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Biomedical subjects

R Mertelsmann

Publications and source records attributed to R Mertelsmann.

At least 127 records · Page 7Linked to original sources
PubMed1995

Translocation t(8;13) in a patient with T cell lymphoma and features of a myeloproliferative syndrome.

A 32-year-old white woman was admitted with a diagnosis of T lymphoblastic lymphoma and a bone marrow and peripheral blood cytology that was suggestive of a myeloproliferative syndrome (MPS). In addition, islets of myeloid precursors were found in the lymph node where the lymphoma had been diagnosed. Cytogenetic examination was negative for the Philadelphia chromosome (Ph) as well as the RT-PCR for bcr/abl rearrangement, but surprisingly a t(8;13)(q10;p10) was detected. To our knowledge, this translocation has not been reported in such a clinical setting. The patient was treated for the lymphoblastic lymphoma and underwent autologous bone marrow transplantation. She has been in complete remission since induction chemotherapy with a Karnofsky score of 100%. The difficulty of classifying this case is discussed.

Adult↗
PubMed1995

[Immunoscintigraphy of bone marrow in plasmacytoma].

In 26 patients with plasmocytoma and 4 patients with benign monoclonal gammopathy bone marrow scintigraphy using 99mTc-labelled monoclonal antigranulocyte-antibodies was performed. Focal marrow defects were found in 18/26 patients with plasmocytoma but in none with benign monoclonal gammopathy. The results in plasmocytoma patients correlated well with the clinical staging system of Durie and Salmon. Quantification showed a suppressed bone marrow uptake ratio in 8/26 patients. A marked bone marrow expansion was present in only 2/26 patients. Bone marrow scintigraphy seems to be a valuable diagnostic tool in patients with plasmocytoma, especially as it is able to visualize the degree of bone marrow infiltration in a single protocol and so allows to follow up patients in a simple noninvasive manner.

Antibodies, Monoclonal↗
PubMed1995

GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Adolescent↗
PubMed1995

Endotoxin (Salmonella abortus equi) in cancer patients. Clinical and immunological findings.

1. LPS phase I trial revealed MTD I of 1.0 ng/kg body weight and MTD II of 5.0 ng/kg body weight, the latter given together with ibuprofen (1,600 mg). 2. LPS phase II trial, using 4,0 ng/kg body weight plus ibuprofen in a biweekly schedule didn't show any response in patients with non-small cell lung cancer but 1 CR and 2 PR (13% response rate) in colorectal cancer patients. 3. The LPS tolerance is specific for each cytokine and mediator in regard to the kinetic and degree of its development. INF-gamma prevents the tolerance development to several cytokines with the exception of IL-8. 4. No tolerance was found in cell adhesion, phospholipase A2, and soluble TNF receptor I and II. Priming of ex vivo cytokine production of cytokines was found in mononuclear cells. 5. Synthetic LPS partial structure SDZ-MRL 953 (I) induces a cytokine pattern, which is profoundedly different from that of LPS, (II) with an inverse TNF to G-CSF relation, (III) is (without any ibuprofen treatment) remarkably low toxic, (IV) and downregulates the TNF-response to LPS markedly.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Modulation of vindesine and doxorubicin resistance in multidrug-resistant pleural mesothelioma cells by tumor necrosis factor-alpha.

Tumor necrosis factor-alpha (TNF-alpha) has been shown to enhance the cytotoxicity of a variety of antineoplastic agents. To examine whether multidrug-resistant cells are targets of TNF-alpha, and whether TNF-alpha is capable of modulating chemoresistance of these cells, a pleural mesothelioma cell line (PXF1118L) and two multidrug-resistant sublines thereof were used as experimental models. Drug resistance of these cells was due to P-glycoprotein expression, as confirmed by (1) staining with a monoclonal antibody (MRK16) specific for human P-glycoprotein, (2) decreased accumulation of [3H]vinblastine that was reversed by verapamil, and (3) enhanced cytotoxicity of vindesine in the presence of verapamil. Parental and multidrug-resistant cells exhibited little but comparable sensitivity to TNF-alpha alone. Combining TNF-alpha with vindesine or, to a lesser extent, with doxorubicin, but not with cisplatin, resulted in greater cytotoxicity towards multidrug-resistant cells than seen for each compound alone, indicating a synergism. In contrast, TNF-alpha failed to modulate vindesine or doxorubicin cytotoxicity in parental cells. [3H]Vinblastine accumulation was unaffected by TNF-alpha, and chemoresistance was reduced by TNF-alpha also in the presence of verapamil (10 microM), indicating that TNF-alpha was acting in a way different from calcium-channel blockers. Though the molecular mechanism by which TNF-alpha was enhancing vindesine and doxorubicin cytotoxicity remained undefined in this study, the numbers of TNF-alpha binding sites on parental and on multidrug-resistant cells were similar, and P-glycoprotein expression was unmodulated during the entire 48 h incubation period. In conclusion, we show that TNF-alpha increases the cytotoxicity of anticancer drugs in multidrug-resistant tumor cells by a mechanism that differs from most chemosensitizing agents, including verapamil. Further studies will be needed to clarify the mechanism by which TNF-alpha synergizes with anticancer drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Maintenance of transplantation potential in ex vivo expanded CD34(+)-selected human peripheral blood progenitor cells.

CD34(+)-selected hematopoietic progenitor cells are being increasingly used for autotransplantation, and recent evidence indicates that these cells can be expanded ex vivo. Of 15 patients with solid tumors undergoing a phase I/II clinical trial using CD34(+)-selected peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy, we analyzed the frequency of long-term culture-initiating cells (LTCIC) as a measure of transplantation potential before and after ex vivo expansion of CD34+ cells. PBPCs were mobilized by combination chemotherapy and granulocyte colony-stimulating factor (G-CSF). The original unseparated leukapheresis preparations, the CD34(+)-enriched transplants, as well as nonabsorbed fractions eluting from the CD34 immunoaffinity columns (Ceprate; CellPro, Bothell, WA) were monitored for their capacity to repopulate irradiated allogeneic stroma in human long-term bone marrow cultures. We found preservation of more than three quarters of fully functional LTCIC in the CD34(+)-selected fractions. Quantitation of LTCIC by limiting dilution analysis showed a 53-fold enrichment of LTCIC from 1/9,075 in the unseparated cells to an incidence of 1/169 in the CD34+ fractions. Thus, in a single apheresis, it was possible to harvest a median of 1.65 x 10(4) LTCIC per kg body weight (range, 0.71 to 3.72). In addition, in six patients, large-scale ex vivo expansions were performed using a five-factor cytokine combination consisting of stem cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (EPO), previously shown to expand committed progenitor cells. LTCIC were preserved, but not expanded during the culture period. Optimization of ex vivo expansion growth factor requirements using limiting dilution assays for LTCIC estimation indicated that the five-factor combination using SCF, IL-1, IL-3, IL-6, and EPO together with autologous plasma was the most reliable combination securing both high progenitor yield and, at the same time, optimal preservation of LTCIC. Our data suggest that ex vivo-expanded CD34+ PBPCs might be able to allow long-term reconstitution of hematopoiesis.

Antigens, CD↗
PubMed1994

Cytokine therapy with gene-transfected cells: single injection of irradiated granulocyte-macrophage colony-stimulating factor-transduced cells accelerates hematopoietic recovery after cytotoxic chemotherapy in mice.

Development of cell-based delivery systems that can release therapeutic levels of hematopoietic growth factors into the systemic circulation would facilitate treatment of patients requiring cytokine therapy. In this study, we have investigated the potential of granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, irradiated syngeneic murine cells to accelerate hematopoietic recovery after cytotoxic chemotherapy. As a model, CMS-5 fibrosarcoma cells, were transduced with a retroviral vector containing the murine GM-CSF cDNA. Transduced cells secreted 38 ng GM-CSF/10(6) cells in 24 hours. After irradiation, in vitro GM-CSF production initially increased up to fivefold and was measurable for about 2 weeks. One and 2 days after injection of irradiated, GM-CSF-secreting CMS-5 cells (N2/CMVGM-CSF/CMS5 # 6 cells) into mice, GM-CSF serum levels of 405 +/- 58 pg/mL and 183 +/- 36 pg/mL were measured, respectively. Serum levels were comparable with levels detected 3 hours after injection of 100 ng recombinant murine GM-CSF (rmGM-CSF) subcutaneously (90 pg/mL). Injection of N2/CMVGM-CSF/CMS5 # 6 cells in cyclophosphamide-treated mice was as effective in accelerating neutrophil recovery as twice daily subcutaneous injections of rmGM-CSF. These data suggest that irradiated hematopoietic growth factor-secreting cells might offer an alternative to parenteral injections of recombinant cytokines in the treatment of neutropenic patients.

Animals↗
PubMed1994

Positively selected autologous blood CD34+ cells and unseparated peripheral blood progenitor cells mediate identical hematopoietic engraftment after high-dose VP16, ifosfamide, carboplatin, and epirubicin.

To investigate the feasibility of peripheral blood CD34+ cell selection and to analyze CD34+ cell-mediated engraftment after high-dose chemotherapy, we performed a phase I/II trial in 21 patients with advanced malignancies. The rationale for the selection of CD34+ cells from peripheral blood progenitor cell (PBPC) collections is based on the observation that contaminating tumor cells can be depleted approximately 3 logs using this procedure. CD34+ cells from chemotherapy+granulocyte colony-stimulating factor-mobilized PBPCs were positively selected with an avidin-biotin immunoadsorption column (CEPRATE SC system). One leukapheresis product with a median number of 2.8 x 10(6) CD34+ cells/kg was labeled with a biotinylated anti-CD34 monoclonal antibody and subsequently processed over the column. The yield of selected CD34+ cells was 73% +/- 24.6%. The purity of the CD34+ cell fraction was 61.4% +/- 19.7%. CD34+ cells were shown to represent predominantly committed progenitors coexpressing CD33, CD38, and HLA-DR molecules (lin+). They gave rise to myeloid as well as erythroid and multilineage colonies in vitro. In addition, positively selected CD34+ cells also comprised early hematopoietic progenitor cells, as shown by the presence of CD34+/lin- cells. Transfusion of positively selected CD34+ cells (2.5 x 10(6) CD34+/kg; range, 0.45 to 5.1) after high-dose VP16 (1,500 mg/m2), ifosfamide (12 g/m2), carboplatin (750 mg/m2), and epirubicin (150 mg/m2) (VIC-E) in 15 patients resulted in a rapid and stable engraftment of hematopoiesis without any adverse events. As compared with 13 historical control patients reconstituted with a comparable number of unseparated PBPCs, time to neutrophil and platelet recovery was identical in both groups (absolute neutrophil count > 500/microL, day + 12; platelet count > 50,000/microL, day + 15). These data indicate that autologous peripheral blood CD34+ cells and unseparated PBPCs mediate identical reconstitution of hematopoiesis after high-dose VIC-E chemotherapy. Because positive selection of CD34+ cells from mobilized blood results in a median 403-fold depletion of T cells, allogeneic CD34+ cells from mobilized blood should be investigated as an alternative to bone marrow cells for allotransplantation.

Adult↗
PubMed1994

Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors.

Peripheral blood progenitor cells (PBPCs) are increasingly used for autografting after high-dose chemotherapy. One advantage of PBPCs over the use of autologous bone marrow would be a reduced risk of tumor-cell contamination. However, the actual level of tumor cells contaminating PBPC harvests is poorly investigated. It is currently not known whether mobilization of PBPCs might also result in mobilization of tumor cells. We evaluated 358 peripheral blood samples from 46 patients with stage IV or high-risk stage II/III breast cancer, small cell (SCLC) or non-small cell (NSCLC) lung cancer, as well as other advanced malignancies for the detection of epithelial tumor cells. Monoclonal antibodies against acidic and basic cytokeratin components and epithelial antigens (HEA) were used in an alkaline phosphatase-anti-alkaline phosphatase assay with a sensitivity of 1 tumor cell within 4 x 10(5) total cells. Before initiation of PBPC mobilization, circulating tumor cells were detected in 2/7 (29%) patients with stage IV breast cancer and in 2/10 (20%) patients with extensive-disease SCLC, respectively. In these patients, an even higher number of circulating tumor cells was detected after chemotherapy with VP16, ifosfamide, and cisplatin (VIP) followed by granulocyte colony-stimulating factor (G-CSF). This approach has previously been shown to be highly effective in mobilizing PBPCs. In the 42 patients without circulating tumor cells during steady state, tumor cells were mobilized in 9/42 (21%) patients after VIP+G-CSF induced recruitment of PBPCs. The overall incidence of tumor cells varied between 4 and 5,600 per 1.6 x 10(6) mononuclear cells analyzed. All stage IV breast cancer patients and 50% of SCLC patients were found to concomitantly mobilize tumor cells and PBPCs. Kinetic analyses showed two patterns of tumor cell recruitment depending on the presence or absence of bone marrow disease: (1) early after chemotherapy (between days 1 and 7) in patients without marrow infiltration, and (2) between days 9 and 16 in patients with marrow infiltration, ie, within the optimal time period for the collection of PBPCs. We show that there is a high proportion of patients with circulating tumor cells under steady-state conditions, and in addition a substantial risk of concomitant tumor cell recruitment upon mobilization of PBPCs, particularly in stage IV breast cancer patients with bone marrow infiltration. The biologic and clinical significance of this finding is unknown at present.

Adult↗
PubMed1994

Peripheral blood stem cells: in vivo biology and therapeutic potential.

Peripheral blood stem cells (PBSC) have been studied for their use after high-dose chemotherapy. The combination of a standard-dose chemotherapy [VIP: VP16 (etoposide), ifosfamide, cisplatin] in combination with hematopoietic growth factors was shown to provide effective anti-cancer activity as well as to enable sufficient stem cell mobilization for clinical use. Different growth factor regimens [granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, interleukin (IL)-3/GM-CSF] resulted in a differential induction of high levels of circulating PBSC after VIP chemotherapy, with the sequential combination of IL-3 and GM-CSF inducing maximal numbers of CD34+ cells as well as clonogenic progenitors. Our studies revealed a correlation between prior treatment and PBSC recruitment: the highest numbers of PBSC were mobilized in untreated patients whereas stem cell harvest was considerably impeded in heavily pretreated patients. Phase I/II trials demonstrated that transplantation of PBSC collected after VIP plus growth factor mobilization was safe, and engraftment was rapid and sustained. However, PBSC mobilization carried the risk of concomitant tumor cell recruitment in patients with detectable levels of tumor cells prior to therapy and in 21% of patients without circulating tumor cells. Positive selection of CD34+ cells by immunoadsorption that leads to an approximately three-log depletion of contaminating tumor cells therefore was investigated with regard to feasibility and capability as a source for PBSC transplantation. Twenty-one patients with advanced malignancies received autologous CD34+ cell transplantation after high-dose chemotherapy. Hematological recovery was as rapid as recorded for unseparated PBSC preparations, indicating that CD34+ cells can be safely used for autologous PBSC transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1994

Primary fibroblasts from human adults as target cells for ex vivo transfection and gene therapy.

Diploid fibroblast (dFb) cultures were established from a total of 106 skin and serosa biopsies of human adults. Using an optimized enzymatic dissociation procedure, 10(11) dFb/cm2 skin were obtained from patients younger than 60 years after an average time of 89 +/- 8 days, with a mean population doubling time of 3.87 +/- 1.4 days. Enzymatic dissociation of skin biopsies yielded cultures of significantly higher growth capacity of dFb than those prepared by mechanical dissociation followed by spontaneous outgrowth of cells. The plating efficiency that may be crucial for clonal selection of transfected cells was negligible when dFb were plated without feeder cells at low density, while it was enhanced to 9-24% by the addition of a feeder layer of irradiated human embryonal fibroblasts. DFb secreted various cytokines with spontaneous release of interleukin-6 (IL-6) in high quantities of up to 20 ng/10(6) cells/24 hr. In addition, one-third of the culture secreted substantial amounts of granulocyte-macrophage colony-stimulating factor (GM-CSF), while low amounts of tumor necrosis factor-alpha (TNF-alpha) were detectable in some cases after irradiation of the cells. Comparison of various transfection methods by a transient luciferase expression assay demonstrated that receptor-mediated gene transfer was approximately 10-fold more efficient than cationic lipofection of dFb, while electroporation resulted in substantially less expression of the reporter gene. We conclude that primary dFb can be obtained reproducibly from human adults and represent a suitable target cell population for receptor-mediated gene transfer and cationic lipofection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2.

Interleukin-2 (IL-2) induces secondary cytokines in vivo that may mediate antitumor effects as well as toxicity. The course and quantity of this in vivo reaction may depend on scheduling of IL-2 due to changes in responsiveness of the respective producer cells. This was evaluated in a phase-Ib study with ultra-low-dose IL-2 at 0.9 and 4.5 MIU/m2 administered once daily subcutaneously either once weekly (4 doses, stratum I), three times a week every other day (9 doses, stratum II), or five times a week every other week (10 doses, stratum III). Twenty-eight patients with advanced cancer were randomly assigned to the six treatment groups. Serum levels of IL-2, secondary cytokines, and soluble receptors were significantly increased after a single dose of 0.9 MIU/m2 s.c. demonstrating systemic efficacy. Baseline levels and native responsiveness were recovered after a 1-week treatment-free interval in stratum I patients with the exception of sCD8 that was still increased although readily inducible at that time. Stratum II patients exhibited a prolonged and possibly continuous elevation of all serum parameters studied. Values did not increase beyond the 2nd week of therapy and even decreased with respect to sCD8 and neopterin. A sequential mode of administration (stratum III) may obviate some of these adaptive mechanisms as evidenced from a progressive increase of neopterin and sCD8 levels after the second treatment cycle, although induction of sTNFRI was saturable under these conditions. Thus, scheduling of IL-2 profoundly affects in vivo responses as evidenced from cytokine and soluble receptor serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗