysis, whereas four of 15 metaphases of the sorted CD34+/CD38+ subpopulation revealed the inversion 16. These observations underline that leukemic cells can survive intensive chemotherapy in the niche of the stem cell compartment. In some patients the sensitivity for the detection of persistent leukemic cells seems to be higher in FACS-sorted subpopulations than conventional cytogenetic analysis of the unseparated bone marrow. Immunophenotyping revealed minimal residual disease in four of the patients. Functional analysis has to be performed to investigate the leukemogenic potential of these residual cells.

ADP-ribosyl Cyclase↗
PubMed1999

Analysis of progenitor cell involvement in B-CLL by simultaneous immunophenotypic and genotypic analysis at the single cell level.

B-cell chronic lymphocytic leukaemia (B-CLL) results from the clonal expansion of mature B lymphocytes. The detection of leukaemia-associated genetic markers in CD34-positive progenitor cells in a subset of B-CLL patients suggests that malignant transformation in B-CLL occurs in an immature progenitor cell compartment. To further quantify the percentage of B-CLL patients with genetically aberrant progenitor cells we have investigated CD34+ bone marrow cells in 11 B-CLL patients at the single cell level by simultaneous genetic and immunophenotypic analysis (FICTION). In five patients with trisomy 12, CD34+ haemopoietic progenitor cells were detectable on bone marrow smears. In one patient with trisomy 12, CD34+ progenitor cells were isolated by FACS sorting. In all six patients trisomy 12 was not found in the CD34+ cells. Progenitor cells were also analysed in three patients with Rb-deletion and in two patients with deletion of p53. In all patients the genetic marker was not detected in the CD34+ cells. In conclusion, we did not find genetically aberrant progenitor cells in this group of B-CLL patients. These results suggest that the subset of B-CLL patients with genetically aberrant CD34+ cells may be very small. This is of significance for our understanding of B-CLL biology and for future strategies using autologous stem cell transplantation.

Aged↗