Peter Geyer

Patient position reproducibility in fractionated stereotactically guided conformal radiotherapy using the BrainLab mask system.

Purpose: Dedicated mask systems nowadays allow the use of stereotactic radiotherapy in fractionated regimes, therefore combining the advantages of high precision radiotherapy with the biological benefit of fractionation. Therefore the knowledge of institution specific isocenter accuracy is essential for decision-making about margins to be allowed to form the planning target volume. Patients and Methods: Measurements of isocenter deviations during fractionated treatments were performed in 33 patients using the simulator Simulix-xy (Oldelft) in connection with the BrainLab® angiographic localizer-box as well as port-films. In both cases repeated images were overlaid by use of anatomical landmarks with a methodical accuracy in the order of 0.5 mm. Results: Both methods yield random isocenter deviations of less then 2 mm (standard deviation) in all three directions and no significant systematic deviations. These values are in the order of the accuracy of the method, obtained by comparison of two independent investigators, as well as they are comparable with the literature. Conclusions: The accuracy of less than 2 mm indicates safety margins of 3–4 mm as sufficient for clinical routine to cover the target in 95.5% of all set-ups (2 SD).Ziel: Spezielle Maskensysteme erlauben heutzutage die Anwendung der stereotaktischen Strahlentherapie in fraktionierten Regimes und damit die Kombination der Vorteile der Hochpräzisionsbestrahlung mit dem biologischen Nutzen der Fraktionierung. Deshalb ist die Kenntnis der institutsspezifischen Genauigkeit der Isozentrumseinstellung eine notwendige Voraussetzung für die Entscheidung über die erforderlichen Sicherheitsabstände. Patienten und Methode: Die Messung der Isozentrumsgenauigkeit erfolgte bei 33 Patienten sowohl durch Simulatorkontrollen in Verbindung mit der BrainLab®-Localizer-Box oder durch Verifikation mit Portfilmen. In beiden Fällen wurden die Filme anhand anatomischer Lankdmarken mit einer methodischen Sicherheit von unter 0,5 mm überlagert. Ergebnisse: Beide Methoden zeigten zufällige Isozentrumsabweichungen von weniger als 2 mm (Standardabweichung) in allen drei Raumebenen (Abbildung 1, Tabelle 2) und keine signifikanten systematischen Abweichungen. Damit liegen die Ergebnisse im Bereich der methodischen Genauigkeit, wie durch den Vergleich der Befunde zweier unabhängiger Untersucher gezeigt wird (Tabelle 1), und sind mit Literaturdaten gut vergleichbar. Schlussfolgerung: Die Genauigkeit von unter 2 mm zeigt, dass ein Sicherheitsabstand von 3–4 mm für die klinische Routine ausreichend ist, um bei 95,5% der Einstellung die sichere Erfassung des Targets zu garantieren.

Enhanced Susceptibility of Irradiated Tumor Vessels to Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibition

Previous experiments with PTK787/ZK222584, a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, using irradiated human FaDu squamous cell carcinoma in nude mice, suggested that radiation-damaged tumor vessels are more sensitive to VEGFR inhibition. To test this hypothesis, the tumor transplantation site (i.e., the right hind leg of nude mice) was irradiated 10 days before transplantation of FaDu to induce radiation damage in the host tissue. FaDu tumors vascularized by radiation-damaged blood vessels appeared later, grew at a slower rate, and showed more necrosis and a smaller vessel area per central tumor section than controls. PTK787/ZK222584 at a daily dose of 50 mg/kg body weight had no impact on growth of control tumors. In contrast, tumors vascularized by radiation-damaged vessels responded to PTK787/ZK222584 with longer latency and slower growth rate than controls, and a trend toward further increase in necrosis, indicating that irradiated tumor vessels are more susceptible to VEGFR inhibition than unirradiated vessels. Although not proving causality, expression analysis of VEGF and VEGFR2 shows that enhanced sensitivity of irradiated vessels to a specific inhibitor of VEGFR tyrosine kinases correlates with increased expression of the molecular target.

Triple angiokinase inhibition, tumour hypoxia and radiation response of FaDu human squamous cell carcinomas

BACKGROUND AND PURPOSE To test the effect of BIBF 1120, a novel small molecule inhibitor of multiple angiogenic receptor tyrosine kinases, on the hypoxia and radiation response of tumours. MATERIALS AND METHODS Poorly differentiated human squamous cell carcinoma FaDu growing in nude mice was treated with BIBF 1120 and investigated by functional histology. To test the effect of BIBF 1120 on the radiobiological hypoxic fraction (rHF), the number and intrinsic radiation sensitivity of tumour stem cells and the outcome after fractionated irradiation, a series of local tumour control assays were performed. RESULTS BIBF 1120 significantly reduced the vessel area, vessel area with a perfusion signal and tumour growth rate but did not affect tumour hypoxia or the number and intrinsic radiation sensitivity of tumour stem cells. Concurrent BIBF 1120 had no effect on local tumour control after fractionated irradiation. CONCLUSION Triple angiokinase inhibition resulted in a clear-cut decrease of angiogenesis, vessel area with a perfusion signal and tumour growth but did not change tumour hypoxia or radiation response of tumour stem cells. Further experiments into mechanisms of interaction between anti-angiogenic strategies and irradiation appear to be necessary to better define and exploit the potential of this strategy to improve local tumour control after fractionated radiotherapy.

Filmless evaluation of the mechanical accuracy of the isocenter in stereotactic radiotherapy.

Background and Purpose:The Winston-Lutz test verifies the mechanical accuracy of the isocenter in stereotactic radiotherapy. A lead ball inside a small beam is exposed to film applying different combinations of the gantry angle and the table angle. The increasing replacement of films by digital images requires alternative imaging methods. The suitability of two different electronic portal imaging systems and of a system based on digital luminescence radiography was investigated.Material and Methods:The imaging systems included the portal imaging devices BEAMVIEW PLUS® and OPTIVUE®1000 (both Siemens Medical Solutions, Erlangen, Germany) and the luminescence system KODAK ACR 2000 RT (Eastman Kodak Comp., Rochester, NY, USA). 6-MV photons from the linear accelerators PRIMUS® and ONCOR® (both Siemens Medical Solutions) were applied. First, only the small beam covering the lead ball was exposed. Second, an additional bigger open beam part in a certain distance to the small beam was applied.Results:For all three investigated imaging systems, which are using preprocessing imaging software, only for the beam arrangement with additional open beam parts, the lead ball could be detected inside the small beam. Only for the application of a dosimetric software tool to the luminescence system, the metal ball inside the small beam became visible without an additional open beam part.Conclusion:Applying the proposed beam arrangements, the Winston-Lutz test can be done by digital and filmless imaging systems, thereby saving time as well.Hintergrund und Ziel:Der Winston-Lutz-Test verifiziert die mechanische Genauigkeit des Isozentrums in der stereotaktischen Strahlentherapie. Abbildungen einer Bleikugel innerhalb eines kleinen Bestrahlungsfeldes erfolgen für verschiedene Gantry- und Tischwinkelkombinationen auf Film. Die zunehmende Abkehr von der Filmanwendung erfordert den Einsatz alternativer bildgebender Verfahren für diesen Test. Die Eignung zweier verschiedener elektronischer Portal-Imaging-Systeme und eines Systems der digitalen Lumineszenzradiographie wurde untersucht.Material und Methodik:Als bildgebende Systeme wurden die Portal-Imaging-Systeme BEAMVIEW PLUS® und OPTIVUE®1000 (beide Siemens Medical Solutions, Erlangen) und das Lumineszenzsystem KODAK ACR 2000 RT (Eastman Kodak Comp., Rochester, NY, USA) eingesetzt. Die Bestrahlung erfolgte mit 6-MV-Photonen an den Linearbeschleunigern PRIMUS® und ONCOR® (beide Siemens Medical Solutions). Die Belichtungen für die untersuchten Systeme erfolgten zum einen nur mit dem sehr kleinen Feld, das die abzubildende Metallkugel enthält. Zum anderen wurden in räumlicher Trennung zu diesem kleinen Feld zusätzliche und deutlich größere Feldanteile aufbelichtet.Ergebnisse:Für die drei untersuchten bildgebenden Systeme und die Bildsoftware mit unbeeinflussbarer Vorbearbeitung war nur bei den Feldanordnungen mit zusätzlichen offenen Feldbereichen eine Detektion der Kugel innerhalb des umgebenden kleinen Feldes möglich. Allein eine Dosimetriesoftware für das System der Lumineszenzradiographie erlaubte die Erkennung der Kugel innerhalb des kleinen Feldes ohne zusätzliche offene Feldteile.Schlussfolgerung:Die vorgeschlagenen Feldanordnungen erlauben die Durchführung des Winston-Lutz-Tests mit digitalen, filmlosen Bildsystemen. Damit kann der Test auch in kürzerer Zeit durchgeführt werden.

Fractionation Effect on Radiation-Induced Growth Retardation of Tibia in Rabbits and Rats

A study of the sensitivity to fractionation of the growing tibia of rabbits and rats was conducted by comparing the growth of the treated right bone to that of the untreated left side in each individual animal using radiographic measurements. The experimental endpoint was the percentage of normal growth 24 weeks after irradiation in rabbits and 14 weeks after treatment in rats. The results show clear dose-response relationships in all experimental arms. A clear-cut fractionation effect was demonstrated in both species. The alpha/beta-ratios determined by maximum likelihood analysis according to the LQ-model with graded responses were 3.2 Gy (95% C.I. 1.1; 5.6) in rabbits and 6.9 Gy (5.3; 8.7) in rats, when all data were included in the calculations. When single-dose data were excluded the alpha/beta-values were -0.6 Gy (-3.1; 2.3) in rabbits and 5.0 Gy (3.5; 7.0) in rats. Our data provide further evidence that low doses per fraction should be used when irradiation of the epiphysis cannot be avoided in pediatric patients.

Inactivation of AP1 Proteins by a Nuclear Serine Protease Precedes the Onset of Radiation-Induced Fibrosing Alveolitis1

Abstract Haase, M. G., Klawitter, A., Bierhaus, A., Yokoyama, K. K., Kasper, M., Geyer, P., Baumann, M. and Baretton, G. B. Inactivation of AP1 Proteins by a Nuclear Serine Protease Precedes the Onset of Radiation-Induced Fibrosing Alveolitis. Radiat. Res. 169, 531–542 (2008). Radiation-induced lung damage comprises inflammation (alveolitis) as well as disturbed regulation of cell differentiation and proliferation (fibrosis). The transcriptional regulation of this process is poorly understood. One key transcription factor involved in the regulation of proliferation and differentiation is AP1 (activator protein 1). The present study examined changes in the DNA-binding activity of AP1 after irradiation and defined the underlying molecular mechanisms in an animal model. The right lungs of Fischer rats received a single radiation dose of 20 Gy. Lung tissue was tested for AP1 DNA-binding activity, AP1 mRNA, and levels of AP1 proteins as well as for c-Jun specific proteolytic activity. After an initial increase, the AP1 DNA-binding activity was completely lost starting at 5.5 weeks after irradiation, which is 2.5 weeks before the onset of fibrosing alveolitis. This was not caused by reduction of mRNA levels or size. Instead, a selective nuclear cleavage of c-Jun by a serine protease caused the loss of AP1 activity. Considering the central role of AP1 in cell proliferation and differentiation and the strict timely correlation to the onset of the disease, the complete loss of AP1 function is likely to play a critical role in radiation-induced fibrosing alveolitis.

Expression of the Immunomodulator IL-10 in Type I Pneumocytes of the Rat: Alterations of IL-10 Expression in Radiation-induced Lung Damage

Fibrosing alveolitis is a disease with inflammatory, proliferative, and fibrotic components. In different models, it has been shown that the cytokine interleukin-10 (IL-10) plays a conflicting role in inflammation-associated fibrotic processes, inasmuch as it is an antiinflammatory cytokine but also a TH2 cytokine with inherent pro-fibrotic effects. IL-10 is produced primarily by inflammatory cells. In this report, we show in a rat model of radiation-induced fibrosing alveolitis that IL-10 is also produced by type I alveolar epithelial cells in both normal and fibrotic lungs. The total amount of IL-10 in the lung is increased after irradiation, but type I pneumoyctes contain less IL-10. The R3/1 permanent type I pneumocyte cell line also contains IL-10, which is reduced after irradiation. Whereas in the normal lung, the entire alveolar surface is covered by IL-10—producing pneumocytes, this continuity is interrupted in fibrotic lungs, because type I pneumocytes lack full differentiation and thus full spreading over the alveolar surface. The exposure of the IL-10—negative epithelial basal membrane may allow for an easier attachment of inflammatory cells such as alveolar macrophages. These cells have the potential to act in a pro-inflammatory way by tumor necrosis factor α and also in a pro-fibrotic way by activating TH2 cytokines.

Portal Verification Using the KODAK ACR 2000 RT Storage Phosphor Plate System and EC® Films

Background and Purpose:The suitability of the storage phosphor plate system ACR 2000 RT (Eastman Kodak Corp., Rochester, MN, USA), that is destined for portal verification as well as for portal simulation imaging in radiotherapy, had to be proven by the comparison with a highly sensitive verification film.Material and Methods:The comparison included portal verification images of different regions (head and neck, thorax, abdomen, and pelvis) irradiated with 6- and 15-MV photons and electrons. Each portal verification image was done at the storage screen and the EC® film as well, using the EC-L® cassettes (both: Eastman Kodak Corp., Rochester, MN, USA) for both systems. The soft-tissue and bony contrast and the brightness were evaluated and compared in a ranking of the two compared images. Different phantoms were irradiated to investigate the high- and low-contrast resolution. To account for quality assurance application, the short-time exposure of the unpacked and irradiated storage screen by green and red room lasers was also investigated.Results:In general, the quality of the processed ACR images was slightly higher than that of the films, mostly due to cases of an insufficient exposure to the film. The storage screen was able to verify electron portals even for low electron energies with only minor photon contamination. The laser lines were sharply and clearly visible on the ACR images.Conclusion:The ACR system may replace the film without any noticeable decrease in image quality thereby reducing processing time and saving the costs of films and avoiding incorrect exposures.Hintergrund und Ziel:Die Eignung des Speicherfoliensystems ACR 2000 RT (Eastman Kodak Corp., Rochester, MN, USA), das sowohl für die Feldverifikation als auch für die Therapiesimulation bestimmt ist, sollte durch den Vergleich mit einem hochempfindlichen Verifikationsfilm untersucht werden.Material und Methodik:Der Vergleich beinhaltete Verifikationsaufnahmen verschiedener Körperregionen (Kopf-Hals-Region, Thorax, Abdomen und Becken), die mit 6- und 15-MV-Photonenstrahlung und Elektronen angefertigt wurden. Jedes Feld wurde sowohl mittels Speicherfolie als auch mit dem EC®-Film abgebildet, wobei stets die EC®-L-Kassette (beide: Eastman Kodak Corp., Rochester, MN, USA) eingesetzt wurde. Der Weichteilkontrast und die Darstellung knöcherner Strukturen sowie die Bildhelligkeit wurden bewertet und in einem Ranking der zwei Bilder verglichen. Verschiedene Phantome wurden abgebildet, um die Hoch- und Niedrigkontrastauflösung zu ermitteln. Für Qualitätssicherungsaufgaben wurde die Kurzzeitbelichtung der bestrahlten, unverpackten Folie mit grünen und roten Raumlasern untersucht.Ergebnisse:Insgesamt wurde die Abbildungsqualität der bearbeiteten ACR-Aufnahmen geringfügig besser bewertet als die der Filme, was meist in einer nicht optimalen Filmbelichtung begründet war. Die Speicherfolie konnte Elektronenportale selbst bei niedrigen Elektronenenergien mit nur geringer Photonenkontamination abbilden. Die Laserlinien wurden scharf und klar erkennbar auf den ACR-Aufnahmen sichtbar.Schlussfolgerung:Das ACR-System kann den Verifikationsfilm ohne wesentliche Qualitätseinbußen ablösen und damit zugleich Arbeitszeit und Filmkosten sparen sowie Fehlbelichtungen vermeiden.

Portal Verification of High-Energy Electron Beams Using their Photon Contamination by Film-Cassette Systems

Background and Purpose:Though electron beams are widely used in radiotherapy, their verification is not well established in clinical practice. The present study compares the suitability of several sensitive film-cassette systems for electron-portal verification by contaminating photons.Material and Methods:The characteristics of the optical density curves of film-cassette combinations were determined by exposing them to the bremsstrahlung contamination of a variety of electron beams. Using a Las-Vegas Phantom the spatial low-contrast resolution of the combinations was investigated. The absorbed dose rates due to the contaminant photons were measured for different geometric conditions.Results:Suitable film-cassette combinations were found for portal verification of all usual electron energies. The best image quality was obtained using the EC® film and the EC-L® cassettes (Eastman Kodak Comp., Rochester, NY, USA). For electron energies higher than 6 MeV some film-cassette combinations are suitable to verify abutted electron and photon portals using the same film sheet.Conclusion:The verification of electron portals and of abutted electron-photon portals can be performed by sensitive film-cassette systems with an image quality comparable to photon-beam verification.Hintergrund und Ziel:Obwohl Elektronenfelder in der Strahlentherapie breite Anwendung finden, ist ihre Verifikation in der klinischen Praxis noch wenig verbreitet. Die dargestellten Untersuchungen vergleichen die Eignung verschiedener empfindlicher Film-Kassetten-Systeme zur Verifikation der Elektronenfeldform mittels deren Photonenkontamination.Material und Methodik:Die Charakteristika der Verläufe der optischen Dichte der Film-Kassetten-Kombinationen wurden durch Bestrahlung mit der Bremsstrahlungskomponente verschiedener Elektronenfelder ermittelt. Die Niedrigkontrastauflösung der Kombinationen wurde mit einem Las-Vegas-Phantom untersucht. Die Energiedosisleistungen der Photonenkontamination wurden für verschiedene Bestrahlungsgeometrien gemessen.Ergebnisse:Für die Verifikation der Feldportale aller therapeutisch genutzten Elektronenenergien wurden geeignete Film-Kassetten-Kombinationen gefunden. Die höchste Abbildungsqualität wiesen der EC®-Film und die EC-L®-Kassetten (Eastman Kodak Comp., Rochester, NY, USA) auf. Für höhere Elektronenenergien als 6 MeV sind einige Film-Kassetten-Kombinationen zur Verifikation angrenzender Elektronen- und Photonenportale auf dem gleichen Filmblatt geeignet.Schlussfolgerung:Die Verifikation sowohl einzelner Elektronenportale als auch aneinander grenzender Elektronen- und Photonenportale ist durch empfindliche Film-Kassetten-Systeme mit einer gegenüber Photonenfeldkontrollaufnahmen vergleichbaren Abbildungsqualität möglich.

Down-regulation of Heat Shock Protein HSP90ab1 in Radiation-damaged Lung Cells other than Mast Cells

Ionizing radiation (IR) leads to fibrosing alveolitis (FA) after a lag period of several weeks to months. In a rat model, FA starts at 8 weeks after IR. Before that, at 5.5 weeks after IR, the transcription factors Sp1 (stimulating protein 1) and AP-1 (activator protein 1) are inactivated. To find genes/proteins that were down-regulated at that time, differentially expressed genes were identified in a subtractive cDNA library and verified by quantitative RT-PCR (reverse transcriptase polymerase chain reaction), western blotting and immunohistochemistry (IH). The mRNA of the molecular chaperone HSP90AB1 (heat shock protein 90 kDa alpha, class B member 1) was down-regulated 5.5 weeks after IR. Later, when FA manifested, HSP90ab1 protein was down-regulated by more than 90% in lung cells with the exception of mast cells. In most mast cells of the normal lung, both HSP90ab1 and HSP70, another major HSP, show a very low level of expression. HSP70 was massively up-regulated in all mast cells three months after irradiation whereas HSP90AB1 was up-regulated only in a portion of mast cells. The strong changes in the expression of central molecular chaperones may contribute to the well-known disturbance of cellular functions in radiation-damaged lung tissue.