Search PubMed⌕ Search

Biomedical subjects

W Wilmanns

Publications and source records attributed to W Wilmanns.

At least 37 records · Page 2Linked to original sources
PubMed1997

Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication after bone marrow transplantation (BMT). We previously have described plasminogen activator inhibitor-1 (PAI-1) as a possible marker of VOD. To confirm the significance of this finding, we now determined PAI-1 levels in 31 of 186 consecutive patients undergoing BMT who developed hyperbilirubinemia greater than 3 mg/dL for various reasons. Diagnoses were made by clinical criteria and confirmed by biopsy in 23 of 31 patients. They included VOD (n = 7), acute graft-versus-host disease (GVHD) of the liver (n = 7), and other hepatic injury (n = 17). PAI-1 (mean +/- SD) was significantly (P < .001) elevated in patients with VOD (321.6 +/- 161.2 ng/mL) as compared with patients with GVHD (22.8 +/- 8.4 ng/mL) or other hepatic damage (32.8 +/- 30.8 ng/mL) at the timepoint of bilirubin increase. At the peak bilirubin concentration, the corresponding PAI-1 levels were 426.1 +/- 230.0 ng/mL in patients with VOD, 41.0 +/- 20.6 ng/ mL in patients with GVHD, and 44.6 +/- 32.9 ng/mL in patients with other hepatic injury (P < .001 VOD v GVHD/other hepatic injury). Our results underline the relevance of PAI-1 in the differential diagnosis of hyperbilirubinemia after BMT and its significance as a sensitive and specific marker of severe VOD.

Adult↗
PubMed1997

Phase I and pharmacokinetic study of the P-glycoprotein modulator dexniguldipine-HCL.

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Adoptive immunotherapy in canine chimeras.

Chimerism and tolerance after bone marrow transplantation provide excellent conditions for adoptive immunotherapy with T cells of the marrow donor. We studied adoptive immunotherapy in dog leukocyte antigen-identical canine littermate chimeras. Mixed chimeras were produced by conditioning treatment with total body irradiation of a dose of 10 Gy, a uniformly lethal dose in dogs, and infusion of between 1 x 10(8) and 2 x 10(8)/kg mononuclear marrow cells treated with absorbed antithymocyte globulin for inactivation of T cells. Donors were of opposite sex. Persistent mixed chimerism was induced in six of nine dogs, chimerism was complete in one dog, and only transient in two dogs. Tolerance to donor skin grafts was demonstrated in eight dogs, including a dog without cytogenetic evidence of chimerism. Lymphocytes of the marrow donor (between 3.2 x 10(8)/kg and 4.1 x 10(8)/kg) were transfused at various times after transplantation. Nontransfused dogs survived without graft-versus-host disease (GVHD), whereas dogs transfused on days 1 and 2 and dogs transfused on days 21 and 22 developed GVHD and died. In contrast, dogs transfused on days 61 and 62 or later survived without GVHD. Chimerism converted from mixed to complete in six of six transfused dogs and in one of eight nontransfused dogs (P<0.005). Donor lymphocyte transfusions 2 years and 4.5 years after transplantation induced split chimerism with lymphoid cells of donor origin and myeloid cells of host origin in one dog and complete chimerism in the other dog. Before lymphocyte collection, donors were immunized against tetanus toxin. Seven days after lymphocyte transfusion, recipients were given booster injections of tetanus toxoid and primary immunization against diphtheria toxin. In transfused animals, antibody titers against tetanus were demonstrated already before the booster injection. Transfused animals developed higher titers of antibody against tetanus and diphtheria toxin than nontransfused animals. Donor lymphocytes converted mixed chimerism into complete chimerism without producing GVHD, when the transfusion was delayed for 2 months or later after transplantation. Transfusion of donor lymphocytes transferred immune reactivity against tetanus toxin and improved reactivity against diphtheria toxin as a new antigen.

Animals↗
PubMed1997

Idarubicin monotherapy in multiply pretreated leukemia patients: response in relation to P-glycoprotein expression.

The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp. expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m2/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m2/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Chronic myeloid leukemia associated hypereosinophilic syndrome with a clonal t(4;7)(q11;q32).

Patients with chronic myeloid leukemia (CML) show the Philadelphia (Ph) translocation in more than 95% of the cases. The remaining cases, without the cytogenetic or molecular equivalent of the BCR-ABL rearrangement, are "Philadelphia negative" and may have alternate chromosomal aberrations. Ph negative CML patients are known to have a poor prognosis. We report on a young patient with a hypereosinophilic syndrome in the presence of a clonal translocation t(4;7) with a peripheral leukocytosis, a severe thrombocytopenia, and anemia at first presentation, who developed bone marrow changes typical of CML. Bone marrow function and hypereosinophilia improved only partially and temporarily under therapy. The patient died 10 months after diagnosis of diffuse leukemic embolism and organ infiltration resulting in paraplegia. The case demonstrates that beside "idiopathic" hypereosinophilic syndromes (HES), a proportion of such patients suffer from eosinophilic leukemias. In these cases, karyotype analysis may help to distinguish these states by the identification of clonal chromosomal abnormalities. A karyotype anomaly hitherto not reported can be added to the list of aberrations in hypereosinophilic states associated with myeloproliferative processes.

Adult↗
PubMed1997

Late relapse of germ cell tumors after cisplatin-based chemotherapy.

BACKGROUND: Sparse data are available with regard to the incidence, clinical characteristics, therapeutic management and prognosis of male patients with germ cell tumors, who relapse more than two years after completion of cisplatin-based chemotherapy. PATIENTS AND METHODS: A review of 530 patients treated at two institutions from 1978 to April 1994 was conducted. Twenty-five cases of late relapse were identified. Cumulative risk of late relapse was calculated according to the Kaplan-Meier method. RESULTS: 418 of 523 patients (80%) who received their first-line treatment at our institutions were relapse-free at two years. Among these 418 patients 18 cases (4.3%) developed a late relapse. The cumulative risk of late relapse was 1.1% at five years and 4.0% at ten years excluding patients with prior early relapses who carried risks of 9.4% and 29%, respectively (P < 0.0001). No case of late relapse was observed among patients receiving adjuvant chemotherapy. The risk of late relapse was lower in patients with good-risk non-seminomatous germ cell tumors than in poor-risk patients according to Medical Research Council criteria (P < 0.01). Seven further patients were referred from other institutions for treatment of late relapse. At a median follow-up of 38 months (range, 3 to 121) after treatment of late relapse 9 of 25 patients (36%) are continuously disease-free. Six of these nine patients had surgical resection of carcinoma or teratoma as a component of their therapy. CONCLUSION: The incidence of late relapse after cisplatin-based chemotherapy of germ cell tumors is related to initial tumor burden and is somewhat higher than previously expected. Chemotherapy seems to have only minor curative potential, but localized resectable disease can be cured by surgery. Annual follow-up evaluations allow to detect the majority of late relapses at an asymptomatic stage and should be extended throughout the patient's life.

Adult↗
PubMed1997

Clonality analysis as a tool to study the biology and response to therapy in myelodysplastic syndromes.

We examined the bone marrow of 45 patients with MDS at the time of diagnosis and in the course of the disease by means of Southern blot analysis and cytogenetic studies to detect and evaluate clonal markers and their implication on the prognosis of the disease and the response to treatment. All patients were enrolled in an EORTC study and received low-dose Ara-C with or without growth factors according to the study protocol. Thirty patients (67%) were characterized by different clonal markers, such as various gene rearrangements (eg Ig-JH, tcR-beta, bcr, GM-CSF, G-CSF or IL-3) and/or chromosomal markers at the time of diagnosis or early in the course of the disease. In 23 of 30 cases that could be studied in the course of the disease, a statement about the clonal situation was possible: in three cases (8%) the clonal situation did not change, in nine cases (39%) at least a transient reduction of clonal cells could be demonstrated, suggesting partial or complete response to therapy. In eight cases (35%) a change for the worse could be seen. In four cases (17%) involvement of multiple clones could be demonstrated with the clones exhibiting different susceptibilities to treatment. Clinical evaluation showed that patients without clonal markers at diagnosis had a better prognosis as compared to patients who presented with clonal markers. We suggest that clonality analysis at diagnosis and in the course of the disease will be a useful tool to study the biology and response to treatment in MDS.

Blotting, Southern↗
PubMed1997

Enhanced pulmonary accumulation of liposomal amphotericin B (AmBisome) in acute liver transplant failure.

Plasma and tissue concentrations of amphotericin B were determined in a patient treated with liposomal amphotericin B during liver transplant failure. A cumulative rise in amphotericin B plasma concentrations was observed accompanied by an enhanced pulmonary deposition of the drug. Failure of the liver as a major component of the reticuloendothelial system may cause elevated plasma concentrations of liposomal amphotericin B and may consequently enhance deposition of liposomes in the lungs as a substitutive clearing organ.

Acute Disease↗
PubMed1997

Serum pharmacology of amphotericin B applied in lipid emulsions.

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

Adult↗
PubMed1997

Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients.

The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (Cmax) and areas under concentration-time curves (AUC) were 8- to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median Cmaxs were 8.4-fold higher (14.4 versus 1.7 microg/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P = 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P = 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.

Adult↗
PubMed1997

Inflammatory reactions induced by pretransplant conditioning--an alternative target for modulation of acute GvHD and complications following allogeneic bone marrow transplantation?

Intensity of pretransplant conditioning has been closely correlated with regimen related toxicity in patients receiving allogeneic bone marrow transplantation (BMT). In this review, we summarize evidence for a direct link between inflammatory reactions induced by irradiation and cytotoxic treatment and occurrence of acute graft-versus-host disease (GvHD) as well as endothelial complications: In our studies, de novo release of TNFalpha during conditioning was associated with an increased risk of severe GvHD and mortality following BMT, whereas increased spontaneous production of IL-10, an endogenous TNF-antagonist, prior to conditioning protected from these complications. Immunogenetic differences in cytokine regulation and costimulation by endotoxin proved to be important cofactors determining the extent of inflammatory cytokine release in individual patients. Pathophysiological relevance of these findings seems to be confirmed by experimental as well as first clinical trials using TNF-antibodies and related antagonists during pretransplant conditioning. Preclinical experiments suggest additional, cytokine independent inflammatory reactions induced by irradiation such as expression of ICAM-1 and endothelial cell apoptosis. Although the exact impact of these findings on pathophysiology of BMT related complications needs further clarification by future studies, conditioning related inflammation as a first crucial step in induction of GvHD and complications has to be considered when designing new protocols for preparation of patients for allogeneic BMT.

Animals↗
PubMed1997

Functional P-gp expression in multiple myeloma patients at primary diagnosis and relapse or progressive disease.

In this study, 25 multiple myeloma (MM) patients at primary diagnosis and 18 MM patients at relapse or progressive disease (PD) were examined in order to investigate the incidence of P-glycoprotein (P-gp) expression at initial diagnosis and relapse or PD. Furthermore, P-gp expression in relation to VAD regimen response was determined. P-gp expression in the myeloma cells was determined using monoclonal antibody 4E3.16 and the rhodamine 123 functional test. The percentage of patients with P-gp overexpression at primary diagnosis ranged between 0 and 41% in the literature vs 32% in our study. The percentage of P-gp positive patients at relapse or PD ranged between 29 and 59% in the literature vs 33% in this analysis. All P-gp positive patients had a functional P-gp, ie a pumping P-gp. A significant difference concerning response (50 vs 58.3%) to VAD treatment and median survival (10 vs 12.5 months) between P-gp positive and P-gp negative patients could not be determined. Six of 12 P-gp negative MM patients at relapse or PD developed after VAD therapy a relapse combined with P-gp overexpression. These results do not confirm the suggestions that P-gp overexpression influences response to VAD treatment. However, the results described in the literature and our own emphasize the need for careful accompanying research programmes aimed at detecting the complexity of chemotherapy resistance in the light of developing a risk-adapting therapy for MM patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Cisplatin-based chemotherapy of primary extragonadal germ cell tumors. A single institution experience.

BACKGROUND: Extragonadal germ cell tumors account for only 2-5% of all germ cell neoplasms in adult males. Because these tumors are rare and, in part, biologically distinct from their testicular counterparts, their optimal management continues to be defined. METHODS: The medical records of 51 patients with extragonadal germ cell tumors were reviewed. All patients were treated with cisplatin-based chemotherapy at a single institution between 1981 and 1994. RESULTS: Thirty-five patients had nonseminomatous germ cell tumors and 16 had pure seminomas. Sixteen tumors arose in the mediastinum (12 nonseminomas, 4 seminomas), and 35 in the retroperitoneum (23 nonseminomas, 12 seminomas). Six of 12 patients (50%) with mediastinal nonseminomas survived with no evidence of disease (NED) at 33-137 months (median, 96 months); all had undergone surgery as part of their treatment. Fifteen of 23 patients (65%) with retroperitoneal nonseminomas are alive with NED at 2-145 months (median, 39 months). Fifteen of 16 patients (94%) with extragonadal seminomas survived with NED at 2-141 months (median, 66 months), and 1 patient died from late irradiation-related toxicity. Three patients with retroperitoneal nonseminomas developed a testicular seminoma at 35, 42, and 77 months, respectively; all are currently disease free. CONCLUSIONS: Mediastinal and retroperitoneal nonseminomas have distinct clinical features. As in other series, clinical outcome is somewhat inferior for mediastinal nonseminomas compared with retroperitoneal nonseminomas. Regardless of the site of presentation, the vast majority of patients with extragonadal seminomas can expect cure. It remains controversial, however, whether retroperitoneal germ cell tumors are metastatic from a primary testicular germ cell tumor.

Adolescent↗
PubMed1996

Autoantibodies against p53 are not increased in human ascites and pleural effusions.

Mutated human p53 may give rise to the formation of autoantibodies and may be a marker for a worse prognosis. We speculated that ascites or pleural effusions may enhance the formation of such autoantibodies in cancer patients and, therefore, we measured the presence of autoantibodies in the ascites or pleural effusion of 40 patients with advanced malignancies. As controls, p53 autoantibodies were measured in 15 patients with effusions who did not have a malignancy. Using a specific enzyme-linked immunosorbent assay, p53 autoantibodies could only be detected in the effusions of 5/40 patients (12.5%) with known malignancies. The formation of autoantibodies did not correlate with the presence or absence of tumor cells in the effusion. The effusions of the patients without tumor were all negative for p53 autoantibodies. Our study shows that malignant or reactive effusions do not stimulate the local or systemic production of autoantibodies against p53.

Antibody Specificity↗
PubMed1996

Advances in the management of metastatic non-seminomatous germ cell tumours during the cisplatin era: a single-institution experience.

Long-term outcome was reviewed in 266 consecutive patients with metastatic non-seminomatous germ cell tumours treated at a single institution. The overall 3 year survival was 77%, and 3 year progression-free survival was 71%. Multivariate analysis identified the following clinical features as independent prognostic factors: the presence of liver, bone or brain metastasis, serum human chorionic gonadotropin > or = 10000 U l-1 and/or alpha-fetoprotein > or = 1000 ng ml-1, a mediastinal mass > 5 cm and the presence of 20 or more lung metastases. Age was not of prognostic significance. Patients without any of the above poor-risk factors had a 3 year survival of 91% regardless of etoposide- or vinblastine-containing chemotherapy compared with 61% for the remaining patients. However, etoposide-containing protocols led to significantly improved survival in patients with at least one poor risk factor. After 612 patient-years of observation no case of secondary leukaemia was observed among 119 surviving patients who had received etoposide as part of their treatment. With a median follow-up of 93 months, five patients developed a second germ cell tumour, two patients nongerm cell malignancies. Fourteen patients relapsed after a disease-free interval of more than 2 years, and nine patients died more than 5 years after commencement of treatment underscoring the need to report long-term results. There is some evidence that cumulative experience translates into improved survival and cure rates for patients with poor-risk metastatic disease.

Adolescent↗
PubMed1996

Antitumor activity of paclitaxel after failure of high-dose chemotherapy in a patient with late relapse of a non-seminomatous germ cell tumor.

Although cisplatin-based chemotherapy considerably improved the clinical outcome of patients with metastatic germ cell tumors, approximately 20% of patients fail to achieve a durable remission to first-line treatment and require effective salvage treatment. As only 20-30% of patients can expect disease-free long-term survival after conventional salvage treatment, an increasing proportion of patients has been referred to high-dose chemotherapy with autologous stem cell rescue during recent years. However, high-dose chemotherapy still fails to cure a considerable number of patients, emphasizing the need to continue the search for new active drugs. We report here the case of a patient with late relapse of a non-seminomatous germ cell tumor who failed to respond to high-dose chemotherapy after heavy pretreatment with 11 cycles of cisplatin-based chemotherapy. The patient received paciltaxel for symptomatic disease with hepatic and pulmonary metastases, and attained a partial remission. Despite the heavy pretreatment, hematologic toxicity of paciltaxel was tolerable. As recent reports described responses to single-agent paciltaxel in a quarter of pretreated patients with germ cell tumors, further clinical trials seem justified to study the role of paciltaxel in combination regimens against this cancer type.

Adult↗
PubMed1996

Detection of acute myeloid leukemic cells in complete remission and in extramedullary sites by clonal analyses.

We report the case of a 49-year-old woman with acute myeloid leukemia (AML, M5b). The leukemic cells expressed blast as well as myelomonocytic antigens and were characterized by a clonal gene rearrangement of the immunoglobulin (Ig) JH gene. During the course of the disease in clinical/cytological complete remission (CR) the persistence of leukemic cells was shown by surface marker analyses on bone marrow (BM) cells or BM clones grown in agar. Moreover, clonal leukemic cells could be detected by Southern blot analyses indicating the persistence of blasts. Occasionally BM cells obtained in CR showed a cytologically, immunologically differentiated phenotype, but nevertheless DNA-rearranged cells indicated differentiated blasts ('clonal remission'). Five years after diagnosis the patient presented with an isolated pleural effusion. Southern blot analysis identified the original leukemic clone because pleural cells showed the same clonal Ig gene rearrangement as the cells at diagnosis. The patient died 6 years after diagnosis during her fourth relapse of AML. This shows the value of Southern blot analyses, immunophenotyping and culture techniques to monitor the course of leukemic tumor burden even if it is not cytologically identifiable.

Antigens, CD↗