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M Stuschke

Publications and source records attributed to M Stuschke.

At least 19 recordsLinked to original sources
PubMed1995

Radiation-induced apoptosis in human sarcoma and glioma cell lines.

Six human soft-tissue sarcoma and 14 glioma cell lines, exhibiting considerable differences in radioresponsiveness and histological grade of differentiation of the parental tumour, were examined with respect to apoptosis development after irradiation with 60Co gamma-rays. After test doses of 6 and 25 Gy, significant changes characteristic of apoptosis occurring within 6 to 30 hr were exhibited by only 2 differentiated sarcoma cell lines, EL7 and ESS2. The characteristic internucleosomal fragmentation of DNA was detected as early as 6 hr after exposure of subconfluent monolayer cultures to 6 Gy. It was limited to cells that had detached from the culture plate, whereas adherent cells showed random degradation of DNA, namely after higher doses (25Gy) or longer incubation times (30 hr). As assessed by fluorescence microscopy of unfixed cultures stained with Hoechst 33342 and propidium iodide, the proportion of cells showing apoptotic bodies in non-irradiated controls was < 0.1% and 0.3% for EL7 and ESS2, respectively. The dose-response relationship for apoptosis was determined at 9 hr post-irradiation. After 2 Gy, the percentage of apoptotic cells was elevated to 3.4% in EL7 and 4.5% in ESS2 cultures. Saturation was obtained above 6 Gy, with 8.4% apoptosis in EL7 and 15% in ESS2 after 25 Gy. Taken together, rapid ionizing-radiation-induced apoptosis seems to be limited to a subgroup of sarcomas and is unlikely to occur in gliomas.

Animals↗
PubMed1995

Heterogeneity in the fractionation sensitivities of human tumor cell lines: studies in a three-dimensional model system.

PURPOSE: Current concepts to optimize the therapeutic gain of radiotherapy by hyperfractionation assume that human tumors are less sensitive to fractionation than late reacting normal tissues. The aim of this study was to investigate the extent of the intercell line heterogeneity of fractionation sensitivity of a wide variety of human tumor cell lines in a three-dimensional model system under fully oxic conditions using schedules with one to eight fractions. Biological characteristics of the tumors that correlate with fractionation sensitivity should be identified. METHODS AND MATERIALS: A total of 21 cell lines from human tumors maintained as multicellular spheroids consisting of 1000-1500 cells were given fractionated irradiation within a total treatment time of maximally 50 h. Complete dose-spheroid control curves were determined for each fractionation scheme. The spheroid control data were adequately described by the linear quadratic model assuming Poisson statistics. In addition, the induction of a G2 block by a fractionated test dose of seven 3 Gy fractions given at 6-h intervals was determined in spheroid cells using flow cytometry of propidium bromide stained cell nuclei. RESULTS: The fractionation sensitivities of human tumor cells in multicellular spheroids could be characterized by alpha/beta values, ranging from 2.8-37 Gy in dependence on the cell line. The log normally distributed alpha/beta values were positively correlated with the percentage increase in G2/M phase after the fractionated test dose compared to the controls (r = 0.72, p < 0.01), and were associated with the degree of tumor differentiation (p = 0.01, ANOVA F-test). No significant correlation between the log (alpha/beta) values and the surviving fractions at 2 Gy (SF2) or the total doses with 2 Gy per fraction necessary to control 50% of the spheroids (SCD50) was observed. Despite the intercell line variability of the alpha/beta values, the SCD50 values of the different cell lines, given with one and eight fractions or one fraction and 2 Gy per fraction, were closely associated (Spearman rank correlation coefficients: r = 0.89 or r = 0.90, p < 0.0001). CONCLUSION: Human tumor cell lines showed a marked heterogeneity in the fractionation sensitivity when irradiated as multicellular spheroids and assayed in situ using the spheroid control end point. Therefore, the therapeutic gain of altered fractionation also depends on those biological characteristics of each individual tumor that affects its fractionation sensitivity. Parameters that correlate with fractionation sensitivity of the tumor lines in the spheroid system were identified as grade of tumor differentiation and percentage increase in G2/M cells at the end of an eight-fraction schedule.

Humans↗
PubMed1994

Local recurrences of soft tissue sarcomas in adults: a retrospective analysis of prognostic factors in 102 cases after surgery and radiation therapy.

Between 1974 and 1990, 102 adult patients (age 18-86 years) with the diagnosis of a soft tissue sarcoma (STS) were treated with photons and/or electrons in combination with surgery. The total doses in the initial treatment volume (second order target volume) was 40-50 Gy. For the coning down volume (first order target volume) the median total dose was 59 Gy (range 45-72 Gy). A total of 18% (18/102) local failures was observed. In multivariate analysis, prognostic factors for the occurrence of a local failure were identified as follows: treatment of a primary or recurrent STS (P = 0.02), total dose (P = 0.025) and tumour grade (P = 0.05). Mode of surgery, tumour size (trunk versus extremity), pre- or postoperative radiotherapy, combined chemotherapy and tumour size (T1 versus T2) had no significant impact on the local relapse-free survival. These data give further evidence that combined surgery and radiotherapy is an effective modality in treatment of soft tissue sarcomas.

Adolescent↗
PubMed1994

DNA content as a predictor of clinical outcome in soft tissue sarcoma patients.

The prognostic relevance of cellular DNA content has been shown for a variety of human malignancies. However, only a few studies concerning soft tissue sarcomas have been published. Biopsies of 81 patients with soft tissue sarcomas, referred for primary or secondary surgery, were analysed by flow cytometry to determine cellular DNA content of tumours. Most patients (60/81) already had one or more local recurrences at the time of first presentation at Essen University. The median age of the patients was 45 years (range 14-79). 44 (54%) patients had euploid and 37 (46%) had aneuploid tumours. Age, sex, and tumour localisation (trunk versus extremity) were equally distributed between euploid and aneuploid sarcoma patients. The median follow-up was 69 months (range 9-312). The median survival time for euploid and aneuploid tumours was 84 and 30 months, respectively (P < 0.0005). In the univariate analysis, ploidy, S-phase percentage, localisation and tumour grading were significant predictors of survival, whereas in the multivariate analysis, only DNA content and tumour localisation were independent prognostic variables for survival.

Adolescent↗
PubMed1994

Efficacy of ifosfamide, dacarbazine, doxorubicin and cisplatin in human sarcoma xenografts.

The primary chemosensitivity of 16 highly malignant xenografted human soft-tissue sarcomas to ifosfamide, dacarbazine, adriamycin and cisplatin and the development of secondary drug resistance in two chemosensitive sarcoma cell lines was tested in the xenograft system. Single-dose, single-agent treatments with 350 mg kg-1 ifosfamide, 200 mg kg-1 dacarbazine, 10 mg kg-1 doxorubicin and 6.6 mg kg-1 cisplatin were administered and response measured as specific growth delay. Since ifosfamide induced unexpectedly higher toxicity, response was corrected based on the shape of the dose-response curve for ifosfamide. Taking a specific growth delay > 3 as the cut-off point for chemosensitivity, ifosfamide, dacarbazine, doxorubicin and cisplatin were effective in 10/16, 4/16, 2/16 and 1/16 sarcoma cell lines respectively. Five out of 16 sarcoma cell lines were resistant to all tested drugs. Ifosfamide-resistant sarcoma lines were also resistant to doxorubicin and cisplatin, indicating a high degree of cross-resistance. Dacarbazine was still effective in 1/6 ifosfamide-resistant sarcoma cell lines. Secondary drug resistance developed slowly after doxorubicin and ifosfamide pretreatments at moderate selection pressure and developed rapidly after dacarbazine pretreatment at high selection pressure.

Animals↗
PubMed1994

[Accelerated hyperfractionated radiotherapy combined with simultaneous chemotherapy in locally advanced pharyngeal and oral carcinomas].

PURPOSE: To evaluate the feasibility and effectiveness of a concurrent radio-chemotherapy regimen for locally advanced carcinomas of the pharynx and floor of the mouth. PATIENTS AND METHODS: Since January 1990, 97 patients with locally advanced carcinomas of the naso-, oro-, hypopharynx and the oral cavity in UICC stages III and IV were treated according to an accelerated hyperfractionated radiotherapy schedule with concurrent chemotherapy. The primary tumor and positive lymph nodes received a total dose of 72 Gy in 6 weeks. In the first 3 weeks, large fields were irradiated 5 times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving 2 daily fractions of 1.4 Gy with minimal intervals of 6 hours. Target volumes were reduced after 49.6 and 59.4 Gy, excluding clinically uninvolved lymph node regions of low and high risk. On day 1, 350 mg/m2 5-FU and 50 mg/m2 folinic acid were given as intravenous bolus followed by continuous infusion of 350 mg/m2 5-FU and 100 mg/m2 folinic acid, days 1 to 5. 10 mg/m2 mitomycin C was given on day 5 and 36 of the treatment. Salvage surgery was offered for residual disease 5 to 6 weeks after the end of radiotherapy. PATIENT CHARACTERISTICS: 70 male, 27 female; age: 27 to 81 years; T2/T3/T4: 7/30/60; N0/N1/N2/N3: 20/18/53/6; nasopharynx/oropharynx/hypopharynx/oral cavity: 16/33/36/12. Median follow-up is 26 months. RESULTS: Overall survival and recurrence-free survival at 2 years were RESULTS: Overall survival and recurrence-free survival at 2 years were 68 +/- 5% and 74 +/- 5%. Multivariate analysis revealed a significant influence of the geometric mean neck node diameter or the N-stage on loco-regional control and survival. T-stage, tumor volume, or tumor localisation did not become significant. Acute toxicity of this schedule was acceptable but required optimised supportive care. Treatment related grade 4+ late toxicity of mucosa, soft tissue and bone were observed with a cumulative frequency of 13% at 2 years. Two patients died during a phase of severe leuko- or thrombocytopenia. CONCLUSION: This phase I to II trial shows favourable results using an intensified treatment radio-chemotherapy protocol. A phase III study is now planned, comparing this regime with an accelerated hyperfractionated radio-therapy alone to an increased total dose of 77.6 Gy.

Adult↗
PubMed1994

[Surgery of locally advanced non-small-cell bronchial cancer after intensive preoperative chemo-/radiotherapy].

From March 1991 to June 1993 50 patients with local advanced NSCLC (mediastinoscopy obligatory) have been entered into an ongoing trial with preoperative chemotherapy and simultaneous chemo-/radiotherapy, followed by re-mediastinoscopy and surgery. Clinical response rates after chemotherapy amounted to 66.8% after chemo/radiotherapy 77.5%, no severe toxicity was observed. 36 patients ultimately underwent operation, 29 with a curative, 5 with a palliative resection and 2 with an explorative thoracotomy. Pathological complete remission rates of the primary tumor were found in 11 (32.3%), R0-resection in 18 (52.9%) and R1-resection in 5 (14.7%) cases. Sterilisation rates of mediastinal nodes were found in 86.3% of N2 tumors and 66.6% of N3 tumors. Median survival time ranged between 21 months for stage III a and 16 months for III b disease. This intensive preoperative neoadjuvant treatment is tolerable and effective, the requirements for a randomised comparative trial was met.

Adult↗
PubMed1993

Radioresponsiveness of human glioma, sarcoma, and breast cancer spheroids depends on tumor differentiation.

PURPOSE: Differences in the intrinsic radiosensitivity within and between different tumor classes have been noticed for human tumor cell lines using the clonogenic assay. By far, most of the cell lines studied up to now were derived from poorly differentiated tumors. In this study, the influence of tumor differentiation on the radiation doses necessary to control 50% of small oxic spheroids (SCD50) was determined. Evidence of a distinct dependence of radioresponsiveness on tumor progression provides a background for an investigation of the underlying mechanisms. METHODS AND MATERIALS: Spheroids were aggregated from 1000-1500 cells in agarose coated 24 multi-well plates. Their diameters ranged from 156 to 405 microns, depending on the cell line. Spheroids were irradiated with graded 60Co single doses using spheroid control as end point and a minimum follow-up period of 3 months. RESULTS: Cell lines from three low grade gliomas and 10 malignant gliomas were studied in the spheroid control assay. The group mean SCD50 values were 6.1 +/- 1.6 Gy and 13.1 +/- 3.3 Gy, respectively. Four cell lines from grade 2 soft tissue sarcomas had a mean SCD50 value of 6.2 +/- 0.5 Gy and one undifferentiated sarcoma line of 11.0 Gy. Three well-differentiated breast cancer lines expressed the cell adhesion molecule E-cadherin, had an epithelioid morphology in monolayer culture, were estrogen receptor positive or contact inhibited in multicellular spheroids. Two undifferentiated breast cancer lines had a fibroblastoid morphology and were marker negative. The mean SCD50 value of the former was 10.5 +/- 1.0 Gy while that of the undifferentiated lines was 14.8 +/- 2.8 Gy. Analysis of variance revealed a significant effect of the tumor type as well as the grade of dedifferentiation on the SCD50 after irradiation with one fraction or 2Gy/fraction. The surviving fractions at 2 Gy (SF2), obtained from the spheroid control rates after different fractionation schedules by approximation of the linear quadratic model assuming Poisson statistics were significantly dependent on tumor type (p = 0.001, ANOVA F-test) but not on tumor differentiation (p = 0.27). The alpha/beta ratios did not depend on tumor type (p = 0.08, ANOVA F-Test) but significantly increased with the grade of tumor cell dedifferentiation (p = 0.03). CONCLUSION: The spheroid model is suitable for measuring the radioresponsiveness of differentiated cell lines with very low colony forming efficiencies. Tumor cell differentiation is an important factor for the radioresponsiveness and recovery capacity of human tumor cells.

Breast Neoplasms↗
PubMed1993

Spheroid control of malignant glioma cell lines after fractionated irradiation: relation to the surviving fractions at 2 Gy and colony forming efficiencies in a soft agar clonogenic assay.

Spheroid control doses (SCD50) were determined for ten human glioma lines after fractionated irradiation under oxic conditions. In addition, SF2 values and colony forming efficiencies (CFE) were measured in a soft agarose clonogenic assay. A significant relationship existed between the SCD50 values and the SF2-CFE data pairs (p = 0.01) but the SCD50 values were higher than expected from the SF2 and CFE values. This comparison shows the influence of environmental factors (different in both model systems) on reproductive tumour cell death after irradiation.

Cell Aggregation↗
PubMed1993

[Malignant paragangliomas--the results of radiotherapy in 6 patients].

Between February 1984 and May 1989, six patients (four male, two female) with malignant paragangliomas of the carotid body (n = 4) and glomus jugulare (n = 2) were irradiated in the Department of Radiation Oncology at Essen University. All patients had macroscopic (residual) tumor at the start of treatment. Five out of six paragangliomas had to be considered malignant, since histological lymph node involvement or distant metastasis was confirmed. In the sixth case extra- and intracranial tumor growth was observed. Total doses between 40 and 55 Gy using cobalt 60, 10 or 15 MeV photons were administered. Radiation therapy was canceled at 30.6 Gy in one patient because of multiple distant metastasis. Three out of four patients, who received curative treatments, were locally controlled (25 to 91 months). A local recurrence in one patient was detected 18 months after irradiation; this patient died of distant metastasis 23 months after treatment. In one out of two palliatively irradiated patients, local control could be achieved until the patient died of distant metastasis twelve months after treatment. Grade III- or grade IV-treatment toxicity was not observed. Radiation therapy of malignant paragangliomas with doses between 45 and 54 Gy in five to six weeks is an effective treatment with low toxicity and should be preferred to surgery in glomus jugulare and advanced carotid body tumors.

Adult↗
PubMed1992

Radiosensitivity, repair capacity, and stem cell fraction in human soft tissue tumors: an in vitro study using multicellular spheroids and the colony assay.

Radiation doses necessary to control 50% of spheroids (SCD50) were determined for five human soft tissue tumor lines after single dose and fractionated irradiation. Spheroids with 1000-1500 cells were used throughout. A similar number of cells per spheroid resulted in different sized spheroids for the respective cell lines. The parameters alpha, beta, and the number of regenerating cellular units per spheroid (SRU) were estimated from the spheroid control data using a direct fit according to the linear quadratic model assuming Poisson statistics. The number of spheroid regenerating cellular units was also determined from the growth delay at doses required for 10% spheroid control. In addition, alpha, beta, and the fraction of clonogenic cells of the five cell lines were obtained from a soft agar colony forming assay. The most precise parameter for radiation sensitivity was the SCD50, with a coefficient of variation smaller than 5%. SCD50 values ranged from 5.9 to 11.0 Gy for the five soft tissue tumor lines. Two of the five cell lines showed significantly higher alpha values and lower calculated survival fractions after 2 Gy (SF2) in the soft agar clonogenic assay than in the spheroid control assay. This points to a resistance-enhancing effect in the spheroid system. Whereas the fractions of SRU from the number of cells per spheroid, estimated from the spheroid control and growth delay assays, agreed well, no significant correlation existed between the fraction of SRU and the fraction of clonogenic cells in the soft agar colony forming assay. The alpha/beta ratios as a descriptive measure of the fractionation sensitivity of the tumor cell spheroids in the spheroid control assay corresponded well with those derived from the dose-cell survival data using a soft agar colony forming assay. Two of the five cell lines showed high fractionation sensitivities with alpha/beta values smaller than 5 Gy while those of the remaining three ranged from 7.8 to 10.8 Gy. Spheroids are structurally more similar to in vivo tumors than monolayer cultures. From the observed lack of correlation in the radiosensitivity parameters alpha and SF2 as well as in the fraction of SRU or clonogenic cells obtained from the spheroid control assay or the colony forming assay, one would expect even greater differences between results from colony forming assays and the radiosensitivity of in vivo tumors, at least for human soft tissue sarcomas.

Cell Aggregation↗
PubMed1992

Radioresponsiveness, sublethal damage repair and stem cell rate in spheroids from three human tumor lines: comparison with xenograft data.

Dose-control curves after fractionated irradiation were generated for small oxic spheroids from the two human glioma cell lines, U87 and A7, as well as the squamous cell carcinoma line FaDu. These data were fitted by the linear quadratic model assuming Poisson statistics. The alpha/beta values of A7, U87, and FaDu spheroids, respectively were 10.3 (8.1-12.9) Gy, 17.8 (15.1-21.1) Gy, and 37.9 (29.1-51.5) Gy. These data were compared with those previously published by Suit et al. (31) and Zietman et al. (40) for 6 mm xenografts of U87 and FaDu after fractionated irradiation and for A7 after single dose irradiation under clamped conditions. A good agreement in the alpha/beta values was observed for U87 and Fadu xenografts and spheroids assuming an oxygen enhancement ratio (OER) of 2.7. In addition, the ranking according to the single doses needed to control 50% of the tumors agreed for xenografts and spheroids from the three cell lines. U87 was the most resistant line in both model systems, followed by A7 and FaDu. However, the absolute values of alpha and beta, obtained from the direct fit to the dose-control data were only about half as high for U87 and FaDu xenografts than for the spheroids. Monte Carlo simulations showed that this discrepancy can be explained by a greater tumor heterogeneity of the xenografts. While the number of critical stem cells or spheroid rescuing units equaled the number of cells per spheroid for the three cell lines, the percentage of tumor rescuing units for Fadu and U87 xenografts was estimated to be below 1%. In a next step, survival curves were generated for exponentially growing cells of the three lines. A7 cells were significantly more radioresistant when plated on tissue plastic than in soft agar. Using the most resistance-promoting colony assay conditions for each cell line, a good agreement was observed for the alpha and SF2Gy values calculated from the colony and spheroid control data. This study shows that the spheroid model can quantitatively predict the repair capacity of sublethal damage as well as the rank order of radiation sensitivity of in vivo tumors.

Animals↗
PubMed1991

Angioplasty of renal arteries: a report of ten year's experience.

Report of PTA of renal arteries in 288 patients. Primary results show good to optimal dilatation of the arteries (60.6% to 78.6%). One third of all cases achieved optimal blood pressures. In about 40% antihypertensive drugs had to be administered, in about 30% blood pressure remained unchanged although PTA was effective. PTA of renal arteries is the best method of treating renal hypertension, also because of the low rate of complications.

Angioplasty, Balloon↗
PubMed1991

Repair capacity and kinetics in spheroids from a lung metastasis of a human soft tissue sarcoma: a growth delay study.

Spheroids grown from the human cell line EF8 of a lung metastasis of a human malignant fibrous histiocytoma were given fractionated irradiation with 60Co gamma rays at passages 31 and 32. The mean diameter of the spheroids at the time of treatment was 250 microns. Growth delay was used as the end point in these studies. Two experiments were carried out to determine the capacity and kinetics of repair of sublethal damage. In the first experiment, one, two, and five fractions were given at three or four dose levels with fixed intervals of 360 min. In the second experiment, schedules with two and four dose fractions and intervals of 0, 20, 60, 120, and 360 min were used, each at two dose levels. Data analysis was performed by a direct method based on the alpha/beta model and first-order repair kinetics of radiation damage. In both experiments, the alpha/beta value of EF8 spheroids was estimated to be about 8 (6-10) Gy. The rate constant of repair, mu, and its 95% confidence interval were estimated to be 0.62 (0.40-0.84) 10(-2) min-1, equivalent to a half-time of repair (T1/2) of 112 (83-172) min. A more detailed analysis of the data of the second experiment revealed a significant dependence of the rate constant of repair, mu, on the total radiation effect induced by the fractionated radiation treatments with short overall times. With increasing level of effect, mu decreased. These data indicate that the half-time of recovery of a human tumor can be longer than that of the surrounding normal tissue, in this case lung, at least for a limited range of doses and for some fractionation schedules.

Cobalt Radioisotopes↗
PubMed1990

Radiation response in 10 high-grade human soft tissue sarcoma xenografts to photons and fast neutrons.

From a panel of 48 human soft tissue sarcomas growing as permanent xenografts, 10 tumor lines (five leiomyosarcomas, three malignant fibrous histiocytomas, two neurofibrosarcomas) have been selected to determine the radiation response to photons and fast neutrons. Using the specific growth delay (SGD) as an end-point, considerable variability of inherent radiosensitivity was observed. Isoeffective radiation doses varied by a factor of 27 for photons and of 9.4 for neutrons at a specific growth delay level of 0.5. The heterogeneity of the relative biological effectiveness (RBE) at this specific growth delay-level differed by a factor of 8. Relative biological effectiveness values for clamped tumors exceeded those of the normal tissues (RBE approximately 3) in 6 out of 10 tumor lines. Assuming a ratio of 0.5 for oxygen enhancement ratio-values of neutrons and photons, a therapeutic gain for neutrons existed in 4 out of 10 tumor lines under oxic conditions. No correlation between volume doubling times and relative biological effectiveness was seen.

Animals↗