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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 235 records · Page 13Linked to original sources
PubMed1997

Stimulation of B-chronic lymphocytic leukemia cells by murine fibroblasts, IL-4, anti-CD40 antibodies, and the soluble CD40 ligand.

Analysis of growth regulation in B-chronic lymphocytic leukemia (B-CLL) is of pivotal importance for understanding the pathophysiology and the development of new therapeutic approaches. We investigated the effect of soluble ligands and the interaction with fibroblasts in an in vitro system developed for the expansion of normal B lymphocytes. A total of 17 peripheral blood and bone marrow samples from patients with untreated B-CLL were analyzed for survival, apoptosis, and bcl-2 protein expression. The most efficient stimulus for cell survival was cocultivation with CDw32-transfected murine fibroblasts, which achieved a median of 56% surviving CD5 positive B cells with a plateau between Day 3 and Day 13 (p < 0.0001). IL-4 alone had a significant, but less profound, effect on cell survival: cell viability was increased by a factor of 1.7 on Day 3 (p = 0.001), but cell viability continued to decline. In contrast, the soluble recombinant human CD40 ligand and two different anti-CD40 antibodies did not prolong cell survival. In all experiments prolongation of cell survival was accompanied by a significant reduction of apoptosis of the leukemic B cells: in CDw32-transfected fibroblasts apoptosis was reduced by a mean of 90%, in IL-4 by a mean of 55%. Reduction in apoptotic cell death was associated with elevated bcl-2 protein levels. Our results emphasize the critical role of the interaction between B-CLL cells and CDw32-transfected fibroblasts for cell viability in vitro. Prolongation of cell survival is caused by a reduction of apoptosis and correlates with bcl-2 protein expression.

Adult↗
PubMed1997

Purine analogs in the treatment of chronic lymphocytic leukemia.

The purine analogs fludarabine (FAMP) and 2-chlorodeoxyadenosine (2-CDA) are highly active in chronic lymphocytic leukemia (CLL). In second-line therapy response rates are in the range of 30 to 60% and exceed 70% when applied to previously untreated patients. While FAMP in particular is thus well established for salvage treatment and can be considered as the present treatment of choice, more data are needed to define the role of purine analogs for first-line therapy.

Antineoplastic Agents↗
PubMed1997

Primary lymphoma of the stomach: three-year results of a prospective multicenter study. The German Multicenter Study Group on GI-NHL.

BACKGROUND: In October 1992, an ongoing prospective study on primary gastrointestinal (GI) lymphoma was initiated to evaluate histological features, sites of involvement, and management. PATIENTS AND METHODS: Until May 1996, 352 patients were enrolled, with 279 being evaluable for clinical features (208 patients presented with primary gastric lymphoma). Standardized diagnostic workup included central histologic review and endoscopic and radiologic evaluation of the complete GI tract. Primary surgery or conservative management depended on the physician's decision, followed by radiotherapy with or without chemotherapy. Treatment outcome is evaluable in 122 patients with gastric lymphoma. RESULTS: In 279 evaluable patients, the distribution of NHL was as follows: stomach 74.6%, small bowel 8.6%, ileocoecal region 6.5%, multilocal GI involvement 6.8%. In gastric lymphoma, low-grade NHLs accounted for 39%. Of the remaining high-grade NHLs, 36.1% showed simultaneous low-grade components, thus being also of MALT origin. Of 208 patients with gastric NHL, 71.1% were classified as stage I and II1. CCR rate in stomach lymphoma is significantly higher compared to those of the small bowel, whereas involvement of multiple GI organs has the worst prognosis. So far only 7 patients with gastric NHL in stages I and II presented with progressive disease or relapse. Over all stages there seems to be no difference in therapeutic outcome in surgically or conservatively treated patients. Even after R0-resection in limited stages patients appear to have no better outcome. CONCLUSION: The value of surgery in treatment of primary gastric lymphoma--as favored by most authors--should be reexamined.

Adult↗
PubMed1997

Detection of trisomy 12 in CD34+ progenitor cells in a patient with B-cell chronic lymphocytic leukemia by fluorescence in situ hybridization.

B-cell chronic lymphocytic leukemia (B-CLL) is a slowly progressive disease resulting from the clonal expansion of mature B lymphocytes. The most frequent chromosomal abnormality is trisomy 12. Recently more aggressive therapeutic approaches using myeloablative therapy and autologous stem-cell support have been developed. Phase I/II studies have resulted in molecular remission and prolonged survival. One cause of relapse may be tumor-cell contamination of the transplant. We asked whether immunophenotypically identified hematopoietic progenitor cells are part of the malignant cell population in B-CLL. In a patient with trisomy 12, two subpopulations of hematopoietic progenitor cells, CD34+/CD38+ and CD34+/CD38- cells, were isolated by fluorescence-activated-cell-sorting; the sort purity was 98%. Trisomy 12 was detected in 13% of CD34+/38+ cells and in 34% of CD34+/38- cells. These data suggest that CD34+ cells are involved in the malignant clone of patients with B-CLL. The results are of significance for future strategies using autologous stem-cell transfusion.

ADP-ribosyl Cyclase↗
PubMed1997

Treatment of follicular follicle centre lymphomas: current status and future perspectives.

Follicle centre lymphomas (FCLs) comprise the predominant subtype of indolent nodal lymphomas. Therapy is based on the stage of the disease and consists of extended field or total nodal irradiation in stages I and II. Patients with advanced stages III and IV may initially remain untreated and be watched until the occurrence of disease-related symptoms such as B-symptoms, haematopoietic insufficiency, lymphoma progression or bulky disease. On the occurrence of these signs a cytoreductive chemotherapy of mild to moderate intensity such as cyclophosphamide, vincristine, prednisone (COP) or mitoxantrone, chlorambucil, prednisone (MCP) should be initiated. In responding cases maintenance with interferon-alpha (IFN alpha) leads to a significant prolongation of the progression-free interval. Modifications of this approach include the upfront combination of IFN alpha with anthracycline containing combinations such as cyclophosphamide, doxorubicin, teniposide, prednisone (CHVP). New perspectives arise from the introduction of myelo-ablative radio-chemotherapy with subsequent stem-cell transplantation and antibody-based immunobiological therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve.

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicinol in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24 h trough levels show a high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r = 0.78, indicating that the interindividual variation of idarubicin AUC reflects differences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impact of interindividual variations in AUC on clinical outcome and toxicity.

Administration, Oral↗
PubMed1997

[Brief interdisciplinary oncology: a model for ambulatory, multimodal treatment of tumor patients].

Since 10/1994 the Interdisziplinäre Kurzzeit-Onkologie (IKO) is an outpatient department for the treatment of patients with cancer used by the departments of hematology/oncology and surgery. Between 09/1995 and 02/1997, 818 patients received 2024 cytotoxic therapies with neoadjuvant (15%), adjuvant (65%) or palliative (20%) intention-mostly within multicenter clinical studies. Ambulatory operations like removal of lymph nodes for diagnosis or the implantation of venous catheter systems prepared the way for specialized modalities of cancer therapy. The high compliance and consent of patients, combined with better understanding of cancer therapy, resulted in an enhanced quality of life and optimized therapy. Standardization in diagnostics and fast realisation of interdisciplinary treatment schedules lead to reduction of costs and to enhancement of quality and security in cancer therapy.

Ambulatory Care↗
PubMed1996

Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL.

BACKGROUND: Fludarabine seems to be a promising treatment for patients with advanced chronic lymphocytic leukaemia (CLL). We compared fludarabine therapy with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of CLL in a randomised, multicentre prospective trial. METHODS: Patients older than 18 years of age were entered into the study if they presented with previously untreated B-cell lineage CLL (B-CLL) of Binet stages B or C or relapsed B-CLL pretreated with chorambucil or similar non-anthracycline-containing regimens. Patients were randomly assigned to either fludarabine (25 mg/m2 per day on days 1-5) or CAP (cyclophosphamide 750 mg/m2 per day and doxorubicin 50 mg/m2 per day on day 1, and prednisone 40 mg/m2 per day on days 1-5), both given for six courses. FINDINGS: Of 196 evaluable patients, 100 were previously untreated whereas 96 patients had received prior therapy. Remission rates were significantly higher after fludarabine than CAP, with overall response rates of 60% and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71% vs 60%, p = 0.26) and pretreated (48% vs 27%, p = 0.036) cases, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 days after fludarabine and 179 days after CAP (p = 0.22) and median survival times of 728 days and 731 days, respectively. In untreated cases, on the other hand, fludarabine induced significantly longer remissions than CAP with the median not yet reached after fludarabine and a median of 208 days after CAP (p < 0.001). This effect also translated into a tendency towards longer overall survival after fludarabine (p = 0.087). Treatment-associated side-effects consisted in both regimens of predominantly myelosuppression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25% vs 5%, p < 0.001) and alopecia (65% vs 2%, p < 0.001). INTERPRETATION: Fludarabine provided an effective and well-tolerated therapy for patients with advanced CLL, which compared favourably with CAP as one of the most effective standard regimens. In second-line therapy, fludarabine induced a significantly higher rate of complete and partial remissions, while in first-line therapy a significant prolongation of remission was obtained, which may translate into an improvement of overall survival.

Agranulocytosis↗
PubMed1996

[Therapy of low-grade non-Hodgkin lymphomas].

Low-grade non-Hodgkin's lymphomas are characterized by a low proliferative activity and prolonged clinical course. Most of them reveal distinct cytogenetic and molecular aberrations, such as the translocation t (14; 18) in centrocytic/centroblastic or follicular lymphomas, which is combined with an overexpression of the bcl 2 oncogene or the translocation t (11; 14), which is associated with a deregulation of the PRAD 1 gene and is mainly found in centrocytic or mantle-cell lymphomas. The therapy of low-grade non-Hodgkin's lymphoma depends on the extent of the disease. In early stages I and II, in which only 15 to 25% of low-grade lymphomas are diagnosed, radiotherapy represents the treatment of choice and may be applied with curative intention. The appropriate treatment of more advanced stages III and IV is a matter of controversial debates. Currently, it still seems justified to watch the natural course of the disease and to start therapy not before the occurrence of B-symptoms, hematopoietic insufficiency or progression of lymphoma. Intensification of initial cytoreductive chemotherapy does not result in a prolonged survival or a higher remission rate. However, maintenance therapy with interferon alpha following successful initial cytoreductive chemotherapy appears to have a favorable impact on disease-free and possibly also overall survival. New perspectives result from the introduction of new cytostatic compounds and the purine analogues in particular as well as the development of effective immunotoxins and antibody-conjugated radio-isotoes. Furthermore, myeloablative radiochemotherapy followed by autologous bone marrow or peripheral stem cell transplantation provides a promising approach with curative potential even in advanced stages of the disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Detection and determination of the major metabolites of [3H]cytosine arabinoside by high-performance liquid chromatography.

An ion-pair high-performance liquid chromatographic assay involving solid-phase scintillation detection was established for the rapid identification and determination of all major metabolites of tritium-labelled cytosine arabinoside (Ara-C) in an in vitro system. In a single run of 50 min, Ara-C, Ara-CMP, Ara-CDP-choline, Ara-CDP, Ara-U, Ara-UMP, Ara-CTP, Ara-UDP and Ara-UTP can be measured. The method is fast, sensitive, with limits of detection ranging from 40 to 200 pg (absolute), and highly reproducible.

Calibration↗
PubMed1996

Improved outcome in adult B-cell acute lymphoblastic leukemia.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

Adolescent↗
PubMed1996

A cell-surface epitope associated with liver-preferential metastasis detected by the new monoclonal antibody 3H4 in the murine tumor model ER 15-P.

In the tumor model ER 15-P, a chemically induced pleomorphic myofibrosarcoma of the C57/Bl6J mouse, cell lines with liver-preferential metastatic tumor spread were selected in vivo. In order to describe cell-surface molecules relevant for hepatic metastasis, monoclonal antibodies were raised against the liver-preferential variants. In a syngeneic immunization with viable tumor cells cyclophosphamide was used for augmentation of the humoral antitumor immunity. The monoclonal antibody mAb 3H4, an IgG2b isotype, reacted with a cell-surface epitope exclusively detected on the liver-preferential metastatic phenotype (Me) of the tumor model ER 15-P; no reactivity with the non-organ-specific metastatic phenotype (P) was observed. Regarding the morphological heterogeneity of different Me and P tumor cell populations, mAb 3H4 antigen expression was consistently associated with liver-preferential metastasis, not with different morphological stages of differentiation. It showed no cross-reaction with other tumor cell lines tested except MethA murine fibrosarcoma. The antibody was unreactive with normal tissue cells in C57/Bl6J mice. mAb 3H4 antigen expression was not dependent on the cell cycle. In an experimental assay of hematogenous metastasis, preincubation with mAb 3H4 significantly reduced the number of liver metastases of the liver-preferential tumor cells. Although no crossreaction of the primary ER 15-P with mAb 3H4 was observed, the antibody also significantly reduced the number of renal metastases of the P tumor cell population. The syngeneic IgG2b monoclonal antibody mAb 3H4 identified a new tumor-associated cell-surface antigen correlating with liver-preferential metastasis. mAb 3H4 antigen expression was a stable property of the liver-preferential tumor cells regardless of morphological diversity or functional cell status. In an in vivo blocking assay mAb 3H4 reduced liver colonization in vivo.

Animals↗
PubMed1996

Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells.

Hypokalemia due to renal potassium loss has frequently been observed in patients with acute myeloid leukemia (AML). The pathogenic mechanism for this hyperkaluresis is unclear. In this report we describe a patient with AML FAB M4, in whom the clinical course, the electrolyte disturbances, the serum aldosterone levels, and the diffuse hyperplasia of the adrenal cortex documented a typical case of marked secondary hyperaldosteronism. On analysis of the leukemic cells of this patient compared with normal bone marrow cells, a significant increase of renin-like activity in the cytosol of the blast cells was noted. Activation of the renin-angiotensin-aldosterone system by paraneoplastic production of renin-like activity in AML blast cells might contribute to the hypokalemia often observed in patients with acute myeloid leukemia.

Acute Disease↗