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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  90. Versammlung des Vereins Rhein-Mainischer Augenärzte; 20171104-20171104; Marburg; DOC30 /20171103/
    Publication Date: 2017-11-03
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2012); 20121023-20121026; Berlin; DOCWI35-1449 /20121002/
    Publication Date: 2012-10-03
    Keywords: Weichteilsarkom ; adjuvante Therapie ; neoadjuvante Therapie ; Tumorresektion ; ddc: 610
    Language: German
    Type: conferenceObject
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  • 4
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; CANCER ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; ADVANCED SOLID TUMORS ; AGENTS ; ANGIOSTATIN ; BLOOD ; carcinoma ; CELL ; CELL LUNG-CANCER ; CELL-PROLIFERATION ; CLINICAL-TRIAL ; COMBINATION ; DOPPLER ; ENDOTHELIAL GROWTH-FACTOR ; evaluation ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MICROSCOPY ; MICROVESSEL DENSITY ; MODEL ; MODELS ; neoplasms ; PATHWAY ; PATHWAYS ; PERFUSION ; PHASE-I ; PROSTATE ; RECOMBINANT HUMAN ENDOSTATIN ; THERAPY ; TOXICITY ; tumor growth ; TYROSINE KINASE ; VITRO ; VIVO
    Abstract: The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (M), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested
    Type of Publication: Journal article published
    PubMed ID: 14695206
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  • 5
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; COMBINATION ; Germany ; human ; INHIBITION ; KINASE ; MODEL ; MODELS ; PROSTATE ; THERAPY ; TYROSINE KINASE ; VITRO ; EXPOSURE ; NEW-YORK ; DRUG ; cell line ; LINES ; radiation ; ACTIVATION ; DNA ; primary ; FLOW ; CELL-LINES ; PHOSPHORYLATION ; treatment ; ASSAY ; EFFICACY ; prostate cancer ; PROSTATE-CANCER ; CELL-LINE ; chemotherapy ; LINE ; CANCER-CELLS ; INVOLVEMENT ; STRATEGIES ; FLOW-CYTOMETRY ; TUMOR CELLS ; TUMOR-CELL-LINES ; NECK-CANCER ; alimta ; ANGIOGENESIS INHIBITION ; antiangiogenesis ; CONCURRENT ; MEDICAL PROGRESS ; MULTITARGETED ANTIFOLATE ; pemetrexed ; SU5416 ; triple combination ; XENOGRAFTS
    Abstract: Purpose: This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines. Methods and Materials: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 muM) and SU5416 (1.0 muM) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement. Results: Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelial and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells. Conclusions: Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of irradiation, chemotherapy, and angiogenesis inhibition in vitro. A potential explanation for the favorable combination would be that VEGF signaling inhibition downregulates Akt survival signaling upon activation by radiation and/or chemotherapy. The data also suggest that endothelial cell apoptosis may have an important role in the benefits of the presented therapy. (C) 2004 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 15519795
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  • 6
    Keywords: IRRADIATION ; radiotherapy ; tumor ; carcinoma ; Germany ; THERAPY ; radiation ; RADIATION-THERAPY ; COLORECTAL-CANCER ; RECURRENT ; ONCOLOGY ; THERAPIES ; IORT
    Abstract: CONTROVERSIES IN GASTROINTESTINAL TUMOR THERAPY
    Type of Publication: Journal article published
    PubMed ID: 15458187
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; IONIZING-RADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS ; BLOOD ; CELL-PROLIFERATION ; COMBINATION ; ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TOXICITY ; TYROSINE KINASE ; VITRO ; imaging ; MICE ; radiation ; PHOSPHORYLATION ; TYROSINE KINASE INHIBITOR ; MAGNETIC-RESONANCE ; MOLECULE ; magnetic resonance imaging ; CELL-SURVIVAL ; ASSAY ; COLORECTAL-CANCER ; chemotherapy ; MIGRATION ; STRATEGIES ; RANDOMIZED-TRIAL ; AKT ; REGIMENS ; signaling ; FACTOR RECEPTORS ; SINGLE ; molecular ; RE ; MULTITARGETED ANTIFOLATE ; TUMOR-GROWTH ; cancer therapy ; endothelial cells ; BLOOD-VESSELS ; normalization ; cell proliferation ; TYROSINE KINASES ; ionizing radiation ; TUMOR VASCULATURE ; ASSAYS ; KINASES ; COMBINED THERAPY ; PEMETREXED DISODIUM
    Abstract: It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G, and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/ chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy
    Type of Publication: Journal article published
    PubMed ID: 15867359
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  • 8
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; KINASE ; MODEL ; MODELS ; THERAPY ; TOXICITY ; TYROSINE KINASE ; VITRO ; VIVO ; VOLUME ; DRUG ; TUMORS ; MICE ; radiation ; REDUCTION ; SKIN ; treatment ; ALPHA ; MOUSE ; MALIGNANCIES ; ASSAY ; leukemia ; DIET ; RECEPTORS ; BEHAVIOR ; CHRONIC MYELOGENOUS LEUKEMIA ; imatinib ; TUMOR CELLS ; radiosensitivity ; MALIGNANCY ; RE ; CONCURRENT ; TUMOR-GROWTH ; WEIGHT ; cell proliferation ; IMATINIB MESYLATE ; KINASE INHIBITORS ; TUMOR-CELL ; ASSAYS ; function ; STI571 ; CANCER-TREATMENT ; in vivo ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; MONOTHERAPY ; Gleevec (R) ; GROWTH-FACTOR RECEPTORS
    Abstract: Background and Purpose: Imatinib (Gleevec (R), GLivec (R)) is an inhibitor of alpha- add beta-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here. Material and Methods: In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothetial cells) were treated with imatinib atone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0-10 Gy). In vivo, U87 and A431 cells (5 x 101) were subcutaneously injected into hind Limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400-500 mm(3). Tumors were treated with 5 x 5 Gy (U87) or 6 x 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed. Results: In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior. Conclusion: Imatinib (GLeevec (R)), a "molecular targeted" approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination
    Type of Publication: Journal article published
    PubMed ID: 16826359
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  • 9
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    Abstract: PURPOSE: We analyzed our experience with intraoperative electron radiotherapy (IOERT) followed by moderate doses of external beam radiotherapy (EBRT) after organ-sparing surgery in patients with primary or recurrent aggressive fibromatosis. METHODS AND MATERIALS: Indication for IOERT and postoperative EBRT as an individual treatment approach to avoid mutilating surgical procedures was seen when complete surgical removal seemed to be unlikely or impossible. A total of 31 lesions in 30 patients were treated by surgery and IOERT with a median dose of 12 Gy. Median age was 31 years (range, 13-59 years). Resection status was close margin in six lesions, microscopically positive in 13, and macroscopically positive in 12. Median tumor size was 9 cm. In all, 25 patients received additional EBRT, with a median dose of 45 Gy (range, 36-54 Gy). RESULTS: After a median follow-up of 32 months (range, 3-139 months), no disease-related deaths occurred. A total of five local recurrences were seen, resulting in actuarial 3-year local control rates of 82% overall and 91% inside the IOERT areas. Trends to improved local control were seen for older age (〉31 years) and negative margins, but none of these factors reached significance. Perioperative complications were found in six patients, in particular as wound healing disturbances in five patients and venous thrombosis in one patient. Late toxicity was seen in five patients. CONCLUSION: Introduction of IOERT into a multimodal treatment approach in patients with aggressive fibromatosis is feasible with low toxicity and yielded good local control rates even in patients with microscopical or gross residual disease. Copyright 2010 Elsevier Inc. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 19647952
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