W Wilmanns

Ludwig-Maximilians-University of Munich, München, Bavaria, Germany

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Publications (434)1090.28 Total impact

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    ABSTRACT: Prevention of graft-versus-host disease by depletion of CD6-positive T cells was studied in the dog. Donors were DLA-homozygous, recipients DLA-heterozygous with one DLA haplotype identical to the donor. Seven control dogs received untreated marrow and died of GvHD after full hemopoietic recovery within 28 days of transplantation. For prevention of GvHD, immunomagnetic separation of T cells with a monoclonal antibody against human CD6 that crossreacted with canine T cells was evaluated. Depletion of CD6-positive cells depleted CD4-positive cells completely, but only part of CD8-positive cells and DR-positive cells. CD6-depleted marrow exhibited strong nonspecific “natural” suppression of the generation of cytotoxic T cells in vitro. Eleven dogs received CD6-depleted marrow. Only 1 dog developed GvHD and died. Sustained engraftment was seen in 8 dogs. Hemopoietic recovery was delayed and slower after transplantation of CD6-depleted marrow than after transplantation of untreated marrow. Four of these dogs were treated with G-CSF, and this accelerated the recovery of leukocytes, but did not prevent rejection. Chimerism was mixed in 7 of 10 evaluable dogs and 1 dog recovered its own hemopoiesis 2 years after transplantation. CD6 depletion prevents GvHD across a DLA-haplotype difference, but rejection and mixed chimerism may occur. Treatment with G-CSF accelerates leukocyte recovery, but cannot prevent rejection.
    Tissue Antigens 12/2008; 43(3):170 - 178. · 2.93 Impact Factor
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    ABSTRACT: Between 1979 and 1985 61 consecutive patients with non-Hodgkin's lymphomas of unfavourable histology (mostly diffuse large cell lymphomas subclassified according to Kiel nomenclature) were treated in our departments by either the CHOP- (n = 34) or the COPBLAM-regimen (n = 27). A retrospective analysis revealed that prognostic variables, excluding primary central nervous system (CNS)-involvement (n = 5), were equally distributed between both groups. Remission rates were significantly higher in the COPBLAM treated patients as compared with the CHOP treated group (85 per cent versus 38 per cent CR, P = 0.001) even when cases with primary CNS-disease were excluded. The survival curve did not reach a plateau in CHOP treated cases, whereas 85 per cent of the COPBLAM treated group reached a plateau by 15 months. The mean observation time, however, was shorter in the COPBLAM treated group (37 versus 30 months, respectively).It is concluded that the COPBLAM regimen is superior to the CHOP-protocol in inducing complete responses in aggressive non-Hodgkin's lymphomas. Longer follow-ups are needed to definitely show if this corresponds to an increased proportion of ‘cures’.
    Hematological Oncology 03/2007; 6(1):13 - 19. · 2.04 Impact Factor
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    ABSTRACT: Concentrations of soluble c-erbB-2 were determined in the sera of 64 patients with distant metastasis from advanced breast cancer receiving second-line hormone or chemotherapy in comparison to 35 breast cancer patients without detectable recurrent disease and 17 healthy blood donors. The sera of non-metastatic breast cancer patients contained s-erbB-2 concentrations similar to those of healthy blood donors. Patients with distant metastasis from advanced breast cancer had significantly higher values of s-erbB-2 in comparison to patients with non-disseminated disease (mean: 59.6 vs. 11.6 U/ml; p = 0.022). A significant correlation was observed between s-erbB-2 serum levels and serum LDH concentrations (p < 0.001), levels of alkaline phosphatase (p < 0.001), and the presence of hepatic metastasis (p = 0.001). Time to tumor progression was significantly shorter in patients with s-erbB-2 levels above 40 U/ml (mean: 23.4 vs. 56.7 months; p = 0.002). Furthermore, breast cancer patients with hepatic metastasis and those with elevated s-erbB-2 serum levels above 40 U/ml had limited response to hormone or chemotherapy. Non-responders had significantly higher s-erbB-2 levels (mean: 270.3, range: 42-500 U/ml;) compared with the responder group (mean: 23.1, range: 0-149 U/ml; p < 0.001). Logistic regression analysis indicated that elevated s-erbB-2 serum levels above 40 U/ml independently predicted an unfavorable response to second-line hormone or chemotherapy in patients with advanced metastatic breast cancer.
    Tumor Biology 01/2002; 23(2):70-5. · 2.52 Impact Factor
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    ABSTRACT: After adoptive transfer of pre-activated lymphocytes into the operation cavity of glioma patients, tumor regression and improved survival have been reported in some patients. Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied. In this study, we attempted to avoid time-consuming pre-activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells. Eleven patients with high-grade malignant glioma received 3 injections of 2 bispecific antibody fragments (EGFR x CD3 and EGFR x CD28) together with freshly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary fluid aspirated during immunotherapy was examined for markers of T-cell activation. Increased levels of soluble IL-2 receptor and TNF-alpha were detected in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and aggravation of pre-existing neurologic deficits. These adverse effects were most likely due to the antibody construct containing anti-CD3 specificity. Two patients developed cerebral edema and required steroid treatment.
    International Journal of Cancer 02/2001; 91(2):225-30. · 6.20 Impact Factor
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    ABSTRACT: After adoptive transfer of pre-activated lymphocytes into the operation cavity of glioma patients, tumor regression and improved survival have been reported in some patients. Results were most impressive when bispecific antibodies with tumor × CD3 specificity were also applied. In this study, we attempted to avoid time-consuming pre-activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells. Eleven patients with high-grade malignant glioma received 3 injections of 2 bispecific antibody fragments (EGFR × CD3 and EGFR × CD28) together with freshly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary fluid aspirated during immunotherapy was examined for markers of T-cell activation. Increased levels of soluble IL-2 receptor and TNF-α were detected in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and aggravation of pre-existing neurologic deficits. These adverse effects were most likely due to the antibody construct containing anti-CD3 specificity. Two patients developed cerebral edema and required steroid treatment. © 2001 Wiley-Liss, Inc.
    International Journal of Cancer 01/2001; 91(2):225 - 230. · 6.20 Impact Factor
  • R Munker, P Koeffler, R Haas, W Wilmanns
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    ABSTRACT: Retinoids are highly active for the treatment of acute promyelocytic leukemia, but have effects on many different types of normal and transformed cells. CD95 is a member of the TNF-receptor superfamily and can mediate apoptosis. In this study, we screened a series of 7 myeloid and 12 lymphoid cell lines for the expression of CD95 and for the induction of CD95 by retinoids. A differential response was observed: in 3/7 myeloid cell lines a significant down-regulation of CD95 happened which correlated with the induction of differentiation. A significant induction of CD95 was observed in 4/ 12 lymphoid lines (2 HHV8+ cell lines, one Burkitt line and another lymphoma line). The modulation of CD95 was both time- and dose- dependent (maximum reached after 3-5 days of culture with 10-6 M retinoid). The 3 retinoid compounds studied (all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid) had comparable activity. Taken together, we describe a new mode of induction of CD95 in lymphoma cells. More work is needed to define the functional consequences of these changes in CD95 surface expression.
    European journal of medical research 07/2000; 5(6):273-6. · 1.10 Impact Factor
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    ABSTRACT: IL-10 is a potent immunosuppressant which inhibits allo-antigen-specific T cell responses. In addition, IL-10 is a strong endogenous anti-inflammatory cytokine. To investigate the role of IL-10 in the induction of acute GVHD following allogeneic bone marrow transplantation (BMT) we performed a prospective study on spontaneous IL-10 production by peripheral blood mononuclear cells (PBMNC) in 84 patients admitted for allogeneic BMT. High spontaneous IL-10 production by PBMNC at the time of admission and prior to any preparative treatment correlated with a subsequent low incidence of GVHD and transplant-related mortality (8%), as compared to patients with low or intermediate IL-10 production (50%, P < 0. 01). Our data demonstrate the prognostic significance of increased IL-10 production in BMT patients and suggest a major role of IL-10 in maintaining immunobalance in the setting of allogeneic BMT. Bone Marrow Transplantation (2000) 25, 237-241.
    Bone Marrow Transplantation 02/2000; 25(3):237-41. · 3.54 Impact Factor
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    ABSTRACT: The occurrence of second malignancies (SM) is an important late event following the treatment of Hodgkin's disease (HD). We sought to determine the incidence, the risk factors, and the prognosis of SM in our population of patients with HD. A total of 1120 patients diagnosed with HD were registered at six participating institutions in Munich (calendar period 1974-1994). The mean follow-up for the development of SM was 9.1 years. A cumulative treatment score was calculated for both radio- and chemotherapy. The relative and absolute risks of SM were established. All SM were investigated for response to treatment and outcome. We observed 85 SM [eight leukemias, 22 non-Hodgkin's lymphomas (NHL), two plasma cell neoplasias, and 53 solid tumors]. Five patients developed third malignancies. The relative risk of developing a second neoplasm was compared with that within the normal population and was 3.1-fold. The risk varied according to the category of SM. Higher relative risks (20.5 and 25.9-fold), but lower absolute risks were observed for leukemias and non-Hodgkin's lymphomas. Solid tumors had lower relative risks (1.8-fold). Splenectomy increased the risk of SM (relative risk 4.4-fold versus 2.7-fold). The risk of SM did not correlate with the initial treatment (radio- or chemotherapy) and did not decrease with prolonged follow-up. The cumulative intensity of radiotherapy, chemotherapy, or the two modalities combined correlated with the risk of SM. Since some cases occurred early after diagnosis, not all second neoplasms can be considered treatment-associated. After 15 years, an actuarial risk of 11.7% was calculated for all SM, of 1.0% for leukemias, of 3.0% for NHL, and of 7.7% for solid tumors. The prognosis of SM varied between good (thyroid cancer, melanoma: median survival 5+ years), average (breast cancer, NHL), and poor (acute myeloid leukemias, lung cancers: median survival 9 months). With the exception of NHL, second cancers often occurred in topographic relation to the field of previous radiotherapy. Taken together, in our patient population, we observed all three categories of SM (solid tumors, leukemias, NHL). The risk for second leukemias is lower than in previous studies, whereas the risk of second NHL is somewhat higher. We confirm that splenectomy is a possible risk factor for SM. Even after correction for the age-specific cancer incidence, treatment intensity is associated with the development of second malignant tumors. Continued follow-up is mandatory after treatment for HD. Since the prognosis of most SM is unfavorable, early recognition and prevention are of the utmost importance.
    Annals of Hematology 01/2000; 78(12):544-54. · 2.87 Impact Factor
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    ABSTRACT: With the growing understanding of cytostatic drug-induced programmed cell death new drug-resistance mechanisms based on the altered ability of cells to die by apoptosis have been defined. At first, the sensitive and P-glycoprotein (P-gp)-related resistant cell lines were tested to induce apoptosis by a non-P-gp transported drug, such as cytosine arabinoside (ara-C). It was demonstrated that ara-C induces apoptosis in sensitive as well as in P-gp-related resistant cell lines, as expected. Furthermore, the role of bcl-2 and bcl-xL apoptosis inhibitors as well as bax expression (apoptosis inducer) in human sensitive leukemic cell lines (CCRF-CEM and HL-60) as compared to their resistant variants such as CCRF-CEM/ACT400, CCRF-CEM/VCR1000, HL-60/IDA40, HL-60/DNR250 was evaluated. In addition to the P-gp-related resistance, a possible multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP)-related resistance were assessed by flow cytometry using the monoclonal antibodies 4E3.16, MRPr1 and LRP56. Furthermore, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test. Bcl-2 and bax were analyzed by both flow cytometry and ECL Western blot, bcl-xL by ECL-Western blot alone. Comparison of the two sensitive cell lines demonstrated different bcl-2, bax and bcl-xL patterns. The common characteristic was the increased expression of one of the apoptosis inhibitor proteins, such as bcl-2 or bcl-xL. The sensitive CCRF-CEM showed a high bax level, where a decrease of about 75% in resistant variants was measured. Compared to their sensitive counterpart HL-60, a low bax expression was analyzed, which increased in the resistant variant. The common characteristic of all resistant cell lines was the decreased expression of bax compared to bcl-2 or bcl-xL. In the P-gp-related resistant HL-60/DNR250 only an increase in bcl-xL was seen, whereas in the LRP-expressing as well as P-gp and MRP negative resistant HL-60/IDA40 both apoptotic inhibitor proteins bcl-2 and bcL-xL showed maximum increase, compared to the other resistant cell lines. The P-gp-related resistant cell lines CCRF-CEM/ACT400 and CCRF-CEM/VCR1000 also showed an increased expression of both bcl-2 and bcl-xL. Summarizing these results, it was shown that the examined sensitive human leukemic cell lines and their resistant variants demonstrated a different pattern of markers for preventing and promoting apoptosis. An association between P-gp and possible LRP-expressing leukemic cells as well as apoptosis-preventing markers (bcl-2, bcl-xL) seems to exist. The clinical relevance of the coexpression of various resistance mechanisms remains to be confirmed in large leukemia patient groups.
    Leukemia 12/1999; 13(11):1864-72. · 10.16 Impact Factor
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    ABSTRACT: Glucocorticoids and fludarabine are able to induce typical features of apoptosis in CLL lymphocytes. Cysteinyl aspartate specific proteases (caspases) play a key biochemical role in the apoptotic pathway. Caspase activation following cytotoxic stimuli leads to highly specific proteolytic cleavage of functionally important cellular enzymes. One of them is poly ADP-ribose) polymerase (PARP). To some extent caspase activation seems to be under the control of the Bcl-2 family of interacting proteins. We determined the role of Bcl-2-family proteins Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), activation of caspase-3 (CPP32/Yama) and activation of PARP in CLL apoptosis. All 21 analyzed CLL samples expressed Bcl-2 and Bax. Four of 13 (31%) samples with a low Bcl-2/Bax ratio exhibited in vitro prednisolone resistance, whereas eight of nine (88%) samples with a high Bcl-2/Bax ratio were in vitro resistant (</=0.025). There was no significant correlation between clinical pre-treatment status and Bcl-2/Bax ratio. Caspase-3/CPP32 activity increase was registered after dexamethasone as well as after fludarabine treatment in CLL lymphocytes in vitro. Caspase inhibitor Z-VAD.fmk was only able to partially block dexamethasone-induced and spontaneous apoptosis but not fludarabine-induced apoptosis in CLL lymphocytes. PARP activity decreased after dexamethasone and fludarabine treatment. PARP inhibitor 3-aminobenzamide (3-AB) was able to partially inhibit dexamethasone-induced apoptosis but not fludarabine-induced and spontaneous apoptosis.
    Leukemia 11/1999; 13(11):1873-80. · 10.16 Impact Factor
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    ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to stimulate granulocytes, monocytes, and macrophages. We studied the effect of GM-CSF on (clonal) bone marrow (BM) cells obtained from AML patients after 7 days of culture in vitro: BM samples were obtained from 19 AML patients at diagnosis (DIA), from two patients with persisting disease (PERS), from eight patients in complete remission (CR), and from 12 healthy donors. Flow-cytometric comparison of differentiated, CD 15-positive cells or of CD34-positive blast cells before and after cultivation showed that the proportion of CD15-positive cells was increased in nine of 12 healthy BM samples, in 14 of 19 cases at DIA, in one of three cases during PERS, and in five of six cases in CR of AML. The proportion of CD34-positive cells was increased in one of 12 healthy BM samples, in seven of 19 cases at DIA, in one of two cases during PERS, and in three of seven cases in CR of AML. Southern blot analysis (SBA) performed in six cases during the course of AML, before and after cell culture, showed that clonal DNA increased after GM-CSF treatment in three of five cases studied at DIA, in six of nine cases studied in CR, in the one case studied at PERS, and in the one studied at relapse (REL). In one case of trisomy 8 at DIA a normal karyotype was demonstrated in CR. However, after 7 days of cultivation of the cells in GM-CSF the trisomy 8 was detected in two of 17 metaphases isolated from colony-cells from methylcellulose cultures. Our data show that a 7-day treatment of BM cells with GM-CSF induced a differentiation of healthy and leukemic BM cells in the great majority of cases. An enrichment of CD34-positive cells was not achieved in healthy BM samples. However, in 70% of the cases in CR and in 30% of the cases at DIA of AML, clonal CD34-positive cells were enriched. This means that GM-CSF stimulates ('primes') leukemic cell growth in vitro.
    Annals of Hematology 11/1999; 78(10):449-55. · 2.87 Impact Factor
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    ABSTRACT: The diagnosis of malignancy in peritoneal and pleural effusions can be difficult, because activated mesothelial cells may resemble malignant cells. P53 mutations are the most frequent genetic changes in human cancer and translate into an overexpression of the p53 protein detectable by immunocytochemistry. In this study, we investigated the sensitivity and specificity of 4 different monoclonal antibodies (moAB) against p53 for the diagnosis of malignancy in effusions. We also compared p53 staining with CEA immunocytochemistry which previous work had established as a specific marker of malignancy in body cavity effusions. Normal and malignant cells from 28 benign and 52 malignant effusions (pleura and ascites) were examined by indirect immuno-alkaline phosphatase method. Four different moAB against p53 (PAB 1801, PAB 240, DO-1 and DO-7) and one moAB against CEA (CEA-84) were used. Antibodies p1801, p240 and DO-1 react with 52-75% of cases of effusions with malignant cells, but also with 38-80% of benign effusions. Only the antibody DO-7 and the CEA moAB show specificity for malignant cells reacting respectively with 20 (55%) of cases. A combination of these 2 markers does not enhance the sensitivity for the detection of tumor cells. No direct correlation between CEA and p53 immunostaining could be established. The sensitivity and specificity of staining p53 in malignant cells by immunocytochemistry depend strongly on the antibody used. Some p53 moAB are positive with reactive cells in ascites and pleural effusions. Currently, p53 staining of expressing cells does not improve the identification of malignant cells in comparison with CEA immunocytochemistry, but may help to screen for patients with p53 mutations.
    Oncology Reports 03/1999; 6(2):455-8. · 2.30 Impact Factor
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    ABSTRACT: The ability of bispecific antibodies with anti-tumor x anti-CD3 specificity to mediate the killing of tumor cells by activated T cells has been demonstrated in many in vitro experiments. Moreover, long-term survival of lymphoma-bearing mice has been observed after treatment with such reagents. The therapeutic effect of bispecific antibodies in solid-tumor models has been less impressive, in particular if fragmented antibodies were used to avoid systemic T-cell activation by bispecific constructs binding to Fc-receptor-positive cells. Here we report that bispecific anti-tumor x anti-CD3-fragments markedly inhibit intraperitoneal as well as pulmonary tumor growth in mice inoculated with B16 melanoma cells, resulting in the long-term survival of animals. Therapeutic success critically depends on the number of recruitable effector cells at the site of tumor growth. A second bispecific construct triggering the co-stimulatory CD28-molecule on the T-cell surface increased tumor-cell killing in vitro and in vivo, despite rather low avidity of this reagent to mouse T cells. Finally, long-term-surviving animals showed improved survival after i.v. rechallenge with tumor cells, indicating that bispecific antibodies are capable of inducing long-lasting protective immunity.
    International Journal of Cancer 02/1999; 80(1):138-44. · 6.20 Impact Factor
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    ABSTRACT: The ability of bispecific antibodies with anti-tumor × anti-CD3 specificity to mediate the killing of tumor cells by activated T cells has been demonstrated in many in vitro experiments. Moreover, long-term survival of lymphoma-bearing mice has been observed after treatment with such reagents. The therapeutic effect of bispecific antibodies in solid-tumor models has been less impressive, in particular if fragmented antibodies were used to avoid systemic T-cell activation by bispecific constructs binding to Fc-receptor-positive cells. Here we report that bispecific anti-tumor × anti-CD3-fragments markedly inhibit intraperitoneal as well as pulmonary tumor growth in mice inoculated with B16 melanoma cells, resulting in the long-term survival of animals. Therapeutic success critically depends on the number of recruitable effector cells at the site of tumor growth. A second bispecific construct triggering the co-stimulatory CD28-molecule on the T-cell surface increased tumor-cell killing in vitro and in vivo, despite rather low avidity of this reagent to mouse T cells. Finally, long-term-surviving animals showed improved survival after i.v. rechallenge with tumor cells, indicating that bispecific antibodies are capable of inducing long-lasting protective immunity. Int. J. Cancer 80:138–144, 1999. © 1999 Wiley-Liss, Inc.
    International Journal of Cancer 01/1999; 80(1):138 - 144. · 6.20 Impact Factor
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    ABSTRACT: Human parvovirus B19 can persist in immunocompromised patients and may produce severe clinical illness. In this retrospective study the incidence of B19-associated infections in bone marrow transplant patients was investigated. During 1 year 60 patients received bone marrow grafts (eight autografts and 52 allogeneic transplantations). In case of early onset, atypical or steroid-resistant erythrodermia the patients' blood and/or tissue specimens were screened for B19 infection by polymerase chain reaction (PCR). Additionally, specimens of patients with severe organ failure were tested. A total of 64 PCRs was performed in 27 patients. Seven patients with erythrodermia and one with vulvovaginitis proved to be PCR positive. In patients with organ failure B19 DNA was detected in the myocardium and liver. The incidence of B19 infections in this cohort was 15% and the B19-associated mortality rate 7%. In conclusion, parvovirus B19-associated infections may be more common in immunocompromised patients than previously anticipated.
    Infection 01/1999; 27(2):114-7. · 2.44 Impact Factor
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    ABSTRACT: Human chorionic gonadotropin (HCG) is expressed in germ cell tumors and urothelial, breast, lung and colon cancers. The aim of the study was to investigate if the determination of HCG in comparison with CEA is able to discriminate between malignant and benign effusions. Effusion and partially serum samples of 61 patients with benign (g.i., heart/kidney isnuff.) and 116 patients with malignant diseases (g.i., gynec., lung, misc., CUP) were investigated. HCG was specifically determined by an IRMA using 2 monoclonal antibodies, CEA by a conventional double Ab RIA. Cytological staining was preformed using the Pappenheim-method on cytospin preparations. Significant differences (p < 0.001) were found for HCG between benign and malignant ascitic effusions with the best discrimination at 5 IU/l (ROC) and an overall sensitivity of 31.3% (spec. vs benign eff. 93.4%) increasing in subgroups from hematol. (5.8%) < misc. (31.3%) < gynec. (32.1%) < g.i. (36%) < lung (38.1%) to CUP (50%). CEA also showed significant differences between benign and malignant total and ascitic effusions, and weaker for the pleural subgroup (cutoff 9 ng/ml) with a total sensitivity of 44.6% (sp = 100%) increasing from misc. (30.8%) < lung (47.1%) < CUP (50%) < gynec. (60%) < g.i. (60.9%). Comparative cytology and TM determinations increased the positiverate of cytology (45.2%) to 58.3% for either cytology or HCG positive cases, or to 61.6% for either cytology or CEA positive cases. For the combined determination of cytologoy and HCG and CEA, the overall TM positive rate for 33 cytology-pos. cases was 78.8%, but in 40 cytology-negative cases 37.5% for TM positive cases. In conclusion HCG is useful in ascitic > pleural effusions with high specificity (90% at 5 IU/l) but low sensitivity of 31% increasing in g.i., lung and gynecologic cases, CEA a more general TM with higher sensitivity of 45% increasing in g.i., gynecologic and lung cases (sp. 100% at 9 ng/ml) both adding significantly to cytology-negative effusions.
    Anticancer research 01/1999; 19(4A):2421-5. · 1.71 Impact Factor
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    ABSTRACT: A high-performance liquid chromatographic (HPLC) method has been developed for measuring thymidine and thymine levels, so these could be used to determine thymidine phosphorylase (TP) activity. The method described has the selectivity to separate the analytes from an enzymatic reaction mixture without mutual disturbance. Correlation of peak areas of thymine, thymidine, and 2-thio-6-azauridine with amounts in standards and spiked matrices was linear in the concentration range 0.04–2 μg mL−1 for 2-thio-6-azauridine, 0.08–3 μg mL−1 for thymine, and 0.02–2.5 μg mL−1 for thymidine. Intra- and interday precision were measured by analyzing the retention times of replicate standards or spiked matrices within one (intra assay,n=8) and eight consecutive days (inter assay,n=8) over the concentration ranges 0.1–0.8 μg mL−1 for thymine, 0.02–0.4 μg mL−1 for thymidine, and 0.1–0.5 μg mL−1 for 2-thio-6-azauridine. Recovery was monitored by use of 2-thio-6-azauridine as internal standard. The precision, accuracy, and speed of the method were excellent. The smallest detectable (LOD) and quantifiable (LOQ) quantities were, respectively, 1.3 ng mL−1 and 3.4 ng mL−1 for thymine, 2.68 ng mL−1 and 7.46 ng mL−1 for thymidine, and 1.7 ng mL−1 and 4.92 ng mL−1 for 2-thio-6-azauridine. At 25°C the TP reaction was linear for at least 45 min. At 37°C the reaction occurred much faster and was linear for 15 min only. We decided, therefore, to quantify thymidine and thymine after an incubation time of 30 min at 25°C. The Michaelis constant (K M=59 nmol) and maximum enzymatic reaction velocity (v max=1.626 nmol min−1×106 cells) for TP were determined by extrapolation of the regression line (y=32.53x+90.73;r=0.992) to thex andy axes, respectively. Enzymatic activity was calculated from: – - Activity (units×1010 cells)=(A thymidine 30 min−A thymidine 0 min)×0.00021, – - whereA is the peak area from the chromatogram.
    Chromatographia 01/1999; 49(3):173-178. · 1.44 Impact Factor
  • International Journal of Cancer - INT J CANCER. 01/1999; 80(1):138-144.
  • E Holler, H J Kolb, G Eissner, W Wilmanns
    Bone Marrow Transplantation 01/1999; 22 Suppl 4:S3-6. · 3.54 Impact Factor
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    ABSTRACT: P-glycoprotein(P-gp)- related resistance is one of the major obstacles in treating leukemia patients. Therefore, it is of clinical interest to find new potential modulators and compare their P-gp-modulating efficacy. The present analysis investigated the influence of P-gp modulators, such as verapamil, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexniguldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant counterparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also expressed as a D value by using the Kolmogorov Smirnov statistic. The efficacy of P-gp modulators was determined with the rhodamine-123 accumulation test and the MTT test. An in vitro modulator concentration between 0.1 microM and 3 microM was determined, where no genuine antiproliferative effect was apparent. The modulators PSC 833 and dexniguldipine were the significant (p<C0.05) most potent chemosensitizers followed by verapamil, droloxifene Z, tamoxifen and droloxifene E in descending order. In addition to the modulators PSC 833 and dexniguldipine, droloxifene Z should especially be considered as a candidate for future ex vivo and in vivo studies. The main advantage of droloxifene Z could be the low rate of expected side effects. This fact permits the use of high Drol Z dosage in order to achieve a relevant modulating effect in vivo and to use this drug in combination with a further modulator so as to reach maximum efficacy with tolerable side effects.
    Leukemia and Lymphoma 12/1998; 31(5-6):589-97. · 2.61 Impact Factor

Publication Stats

3k Citations
1,090.28 Total Impact Points

Institutions

  • 1978–2008
    • Ludwig-Maximilians-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
  • 2000
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 1985–1999
    • Technische Universität München
      • • Medizinische Klinik und Poliklinik III - Hämatologie/Onkologie
      • • Medizinische Klinik und Poliklinik II
      München, Bavaria, Germany
  • 1996
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1995
    • Munich Re
      München, Bavaria, Germany
  • 1992
    • Klinikum München-Ost
      München, Bavaria, Germany
  • 1988–1992
    • University Hospital München
      München, Bavaria, Germany
    • ATOS Klinik Munich
      Münchenbernsdorf, Thuringia, Germany
  • 1973–1977
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 1972
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 1968–1972
    • University of Tuebingen
      • Department of Internal Medicine
      Tübingen, Baden-Württemberg, Germany
  • 1963
    • University of Cologne
      • Institute of Physical Chemistry
      Köln, North Rhine-Westphalia, Germany