Search PubMed⌕ Search

Biomedical subjects

R Mertelsmann

Publications and source records attributed to R Mertelsmann.

At least 109 records · Page 6Linked to original sources
PubMed1996

Mobilization of peripheral blood progenitor cells for allogeneic transplantation: efficacy and toxicity of a high-dose rhG-CSF regimen.

Mobilization of PBPC was investigated in 19 healthy matched sibling donors using two different rhG-CSF regimens. Five donors (median age 39 years, range 17 to 57 years) received 10 micrograms rhG-CSF/kg bw once daily subcutaneously (s.c.), while 14 donors (median age 34 years, range 19 to 56 years) were treated with 10-12 micrograms rhG-CSF/kg bw twice daily s.c.. Leukapheresis was started on day 4 of rhG-CSF administration. Cytokine priming as well as collection of PBPCs were well tolerated. Application of twice daily rhG-CSF resulted in a higher yield of CD34+ cells in leukapheresis products than injection of once daily rhG-CSF. This high-dose twice daily rhG-CSF regimen is well tolerated and results in reliably high numbers of progenitor cells in the leukapheresis product in healthy donors, therefore collection as well as subsequent selection has been facilitated.

Adolescent↗
PubMed1996

Allogeneic transplantation of positively selected peripheral blood CD34+ progenitor cells from matched related donors.

Hematopoietic progenitor and stem cells are contained within the CD34+ cellular compartment of the bone marrow. Positively selected cytokine primed peripheral blood derived CD34+ cells have been shown to support autologous hematopoiesis after myeloablative therapy. We investigated hematologic reconstitution and incidence of graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood CD34+ cells. CD34+ cells were selected from the peripheral blood of 10 matched related donors after treatment with rG-CSF followed by one to four apheresis procedures and biotin-avidin immune affinity purification. Ten patients with advanced hematologic malignancies were subsequently transplanted with cryopreserved allogeneic CD34+ cells after myeloablative chemotherapy. Immune affinity purification of CD34+ cells resulted in a 370-fold T cell reduction. Patients were grafted with a median number of 4.1 x 10(6) kg (1.6-6.4) CD34+ cells and 0.42 x 10(6)/kg (0.29-2.2) CD3+ cells. All patients received rG-CSF 5 micrograms/kg post-transplant and completely engrafted with neutrophils > 500/microliter after a median time of 10 days (9-15) and platelets > 20,000/microliter after 16 days (10-74). Complete donor chimerism was demonstrated by cytogenetic and molecular methods up to day +385 post-transplant. Cyclosporin A only was used for GVHD prophylaxis. Four of 10 patients developed acute GVHD with grade I (one) and II (three) which completely resolved with treatment. Two patients died from infectious complications. Three patients died from relapse or progressive disease. Five patients are alive in remission without GVHD with a median follow-up time of 254 (93-457) days and three of five are without immunosuppression. Allogeneic transplantation of positively selected peripheral blood-derived CD34+ cells is feasible and safe and leads to long-term engraftment without severe GVHD suggesting that peripheral blood-derived CD34+ cells contain pluripotent hematopoietic stem cells. The reduced number of T cells transplanted appears to be sufficient for engraftment.

Adult↗
PubMed1996

An aerobic exercise program for patients with haematological malignancies after bone marrow transplantation.

We describe the effects of an aerobic exercise program designed to improve the physical performance of patients undergoing bone marrow transplantation. Twenty patients entered the rehabilitation program, consisting of walking on a treadmill, and carried it out for 6 weeks. Patients started the training program 30 +/- 6 days (range 18-42) post-BMT. By the end of the program we observed a significant improvement in maximal physical performance and maximum walking distance, and a significant lowering of the heart rate with equivalent workloads (P for all significances < 0.001). All participants of the program reached a peak performance (calculated in metabolic equivalents, METs) more than sufficient for carrying out all basic activities of daily living. These results contrast with literature reports indicating that spontaneous recovery of physical functioning after BMT can take many months and that about 30% of patients experience long-lasting impairment of physical performance. We conclude that that fatigue and loss of physical performance in patients undergoing BMT can be corrected with adequate rehabilitative measures.

Adult↗
PubMed1995

Delineation of the dendritic cell lineage by generating large numbers of Birbeck granule-positive Langerhans cells from human peripheral blood progenitor cells in vitro.

It is well established by in vivo and in vitro studies that dendritic cells (DCs) originate from hematopoietic progenitor cells. However, the presumed intermediate of Birbeck granule (BG)+ Langerhans cells (LCs) has not been detected in cultures derived from bone marrow or peripheral blood progenitor cells (PBPCs), thus contrasting with the data obtained with cord blood. We show here that large numbers of BG+ LCs can be generated from human CD34+ PBPCs in vitro, when granulocyte-macrophage colony-stimulating factor and interleukin-4, potent promotors of LC/DC differentiation, are combined with a cocktail of early acting hematopoietic growth factors. LCs were found to emerge from CD33+CD11b+CD14- progenitor cells that they share with the monocytic lineage. During culture, these cells exhibited a sequence of dramatic morphologic changes, starting with a major increase in granularity followed by an increase in size herein exceeding that of all peripheral blood cells. At the same time, CD1a and major histocompatibility complex class II expression were upregulated and virtually all CD1a++ cells were BG+ by electron microscopy. With prolonged culture, CD1a was downregulated on a major population of cells, paralleled by a loss of BG and an increase of CD4, CD25, and CD80 expression that may correspond to the maturation of epidermal LC in vitro. However, these cells were consistently CD5- and did not exhibit changes in the CD45-isoform expression during culture. The availability of large numbers of these highly purified BG+ LCs and mature DCs allows for specific analysis of these subpopulations and provides a source of potent antigen-presenting cells from individual patients for vaccination protocols against infectious or tumor-associated antigens.

Antigen-Presenting Cells↗
PubMed1995

Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo.

BACKGROUND: Autologous peripheral-blood progenitor cells can restore hematopoiesis after high-dose chemotherapy in patients with solid tumors or hematologic cancers. We investigated the ability of peripheral-blood progenitor cells generated ex vivo to restore hematopoiesis in patients with cancer who have undergone high-dose chemotherapy. METHODS: Ten patients who had received high-dose chemotherapy were given transplants of autologous progenitor cells that had been generated ex vivo. We used 11 million CD34+ hematopoietic progenitor cells as the starting population for the cell growth. This number corresponds to less than 10 percent of the usual preparation of peripheral-blood CD34+ mononuclear cells used in leukapheresis. The CD34+ cells were grown in medium containing autologous plasma, recombinant human stem-cell factor, interleukin-1 beta, interleukin-3, interleukin-6, and erythropoietin. RESULTS: No toxic effects were observed with the infusion of the generated cells. The cells promoted a rapid and sustained hemopoietic recovery when transplanted after treatment with high-dose etoposide (1500 mg per square meter of body-surface area), ifosfamide (12 g per square meter), carboplatin (750 mg per square meter), and epirubicin (150 mg per square meter). The pattern of hematopoietic reconstitution was identical to that in historical controls treated with unseparated mononuclear cells or positively selected CD34+ cells. CONCLUSIONS: A small number of peripheral-blood CD34+ cells, when grown ex vivo, can supply a population of hematopoietic precursors that have the ability to restore blood formation in patients treated with high doses of chemotherapy. This method, which requires only a small volume of the patient's blood, may reduce the risk of tumor-cell contamination, circumvent the need for leukapheresis, and allow repeated cycles of high-dose chemotherapy.

Adult↗
PubMed1995

Complete response of metastatic renal cell carcinoma to low-dose interferon-gamma treatment.

The course of metastatic renal cell carcinoma may be positively influenced by immunotherapeutic agents. We report a case of renal cell carcinoma showing a complete response to once-weekly low-dose s. c. interferon-gamma (IFN gamma) treatment in multiple metastatic sites (lung, chest wall, abdomen, vertebral body), but concomitantly developing a solitary brain metastasis. High initial interleukin-6 (IL-6) levels returned to normal during IFN treatment suggesting that IFN gamma may have interrupted an autocrine IL-6/IL-6-receptor loop of the tumor cells. The duration of complete remission in the extracerebral sites is now 46+ months. IFN gamma may be less active beyond the blood/brain barrier.

C-Reactive Protein↗
PubMed1995

Leukocytoclastic vasculitis and long-term remission in a patient with secondary AML and post-remission treatment with low-dose interleukin-2.

Interleukin-2 (IL-2) has been licensed for the treatment of renal cell carcinoma and is currently being evaluated as a therapeutic agent in hematological malignancies. It is associated with a variety of side effects due to induction of a nonspecific inflammatory response. However, phenomena of autoimmunity have also been reported. Here we describe a patient with secondary acute myeloid leukemia who developed a leukocytoclastic vasculitis during long-term post-remission treatment with very low doses of IL-2.

Adrenal Cortex Hormones↗
PubMed1995

Expression of the Fas antigen on primary human leukemia cells.

The antigen defined by the monoclonal antibody anti-Fas can mediate apoptosis, is associated with the receptor for tumor necrosis factor, and is expressed on a limited number of human tissues. In this study we analyzed the expression of Fas on primary human leukemic cells and on mononuclear cells from other hematologic disorders. A total of 95 samples of blood or bone marrow were studied by indirect immunofluorescence. These samples included the normal controls, 47 cases of acute myelogenous leukemia (AML), 11 cases of acute lymphoblastic leukemia (ALL), 21 cases of leukemic lymphoma, seven cases of chronic myelogenous leukemia (CML), five cases of plasma cell leukemia or multiple myeloma, and five cases of myelodysplastic or myeloproliferative syndromes. Normal controls were negative without exception. Among AML, 13/47 cases (28%) were positive; among ALL, 1/11 cases (9%) was positive; among leukemic lymphomas, 3/21 cases (14%) were positive. In a case of plasma cell leukemia which strongly expressed the Fas antigen, we demonstrated that the antibody mediates cell lysis, which was synergistically enhanced by the addition of rabbit complement. In patients with AML, Fas positivity had no obvious clinical relevance. Taken together, our results show that approximately 30% of cases of AML and occasionally other leukemias express the Fas antigens, whereas normal controls are negative in our test system. These findings may be useful in the treatment of refractory leukemias or may permit the purging of autologous transplants.

Antigens, Surface↗
PubMed1995

Cytotoxicity of TGF alpha-PE40 and correlation to expression of epidermal growth factor receptor.

TGF alpha-PE40 is a chimeric protein composed of transforming growth factor alpha (TGF alpha) linked to a modified Pseudomonas exotoxin (PE40). We tested the in vitro cytotoxicity of TGF alpha-PE40 on 23 different solid human tumour xenografts established in nude mice and human bone marrow cells from healthy donors, utilising a modified clonogenic assay. In order to distinguish non-specific toxicity from the targeted effects of TGF alpha-PE40, epidermal growth factor receptor (EGFR) expression of the tumours studied was assessed by Northern blot, slot blot and immunohistochemistry. TGF alpha-PE40 demonstrated differential cytotoxicity on human tumour xenografts in the clonogenic assay. No toxicity on human bone marrow cells was observed. In vitro activity of TGF alpha-PE40 showed a significant correlation with the expression of EGF receptors as determined by immunohistochemistry and slot blot. Further studies will be performed in order to determine the in vivo activity of this compound in tumour-bearing nude mice.

Animals↗
PubMed1995

Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a polypeptide with specific effects on endothelial cell growth and blood vessel permeability. Recent studies demonstrated a key role for VEGF in tumor neovascularization, which is a prerequisite for tumor proliferation and metastasis. MATERIALS AND METHODS: We studied the expression of VEGF mRNA in a panel of 65 different human tumor xenografts of various histologies using Northern and slot blot analyses. Analyis of vessel density was performed morphologically and after immunohistochemical staining of endothelial cells. RESULTS: High expression levels were observed in 22/65 tumors. In melanoma, colorectal, gastric, breast and lung cancers only single tumors showed strong expression signals, whereas 7/10 renal cell carcinoma (RCC) xenografts demonstrated high levels of VEGF mRNA. Vessel density analysis revealed a clear correlation of VEGF mRNA expression with vascularization in RCC (p = 0.0048). Patient survival time was compared for tumors showing high versus low expression values. The overall 5-year survival rate was significantly lower for patients with high expression of VEGF mRNA (p = 0.0306). CONCLUSIONS: These data support the hypothesis that tumor cells of various histologies secrete VEGF, which acts as a paracrine factor to induce endothelial cell proliferation and vessel formation and mediates tumor progression.

Animals↗
PubMed1995

Development of a propidium iodide fluorescence assay for proliferation and cytotoxicity assays.

A propidium iodide fluorescence assay (PIA) was developed to characterize the in vitro growth of human tumor cell lines as well as to test the cytotoxic activity of standard compounds. Propidium iodide (PI) was used as a dye which penetrates only damaged cellular membranes. Intercalation complexes are formed by PI with double-stranded DNA which effect an amplification of the fluorescence. Incubation of the total cell population with PI and subsequent fluorescence detection allowed assessment of the number of non-vital cells (first measurement). After freezing the cells at -20 degrees C for 24 h PI had access to total DNA leading to total cell population counts (second measurement). The number of viable cells was calculated by the difference between these two measurements. In the proliferation and cytotoxicity assays 5 x 10(3) cells per well were plated in 96 multiwells and finally stained with 50 micrograms/ml PI in 25 microliters for 10 min. A correlation between the log of cell number and the log of fluorescence units could be demonstrated over a 2.5-3 log range (r = 0.97). The lower limit of cell detection was 150-500 cells/wells. In cytotoxicity assays eight clinically used cytostatics were tested which effected a clear dose-response relationship (r = 0.93-0.98) and high reproducibility (r = 0.92). In conclusion, this assay is a simple and rapid test system, the main advantages are the absence of any washing steps and the small number of tumor cells necessary for drug testing. The PIA can easily be used for cell number determinations in biological and pharmacological studies.

Antimetabolites, Antineoplastic↗
PubMed1995

Hematopoietic cell proliferation and hematopoietic growth factors.

In vivo studies using hematopoietic growth factors in humans have more clearly defined the ability of these molecules to accelerate hematopoietic cell proliferation in postchemotherapy aplasia and constitutive marrow deficiency states. Studies applying combinations of two growth factors have been added. Investigation of negative regulators of hematopoietic cell proliferation has opened new approaches to protect against damage or loss of candidate stem cells in vitro or in vivo, as well as to selectively recruit malignant cell populations into cell cycle while protecting benign cells. New insights into the synergism of positive regulators of hematopoietic cell proliferation have come from a panoply of in vitro studies, underscoring the value of growth factors previously not associated with effects on hematopoietic cells that have now been found to confer significant synergism with known hematopoietic regulators.

Animals↗
PubMed1995

Use of high-dose etoposide/ifosfamide/carboplatin/epirubicin and peripheral blood progenitor cell transplantation in limited-disease small cell lung cancer.

Conventional-dose chemotherapy for limited-disease small cell lung cancer has resulted in high response rates, but rarely in a cure. In an ongoing phase I-II trial, limited-disease small cell lung cancer patients received high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation as part of an early intensification strategy after two cycles of induction chemotherapy. Eligible patients (n = 18) were initially treated with two cycles of etoposide (500 mg/m2), ifosfamide (4 g/m2), cisplatin (50 mg/m2), epirubicin (50 mg/m2) and granulocyte colony-stimulating factor to combine an effective, standard-dose chemotherapy regimen with simultaneous mobilization of PBPCs. Patients who were in partial remission or complete remission after two cycles of induction chemotherapy received high-dose intensification chemotherapy with cumulative doses of 1,500 mg/m2 etoposide, 12 g/m2 ifosfamide, 750 mg/m2 carboplatin, and 150 mg/m2 epirubicin, followed by autologous PBPC transplantation and granulocyte colony-stimulating factor. The duration of the complete chemotherapy program was 9 weeks. All patients received chest irradiation posttransplantation (50 Gy), and those in complete remission received additional prophylactic cranial irradiation (30 Gy). To date, 13 patients with a median age of 49 years (age range, 34 to 62 years) have been treated within this combined-modality treatment protocol. At a median follow-up of 14 months (range, 3 to 45 months) after transplantation, 11 patients were alive and nine were still in complete remission. Nonhematologic toxicity was acceptable; World Health Organization grades 2 to 4 oral mucositis was the most frequently observed (85%) adverse event. No toxic deaths were observed, and hematopoietic reconstitution occurred rapidly after PBPC transplantation; platelet transfusion independence (> 20,000 microL) and neutrophil counts greater than 500 microL were observed at study day 12+. The median survival time was not yet reached. These preliminary data demonstrate that early, high-dose chemotherapy and PBPC transplantation followed by local radiotherapy is safe and may lead to prolonged disease-free survival in some patients. Prospective, randomized studies in a larger series of patients will be required to provide definitive proof of the role of early high-dose chemotherapy in the management of limited-disease small cell lung cancer.

Adult↗