Biomedical subjects

Günther Gademann

Publications and source records attributed to Günther Gademann.

9 recordsLinked to original sources

PubMed2005

Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-93)--the German Adjuvant Breast Cancer Group.

PURPOSE: To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer. METHODS: Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes. RESULTS: Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients. CONCLUSION: This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.

Aged↗

PubMed2005

Dosimetric characteristics of a new unshielded silicon diode and its application in clinical photon and electron beams.

Shielded p-silicon diodes, frequently applied in general photon-beam dosimetry, show certain imperfections when applied in the small photon fields occurring in stereotactic or intensity modulated radiotherapy (IMRT), in electron beams and in the buildup region of photon beam dose distributions. Using as a study object the shielded p-silicon diode PTW 60008, well known for its reliable performance in general photon dosimetry, we have identified these imperfections as effects of electron scattering at the metallic parts of the shielding. In order to overcome these difficulties a new, unshielded diode PTW 60012 has been designed and manufactured by PTW Freiburg. By comparison with reference detectors, such as thimble and plane-parallel ionization chambers and a diamond detector, we could show the absence of these imperfections. An excellent performance of the new unshielded diode for the special dosimetric tasks in small photon fields, electron beams and build-up regions of photon beams has been observed. The new diode also has an improved angular response. However, due to its over-response to low-energy scattered photons, its recommended range of use does not include output factor measurements in large photon fields, although this effect can be compensated by a thin auxiliary lead shield.

Biophysical Phenomena↗

PubMed2004

Characterization of the combined cellular survival effects of benzoquinone-ansamycins and ionizing radiation.

PURPOSE: Benzoquinone-ansamycins were the first compounds characterized with the ability to inhibit the function of heat shock protein 90 and its related family members. We investigated the composite effect of ionizing radiation and of these novel substances on the survival of malignant cells. METHODS: PC-3M prostate carcinoma cells were treated in vitro with increasing radiation doses in the presence or absence of Hsp90-active and Hsp90-inactive benzoquinone-ansamycins. Cytotoxicity was determined by the crystal violet dissolution assay. RESULTS: Twenty-four hour treatment with increasing geldanamycin doses (10 nM-1 microM) reduced cellular survival by 1.5 logs for all drug dose levels. Concomitant irradiation with a single fraction of 3 Gy reduced cellular survival by 2 logs, independently of drug dose. The treatment with 100 nM geldanamycin for 24 h combined with ionizing radiation (1-5 Gy) during the first hour of drug exposure reduced cellular survival by 1.5-2 logs depending on radiation-energy dose level, while no changes in cell survival were detectable with equimolar geldampicin, a benzoquinone-ansamycin known not to inhibit Hsp90. CONCLUSIONS: The inhibition of Hsp90 and the concomitant exposure to ionizing radiation decrease cellular survival of malignant cells. These data contribute to laying the foundation for the translational use of Hsp90 inhibitors in the multimodal therapy of cancer.

Animals↗

PubMed2004

Destabilization of the non-pathogenic, cellular prion-protein by a small molecular drug.

The presence of the normal cellular prion-protein (PrPc) is a prerequisite for the development of fatal, neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). We discovered a new biological activity of the well-known coumarin antibiotic novobiocin; the treatment of eukaryotic cells with novobiocin induces the rapid depletion of PrPc. This activity is shared by coumermycin A1, another coumarin with a related molecular structure. Novobiocin's effects on the prion-protein are time- and dose-dependent. No permanent damage to the treated cells was observed, which continue to proliferate after cessation of drug exposure. Most of the cellular proteins are unaffected by novobiocin treatment. Pretreatment with geldanamycin, an inhibitor of the aminoterminal ATPase of heat-shock protein 90 (Hsp90) partially antagonizes novobiocin's depletory activity. Concurrent treatment with the protease inhibitor chymostatin completely prevents PrPc loss. Here we show that the stability of the normal cellular prion-protein may be targeted pharmacologically. These findings open up a hitherto unknown avenue to the study of TSEs in general and may have therapeutic implications.

Benzoquinones↗

PubMed2003

[Induratio penis plastica].

BACKGROUND: To evaluate the benefit of radiotherapy with fast electrons in induratio penis plastica (IPP). PATIENTS AND METHODS: Within 7 years we treated 58 patients with manifested clinically induratio penis plastica. We applied single dose of 3 Gy 2-3 times weekly and a maximum dose of 24-30 Gy. Follow-up was 2 years and included documentation of subjective discomforts (induration, deviation and painful erection). RESULTS: Induration (27.6%) and deviation (24.1%) of the erected penis are little improved, but in two-third of patients (65%) with painful erection defined relief could be obtained. It could also be shown that patients with short history of symptoms had best chances for a successful treatment. Side effects were not seen. CONCLUSION: In our experience radiotherapy is not suitable for all stages of IPP. Only patients in the early stages of IPP-especially the ones who suffer from painful erection-should be considered suitable for treatment with ionising radiation.

Adult↗

PubMed2003

[Early and late effects of local high dose radiotherapy of the brain on memory and attention].

BACKGROUND: Stereotactic radiotherapy of benign tumors of the base of skull shows excellent tumor control and long survival. Aim is to study the impact of high dose radiation therapy on functions of memory and attention over time. PATIENTS AND METHODS: 21 patients (age 42 +/- 11 years) with tumors of the base of skull (meningiomas, pituitary gland adenomas) were treated by fractionated stereotactic radiotherapy (mean total dose 56.6 Gy/1.8 Gy). Comprehensive neuropsychological tests and MRI brain scans were performed before, 3, 9 and 21 months after therapy. 14 healthy volunteers were tested in parallel at baseline. In the follow-ups patients were their own controls. RESULTS: In pretreatment tests there were significantly worse test results in comparison to the control group in ten of 32 tests. In postradiation tests only few changes were found in the early-delayed period and not much difference was seen in comparison to the baseline tests. In MRI scans tumor recurrences or radiation induced changes were not found. CONCLUSION: Radiation with high local doses in target volume extremely close to sensitive brain structures like temporal lobes did not induce significant decline of cognitive functions.

Adenoma↗

PubMed2002

Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin/cyclophosphamide/docetaxel in operable breast cancer: second interim analysis.

Timing of systemic treatment in primary operable breast cancer is subject to extensive investigation, suggesting that pathologic complete remission (pCR) might improve survival in this setting. The German Adjuvant Breast Cancer Group previously demonstrated the feasibility of a dose-dense biweekly schedule of 4 cycles doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (ddAT) +/- tamoxifen in the neoadjuvant setting to yield a pCR of 9.7% (Gepardo trial). Patients assigned to ddAT received prophylactic granulocyte colony-stimulating factor support (5 micro g/kg days 5-10). The current study (GeparDUO) was designed to assess whether the pCR rate, including no viable invasive and preinvasive tumor cells, achieved with ddAT was equivalent to sequential administration of doxorubicin/cyclophosphamide followed by docetaxel (AC-DOC) over 24 weeks in primary operable breast cancer. From June 1999 to September 2001, 913 patients were enrolled in this trial. In total, 395 patients randomized before August 1, 2000, were included in the second interim analysis. Safety data were available from 369 patients (ddAT, n = 191; AC-DOC, n = 178) demonstrating that toxicity of both regimens was tolerable. Grade 3/4 neutropenia occurred in 39.8% of patients receiving ddAT and in 69.3% of patients treated with AC-DOC. Efficacy data were available in 378 patients. A pCR occurred in 14.8% of the primary breast tumors. According to the recommendations of the data monitoring committee, recruitment to the study was halted as of September 2001 (n = 913/1000) due to the significant difference in pCR rates observed between the treatment arms. Surgery was documented in 380 patients. Breast conservation was possible in 288 cases (75.8%). The application of both schedules is safe and feasible in an outpatient setting. Although, results obtained from this interim analysis are encouraging, caution is recommended until the results obtained show statistical difference in pCR.

Adult↗

PubMedDate not supplied

Effects of imatinib mesylate on adenoid cystic carcinomas.

BACKGROUND: Adenoid cystic carcinomas (ACCs) are rare tumors which most often arise in the salivary glands. They have a propensity for local relapse and tend to metastasize, frequently with a protracted clinical course. A substantial fraction of the tumors expresses c-Kit or the platelet-derived growth factor receptor beta (PDGFRbeta), both targets for imatinib mesylate. No standard systemic therapy is known for these neoplasms. PATIENTS AND METHODS: c-kit and PDGFRbeta-expression were determined by immunohistochemistry. Four patients with distant metastases and with at least one positive result were treated with 400 mg imatinib mesylate once daily and their response assessed. RESULTS: c-Kit and PDGFRbeta expressions were variable among the tumor samples. Toxicity was mild. No remissions were observed. CONCLUSION: These data support that c-Kit or PDGFRbeta expression per se are not prognostic for the therapeutic response of metastasized ACCs to imatinib mesylate.

Adult↗

PubMedDate not supplied

In vitro combined modality treatment of prostate carcinoma cells with 17-(allylamino)-17-demethoxygeldanamycin and ionizing radiation.

BACKGROUND: The effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a benzoquinone-ansamycin-type Hsp90-inhibitor, on the expression of focal adhesion kinase (FAK) and, when combined with ionizing radiation, on the clonogenicity of prostate cancer cells were determined. MATERIALS AND METHODS: FAK was analyzed by Western immunoblot. Prostate carcinoma cells were exposed either to 17-AAG alone or combined with a single radiation fraction of 3 Gy. RESULTS: FAK concentrations were reduced by 17-AAG in a time-dependent manner. Treatment with 100 nM 17-AAG for 24 h reduced clonogenicity by 90%. The plot of surviving fraction versus radiation energy dose yielded roughly parallel graphs for solvent- and 17-AAG-treated cells. CONCLUSION: 17-AAG induced rapid degradation of FAK A single radiation fraction of 3 Gy did not enhance the dose-dependent drug-effect on survival. In this sequence, the combined effect of both modalities towards clonogenicity was largely additive.

Benzoquinones↗