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H Kirchner

Publications and source records attributed to H Kirchner.

At least 199 records · Page 11Linked to original sources
PubMed1994

[Relevance of transmission of Epstein-Barr virus through blood transfusion].

In order to investigate the risk of transmission of Epstein-Barr Virus (EBV) by red cell concentrates (RCCs, bottom and top system), we examined 15 EBV-seronegative pediatric patients who received EBV-seropositive red cell concentrates prior to and up to 11 weeks after transfusion. None of these children showed serological or clinical signs of active EBV infection. To further explore this situation we estimated the number of EBV genomes in RCCs in comparison with whole blood units and found a significant reduction (1-2 EBV genomes in one RCC compared with 600-700 in one whole blood unit, p < 0.1%). The use of modern leukocyte depletion systems dramatically reduces the number of EBV-positive cells in RCCs, minimizing the risk of EBV infection. As there were no hints of transmission of EBV in current transfusion practice, the provision of EBV-seronegative RCCs for patients with high risk of infection does not seem to be necessary.

Child↗
PubMed1994

[Effect of leukocyte contamination on storage of platelet concentrates from buffy coats].

We examined the effect of white cell contamination on thrombocytes prepared from pooled buffy coats over a storage period of 8 days. Using this novel technique, a leukocyte depletion filter can be easily integrated during PC preparation. In a paired study (n = 14) eight ABO-identical BC were pooled in a 2-liter PVC bag within 8 h after whole-blood donation, thoroughly mixed and divided into two identical fractions. After soft-spin centrifugation the platelet-rich plasma (PRP) was transferred either (fraction A) using a leukocyte filter (PL 50-HF, Pall) or (fraction B) directly into the storage bag (Pl-732, Baxter), and stored under routine conditions. On days 1, 3, 5, and 8, aliquots of PC were withdrawn for determination of cell count and different biochemical parameters and for morphometric analyses of platelet ultrastructure by electron microscopy. Results showed a lower thrombocyte yield and white cell count (p < 0.01) in fraction A (268 x 10(9) vs. 240 x 10(9); 51.1 x 10(6) vs. 0.04 x 10(6)), whereas no differences between the preparations could be detected by analysis of pH, pCO2, bicarbonate, and in LDH release over the storage period of 8 days. These results were supported in the study on the ultrastructural level where a good morphological integrity of the platelets was observed during the whole storage period in both fractions. In conclusion, storage lesions on platelets due to leukocyte effects are unlikely to occur in PC with white cell counts lower than 10(8)/l.

Blood Platelets↗
PubMed1994

[Lymphocyte interactions in platelet concentrates from buffy coats. Determination of proliferating cells using Ki-67 antibodies].

The preparation of platelet concentrates (PC) from pooled buffy coats has raised concern as to whether activation of lymphocytes may take place during the period of storage. Lymphocytes and HLA-DR-positive cells are of particular relevance, as they may induce a mixed lymphocyte reaction (MLR). Therefore we investigated the degree of leukocyte contamination and determined the quantity of proliferating leukocytes using the monoclonal antibody KI-67. The content of total leukocytes was (0.07 +/- 0.05) x 10(9). Immunostaining of KI-67-positive cells proved that, directly after preparation, only single leukocytes were activated. On days 1, 3 and 5 after preparation the results were identical. Isolated cells were found to be KI-67-positive but there was no significant increase in proliferating cells as would have been expected in an MLR. We conclude that there is no allogenic activation of lymphocytes taking place in these PC during storage. Therefore transfusion of activated lymphocytes seems to be extremely unlikely.

Antibodies↗
PubMed1993

Investigations of the lymphokine system in elderly individuals.

Elderly people are at risk from an increased incidence of infections. Therefore we have studied the correlation between the production of several immunological parameters such as interferon-gamma (IFN-gamma), interferon-alpha-2 (IFN-alpha-2), interleukin-2 (IL-2), soluble interleukin-2 receptors (sIL-2R) and interleukin-6 (IL-6) in young controls of 25-34 years old and old individuals with a minimum age of 65 years. All persons were selected according to the basic concept of the 'Senieur protocol'. Heparinized blood was taken and cultured in the whole-blood assay. The determination of all cytokines in the supernatants of stimulated cultures was done by the ELISA technique. We found significantly decreased levels of sIL-2R and IFN-alpha-2 after stimulation, whereas the values of IFN-gamma and IL-2 showed no significant difference between elderly and young persons. The values of IL-6 showed a distinct trend towards an increased synthesis for the elderly. We also studied the lymphocyte subpopulations T4 and T8 by flow cytometry. Elderly individuals showed a significantly increased T4/T8 ratio, caused by a slightly but not significantly decreased level of T8 cells. These results show that the elderly have decreased values of some immunological parameters such as IFN-alpha-2 and sIL-2R, which might explain an increased susceptibility of elderly individuals to bacterial and viral infections.

Adult↗
PubMed1993

A longitudinal prospective study of cytomegalovirus pp65 antigenemia in renal transplant recipients.

Cytomegalovirus (CMV)-encoded pp65 antigen in peripheral blood leukocytes (CMV antigenemia) was investigated in 1017 serial samples from 64 patients for 16 weeks after renal transplantation in a prospective study. In 110 samples from 24 patients, at least one antigen-positive leukocyte was identified. The median number of stained cells was 4 (range 1-1000) per 4 x 10(5) leukocytes. Twenty-one of 24 patients with serological signs of an active CMV infection were antigen-positive (sensitivity 87.5%), whereas 3 patients with antigenemia did not show serological signs of infection during the observation period (specificity 92.5%). Positive results were obtained 19 days (median) before serological response and 9 days (median) before the onset of CMV syndrome. The sensitivity in defining a CMV syndrome was 100% (n = 8). In all patients who presented with CMV syndrome, antigenemia was present prior to the onset of symptoms or on the same day. In contrast, serological monitoring rendered the diagnosis of CMV infection possible at the onset of clinical symptoms in only two of eight patients. We conclude that (1) insufficient results obtained with the CMV antigenemia assay by other investigators are mainly due to technical problems that can easily be overcome by the protocol presented and (2) the detection of CMV pp65 antigen in peripheral blood leukocytes is an excellent tool for rapid and early diagnosis of CMV infection.

Antibodies, Viral↗
PubMed1993

Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha: evidence of a risk/benefit advantage of subcutaneous therapy.

Systemic immunotherapy with recombinant interleukin-2 (rIL-2) via intravenous (i.v.) and subcutaneous (s.c.) administration produces objective responses in a proportion of advanced cancer patients. While most of the previous investigations chose the i.v. route for cytokine application, there is an increasing number of trials employing s.c. rIL-2 therapy. The comparison of reported response rates for i.v. versus s.c. therapy reveals no significant differences between these modalities. In an effort to describe systemic toxicities of s.c. cytokine therapy with regard to renal, metabolic, and hemodynamic abnormalities and to compare these effects to toxicities reported upon i.v. therapy, we retrospectively evaluated 148 treatment cycles of s.c. immunotherapy given to 107 outpatients. Our study cohorts consisted of 15 patients who received s.c. rIL-2 at doses of (4.8-14.4) x 10(6) IU m-2 day-1 5 days/week for a total of 8 weeks, 20 patients who received rIFN alpha 2b at (3.0-6.0) x 10(6) m-2 day-1 thrice weekly for a total of 6 weeks, and 72 patients who were given s.c. rILFN alpha 2b at 6.0 x 10(6) U/m2, three times per week, plus s.c. rIL-2 at (14.4-18.0) x 10(6) IU/m2 on days 1 and 2, followed by 4.8 x 10(6) IU m-2 day-1 5 days/week for 6 consecutive weeks. These treatment regimens were well tolerated in the outpatient setting; no toxic death occurred, and none of the patients developed life-threatening toxicity due to a capillary leak syndrome. Upon s.c. combination therapy, dyspnea at rest occurred in 6% of patients and grade III and IV hypotension occurred in 7% and 4%, respectively; plasma protein was significantly decreased (mean nadir +/- standard deviation, 67 +/- 5 g/l). In addition, s.c. therapy led to a significant increase in serum creatinine (mean peak +/- standard deviation, 115.1 +/- 21.4 mumol/l) and urea nitrogen (mean peak +/- standard deviation, 6.5 +/- 2.5 mmol/l); electrolyte disturbances and direct nephrotoxicity never caused major clinical symptoms. This was in marked contrast to a multitude of dose-limiting and life-threatening adverse reactions reported upon i.v. rIL-2 therapy. We conclude that palliative low to intermediate-dose s.c. rIL-2/rIFN alpha combination therapy, in contrast to i.v. treatment, can be administered in the ambulatory setting with good practicability and excellent safety. This outpatient regimen is as effective against metastatic renal cell cancer as the most aggressive i.v. rIL-2 protocol reported.

Adult↗
PubMed1993

Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer.

Recent clinical trials for the biological therapy of solid tumours have used recombinant human cytokines in combination with conventional chemotherapy. In patients with progressive metastatic renal cell carcinoma, we established a three-drug combination comprising interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU), using a regimen which allows outpatient therapy. Treatment consisted of 8 weeks each of IFN-alpha [6-9 MU/m2 once to three times weekly subcutaneously (sc)] combined sequentially with IL-2 (5-20 MU/m2 thrice weekly sc for 4 weeks) and 5-FU [750 mg/m2 intravenously (i.v.) weekly for 4 weeks]. Among the first 35 patients treated, there were 4 complete (11.4%) and 13 partial responders (37.1%), with an overall objective response rate of 48.6% (95% confidence interval 32-66%). Regressions occurred in local relapse, in lung, lymph node, bone, pleural, renal and thyroid metastases. Median response duration was calculated at 7+ months. An additional 13 patients (37.1%) were stable throughout therapy and thereafter (median of 6+ months). Response rate of this three-drug combination regimen compared favourably with single agent IFN-alpha (objective response rate approximately 16%) and against the sc IFN-alpha/IL-2 combination (objective response rate approximately 28%). Systemic toxicity was mild to moderate with no severe 5-FU-related mucositis and no dose-limiting adverse effects of sc IL-2. While the exact mechanisms of the potentially additive or synergistic effects of 5-FU and IFN-alpha/IL-2 remain to be established in more detail, it appears that the sequential use of IFN-alpha/IL-2 and IFN-alpha/5-FU in metastatic renal carcinoma further enhances the therapeutic index of IFN-alpha/IL-2-based biological therapy. Based on the present data, combined biochemotherapy may be a promising new approach to the therapy of advanced renal cancer.

Adult↗
PubMed1993

Cytokine production of the human monocytic cell line Mono Mac 6 in comparison to mature monocytes in peripheral blood mononuclear cells.

Mono Mac 6 is a human monocytic cell line with several features of mature blood monocytes such as CD 14 antigen expression, phagocytotic ability, and the functional ability to produce cytokines. This line is often used as an in vitro model to demonstrate the actions of monocytes. In our study, the production of cytokines by Mono Mac 6 cells in response to various stimulants was analyzed and compared to that of mature monocytes in peripheral blood mononuclear cells (PBMC). Interestingly, the Mono Mac 6 cells produced IL-1 alpha/beta, IL-6, and TNF-alpha after induction with the lectin phytohaemagglutinin A (PHA), mainly known as a T cell activator. The amount of cytokine release did not decrease in the presence of polymyxin B (Pmb), an inhibitor of LPS-induced effects. Kinetic studies revealed maximum cytokine levels 24h after stimulation, whereas human PBMC produced higher yields of all cytokines and enhancement was observed up to 48 hours after induction. Stimulation with the superantigen derived from the supernatant of mycoplasma arthritidis (MAS) induced expression of IL-1 beta, IL-6, and TNF-alpha, whereas staphylococcus enterotoxin B (SEB) did not induce any cytokine release. Further experiments analyzed the ability of Mono Mac 6 cells to produce IFN-alpha which is an important characteristic of mature monocytes. The cells were induced either with inactivated Newcastle Disease Virus (NDV), Sendai Virus, or the synthetic stimulus poly I:C IFN-alpha expression was not detected on the transcriptional or the protein level. In addition, no co-expression of IL-1 and IL-6 was observed in response to these stimuli. Since NDV, Sendai Virus, and poly I:C represent strong IFN-alpha inducers in peripheral blood monocytes, these data indicate that Mono Mac 6 cells lack the ability to express IFN-alpha. In conclusion, our findings show that this cell line is a potent cytokine producer, but the capacity to produce IFN is apparently deficient.

Cell Line↗
PubMed1993

Lack of therapeutic efficacy of tamoxifen in advanced renal cell carcinoma.

In the present study, we treated a total of 62 patients with advanced renal cell carcinoma with high-dose tamoxifen (100 mg/m2/day). Patients were treated in the outpatient setting, and were evaluated 8-12 weeks after initiation of therapy or sooner, when clinical disease progression was evident; a total of 15 patients were seen at short regular intervals for evaluation of clinical and laboratory parameters. Of these 62 patients, 59 were evaluable for treatment response, survival and systemic toxicity. One partial remission was achieved (1.7%; 95% confidence interval, 0.04-9.09%), response duration was 3 months. 10 patients presented with stable disease, for a median duration of 4.0 months, and 48 patients exhibited disease progression upon and after therapy. Systemic toxicity was significant; severe fatigue occurred in 5% of patients, and moderate anaemia, dyspnea, alopecia and malaise in almost 20% of patients. Antineoplastic efficacy of tamoxifen at this dosage in this cohort of patients was at best marginal and well in the range associated with the occurrence of spontaneous remissions. Toxicity was substantial, and it was not balanced by therapeutic benefit. This is consistent with the known lack of therapeutic efficacy of endocrine therapy in advanced renal cell carcinoma.

Adult↗
PubMed1993

A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma.

PURPOSE: To compare 2 treatment modalities with recombinant Interleukin-2 (rIL-2) for patients with advanced Renal Cell carcinoma (RCC): continuous intravenous infusion (CIV) alone versus subcutaneous (s/c) rIL-2 + Interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Data have been collected on 425 patients with RCC, treated CIV rIL-2 alone, (225 patients), or rIL-2 by the s/c route (200 patients). Patients receiving s/c rIL-2 also received s/c IFN-alpha both drugs being administered on an outpatient basis. Patients receiving CIV rIL-2 were treated as inpatients. Patient eligibility criteria were similar on all studies, and included patients with progressive, advanced disease, but with an ambulatory performance status. RESULTS: The overall response rate for the CIV schedules was not significantly different from the s/c regimens: 15% (95% confidence limits (CL) 10-20%) vs 20% (95%CL 14-26%) with 4% CR in both approaches. Durable responses were seen in both CIV and s/c schedules and there was no evidence of a significant difference in survival in multivariate analysis. There was however an important shift in the toxicity profile. The s/c regimens do not induce a clinically detectable capillary leak syndrome, which is the dose limiting toxicity for CIV regimens. CONCLUSION: Although the introduction of CIV regimens of rIL-2 was a major step forward compared to high-dose bolus, because most patients could be treated in a normal oncology ward, the s/c schedule of rIL-2 + IFN-alpha offers the possibility of outpatient (home) therapy, with no evidence of a reduction in efficacy.

Adult↗
PubMed1993

Clinical and preclinical evaluation of recombinant PEG-IL-2 in human.

High dose interleukin-2 alone or in combination with lymphokine activated killer (LAK) cells has demonstrated antitumor activity in a variety of malignant diseases. The currently formulated recombinant human interleukin-2 (IL-2) has limited solubility and short circulatory half life resulting in limited bioavailability. To improve the bioavailability of IL-2 the protein was covalently bound to activated Polyethylenglycol (PEG). We designed a phase I/II trial to evaluate the bioactivity of PEG-IL-2 in man, given as intravenous (iv) bolus injection every two weeks, and to determine safety, efficacy, and the maximum tolerated dose (MTD) in patients with advanced malignancies. Assessment of cytokine levels, phenotypic analyses and differential blood counts were performed to investigate the effects of PEG-IL-2 in-vivo. To compare in-vitro PEG-IL-2 activity to activities of IL-2 we evaluated proliferation, cytotolytic activity, morphology, and phenotype of cytokine activated lymphocytes. Among seven patients treated with PEG-IL-2, there was no objective remission, three patients exhibited stabilisation of disease. Four patients presented with further disease progression. Treatment-related toxicity was mild to moderate (mainly WHO grades I and II) in patients receiving dose levels up to 10 x 10(6) IU/m2 (maximum tolerated single dose in the outpatient setting). No toxic deaths occurred. In comparison to IL-2, the pharmacokinetic profile of PEG-IL-2 exhibited increased plasma levels and a decreased clearance (alpha and beta half-life estimates of 4 and 14 hours, respectively). The analysis of a variety of immunologic parameters demonstrated that PEG-IL-2 has significant biologic activity both in vitro, and in man.

Adult↗
PubMed1993

Subcutaneous recombinant interleukin-2 and alpha-interferon in patients with advanced renal cell carcinoma: results of a multicenter Phase II Study.

A phase II multiinstitutional clinical trial was conducted to evaluate the safety and efficacy of the subcutaneous outpatient administration of recombinant human interleukin-2 and alpha-interferon in patients with progressive metastatic renal cell carcinoma. One hundred and forty-five patients were entered on this study between October 1989 and May 1991. Among 134 patients evaluable for treatment response, there were six complete (4.5%) and twenty partial (14.9%) responders, with an overall response rate of 19.4% (95% confidence interval, 13-26%). The median duration of complete remissions was 228 (range 51(+)-520+) days; the median duration of partial tumor regressions was calculated at 226 (range 112-473+) days. The overall median survival from start of therapy was 14.2 (range 1-23+) months. Fever, chills and general fatigue occurred in the majority of patients treated and were measured at grade II, III and IV in up to 55%, 24% and 3% of all evaluable patients, respectively. Three patients each developed grade III hypotension, dyspnea and diarrhea; two patients each had grade III and grade IV elevations of alkaline phosphatase; two and one patients respectively, exhibited grade III anemia and grade IV thrombocytopenia; two patients experienced severe cutaneous toxicity. The majority of patients received treatment in the outpatient setting. In summary, the outpatient use of subcutaneous interleukin-2 and alpha-interferon was effective in patients with advanced metastatic renal cell carcinoma; it was associated with less toxicity and thus, could improve the therapeutic index of interleukin-2 based biologic therapy when compared against high dose intravenous therapy.

Adult↗
PubMed1993

Limited efficacy of interferon-alpha and vinblastine as second line biochemotherapy regimen in patients with progressive metastatic renal cell carcinoma.

We report on thirty-four patients with metastatic renal cell carcinoma who were treated with a combination of subcutaneous recombinant interferon-alpha and intravenous vinblastine upon progression after previous antineoplastic therapy. Pretreatment included chemotherapy (n = 3), hormonal therapy (n = 6) and immunotherapy (interleukin-2/interferon-alpha, n = 25). In this study, treatment courses consisted of subcutaneous doses thrice weekly of recombinant interferon-alpha at 6 million U/m2 (20 patients, group 2), respectively. Treatment was given over 8 consecutive weeks. Additionally, in all patients, vinblastine was administered intravenously at a dose of 6 mg/m2 in weeks 2, 5 and 8. Of 14 patients treated in group 1, one had a partial response for 6 months (overall response rate 7.14%; 95% confidence interval, 0.18-33.87%), and four had disease stabilization (median duration, 5.0 months). Of 20 patients treated in group 2, there was one patient who achieved a complete response (response duration, 34+ months); in addition, two patients had a partial response (median response duration, 10.5+ months; overall response rate, 15%; 95% confidence interval 3.21-37.89%), and 13 patients exhibited disease stabilization (median duration 5.9+ months). Response rates showed no significant differences when comparing treatment results in patients in group 1 vs group 2. In contrast, significantly less patients treated in group 2 had progressive disease (p = 0.024), as compared to patients in group 1. This treatment combination was overall well tolerated with low to moderate systemic toxicity. In addition, there were no significant differences in frequency or intensity of therapy-related systemic toxicities when comparing patients in group 1 and group 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

T-cell surface molecule expression and interferon-gamma production in human cord blood.

We investigated T-cell surface antigen expression and the production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) by human cord and adult blood cells. Cord blood lymphocytes stimulated with Staphylococcus enterotoxin B (SEB) released only minimal titers of IFN-gamma and IL-2 in comparison with adult blood lymphocytes. Systematic analyses of several cell-surface molecules on untreated cord blood and adult blood T cells demonstrated a significant reduction of CD8+ subset numbers in cord blood. Furthermore, cord blood lymphocytes did not express the memory T-cell marker CD45RO. No differences were found in gamma/delta T-cell receptor (TCR), CD5, and CD25 antigen expression between untreated cord blood and adult blood. However, cord blood mononuclear cells showed a decreased CD25 antigen expression in comparison to those of adults following activation with SEB. These observations suggest that the decrease in the proportion of some T-cell subsets and the absence of CD45RO memory T cells may be responsible for the diminished lymphokine production of cord blood lymphocytes.

Adult↗
PubMed1993

Cytomegalovirus transcripts in peripheral blood leukocytes of actively infected transplant patients detected by reverse transcription-polymerase chain reaction.

In an effort to examine human cytomegalovirus (CMV) infections on the transcript level in vivo, a reverse transcription-polymerase chain reaction (RT-PCR) for the detection of CMV mRNA in human peripheral blood leukocytes (PBL) was developed. Oligonucleotide primers were derived from the major immediate-early (MIE) and the pp150 genes of CMV, which allowed the exact differentiation between viral mRNA and DNA. With these primers, 8 renal transplant patients who revealed some evidence of active CMV infection were investigated. CMV-specific transcripts were found in 5 patients, all of them presenting MIE mRNA. pp150 transcripts were demonstrated in only one symptomatic patient who showed RNAemia for several weeks. These findings suggest that during active infection, CMV replicates in PBL and, furthermore, that a detailed analysis of mRNA patterns may make it possible to identify those patients at highest risk of developing symptomatic infection.

Antigens, Surface↗
PubMed1993

Low dose megestrol acetate can abrogate cachexia in advanced tumor patients receiving systemic interferon-alpha and/or interleukin-2 based antineoplastic therapy.

The progression of advanced malignancies is often associated with anorexia and cachexia, especially when patients receive concomitant systemic antitumor treatment. Megestrol acetate has been reported to increase appetite and body weight, and a linear dose-response relation for doses from 160 up to 1600 mg/day has been proposed. In our study, we were able to show that megestrol acetate at doses as low as 60 mg/day was sufficient to abrogate anorexia and weight loss. In contrast to previous studies, this effect was achieved while patients continued systemic antineoplastic therapy.

Anorexia↗