Multi-scale dosimetry for targeted radionuclide therapy optimisation

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).Targeted Radionuclide Therapy (TRT) consists in killing tumour targets by using radiolabeled vectors (radiopharmaceuticals) that selectively bind to tumour cells. In a context of TRT optimization, a better determination of energy deposition within biologic material is a prerequisite to the definition of the absorbed dose-effect relationship and the improvement of future cancer treatment. This requires being able to quantitatively assess activity distribution (with the most appropriate molecular imaging technique) and perform radiation transport at the scale at which biologically relevant phenomena occur. The methodologies that should be applied and the problematic to be faced strictly depend on the scale (cell, tissue, body) of the application considered, and on the type of radiation involved (photons, electrons, alpha). This research work consisted in developing dedicated dosimetric techniques (single-scale dosimetry) capable of taking into account the peculiarity of different experimental scenarios (cellular, pre-clinical, clinical TRT)

Advanced radiation measurement techniques in diagnostic radiology and molecular imaging.

This paper reports some technological advances recently achieved in the fields of micro-CT and small animal PET instrumentation. It highlights a balance between image-quality improvement and dose reduction. Most of the recent accomplishments in these fields are due to the use of novel imaging sensors such as CMOS-based X-ray detectors and silicon photomultipliers (SiPM). Some of the research projects carried out at the University of Pisa for the development of such advanced radiation imaging technology are also described

Silicon Photomultipliers (SiPM) as novel photodetectors for PET

Next generation PET scanners should fulfill very high requirements in terms of spatial, energy and timing resolution. Modern scanner performances are inherently limited by the use of standard photomultiplier tubes. The use of Silicon Photomultipliers (SiPMs) is proposed for the construction of a 4D-PET module of 4.8×4.8 cm2 aimed to replace the standard PMT based PET block detector. The module will be based on a LYSO continuous crystal read on two faces by Silicon Photomultipliers. A high granularity detection surface made by SiPM matrices of 1.5 mm pitch will be used for the x–y photon hit position determination with submillimetric accuracy, while a low granularity surface constituted by 16 mm2 SiPM pixels will provide the fast timing information (t) that will be used to implement the Time of Flight technique (TOF). The spatial information collected by the two detector layers will be combined in order to measure the Depth of Interaction (DOI) of each event (z). The use of large area multi-pixel Silicon Photomultiplier (SiPM) detectors requires the development of a multichannel Data Acquisition system (DAQ) as well as of a dedicated front-end in order not to degrade the intrinsic detector capabilities and to manage many channels. The paper describes the progress made on the development of the proof of principle module under construction at the University of Pisa

Timing performances of a data acquisition system for time of flight PET

We are investigating the performances of a data acquisition system for Time of Flight PET, based on LYSO crystal slabs and 64 channels Silicon Photomultipliers matrices (1.2 cm2 of active area each). Measurements have been performed to test the timing capability of the detection system (SiPM matices coupled to a LYSO slab and the read-out electronics) with both test signal and radioactive source

Detectors for the next-generation PET scanners

Next-generation PET scanners are expected to fulfill very high requirements in terms of spatial, energy and timing resolution. Modern scanner performances are inherently limited by the use of standard photomultiplier tubes. The use of Silicon Photomultiplier (SiPM) matrices is proposed for the construction of a small animal PET system with depth of interaction capabilities. Measurements showing that SiPM matrices are highly ideal for PET applications, have been reported

Characterization and Test of a Data Acquisition System for PET

A small Positron Emission Tomography demonstrator based on LYSO slabs and Silicon Photomultiplier matrices is under construction at the University and INFN of Pisa. In this paper we present the characterization results of the read-out electronics and of the detection system. Two SiPM matrices, composed by 8 × 8 SiPM pixels, 1.5 mm pitch, have been coupled one to one to a LYSO crystals array. Custom Front-End ASICs were used to read the 64 channels of each matrix. Data from each Front-End were multiplexed and sent to a DAQ board for the digital conversion; a motherboard collects the data and communicates with a host computer through a USB port. Specific tests were carried out on the system in order to assess its performance. Futhermore we have measured some of the most important parameters of the system for PET application

Proof of concept of an imaging system demonstrator for PET applications with SiPM

A PET imaging system demonstrator based on LYSO crystal arrays coupled to SiPM matrices is under construction at the University and INFN of Pisa. Two SiPM matrices, composed of 8×8 SiPM pixels, and 1,5 mm pitch, have been coupled one to one to a LYSO crystals array and read out by a custom electronics system. front-end ASICs were used to read 8 channels of each matrix. Data from each front-end were multiplexed and sent to a DAQ board for the digital conversion; a motherboard collects the data and communicates with a host computer through a USB port for the storage and off-line data processing. In this paper we show the first preliminary tomographic image of a point-like radioactive source acquired with part of the two detection heads in time coincidence

Silicon Photomultipliers (SiPM) as novel photodetectors for PET

a b s t r a c t Next generation PET scanners should fulfill very high requirements in terms of spatial, energy and timing resolution. Modern scanner performances are inherently limited by the use of standard photomultiplier tubes. The use of Silicon Photomultipliers (SiPMs) is proposed for the construction of a 4D-PET module of 4.8 Â 4.8 cm 2 aimed to replace the standard PMT based PET block detector. The module will be based on a LYSO continuous crystal read on two faces by Silicon Photomultipliers. A high granularity detection surface made by SiPM matrices of 1.5 mm pitch will be used for the x-y photon hit position determination with submillimetric accuracy, while a low granularity surface constituted by 16 mm 2 SiPM pixels will provide the fast timing information (t) that will be used to implement the Time of Flight technique (TOF). The spatial information collected by the two detector layers will be combined in order to measure the Depth of Interaction (DOI) of each event (z). The use of large area multi-pixel Silicon Photomultiplier (SiPM) detectors requires the development of a multichannel Data Acquisition system (DAQ) as well as of a dedicated front-end in order not to degrade the intrinsic detector capabilities and to manage many channels. The paper describes the progress made on the development of the proof of principle module under construction at the University of Pisa

Proof of concept of an imaging system demonstrator for PET applications with SiPM

a b s t r a c t A PET imaging system demonstrator based on LYSO crystal arrays coupled to SiPM matrices is under construction at the University and INFN of Pisa. Two SiPM matrices, composed of 8 Â 8 SiPM pixels, and 1,5 mm pitch, have been coupled one to one to a LYSO crystals array and read out by a custom electronics system. front-end ASICs were used to read 8 channels of each matrix. Data from each frontend were multiplexed and sent to a DAQ board for the digital conversion; a motherboard collects the data and communicates with a host computer through a USB port for the storage and off-line data processing. In this paper we show the first preliminary tomographic image of a point-like radioactive source acquired with part of the two detection heads in time coincidence

Dosimétrie multi-échelle pour l'optimisation de la radiothérapie interne vectorisée

Targeted Radionuclide Therapy (TRT) consists in killing tumour targets by using radiolabeled vectors (radiopharmaceuticals) that selectively bind to tumour cells. In a context of TRT optimization, a better determination of energy deposition within biologic material is a prerequisite to the definition of the absorbed dose-effect relationship and the improvement of future cancer treatment. This requires being able to quantitatively assess activity distribution (with the most appropriate molecular imaging technique) and perform radiation transport at the scale at which biologically relevant phenomena occur. The methodologies that should be applied and the problematic to be faced strictly depend on the scale (cell, tissue, body) of the application considered, and on the type of radiation involved (photons, electrons, alpha). This research work consisted in developing dedicated dosimetric techniques (single-scale dosimetry) capable of taking into account the peculiarity of different experimental scenarios (cellular, pre-clinical, clinical TRT).All methods developed were tested in the framework of actual research applications and experiments:• The development and validation of a 3D cellular model allowed a better understanding of the radiative and non-radiative processes associated to cellular death in the case of clonogenic survival experiments involving beta emitters.• A Monte Carlo based application for the calculation of the absorbed dose distributions in ex-vivo mouse tumours helped in assessing the absorbed dose- effect relationship for three different antibodies labelled with an alpha emitter (212Pb).• In addition, a comparison of different absorbed dose calculation algorithms in a diagnostic context highlighted the potential limits of standard dosimetric approaches currently employed in the clinic.• An adaptive resolution approach to clinical dosimetry (multi-scale dosimetry) is also proposed in order to increase the accuracy of absorbed dose delivery in small radiosensitive organs.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). Les méthodes mises en œuvres au cours de cette thèse (dans le cadre d’application dosimétrique réelles) sont : • Le développement et la validation d'un modèle cellulaire 3D qui ont permis une meilleure compréhension des processus radiatifs et non radiatifs associés à la mort cellulaire dans le cadre d'expériences de survie clonogénique avec des émetteurs bêta. • Une application Monte-Carlo pour le calcul des distributions de dose absorbée dans les tumeurs de souris ex vivo qui a permis d’établir une relation dose absorbée - effet pour trois anticorps différents marqués par un émetteur alpha (212Pb). • Une comparaison des différents algorithmes de calcul de dose absorbée dans un contexte de diagnostic qui a mis en évidence les limites potentielles des approches dosimétriques standards actuellement utilisées en clinique. • Une approche de résolution adaptative pour la dosimétrie clinique (dosimétrie multi-échelle) également proposée afin d'augmenter la précision sur la dose absorbée dans de petits organes radiosensibles