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Biomedical subjects

K Havemann

Publications and source records attributed to K Havemann.

At least 19 recordsLinked to original sources
PubMed1992

Characterization of insulin-like growth factor I receptors and growth effects in human lung cancer cell lines.

Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines were studied for insulin-like growth factor I (IGF-I) receptor expression and with regard to the influence of IGF-I on cell proliferation. IGF-I receptors on the cells were characterized by competitive binding assays, chemical crosslinking and northern blot hybridization of IGF-I receptor mRNA. All SCLC and NSCLC cell lines showed specific IGF-I binding sites with an affinity (KD) of 0.69-5.21 nM. The amount of binding sites ranged from 59 fmol/mg to 1230 fmol/mg protein. The IGF-I binding was inhibited by the IGF-I receptor antibody (alpha-IR-3). Northern blot hybridization indicated that IGF-I receptor mRNA was being produced by all SCLC and NSCLC cell lines. We used the soft-agarose clonogenic assay to evaluate the influence of IGF-I on the in vitro proliferation of the cells. Our results have shown that IGF-I stimulates the growth of all tested cell lines ranging from a factor of 1.6 to 4.2 in SCLC and from 1.1 to 2.7 in NSCLC. The data indicate that the IGF-I receptor thus appears to be the common pathway for the mitogenic activity of IGF-I and IGF-II with regard to human lung cancer cells.

Binding, Competitive↗
PubMed1992

Experience with GM-CSF in the treatment of solid tumors.

The efficiency of GM-CSF to reduce myelosuppression after chemotherapy depends on the schedule of administration and the dose of chemotherapy. If conventional chemotherapy doses are given, a seven to ten day administration starting one day after the end of chemotherapy is able to reduce both degree and duration of leucopenia. A later onset is less effective, an earlier one aggravates leuco- and thrombocytopenia. The reduction of myelosuppression is accompanied by a reduction of infection rates and hospitalisation of patients due to these complications. If high-dose chemotherapy is given, GM-CSF does not markedly affect nadir values for leuco- and thrombocytes, but still shortens the duration of leucopenia. This effect is consistently seen after the initial cycles of chemotherapy, but seems to be less pronounced in later cycles. Thus, the growth factor administration allows a treatment intensification mainly by shortening of treatment intervals. Whether these modifications will improve the prognosis of patients with solid tumors is currently being investigated in small cell lung cancer in a German multicenter randomized trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Differential expression of insulin-like growth factor binding proteins in human non-small cell lung cancer cell lines.

The possible expression and secretion of insulin-like growth factor binding proteins (IGFBPs) by non-small cell lung cancer (NSCLC) cell lines was investigated and compared with possible IGFBP expression by primary NSCLC tumours. Cells growing under serum-free conditions released binding proteins with apparent molecular masses of 26-43 kD when analysed by a ligand blotting method under non-reducing conditions. Additionally, northern blot analysis of total RNA from NSCLC cell lines and tumours was performed using cDNAs coding for each of IGFBP-1, IGFBP-2, and IGFBP-3. This analysis revealed expression of all three mRNAs to varying degrees by all cell lines. In contrast all primary tumours analysed expressed predominantly IGFBP-2 and IGFBP-3 and none showed any evident expression of IGFBP-1. Both NSCLC cell lines and tumours synthesise IGFBPs but the pattern of expression differs significantly between cell lines and primary tumours.

Blotting, Northern↗
PubMed1992

Adrenal masses in lung cancer: sonographic diagnosis and follow-up.

Ultrasound has become an important diagnostic modality in the staging of patients with lung cancer. Between 1980 and 1990, 410 patients with histologically proved lung cancer were evaluated. In 44 patients (11%) an adrenal mass was discovered on ultrasound; in 13 patients it was isolated, and in 31 further evidence of abdominal disease was shown. Sonographic follow-up examinations of adrenal masses showed changes of size in all but 2 patients, and were therefore found to be adrenal metastases. In the 2 patients with isolated and stable adrenal disease, fine-needle biopsy revealed adenomas. Adrenal masses in patients with lung cancer are more likely to be metastatic than benign. The existence of neoplastic adrenal disease can be retrospectively confirmed by changes of size during sonographic follow-up examinations in almost all patients. Histologically verification would only appear necessary in stable adrenal disease and in cases with isolated adrenal disease in which prompt diagnosis affects treatment decision.

Adrenal Gland Neoplasms↗
PubMed1992

Preclinical and clinical experience with cisplatin and carboplatin and simultaneous radiation in non-small cell lung cancer.

Preclinical experiments with cisplatin and carboplatin showed radiosensitizing capability for these drugs against non-small cell lung cancer (NSCLC) cell lines and phase II clinical investigations were undertaken in patients with stage IIIA/B NSCLC. In the first trial, cisplatin 20 mg/m2 was infused on the first day of every treatment week, followed in about 1 hour by radiotherapy. Radiotherapy was given in single daily 2-Gy doses 5 days a week for 3 weeks, and, after a 2-week interval, for an additional 2 weeks. There were 5 complete responses (CRs) and 15 partial responses (PRs), while 6 patients had no change and 4 progressive disease, for a 67% overall response. Median survival was 14 months; the 2-year survival rate was 20%. To investigate the maximum tolerated dose of carboplatin, escalating doses were given on day 1 of each treatment week; simultaneous radiotherapy was administered as in the cisplatin study. Drug doses began at 100 mg/m2 and were increased by increments of 10 or 20 mg/m2 to a maximum of 200 mg/m2, with 5 patients treated at each dose level. Dose escalation was to stop when 3 of 5 patients developed intolerable World Health Organization (WHO) grade 3 myelosuppression. No grade 3 or 4 leukopenia occurred at carboplatin doses less than or equal to 140 mg/m2. Grade 3 leukopenia was seen in only 1 patient from the groups receiving 150, 160, or 180 mg/m2. Of the 35 patients evaluable thus far, 1 achieved CR and 18 PR, while 10 had no change and 6 progressive disease despite treatment, for a 54% overall response rate. Response rate in patients with stage IIIB disease was 48%.(ABSTRACT TRUNCATED AT 250 WORDS)

Carboplatin↗
PubMed1992

Felty's syndrome: favorable response to granulocyte-macrophage colony-stimulating factor in the acute phase.

We report a case of Felty's syndrome in which infectious complications due to severe neutropenia could be overcome by short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 7 micrograms/kg/day s.c.). Leukocyte counts rose from 1,050/mm3 at presentation to 4,470/mm3 after 15 days of treatment. A flare-up of arthritis was not noted. Defects in granulocyte function and clinical improvement prior to leukocyte rise suggest that the beneficial effect of GM-CSF is mainly due to an improvement of granulocyte function.

Acute Disease↗
PubMed1992

Carboplatin and simultaneous radiation in the treatment of stage IIIA/B non-small cell lung cancer.

The radiosensitizing properties of carboplatin were investigated in preclinical and clinical studies. In human non-small cell lung cancer (NSCLC) cell lines (EPLC 65 H and LCLC 97 TM1) combined carboplatin and radiation therapy was superior to chemotherapy or radiotherapy alone, indicating the existence of additive effects for both treatment modalities. In a subsequent clinical phase II trial, escalating doses of carboplatin were given concurrently with radiation to patients with stage IIIA/B NSCLC. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, during weeks 1-3 and 6 and 7. Carboplatin was given on day 1 in weeks 1-3 and 6 and 7. The starting dose level was 100 mg/m2, followed by dose escalations to 120, 130, 140, 150, 160, 180, and 200 mg/m2. Five patients were to be treated at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in 3 of the 5. To date, 34 patients have been entered into the study. Toxicity was mild and, even at the 180-mg/m2 dose level, no severe myelosuppression was observed. Thus, the maximum tolerated dose of carboplatin has not yet been reached. Preliminary analysis of response and survival shows an overall response rate of 53% and a median survival of 10 months. Patients receiving higher carboplatin doses (140-160 mg/m2) survived longer than patients who received lower doses (100-130 mg/m2). These preliminary results indicate that combination carboplatin and radiation therapy is a well-tolerated, active regimen in patients with locally advanced NSCLC. Splitting carboplatin administration may reduce its hematologic toxicity.

Carboplatin↗
PubMed1992

Hemophan versus hemophan--a philippic against the suggestion of constant membrane quality.

All statements referring to biocompatibility of dialyzers depend on the suggestion of a constant and reproducible structure of the investigated membrane material. The data presented here strike this concepts in case of hemophane. Two commercially available hemophane dialyzers, the GF MC 120 (Gambro) and the MO 450 (SMAD) membranes, were compared. Significant differences could be seen in the induction of leukopenia and leukocyte sequestration reaction within patients lungs, but also in capacity to influence granulocyte oxidative metabolism and release of granular enzymes. According to these data it seems questionable whether hemophane is a membrane material with constant structure and quality normally expected for products bearing trade names. Excluding other differences (like surface-area or sterilization method) variable amounts of DEAE substituents and/or an inconstant distribution of the DEAE groups within the membranes may be the most possible reason responsible for the differences found. The study underlines the urgent need of an exact physico-chemical characterization of dialyzer membranes and is therefore a challenge for free publication of such basic data by the producers.

Biocompatible Materials↗
PubMed1992

Regulation of neutrophil functions by elastase-generated IgG fragments.

IgG is split by neutrophil elastase into Fc and Fab fragments. These IgG fragments influence the functions of stimulated neutrophils such as chemotaxis, oxidative burst, and enzyme release. FMLP stimulated leukocyte chemotaxis is specifically inhibited by the elastase generated Fc fragments. Seven nmol Fc/10(6) PMN totally inhibit the chemotaxis stimulated by 16 to 125 nM FMLP. Native IgG and Fab fragments show no effect. FMLP-stimulated superoxide anion generation is specifically inhibited by Fc fragments with half maximal inhibition by 1.2 nmol/10(6) PMN. The generation of hydrogen peroxide is concomitantly stimulated, resulting in a superoxide dismutase-like effect. FMLP-stimulated elastase and myeloperoxidase release are enhanced by Fab fragments (10 nmol/10(6) PMN) to 206 and 155%, respectively, of reference values by 25 nM FMLP, while Fc and native IgG stimulate to a less extent. Consequently, elastase-generated Fc fragments have an inhibitory effect on inflammation by reducing chemotaxis and oxidative burst of stimulated neutrophils. The release stimulating activity of Fab fragments results in an up-regulation of elastase induced IgG degradation.

Chemotaxis, Leukocyte↗
PubMed1991

Combined chemo- and radiosensitivity testing with ifosfamide and ACNU in human lung cancer cell lines.

The combination of radiotherapy and cytostatic drugs is of interest in the treatment of several solid tumors. In these preclinical investigations we tested whether ifosfamide and ACNU are able to enhance radiation effects. The experiments were performed by using the MTT assay. Two small cell and 2 non small cell lung cancer cell lines were involved. Ifosfamide, ACNU or both drugs together were tested in 6 different concentrations adjusted to the peak blood level. During the 1 hour drug incubation time, the cell lines were either irradiated with a single dose of 4 Gy or not. The main results were that ACNU possessed only little cytostatic activity in the cell lines under examination. In contrast, ifosfamide caused a dose related cytostatic activity in all cell lines. Concentrations of 26 micrograms/ml (NCC-SCLC H 82) or 10-12 micrograms/ml (3 other cell lines) were able to reduce the surviving cell fraction to less than 50% (IC50). While ACNU showed no clear outlined radiosensitizing properties, ifosfamide reinforced the radiation effects in 3 out of 4 cell lines indicating radiosensitizing properties of this drug. Synergistic effects of ifosfamide and ACNU have not been noticed. These preclinical investigations may constitute the basis for combined ifosfamide and irradiation therapy in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Effect of rhGM-CSF on haematopoietic reconstitution after chemotherapy in small-cell lung cancer.

In three consecutive pilot studies the effect of recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF) on haematopoetic recovery after chemotherapy in patients with small-cell lung cancer was investigated. In study I, 20 patients received AIO chemotherapy (A, Adriamycin 25 mg/m2 on days 1 + 2; I, ifosfamide 2 g/m2 on days 1-5; O, vincristine 2 mg on day 1) at 4-week intervals either with or without rhGM-CSF (250 micrograms/m2 sc) from day 8 until recovery of leucocytes. Neither the degree nor the duration of myelosuppression was markedly influenced by rhGM-CSF. Suggesting that these disappointing results were caused by the late onset of GM-CSF application, in the following study we shortened chemotherapy to 3 days and started with GM-CSF on day 4. The main objective of this study was to test whether the earlier administration of GM-CSF allowed treatment intervals to be reduced or the dose to be escalated. After 10 patients had received a starting dose of AIO (A, 50 mg/m2 on day 1; I, 2 g/m2 on days 1-3; 0,2 mg on day 1) alternating with cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 1-3), the dose of ifosfamide and etoposide was escalated to 2.5 g/m2 on days 1-3 and 200 mg/m2 on days 1-3 in the next 10 patients. Treatment was given at 2-week intervals when leucocytes were greater than 3500/mm3 and thrombocytes were greater than 100,000 mm3 on day 14. At each dose level patients were randomized to receive either rhGM-CSF 250 micrograms/m2 s.c. on days 4-12 or no GM-CSF. In this study, rhGM-CSF markedly shortened the duration of leukopenia. Reinstitution of chemotherapy on day 15 was possible at dose level 1 in 1/4 patients without and in 3/4 patients with GM-CSF, and at dose level 2 in 0/5 patients without and in 5/5 patients with GM-CSF. However, the degree of myelosuppression was not improved by GM-CSF. In a third study we tried to apply rhGM-CSF simultaneously with chemotherapy. After 3 patients had received GM-CSF starting on day 1 concurrent to AIO chemotherapy, we noticed an increase of myelosuppression with prolonged neutropenia and thrombocytopenia and stopped this investigation. Considering all patients included in these three consecutive pilot studies, there is no difference in response rates and survival between patients with and without rhGM-CSF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Hematopoietic reconstitution after high-dose chemotherapy and autologous nonfrozen bone marrow rescue.

The kinetics of marrow engraftment were analyzed in 50 patients with acute leukemia (21), malignant lymphoma (15), and solid tumors (14) after high-dose multiagent chemotherapy followed by autologous bone marrow transplantation (ABMT) with nonfrozen bone marrow. Unseparated heparinized whole bone marrow was stored in 10% CPDA1 at 4 degrees C for 72 h, then filtered and reinfused. The median number of nucleated cells reinfused was 1.6 x 10(8)/kg (range 0.5-3.8 x 10(8)/kg). All patients had a full hematopoietic reconstitution. Median time to achieve a neutrophil count greater than 500/microliters was 20 days (range 12-39) and median time to achieve an unsupported platelet count greater than 20,000/microliters was 20 days (range 10-55). The main factor associated with delayed engraftment was the number of prior chemotherapy cycles. We conclude that high-dose chemotherapy with nonfrozen ABMT is a safe procedure, without the requirement for costly cryopreservation facilities.

Acute Disease↗
PubMed1991

Insulin-like growth factor binding protein expression in human small cell lung cancer cell lines.

Insulin-like growth factor binding proteins (IGF-BP) are secreted by several human small cell lung cancer cell lines (SCLC). In order to identify the IGF-BPs from SCLC cell lines the RNA from 10 different SCLC cell lines was analyzed by Northern blot analysis with the probes for three different IGF-BPs, IGFBP-1, IGFBP-2, and IGFBP-3. No hybridization signal could be detected with the probes encoding for IGFBP-1 and IGFBP-3. The hybridization with different IGFBP-2-specific oligodeoxynucleotide probes and with the corresponding full-length cDNA showed that all SCLC cell lines which secreted IGF-BPs express IGFBP-2.

Base Sequence↗
PubMed1991

Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival.

The data of 766 patients participating in three German multicentre trials were analysed with regard to the relationship between baseline characteristics and prognosis in small cell lung cancer (SCLC). The central aim of this analysis has been to evaluate the role of gender as an independent prognostic factor in SCLC. The minimum follow-up period for the 652 male and 114 female patients was 36 months. Female patients were shown to have a higher complete remission rate (35% vs 25%), a superior median survival (ms) (12.1 months (mo) vs 9.8 mo), and a favourable 2-year survival rate (2ys) (19% vs 8%) to male ones. Various other prognostic factors have been proved to be significant, such as extent of disease, clinical performance status, and history of smoking, whereas weight loss prior to chemotherapy and age have been less important factors. We have been able to ascertain that women's responses were better than those of male patients independent of any other relevant prognostic variable. Furthermore, results were found to be even more advantageous for female patients with additional favourable prognostic parameters, i.e. for patients with limited disease (ms 15.2 mo vs 12.0 mo; 2ys 29% vs 9%) or with good performance status (ms 13.4 mo vs 10.4 mo; 2ys 24% vs 7%). A most remarkable observation was made in that the favourable prognostic effect of the female gender was restricted to patients aged less than 60 years (ms 13.3 mo vs 10.1 mo; 2ys 26% vs 5%), whereas for older women no advantages over men's results were established (ms 9.3 ml vs 9.1 mo; 2ys 8% vs 7%). A proportion of 32% of female patients with limited disease aged less than 60 years achieved a 3-year survival rate. We conclude (a) that sex constitutes a major prognostic factor in SCLC and is especially useful as a predictor for long-term survival, and (b) that the favourable prognostic value of the female sex is restricted to younger patients.

Age Factors↗
PubMed1991

Determining carboplatin/etoposide dosage in extensive stage small-cell lung cancer (SCLC).

In order to define the maximum tolerance level of combined carboplatin/etoposide dosage, patients with extensive stage small-cell lung cancer (SCLC) were treated with a fixed dose of carboplatin (300 mg/m2 iv on day 1) and escalating doses of etoposide starting with 80 mg/m2 iv on days 1-3. Five patients were given this starting and every following dose level. The daily dose of etoposide was increased in increments of 20 mg/m2 iv until severe myelosuppression occurred in 3 of 5 patients. Leuko- or thrombocytopenia WHO grade 3 or 4 occurred in 0/5 of the patients at the dose levels of 80 and 100 mg/m2, in 1/4 of the patients at the level of 120 mg/m2, in 2/5 of the patients at a level of 140 mg/m2, and 3/5 patients at a level of 160 mg/m2. Thus, increase in dosage was stopped at an etoposide dose of 160 mg/m2. Other side effects were mild and consisted predominantly of nausea and vomiting in 14/25 of the patients. The overall response rate was 40% with a 12% complete remission rate, median survival was 9.3 months and median progression-free survival totalled 4.3 months. These results indicate that combined carboplatin/etoposide is a well tolerated regimen in extensive-stage SCLC, with response rates comparable to those of other standard protocols. Using treatment intervals of 4 weeks the recommended dose of etoposide in combination with 300 mg/m2 carboplatin was identified as 140 mg/m2 iv for 3 consecutive days.

Aged↗