What is the Best Radionuclide for Immuno-PET of Multiple Myeloma? A Comparison Study Between 89Zr- and 64Cu-Labeled Anti-CD138 in a Preclinical Syngeneic Model.

Although positron emission tomography (PET) imaging with 18-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker for the identification of myeloma cells and could be used in phenotype tumor imaging. In this study, we used an anti-CD138 murine antibody (9E7.4) radiolabeled with copper-64 (64Cu) or zirconium-89 (89Zr) and compared them in a syngeneic mouse model to select the optimal tracers for MM PET imaging. Then, 9E7.4 was conjugated to TE2A-benzyl isothiocyanate (TE2A) and desferrioxamine (DFO) chelators for 64Cu and 89Zr labeling, respectively. 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 antibodies were evaluated by PET imaging and biodistribution studies in C57BL/KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions and were compared to 18F-FDG-PET imaging. In biodistribution and PET studies, 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 displayed comparable good tumor uptake of subcutaneous tumors. On the bone lesions, PET imaging with 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 showed higher uptake than with 18F-FDG-PET. Comparison of both 9E7.4 conjugates revealed higher nonspecific bone uptakes of 89Zr-DFO-9E7.4 than 64Cu-TE2A-9E7.4. Because of free 89Zr's tropism for bone when using 89Zr-anti-CD138, 64Cu-anti-CD138 antibody had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a specific new imaging radiopharmaceutical agent in MM.

Synthesis of C-functionalized TE1PA and comparison with its analogues. An example of bioconjugation on 9E7.4 mAb for multiple myeloma 64Cu-PET imaging.

In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the ß-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h.

Immuno-PET for Clinical Theranostic Approaches.

Recent advances in molecular characterization of tumors have allowed identification of new molecular targets on tumor cells or biomarkers. In medical practice, the identification of these biomarkers slowly but surely becomes a prerequisite before any treatment decision, leading to the concept of personalized medicine. Immuno-positron emission tomography (PET) fits perfectly with this approach. Indeed, monoclonal antibodies (mAbs) labelled with radionuclides represent promising probes for theranostic approaches, offering a non-invasive solution to assess in vivo target expression and distribution. Immuno-PET can potentially provide useful information for patient risk stratification, diagnosis, selection of targeted therapies, evaluation of response to therapy, prediction of adverse effects or for titrating doses for radioimmunotherapy. This paper reviews some aspects and recent developments in labelling methods, biological targets, and clinical data of some novel PET radiopharmaceuticals.

Tumor immunotargeting using innovative radionuclides.

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality.

Production of 203Pb from enriched 205Tl using deuteron beams.

Lead-203 is a SPECT emitter that can be used in theranostic applications as an imaging counterpart of lead-212 which is intended to be used for alpha therapy as lead-212/bismuth-212 in-vivo generator. In our study, we explore the production of lead-203 using enriched thallium-205 target irradiated by a deuteron beam. Excitation functions of deuteron induced reactions leading to the formation of 204m,203m2+m1+g,202m,201m+gPb, 202Tl and 203m+gHg isotopes were determined experimentally in the energy range from 21 MeV to 34 MeV. Cross sections were measured using the stacked foils technique and a set of two monitor foils, natNi and natTi for beam intensity evaluation. The experimental excitation functions of the investigated reactions were compared with the published data and also with the TENDL-2021 nuclear database. From our experimental data, we calculated lead-203 thick target yield in the energy range between 30 MeV and 32.5 MeV to be 56.7 MBq/µAh ±6.1 MBq/µAh. This value is compatible with large batch production showing that deuteron beams can be used for a routine production process. However, special attention must be paid to 203Hg and other lead contaminants.

In vivo biodistribution and tumor uptake of [64Cu]-FAU nanozeolite via positron emission tomography Imaging.

Nanoparticles have emerged as promising theranostic tools for biomedical applications, notably in the treatment of cancers. However, to fully exploit their potential, a thorough understanding of their biodistribution is imperative. In this context, we prepared radioactive [64Cu]-exchanged faujasite nanosized zeolite ([64Cu]-FAU) to conduct positron emission tomography (PET) imaging tracking in preclinical glioblastoma models. In vivo results revealed a rapid and gradual accumulation over time of intravenously injected [64Cu]-FAU zeolite nanocrystals within the brain tumor, while no uptake in the healthy brain was observed. Although a specific tumor targeting was observed in the brain, the kinetics of uptake into tumor tissue was found to be dependent on the glioblastoma model. Indeed, our results showed a rapid uptake in U87-MG model while in U251-MG glioblastoma model tumor uptake was gradual over the time. Interestingly, a [64Cu] activity, decreasing over time, was also observed in organs of elimination such as kidney and liver without showing a difference in activity between both glioblastoma models. Ex vivo analyses confirmed the presence of zeolite nanocrystals in brain tumor with detection of both Si and Al elements originated from them. This radiolabelling strategy, performed for the first time using nanozeolites, enables precise tracking through PET imaging and confirms their accumulation within the glioblastoma. These findings further bolster the potential use of zeolite nanocrystals as valuable theranostic tools.

Methodology for small animals targeted irradiations at conventional and ultra-high dose rates 65 MeV proton beam.

As part of translational research projects, mice may be irradiated on radiobiology platforms such as the one at the ARRONAX cyclotron. Generally, these platforms do not feature an integrated imaging system. Moreover, in the context of ultra-high dose-rate radiotherapy (FLASH-RT), treatment planning should consider potential changes in the beam characteristics and internal movements in the animal. A patient-like set-up and methodology has been implemented to ensure target coverage during conformal irradiations of the brain, lungs and intestines. In addition, respiratory cycle amplitudes were quantified by fluoroscopic acquisitions on a mouse, to ensure organ coverage and to assess the impact of respiration during FLASH-RT using the 4D digital phantom MOBY. Furthermore, beam incidence direction was studied from mice µCBCT and Monte Carlo simulations. Finally,in vivodosimetry with dose-rate independent radiochromic films (OC-1) and their LET dependency were investigated. The immobilization system ensures that the animal is held in a safe and suitable position. The geometrical evaluation of organ coverage, after the addition of the margins around the organs, was satisfactory. Moreover, no measured differences were found between CONV and FLASH beams enabling a single model of the beamline for all planning studies. Finally, the LET-dependency of the OC-1 film was determined and experimentally verified with phantoms, as well as the feasibility of using these filmsin vivoto validate the targeting. The methodology developed ensures accurate and reproducible preclinical irradiations in CONV and FLASH-RT without in-room image guidance in terms of positioning, dose calculation andin vivodosimetry.

Monte Carlo simulations of microdosimetry and radiolytic species production at long time post proton irradiation using GATE and Geant4-DNA.

BACKGROUND: Radiobiological effectiveness of radiation in cancer treatment can be studied at different scales (molecular till organ scale) and different time post irradiation. The production of free radicals and reactive oxygen species during water radiolysis is particularly relevant to understand the fundamental mechanisms playing a role in observed biological outcomes. The development and validation of Monte Carlo tools integrating the simulation of physical, physico-chemical and chemical stages after radiation is very important to maintain with experiments. PURPOSE: Therefore, in this study, we propose to validate a new Geant4-DNA chemistry module through the simulation of water radiolysis and Fricke dosimetry experiments on a proton preclinical beam line. MATERIAL AND METHODS: In this study, we used the GATE Monte Carlo simulation platform (version 9.3) to simulate a 67.5 MeV proton beam produced with the ARRONAX isochronous cyclotron (IBA Cyclone 70XP) at conventional dose rate (0.2 Gy/s) to simulate the irradiation of ultra-pure liquid water samples and Fricke dosimeter. We compared the depth dose profile with measurements performed with a plane parallel Advanced PTW 34045 Markus ionization chamber. Then, a new Geant4-DNA chemistry application proposed from Geant4 version 11.2 has been used to assess the evolution of HO • ${\mathrm{HO}}^ \bullet $ , e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , H 3 O + ${{\mathrm{H}}}_3{{\mathrm{O}}}^ + $ , H 2 O 2 ${{\mathrm{H}}}_2{{\mathrm{O}}}_2$ , H 2 ${{\mathrm{H}}}_2$ , HO 2 • ${\mathrm{HO}}_2^ \bullet $ , HO 2 - , O 2 • - ${\mathrm{HO}}_2^ - ,{\mathrm{\ O}}_2^{ \bullet - }$ and HO - ${\mathrm{HO}}^ - $ reactive species along time until 1-h post-irradiation. In particular, the effect of oxygen and pH has been investigated through comparisons with experimental measurements of radiolytic yields for H 2 O 2 ${{\mathrm{H}}}_2{{\mathrm{O}}}_2$ and Fe3+. RESULTS: GATE simulations reproduced, within 4%, the depth dose profile in liquid water. With Geant4-DNA, we were able to reproduce experimental H 2 O 2 ${{\mathrm{H}}}_2{{\mathrm{O}}}_2$ radiolytic yields 1-h post-irradiation in aerated and deaerated conditions, showing the impact of small changes in oxygen concentrations on species evolution along time. For the Fricke dosimeter, simulated G(Fe3+) is 15.97 ± 0.2 molecules/100 eV which is 11% higher than the measured value (14.4 ± 04 molecules/100 eV). CONCLUSIONS: These results aim to be consolidated by new comparisons involving other radiolytic species, such as e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ or , O 2 • - $,{\mathrm{\ O}}_2^{ \bullet - }$ to further study the mechanisms underlying the FLASH effect observed at ultra-high dose rates (UHDR).

Can we reach suitable 161Tb purity for medical applications using the 160Gd(d,n) reaction?

Terbium is a chemical element that has several radioactive isotopes with suitable physical characteristics to be used in medical applications either for imaging or for therapy. This makes terbium a promising element to implement the theranostic approach. For therapeutic applications, 161Tb (T1/2 = 6.89 d) is suitable for targeted ß-therapy. The main production route is through neutron capture reaction in nuclear reactors. In this work, we explored an alternative production route, the 160Gd(d,n)161Tb reaction. We have measured its production cross-section as well as those of possible co-produced contaminants, with a special focus on 160Tb (T1/2 = 72.3 d). To achieve this, cross-section measurements were made from natural gadolinium target. Production yields of 10.3 MBq/µA/h for the 161Tb and 1.5 MBq/µA/h for the 160Tb were obtained at 20 MeV. A161Tb radionuclidic purity of 86% was achieved over the 8 MeV-20 MeV energy range. The co-production of other terbium isotopes limits the interest of using higher energies. Based on the limited purity of 161Tb using the 160Gd(d,n)161Tb reaction, we conclude that it is not a production route suitable for medical applications. Although, this may be reconsidered when mass separation technique with high efficiency will be available.

Study of terbium production from enriched Gd targets via the reaction 155Gd(d,2n)155Tb.

The terbium (Tb) family has attracted much attention in recent years thanks to the diagnostic and therapeutic applications of the quadruplet 149Tb, 152Tb, 155Tb and 161Tb. However, the scarce availability of Tb radioisotopes is one of the main reasons hindering its clinical applications. To increase its availability, this work proposes to use enriched gadolinium (Gd) targets to produce some Tb radioisotopes (149Tb, 152Tb, and 155Tb) via deuteron-induced reactions in cyclotrons. The production of the Auger and gamma emitter 155Tb was chosen as a case study because the 155Gd enrichment (92.8%) is the highest available from all Gd stable isotopes. The involved reaction is 155Gd(d,2n)155Tb. Using enriched thin Gd-containing targets, cross-sections of the reactions 155Gd(d,x)153,154,155,156Tb have been measured at the GIP ARRONAX cyclotron facility with a beam energy ranging from 8 MeV to 30 MeV. This measurement allows for estimating the production yield and the purity of 155Tb, and for determining the irradiation parameters for large production batches. A thick enriched 155Gd2O3 target has been then irradiated with an incident energy of 15.1 MeV and a beam current of 368 nA for 1 h. The production yield of 155Tb is 10.2 MBq/µA/h at End Of Bombardment (EOB) and the purity is 89% after 14 days of decay. These experimental values are consistent with estimation based on measured cross-sections. A comparison of the deuteron-induced and proton-induced production routes is also presented in this paper.

Ultrahigh-Dose-Rate Proton Irradiation Elicits Reduced Toxicity in Zebrafish Embryos.

Purpose: Recently, ultrahigh-dose-rate radiation therapy (UHDR-RT) has emerged as a promising strategy to increase the benefit/risk ratio of external RT. Extensive work is on the way to characterize the physical and biological parameters that control the so-called "Flash" effect. However, this healthy/tumor differential effect is observable in in vivo models, which thereby drastically limits the amount of work that is achievable in a timely manner. Methods and Materials: In this study, zebrafish embryos were used to compare the effect of UHDR irradiation (8-9 kGy/s) to conventional RT dose rate (0.2 Gy/s) with a 68 MeV proton beam. Viability, body length, spine curvature, and pericardial edema were measured 4 days postirradiation. Results: We show that body length is significantly greater after UHDR-RT compared with conventional RT by 180 µm at 30 Gy and 90 µm at 40 Gy, while pericardial edema is only reduced at 30 Gy. No differences were obtained in terms of survival or spine curvature. Conclusions: Zebrafish embryo length appears as a robust endpoint, and we anticipate that this model will substantially fasten the study of UHDR proton-beam parameters necessary for "Flash."

First evidence of in vivo effect of FLASH radiotherapy with helium ions in zebrafish embryos.

The ability to reduce toxicity of ultra-high dose rate (UHDR) helium ion irradiation has not been reported in vivo. Here, we tested UHDR helium ion irradiation in an embryonic zebrafish model. Our results show that UHDR helium ions spare body development and reduce spine curvature, compared to conventional dose rate.

Nuclear Cross-Section of Proton-Induced Reactions on Enriched 48Ti Targets for the Production of Theranostic 47Sc Radionuclide, 46cSc, 44mSc, 44gSc, 43Sc, and 48V.

The cross-sections of the 48Ti(p,x)47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V nuclear reactions were measured from 18 to 70 MeV, with particular attention to 47Sc production. Enriched 48Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: 47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V. 47Sc production was also discussed, considering yield and radionuclidic purity, for different 47Sc production scenarios.

Preclinical Evaluation of a 64Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma.

Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both ß+ and ß- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [64Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [64Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [64Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.

How Efficient Are Monte Carlo Calculations Together With the Q-System to Determine Radioactive Transport Limits? Case Study on Medical Radionuclides.

The development of the so-called theranostics approach, in which imaging information are used to define a personalized therapeutic strategy, is driving the increasing use of radionuclides in nuclear medicine. They are artificially produced either in nuclear reactors, charged particle accelerators, or using radionuclide generators. Each method leads to radioisotopes with different characteristics and then clinical utility. In the first two cases they are extracted from stable or radioactive target bombarded with a particle beam. After extraction/purification of the target, the radionuclides, either implanted on solid or in liquid form, needs to be transported to a centralized production site, a radiopharmacy or an hospital. The transport of needed radioactive material must obey strict rules. For a radionuclide, a limit in activity that it is possible to transport has been established for each type of allowed packages. For type A package these limits are called A1 (for special form sources, i.e., certified perfectly sealed and encapsulated sources) and A2 (for non-special form sources). However, these limits can be easily reached if the activity to transport is high or if the radionuclide of interest is a "non-conventional" one. Indeed, for many radionuclides, there are no available/tabulated A1 and A2 and, in these cases, a very conservative set of values is imposed. This is in particular the case for some of the non-conventional radionuclide of interest in medicine (as for example Tb-149 or Tb-161). The non-tabulated values, and in general the A1/A2 limit, can be evaluated following the so-called Q-system and using Monte Carlo calculations. In the present work, we have used the MCNPX Monte Carlo code to evaluate dose rate values in different exposure scenarios. This has allowed us to determine A1/A2 coefficients for several non-conventional radionuclides of interest for medical applications. The developed technique can be extended easily to other radionuclides and can be adapted in case of changes in regulatory rules.

Electrochemical co-deposition of Ni-Gd2O3 for composite thin targets preparation: Production of 155Tb as a case study.

In the last years, 155Tb has attracted enormous interest due to its potential role in theranostics in nuclear medicine. To estimate its production yield, the aim of this study was to develop a method to prepare thin Gd-enriched-containing targets aimed at the 155Gd(d, 2n)155Tb nuclear cross section measurement. To this end, the electrochemical co-deposition method has been chosen to manufacture Ni-Gd2O3 composite targets. Several process parameters that have an impact on the deposit quality, have been investigated to increase the incorporation of Gd mass (up to 3 mg). To validate the concept, seven targets made by natural Gd were irradiated with deuteron beams at the GIP ARRONAX facility cyclotron, with an energy range ranging from 8 MeV to 30 MeV to extract the cross section values by using the stacked-foils method. Results obtained turned out to have great consistency with existing published data thus validating the proposed method. Therefore, an alternative target manufacturing concept aimed at cross section measurement is presented in this work.

Proton Irradiations at Ultra-High Dose Rate vs. Conventional Dose Rate: Strong Impact on Hydrogen Peroxide Yield.

During ultra-high dose rate (UHDR) external radiation therapy, healthy tissues appear to be spared while tumor control remains the same compared to conventional dose rate. However, the understanding of radiochemical and biological mechanisms involved are still to be discussed. This study shows how the hydrogen peroxide (H2O2) production, one of the reactive oxygen species (ROS), could be controlled by early heterogenous radiolysis processes in water during UHDR proton-beam irradiations. Pure water was irradiated in the plateau region (track-segment) with 68 MeV protons under conventional (0.2 Gy/s) and several UHDR conditions (40 Gy/s to 60 kGy/s) at the ARRONAX cyclotron. Production of H2O2 was then monitored using the Ghormley triiodide method. New values of GTS(H2O2) were added in conventional dose rate. A substantial decrease in H2O2 production was observed from 0.2 to 1.5 kGy/s with a more dramatic decrease below 100 Gy/ s. At higher dose rate, up to 60 kGy/s, the H2O2 production stayed stable with a mean decrease of 38% ± 4%. This finding, associated to the decrease in the production of hydroxyl radical (•OH) already observed in other studies in similar conditions can be explained by the well-known spur theory in radiation chemistry. Thus, a two-step FLASH-RT mechanism can be envisioned: an early step at the microsecond scale mainly controlled by heterogenous radiolysis, and a second, slower, dominated by O2 depletion and biochemical processes. To validate this hypothesis, more measurements of radiolytic species will soon be performed, including radicals and associated lifetimes.

Technical note: Proton beam dosimetry at ultra-high dose rates (FLASH): Evaluation of GAFchromic™ (EBT3, EBT-XD) and OrthoChromic (OC-1) film performances.

PURPOSE: The ARRONAX cyclotron facility offers the possibility to deliver proton beams from low to ultra-high dose rates (UHDR). As a good control of the dosimetry is a prerequisite of UHDR experimentations, we evaluated in different conditions the usability and the dose rate dependency of several radiochromic films commonly used for dosimetry in radiotherapy. METHODS: We compared the dose rate dependency of three types of radiochromic films: GAFchromic™ EBT3 and GAFchromic™ EBT-XD (Ashland Inc., Wayne, NJ, USA), and OrthoChromic OC-1 (OrthoChrome Inc., Hillsborough, NJ, USA), after proton irradiations at various mean dose rates (0.25, 40, 1500, and 7500 Gy/s) and for 10 doses (2-130 Gy). We also evaluated the dose rate dependency of each film considering beam structures, from single pulse to multiple pulses with various frequencies. RESULTS: EBT3 and EBT-XD films showed differences of response between conventional (0.25 Gy/s) and UHDR (7500 Gy/s) conditions, above 10 Gy. On the contrary, OC-1 films did not present overall difference of response for doses except below 3 Gy. We observed an increase of the netOD with the mean dose rate for EBT3 and EBT-XD films. OC-1 films did not show any impact of the mean dose rate up to 7500 Gy/s, above 3 Gy. No difference was found based on the beam structure, for all three types of films. CONCLUSIONS: EBT3 and EBT-XD radiochromic films should be used with caution for the dosimetry of UHDR proton beams over 10 Gy. Their overresponse, which increases with mean dose rate and dose, could lead to non-negligible overestimations of the absolute dose. OC-1 films are dose rate independent up to 7500 Gy/s in proton beams. Films response is not impacted by the beam structure. A broader investigation of the usability of OC-1 films in UHDR conditions should be conducted at intermediate and higher mean dose rates and other beam energies.

Therapeutic efficacy of 166Holmium siloxane in microbrachytherapy of induced glioblastoma in minipig tumor model.

Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a preclinical experiment to evaluate therapeutic efficacy of 166Ho microparticle suspension administered by microbrachytherapy on a minipig glioblastoma model. Twelve minipigs were divided in 3 groups. Minipigs had injections into the tumor, containing microparticle suspensions of either 166Ho (group 1; n = 6) or 165Ho (group 2; n = 3) and control group (group 3; n = 3). The survival time from treatment to euthanasia was 66 days with a good state of health of all minipigs in group 1. The median survival time from treatment to tumor related death were 8.6 and 7.3 days in groups 2 and control, respectively. Statistically, the prolonged life of group 1 was significantly different from the two other groups (p < 0.01), and no significant difference was observed between group 2 and control (p=0.09). Our trial on the therapeutic effect of the 166Ho microparticle demonstrated an excellent efficacy in tumor control. The histological and immunohistochemical analysis showed that the efficacy was related to a severe 166Ho induced necrosis combined with an immune response due to the presence of the radioactive microparticles inside the tumors. The absence of reflux following the injections confirms the safety of the injection device.