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Biomedical subjects

M Stuschke

Publications and source records attributed to M Stuschke.

At least 19 recordsLinked to original sources
PubMed1999

Increased levels of vascular endothelial growth factor in bronchoalveolar lavage of patients with bronchial carcinoma effect of tumour activity and oxidative stress due to radio-chemotherapy?

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a crucial role in physiological and neoplastic angiogenesis. Moreover, VEGF has been found to be upregulated by conditions associated with the generation of free radicals and reactive oxygen intermediates. In patients with cancer, studies to evaluate VEGF as a measure of tumour activity were carried out. We tested the hypothesis that VEGF is additionally affected by oxidative stress due to anticancer therapy. Moreover, the suitability of epidermal growth factor (EGF) to estimate tumour activity was studied. PATIENTS AND METHODS: 60 patients with non-small cell lung cancer (NSCLC) covering different therapy progress and modalities underwent bronchoalveolar lavage. VEGF-, EGF-, albumin- and total protein-concentrations in bronchoalveolar lavage fluid (BALF) and VEGF-levels in blood plasma were studied. RESULTS: BALF VEGF-levels were increased in patients with advanced NSCLC before and in anticancer therapy. In patients who had received radiotherapy to the lung prior to chemotherapy, VEGF concentrations were noticeably higher than under sole chemotherapy. Pulmonary endothelial hyperpermeability was found in patients with recently diagnosed tumours and patients undergoing anti-cancer therapy. Evaluation of EGF-levels in BALF revealed no significant influence of tumour activity or cancer therapy on this parameter. CONCLUSION: BALF-levels of VEGF are affected by tumour activity and oxidative stress due to anticancer therapy.

Adult↗
PubMed1999

Oxidant-induced lung injury in anticancer therapy.

Lung injury is one of the most frequent side effects in anticancer therapy. Especially simultaneous application of high doses of ionising radiation and radiosensitising cytotoxic drugs is considered to cause deleterious pneumonitis and pulmonary fibrosis. Growing evidence indicates that reactive oxygen species (ROS) play a key role in the development of these disorders. They are capable of causing cell component alterations and changing cellular protein expression. Observing these disease mechanisms reveals an impressive self-amplifying cascade of secondary ROS generation. Through intricate interactions between cells, cytokines and growth factors, fibroblasts are activated and thus pulmonary matrix content is massively increased. - As clinical appearance is uniform and unspecific, an early, reliable diagnosis of therapy-associated lung damage is not possible so far. However, improving this situation could enable us to take advantage of new multimodal therapeutic facilities. This review discusses mechanisms of ROS generation during radio-chemotherapy in the lung, antioxidant defense strategies and responses to oxidants, thereby assessing current diagnostic tools.

Animals↗
PubMed1999

[CT densitometry for the grading of subcutaneous fibrosis after the photon-neutron therapy of malignant salivary gland tumors].

BACKGROUND: To evaluate alternative treatment regimen e.g. neutron therapy determination of treatment efficacy as well as side effects is important. Sensitivity of computed tomography (CT) in detecting changes of connective tissue after neutron therapy was examined. PATIENTS AND METHODS: In the course of their follow-up period (median 45 months) 12 patients with malignant salivary gland tumors who had postoperatively received neutron (1/12) or photon/neutron therapy (11/12) were examined by means of CT densitometry on 3 representative scans in the area of radiotherapy. In 3 ROI (regions of interest) in subcutaneous fatty tissue the density at the irradiated and the non-irradiated side was determined according to Hounsfield units (HU) and the average density was calculated. The average density of both sides was compared and correlated with the clinical grade of fibrosis according to LENT SOMA. RESULTS: All CT measurements (216 ROI, 18 ROI per patient) showed higher density levels on the irradiated side than on the non-irradiated side. The average density on the irradiated side was -57.7 +/- 4.7 HU and on the non-irradiated side -69.4 +/- 5.8 HU (p = 0.002). In 3/12 patients a clinical fibrosis was not seen; however, the relative density measured on the irradiated and non-irradiated side deviated by up to 8%. This could have been caused by minimal changes not being noticed by either patient and examiner. In patients with determined fibrosis Grade 1 (8/12) the relative density deviation was 4 to 39%. In 1/12 patients with determined fibrosis Grade 2 the relative density deviation was 50% (Figures 1a and 1b). Fibrosis Grade 3 and 4 did not occur (Table 1). CONCLUSIONS: Fibrosis is correlated with an increasing value of HU of the tissue density in CT. With the described method it is possible to graduate radiation induced subcutaneous fibrosis in correlation to the clinical fibrosis grade according to LENT SOMA. In the patients we examined subcutaneous fibroses after photon/neutron therapy were moderate. Especially in characterising subclinical or slight changes of connective tissue after radiotherapy computed tomography is of value.

Absorptiometry, Photon↗
PubMed1999

Fractionation sensitivities and dose-control relations of head and neck carcinomas: analysis of the randomized hyperfractionation trials.

PURPOSE: A therapeutic benefit can be achieved by hyperfractionation (HF) if tumours have small fractionation sensitivities characterized by alpha/beta values greater than those for late effects of dose limiting normal tissues. It is the purpose of the present paper to estimate alpha/beta values for head and neck carcinomas from randomized HF trials. MATERIALS AND METHODS: Maximum likelihood estimates the alpha/beta ratio were obtained from tumour control data from the randomized HF trials using the LQ model and a logit or probit type dose-response curve. A joint analysis of five randomized HF trials for head and neck carcinomas was performed to estimate overall alpha/beta and gamma50 values for tumour control. In addition, alpha/beta ratios for the individual trials were estimated using fixed gamma50 values (characteristic quantifying the steepness of dose-response curves) between 1.4 and 5 for tumours. RESULTS: An overall gamma50 of 3.1 (1.5-4.7) was estimated for the dose-tumour control relation from the HF trials, assuming a logit or probit dose-response curve. The tumours showed small fractionation sensitivities characterized by an overall alpha/beta of 10.5 (6.5-29) Gy. One trial allowed quantitative estimation of the alpha/beta values for late normal tissue damage: The alpha/beta estimate for late effects of grade 2 + was 4.0 (3.3-5.0) Gy, assuming a fixed gamma50 of 5 and was even smaller for smaller gamma50 values. CONCLUSION: Head and neck carcinomas showed small fractionation sensitivities with alpha/beta values greater than those typical for bone, soft tissues, and skin, as well as steep dose response curves. Thus, important prerequisites for improving the therapeutic benefit of radiotherapy of head and neck carcinomas by HF are fulfilled for patients who met the accession criteria of the trials.

Algorithms↗
PubMed1999

Tumour oxygenation during fractionated radiotherapy--comparison with size-matched controls.

The effect of fractionated irradiation on the oxygenation status of experimental tumours was investigated using polarographic assessment of the pO2 distribution. Since an improvement in tumour oxygenation could simply be the result of tumour shrinkage, a comparison of pO2 readings of untreated size-matched control tumours was performed. Irradiation was carried out using 6 fractions of 6 Gy applied within 11 days. A comparison of polarographic pO2 data with size-matched untreated tumours revealed a significant improvement in oxygenation after the irradiation. The median pO2 was 0.9+/-0.1 mm Hg for unirradiated tumours at a volume of 180 mm3, while the corresponding data for irradiated tumours of comparable size were 2.3+/-0.5 mm Hg on day 21 and 4.8+/-0.9 mm Hg on day 28 after start of irradiation. From these results it can be concluded that the improvement of oxygenation after fractionated irradiation is not solely the result of a reduced tumour volume.

Animals↗
PubMed1999

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

Adult↗
PubMed1998

[Radiotherapy of follicle center lymphoma. Results of a German multicenter and prospective study. Members of the Study Group "NHL-early stages"].

PURPOSE: Follicle centre lymphoma grade I, II (REAL) or centroblastic-centrocytic lymphoma (Kiel classification) present a well defined clinical entity from a clinical point of view. These lymphomas are not curable by chemotherapy in early or advanced stages. They are treated by radiation therapy in early stages, but up to now the curative potency of radiotherapy has not been confirmed by prospective clinical trials. PATIENTS AND METHODS: Between January 1986 and August 1993 117 adults with follicle centre lymphoma were recruited from 24 institutions to enter the multicentric prospective, not randomised clinical trial. Patients with histologically proven nodal follicle centre lymphoma of stages I, II and limited III were included. They were treated by a standardised radiotherapy regimen, in stage I by extended field and in stages II and III by total nodal irradiation. Dose per fraction was 1.8 to 2.0 Gy, in the abdominal bath 1.5 Gy up to a total dose of 26 Gy in adjuvant situation and 36 Gy to enlarged lymphoma. RESULTS: All patients developed a complete remission at the end of radiotherapy. Median follow-up is 68 months. Overall survival of all patients in 86 +/- 3% at 5 and 8 years. Stage adjusted survival at 5 and 8 years was 89% for stage I, 86% for stage II and 81% for III. Patients in stages I and II < 60 years had survival rates of 94% at 5 and 8 years, patients > 60 years 63% (p < 0.0001). Recurrence free survival of all patients is 70% at 5 and 60 +/- 5% at 8 years. The number of recurrences is high with 29% at 5 and 41% at 8 years. All recurrences were seen within 7 years. The probability of localised nodal in-field recurrences is 11% and 22% at 5 and 8 years, respectively. Adverse prognostic factors were identified by multivariate analysis: age > 60 years, treatment breaks > or = 7 days and dose deviations > 20% from prescribed doses. Acute side effects of extended field irradiation were moderate. CONCLUSIONS: On the basis of these results radiotherapy is a potentially curative therapeutic approach in stages I, II and limited III of follicle centre lymphoma. The optimal technique is total lymphoid irradiation with doses of 30 Gy in the adjuvant situation and 40 to 44 Gy in enlarged lymphomas. The number of local recurrences leads to the assumption, that the extension of radiotherapy to the total lymphoid system might reduce their frequency.

Adult↗
PubMed1998

[Hyperfractionated accelerated simultaneous radiochemotherapy in advanced hypopharyngeal carcinomas. Survival rate, retained function quality of life in a phase II study].

Forty-one patients with locally advanced hypopharyngeal carcinomas were followed for at least 3 years (median, 60 months) after simultaneous radiochemotherapy. Conventionally fractionated radiotherapy was administered as 5 x 2 Gy/week to a total dose of 30 Gy within 3 weeks. From the fourth week an accelerated hyperfractionated schedule was used as 2 x 1.4 Gy/day five days weekly given exclusively to the first order target volume of macroscopic tumor (adding up to a total dose of 72 Gy in six weeks). The second and third order target volumes received conventional fractionation only to 60 Gy and 50 Gy, respectively. The moderate acceleration of the concomitant boost scheme in the second half was counterbalanced during the first week by the introduction of a 5-fluorouracil bolus of 350 mg/M2 with 200 mg/M2 folinic acid and a subsequent continuous infusion using the same dose each 24 h for 5 days. Additionally, a Mitomycin-C bolus of 10 mg/M2 was infused at the fifth day and on the first day of the sixth week. Six weeks after treatment the patients were restaged. In cases with residual carcinoma salvage surgery was performed (11 patients). Late effects of therapy were analyzed according to the Lent-Soma index and life quality according to the European Organisation for Research and Treatment of Cancer-Module. Late effects of treatment were tolerable and were controlled locally. The 3-year-survival rate was 39%, with a local-regional recurrence-free control rate of 71%. Fifty-two percent of all cases of death were caused by distant metastases, secondary carcinomas or other diseases not related to tumor recurrence. The poor prognosis of hypopharyngeal carcinomas despite acceptable local tumor control may be due to specific biological factors present in affected patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

The effect of combined nicotinamide and carbogen treatments in human tumour xenografts: oxygenation and tumour control studies.

BACKGROUND AND PURPOSE: This was an investigation to study the effect of giving carbogen and nicotinamide (CON) on pO2 and the radiation response of human xenografted tumours. MATERIALS AND METHODS: The human xenografts were two sarcomas (ENE2 and ES3) and a glioblastoma (HTZ17). Nicotinamide (500 mg/ kg, i.p.) was administered 60 min before PO2 measurements and irradiation, while carbogen was given for 5 min before and during these treatments. Tumour pO2 was measured with an Eppendorf electrode and radiation response was assessed by local tumour control following irradiation with 10 daily fractions. RESULTS: All three xenografts were found to be poorly oxygenated (about 80% of all pO2 values were < or =2.5 mmHg). CON treatment improved the oxygenation status in all three tumours such that 65, 52 and 71% of the pO2 values were < or =2.5 mmHg in ENE2, ES3 and HTZ17, respectively. However, only in ES3 was this decrease significant. The TCD50 doses for all tumours were around 52-54 Gy. No significant improvement was seen with CON in ENE2 (TCD50 = 48 Gy) and HTZ17 (TCD50 = 56 Gy), but for the ES3 xenograft a significant decrease to 42 Gy was found. CONCLUSIONS: The three tumours used in this study appeared to show the same level of hypoxia as measured both by pO2 and radiation response. However, only one tumour showed a significant improvement after CON treatment, suggesting that not all hypoxic human tumours might benefit from this type of therapy.

Administration, Inhalation↗
PubMed1998

Pre-operative sequential chemo- and radiochemotherapy in locally advanced carcinomas of the lower oesophagus and gastro-oesophageal junction.

The purpose of this trial was to examine the feasibility of intensive, sequential chemo- and radiochemotherapy followed by surgery in patients with locally advanced carcinomas of the lower oesophagus and the gastro-oesophageal junction (GO junction). The chemotherapy consisted of two courses of 6 weekly administrations of 5-fluorouracil (5-FU) (2.0 g/m2, 24 h infusion) and folinic acid (FA) (500 mg/m2, 2 h infusion) combined with twice weekly cisplatin (50 mg/m2, 1 h infusion). Irradiation of 30 Gy was given concurrently with one course of cisplatin and etoposide. 25 patients with locally advanced (T3-T4 NX M0) squamous cell or adenocarcinoma of the lower oesophagus and GO junction were included and evaluated. Toxicity was usually mild to moderate (WHO grade 1 and 2) with mucositis as the most important side-effect of the pre-operative treatment. Of the patients, 94 and 88% completed the chemo- and radiochemotherapy according to the protocol, respectively. A major response (= partial remission with subjective improvement) to chemotherapy was achieved in 6/10 patients with squamous cell carcinoma and 10/15 with adenocarcinoma. 19 patients had subsequent surgery and complete resection was achieved in 16 (3 patients had intra-abdominal metastases observed at laparotomy). The operative mortality rate was 16% (3/19). 10 of the 16 patients with tumour resection had a pathological complete response. 15 patients (43%) remain alive at a median follow-up of 20 months and the median survival exceeds 16+ months. Our data suggest that this intensive pre-operative chemoradiotherapy programme is feasible and remarkably effective in patients with locally advanced carcinomas of the lower oesophagus or GO junction.

Adenocarcinoma↗
PubMed1998

Experimental studies on the possible influence of invasive oxygen measurements on tumour radiosensitivity.

The effects of tissue damage associated with invasive pO2 measurements on radiation sensitivity were investigated using a xenografted squamous cell carcinoma model. For the tumour cure experiments, single dose irradiations were given following different regimens of polarographic pO2 measurements associated with different degrees of mechanical tissue damage. With a dose of 32 Gy, 57% of animals were cured. Following 3 tracks of needle measurements, 73% of tumours were locally controlled, and 75% were cured after 8 needle tracks. The polarographic measurements gave virtually identical oxygenation data for recurrent or cured tumours (both median pO2 1.0 mmHg), respectively. There was thus no evidence of decreased radiosensitivity associated with tissue damage after invasive pO2 measurements. The pre-therapeutic oxygenation status gave no evidence for a prediction of radiation response on an individual basis.

Animals↗
PubMed1998

Repair of ionizing radiation induced DNA double-strand breaks (dsb) at the c-myc locus in comparison to the overall genome.

PURPOSE: The aim of this study was to determine the repair of radiation-induced DNA double-strand breaks (dsb) in actively transcribed regions and in the overall genome. MATERIALS AND METHODS: Pulsed-field gel electrophoresis was performed on Sfi I restriction enzyme digested DNA, labelled with a c-myc probe and on non-specifically 14C-labelled DNA of the adenocarcinoma cell line COLO320HSR after 400 Gy irradiation with 7 MeV electrons and repair incubation. RESULTS: At the 130 kbp c-myc locus 68 +/- 5% of all dsb induced at a dose of 400 Gy were repaired by a fast mechanism with a repair half time of 9.4 +/- 3.2 min in comparison to the overall genome where all dsb induced at 400 Gy were repaired with a half time of 86 +/- 23 min. The fraction of residual dsb was about 30% higher in the c-myc locus than in the overall genome. CONCLUSIONS: This study demonstrates intragenomic heterogeneity in half times of dsb repair with faster repair at the c-myc locus. In addition, differences in the residual dsb were found to represent region specific heterogeneity in residual damage or to possibly be attributed to the different assays used. The approach with gene probing can distinguish between correct and incorrect rejoining of dsb within the resolution of the experiments (< or = 20 kbp), in contrast to the assay at the overall genome.

DNA↗