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1.
Br J Cancer ; 100(2): 291-7, 2009 Jan 27.
Article in English | MEDLINE | ID: mdl-19127261

ABSTRACT

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 x 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m(-2) day(-1) x 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3-752/4-433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3-399/4-228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/therapy , Cranial Irradiation , Lung Neoplasms/therapy , Small Cell Lung Carcinoma/therapy , Topotecan/therapeutic use , Adult , Aged , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/secondary , Combined Modality Therapy , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/radiotherapy , Male , Middle Aged , Neoplasm Staging , Prognosis , Prospective Studies , Quality of Life , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/radiotherapy , Small Cell Lung Carcinoma/secondary , Survival Rate , Treatment Outcome
2.
Amino Acids ; 32(3): 373-9, 2007.
Article in English | MEDLINE | ID: mdl-17077962

ABSTRACT

OBJECTIVES: Human gliomas have a catastrophic prognosis with a median survival in the range of one year even after therapeutic treatment. Relatively high resistance towards apoptotic stimuli is the characteristic feature of malignant gliomas. Since cell cycle control has been shown to be the key mechanism controlling both apoptosis and proliferation, this study focuses on DNA damage analysis and protein expression patterns of essential cell cycle regulators P53 and P21waf1/cip1 in glioma under clinically relevant therapeutic conditions. MATERIAL AND METHODS: U87MG cell line, characterised by wild p53-phenotype relevant for the majority of primary malignant glioblastomas, was used. Glioma cells underwent either irradiation or temozolomide treatment alone, or combined radio/chemo treatment. DNA damage was analysed by the "Comet Assay". Expression rates of target proteins were analysed using "Western-Blot" technique. RESULTS AND CONCLUSIONS: "Comet Assay" demonstrated extensive DNA damage caused by temozolomide treatment alone and in combination with irradiation, correlating well with the low survival rate observed under these treatment conditions. In contrast, irradiation alone resulted in a relatively low DNA damage, correlating well with a high survival rate and indicating a poor therapeutic efficiency of irradiation alone. Unusually low up-regulation of P53 and P21waf1/cip1 expression patterns was produced by the hereby tested stressful conditions. A deficit in cell cycle control might be the clue to the high resistance of malignant glioma cells to established therapeutic approaches.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Cell Cycle/drug effects , Cell Cycle/radiation effects , Dacarbazine/analogs & derivatives , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/radiation effects , Glioma/metabolism , Glioma/therapy , Antineoplastic Agents, Alkylating/therapeutic use , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Combined Modality Therapy , Comet Assay , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Damage/drug effects , DNA Damage/radiation effects , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Glioma/pathology , Humans , Temozolomide , Tumor Suppressor Protein p53/metabolism
3.
Urology ; 61(2): 468-73, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12597983

ABSTRACT

OBJECTIVES: Despite clinical use, the radiosensitizing effect of gemcitabine (2'2'-difluorodeoxycytidine) in human transitional cell carcinoma (TCC) has not been shown to date. We investigated gemcitabine as a radiosensitizer for human TCC cells. METHODS: Monolayer cultures of RT112 (G1, p53 wild type), RT4 (G1-G2, p53 wild type), T24 (G3, p53, mutant type), and SUP (G4, p53 mutant type) cells were incubated in medium with gemcitabine. Electron beam radiation was applied alone, simultaneous, or 3, 6, 12, and 24 hours after gemcitabine. Jurkat leukemia cells were used as controls for radiation toxicity. Cell survival was determined 6, 12, 24, 48, and 72 hours after radiation by microculture tetrazolium assay. DNA damage was evaluated by flow cytometric assessment of poly(ADP-ribose) polymerase, and apoptosis was determined by terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling and flow cytometric assessment after annexin-V and propidium iodide labeling. RESULTS: In all TCC cell lines, radiation alone caused only little and insignificant growth inhibitory effects at 10 Gy. Gemcitabine alone had a dose-dependent cytotoxic and apoptosis inducing effect on all TCC cell lines independent of p53 status. Assays combining radiation with gemcitabine in different dose and time schedules demonstrated no radiosensitizing effect in TCC cells. CONCLUSIONS: Gemcitabine is effective in TCC cell lines independent of p53 status. A radiosensitizing effect could not be demonstrated. Again, p53 status was not predictive of the radioresponse in the bladder cancer cell lines. Clinical studies with gemcitabine and radiotherapy might nevertheless yield different results but should be performed with utmost caution.


Subject(s)
Carcinoma, Transitional Cell/radiotherapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Urinary Bladder Neoplasms/radiotherapy , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/genetics , Cell Division/drug effects , Cell Division/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Flow Cytometry , Genes, p53/genetics , Genes, p53/physiology , Humans , In Situ Nick-End Labeling , Mutation , Radiation-Sensitizing Agents/pharmacology , Radiotherapy Dosage , Radiotherapy, Conformal , Tumor Cells, Cultured , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Gemcitabine
4.
Pacing Clin Electrophysiol ; 6(2 Pt 2): 436-9, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6189089

ABSTRACT

The development of the carbon tip electrode and its low chronic threshold behavior are described. Compared to presently used electrode material, carbon tip electrodes result in lower chronic stimulation thresholds. In a group of 43 patients, chronic pulse generator output has been favorably reduced in association with this type of electrode. Thus the use of activated carbon tip electrodes may result in the routine implantation of low output pacemakers.


Subject(s)
Biocompatible Materials/therapeutic use , Carbon/therapeutic use , Pacemaker, Artificial , Animals , Biocompatible Materials/adverse effects , Carbon/adverse effects , Chronic Disease , Electric Conductivity , Electric Stimulation , Electrodes, Implanted , Humans , Myocardium/pathology , Platinum/therapeutic use , Surface Properties , Titanium/therapeutic use
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