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Biomedical subjects

M Micksche

Publications and source records attributed to M Micksche.

At least 37 records · Page 2Linked to original sources
PubMed1991

Respiratory burst capability of polymorphonuclear neutrophils and TNF-alpha serum levels in relationship to the development of septic syndrome in critically ill patients.

Activated polymorphonuclear neutrophils (PMN) and neutrophil activating mediators such as tumor necrosis factor-alpha (TNF-alpha) are thought to be involved in the pathophysiology of sepsis and multiple organ failure syndrome (MOFS). In critically ill patients at high risk for the development of septic syndrome (n = 17) peripheral blood PMN were assayed for O2- and H2O2 production after stimulation with phorbol myristate acetate (PMA, 40 nM). Serum TNF-alpha levels were determined by ELISA. At the time of admission to the intensive care unit we found significant higher levels of TNF-alpha (P = 0.0001) in the serum of patients finally developing sepsis correlating to higher respiratory burst capability in comparison to nonseptic patients. Additionally we were able to demonstrate a significant (P = 0.0016) lower dismutation rate of O2- to H2O2 in deceased patients in comparison to survivors. These results give further evidence that elevated levels of circulating TNF-alpha and activated PMN play a significant role in the pathogenesis of septic syndrome in critically ill patients.

Biomarkers↗
PubMed1991

Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids.

In a pilot study the therapeutic effect and side effect profile of low-dose interferon alfa-2b in combination with a retinoid for the treatment of cutaneous T cell lymphoma were evaluated. Seven patients (four women, three men) with histologically confirmed cutaneous T cell lymphoma were included. Four patients had received therapy previously. The treatment schedule consisted of 2 million U of interferon alfa-2b administered subcutaneously three times per week and oral 13-cis-retinoic acid, 1 mg/kg/day, with subsequent dose reduction in case of response. The combination therapy produced two complete and two partial remissions. Responses were maintained by continuous therapy for up to 15 months even after dose reduction of both agents by 50%. Side effects were negligible and did not result in discontinuation of treatment in any patient.

Administration, Oral↗
PubMed1990

[Pharmacokinetic aspects of dosage increase of recombinant interferon alpha-2B in patients following intraperitoneal and intra-arterial application].

Interferon-alpha-2 b (IFN) was administered as an i.a. bolus at doses of 3 and 5 million international units (MIU), as an i.a. 24h long-time infusion at 3 and 5 MIU and as an i.p. 90 min short-time infusion at 5, 10 and 15 MIU. Dose escalation of IFN on i.p. administration leads to correspondingly elevated AUC values of IFN (correlating to the dose) in the peritoneal fluid (PF) and blood, with a shift of the steady-state at about 2h. Bioavailability of IFN is 30 times higher for PF than for blood. t1/2 el, Vd and total clearance are not influenced by dose escalation in both compartments due to their dose-independency. IFN is eliminated from the PF with t1/2 el = 10-32h and from the blood with t1/2 el = 5-13h. After an i.a. bolus at either dosage IFN is distributed from the blood with a half-life of below 2h. 24h infusion leads to a steady-state within 4-6h and a cmax of 8.5 or 12.5 units/ml, respectively. IFN is slowly eliminated during infusion with a t1/2 el of 16h.

Dose-Response Relationship, Drug↗
PubMed1990

Experimental treatment of chronic lymphocytic leukemia with extracorporeal photochemotherapy. Initial observations.

Based on the encouraging results obtained with extracorporeal photochemotherapy (EP) in the treatment of the exfoliative erythrodermic form of cutaneous T-cell lymphoma (CTCL), leukemic form, as well as other T-cell-mediated diseases we evaluated the therapeutic potential of EP in patients with chronic lymphocytic leukemia (B-CLL). Three patients with B-CLL were treated for a period of 1 year. Two patients showed stabilization of disease, as demonstrated by reduction in their peripheral white blood cell count, with one patient showing lymph-node resolution. A third patient with significant intolerance to previous chemotherapy did not respond within the observed period. No significant side effects of EP were observed. Our observations suggest that EP may have a positive effect on the course of B-CLL in selected patients. Additional clinical trials are warranted to further define the role of EP alone or in combination therapy in the management of B-CLL.

Adult↗
PubMed1990

Long-term adjuvant therapy of high-risk malignant melanoma with interferon alpha 2b.

Fifty-three high-risk melanoma patients in stage I and 15 patients in stage II were treated after standard surgical intervention with adjuvant therapy with recombinant interferon alpha-2b (rIFN alpha 2b) therapy for a total period of 20 months. Concomitant patients (stage I, n = 82; stage II, n = 33) with identical stages and prognostic factors without adjuvant therapy were used to evaluate the efficacy of rIFN alpha 2b therapy. No difference in 5-year relapse incidence and overall survival rates could be detected. However, it appears that patients of both stage I and stage II benefit from long-term adjuvant rIFN alpha 2b therapy, because during the treatment period (20 months), the incidence of relapses was lower in comparison to controls. After stopping treatment the incidence of relapse is equal in treated and control groups. According to the results of our study, we suggest using continuous low-dose rIFN alpha 2b therapy for adjuvant treatment of malignant melanoma.

Adult↗
PubMed1989

IFN-beta 2/IL-6 augments the activity of human natural killer cells.

MHC nonrestricted cytotoxic cells play an important role in the killing of tumor cells in vitro and potentially in vivo. The activity of these cells is regulated by several cytokines such as IL-2 and IFN. In the present study we provide first evidence that IL-6 significantly augments the cytotoxic activity of human NK cells. IL-6 is produced by many different cells and is also known as IFN-beta 2, B cell stimulatory factor 2, hybridoma growth factor, hepatocyte-stimulating factor, and 26 kDa protein. IL-6 stimulates the activity of human CD3- NK cells but not that of CD3+ non-MHC-restricted cytotoxic T lymphocytes. As is the case with IL-2, the IL-6-mediated augmented cytotoxicity was a result of a more efficient lysis, but was not caused by an increased effector to target cell binding. Moreover, the effect of IL-6 on NK cell activity was blocked by a mAb directed against IL-2, and IL-6 itself was found to be a potent inducer of IL-2 production in cultured human PBMC. Thus it may be concluded that IL-6 enhances the cytotoxic activity of NK cells via IL-2. This newly recognized property of IL-6, which is produced by almost any cell, may be of importance in host defense against microbes and malignancies and therefore could contribute to improve the adoptive immunotherapy by using lymphokine-activated killer cells.

Adjuvants, Immunologic↗
PubMed1989

Expression and release of interleukin-1 by different human melanoma cell lines.

The influence of immunologic parameters on the clinical course of malignant melanoma is increasingly evident. However, it is not known which factors contribute to the immunologic host reaction against malignant melanoma. Because epidermal cells and, in particular, normal as well as transformed keratinocytes recently have been demonstrated to release various immunomodulating cytokines, the capacity of melanoma cells to produce interleukin-1 (IL-1) was examined. Accordingly, supernatants derived from different melanoma cell lines contained significant levels of IL-1 activity. Upon high-performance liquid chromatography (HPLC) gel filtration, melanoma cell-derived IL-1 (MEL-IL-1) exhibited molecular weight heterogeneity, and HPLC chromatofocusing revealed major activity at pH 5.0 and minor activity at pH 7.0. A monoclonal antibody directed against monocyte-derived IL-1 blocked MEL-IL-1 activity significantly and was able to precipitate four species of biosynthetically radiolabeled MEL-IL-1 (25, 17, 6, and 4 kilodaltons), suggesting that MEL-IL-1 is identical to monocyte-derived IL-1. This was also confirmed by Northern blot analysis detecting IL-1 alpha specific mRNA in melanoma cells by hybridization with a cDNA fragment encoding for IL-1 alpha. Thus, melanoma cells, like other epidermal cells, exhibit the capacity to release the immunomodulating cytokine IL-1 and, therefore, probably have the potency to influence host defense mechanisms directed against malignant melanoma.

Cell Line↗
PubMed1989

Influence of brachytherapy (192Ir afterloading) on cell-mediated immune reactions in patients with stage I endometrial cancer.

The influence of radiation therapy on cell-mediated immune reactions in cancer patients seems to depend on source, dose, and area of irradiation, as well as on the variables reflected by the patient population investigated. In the present study we demonstrated that brachytherapy (192Ir afterloading), applied to patients with inoperable stage I endometrial cancer, has no immediate or sustained effect on lymphocyte function. Both lymphocyte mitogen response and natural killer cell (NK) activity are not significantly changed in terms of baseline values compared with test results during and after therapy. Brachytherapy, as used in this study, has no influence on cell-mediated immunity in patients with endometrial cancer stage I.

Aged↗
PubMed1989

Use of CA 125 monoclonal antibody to monitor patients with ovarian cancer.

The monoclonal antibody (mAb) OC 125 reacts with an antigen on human ovarian carcinoma (OVCA) cells that is also shed into the body fluids and can be detected in patients' sera and/or ascites with a radioimmunometric assay. For the present study, serum CA 125 levels of patients (n = 36) with different stages of OVCA were investigated. Serum levels seem to correlate with tumor burden. In stages I and II (n = 12), 33% of patients were CA 125 positive, whereas 70% of stage III and IV patients (n = 24) were CA 125 positive. Mean serum levels were in 93 U/ml (stages I, II) and 279 U/ml (stages III, IV). CA 125 levels in ascites and in pleural effusions were manyfold higher than serum levels of the same patients (P less than 0.0001). Immunohistochemical investigations of CA 125 in different ovarian tumors (n = 91) revealed that 85% of malignant and 75% of borderline serous cystadenocarcinomas had detectable CA 125 surface expression. Furthermore, 71% of benign tumors showed the CA 125 epitope, whereas mucinous tumors were negative for this marker. One of six ovarian cancer cell lines was CA 125 positive, whereas in 6 of 11 patients, ascites-derived ovarian cancer cells (fresh and gradient isolated) were positive for this marker. The proportion of positive cells ranged from 10 to 90% in these samples. Intraperitoneal recombinant interferon-gamma (rIFN-gamma) therapy resulted in an increase in the number of cells reacting with CA 125. The results of monitoring in patients receiving different therapeutic regimens and/or agents demonstrate the usefulness of this marker.

Antibodies, Monoclonal↗
PubMed1989

GM-CSF treatment in aplasia after cytotoxic therapy.

GM-CSF was used to overcome fatal myelosuppression after cytotoxic chemotherapy. Two different application modalities were compared: a continuous 24 h infusion was more effective compared to a 30 min short term infusion. Using the former modality at a dose of 10 micrograms/kg/d for five days very impressive responses were observed. No major side effects did occur. The first 13 patients treated in this way included 8 AML cases. Only one of these latter patients had a leukemia relapse. However, in this patient the immediate GM-CSF response was clearly separated from the relapse occurring later in the observation period. Thus, the preliminary results of the present paper suggest that GM-CSF besides of being very efficient in accelerating granulocyte recovery does not stimulate the growth of AML blasts in vivo in patients with only minimal residual disease.

Adolescent↗
PubMed1987

[Recombinant (IFN-alpha 2b) therapy in hairy cell leukemia].

Eighty-five patients with hairy-cell leukemia were treated in a multicentric "open label" study with IFN-alpha 2b and evaluated. Induction therapy was 2 X 10(6) U IFN-alpha 2b/m2, 3 times a week, s.c. The results show this regimen to be highly effective with only a few tolerable and transient side effects consisting mainly of flu-like symptoms. After 6 months of therapy 4% CR, 69% PR, and 16% MR, were noted. In a small group of four patients who had achieved CR or PR, we tested the effect of varying doses for maintenance therapy. Our preliminary results indicate that a relapse caused by interruption of IFN therapy or dose reduction to 3 X 10(6) U given once a week, o.c. could be successfully treated by readministration, or escalating the dosage of IFN. It seems that remission maintenance requires long-term treatment with IFN. In a short-term in vitro test we studied the effect of IFN-alpha 2 on the incorporation of 3H-thymidine and 3H-uridine into hairy cells of five patients. Fort both precursors no appreciable effect was detected. However, after prolonged incubation for 48 h, a significant enhancement of 3H-uridine incorporation was observed, while 3H-thymidine incorporation remained unaffected. Cell marker analysis performed with monoclonal antibodies before and after incubation of hairy cells with IFN-alpha 2 for up to 7 days did not reveal any change of the phenotype of hairy cells.

Clinical Trials as Topic↗
PubMed1987

Interferon-alfa corrects thrombocytosis in patients with myeloproliferative disorders.

During previous therapeutic trials with interferon, decreased levels of peripheral platelet counts have been observed. Taking advantage of this effect, we investigated the efficacy of recombinant interferon (rec-IFN) in the treatment of thrombocytosis in myeloproliferative diseases. A total of 15 patients with polycythemia vera, essential thrombocytosis, or chronic myeloid leukemia received rec-IFN-alfa at initial doses of 25-70 x 10(6) units/week; maintenance therapy following week 8 of treatment consisted of 20-35 x 10(6) units/week rec-IFN. Observation periods ranged from 24 to 48 weeks. Significant reductions in the number of platelets were noted in all cases; 12/15 patients achieved platelet counts below 440 x 10(9)/l and maintained those normal values for at least 4 weeks. The number of bone marrow megakaryocytes, which had been increased prior to treatment, diminished during rec-IFN therapy, while the previously shortened platelet half-life further decreased with rec-IFN treatment. During rec-IFN-induced remission, the plasma levels of platelet factors, the activity of natural killer cells, and platelet aggregation showed changes between slight improvement and normal values. Severe side effects were only observed with the highest rec-IFN doses; dosage adjustments were effective in improving or eliminating all treatment-related symptoms. Rec-IFN may prove to be a valuable therapeutic alternative to cytostatic treatment of thrombocytosis in myeloproliferative disorders.

Aged↗
PubMed1987

Natural cytotoxicity in draining lymph nodes of squamous cell cancer in the maxillofacial region.

There is at present very little information available, including the presented preliminary data, concerning NK activity in patients with head and neck cancer. The objective of the present investigation was to study NK activity in peripheral blood (PB) and regional lymph nodes (LNs) in patients with different stages of head and neck cancer. Furthermore, phenotypic characterization of lymph node cells was performed. Finally, the in vitro response of mononuclear cells isolated from blood and lymph nodes to interferon was investigated.

Carcinoma, Squamous Cell↗
PubMed1987

Interferon alpha-2 for hairy cell leukemia: evidence for induction of RNA synthesis in hairy cells and failure to correlate enhancement of natural killer cells with elimination of hairy cells.

The effect of human recombinant interferon alpha 2 (IFN alpha 2) on hairy cells obtained from 16 patients was evaluated. All patients promptly responded to induction of remission with 2 X 10(6) U/m2 interferon alpha 2 b, three times a week, sc. In order to achieve a more detailed insight into the mode of action of interferon in this disease, we determined the influence of IFN alpha 2 on the incorporation of radiolabeled thymidine and uridine into hairy cells. While both 3H-thymidine and 3H-uridine incorporation were unaffected by IFN alpha 2 in a 3-hour incubation period, a significant increase in uridine incorporation into hairy cells, but not CLL cells, was observed after 24 h. Cell surface marker analysis performed with monoclonal antibodies did not reveal a quantitative alteration of the immunophenotype of hairy cells in vitro. In addition, natural killer cells, assessed by monoclonal antibodies and a cytotoxicity assay against K 562 cells, were found to be decreased in 9 out of 10 patients prior to therapy. Although IFN alpha 2 could stimulate natural killer cells in vivo, we did not find a consistent correlation between the activation of these cells and the response to therapy. We conclude, therefore, that NK cells play no major role in the regression of hairy cells. Furthermore, IFN alpha 2 does not alter antigenic determinants in vitro, but leads to an enhanced incorporation of 3H-uridine into hairy cells in vitro, thus indicating a possible role for the induction of RNA synthesis in vivo.

Adult↗
PubMed1987

Modulation of NK activity in regional lymph nodes by preoperative immunotherapy with OK-432 in patients with cancer of the oral cavity.

The influence of preoperative perilesional therapy with the potent bacterial biological response modifier (BRM) OK-432 on natural killer (NK) cell activity in peripheral blood and tumor draining lymph nodes (LNs) of patients with head and neck cancer (HNC) has been investigated. Pretreatment NK activity in peripheral blood (PB) was comparable within the group of HNC patients. However, after perilesional OK-432 therapy, a significant increase in cytotoxicity was observed by day 8. Furthermore, postoperative suppression of PB NK activity was less pronounced in patients with OK-432 therapy. In tumor draining LNs, NK activity was significantly higher in patients receiving OK-432 therapy than in those treated by surgery alone. No differences were detected concerning the in vitro stimulatory capacity of interferon (IFN) and/or Staphylococcus protein A (SPA) on LN NK activity in both the OK-432 treated and untreated group. Furthermore, by immunoperoxidase technique, LNs of OK-432 treated patients were found to express a higher number of cells reacting with the monoclonal antibody HNK-1 compared to LNs of the untreated group. Both these results suggest that perilesional OK-432 therapy leads to an increase in number and function of NK cells in regional LNs, together with an increase in NK activity in PB in some but not all patients.

Adult↗
PubMed1986

Systemic and regional natural cytotoxicity in patients with head and neck cancer.

Forty patients with squamous carcinoma of the oral cavity (head and neck cancer) were investigated for natural killer-cell (NK) activity in peripheral blood (PB) and tumour-draining lymph nodes (LNs). For measuring NK activity a 4 hrs 51Cr release assay and K 562 target cells were used. Mononuclear cells of PB (PBMNC) and LNs (LNMNC) were separated by Ficoll Hypaque gradient centrifugation. NK activity was determined before tumour surgery. LNs were obtained either at the time of surgery of the primary tumour (en bloc neck dissection)--"immediately dissected LNs (ID-LNs)" or some time after removal of the primary tumour, especially for prophylactic purposes,--"delayed dissected LNs (DD-LNs)". Preoperatively, NK activity was clearly stage-dependent, patients with stages T1-2 displaying mean values similar to those of a control group without malignant disease, whereas values were significantly lower in patients with stages T3-4. Spontaneous cytotoxicity was significantly lower in LNMNC than in PBMNC of identical donors. NK activity was significantly lower in ID-LNs than in DD-LNs. These results suggest some negative influence of the primary tumour in the spontaneous cytotoxicity in both PB and tumour-draining LNs. In vitro incubation at +37 degrees together with addition of lymphoblastoid interferon (IFN-alpha) achieved a significantly stimulation of NK activity in both PBMNC and LNMNC.

Cytotoxicity, Immunologic↗