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Recent oncological studies identified beneficial properties of radiation applied at ultra-high dose rates several orders of magnitude higher than the clinical standard of the order of Gy/min. Sources capable of providing these ultra-high dose rates are under investigation. Here, we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumors in a mouse model, showing the concerted preparation of mice and laser accelerator, the dose-controlled, tumor-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumor growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimeter-scale volumes on nanosecond time scales, equivalent to around 1E9 Gy/s, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultra-high dose rate.

Laser-plasma based proton accelerators as a novel accelerator technology have matured to a level at which laboratory-scale setups for the emerging topic of image-guided precision small animal irradiation studies come into reach [Bra2019]. Providing a high proton energy bandwidth [Sch2016] which is filtered in a tunable pulsed magnet beam transport, these accelerators enable flexibility in terms of scattering-free irradiation field formation [Mas2014, Mas2015]. Regarding temporal dose delivery, with single pulse doses reaching the Gy level at unprecedented peak dose rates of up to 1012 Gy/s [Sch2016], laser-plasma based proton accelerator setups can give access to the dose rate regime of FLASH [Fav2014, Voz2019]. The realization of a full-scale setup for image-guided precision radiobiological studies for small animals focusing on dose rate dependent effects is currently prepared at the PENELOPE laser-plasma based proton accelerator at HZDR and will be presented with a focus on the technological requirements and solutions for dose delivery at laser-plasma based sources. This development relies on our experience in performing dose-controlled radiobiological in vitro studies [Kra2010, Zei2013] and first in vivo irradiation experiments at the DRACO laser-plasma based proton accelerator at HZDR, where we have established a pulsed solenoid beamline for 3D irradiation field formation, yielding a (5 mm)³ homogeneous volumetric dose distribution at a Gy single pulse dose level [8]. [Bra2019] F.-E. Brack, F. Kroll, L. Gaus, C. Bernert, E. Beyreuther, T. E. Cowan, L. Karsch, S. D. Kraft, L. A. Kunz-Schughart, E. Lessmann, J. Metzkes-Ng, L. Obst-Hübl, J. Pawelke, M. Rehwald, H.-P. Schlenvoigt, U. Schramm, M. Sobiella, E. R. Szabó, T. Ziegler, K. Zeil, Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline. arXiv:1910.08430 (2019) [Sch2016] J. Schreiber, P. Bolton, K. Parodi, “Hands-on” laser-driven ion acceleration: A primer for laser-driven source development and potential applications, Rev. Sci. Instr. 87, 071101 (2016)

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The development of new radiotherapeutic approaches is a long-time process where the general concept should be proven from time to time even though clinical requirements, i.e. on particle energy, are not yet fulfilled. Examples are laser accelerated particle beams, which are promised to replace classical ion radiotherapy, and proton and X-ray micro beams. For these low penetrating beams in vivo models are required that allow for full penetration, e.g. by ~25 MeV proton beams with a penetration depth of ~4 mm, currently available at laser driven accelerators. As the standard tumour model on mice leg cannot be applied for this purpose a new small animal tumour model on mice ear was established for the investigation of tumour response, whereas for the study of normal tissue toxicity Zebrafish embryos were applied. For the mouse ear tumour model, human tumour cells of three different entities (HNSCC FaDu, LN229 glioblastoma, A549 adenocarcinoma) were injected subcutaneously in the right ear of NMRI nude mice and growing tumours were characterized with respect to growth parameters, histology and 200 kV X-ray dose dependent tumour growth delay. Histological analyses reveal bordered tumours at treatment size (~10 mm³) that interact with the surrounding tissue and activate endothelial cells to form vessels. By X-ray treatment optimised dose ranges for inducing tumour growth delay but not tumour control were determined and a full scale radiobiological experiment at a clinical and a laser-accelerator was performed with FaDu tumours. In order to quantify the normal tissue toxicity after irradiation with low energy beams wildtype Zebrafish embryos were applied whose size of ~1 mm allow for the full penetration, e.g. by ~10 MeV proton beams. Measurements of the radiobiological response to high (150 MeV) and low energy protons from a conventional therapy facility provide comparative data on survival and immune response for further studies with laser driven beams. The results obtained during the establishment of the mouse ear tumour model and the Zebrafish embryo normal tissue model will be presented together with first findings of experiments with conventional and laser driven particle beams. Acknowledgement: The work was supported by German BMBF, grant nos. 03ZIK445 and 03Z1N511 and ELI-ALPS project (GINOP-2.3.6-15-2015-00001).

The long-term aim of developing laser based particle acceleration towards clinical application requires not only substantial technological progress, but also new technical solutions for dose delivery and quality assurance as well as comprehensive research on the radiobiological consequences of ultra-short radiation pulses with high pulse dose. During the last years the laser driven technology was developed at such a rate that cell samples and small animals can be irradiated. Within the joint research project “onCOOPtics” extensive in vitro studies with several human tumor and normal tissue cells were already performed revealing comparable radiobiological effects of laser driven and conventional electron and proton beams1,2. Using the same cell lines, these results were substantiated comparing the radiobiological response to ultra-short pulsed electron bunches (pulse dose rates of ≤1012 Gy/min) and continuous electron delivery at the radiation source ELBE3. In a second translational step, in vivo experiments were established. Although the experiments were motivated by future proton trials, first attempts were performed with electrons at the laser system JETI4, since the delivery of prescribed homogeneous doses to a 3D target volume is easier for electrons than for protons. A full scale animal experiment was realized for the HNSCC FaDu grown on nude mice ear. The radiation induced tumor growth delay was determined and compared to those obtained after similar treatment at a conventional clinical LINAC. Again, no significant difference in the radiation response to both radiation qualities was revealed, whereas the successful performance of such a comprehensive experiment campaign underlines the stability and reproducibility of all implemented methods and setup components5. During this experiment campaign the changing tumour take rate and a high rate of secondary tumours were identified as limitations of the model that have to be improved before proton experiments and tumour control studies can be performed. In order to optimize the model Matrigel as medium for tumor cell injection and the glioblastoma cell line LN229 as interesting entity for proton treatment were introduced. Results of this optimization process and the status of the experiments with laser driven protons at the laser system DRACO will be presented. The work was supported by the German Government, Federal Ministry of Education and Research, grant nos. 03ZIK445 and 03Z1N511. 1Laschinsky L, Baumann M, Beyreuther E, Enghardt W, Kaluza M et al. (2012) Radiobiological effectiveness of laser accelerated electrons in comparison to electron beams from a conventional linear accelerator. J. Radiat. Res. 53(3): 395-403. 2Zeil K, Baumann M, Beyreuther E, Burris-Mog T, Cowan TE et al. (2012) Dose-controlled irradiation of cancer cells with laser-accelerated proton pulses. Appl. Phys. B 110(4): 437-444. 3Beyreuther E, Karsch L, Laschinsky L, Leßmann E, Naumburger D et al. (2015) Radiobiological response to ultra-short pulsed megavoltage electron beams of ultra-high pulse dose rate. Int. J. Radiat. Biol. 91(8): 643-652. 4Brüchner K, Beyreuther E, Baumann M, Krause M, Oppelt M et al. (2014) Establishment of a small animal tumour model for in vivo studies with low energy laser accelerated particles. Radiat. Oncol. 9(1): 57. 5Oppelt M, Baumann M, Bergmann R, Beyreuther E, Brüchner K et al. (2015) Comparison study of in vivo dose response to laser-driven versus conventional electron beam. Radiat. Environ. Biophys. 54(2): 155-166.

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Introduction: The long-term aim of developing 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 and ultra-intensive particle beam pulses. Recent in vitro data showed similar effects of laser-accelerated versus “conventional” protons on clonogenic cell survival and DNA double-strand breaks. As the proton energies currently achieved for radiobiological experiments by laser driven acceleration are too low to penetrate standard tumour models on mouse legs, a small animal tumour model allowing for the penetration of low energy protons (~20 MeV) was developed to further verify the effects in vivo. Methods: The originally for human HNSCC FaDu established mouse ear tumour model was adapted for LN229 human glioblastoma cells. For this, cells were injected subcutaneously in the right ear of NMRI nude mice and the growing tumours were characterized with respect to growth parameters and histology. After optimizing the number of injected cells and used medium (PBS, Matrigel) the radiation response was studied by 200 kV X-ray irradiation. Furthermore, a proof-of-principle full scale experiment with laser accelerated electrons was performed to validate the FaDu tumour model under realistic, i.e. harsh, conditions at experimental laser accelerators. Results: Both human tumour models showed a high take rate and continuous tumour growth after reaching a volume of ~5 – 10 mm3. Moreover, immunofluorescence analysis revealed that already the small tumours interact with the surrounding tissue and activate endothelial cells to form vessels. By analysing the dose dependent tumour growth curves after 200 kV X-ray treatment a realistic dose range, i.e. for inducing tumour growth delay but not tumour control, was defined for both tumour entities under investigation. Beside this basic characterization, the comparison of the influence of laser driven and conventional (clinical Linac) electrons on the growth of FaDu tumours reveal no significant difference in the radiation induced tumour growth delay. Conclusion: The already established mouse ear tumour model was successfully upgraded now providing stable tumour growth with high take rate for two tumour entities (HNSCC, glioblastoma) that are of interest for future proton treatment. Experiments comparing laser driven and conventional proton beams in vivo as the next step towards clinical application of laser driven particle acceleration are under way. Acknowledgement: The work was supported by the German Government, Federal Ministry of Education and Research, grant nos. 03ZIK445 and 03Z1N511.

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The long-term goal to integrate laser-based particle accelerators into radiotherapy clinics not only requires technological development of high-intensity lasers and new techniques for beam detection and dose delivery, but also characterization of the biological consequences of this new particle beam quality, i.e. ultra-short, ultra-intense pulses. In the present work, we describe successful in vivo experiments with laser-driven electron pulses by utilization of a small tumour model on the mouse ear for the human squamous cell carcinoma model FaDu. The already established in vitro irradiation technology at the laser system JETI was further enhanced for 3D tumour irradiation in vivo in terms of beam transport, beam monitoring, dose delivery and dosimetry in order to precisely apply a prescribed dose to each tumour in full-scale radiobiological experiments. Tumour growth delay was determined after irradiation with doses of 3 and 6 Gy by laser-accelerated electrons. Reference irradiation was performed with continuous electron beams at a clinical linear accelerator in order to both validate the dedicated dosimetry employed for laser-accelerated JETI electrons and above all review the biological results. No significant difference in radiation-induced tumour growth delay was revealed for the two investigated electron beams. These data provide evidence that the ultra-high dose rate generated by laser acceleration does not impact the biological effectiveness of the particles.

Objective To investigate the effect of radiation dose-escalation on local control in hypoxic versus non-hypoxic hypoxic tumours defined using [18F]fluoromisonidazole ([18F]FMISO) PET. Materials and methods FaDu human squamous cell carcinomas (hSCCs) growing subcutaneously in nude mice were subjected to [18F]FMISO PET before irradiation with single doses of 25 or 35 Gy under normal blood flow conditions. [18F]FMISO hypoxic volume (HV) and maximum standardised uptake value (SUVmax) were used to quantify tracer uptake. The animals were followed up for at least 120 days after irradiation. The endpoints were permanent local tumour control and time to local recurrence. Results HV varied between 38 and 291 mm3 (median 105 mm3). Non-hypoxic tumours (HV below median) showed significantly better local control after single dose irradiation than hypoxic tumours (HV above median) (p = 0.046). The effect of dose was significant and not different in non-hypoxic and in hypoxic tumours (HR = 0.82 [95% CI 0.71; 0.93], p = 0.002 and HR = 0.86 [0.78; 0.95], p = 0.001, respectively). Dose escalation resulted in an incremental increase of local tumour control from low-dose hypoxic, over low-dose non-hypoxic and high-dose hypoxic to high-dose non-hypoxic tumours. SUVmax did not reveal significant association with local control at any dose level. Conclusions The negative effect of [18F]FMISO HV on permanent local tumour control supports the prognostic value of the pre-treatment [18F]FMISO HV. Making the assumption that variable [18F]FMISO uptake in different FaDu tumours which all have the same genetic background may serve as an experimental model of intratumoural heterogeneity, the data support the concept of dose-escalation with inhomogeneous dose distribution based on pre-treatment [18F]FMISO uptake. This result needs to be confirmed in other tumour models and using fractionated radiotherapy schedules.

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 [(90)Y]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 ([(86)Y]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.

The novel technology of particle acceleration by high intensity lasers promises more compact and cost effective ion sources as well as electron beams of very high energy for radiotherapeutic application. However, compared to conventional beams, laser-driven acceleration results in different beam properties like ultra-short and very intensive pulses, inherent pulse-to-pulse fluctuations, low pulse repetition rate, large beam divergence and broad energy distribution. In consequence, the future medical application of these particle beams requires not only a high power laser system but also new technical solutions for dose delivery and quality assurance as well as comprehensive research on the radiobiological consequences of ultra-short radiation pulses with high pulse dose. During the last years the laser-driven technology was developed at such a rate that cell samples and small animals can be irradiated. Within the joint research project “onCOOPtics” extensive in vitro dose response studies were already performed comparing the radiobiological effects of laser driven electron and proton beams to their conventional equivalents. As overall result, the obtained dose-effect relationships for human tumor and human normal tissue cells reveal no difference between conventional and laser-driven beams. In a second translational step, in vivo experiments were recently established at the laser system JETI. Although the experiments were motivated by future proton trials, first attempts were performed with laser accelerated electrons, since the homogeneous delivery of prescribed doses to a 3D target volume is easier for electrons than for protons. Tumor irradiation was realized for the murine sarcoma KHT and the human squamous cell carcinoma FaDu grown on nude mice ear. Doses of up to 14 Gy were applied and the radiation induced tumor growth delay was investigated and later on compared to those obtained after similar treatment at a conventional electron Linac. Moreover, the successful performance of such an experiment campaign over a period of several weeks underlines the stability and reproducibility of all implemented methods and setup components. Further experiments with laser accelerated protons are in progress. The work was supported by the German Federal Ministry of Education and Research (BMBF), grant nos. 03ZIK445 and 03Z1N511.

Purpose. The novel technology of proton and ion acceleration by ultra high intensity lasers promises the realization of compact and economic particle accelerators for cancer therapy that can be integrated in already existing clinics. Before potential clinical application possible biological consequences of laser accelerated and therewith ultra-short pulsed particle beams with high pulse dose have to be investigated. As first step in the chain of translational research extensive in vitro dose response studies with laser driven electron and proton beams were performed within the joint research project “onCOOPtics”. We now report on first experiments comparing laser and conventional accelerated particle beams in vivo. Material and methods. A mouse tumor model suitable for the currently available still low energy (up to ~30 MeV) of laser accelerated protons was established and successfully implemented using laser accelerated electrons, likewise providing information about biological consequences of ultra-short pulsed beams. To apply a prescribed dose to each tumor the prior established laser based 2D in vitro irradiation technology was enhanced for the 3D animal model in terms of beam transport, beam monitoring, dose delivery and dosimetry. A system for mouse fixation, precise tumor positioning and verification at the irradiation site was realized (Schürer et al. 2012). In vivo tumor irradiation was performed at the 30 TW Jena Titanium: Sapphire (JeTi) laser system. Electron pulses of energies up to a few 10 MeV were generated focusing laser pulses of 28 fs duration into a hydrogen gas jet. Murine sarcoma KHT and human squamous cell carcinoma FaDu tumors were irradiated with doses up to 14 Gy at mean dose rates of 1–2 Gy/min. Reference electron irradiation was performed with the same setup and dosimetry system at a conventional therapy LINAC. The radiation induced tumor growth delay was investigated for several hundred mice. Results. The irradiation campaign was conducted over a period of several months proving the reliability and stability of all implemented setup components and methods. Dose response curves of both beam qualities have been obtained for the direct comparison of ultra-short pulsed laser accelerated and conventional continuous electron beams. The current status of the ongoing data evaluation gives no evidence for a different RBE of laser driven electrons. Conclusion. The successful establishment of all technical requirements for and the world wide first performance of systematic animal studies with laser accelerated electrons mark an important step towards the clinical application of laser accelerated particle beams. The realization of in vivo studies with laser driven proton beams is now feasible. 1. M Schürer et al (2012) Irradiation system for pre-clinical studies with laser accelerated electrons. Biomed Tech 57(Suppl. 1):62–65 Supported by BMBF grant nr. 03ZIK455 and 03Z1N511.

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The development of proton and ion acceleration by ultra-high intensity lasers for cancer therapy promises the realization of compact and economic particle accelerators that can be integrated in already existing clinics. However, particle acceleration with high intensity lasers, in comparison to the conventional used acceleration technique, leads to ultra-short beam pulses, generated with low pulse frequency, that apply a very high pulse dose. Prior to a clinical application the radiobiological consequences of laser accelerated and therewith ultra-short pulsed particle beams have to be investigated. After extensive in vitro dose response studies, for several cell lines and endpoints with laser driven electron and proton beams, the translational step to perform in vivo experiments has been taken. A tumor model suitable for currently available low energy laser protons was developed, tested and successfully used. The already in vitro established laser based irradiation technology was further developed for the animal model in terms of beam transport, beam monitoring, dose delivery and dosimetry, allowing to apply a prescribed dose to each tumor and to determine the absolute dose received. The utilized high power laser system delivered a stable and reproducible particle beam over a period of months to allow systematic in vivo dose response studies of a human xenograft line. 300 mice hosting two different tumor lines were irradiated with various defined doses and monitored for several weeks to determine tumor growth delay. In parallel irradiation by a continuous beam of a conventional accelerator has been performed. Results of the still ongoing data evaluation will be presented and discussed. Experiments were carried out within the onCOOPtics project in cooperation between Oncoray Dresden and Ultraoptics Jena. The work was supported by the German Ministry of Education and Research (BMBF), grant no. 03ZIK445

Objectives: Radiochemical development, characterisation and preparation of [90Y]Y-CHX-A´´-DTPA-Cetuximab ([90Y]C225). Preclinical evaluation of [90Y]C225 by combination of radioimmunotherapy and external radiotherapy. Methods: CHX-A´´-DTPA was conjugated to C225 via thiourea bond formation in HEPES-buffer at pH 7.2 by reacting 20 equivalents of chelator with C225 for 24 h. Purification of the conjugate was done by ultrafiltration. Chelator to C225 ratio was determined by MALDI-TOF MS and the conjugate’s affinity determined by flow cytometric analysis. Radiolabeling was performed in MES buffer at pH 6.1 at 30°C for 30 min using [90Y]YCl3. Free DTPA chelator (0.1 μg/μL) was added to the reaction mixture for quenching the labeling reaction and fixing unreacted radionuclide. Ex vivo autoradiography ([90Y]C225) was performed, in vivo kinetics were measured with PET using 86Y as radiolabel and biodistribution studies were performed. FaDu tumour bearing nude mice were treated with [90Y]C225 (2.8 MBq 13 g C225 / mouse, i.v.) and external beam irradiation (X-rays, single dose, 1.1 Gy/min). Experimental endpoints are the tumour growth delay and the local tumour control. Some animals are still in follow-up and not all cohorts are completed. The data are preliminary (figure 1B). Results: MALDI-TOF MS analysis of the purified conjugate showed that approximately 5 CHX-A´´-DTPA moieties have been conjugated to C225. The conjugate has not lost affinity to EGFR on cell surfaces when compared to the unconjugated C225 at 0.33 nM (flow cytometry). CHX-A´´-DTPA-C225 was labelled with [90Y]YCl3 with radiolabelling yields >95% and a reproducible specific activity of 1.2 GBq/mg was achieved. Autoradiography studies revealed high tumour accumulation 48 h p.i., also PET showed an increasing antibody accumulation in the tumour, which was abundant after 24 h p.i. These data validate the conjugate to be suitable for therapeutical studies: The combined treatment (internal and external irradiation) was well tolerated by all mice and no histological alterations in organs could be found. The preliminary data in Figure 1B clearly show a dose-effect of the external irradiation. A significant improvement of the local tumour control after external irradiation with 26 Gy was achieved after application of 13 g of radiolabelled C225 compared to unlabelled C225 or to the treatment by external irradiation solely. Conclusions: [90Y]C225 has been successfully prepared, characterized and it can be produced in routine with high avidity and specific activity as prerequisite for long-term preclinical therapeutic studies. Our in-vivo preliminary data support the concept that multimodal cancer treatment results in a potentially relevant improvement of local tumour control in an experimental tumour model. Research Support: The Bundesministerium für Bildung und Forschung (grant 02NUK006, framework “Kompetenzverbund Strahlenforschung” (KVSF)) is gratefully acknowledged for the financial support.

Hintergrund: Der epidermale Wachstumsfaktor-Rezeptor (EGFR) wird in einer Vielzahl maligner Tumore überexprimiert. Die Hemmung des Rezeptors durch den monoklonalen Antikörper Cetuximab (C225) in Kombination mit fraktionierter Bestrahlung führte bei dieser Tumorentität (prä)klinisch zu einer verbesserten lokalen Tumorkontrolle (1). Ziel: Radiochemische Entwicklung, Charakterisierung und Herstellung von [90Y]Y-CHX-A´´-DTPACetuximab ([90Y]C225). Präklinische Evaluierung von [90Y]C225 in Kombination mit externer Bestrahlung. Kann [90Y]C225 die lokale Tumorkontrolle in Mäusen nach externer Bestrahlung weiter verbessern? Methoden: CHX-A´´-DTPA wurde über Thioharnstoffkupplung in HEPES-Puffer bei pH 7,2 mit C225 konjugiert. Die Reinigung des Konjugates erfolgte durch Ultrafiltration. Das Chelator-C225-Verhältnis wurde durch MALDI-TOF-MS bestimmt. Die Affinität gegenüber EGFR wurde durchflusszytometrisch ermittelt. Die Radiomarkierung erfolgte in MES-Puffer durch 30-minütige Inkubation mit [90Y/86Y]YCl3 bei pH 6,1 und 30°C. Die radiopharmakologische Charakterisierung erfolgte mittels Ex-vivo-Autoradiographie ([90Y]C225) und Kleintier-Positronen-Emissions-Tomographie ([86Y]C225) nach intravenöser Applikation in NMRI-Nacktmäusen (nu/nu) mit subkutan xenotransplantiertem humanen Plattenepithelkarzinom (FaDu) als Modell. Im Rahmen der Therapieexperimente wurden FaDu-NMRI(nu/nu)-Mäuse mit [90Y]C225 (je 2,8 MBq/13 μg C225 i.v.) und/oder externer Bestrahlung (26, 32 und 38 Gy, 200 kV Röntgen, 0,5 mm Cu-Filter, 1,1 Gy/min, Einzeldosis) behandelt. Endpunkte der Therapieexperimente waren Wachstumsverzögerung und lokale Tumorkontrolle 180 Tage nach externer Bestrahlung. Ergebnisse: Es wurden 4 CHX-A´´-DTPA-Moleküle an C225 gekuppelt. Das Konjugat weist mit einem KD-Wert von 0,33 nM im Vergleich zu nativem C225 keinen Affinitätsverlust gegenüber EGFR auf. Bei der Radiomarkierung mit [90Y]YCl3 wurden reproduzierbar spezifische Aktivitäten bis zu 9 GBq/mg C225 und radiochemische Ausbeuten von >95% erzielt. Autoradiographie und PET zeigten 48 h p.i. eine hohe Anreicherung im Tumor. Diese Ergebnisse zeigen, dass das Konjugat für Therapieversuche geeignet ist. Die Kombinationstherapie wurde gut toleriert und es konnten im Vergleich zu den Kontrolltieren histologisch keine Organveränderungen festgestellt werden. Die Tumorkontrolle nach alleiniger externer Bestrahlung zeigt einen klaren Dosiseffekt. Nach 26 Gy externer Bestrahlung war eine signifikant höhere Tumorkontrolle nach Applikation von 13 μg [90Y]C225 im Vergleich zu alleiniger externer Bestrahlung oder zu externer Bestrahlung und unmarkiertem Cetuximab zu verzeichnen. Referenzen: (1) Krause et al. Radiother Oncol. 2005 Feb;74(2):109-15 Gefördert durch das BMBF (02NUK006), Kompetenzverbund Strahlenforschung

Hintergrund: Das Beherrschen von biomedizinischem Wissen ist die unabdingbare Basis von ärztlichem Kompetenzerwerb. Es ist jedoch unklar, welche Rolle es beim Erlernen und Ausüben ärztlicher Fertigkeiten spielt. In einer Reihe von Studien wurde gezeigt, dass die Vermittlung von biomedizinischem[for full text, please go to the a.m. URL], 14. Workshop der gmds-Arbeitsgruppe "Computerunterstützte Lehr- und Lernsysteme in der Medizin (CBT)" und des GMA-Ausschusses "Neue Medien"

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Ziel/Aim: Die Mehrzahl maligner Tumore weisen einen erhöhten Glukosestoffwechsel auf, ein Mechanismus der bei der Positronen-Emissions-Tomographie mit F-18-FDG in der Onkologie diagnostisch genutzt wird. Ziel dieser Untersuchung war es, die unterschiedlichen Einflüsse von Tumorhypoxie und Proliferation auf die intratumorale FDG-Aufnahme in 2 menschlichen Tumormodellen auf Nacktmäusen zu untersuchen. Methodik/Methods: Je 10 Nacktmäusen mit transplantiertem menschlichen Plattenepithel-Carcinom Fadu oder humanem Adeno-Carcinom HT29 wurden mit FDG und PET (MicroPET P4, CTI Molecular Imaging, gemessenen Transmission, 8 MBq FDG i.v., Untersuchung 30-60min p.i.) untersucht (Tumorvolumina 0,4 ± 0,2cc). Aus den PET-Aufnahmen wurde der SUVmax der Tumore bestimmt. Vor dem PET wurde den Mäusen Pimonidazol (Pimo) und Bromdesoxyuridin (BrdU) injiziert, die Mäuse wurden unmittelbar nach der PET getötet, die Tumore entnommen, tiefgefroren, serielle Schnitte von 20 µm angefertigt und die intratumorale FDG-Verteilung per Autoradiographie (BAS 5000, Fuji) bestimmt. Leberschnitte von 20µm dienten als Referenzgewebe. Anschließend erfolgte die Färbung der Schnitte mit Hämatoxylin/Eosin, Antikörper gegen Pimonidazol, BrdU oder Ki-67. Die Tumorschnitte wurden mit einer digitalen Kamera gescannt und per Bildanalyse wurden Masken für vitalen Tumor, Nekrose und funktionelle Färbungen (Pimo, BrdU, Ki-67) angefertigt. Die digitalen Histologien wurden mit der korrespondierenden Autoradiographie koregistriert und die quantitative FDG-Aufnahme in den definierten Tumorarealen bestimmt. Ergebnisse/Results: Der SUVmax in Fadu (1,55 ± 0,26) lag etwas höher als in HT29 (1,30 ± 0,17; p=0,03). Fadu bildet größere hypometabole Bereich aus, die sich in der Histologie als Nekrose identifizieren liessen. Bei ähnlicher Größe der Pimo-positiven Areale in Fadu und HT29 fand sich nur in Fadu eine signifikant höhere FDG-Aufnahme in den hypoxischen Arealen im Vergleich zu vitalem Pimo-negativem Tumorgewebe (Fadu: 3,1 ± 0,2 versus 2,2 ± 0,2 %ID/g, p=0,002, HT29: 2,4 ± 0,2 versus 2,2 ± 0,2%ID/g, p=0,4). In beiden Tumormodellen fand sich keine regional erhöhte FDG-Aufnahme in Tumorregionen mit proliferativer Aktivität im Vergleich zu nicht in Teilung begriffenen vitalen Tumorarealen. Schlussfolgerungen/Conclusions: In den zwei untersuchten Tumormodellen war nur bei dem Plattenepithel-Ca Fadu ein Einfluß der Hypoxie auf die FDG-Aufnahme zu erkennen, die höhere FDG-Aufnahme in Hypoxiearealen könnte sich in dem höheren SUVmax im Vergleich zum Adeno-Ca HT29 widerspiegeln. Weder in Fadu noch in HT29 fand sich eine Korrelation zwischen Proliferation (BrdU, Ki-67) und Intensität der FDG-Aufnahme. Die Daten wurden im Rahmen des 6.Rahmenprogrammes der EU, Projekt Biocare, proposal Nr. 505785, erhoben.