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Biomedical subjects

L Bergmann

Publications and source records attributed to L Bergmann.

At least 91 records · Page 5Linked to original sources
PubMed1993

Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. A phase II study.

BACKGROUND: Both interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) have some efficacy in renal cell cancer (RCC) as single agents. Additionally, there is some evidence for additive or synergistic antitumoral activity of IL-2 and alpha-IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combination of recombinant IL-2 (rIL-2) and recombinant alpha-IFN (alpha-rIFN) in advanced RCC. METHODS: Thirty-six assessable patients with metastatic RCC were entered in this Phase II trial using a daily alternating schedule of alpha-rIFN and rIL-2. Over a period of 14 days, the patients received daily alternating treatment with 10 x 10(6) IU/m2 of recombinant alpha-2b-interferon subcutaneously and 18 x 10(6) IU/m2 of rIL-2 as a 1-hour intravenous infusion. This treatment schedule was repeated every sixth week up to a maximum of four cycles. After the second cycle, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with progressive disease were available for other strategies. RESULTS: Thirty-six patients entered the trial and were assessable for toxic effects. Thirty of 36 patients completed at least two cycles and were assessable for response. Nine patients achieved an objective response: 2 had complete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local relapse or bone metastases. A relapse-free survival length of 6 months or longer was seen in both patients with CR (12, 23 + months) and in four of seven patients with PR (6, 7, 12, 12 months). The toxicity was moderate and included fever and nausea in most patients, and hypotension, fatigue, skin rash, and arthralgia in a minority of the patients. No Grade 4 and only occasionally Grade 3 toxicity was observed. Fluid retention was negligible. The monitoring of immunologic parameters showed a significant rebound lymphocytosis including cytotoxic (CD56+) cells; in responders the peak of lymphocytosis occurred up to 1 week later than in nonresponders. Peripheral lymphocytes obtained after therapy showed only a slight increase of natural killer cell and lymphokine-activated killer cell activity. During therapy, there was a great release of secondary cytokines as tumor necrosis factor-alpha, gamma-interferon, and interleukin-6, with a peak level 2-4 hours after rIL-2 infusion. CONCLUSIONS: In conclusion, daily alternating administration of alpha-rIFN and rIL-2 is effective in RCC with less toxicity, and the response rate is comparable to those of other immunotherapeutic schedules, including adoptive immunotherapeutic schedules, including adoptive immunotherapy and combinations of high-dose IL-2 and alpha-IFN.

Aged↗
PubMed1993

Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials.

BACKGROUND: Interferon-alpha (IFN alpha) and interleukin-2 (IL-2) are active agents against malignant melanoma. There is, however, no consensus on the optimal dosing schedule of both drugs. This is a report of two sequential immunotherapy trials in patients with metastatic melanoma using two different IL-2 dosing schedules. METHODS: Schedule A consists of IFN alpha, 10 million U/m2/day subcutaneously for 5 days, followed by continuous intravenous infusion of IL-2, 1 mg/m2/24 hours for 5 days. Schedule B consists of the same dose of IFN alpha, but a modified regimen of IL-2. To improve the induction of high-affinity IL-2 receptors, the initial IL-2 dose was increased (1 mg/m2/6 hours, followed by 1 mg/m2/12 hours, and 1 mg/m2/24 hours). To reduce toxicity, the dose was reduced thereafter to 0.25 mg/m2/24 hours for the following 3 days. Both regimens were repeated after 4 weeks. RESULTS: 27 patients were treated with schedule A with a response rate of 18% (1 complete response [CR], 4 partial responses [PR]), 95% confidence interval, 6-36%. The response rate in 27 patients treated with schedule B was 41% (3 CR, 8 PR), 95% confidence interval, 22-61%. Severe, often dose-limiting toxicity was associated with IL-2 in schedule A, particularly hypotension and fluid retention. Toxicity was reduced significantly in schedule B. Maximal serum levels of soluble CD25 were 17,022 +/- 13,070 U/ml in schedule A, and 31,148 +/- 4227 U/ml in schedule B (P < or = 0.01). Serum levels of TNF alpha were significantly lower in schedule B than in schedule A, as were the side effects. CONCLUSIONS: Toxicity of IL-2 is reduced by modifying the schedule of administration, which also enhances the immunologic response and appears to increase the response rate.

Adult↗
PubMed1993

[Pleomorphic T-cell lymphoma. The diagnostic problems, therapeutic possibilities and infection-induced complications].

A 30-year-old man complained of high fever, resistant to antibiotics, and progressive loss of strength for five weeks. The peripheral blood showed pancytopenia (leucocytes 2200/microliters, platelets 45,000/microliters, haemoglobin 10.7 g/dl). There was also hepatosplenomegaly, abdominal lymph node enlargement, pleural and pericardial effusions and slight excess of lymphocytes in the cerebrospinal fluid. Histological examination of the bone marrow suggested a small-cell pleomorphic T-cell lymphoma, but Hodgkin's disease was also considered. Splenectomy was performed to confirm the diagnosis and treat the pancytopenia. The blood count rapidly returned to normal and the suggestion of Hodgkin's disease was excluded. Intensive chemotherapy (BMFT-ALL protocol) was followed by regression of nearly all the abnormalities, but marrow infiltration persisted. This treatment was discontinued after phase II of induction. After an intercurrent cytomegalovirus infection maintenance treatment with alpha-interferon (up to 5 million units daily) was started. The partial remission remained stable for 22 months. The lymphoma then relapsed but was held in check by further chemotherapy (Dexa-PAMB protocol). For the past 11 months the patient has remained in stable partial remission on treatment with alpha-interferon (3 million units every other day). Frequent infections (sinusitis, diarrhoea, abscess) require close supervision.

Adult↗
PubMed1993

Aggressive chemotherapy combined with G-CSF and maintenance therapy with interleukin-2 for patients with advanced myelodysplastic syndrome, subacute or secondary acute myeloid leukemia--initial results.

Aggressive chemotherapy of advanced myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) evolving from MDS, subacute AML and secondary AML has usually been associated with low complete remission (CR) rates, a high incidence of early death, and low disease-free survival. We therefore have initiated a phase-III trial of aggressive chemotherapy consisting of idarubicin, cytosine arabinoside, and VP-16 to improve the CR rate. Each chemotherapy cycle is followed by G-CSF to accelerate neutrophil recovery and to reduce the incidence of infections. Until now, 19 patients with high-risk AML have been entered. The CR rate is 47%, with only one death during induction. Patients achieving CR are randomized to receive either high-dose or low-dose interleukin-2 to eliminate residual leukemic cells and to prolong the duration of remission.

Adult↗
PubMed1993

Immunosuppressive effects and clinical response of fludarabine in refractory chronic lymphocytic leukemia.

BACKGROUND: Fludarabine monophosphate is a new adenine nucleoside analogue with a promising efficacy in B-cell chronic lymphocytic leukemia (B-CLL) with response rates, including hematological complete remissions, of 50%-60% in previously treated and 75%-80% in previously untreated patients. PATIENTS AND METHODS: Here, the clinical experience with and side effects of fludarabine are reported in 19 patients with refractory CLL (17 B-CLL, 2 T-CLL). All patients were pretreated with one to four different regimens and had progressive disease. Fludarabine was administered at a dosage of 25 mg/m2 daily for 5 days as a 30-minute intravenous infusion. This course was repeated every fifth week. Dosage and time course were adapted to toxicity. RESULTS: 12/18 (67%) evaluable patients achieved partial remissions (PR), 1/18 (6%) had stable disease (SD) and 5/18 (28%) were progressive. The median duration of partial remission until relapse or death was 6 months. Most responses to fludarabine occurred within two treatment courses. Major toxic effects included infections in 11 patients and nausea in 8 (mainly grade 1). Meanwhile, three patients died of progressive disease and 8 of pneumonias or other infections. Two patients had pneumocystis carinii pneumonias and one an aspergillus pneumonia. The high infection rate may be due not only to hypogammaglobulinaemia or fludarabine-induced granulocytopenia but also to a remarkable decrease of CD4(+)-cells during fludarabine therapy. In one case a tumor lysis syndrome was observed. No CNS toxicity was noted. CONCLUSION: It is concluded that fludarabine is effective even in patients with advanced chronic lymphocytic leukemia refractory to multiple chemotherapy regimens. However, fludarabine has a remarkable suppressive effect on T-lymphocytes, predominantly CD4(+)-lymphocytes. Long-term antibiotic prophylaxis is recommended.

Adult↗
PubMed1992

Cytotoxic action of IL-1 beta against pancreatic islets is mediated via nitric oxide formation and is inhibited by NG-monomethyl-L-arginine.

IL-1 beta has been previously shown to act as a cytotoxic agent in islets. Here we show by electron microscopy of alginate encapsulated islets, that islet cell lysis is induced by culturing islets for 24 or 48 h in the presence of IL-1 beta. The extent of lysis depends on the IL-1 beta concentration and is slightly enhanced by the addition of TNF-alpha. Cells can be protected from lysis by NG-monomethyl-L-arginine. Lysis is paralleled by an increase in nitrite concentration in culture supernatants of whole islets but not in supernatants of isolated endocrine cells. The results indicate that IL-1 beta toxicity occurs via inducing in non-endocrine islet cells the synthesis and release of nitric oxide, which has been shown earlier to be highly toxic for islet cells.

Animals↗
PubMed1992

Rapid cytokine release in cancer patients treated with interleukin-2.

Serum concentrations of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) were determined by commercially available enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) in cancer patients treated with recombinant IL-2 (rIL-2) either as 1-h infusion (3 or 5 x 10(6)/m2) or continuous intravenous infusion for 5 days (3 x 10(6)/m2/day). A significant increase of TNF-alpha and IL-6 serum levels was observed in each patient. One-hour infusion of IL-2 induced a very rapid secretion of TNF-alpha, IL-6 and IFN-gamma with considerably higher peak levels than during IL-2 continuous intravenous infusion. IFN-gamma was released into the blood of all patients receiving IL-2 1-h infusion, but only occasionally during or after IL-2 continuous intravenous infusion. Neither IFN-alpha nor IL-1 were detectable in the serum before, during, or following IL-2 treatment in all patients studied. The kinetics of IL-2 after 1-h infusion fitted to a two-compartment model, suggesting the synthesis of considerable amounts of endogenous IL-2. Following IL-2 1-h infusion, rising TNF-alpha serum levels preceded the increase of serum IFN-gamma or IL-6. The serum peak levels of IFN-gamma and IL-6 decreased rapidly with a half-life of 0.29 to 2.5 h. The concentration time profiles of TNF following 1-h infusion of IL-2 demonstrated a considerably longer half-life than that of intravenously administered recombinant TNF as done in other studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Renal Cell↗
PubMed1991

High release of tumor necrosis factor alpha, interferon gamma and interleukin-6 by adherent lymphokine-activated killer cells phenotypically derived from T cells.

Adherent lymphokine-activated killer cells (A-LAK) are highly potent cytotoxic cells, which are shown to be derived not only from natural killer (NK)/K cells but phenotypically also from T cells. The generation and phenotypical and functional characterisation of these T-cell-derived A-LAK are described. In contrast to non-adherent cells (NA-LAK) and unseparated LAK (UN-LAK), these mostly CD3+ CD56+ CD8+ cells display a high degree of expansion following initial interleukin-2 (rIL-2) activation and further culturing in autologous conditioned medium. A comparison of cytotoxic activities of cultured cells reveals a significantly higher oncolytic ability of A-LAK cells against both K562 and Daudi cells than that of cultured controls of NA-LAK and UN-LAK. In addition, A-LAK are characterised by a marked endogenous cytokine release of interferon gamma, tumour necrosis factor alpha and IL-6 as well as by their shedding of p55 IL-2 receptor after exposure to IL-2. The results demonstrate A-LAK to be the lymphocyte subpopulation with the most cytotoxic activity and endogenous cytokine release after exposure to IL-2. The improvement of techniques for long-term cultures may be of interest for future therapeutic approaches.

Cell Adhesion↗
PubMed1991

Cytotoxic activity and phenotypic characteristics of lymphocyte subsets after therapy of cancer patients with interleukin-2.

After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.

Antigens, CD↗
PubMed1991

Cisplatin, etoposide, ifosfamide, vincristine and bleomycin combination chemotherapy for far advanced testicular carcinoma.

Forty-eight patients with advanced testicular cancer, defined as abdominal mass greater than 10 cm, mediastinal mass greater than 5 cm, more than 20 lung metastases, or visceral organ involvement were treated with an intensive, alternating five-drug regimen consisting of cisplatin 50 mg/m2 d 1-3, etoposide 170 mg/m2 d 1-3, ifosfamide 5 g/m2 d 15, vincristine 2 mg weekly, bleomycin 15 mg/m2 weekly, q d 28. Thirty-four (71%) of the patients attained tumor-free status. This was achieved by chemotherapy alone in 14 patients and by surgical resection of residual disease in the remaining 20 patients (histology of resected tissue: necrosis 12, mature teratoma 7, viable carcinoma 1). Patients with pure seminoma responded better than patients with nonseminoma (CR 100% vs. 67%, respectively). In a univariate analysis only the value of HCG (less than vs greater than 10,000 U/L) and the number of involved organ sites (less than or equal to 2 vs greater than to 2) had significant influence on the response rate. After a minimum follow-up of 24 months 3 patients (9%) have relapsed. The survival rate is 76% after 36 months, with 61% remaining disease-free. Though this intensive regimen might bestow some of the therapeutic advantages of standard three-drug protocols in far advanced testicular cancer, the results are still less than optimal and warrant the exploration of new therapeutic strategies.

Adolescent↗
PubMed1991

[Pearl oyster dust as the cause of exogenous allergic alveolitis].

Many different inhalative substances may cause allergic alveolitis (hypersensitivity pneumonitis). We report on a worker who developed lung fibrosis due to the sensitization to pearl oyster shell dust. High concentrations of IgG antibodies to proteins (conchagens) of the shell which appear to represent the relevant antigens were found in the patient's serum.

Aged↗
PubMed1991

[Damage to the corneal endothelium caused by radial keratotomy].

In our experimental study on 53 rabbits we compared the amount of corneal endothelial damage caused by radial keratotomy (RK) referred to (1) the number of incisions (4, 8, or 16), (2) the postoperative interval (0 h, 48 h) and (3) the direction of the incision [centripetal (cp), centrifugal (cf)]. The endothelial damage was quantified by means of the Janus green photometry technique. Morphological changes were evaluated by scanning electron microscopy (SEM). Depending on the group examined, we found endothelial damage extending over 3-7% of an analysed surface of 64 mm2. One perforation caused endothelial damage of up to 17% of the surface examined. Increasing the number of incisions from 4 to 8 or 16 resulted in a statistically significant increase in the amount of endothelial damage (4.2%, 5.1%, 5.8%; P less than 0.05). At 0 h it was significantly higher than after 48 h (5.5%, 4.6%; P less than 0.05). The direction of the incision had no statistically significant influence in our study (zp: 5.2%, zf: 4.9%). The morphological changes in the rabbit corneal endothelium examined directly after the RK procedure were ruptures in the cell membranes, loss of cells, and posterior corneal protrusions beneath the incisions. After 48 h, we found fewer damaged cells and no denuded Descemet's membranes, but larger polymorphy of the cells and a numerical increase in the microvilli of the cells surrounding the damaged cells. Our results support the crucial argument against RK: the alteration and destabilization of healthy corneal tissue up to the endothelium.

Animals↗
PubMed1990

Biotinyl analogues of vasopressin as biologically active probes for vasopressin receptor expression in cultured cells.

Biotinyl analogues of [Arg8]vasopressin were synthesized with the biotinyl moiety at position 4. This involved the substitution of 2, 4-diaminobutyric acid (Dab) for Gln4 in [1-deamino-Arg8]vasopressin to give the parent peptide des-[Dab4,Arg8]vasopressin. Two biotinyl analogues with different spacers between the side chain of Dab4 and the biotinyl residue were then prepared and characterized in detail. The analogues retained high binding affinities for the V2-receptor in both bovine kidney membranes and LLC-PK1 renal epithelial cells and for the V1-receptor in rat liver membranes. Both analogues were as potent as [Arg8] vasopressin in stimulating the cAMP-dependent protein kinase and the production of urokinase-type plasminogen activator in LLC-PK1 cells, with concentration dependence consistent with receptor binding affinities. Avidin or streptavidin did not appear to reduce receptor binding or biological activity of the biotinyl analogues. The use of the biotinylated vasopressin analogue des-[Dab-(biotinylamido)hexanoyl4, Arg8]vasopressin together with fluorescein-labeled streptavidin as a fluorescent probe for the V2-receptor in LLC-PK1 cells demonstrated the following: 1) Specific binding of the biotinyl analogue shown by quantitative single-cell fluorescence measurements using the technique of fluorescence microphotolysis; 2) the V2-receptor visualized by fluorescence microscopy; and 3) the expression of the V2-receptor detected by flow cytometry.

Amino Acid Sequence↗
PubMed1990

Quantitative and functional restorations and alterations of peripheral lymphocytes in patients with autologous spleen implantation.

To reduce the risk of severe infections in splenectomized patients, new methods for splenic preservation or heterotopic autologous spleen implantation have been established. In the latter case, the immunological and functional benefits are still under discussion. In this study we compared immunological parameters in 16 splenectomized patients with and without heterotopic autologous spleen implantation with a nonsplenectomized control group. The total lymphocyte counts--T-cells, CD4+ -, as well as CD8+ - lymphocytes, CD16+ - and B-cells--were highly elevated in both groups, whereby the B-cells were relatively and absolutely higher in the implanted group than in the nonimplanted group. Splenectomized patients had a significantly reduced serum IgM level. The serum IgM of patients with splenic autotransplantation was not significantly lower than that of the controls. In contrast to the impaired in vitro immunoglobulin synthesis in the splenectomized group, the autotransplanted patients showed a normal PWM-induced IgG and IgM synthesis and an increased IgA production compared with the controls. The latter results support the findings of elevated serum IgA levels in this group. The mitogenic-induced proliferation with PHA, ConA, PWM, and OKT3 was not clearly different within the tested groups. The results may indicate a benefit of autologous spleen implantation in regard to the humoral immune response.

Adolescent↗