Sara Marcatili

We developed a novel gamma-ray detection system (TIARA) for range monitoring in Particle Therapy. The system employs Cherenkov-based gamma-ray detection modules arranged around the target or patient, operated in time coincidence with a fast plastic beam monitor (described in a separate paper). This work focuses on the design and comprehensive characterization of the gamma-ray detection module. It consists of a monolithic PbF2 crystal (2 × 1.5 × 1.5 cm³) coupled to a 2 × 2 SiPM matrix from Hamamatsu. A series of beam tests at different clinical facilities (MEDICYC and ProteusOne in France, CNAO in Italy) enabled the determination of the detector time resolution under various conditions, with values ranging from 222 to 283 ps FWHM (Full Width Half Maximum). Monte Carlo simulations including the optical response of PbF₂ allowed for the determination of the detection efficiency as a function of particle type and energy. For the final TIARA prototype, which will be composed of 30 modules, an overall detection efficiency of 0.45% is expected. Comparison with experimental data confirmed that the modules are effectively insensitive to neutrons, yielding an excellent signal-to-noise ratio (SNR), with an estimated SNR of 17 for a module placed at 25 cm from the 148 MeV proton beam axis. These features translate into high range accuracy: while the performance varies with beam energy and irradiation conditions, a range accuracy of 3.3 mm at 2σ significance level was achieved at low intensity with 63 MeV protons at MEDICYC, for a small irradiation spot of ~ 10⁷ protons.

Dosimétrie multi-échelle pour l'optimisation de la radiothérapie interne vectorisée: La Radiothérapie Interne Vectorisée (RIV) consiste à détruire des cibles tumorales en utilisant des vecteurs radiomarqués (radiopharmaceutiques) qui se lient sélectivement à des cellules tumorales. Dans un contexte d'optimisation de la RIV, une meilleure détermination du dépôt d'énergie dans les tissues biologiques est primordiale pour la définition d'une relation dose absorbée - effet biologique et pour l'optimisation des traitement du cancer. Cela nécessite une évaluation quantitative de la distribution de l'activité (avec la technique d'imagerie moléculaire la plus appropriée) et d'effectuer le transport du rayonnement à l'échelle à laquelle se produisent les phénomènes biologiques pertinents. Les méthodologies à appliquer et les problématiques à établir dépendent strictement de l'échelle (cellule, tissu, organe) de l'application considérée, et du type de rayonnement en cause (photons, électrons, particules alpha). Mon travail de recherche a consisté à développer des techniques dosimétriques dédiées (dosimétrie mono-échelle) et innovantes, capables de prendre en compte la particularité de différents scénarios expérimentaux (cellulaire, pré-clinique, RIV clinique).

In the context of particle therapy monitoring, we are developing a gamma-ray detector to determine the ion range in vivo from the measurement of particle time-of-flight. For this application, a beam monitor capable to tag in time the incident ion with a time resolution below 235 ps FWHM (100 ps rms) is required to provide a start signal for the acquisition. We have therefore developed a dedicated detector based on a fast organic scintillator (EJ-204) of 25 ×25 ×1 mm3 coupled to four SiPM strips that allow measuring the particle incident position by scintillation light sharing. The prototype was characterised with single protons of energies between 63 and 225 MeV at the MEDICYC and ProteusONE facilities of the Antoine Lacassagne proton therapy centre in Nice. We obtained a time resolution of 120 ps FWHM at 63 MeV, and a spatial resolution of 2 mm rms for single particles. Two identical detectors also allowed to measure the MEDICYC proton energy with 0.3% accuracy.

We 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 2 σ with 10 ⁸ incident protons in simplified simulation settings. With the same proton statistics, a potential 2 mm sensitivity (at 2 σ with 10 ⁸ 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 2 σ with 10 ⁹ 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.

Online ion range monitoring in hadron therapy can be performed via detection of secondary radiation, such as prompt γ -rays, emitted during treatment. The prompt γ emission profile is correlated with the ion depth-dose profile and can be reconstructed via Compton imaging. The line-cone reconstruction, using the intersection between the primary beam trajectory and the cone reconstructed via a Compton camera, requires negligible computation time compared to iterative algorithms. A recent report hypothesised that time of flight (TOF) based discrimination could improve the precision of the γ fall-off position (FOP) measured via line-cone reconstruction, where TOF comprises both the proton transit time from the phantom entrance until γ emission, and the flight time of the γ -ray to the detector. The aim of this study was to implement such a method and investigate the influence of temporal resolution on the precision of the FOP. Monte Carlo simulations of a 160 MeV proton beam incident on a homogeneous PMMA phantom were performed using GATE. The Compton camera consisted of a silicon-based scatterer and CeBr ₃ scintillator absorber. The temporal resolution of the detection system (absorber + beam trigger) was varied between 0.1 and 1.3 ns rms and a TOF-based discrimination method applied to eliminate unlikely solution(s) from the line-cone reconstruction. The FOP was obtained for varying temporal resolutions and its precision obtained from its shift across 100 independent γ emission profiles compared to a high statistics reference profile. The optimal temporal resolution for the given camera geometry and 10 ⁸ primary protons was 0.2 ns where a precision of 2.30 ± 0.15 mm (1 σ ) on the FOP was found. This precision is comparable to current state-of-the-art Compton imaging using iterative reconstruction methods or 1D imaging with mechanically collimated devices, and satisfies the requirement of being smaller than the clinical safety margins.

Purpose: For the development of new anti-cancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated neighboring cells because they may affect the therapeutic efficacy and contribute to side effects. Experimental Design: Here, we investigated the contribution of non-targeted cytotoxic and genotoxic effects in vitro and in vivo in (xenografted mice) during alpha (²¹²Pb/²¹²Bi, ²¹³Bi) and Auger (¹²⁵I) radioimmunotherapy (RIT). Results: Between 67 and 94% (alpha RIT) and 8 and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7-36% (alpha RIT) and 27-29% (Auger RIT) of cells were killed by non-targeted effects. We then demonstrated that the non-targeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and c-JUN N-terminal kinases (JNK). Reactive oxygen species also played a significant role in these non-targeted effects, as demonstrated by NF-kB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT. Conclusions: Cell membrane-mediated non-targeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

The purpose of this work was to validate GATE-based clinical scale absorbed dose calculations in nuclear medicine dosimetry. GATE (version 6.2) and MCNPX (version 2.7.a) were used to derive dosimetric parameters (absorbed fractions, specific absorbed fractions and S-values) for the reference female computational model proposed by the International Commission on Radiological Protection in ICRP report 110. Monoenergetic photons and electrons (from 50 keV to 2 MeV) and four isotopes currently used in nuclear medicine (fluorine-18, lutetium-177, iodine-131 and yttrium-90) were investigated. Absorbed fractions, specific absorbed fractions and S-values were generated with GATE and MCNPX for 12 regions of interest in the ICRP 110 female computational model, thereby leading to 144 source/target pair configurations. Relative differences between GATE and MCNPX obtained in specific configurations (self-irradiation or cross-irradiation) are presented. Relative differences in absorbed fractions, specific absorbed fractions or S-values are below 10%, and in most cases less than 5%. Dosimetric results generated with GATE for the 12 volumes of interest are available as supplemental data. GATE can be safely used for radiopharmaceutical dosimetry at the clinical scale. This makes GATE a viable option for Monte Carlo modelling of both imaging and absorbed dose in nuclear medicine.

Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin^®, a novel ¹⁷⁷Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of ¹⁷⁷Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

Purpose: The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model‐based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case.Methods: The authors calculated absorbed doses to various organs in six healthy volunteers administered with flutemetamol (¹⁸F) injection. Each patient underwent from 8 to 10 whole body 3D PET/CT scans. This dataset was analyzed using a Monte Carlo (MC) application developed in‐house using the toolkit gate that is capable to take into account patient‐specific anatomy and radiotracer distribution at the voxel level. They compared the absorbed doses obtained with gate to those calculated with two commercially available software: olinda/exm and stratos implementing a dose voxel kernel convolution approach.Results: Absorbed doses calculated with gate were higher than those calculated with olinda. The average ratio between gate absorbed doses and olinda’s was 1.38 ± 0.34 σ (from 0.93 to 2.23). The discrepancy was particularly high for the thyroid, with an average gate/olinda ratio of 1.97 ± 0.83 σ for the six patients. Differences between stratos and gate were found to be higher. The average ratio between gate and stratos absorbed doses was 2.51 ± 1.21 σ (from 1.09 to 6.06).Conclusions: This study demonstrates how the choice of the absorbed dose calculation algorithm may introduce a bias when gamma radiations are of importance, as is the case in nuclear medicine diagnostics.