Biomedical subjects

J Buer

Publications and source records attributed to J Buer.

At least 37 records · Page 2Linked to original sources

PubMed1999

[Chemoimmunotherapy in the systemic treatment of advanced renal carcinoma].

Polychemotherapy and immunomodulating treatment using IL-2 and/or IFN-alpha produce objective responses in a proportion of advanced renal cell carcinoma patients. The goals of an improved cost effectiveness and therapeutic index of interleukin-2 and/or Interferon-alpha in combination with chemotherapeutic agents require the design of risk factor adapted individual therapeutic strategies for the outpatient setting. High dose i. v. IL-2 therapy in metastatic renal cell carcinoma has been proven effective [11]. Other modalities of applying IL-2 have been described [12-14] (Table 1). A cumulative risk-score identified three risk-groups with significant differences in median survival [16]. The SC use of IL-2 and INF-alpha has been established in the treatment of RCC [16, 23]. It appears that combination chemoimmunotherapy including p. o. retinoic acid is far more effective than single agent treatment. Further studies will have to be designed to improve therapeutic index and cost effectiveness in systemic combination therapy in metastatic RCC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Pleiotropic changes controlled by the pre-T-cell receptor.

The construction of various gene-deficient mice has facilitated the understanding of the role of various receptors and signaling pathways that control the generation of alphabeta lineage cells. A predominant role is occupied by the pre-TCR, which not only generates large numbers of alphabeta lineage cells but also controls TCRbeta allelic exclusion as well as commitment to the gammadelta lineage versus the alphabeta lineage.

Alleles↗

PubMed1999

Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma.

Interleukin 10 (IL-10) is an immunosuppressive factor and has been detected in tumour cell cultures of renal cell carcinoma and of malignant melanoma. IL-10 has been described as a cytokine of the Th2 response; it is able to suppress antigen-presenting cells (APCs) and may lead to down-regulation of HLA class I and II molecules on dendritic cells and to anergy of T-lymphocytes. We evaluated pretreatment serum levels of soluble IL-10 and various clinical parameters to determine their prognostic value in 80 advanced renal cell carcinoma patients seen at our institution between May 1990 and April 1996. For statistical evaluation we used both univariate and multivariate Cox proportional hazards models. An elevated pretreatment serum level of IL-10 was a statistically independent predictor of unfavourable outcome (P < 0.0028), in addition to the well-known clinical and biochemical risk factors. These data support risk stratification for future therapeutic trials and identify a predictor which needs to be validated in prospective studies and may potentially influence decision making in palliative management of patients with metastatic renal cell carcinoma. These data also suggest a potential role of IL-10 in the development of advanced renal cell carcinoma and in the future design of therapeutic strategies.

Adult↗

PubMed1999

Prognostic impact of in vivo soluble cell adhesion molecules in metastatic renal cell carcinoma.

The purpose of the study was to determine prognostic significance of pretreatment serum levels of different molecules involved in cell to cell interactions along with other clinical parameters in patients with metastatic renal cell carcinoma. sICAM-1, sVCAM-1 and sELAM-1 serum levels were determined by ELISA assays in sera from 99 patients with histologically confirmed progressive metastatic renal cell carcinoma prior to initiation of systemic therapy. Kaplan-Meier survival analysis, log-rank statistics and two-proportional Cox regression analyses were employed to identify risk factors and to demonstrate statistical independence. In univariate analyses, the following pretreatment risk factors could be identified: serum sICAM-1 level > 360 ng ml(-1), erythrocyte sedimentation rate > 70 mm h(-1), serum C-reactive protein level > 8 mg l(-1), serum lactic dehydrogenase level > 240 U/l and neutrophil count > 6000 microl(-1). Multivariate analyses demonstrated statistical independence for serum sICAM-1 level, erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) level as pretreatment predictors of overall patient survival. The prognostic significance of sICAM-1 might indicate a role of this molecule for tumour progression, potentially in association with the abrogation of anti-tumour immune responses. The possibility of defining a pretreatment risk model based on sICAM-1 level, ESR and CRP also warrants further investigation, with regard to a possible linkage between acute phase proteins and sICAM-1 levels.

Carcinoma, Renal Cell↗

PubMed1999

Autoimmunity resulting from cytokine treatment predicts long-term survival in patients with metastatic renal cell cancer.

PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival. PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-alpha2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test. RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P<.0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P< or =.05), and the Cw7 expression was associated with prolonged overall survival (P = .009). CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2- and IFN-alpha2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.

Adult↗

PubMed1998

Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo.

Continuous antigenic stimulation in vivo can result in the generation of so-called "anergic" CD4(+) or CD8(+) T cells that fail to proliferate upon antigenic stimulation and fail to develop cytolytic effector functions. Here we show that class II major histocompatibility complex-restricted T cells specific for influenza hemagglutinin (HA) that become anergic in mice expressing HA under control of the immunoglobulin kappa promoter exhibit an impaired effector function in causing diabetes in vivo, as compared to their naive counterparts, when transferred into immunodeficient recipients expressing HA under the control of the insulin promoter. Furthermore, HA-specific T cells anergized in vivo contain higher levels of interleukin (IL)-4 messenger RNA (mRNA) than naive and recently activated T cells with the same specificity and more than a 100-fold higher levels of IL-10 mRNA. The higher expression of the IL-10 gene is also evident at the protein level. These findings raise the interesting possibility that T cells rendered anergic in vivo have in fact become regulatory T cells that may influence neighboring immune responses through the release of IL-10.

Adoptive Transfer↗

PubMed1998

Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model.

Mice that express influenza hemagglutinin under control of the rat insulin promoter (INS-HA) as well as a class II major histocompatibility complex (MHC)-restricted HA-specific transgenic TCR (TCR-HA), develop early insulitis with huge infiltrates, but progress late and irregularly to diabetes. Initially, in these mice, INS-HA modulates the reactivity of antigen-specific lymphocytes, such that outside the pancreas they do not cause lethal shock like their naive counterparts in single transgenic TCR-HA mice, when stimulated with high doses of antigen. Inside the pancreas, the antigen-specific cells do not initially attack the islet cells, and produce some IFN-gamma as well as IL-10 and IL-4. Spontaneous progression to diabetes, which can be accelerated by cyclophosphamide injection, is accompanied by a 10-fold increase in IFN-gamma and a 3-fold decrease in IL-10 and IL-4 production by the locally residing antigen-specific T cells. Also, total islets from non-diabetic mice contain more TNF-alpha, compared with diabetic mice. This scenario is consistent with the view that beta cell destruction depends upon the increased production of certain pro-inflammatory cytokines by infiltrating T cells. Our inability to detect Fas expression on beta cells, but not on lymphoid cells, in diabetic and non-diabetic mice, puts some constraints on the role of Fas in beta cell destruction.

Animals↗

PubMed1998

On the role of the pre-T cell receptor in alphabeta versus gammadelta T lineage commitment.

The role of the pre-T cell receptor (TCR) in lineage commitment to the gammadelta versus alphabeta lineage of T cells was addressed by analyzing TCRbeta chain rearrangements in gammadelta T cells from wild-type and pre-TCR-deficient mice by single cell polymerase chain reaction. Results show that the pre-TCR selects against gammadelta T cells containing rearranged Vbeta genes and that gammadelta T cell precursors but not gammadelta T cells express the pre-TCRalpha protein. Furthermore, pre-TCR-induced proliferation could not be detected in gammadelta T cells. We propose that the pre-TCR commits developing T cells to the alphabeta lineage by an instructive mechanism that has largely replaced an evolutionary more ancient stochastic mechanism of lineage commitment.

Animals↗

PubMed1998

Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic malignant melanoma.

Very rapid progression of disease with a median survival of 6-9 months is a common feature of metastatic cutaneous malignant melanoma. Nevertheless, substantial variability of survival suggests that metastatic cutaneous malignant melanoma can be divided into several biological subgroups. Pretreatment serum levels of soluble adhesion molecules and various clinical parameters in cutaneous metastatic malignant melanoma were evaluated to determine their prognostic value. In this study pretreatment serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular cell adhesion molecule 1 (sICAM-1), soluble endothelial leukocyte adhesion molecule 1 (sE-selectin) and multiple clinical factors were assessed in relation to overall survival of 97 consecutive patients with metastatic cutaneous malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, both univariate and multivariate Cox proportional-hazards models were used. Elevated pretreatment serum levels of sVCAM-1 (P < 0.005) and of lactate dehydrogenase (P < 0.002) were rendered statistically independent and were significantly associated with unfavourable outcome. Patients were assigned to one of three risk categories (low, intermediate and high) according to a cumulative risk score defined as the function of the sum of these two variables. There were significant differences in overall survival (P < 0.0001) between low- (n = 53, 5-year survival probability of 23.3%), intermediate- (n = 29, 5-year survival probability of 9.9%) and high-risk (n = 15) patients. Elevated pretreatment serum levels of sVCAM-1 and of lactate dehydrogenase correlate with poor outcome in metastatic cutaneous malignant melanoma. These data support risk stratification for future therapeutic trials and identify factors that need to be validated in prospective studies and may potentially influence decision-making in palliative management of patients with disseminated cutaneous malignant melanoma.

Adult↗

PubMed1998

Risk and outcome in metastatic malignant melanoma patients receiving DTIC, cisplatin, BCNU and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha2a.

Combined chemo-/immunotherapy has shown high objective response rates and a significant though small proportion of long-term complete responders in metastatic malignant melanoma. The purpose of this study was to determine response rates, freedom from treatment failure (FFTF) and overall survival in patients with advanced metastatic malignant melanoma treated with combined chemo-/immunotherapy, and to determine the value of a prognostic model for prediction of treatment outcome, FFTF and survival. Sixty-nine patients with metastatic malignant melanoma received combined chemo-/immunotherapy consisting of up to four cycles of DTIC (220 mg m(-2) i.v. days 1-3), cisplatin (35 mg m(-2) i.v. days 1-3), BCNU (150 mg m(-2) i.v. day 1, cycles 1 and 3 only) and tamoxifen (20 mg orally, daily). Two cycles of chemotherapy were followed by 6 weeks of outpatient immunotherapy with combined interleukin 2 (20 x 10(6) IU m(-2) days 3-5, weeks 1 and 4; 5 x 10(6) IU m(-2) days 1, 3, 5, weeks 2, 3, 5, 6) and interferon-alpha (6 x 10(6) IU m(-2) s.c. day 1, weeks 1 and 4; days 1, 3, 5, weeks 2, 3, 5, 6). All patients were evaluated on an intention-to-treat basis. Of 69 patients entered in the study, seven achieved complete remissions and 20 reached partial remissions with an objective response rate of 39% (95% confidence interval 28-52%). Median survival was 11 months, median FFTF was 5 months. Seven patients achieved ongoing long-term remissions, with maximum survival of 58 + months, and maximum FFTF of 58 + months. By Kaplan-Meier survival analysis and two-proportional Cox regression analysis, pretreatment performance status and serum lactic dehydrogenase were statistically significant and independent predictors of survival; risk groups could be defined as (a) the absence of both or (b) the presence of either one or both of these risk factors. Whereas survival and response were significantly influenced by patient risk, no influence could be demonstrated for FFTF. This combined outpatient chemo-/immunotherapy is feasible and results in objective response rates and survival similar to earlier trials. Pretreatment risk, as defined by serum lactate dehydrogenase (LDH) and performance status, has a significant impact on treatment outcome and patient survival.

Adult↗

PubMed1998

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application.

AIMS: The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens. METHODS: RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20 x 10(6) IU m(-2) once daily and group B 10 x 10(6) IU m(-2) twice daily (every 12 h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated. RESULTS: The mean area under the serum concentration-time curve to 24 h (AUC(0,24 h)) was 627 IU ml(-1) h in treatment group A and 1130 IU ml(-1) h (P=0.029) in treatment group B. In both study groups Cmax and AUC(0,12 h) were not significantly different. Seventy-two hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly (P=0.016), and sIL-2R levels over 1200 pmol l(-1) seemed to reduce the AUC. CONCLUSIONS: In patients with metastatic renal cell cancer administration of 20 x 10(6) IU m(-2) of rhIL-2 s.c. in two daily doses (10 x 10(6) IU m(-2) every 12 h) provides better bioavailability and is preferable to the single dose administration.

Aged↗

PubMed1998

Crucial function of the pre-T-cell receptor (TCR) in TCR beta selection, TCR beta allelic exclusion and alpha beta versus gamma delta lineage commitment.

The analysis of T-cell receptor (TCR) beta selection, TCR beta allelic exclusion and TCR beta rearrangement in gamma delta T cells from normal and pre-TCR-deficient mice has shown that the pre-TCR has a crucial role in T-lymphocyte development: The pre-TCR is by far the most effective receptor that generates large numbers of CD4+8+ T cells with productive TCR beta rearrangements. In the absence of the pre-TCR, TCR beta rearrangement proceeds in developing cells irrespective of whether they already contain a productive TCR beta gene. The pre-TCR directs developing T cells to the alpha beta lineage because gamma delta T cells from pT alpha-/- mice proceed much further in TCR beta rearrangement than gamma delta T cells from wild-type mice. It is argued that the pre-TCR commits developing T cells to the alpha beta lineage by an instructive mechanism, which has largely replaced an evolutionarily more ancient mechanism that involves stochastic alpha beta lineage commitment.

Alleles↗

PubMed1997

T-cell development in the absence of the pre-T-cell receptor.

The development of pre-T-cells with productive T-cell receptor beta (TCR beta) rearrangements can be furthered by each of the pre-T-cell receptors (pre-TCR), the alpha beta TCR as well as the gamma delta TCR, albeit by distinct mechanisms. While the gamma delta TCR affects CD4-8- precursor cells irrespective of their TCR beta rearrangement status both the pre-TCR and the alpha beta TCR select only cells with productive TCR beta genes for expansion and maturation. The alpha beta TCR is much less effective than the pre-TCR because of the paucity of TCR alpha proteins in TCR beta positive precursors.

Animals↗

PubMed1997

Role of different T cell receptors in the development of pre-T cells.

The development of pre-T cells with productive TCR-beta rearrangements can be mediated by each the pre-T cell receptor (pre-TCR), the TCR-alphabeta as well as the TCR-gammadelta, albeit by distinct mechanisms. Although the TCR-gammadelta affects CD4-8- precursor cells irrespective of their rearrangement status by TCR-beta mechanisms not involving TCR-beta selection, both the pre-TCR and the TCR-alphabeta select only cells with productive TCR-beta genes for expansion and maturation. The TCR-alphabeta appears to be much less effective than the pre-TCR because of the paucity of TCR-alpha proteins in TCR-beta-positive precursors since an early expressed transgenic TCR-alphabeta can largely substitute for the pre-TCR. Thus, the TCR-alphabeta can assume a role not only in the rescue from programmed cell death of CD4+8+ but also of CD4-8- thymocytes. In evolution this double function of the TCR-alphabeta may have been responsible for the maturation of alphabeta T cells before the advent of the pre-TCR-alpha chain.

Animals↗

PubMed1997

Essential role of the pre-T cell receptor in allelic exclusion of the T cell receptor beta locus.

Following the recent realization that TCR beta transgenes can severely inhibit the rearrangement of endogenous Vbeta gene segments in the absence of pre-TCR alpha (pT alpha) chains, we tested whether the pre-TCR has an essential role in TCR beta allelic exclusion under more physiological conditions by analyzing TCR rearrangement in immature thymocytes by single-cell PCR. Our results in pT alpha+ mice are consistent with an ordered model of TCR beta rearrangement beginning on one allele and continuing on the other only when the first attempt is unsuccessful. By contrast, a higher proportion of thymocytes from pT alpha-/- mice exhibited two productive TCR beta alleles. Thus, the pre-TCR-independent suppression of rearrangement by TCR beta transgenes represents a transgene artifact, whereas under physiological conditions the pre-TCR is essential for allelic exclusion.

Alleles↗

PubMed1997

Elevated serum levels of S100 and survival in metastatic malignant melanoma.

Current reports suggest serum S100 as a prognostic marker for disease progression in advanced malignant melanoma. In this study, we assessed serum levels of S100 and multiple clinical factors in relation to overall survival in 99 patients with metastatic malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, we used both univariate and multivariate Cox proportional-hazards models. Elevated serum levels of S100 correlated with poor outcome in metastatic malignant melanoma (P < 0.0001), univariate analysis). Upon multivariate analysis, however, S100 added no information to known clinical prognostic parameters.

Aged↗

PubMed1997

Detection of melanoma cells in peripheral blood stem cell harvests of patients with progressive metastatic malignant melanoma.

The detection of melanocyte-specific messenger RNA in patients with malignant melanoma suggests the potential contamination of peripheral blood stem cell (PBSC) harvests by neoplastic cells. In this study, the melanocyte-specific transcripts of tyrosinase and Melan-A/MART-1 were used to detect neoplastic cells in PBSC harvests of nine metastatic malignant melanoma patients. Only one patient's PBSC harvest tested positive for tyrosinase. All harvests were negative for Melan-A/MART-1. Our results suggest that contamination of PBSC harvests with neoplastic cells may not contribute to disease progression following high-dose chemotherapy in advanced malignant melanoma.

Adult↗

PubMed1997

Clinical and in vitro response to 13-cis-retinoic acid in interferon-alpha resistant renal cell carcinoma.

Retinoids are known to control many important biological processes, including differentiation, morphogenesis, growth and tissue homeostasis. More recently, clinical and pre-clinical results provide evidence for an antiproliferative effect of 13-cis-retinoic acid (13cRA) in interferon-alpha (IFN-alpha) treated renal cell carcinoma patients. The manner in which 13cRA augments antitumor effects and modulates biologic and clinical responses of renal cell carcinoma to IFN-alpha remains elusive. In the present study, we report induction of apoptosis and objective tumor regression in response to 13cRA in advanced renal cell carcinoma patients refractory to IFN-alpha. Among 21 patients treated there were one complete and four partial remissions (objective response rate, 24%; median response duration 8+ months). Preliminary evidence suggests that 13cRA acid may reverse IFN-alpha resistance in renal cell carcinoma.

Aged↗