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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung - GMA; 20061110-20061112; Köln; DOC06gma026 /20061023/
    Publication Date: 2006-10-23
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; LUNG-CANCER ; ACTIVATION ; RADIATION-THERAPY ; chemotherapy ; SQUAMOUS-CELL CARCINOMA ; CISPLATIN ; tumor microenvironment ; HIF-1 ; GLUCOSE-METABOLISM ; UNFAVORABLE PROGNOSIS ; HUMAN TUMOR XENOGRAFT ; HIF-1-ALPHA ; Local tumor control ; Fractionated radiation ; HIF pathway inhibition ; INDUCIBLE FACTOR-1-ALPHA
    Abstract: BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy. METHODS: When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations. RESULTS: BAY-87-2243 markedly decreased nuclear HIF-1alpha expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control. CONCLUSIONS: Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.
    Type of Publication: Journal article published
    PubMed ID: 25234922
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  • 3
    Keywords: NUDE-MICE ; SQUAMOUS-CELL CARCINOMA ; NECK-CANCER ; ADVANCED HEAD ; PRECLINICAL EVALUATION ; RADIOIMMUNOTHERAPY ; FRACTIONATED-IRRADIATION ; CANCER STEM-CELLS ; Y-90-LABELED CETUXIMAB ; IBRITUMOMAB TIUXETAN
    Abstract: PURPOSE: The effect of radioimmunotherapy (RIT) using the therapeutic radionuclide Y-90 bound to the anti-EGFR antibody cetuximab combined with external beam irradiation (EBRT) (EBRIT) on permanent local tumor control in vivo was examined. METHODS: Growth delay was evaluated in three human squamous cell carcinoma models after RIT with [90Y]Y-(CHX-A''-DTPA)4-cetuximab (Y-90-cetuximab). The EBRT dose required to cure 50% of the tumors (TCD50) for EBRT alone or EBRIT was evaluated in one RIT-responder (FaDu) and one RIT-non-responder (UT-SCC-5). EGFR expression and microenvironmental parameters were evaluated in untreated tumors, bioavailability was visualized by PET using ([86Y]Y-(CHX-A''-DTPA)4-cetuximab (Y-86-cetuximab) and biodistribution using Y-90-cetuximab. RESULTS: In UT-SCC-8 and FaDu but not in UT-SCC-5 radiolabeled cetuximab led to significant tumor growth delay. TCD50 after EBRT was significantly decreased by EGFR-targeted RIT in FaDu but not in UT-SCC-5. In contrast to EGFR expression, parameters of the tumor micromilieu and in particular the Y-90-cetuximab biodistribution or Y-86-cetuximab visualization in PET correlated with the responsiveness to RIT or EBRIT. CONCLUSION: EGFR-targeted EBRIT can improve permanent local tumor control compared to EBRT alone. PET imaging of bioavailability of labeled cetuximab appears to be a suitable predictor for response to EBRIT. This theragnostic approach should be further explored for clinical translation.
    Type of Publication: Journal article published
    PubMed ID: 24440046
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  • 4
    Abstract: PURPOSE: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. METHODS AND MATERIALS: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD50) was calculated. RESULTS: BAY-84-7296 decreased nuclear HIF-1alpha expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P〈.0001) and in UT-SCC-14 (0.3% vs 19%, P〈.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD50, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD50. CONCLUSIONS: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation.
    Type of Publication: Journal article published
    PubMed ID: 24331663
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  • 5
    Keywords: CELLS ; SURVIVAL ; ELECTRON-BEAMS ; FRACTIONATED-IRRADIATION
    Abstract: BACKGROUND: The long-term aim of developing a laser based acceleration of protons and ions towards clinical application requires not only substantial technological progress, but also the radiobiological characterization of the resulting ultra-short pulsed particle beams. Recent in vitro data showed similar effects of laser-accelerated versus "conventional" protons on clonogenic cell survival. As the proton energies currently achieved by laser driven acceleration are too low to penetrate standard tumour models on mouse legs, the aim of the present work was to establish a tumour model allowing for the penetration of low energy protons (ca. 20 MeV) to further verify their effects in vivo. METHODS: KHT mouse sarcoma cells were injected subcutaneously in the right ear of NMRI (nu/nu) mice and the growing tumours were characterized with respect to growth parameters, histology and radiation response. In parallel, the laser system JETI was prepared for animal experimentation, i.e. a new irradiation setup was implemented and the laser parameters were carefully adjusted. Finally, a proof-of-principle experiment with laser accelerated electrons was performed to validate the tumour model under realistic conditions, i.e. altered environment and horizontal beam delivery. RESULTS: KHT sarcoma on mice ears showed a high take rate and continuous tumour growth after reaching a volume of ca. 5 mm(3). The first irradiation experiment using laser accelerated electrons versus 200 kV X-rays was successfully performed and tumour growth delay was evaluated. Comparable tumour growth delay was found between X-ray and laser accelerated electron irradiation. Moreover, experimental influences, like anaesthesia and positioning at JETI, were found to be negligible. CONCLUSION: A small animal tumour model suitable for the irradiation with low energy particles was established and validated at a laser based particle accelerator. Thus, the translation from in vitro to in vivo experimentation was for the first time realized allowing a broader preclinical validation of radiobiological characteristics and efficacy of laser driven particle accelerators in the future.
    Type of Publication: Journal article published
    PubMed ID: 24533586
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  • 6
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    German Medical Science; Düsseldorf, Köln
    In:  GMS Zeitschrift für Medizinische Ausbildung; VOL: 24; DOC44 /20070216/
    Publication Date: 2007-02-17
    Keywords: ddc: 610
    Language: German
    Type: article
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Zeitschrift für Medizinische Ausbildung; VOL: 26; DOC10 /20090216/
    Publication Date: 2009-02-17
    Description: Objective: The medical faculties of LMU Munich and CAU Kiel have developed a joint blended learning concept for computer-based learning and practical training of clinical skills: "CliSO - Clinical Skills Online" (http://www.cliso.org). CliSO is implemented in their core curricula with the intention to foster students' medical examination skills at the preclinical and clinical level. Methods: Both partners contributed their special competencies in the fields of case-based learning (Munich: CASUS e-learning platform) and systematic learning (Kiel: Nickels e-learning platform). The didactic concept comprises the integration of theory and practice. It combines the standardized teaching of the following three components: clinical examination and sensomotoric skills, biomedical knowledge with regard to the skills, and application of the knowledge and skills in paradigmatic cases. Clinical skills are trained and reviewed in face-to-face courses. In the e-learning environment, the well-directed combination of case-based and systematic learning together with the chosen diversity of media (video, audio, animation) facilitates situated learning as well as the intelligible presentation of clinical skills and their biomedical background. Both faculties agreed on joint learning objectives and standards. Results and prospects: It was possible to apply the concept to the different target groups at both faculties (first and second study phases) and the differently designed face-to-face courses (Kiel: students examine each other; Munich: patients are examined in addition). Evaluations and studies confirmed the success of this approach, so that a transfer of the concept to other faculties is intended.
    Description: Zielsetzung: Mit "KliFO - Klinische Fertigkeiten Online" (http://www.cliso.org) haben die Medizinischen Fakultäten der LMU München und der CAU Kiel ein gemeinsames Blended Learning-Konzept zum computergestützten Lernen und praktischen Trainieren von klinischen Untersuchungstechniken entwickelt und in Pflichtveranstaltungen der Curricula integriert. Ziele sind die Verbesserung der Vor- und Nachbereitung von Untersuchungskursen im vorklinischen und klinischen Studienabschnitt und damit einhergehend verbesserte Untersuchungsfertigkeiten der Studierenden bei den ersten Patientenkontakten. Methodik: Beide Partner brachten ihre speziellen Kompetenzen in den Bereichen fallbasiertes Lernen (München, Lernplattform CASUS) und systematisches Lernen (Kiel, Lernplattform Nickels) ein. Das didaktische Konzept beinhaltet die Integration von Theorie und Praxis. Es kombiniert die standardisierte Vermittlung der folgenden drei Komponenten: klinische Untersuchungstechniken und sensomotorische Fertigkeiten, biomedizinisches Hintergrundwissen zu den Fertigkeiten und Anwendung des Wissens und der Fertigkeiten in Fallbeispielen. Im Präsenzunterricht werden die Untersuchungstechniken geübt und reflektiert. Computerbasiert werden durch gezielte Kombination von fallbasiertem und systematischem Lernen zusammen mit einem vielfältigen Medieneinsatz (Video, Audio, Animation) situiertes Lernen gefördert, Untersuchungstechniken anschaulich dargestellt sowie Hintergrundwissen in inhaltlichem und zeitlichem Zusammenhang mit dessen Anwendung vermittelt. Beide Fakultäten haben sich auf gemeinsame Lernziele und Standards geeinigt. Ergebnisse und Ausblick: Das Konzept lässt sich auf die unterschiedlichen Zielgruppen an beiden Fakultäten (1. bzw. 2. Studienabschnitt) und die unterschiedlich gestalteten Präsenzphasen (Kiel: gegenseitige Untersuchung der Studierenden, München: zusätzlich Untersuchungen an realen Patienten) anwenden. Evaluationsergebnisse und Begleitstudien bestätigen den Erfolg dieses Konzepts, sodass nun ein Transfer von KliFO auf andere Fakultäten angestrebt wird.
    Keywords: blended learning ; physical examination ; clinical skills ; skills lab ; case based learning ; systematic learning ; Blended Learning ; körperliche Untersuchung ; klinischer Untersuchungskurs ; klinische Fertigkeiten ; fallbasiertes Lernen ; systematisches Lernen ; ddc: 610
    Language: German
    Type: article
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  14. Workshop der gmds-Arbeitsgruppe "Computerunterstützte Lehr- und Lernsysteme in der Medizin (CBT)" und des GMA-Ausschusses "Neue Medien"; 20100416-20100417; Witten; DOC10cbt33 /20100413/
    Publication Date: 2010-04-14
    Keywords: ddc: 610
    Type: conferenceObject
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung - GMA; 20071116-20071118; Hannover; DOC07gma138 /20071114/
    Publication Date: 2007-11-14
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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