Fabrication and characterization of a multimodal 3D printed mouse phantom for ionoacoustic quality assurance in image-guided pre-clinical proton radiation research

Objective. Image guidance and precise irradiation are fundamental to ensure the reliability of small animal oncology studies. Accurate positioning of the animal and the in-beam monitoring of the delivered radio-therapeutic treatment necessitate several imaging modalities. In the particular context of proton therapy with a pulsed beam, information on the delivered dose can be retrieved by monitoring the thermoacoustic waves resulting from the brief and local energy deposition induced by a proton beam (ionoacoustics). The objective of this work was to fabricate a multimodal phantom (x-ray, proton, ultrasound, and ionoacoustics) allowing for sufficient imaging contrast for all the modalities. Approach. The phantom anatomical parts were extracted from mouse computed tomography scans and printed using polylactic acid (organs) and a granite/polylactic acid composite (skeleton). The anatomical pieces were encapsulated in silicone rubber to ensure long term stability. The phantom was imaged using x-ray cone-beam computed tomography, proton radiography, ultrasound imaging, and monitoring of a 20 MeV pulsed proton beam using ionoacoustics. Main results. The anatomical parts could be visualized in all the imaging modalities validating the phantom capability to be used for multimodal imaging. Ultrasound images were simulated from the x-ray cone-beam computed tomography and co-registered with ultrasound images obtained before the phantom irradiation and low-resolution ultrasound images of the mouse phantom in the irradiation position, co-registered with ionoacoustic measurements. The latter confirmed the irradiation of a tumor surrogate for which the reconstructed range was found to be in reasonable agreement with the expectation. Significance. This study reports on a realistic small animal phantom which can be used to investigate ionoacoustic range (or dose) verification together with ultrasound, x-ray, and proton imaging. The co-registration between ionoacoustic reconstructions of the impinging proton beam and x-ray imaging is assessed for the first time in a pre-clinical scenario

DIFFERENTIAL EFFECTS OF PROTONTHERAPY AND PHOTONTHERAPY ON HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) POST-TREATMENT AGGRESSIVENESS

International audienceHead and neck cancers, the 7 th cause of death worldwide, are currently treated with a combination of surgical resection of the primary tumor, chemotherapy and radiotherapy, depending on the disease stage. Conventional photontherapy nevertheless remains difficult to apply to tumors such as head and neck squamous cell carcinomas (HNSCC), due to the proximity of numerous organs at risk (i.e. salivary glands, esophagus, larynx). Protontherapy has been proposed to treat such sensitive tumors, due to its high precision in tumor targeting. Despite the current therapeutic strategies, the five-year overall survival rate of HNSCC patients is only 53%, with a high percentage of poor response to therapy and a high recurrence rate. Lymph node metastasis, the first sign of tumor progression, has been directly correlated to Vascular Endothelial Growth Factor-C (VEGF-C) expression levels in HNSCC and to VEGF-C-dependent tumoral lymphatic vessel development. In the present study, we investigated the hypothesis that, beside the advantage in dose deposition, protontherapy may show distinct biological properties than photontherapy (at similar doses). We thus examined several in vitro biological behaviors of HNSCC-derived cells when exposed to photons or protons, focusing on molecules with key roles in the progression and prognosis of HNSCC, such as genes/proteins involved in (lymph)angiogenesis/metastasis, inflammation, tumor cell proliferation and anti-tumor immunity, tumorigenic potential. We showed that cell proliferation decreased with the irradiation dose, both in proton and photon irradiated cells. Proton and photon irradiations increased VEGF-C and PD-L1 expression in HNSCC cells. In cells surviving multiple irradiation, key (lymph)angiogenesis and inflammation genes were down-regulated (except for VEGF-C) after protontherapy and up-regulated after photontherapy. Both irradiation types stimulated VEGF-C promoter activity via NF-kB-dependent transcriptional regulation. We conclude that cell resistance, tumor progression and lymphangiogenesis induction is less pronounced after proton irradiation than after photon irradiation. We validated these results by in vivo experiments: Photon-or proton-irradiated HNSCC-derived cells were xenografted subcutaneously into immunodeficient mice. Cells surviving to multiple irradiations by protons or photons generated tumors with higher volume, anarchic architecture and increased density of blood vessels than non-irradiated cells. Increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in tumors generated with X irradiated cells. Detection of a denser lymphatic vessel network in relapsed tumors from patients receiving conventional X radiotherapy is consistent with these results

Prompt Gamma Energy Integration : a new method for online-range verification in proton therapy with pulsed-beams

International audienceWe propose a method for prompt-gamma verification of proton range during particle therapy. This method, called Prompt-Gamma Energy Integration (PGEI), is based on the measurement of the total energy deposited in a set of detectors located around a patient. It is particularly suited in the case of high-instantaneous beam intensities, like for pulsed beams extracted from a synchro-cyclotron. GATE simulations show that millimetric range shifts can be measured at a beam-spot scale. The sensitivity is slightly degraded as compared to the Prompt-Gamma Peak Integration Method, for which Time-of-Flight can be employed to reduce the background in single-photon detection conditions at cyclotron accelerators. Experimentally, lead tungstate scintillators have shown to cope with the high instantaneous gamma count rates for PGEI at synchro-cyclotrons

GaN Schottky diodes for proton beam monitoring

International audienc

20-year assessment of metastatic latency and subsequent time to death after proton therapy for uveal melanomas

International audienc

Beam monitor chamber calibration of a synchro-cyclotron high dose rate per pulse pulsed scanned proton beam

Objective. Ionization chambers, mostly used for beam calibration and for reference dosimetry, can show high recombination effects in pulsed high dose rate proton beams. The aims of this paper are: first, to characterize the linearity response of newly designed asymmetrical beam monitor chambers (ABMC) in a 100-226 MeV pulsed high dose rate per pulse scanned proton beam; and secondly, to calibrate the ABMC with a PPC05 (IBA Dosimetry) plane parallel ionization chamber and compare to calibration with a home-made Faraday cup (FC). Approach. The ABMC response linearity was evaluated with both the FC and a PTW 60019 microDiamond detector. Regarding ionometry-based ABMC calibration, recombination factors were evaluated theoretically, then numerically, and finally experimentally measured in water for a plane parallel ionization chamber PPC05 (IBA Dosimetry) through k s saturation curves. Finally, ABMC calibration was also achieved with FC and compared to the ionometry method for 7 energies. Main results. Linearity measurements showed that recombination losses in the new ABMC design were well taken into account for the whole range of the machine dose rates. The two-voltage-method was not suitable for recombination correction, but Jaffé’s plots analysis was needed, emphasizing the current IAEA TRS-398 reference protocol limitations. Concerning ABMC calibration, FC based absorbed dose estimation and PPC05-based absorbed dose estimation differ by less than 6.3% for the investigated energies. Significance. So far, no update on reference dosimetry protocols is available to estimate the absorbed dose in ionization chambers for clinical high dose rate per pulse pulsed scanned proton beams. This work proposes a validation of the new ABMC design, a method to take into account the recombination effect for ionometry-based ABMC calibration and a comparison with FC dose estimation in this type of proton beams.</p

RGD-functionalized magnetosomes are efficient tumor radioenhancers for X-rays and protons

International audienceAlthough chemically synthesized ferro/ferrimagnetic nanoparticles have attracted great attention in cancer theranostics, they lack radio-enhancement efficacy due to low targeting and internalization ability. Herein, we investigated the potential of RGD-tagged magnetosomes, bacterial biogenic magnetic nanoparticles naturally coated with a biological membrane and genetically engineered to express an RGD peptide, as tumor radioenhancers for conventional radiotherapy and proton therapy. Although native and RGD-magnetosomes similarly enhanced radiation-induced damage to plasmid DNA, RGD-magnetoprobes were able to boost the efficacy of radiotherapy to a much larger extent than native magnetosomes both on cancer cells and in tumors. Combined to magnetosomes@RGD, proton therapy exceeded the efficacy of X-rays at equivalent doses. Also, increased secondary emissions were measured after irradiation of magnetosomes with protons versus photons. Our results indicate the therapeutic advantage of using functionalized magnetoparticles to sensitize tumors to both X-rays and protons and strengthen the case for developing biogenic magnetoparticles for multimodal nanomedicine in cancer therapy

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

International audiencePurposeLinear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types.Methods and MaterialsATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions.ResultsThe rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling.ConclusionsOur findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity

Radiothérapie stéréotaxique robotisée par CyberKnife®: aspects techniques et indications

National audienceEn 2006, l'Institut national du cancer a lancé un appel d'offres portant sur la radiothérapie stéréotaxique extracrânienne. Trois sites (Lille, Nancy et Nice) ont été sélectionnés pour implanter et évaluer un robot de radiothérapie, le CyberKnife®. Cette machine capable de suivre des tumeurs mobiles en temps réel ouvre de nouvelles perspectives dans le champ de la radiothérapie stéréotaxique, notamment dans sa composante extracrânienne. Les fonctionnalités de cet équipement et le coût de sa mise en oeuvre vont être évalués sur une période de deux ans sur les trois sites considérés

A time-of-flight-based reconstruction for real-time prompt-gamma imaging in proton therapy

International audienceWe propose a novel prompt-gamma (PG) imaging modality for real-time monitoring in proton therapy: PG time imaging (PGTI). By measuring the time-of-flight (TOF) between a beam monitor and a PG detector, our goal is to reconstruct the PG vertex distribution in 3D. In this paper, a dedicated, non-iterative reconstruction strategy is proposed (PGTI reconstruction). Here, it was resolved under a 1D approximation to measure a proton range shift along the beam direction. In order to show the potential of PGTI in the transverse plane, a second method, based on the calculation of the centre of gravity (COG) of the TIARA pixel detectors’ counts was also explored. The feasibility of PGTI was evaluated in two different scenarios. Under the assumption of a 100 ps (rms) time resolution (achievable in single proton regime), MC simulations showed that a millimetric proton range shift is detectable at 2σ with 108 incident protons in simplified simulation settings. With the same proton statistics, a potential 2 mm sensitivity (at 2σ with 108 incident protons) to beam displacements in the transverse plane was found using the COG method. This level of precision would allow to act in real-time if the treatment does not conform to the treatment plan. A worst case scenario of a 1 ns (rms) TOF resolution was also considered to demonstrate that a degraded timing information can be compensated by increasing the acquisition statistics: in this case, a 2 mm range shift would be detectable at 2σ with 109 incident protons. By showing the feasibility of a time-based algorithm for the reconstruction of the PG vertex distribution for a simplified anatomy, this work poses a theoretical basis for the future development of a PG imaging detector based on the measurement of particle TOF