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Biomedical subjects

M Micksche

Publications and source records attributed to M Micksche.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1985

Effect of adjuvant chemo- or immunotherapy on the prognosis of colorectal cancer operated for cure.

After radical surgery for colorectal cancer, 178 patients with a Dukes' B or C tumour were randomly assigned to one of three groups: A, controls (n = 62); B, chemotherapy (n = 59); C, immunotherapy (n = 57). Randomization criteria (age, sex, Dukes' stage, localization of tumour, operative procedure) were evenly distributed throughout the groups. After a median observation time of 30 months, statistical analyses were performed: survival and probability to be free of recurrence was described by Kaplan-Meier estimates of the survival function; for comparison of these survival functions, Breslow's test was used. Overall analyses show no benefit in the treatment group compared to controls. Separate analyses by Dukes' stages showed that in patients with Dukes' C tumours the probability of survival 40 months after surgery was 72 per cent in group C, 51 per cent in group B, and 33 per cent in group A. The differences between groups C and A, and B and A were statistically significant (P less than 0.02 and P less than 0.03 respectively). For a Dukes' C tumour the probability to be free of distant metastases at 30 months after surgery was 80 per cent in group B, 68 per cent in group C and 52 per cent in group A. Also for a Dukes' C tumour the probability to be free of liver metastases at 21 months after surgery was 83 per cent in group B, 81 per cent in group C, and 54 per cent in group A (significant differences: B-A and C-A P less than 0.04 for both). There was no influence on the estimated incidence of local recurrences for stage Dukes' C. Patients with a Dukes' B tumour did not benefit from either of the adjuvant therapy schemes.

Adjuvants, Immunologic↗
PubMed1985

Autologous tumor killing and natural cytotoxic activity of tumor-associated macrophages in cancer patients.

Tumor-associated macrophages (TAM) isolated from pleural effusions and ascites fluids of cancer patients were tested for cytotoxicity against freshly isolated autologous tumor cells and K562 in a 4-h 51Cr-release assay, and in vitro effects of OK432 (a streptococcal preparation) and partially purified human leukocyte interferon (IFN) on their cytotoxicities were examined. Positive cytotoxicities against K562 were recorded for TAM samples from 2 of 23 pleural effusions and 3 of 10 ascites specimens. Tumor-associated macrophages were not cytotoxic to autologous tumor cells, while low but significant lysis was observed with tumor-associated lymphocytes (TAL) samples from 2 of 13 pleural effusions and 1 of 6 ascites specimens. In vitro treatment with OK432 resulted in an enhancement of natural cytotoxicity in 4 of 13 TAM and 10 of 15 TAL samples. An induction or augmentation of autologous tumor killing activity by OK432 was observed in 2 of 10 TAM and 8 of 11 TAL samples. In contrast, IFN failed to induce autologous tumor killing activity, although IFN-enhanced lysis of K562 was detected in 1 of 7 TAM and 2 of 9 TAL samples. These results indicated that autologous tumor killing and natural cytotoxic activities were defective in macrophages and lymphocytes at the site of the tumor growth, and both activities were strongly enhanced by OK432 rather than IFN.

Antibodies, Monoclonal↗
PubMed1985

Therapeutic effect of cryosurgery of murine osteosarcoma--influence on disease outcome and immune function.

Experiments comparing conventional operative treatment and cryosurgery of a murine osteosarcoma showed that local tumor destruction by freezing in situ was similar or superior to amputation concerning survival and formation of metastasis, depending on tumor stage. Limited local resection was less effective. Immune functions affected by cryosurgical tumor destruction included depression of natural killer cell activity and decrease of tumor-specific autologous IgG antibodies in the serum.

Animals↗
PubMed1985

Phase II results with recombinant interferons: renal cell carcinoma and malignant melanoma.

There is as yet no effective treatment for renal cell carcinoma and metastasizing malignant melanoma. This fact, coupled with in vitro investigations showing growth inhibitory or cytotoxic effects of interferon (IFN) on renal cell carcinoma and melanoma cell lines, led to phase II clinical trials with recombinant (r) IFN-alpha 2C and rIFN-gamma. So far 8 patients with renal cell carcinoma have been treated with IFN-alpha 2C and 3 patients with rIFN-gamma. There has been one complete response to IFN-alpha 2C, two mixed responses and one partial response. One patient on rIFN-gamma has stable disease and the other 2 have progressed. Eleven patients with metastasizing malignant melanoma were treated with IFN-alpha 2C. One patient achieved a complete remission and 3 others had stable disease which later progressed in 2 of them. Side-effects were reversible.

Adult↗
PubMed1985

Human epidermal cells and squamous carcinoma cells synthesize a cytokine that augments natural killer cell activity.

Normal as well as transformed epidermal cells (EC) have recently been reported to produce a cytokine--EC-derived thymocyte-activating factor (ETAF), which according to its biologic as well as biochemical properties is indistinguishable from macrophage-derived interleukin 1 (IL 1). In the present study, the effect of supernatants (SN) derived from normal EC and a human squamous carcinoma cell (SCC) line were tested for their effects on natural killer (NK) cell activity. EC- as well as SCC-derived SN were able to augment in vitro NK cell activity of peripheral blood lymphocytes against K 562 cells. In contrast, adherent cell-derived, IL 1-containing SN did not affect NK cell activity. Upon high-pressure liquid chromatography (HPLC) gel filtration, ETAF and the EC-derived NK cell activity-augmenting factor (ENKAF) exhibited a similar m.w. However, by using reverse-phase HPLC, ETAF and ENKAF eluted as distinct peaks of activity, indicating that SCC cell-derived ENKAF is different from ETAF. Furthermore, ENKAF does not contain interleukin 2 (IL 2) or interferon (IFN) activity. The enhancement of NK cell activity was dose dependent and evident after 20 hr of preincubation of effector cells. Pretreatment of target cells with ENKAF did not affect the susceptibility of the target cells. The NK activity of large granular lymphocytes (LGL) purified by discontinuous Percoll gradient centrifugation and further depleted of high-affinity sheep erythrocyte rosetting cells was enhanced by ENKAF. In contrast, no NK cell activity was expressed by LGL-depleted T cell populations before or after treatment with ENKAF. In a single cell cytotoxicity assay in agarose, the number of lymphocyte binding to K 562 was not affected by ENKAF, but the frequency of dead conjugated target cells and presumably of active killer cells was increased by pretreatment with ENKAF. Additional incubation of LGL with ETAF did not further increase ENKAF-mediated augmentation of NK activity. In contrast to ETAF, ENKAF was not chemotactic for polymorphonuclear leukocytes. These results indicate that normal as well as transformed EC release a unique cytokine--ENKAF--which augments NK cell activity of LGL but is distinct from ETAF, IL 2, and IFN.

Biological Products↗
PubMed1985

Natural killer cell activity in tumor-draining lymph nodes: investigations in patients with malignant melanoma and head and neck cancer.

Mononuclear cells isolated from peripheral blood (PB) of patients with malignant melanoma and head and neck cancer were tested for natural killer (NK) cell activity against K562 targets. Significantly lower levels of NK activity were observed in patients with malignant melanoma with metastatic disease in comparison to stage I and control population. In head and neck cancer NK activity was normal in tumor stage 1-2 and significantly impaired in stage 3-4. Mononuclear cells (MNC) isolated from primary tumor-draining lymph nodes (LNs) had significant NK activity in 12 of 25 (48%) of melanoma and 9 of 19 (47%) of head and neck lymph nodes at E:T 40:1. Reactivity was always significantly lower than in autochthonous Preincubation (+37 degrees C, 18 h) of lymph node mononuclear cells (LNMNC) resulted in a significant increase in cytotoxicity in 36% of melanoma and 32% of head and neck LNs. Simultaneous incubation with interferon (IFN)-alpha resulted in 24% of melanoma and 44% of head and neck LNs in a significant further augmentation of NK activity. LNMNC were furthermore found to react in 2-24% (mean 7.79 +/- 2.1) with the monoclonal antibody HNK-1, which identifies a certain proportion of NK cells. No correlation was found between percentage HNK-1+ cells and the expression of NK activity. From these studies it may be concluded that tumor draining LNs contain cells which are active against K562 targets expressing low but variable levels of cytotoxicity. NK cell activity can be increased by incubation of LNMNC at 37 degrees C with or without addition of IFN. These results suggest that modulation of NK activity in tumor draining LNs might be achieved by local application of biological response modifiers, which might finally lead to an increase of local tumor defense mechanisms.

Antibodies, Monoclonal↗
PubMed1984

Intrapleural administration of OK432 in cancer patients: augmentation of autologous tumor killing activity of tumor-associated large granular lymphocytes.

Ten patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) injections of the streptococcal preparation OK432 on day 0 and the effects of i.pl. OK432 on the lysis of fresh or cryopreserved autologous tumor cells isolated from the pleural effusions were observed on day 7. In eight patients tumor cells in the effusions had decreased or disappeared by day 7. The other two patients, however, had no clinical evidence of therapeutic benefit from i.pl. OK432. Effusion tumor cells were relatively resistant to lysis by autologous lymphocytes when tested in a 4-h 51Cr-release assay. Positive reactions were recorded for blood and effusion lymphocytes in two of ten untreated patients. Injection of OK432 i.pl. resulted in an induction or augmentation of cytotoxicity against autologous tumor cells and K562 in the effusions of seven of ten subjects by day 7. In contrast, autologous tumor killing activity of blood lymphocytes was not always modified by i.pl. OK432. Purification of large granular lymphocytes (LGL) by discontinuous Percoll gradient centrifugation enriched autologous tumor killing activity, with no reactivity in LGL-depleted, small T lymphocytes. Significant lysis of autologous tumor cells was observed with effusion LGL from seven of ten untreated patients. Seven days after i.pl. OK432 injection, effusion LGL expressed enhanced cytotoxicity against autologous effusion tumor cells, whereas T cells were still not cytotoxic to autologous tumor cells on day 7. The frequency of LGL among effusion lymphocytes was not altered by i.pl. OK432. Adherent effusion cells were not involved in lysis of autologous effusion tumor cells in either untreated or OK432-treated patients. In vitro treatment of blood and effusion lymphocytes with OK432 induced an enhancement of autologous tumor-killing activity in patients who subsequently responded to i.pl. OK432 treatment. OK432 augmented in vitro autologous tumor killing activity of LGL, whereas T cells failed to lyse autologous tumor cells even after in vitro activation with OK432. These results indicate that i.pl. administration of OK432 to cancer patients will result in an augmentation of autologous tumor killing activity of LGL in the pleural effusions, and that this could be responsible for the antitumor activity of i.pl. OK432 therapy.

Adenocarcinoma↗
PubMed1984

Natural cytotoxicity of lymphocytes and monocytes and its augmentation by OK432 in melanoma patients.

Lymphocytes and monocytes from the peripheral blood of 30 patients with malignant melanoma were tested for natural cytotoxicity against K562 cells in a 3-h 51Cr-release assay, and the effects of OK432 (a streptococcal preparation) on the cytotoxicity were examined. The lymphocyte cytotoxicity of melanoma patients was similar to that of normal donors and control patients with benign skin disease. Furthermore, the lymphocyte cytotoxicity of melanoma patients was not correlated to the stage of the disease. Similarly, lysis of K562 cells by monocytes isolated by adherence to autologous serum-coated plastic dishes in melanoma patients was comparable to that of controls and not associated with the stage of the disease. Positive monocyte reactions were recorded in 10 of 30 (33%) melanoma patients, seven of 21 (33%) normal donors and three of 10 (30%) control patients. There was no correlation between lymphocyte cytotoxicity and monocyte cytotoxicity. Overnight treatment of monocytes and lymphocytes with OK432 resulted in an increase in cytotoxicity. Significant augmentation of cytotoxicity by OK432 was observed in 28% of the monocyte samples and 86% of the lymphocyte samples, while partially purified human interferon augmented cytotoxicity in 63% of the monocyte samples and all the lymphocyte samples. These results suggest that neither lymphocyte nor monocyte cytotoxicities are depressed in melanoma patients as compared with normal donors and patients with benign disease and that OK432 has a stronger stimulatory effect on lymphocytes than on monocytes.

Adult↗
PubMed1984

Natural cytotoxicity of lymphocytes from lymph nodes draining breast carcinoma and its augmentation by interferon and OK432.

Lymphocytes isolated from axillary lymph nodes draining breast carcinoma were tested for natural killer (NK) activity against K562 in a 4-h 51Cr-release assay, and the in vitro effects of interferon (IFN) and OK432 (a streptococcal preparation) on their cytotoxicity were examined in comparison with NK activity of autologous peripheral blood lymphocytes (PBL). The levels of NK activity were lower in lymph node lymphocytes (LNL) than in PBL of the same patients. Significant levels of LNL-mediated lysis were recorded in 14 of 42 (33%) lymph node samples and in nine of 14 (64%) patients. Purification of large granular lymphocytes (LGL) from lymph node cells by discontinuous Percoll density gradient centrifugation resulted in an induction or enhancement of cytotoxic activity, with no reactivity in LGL-depleted, small T-lymphocyte populations. Positive reactions were observed with 10 of 13 (77%) LGL samples. The low reactivity of LNL was not attributable to coexistent suppressor cells for NK function, since lymph node cells failed to suppress NK activity of normal PBL. Partially purified human IFN and OK432 augmented NK activity of patients' PBL in approximately 70% and 90% of the cases, respectively, while LNL-mediated lysis was augmented in only 7% and 36% of the lymph node samples by IFN and OK432, respectively. These results indicate that K562-reactive NK cells and/or their precursors may frequently be present at subthreshold levels in the lymph nodes draining breast carcinoma, and that the augmentation of LNL-mediated cytotoxicity by OK432 might provide a local potentiation of natural immune function at the host-tumor interface rather than IFN.

Axilla↗
PubMed1984

In vitro modulation of human natural killer cell activity by interferon: generation of adherent suppressor cells.

The in vivo and in vitro effects of human alpha-interferon (IFN) on blood natural killer (NK) cell activity were studied in patients with malignant melanoma. The initial response to an i.m. injection of IFN was a depression of blood NK cell activity, being detectable at 4 h and reaching a nadir at 12 h. Blood NK cell activity returned to or exceeded pretreatment levels within 24 h. The frequency of large granular lymphocytes among peripheral blood lymphocytes (PBL), however, remained unchanged during the first 24 h of IFN treatment. In a single cell cytotoxicity assay in agarose the number of lymphocytes forming conjugates with K562 target cells was not affected at 12-h points of IFN treatment, while the frequency of lytic conjugates with dead target cells was decreased by 12 h. Thus, the number of active NK cells was reduced by IFN administration. While in vitro exposure to IFN resulted in an augmentation of NK cell activity of PBL from untreated patients, IFN failed to enhance the activity of PBL obtained 12 h post IFN injection. When PBL obtained 12 h after IFN injection were cultured overnight, they recovered their responsiveness to NK-boosting effects of IFN. Blood monocytes obtained at 12-h points from IFN-treated patients suppressed IFN-induced enhancement of NK cell activity, although these monocytes did not inhibit the base line level of NK cell activity. In contrast, the streptococcal preparation OK432 was able to augment NK cell activity of PBL obtained 12 h post IFN administration and of control PBL even in the presence of suppressor monocytes. PBL obtained 24 h post IFN injection expressing enhanced NK cell activity were also unresponsive to IFN in vitro. However, monocytes obtained 24 h after IFN injection were no longer able to inhibit IFN-induced augmentation of NK cell activity. These results indicate that in vivo administration of IFN-alpha to cancer patients results in rapid and transient generation of suppressor monocytes capable of inhibiting IFN-dependent development of functional NK cell activity, which could be responsible for the initial and transient decline in blood NK cell activity.

Cells, Cultured↗