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It is the reply to the Letter to the Editor by Chen and Lui regarding "Radiotherapy enhances uptake and efficacy of 90 Y-cetuximab: A preclinical trial" by A Dietrich et al. Abstract: Background and purpose: Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a 90Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors.

Purpose: In order to take full advantage of proton radiotherapy the biological effect of protons in normal and tumor tissue as well as the interaction with concomitant therapies should be investigated and understood in detail. Dedicated and systematic in vitro trials are needed to resolve the underlying mechanisms and processes that are necessary to prepare the translation into the clinics. For this purpose, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and, as a reference, a clinical 6 MV photon linear accelerator (Linac). Methods and results: The experimental proton beam is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm² proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different cell sample geometries along the proton path. The depth-dose profiles within the phantom and the dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro trials. Conclusion: In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry, which facilitate irradiation in an aqueous environment, could easily be transferred to other proton, photon or even ion accelerators. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro trials. The close vicinity to the radiotherapy and radiobiology departments provides access to a clinical linacs as well as the interdisciplinary basis for further translational steps.

Die Therapie von Tumorerkrankungen gründet sich stadienabhängig auf die drei Säulen Chirurgie, Strahlen- und Chemotherapie. Grundprinzip der Strahlentherapie ist die gezielte Einwirkung von ionisierender Strahlung auf erkranktes Gewebe, um die Zerstörung maligner Tumorzellen zu erreichen. Neben der klassischen externen Strahlentherapie unter Verwendung von Photonen hat sich die Endoradionuklidtherapie durch Entwicklung geeigneter Targetingvektoren in den letzten Jahren zu einer zunehmend angewandten Therapieform entwickelt. Insbesondere die Radioimmuntherapie hat das Potential, auch (Mikro-) Metastasen zu zerstören. Die Kombination von externer und interner Strahlentherapie ist eine vielversprechende Behandlungsstrategie, da sie unter Schonung gesunden Gewebes potenziell die Vorteile beider Modalitäten kombiniert. Ziel dieses Projektes war es, im Tiermodell zu überprüfen, ob eine interne Bestrahlung mit Hilfe des anti-EGFR-gerichteten, 90Y-markierten Antikörpers Cetuximab (C225) eine lokale Tumorkontrolle nach vorhergehender externer Bestrahlung bei verringerter Dosis ermöglicht. Cetuximab wurde mit dem bifunktionellen Chelator p-SCN-Bn-CHX-A‘‘-DTPA funktionalisiert und nach 90Y-Markierung in einem Kopf-Hals-Plattenepithelkarzinom-Xenograftmodell (FaDu) eingesetzt. Die externe Bestrahlung erfolgte nach klinisch relevanten Protokollen mit 30 Bestrahlungsfraktionen (fx) verteilt über 6 Wochen. Nach 10 Fraktionen wurden jeweils 2,3 MBq des 90Y-markierten Cetuximab-Konjugats injiziert. Die kombinierte Anwendung von externer und interner Bestrahlung erhöhte massiv die Wahrscheinlichtkeit einer lokalen Tumorkontrolle im Vergleich zur externen Bestrahlung allein oder in Kombination mit unmarkiertem Cetuximab. In der Gruppe mit der niedrigsten externen Strahlendosis (1 Gy/Fraktion, Gesamtdosis = 30 Gy,) plus 90Y-Cetuximab wurden alle Tumore noch permanent kontrolliert (Beobachtungszeitraum = 120 d). Im Gegensatz dazu betrug die gesamte externe Strahlendosis, die notwendig ist um 50% der Tumore ohne zusätzliche Gabe von 90Y-Cetuximab zu heilen, 63,9 Gy (58,7, 73,9). Unsere Ergebnisse zeigen, dass die kombinierte Anwendung von radiomarkierten Therapeutika nach fraktionierter externer Strahlentherapie ein bemerkenswertes Potenzial hat, das Behandlungsergebnis zu verbessern. Eine effiziente Aufnahme des Y-90-markierten Cetuximab-Konjugates ist die Voraussetzung für den Erfolg der kombinierten Strahlentherapie.

Solid tumors can be precisely targeted with external beam radiotherapy (EBRT) but dose is limited by the surrounding tissue. The combination with radioimmunotherapy (= combination of internal and external radiotherapy - CIERT) mediates additional internal irradiation with the potential to strike also distant metastases but affecting different organs at risk. Furthermore, patient stratification is possible using corresponding PET-tracers [1]. We showed the effectiveness of CIERT using 90Y-labelled Cetuximab ([90Y]Y-Cet) and single dose EBRT in a head and neck squamous cell carcinoma xenograft model (FaDu, [2]). The presented project aimed to investigate CIERT using clinical relevant fractionated EBRT with 30 fractions (fx) over 6 weeks. However, the timing of [90Y]Y-Cet is crucial in such settings and was first optimized by modeling [90Y]Y-Cet uptake with near-infrared-labeled Cetuximab (NIR-Cet). The tracer was injected in FaDu-bearing mice at different time points during fxEBRT with differing doses. NIR-Cet uptake was longitudinally followed by in vivo optical imaging to find the optimal schedule for tumor control probability experiments to test the curative potential of CIERT. NIR-Cet uptake was enhanced after applying low to moderate doses of fxEBRT. Thus, [90Y]Y-Cet was injected after 10 fx of EBRT in CIERT efficacy experiments. CIERT massively increased local control probability compared to EBRT alone or in combination with unlabeled Cetuximab. In the group with the lowest external dose (1 Gy/fx, total dose = 30 Gy) plus [90Y]Y-Cet all tumors were still permanently controlled (observation period = 120 d). In contrast, the total EBRT dose to cure 50% of the tumors without additional [90Y]Y-Cet injection was 63.9 Gy [58.7, 73.9]. Our results indicate a remarkably potential to improve treatment outcome if radiolabeled therapeutics are combined with fractionated external radiotherapy in a clinical relevant setting. Tumor uptake may be improved by application of some EBRT dose prior to injection. This scheduling would also enable patient stratification via a corresponding PET-tracer during ongoing therapy. [1] A. Dietrich, L. Koi, K. Zöphel, W. Sihver, J. Kotzerke, M. Baumann, M. Krause, Br. J. Radiol. 2015, 88, 20150042 [2] L. Koi, R. Bergmann, K. Brüchner, J. Pietzsch, H.-J. Pietzsch, M. Krause, J. Steinbach, D. Zips, M. Baumann, Radiother. Oncol. 2014, 110, 362-369

In New Zealand, public libraries, academic libraries, a special library, and the National Library were surveyed and compared to the University of Oregon Library in the area of management of collections of government publications. The latter has been a depository for U.S. government publications since 1883. (VT)

Objectives: The function of phagocytic cells is of crucial importance to i) ingest and degrade the infectious agent, and ii) to sensitize the host against secondary infections. Measuring phagocytosis and oxygen radical formation has long been accepted to monitor granulocyte function. Thus chemiluminescence[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)