A high sensitivity Cherenkov detector for prompt gamma timing and time imaging.

We recently proposed a new approach for the real-time monitoring of particle therapy treatments with the goal of achieving high sensitivities on the particle range measurement already at limited counting statistics. This method extends the Prompt Gamma (PG) timing technique to obtain the PG vertex distribution from the exclusive measurement of particle Time-Of-Flight (TOF). It was previously shown, through Monte Carlo simulation, that an original data reconstruction algorithm (Prompt Gamma Time Imaging) allows to combine the response of multiple detectors placed around the target. The sensitivity of this technique depends on both the system time resolution and the beam intensity. At reduced intensities (Single Proton Regime-SPR), a millimetric proton range sensitivity can be achieved, provided the overall PG plus proton TOF can be measured with a 235 ps (FWHM) time resolution. At nominal beam intensities, a sensitivity of a few mm can still be obtained by increasing the number of incident protons included in the monitoring procedure. In this work we focus on the experimental feasibility of PGTI in SPR through the development of a multi-channel, Cherenkov-based PG detector with a targeted time resolution of 235 ps (FWHM): the TOF Imaging ARrAy (TIARA). Since PG emission is a rare phenomenon, TIARA design is led by the concomitant optimisation of its detection efficiency and Signal to Noise Ratio (SNR). The PG module that we developed is composed of a small PbF[Formula: see text] crystal coupled to a silicon photoMultiplier to provide the time stamp of the PG. This module is currently read in time coincidence with a diamond-based beam monitor placed upstream the target/patient to measure the proton time of arrival. TIARA will be eventually composed of 30 identical modules uniformly arranged around the target. The absence of a collimation system and the use of Cherenkov radiators are both crucial to increase the detection efficiency and the SNR, respectively. A first prototype of the TIARA block detector was tested with 63 MeV protons delivered from a cyclotron: a time resolution of 276 ps (FWHM) was obtained, resulting in a proton range sensitivity of 4 mm at 2[Formula: see text] with the acquisition of only 600 PGs. A second prototype was also evaluated with 148 MeV protons delivered from a synchro-cyclotron obtaining a time resolution below 167 ps (FWHM) for the gamma detector. Moreover, using two identical PG modules, it was shown that a uniform sensitivity on the PG profiles would be achievable by combining the response of gamma detectors uniformly distributed around the target. This work provides the experimental proof-of-concept for the development of a high sensitivity detector that can be used to monitor particle therapy treatments and potentially act in real-time if the irradiation does not comply to treatment plan.

Influence of sub-nanosecond time of flight resolution for online range verification in proton therapy using the line-cone reconstruction in Compton imaging.

Online ion range monitoring in hadron therapy can be performed via detection of secondary radiation, such as promptγ-rays, emitted during treatment. The promptγemission 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 theγfall-off position (FOP) measured via line-cone reconstruction, where TOF comprises both the proton transit time from the phantom entrance untilγemission, and the flight time of theγ-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 CeBr3scintillator 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 independentγemission profiles compared to a high statistics reference profile. The optimal temporal resolution for the given camera geometry and 108primary protons was 0.2 ns where a precision of 2.30 ± 0.15 mm (1σ) 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.

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

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 2σwith 108incident protons in simplified simulation settings. With the same proton statistics, a potential 2 mm sensitivity (at 2σwith 108incident 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 2σwith 109incident 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.

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest.

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt's lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.

Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy.

PURPOSE: For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects. EXPERIMENTAL DESIGN: Here, we investigated the contribution of nontargeted 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% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB 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 nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

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.

Internal dosimetry with the Monte Carlo code GATE: validation using the ICRP/ICRU female reference computational model.

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.

A review of the use and potential of the GATE Monte Carlo simulation code for radiation therapy and dosimetry applications.

In this paper, the authors' review the applicability of the open-source GATE Monte Carlo simulation platform based on the GEANT4 toolkit for radiation therapy and dosimetry applications. The many applications of GATE for state-of-the-art radiotherapy simulations are described including external beam radiotherapy, brachytherapy, intraoperative radiotherapy, hadrontherapy, molecular radiotherapy, and in vivo dose monitoring. Investigations that have been performed using GEANT4 only are also mentioned to illustrate the potential of GATE. The very practical feature of GATE making it easy to model both a treatment and an imaging acquisition within the same framework is emphasized. The computational times associated with several applications are provided to illustrate the practical feasibility of the simulations using current computing facilities.