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Biomedical subjects

M Wiesneth

Publications and source records attributed to M Wiesneth.

At least 19 recordsLinked to original sources
PubMed2005

[T-cells activated with a trifunctional bi-specific antibody in head and neck cancer].

BACKGROUND: The trifunctional bi-specific antibody Removab bridges and activates CD3 positive T cells to EpCAM on carcinoma cells and simultaneously binds to an accessory immune cell, thus inducing tumor cell lysis. Following intravenous application, Removab may induce cytokine-related side effects resulting in a sepsis like syndrom. It was questioned, if peripheral mononuclear blood cells (PBMN) already opsonized with Removab could retain antitumor activity and induce less cytokine release than the mere antibody. METHODS: PBMN of patients with head and neck cancer were incubated with Removab and the released cytokines were washed out. Then the Removab-opsonized PBMN were coincubated with genuine tumor cells of the same patient on a chorioallantois membrane for 24 h (T 24) and 48 h (T 48). Tumor cells coincubated with Cisplatin or solely cell culture medium served as control. RESULTS: Coincubation of tumor cells with opsonized PBMN resulted in a 32 % decrease of viable cells at T 24 and a 37 % decrease at T 48, whereas viable cells increased by 10 % at T 24 or 3 % at T 48 when incubated with medium alone (p < 0.05). This tumor cytotoxicity was similar to that of Cisplatin (35 % at T 24/37 % at T 48). CONCLUSION: In an autologous human ex vivo tumor system, Removab-opsonized PBMN induce tumor cell lysis with significantly reduced cytokine release after i. v. application.

Adult↗
PubMed2005

Labeling of adult stem cells for in vivo-application in the human heart.

Tissue regeneration with human hematopoietic or mesenchymal stem cells has become a fashionable research topic. In cardiology, intracoronary injection of adult stem cells has already been used for the treatment of human myocardial infarction and ischemic cardiomyopathy. The experimental background of such therapies, however, i.e. the potential of adult stem cells to regenerate myocardium through "transdifferentiation" of hematopoietic or mesenchymal stem cells into cardiomyocytes described in animal models, has recently been challenged by other experimental data. Nonetheless, clinical trials are continuing. This may be due to the fact that, in open-labeled pilot trials, a benefit of intracoronary injection of adult stem cells for the treatment of myocardial infarction has been described. As pilot trials may overemphasize the beneficial effects of intracoronary injection of bone marrow stem cells, controlled double-blinded randomised multicenter studies are warranted. Furthermore, a careful characterization of the cells involved in the proposed cardiac repair as well as in vivo-monitoring of such cells following intracoronary injection in humans might help to answer many essential questions linked to this important research topic. The latter requires biocompatible labeling. This review focuses on the technologies available for stem cell labeling and summarizes the arguments and contra-arguments to use these labeling technologies for application in humans.

Adult↗
PubMed2004

Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes.

Removab is a trifunctional bispecific antibody which can bridge CD3+ T cells and epithelial cell adhesion molecule positive (EpCAM+) tumor cells, and binds with its Fc fragment to antigen presenting cells. To explore a new approach for the treatment of patients with carcinoma of the upper aerodigestive tract, we investigated whether Removab can induce specific cellular responses to the EpCAM+ carcinoma cell line BHY. Particular emphasis was put on the opsonization of peripheral blood mononuclear cells (PBMN) with respect to clinical application. Tumor cells and allogeneic PBMN of healthy volunteers were incubated with or without Removab. In a third group, PBMN were opsonized with Removab and washed before incubation with tumor cells. Inverse microscopy, ELISPOT, flow cytometry analysis and cytotoxicity assays on the chorioallantois membrane (CAM) were performed. In comparison with PBMN alone, opsonization with Removab resulted in: a) activation of CD83+ antigen presenting cells, b) secretion of interferon gamma, and c) granzyme B mediated lysis of targeted BHY cells by EpCAM specific CD8+ T cells. The secretion of tumor necrosis factor alpha, interferon gamma and interleukin-2 by opsonized PBMN was significantly reduced after 24 h. Washed opsonized PBMN maintained their lytic activity against tumor cells as tested on the CAM. Removab is an appropriate agent for the therapeutic amplification of T cell responses against EpCAM+ tumor cells by opsonization of PBMN without putting patients at risk for severe adverse events caused by a cytokine storm.

Antibodies, Bispecific↗
PubMed2003

Tolerance of granulocyte donors towards granulocyte colony-stimulating factor stimulation and of patients towards granulocyte transfusions: results of a multicentre study.

Data of 507 granulocyte donations from 183 donors were evaluated. No severe granulocyte colony-stimulating factor (G-CSF)-related side-effects were observed. Three donors complained of severe itching following infusion of hydroxyethyl starch (HES). A high proportion (85%) of the donors stated that they would donate granulocytes again. The mean granulocyte yield was 4.3 x 10(10). High-molecular-weight HES resulted in a significantly higher yield compared with low-molecular-weight HES. Mild, but no severe, adverse transfusion reactions were observed in 16% of the recipients. A leucocyte alloimmunization rate of 24% was found. G-CSF stimulation and transfusion of G-CSF-mobilized granulocytes were well tolerated by donors and recipients, respectively.

Adolescent↗
PubMed2001

Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study.

The conditioning regimen prior to stem cell transplantation in 36 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was intensified by treating patients with a rhenium 188-labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy, and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.3 Gy of additional radiation to the marrow; the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy). Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide with or without thiotepa. Patients subsequently received a T-cell-depleted allogeneic graft from a HLA-identical family donor (n = 15) or an alternative donor (n = 17). In 4 patients without an allogeneic donor, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal, and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day +30 and day +100 mortalities were 3% and 6%, respectively, and after a median follow-up of 18 months treatment-related mortality was 22%. Late renal toxicity was observed in 17% of patients. The relapse rate of 15 patients undergoing transplantation in first CR (complete remission) or second CR was 20%; 21 patients not in remission at the time of transplantation had a 30% relapse rate. (Blood. 2001;98:565-572)

Acute Disease↗
PubMed2000

Palliative cytoreduction in refractory acute leukemia: a retrospective study of 57 adult patients.

The efficiency and toxicity of treatment regimens for nonintensive cytoreduction in 57 outpatients with refractory acute leukemia (mean age 56 years, 51 AML, six ALL/AUL) were retrospectively studied. Seventeen patients received one treatment regimen, 19 patients two treatment regimens, and 21 patients three or more treatment regimens. The treatment regimens analyzed were 6-thioguanine p.o. (daily) (T), 6-thioguanine p.o. (4-7 days/week) + cytarabine s.c./i.v. (once a week) (T+C), 6-mercaptopurine p.o. (daily) (MP), 6-mercaptopurine p.o. (daily) + methotrexate p.o./i.v. (once a week) (MP+MTX), etoposide p.o. (daily) (E), and mitoxantrone i.v. (M). The median leukocyte count was higher for M (73 x 10(9)/l) than for the other treatment regimens (T: 27 x 10(9)/l, T+ C: 37 x 10(9)/l, MP: 24 x 10(9)/l, MP + MTX: 30 x 10(9)/l, E: 31 x 10(9)/l). A cytoreduction >50% in the peripheral blood was achieved by T in 11/19, by T+C in 7/11, by MP in 5/8, by MP+MTX in 3/6, by E in 3/4, and by M in 16/22 patients. The period of cytoreduction was regarded as the duration of response - T: median 53 days, range 5-98; T+C: median 61 days, range 14-226; MP: median 37 days, range 4-192; MP + MTX: median 58 days, range 36-59; E: median 121 days, range 26-159; M: median 39 days, range 8-78. T and T + C were well tolerated by all but three patients (stomatitis, diarrhea, WHO grade 2). MP was accompanied by a rise of transaminases (WHO 1-3) in 5/6 patients. E led to stomatitis (WHO 1,2) in 4/5 and M to nausea/vomiting (WHO 1,2) in 5/22 and to stomatitis (WHO 2) in 4/22 cases. The mean survival time after start of palliative cytoreduction was 16 weeks (2-65). In summary, 6-thioguanine +/- cytarabine was best tolerated with effective but in oral monotherapy - often protracted cytoreduction in 60% of patients. Mitoxantrone showed tolerable side effects and potent cytoreduction in 73% of patients even after ineffective palliative pretreatment. Palliative cytoreductive therapy does not reduce the quality of life and can prevent complications of significant leukocytosis in refractory acute leukemia.

Acute Disease↗
PubMed2000

Purging of G-CSF-mobilized peripheral autografts in acute leukemia with mafosfamide and amifostine to protect normal progenitor cells.

In the present study the in vitro growth of CFU-GM from PBPC of patients with AML (n = 11), purged with mafosfamide alone or a combination of mafosfamide and amifostine, was compared to historical controls of mafosfamide-purged bone marrow (AML CR1, n = 16). Two patients were transplanted with mafosfamide and mafosfamide/amifostine pretreated PBPC autografts. The in vitro experiments demonstrated a significantly higher resistance of peripheral blood derived CFU-GM to mafosfamide (median ID95 190 microg mafosfamide/ml) compared with bone marrow derived CFU-GM (median ID95130 microg/ml). Preincubation with amifostine significantly further increased the median ID95 to 245 microg/ml. The clinical results showed short recovery times for neutrophils >500/microl (9 and 13 days) and platelets >20 000/microl (12 and 21 days) and stable long-term engraftment with one relapse at day +118 and one patient in CR at day 760 after transplantation. The in vitro results show a significant advantage of PBPC over bone marrow-derived progenitors for purging with mafosfamide. Furthermore, a protective effect from mafosfamide of amifostine on normal progenitors could be demonstrated. The clinical results demonstrate the clinical feasibility of using mafosfamide-purged autologous PBPCT without impairing the short-term and long-term repopulating capacities of the autografts.

Acute Disease↗
PubMed2000

CD34+ selected cells in mismatched stem cell transplantation: a single centre experience of haploidentical peripheral blood stem cell transplantation.

Over the past 3 years we have performed 10 haploidentical peripheral blood stem cell transplants in patients with incurable haematological malignancies and no prospect of a matched unrelated donor within an adequate time period. Conditioning consisted of ATG, TBI, thiotepa, cyclophosphamide and additional radioimmunotherapy in five patients. All patients received G-CSF mobilized peripheral blood stem cell grafts. GVHD prophylaxis consisted of T cell depletion by CD34+ selection; no post-transplant immunosuppression was given in nine patients. Stable engraftment was achieved in nine patients; one case of acute graft rejection was observed. Seven patients developed grade I acute GVHD, and six patients have developed chronic GVHD. Infections were the most significant clinical problem post transplant. Two patients have suffered a relapse of their disease and two further patients have died of transplant-related complications. After a median follow-up of 13 months (range 5-37 months) six patients are surviving in remission. We conclude that haploidentical PBSCT is a reasonable alternative to a MUD transplant.

Adult↗
PubMed2000

CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 microg/ml and 120 microg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection.

Alemtuzumab↗
PubMed2000

A cell-kinetic model of CD34+ cell mobilization and harvest: development of a predictive algorithm for CD34+ cell yield in PBPC collections.

BACKGROUND: Mobilization and homing of PBPCs are still poorly understood. Thus, a sufficient algorithm for the prediction of PBPC yield in apheresis procedures does not yet exist. STUDY DESIGN AND METHODS: The decline of CD34+ cells in the peripheral blood during apheresis and their simultaneous increase in the collection bag were determined in a prospective study of 18 consecutive apheresis procedures. A cell-kinetic, four-compartment model describing these changes was developed. Retrospective data from 136 apheresis procedures served to further improve this model. A predictive algorithm for the yield was developed that considered the sex, weight, and height of the patient, the number of CD34+ cells in peripheral blood before apheresis, the inlet flow, and the duration of the apheresis. The accuracy of this algorithm was evaluated by comparison of the predicted and the observed yields of CD34+ cells in 105 prospective autologous and 148 retrospective allogeneic apheresis procedures. RESULTS: The correlation between predicted and observed yields was good for the autologous and allogeneic groups with a correlation coefficient (r) of 0.8979 and 0.8311 (p<0.0001), respectively. The regression is described by the equations log (measured value [m]) = 1.0118 + 0.8595 x log (predicted value [p]) for the autologous and log (m) = 2.226 + 0.7559 x log (p) for the allogeneic group. The respective equations for the zero-point regression are log (m) = 1.014 x log (p) and log (m) = 1.026 x log (p). The probability that the measured value was 90 percent or more of the predicted value was 83.8 percent for the autologous and 90.5 percent for the allogeneic apheresis procedures. CONCLUSION: The predictive accuracy of the algorithm and the slope of the zero-point regression curve were higher for allogeneic than autologous PBPC collections. The predictive algorithm may be a useful tool in PBPC harvest, enabling the adaptation of the size of the apheresis to the needs of each patient.

Algorithms↗
PubMed1999

[The effect of ABO, Rhesus and Kell blood group antigens on gallstone prevalence. A sonographic study of 1030 blood donors].

BACKGROUND AND OBJECTIVE: Besides generally accepted risk factors of the pathogenesis of gallstone disease such as age, obesity, female sex and high number of births, hereditary factors are held responsible for different prevalence rates. A number of studies dealt with the question of a correlation between the prevalence of gallstone disease and different blood groups. The Ulm Gall Bladder Stone Study represents the first sonographic prospective study regarding this issue. SUBJECTS AND METHODS: Unselected blood donors (n = 1030, 606 men, mean age 38.0 years, 424 women, mean age 34.1 years) were sonographically examined for presence of gallstones at the German Red Cross blood donor centre in Ulm. Besides AB0, Rhesus and Kell blood group anthropometric data of the test subjects were recorded by means of a semi-standardized interview. RESULTS: The prevalence of gallstone disease in all test subjects was 6.0%. Within the AB0 system the prevalence in subjects with blood group AB was highest (12.1%). The prevalence in Rh-positive and Rh-negative subjects was nearly identical (6.0 vs. 6.1%). Kell factor positive subjects suffered less from gallstone disease than Kell factor negative subjects (2.0 vs. 6.3%). None of these differences in prevalence were statistically significant. CONCLUSION: This study revealed no significant correlation between the distribution of the AB0, Rhesus and Kell blood group antigens and the prevalence of gallstone disease.

ABO Blood-Group System↗
PubMed1999

[Stem cell supported high dose chemotherapy (HDCT) in primary treatment of advanced ovarian carcinoma].

The standard treatment for ovarian cancer consists of staging laparotomy with aggressive debulking, a pelvic and paraaortal lymphadenectomy if indicated and a postoperative chemotherapy. A reappraisal of primary high dose chemotherapy in advanced ovarian cancer seems warranted because of high remission rates of such schedules in palliative situations. For a nation-wide interdisciplinary phase I/II multi-center-study 49 patients were recruited. Induction for stem cell mobilization consists of two cycles of cyclophosphamide and taxol. Three high dose cycles follow with a steady dose-escalation of carboplatin by a factor of 4, this is contrast to a conventionally dosed chemotherapy. During the first two cycles taxol is added, during the third etoposide and melphalane. The plan of primary sequential high dose therapy proved feasible in this study. In a prospective randomized follow-up study primary high dose therapy is compared to conventional chemotherapy (AGO-Ovar-5-study). It results will answer the question whether primary high dose chemotherapy with stem cell support improves the course of ovarian cancer compared to conventional treatment.

Adult↗
PubMed1999

Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children.

The aim of this study was to reduce the rate of graft failure after HLA non-identical stem cell transplantation by using G-CSF mobilized CD34+ peripheral blood progenitor cells (PBPC), either in combination with bone marrow or as single grafts. To prevent GVHD, PBPC were highly purified, resulting in a 5 to 6 log T cell depletion. In additon to T cell depletion no further GVHD prophylaxis was used. We transplanted 23 pediatric patients with life-threatening malignant or non-malignant hematological disorders, who had no available matched donor. Engraftment was obtained in 18 of 21 evaluable patients. Five patients developed acute GVHD of grade II and III, which became chronic in four cases and was fatal in four. The use of highly purified PBPC allowed the exact quantification of residual T cells in the grafts and a strict correlation between the residual T cell load and the development of GVHD was observed: patients with GVHD had received numbers of T cells between 8 and 20 x 104/kg, whereas patients without GVHD were grafted with T cell numbers ranging from 0.7 to 6.0 x 104/kg. We therefore clearly demonstrate that a residual T cell content of <5 x 104/kg is safe for prevention of GVHD after HLA non-identical PBPC transplantation in children.

Adolescent↗
PubMed1999

Comparison of T-cell-depleted BMT and PBPCT with respect to chimerism, graft rejection, and leukemic relapse.

Chimerism analysis by DNA-based methods is a valuable diagnostic tool for monitoring engraftment and leukemic relapse after allogeneic BMT or PBPC transplantation (PBPCT). We investigated the chimerism after T-cell-depleted BMT (n = 32) in comparison with T-cell-depleted PBPCT (n = 39). BM grafts were T-cell depleted using the Campath-IgM antibody plus complement. For T-cell depletion of the PBPC grafts, a selection of CD34+ cells with or without a subsequent CD2/3 depletion was performed. In all patients, the T-cell dose of the transplant was < 10(6)/kg body weight. Between day 13 and day 120 after transplantation, chimerism analysis was done by RFLP or amplified fragment length polymorphism (PCR-AFLP), with a detection limit of 1%-5% recipient cells. In the BMT group, 8 of 32 (25%) patients showed a mixed chimerism, but only one graft rejection and no leukemic relapse occurred after a median follow-up of 41 (3-84) months. All patients with PBPCT revealed a complete chimerism of their granulocytes, and 38 of 39 patients showed complete chimerism of their lymphocytes. Follow-up time in these patients is 7 (2-21) months, with no graft rejection and two leukemic relapses. G-CSF-mobilized PBPC are superior to BM cells for full engraftment even after T-cell-depleted transplantation. The more relevant factor for developing complete chimerism seems to be the quantity and possibly the quality of the stem cells rather than the residual T-cell load of the graft. However, a mixed chimerism of the lymphocytes early after transplantation does not predict a higher rate of graft rejection or leukemic relapse.

Adult↗
PubMed1998

Mobilization and collection of allogeneic peripheral blood progenitor cells for transplantation.

A median dose of 11 (6-17) microg G-CSF per kg and day was given to 96 (49 female, 47 male) healthy family donors in order to mobilize and to collect peripheral blood progenitor cells (PBPC) for allogeneic transplantation. Donor age was 36 (17-76) years. The leukocytes of the donors increased to 46 (12-115) x 10(9)/l on days 4-6 of G-CSF treatment with a median of 71 (2-657) CD34+ cells per microl, respectively. Female and older donors seem to have a lower response to G-CSF. About 32% of the donors suffered from side-effects of G-CSF requiring analgetics. A total of 197 stem cell aphereses were performed using the COBE Spectra cell separator. Median apheresis time was 225 (118-300) min processing 11.8 (5.7-20) l blood, collecting 5.3 (1.7-14.9) x 10(10) nucleated cells and containing 0.7 (0.1-3.7)% CD34+ cells. Severe citrate toxicity occurred in 5% of the donors. Retransfusion of autologous platelets post apheresis was necessary in 16% of the donors because of a platelet count <80 x 10(9)/l. An insufficient number of stem cells was collected in four female donors due to a very poor response to G-CSF. In conclusion, the collection of allogeneic G-CSF-mobilized PBPC is safe and effective. One or two aphereses were sufficient in 91% of the donors to achieve >4 x 10(6) CD34+ cells per kg. In 4% of the donors an additional bone marrow harvest or the use of an alternative donor was necessary because of a poor mobilization.

Adolescent↗
PubMed1997

Gallstone prevalence in relation to smoking, alcohol, coffee consumption, and nutrition. The Ulm Gallstone Study.

BACKGROUND: Besides considering well-known risk factors for the development of gallbladder stones, such as age, sex, fecundity, and hereditary predisposition, efforts at prevention have focused increasingly on other factors, such as nicotine, alcohol, and caffeine consumption, as well as general nutrition, which may be modified. METHODS: A total of 1116 blood donors were examined between April 1994 and February 1995 in the central blood bank of the German Red Cross in Ulm, Germany. Each subject received a questionnaire and underwent to an upper abdominal ultrasound examination. RESULTS: Gallbladder stone disease (current cholecystolithiasis and history of cholecystectomy) was detailed in 5.8% of the men and 6.3% of the women. Neither regularity nor number of daily meals correlated with the frequency of gallstone disease. Vegetarians (n = 48), as a group, were not found to have gallstones. In relation to the consumption of alcohol, tobacco, or caffeine higher prevalence of cholecystolithiasis was found only in heavy drinkers of coffee (P = 0.051; odds ratio (OR), 1.083; 95% confidence interval (CI), 0.999, 1.174). CONCLUSION: Results of the present study do not show a definite relationship between nutritional factors and the consumption of alcohol, tobacco, or caffeine and an increased prevalence of gallbladder stone disease.

Adult↗
PubMed1997

Haematopoietic reconstitution after autologous transplantation of CD34(+)-selected versus non-selected peripheral blood progenitor cells.

Selection of CD34+ cells for autologous transplantation is increasingly being used to reduce potential tumor cell contamination of the autograft. Haematopoietic reconstitution in 40 patients after transplantation of CD34(+)-selected versus non-selected G-CSF-mobilized PBPC was compared and was almost identical in the two groups of patients. Delayed platelet engraftment was only observed in patients transplanted with a CD34+ cell dose of < 2.5 x 10(6)/kg body weight. It has to be shown whether the positive selection of CD34+ cells will improve the disease free survival after autologous PBPC transplantation.

Adolescent↗