A quantitative assessment of Geant4 for predicting the yield and distribution of positron-emitting fragments in ion beam therapy.

PURPOSE: To compare the accuracy with which different hadronic inelastic physics models across ten Geant4 Monte Carlo simulation toolkit versions can predict positron-emitting fragments produced along the beam path during carbon and oxygen ion therapy. Materials and Methods: Phantoms of polyethylene, gelatin or poly(methyl methacrylate) were irradiated with monoenergetic carbon and oxygen ion beams. Post-irradiation, 4D PET images were acquired and parent11C,10C and15O radionuclides contributions in each voxel were determined from the extracted time activity curves. Next, the experimental configurations were simulated in Geant4 Monte Carlo versions 10.0 to 11.1, with three different fragmentation models - binary ion cascade (BIC), quantum molecular dynamics (QMD) and the Liege intranuclear cascade (INCL++) - 30 model-version combinations. Total positron annihilation and parent isotope production yields predicted by each simulation were compared between simulations and experiments using normalised mean squared error and Pearson cross-correlation coefficient. Finally, we compared the depth of maximum positron annihilation yield and the distal point at which positron yield decreases to 50% of peak between each model and the experimental results. Results: Performance varied considerably across versions and models, with no one version/model combination providing the best prediction of all positron-emitting fragments in all evaluated target materials and irradiation conidiations. BIC in Geant4 10.2 provided the best overall agreement with experimental results in the largest number of test cases. QMD consistently provided the best estimates of both the depth of peak positron yield (10.4 and 10.6) and the distal 50%-of-peak point (10.2), while BIC also performed well and INCL generally performed the worst across most Geant4 versions. Conclusions: Best spatial prediction of annihilation yield and positron-emitting fragment production during carbon and oxygen ion therapy was found to be 10.2.p03 with BIC or QMD. These version/model combinations are recommended for future heavy ion therapy research.

Discrimination of inter-crystal scattering events by signal processing for the X'tal cube PET detector.

Inter-crystal scattering (ICS) events cause degradation of the contrast in PET images. We developed the X'tal cube PET detector with submillimeter spatial resolution, which consisted of a segmented LYSO scintillator and 96 MPPCs. For this high spatial resolution PET detector, the ICS event was not negligible. In this study, we proposed a method to discriminate the ICS events and showed its feasibility by the following method. For each 96 MPPC, we measured the mean and standard deviation of the peak in the pulse height distribution obtained by the photoabsorption events in a scintillator pixel. Every time a newly detected event was identified as the segment, we monitored the reduced chi-square value that was calculated with the pulse height and the prepared mean and the standard deviation for each 96 MPPC. Since the pulse height caused by the photoabsorption event resulted in a small reduced chi-square value, we could eliminate the ICS events by setting a threshold on the reduced chi-square value. We carried out both a Monte Carlo simulation and a scanning experiment. By the simulation, we confirmed that the threshold of the reduced chi square significantly discriminated the ICS event. We obtained the response function by a scanning experiment with a 0.2 mm slit beam of 511 keV gamma-ray. The standard deviation of the response function was improved from 1.6 to 1.06 mm by eliminating the ICS events. The proposed method could significantly eliminate the ICS events and retain the true events.

Design study of a novel geometrical arrangement for an in-beam small animal positron emission tomography scanner.

Objective.We designed a geometrical solution for a small animal in-beam positron emission tomography (PET) scanner to be used in the project SIRMIO (Small animal proton irradiator for research in molecular image-guided radiation-oncology). The system is based on 56 scintillator blocks of pixelated LYSO crystals. The crystals are arranged providing a pyramidal-step shape to optimize the geometrical coverage in a spherical configuration.Approach.Different arrangements have been simulated and compared in terms of spatial resolution and sensitivity. The chosen setup enables us to reach a good trade-off between a solid angle coverage and sufficient available space for the integration of additional components of the first design prototype of the SIRMIO platform. The possibility of moving the mouse holder inside the PET scanner furthermore allows for achieving the optimum placement of the irradiation area for all the possible tumor positions in the body of the mouse. The work also includes a study of the scintillator material where LYSO and GAGG are compared with a focus on the random coincidence noise due to the natural radioactivity of Lutetium in LYSO, justifying the choice of LYSO for the development of the final system.Main results.The best imaging performance can be achieved with a sub-millimeter spatial resolution and sensitivity of 10% in the center of the scanner, as verified in thorough simulations of point sources. The simulation of realistic irradiation scenarios of proton beams in PMMA targets with/without air gaps indicates the ability of the proposed PET system to detect range shifts down to 0.2 mm.Significance.The presented results support the choice of the identified optimal design for a novel spherical in-beam PET scanner which is currently under commissioning for application to small animal proton and light ion irradiation, and which might find also application, e.g. for biological image-guidance in x-ray irradiation.

Radioactive Beams for Image-Guided Particle Therapy: The BARB Experiment at GSI.

Several techniques are under development for image-guidance in particle therapy. Positron (ß+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by ß+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using ß+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

Performance evaluation of a staggered three-layer DOI PET detector using a 1 mm LYSO pitch with PETsys TOFPET2 ASIC: comparison of HAMAMATSU and KETEK SiPMs.

In this study, we propose a staggered three-layer depth-of-interaction (DOI) detector with a 1 mm crystal pitch and 19.8 mm total crystal thickness for a high-resolution and high-sensitivity small animal in-beam PET scanner. A three-layered stacked LYSO scintillation array (0.9 × 0.9 × 6.6 mm3crystals, 23 × 22 mm2surface area) read out by a SiPM array (8 × 8 channels, 3 × 3 mm2active area/channel and 50µm microcell size) with data acquisition, signal processing and digitization performed using the PETsys Electronics Evaluations kit (based on the TOFPET v2c ASIC) builds a DOI LYSO detector block. The performance of the DOI detector was evaluated in terms of crystal resolvability, energy resolution, and coincidence resolving time (CRT). A comparative performance evaluation of the staggered three-layer LYSO block was conducted with two different SiPM arrays from KETEK and HAMAMATSU. 100% (KETEK) and 99.8% (HAMAMATSU) of the crystals were identified, by using a flood irradiation the front- and back-side. The average energy resolutions for the 1st, 2nd, and 3rd layers were 16.5 (±2.3)%, 20.9(±4.0)%, and 32.7 (±21.0)% (KETEK) and 19.3 (±3.5)%, 21.2 (±4.1)%, and 26.6 (±10.3)% (HAMAMATSU) for the used SiPM arrays. The measured CRTs (FWHM) for the 1st, 2nd, and 3rd layers were 532 (±111) ps, 463 (±108) ps, and 447 (±111) ps (KETEK) and 402 (±46) ps, 392 (±54) ps, and 408 (±196) ps (HAMAMATSU). In conclusion, the performance of the staggered three-layer DOI detector with 1 mm LYSO pitch and 19.8 mm total crystal thickness was fully characterized. The feasibility of a highly performing readout of a high resolution DOI PET detector via SiPM arrays from KETEK and HAMAMATSU employing the PETsys TOFPET v2c ASIC could be demonstrated.

Towards a novel small animal proton irradiation platform: the SIRMIO project.

Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with in situ multi-modal anatomical image guidance and in vivo verification of the actual treatment delivery. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for in situimaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with on site range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in vivo radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies.

Comparative study of alternative Geant4 hadronic ion inelastic physics models for prediction of positron-emitting radionuclide production in carbon and oxygen ion therapy.

The distribution of fragmentation products predicted by Monte Carlo simulations of heavy ion therapy depend on the hadronic physics model chosen in the simulation. This work aims to evaluate three alternative hadronic inelastic fragmentation physics options available in the Geant4 Monte Carlo radiation physics simulation framework to determine which model most accurately predicts the production of positron-emitting fragmentation products observable using in-beam PET imaging. Fragment distributions obtained with the BIC, QMD, and INCL + + physics models in Geant4 version 10.2.p03 are compared to experimental data obtained at the HIMAC heavy-ion treatment facility at NIRS in Chiba, Japan. For both simulations and experiments, monoenergetic beams are applied to three different block phantoms composed of gelatin, poly(methyl methacrylate) and polyethylene. The yields of the positron-emitting nuclei 11C, 10C and 15O obtained from simulations conducted with each model are compared to the experimental yields estimated by fitting a multi-exponential radioactive decay model to dynamic PET images using the normalised mean square error metric in the entrance, build up/Bragg peak and tail regions. Significant differences in positron-emitting fragment yield are observed among the three physics models with the best overall fit to experimental 12C and 16O beam measurements obtained with the BIC physics model.

Performance evaluation of a whole-body prototype PET scanner with four-layer DOI detectors.

Parallax error caused by the detector crystal thickness degrades spatial resolution at the peripheral regions of the field-of-view (FOV) of a scanner. To resolve this issue, depth-of-interaction (DOI) measurement is a promising solution to improve the spatial resolution and its uniformity over the entire FOV. Even though DOI detectors have been used in dedicated systems with a small ring diameter such as for the human brain, breast and small animals, the use of DOI detectors for a large bore whole-body PET system has not been demonstrated yet. We have developed a four-layered DOI detector, and its potential for a brain dedicated system has been proven in our previous development. In the present work, we investigated the use of the four-layer DOI detector for a large bore PET system by developing the world's first whole-body prototype. We evaluated its performance characteristics in accordance with the NEMA NU 2 standard. Furthermore, the impact of incorporating DOI information was evaluated with the NEMA NU 4 image quality phantom. Point source images were reconstructed with a filtered back projection (FBP), and an average spatial resolution of 5.2 ± 0.7 mm was obtained. For the FBP image, the four-layer DOI information improved the radial spatial resolution by 48% at the 20 cm offset position. The peak noise-equivalent count rate (NECR) was 22.9 kcps at 7.4 kBq ml-1 and the scatter fraction was 44%. The system sensitivity was 5.9 kcps MBq-1. For the NEMA NU 2 image quality phantom, the 10 mm sphere was clearly visualized without any artifacts. For the NEMA NU 4 image quality phantom, we measured the phantom at 0, 10 and 20 cm offset positions. As a result, we found the image with four-layer DOI could visualize the 2 mm-diameter hot cylinder although it could not be recognized on the image without DOI. The average improvements in the recovery coefficients for the five hot rods (1-5 mm) were 0.3%, 4.4% and 26.3% at the 0, 10 and 20 cm offset positions, respectively (except for the 1 mm-diameter rod at the 20 cm offset position). Although several practical issues (such as adding end-shields) remain to be addressed before the scanner is ready for clinical use, we showed that the four-layer DOI technology provided higher and more uniform spatial resolution over the FOV and improved contrast for small uptake regions located at the peripheral FOV, which could improve detectability of small and distal lesions such as nodal metastases, especially in obese patients.

Development of a dual-ended readout detector with segmented crystal bars made using a subsurface laser engraving technique.

Depth of interaction (DOI) information is indispensable to improving the sensitivity and spatial resolution of positron emission tomography (PET) systems, especially for small field-of-view PET such as small animal PET and human brain PET. We have already developed a series of X'tal cube detectors for isotropic spatial resolution and we obtained the best isotropic resolution of 0.77 mm for detectors with six-sided readout. However, it is still challenging to apply the detector for PET systems due to the high cost of six-sided readout electronics and carrying out segmentation of a monolithic cubic scintillator in three dimensions using the subsurface laser engraving (SSLE) technique. In this work, we propose a more practical X'tal cube with a two-sided readout detector, which is made of crystal bars segmented in the height direction only by using the SSLE technique. We developed two types of prototype detectors with a 3 mm cubic segment and a 1.5 mm cubic segment by using 3 × 3 × 20 mm3 and 1.5 × 1.5 × 20 mm3 crystal bars segmented into 7 and 13 DOI segments, respectively, using the SSLE technique. First, the performance of the detector, composed of one crystal bar with different DOI segments and two thorough silicon via (TSV) multi-pixel photon counters (MPPCs) as readout at both ends of the crystal bar, were evaluated in order to demonstrate the capability of the segmented crystal bars as a DOI detector. Then, performance evaluation was carried out for a 4 × 4 crystal array of 3 × 3 × 20 mm3 with 7 DOI segments and an 8 × 8 crystal array of 1.5 × 1.5 × 20 mm3 with 13 DOI segments. Each readout included a 4 × 4 channel of the 3 × 3 mm2 active area of the TSV MPPCs. The three-dimensional position maps of the detectors were obtained by the Anger-type calculation. All the segments in the 4 × 4 array were identified very clearly when there was air between the crystal bars, as each crystal bar was coupled to one channel of the MPPCs; however, it was necessary to optimize optical conditions between crystal bars for the 8 × 8 array because of light sharing between crystal bars coupled to one channel of the MPPCs. The optimization was performed for the 8 × 8 array by inserting reflectors fully or partially between the crystal bars and the best crystal identification performance was obtained with the partial reflectors between the crystal bars. The mean energy resolutions at the 511 keV photo peak for the 4 × 4 array with air between the crystal bars and for the 8 × 8 array with partial reflectors between the crystal bars were 10.1% ± 0.3% and 10.8% ± 0.8%, respectively. Timing resolutions of 783 ± 36 ps and 1.14 ± 0.22 ns were obtained for the detectors composed of the 4 × 4 array and the 8 × 8 array with partial reflectors, respectively. These values correspond to single photon timing resolutions. Practical X'tal cubes with 3 mm and 1.5 mm DOI resolutions and two-sided readout were developed.

Induced radioactivity of a GSO scintillator by secondary fragments in carbon ion therapy and its effects on in-beam OpenPET imaging.

The accumulation of induced radioactivity within in-beam PET scanner scintillators is of concern for its long-term clinical usage in particle therapy. To estimate the effects on OpenPET which we are developing for in-beam PET based on GSOZ (Zi doped Gd2SiO5), we measured the induced radioactivity of GSO activated by secondary fragments in a water phantom irradiation by a (12)C beam with an energy of 290 MeV u(-1). Radioisotopes of Na, Ce, Eu, Gd, Nd, Pm and Tb including positron emitters were observed in the gamma ray spectra of the activated GSO with a high purity Ge detector and their absolute radioactivities were calculated. We used the Monte Carlo simulation platform, Geant4 in which the observed radioactivity was assigned to the scintillators of a precisely reproduced OpenPET and the single and coincidence rates immediately after one treatment and after one-year usage were estimated for the most severe conditions. Comparing the highest coincidence rate originating from the activated scintillators (background) and the expected coincidence rate from an imaging object (signal), we determined the expected signal-to-noise ratio to be more than 7 within 3 min and more than 10 within 1 min from the scan start time. We concluded the effects of scintillator activation and their accumulation on the OpenPET imaging were small and clinical long-term usage of the OpenPET was feasible.

Development of a small single-ring OpenPET prototype with a novel transformable architecture.

The single-ring OpenPET (SROP), for which the detector arrangement has a cylinder shape cut by two parallel planes at a slant angle to form an open space, is our original proposal for in-beam PET. In this study, we developed a small prototype of an axial-shift type SROP (AS-SROP) with a novel transformable architecture for a proof-of-concept. In the AS-SROP, detectors originally forming a cylindrical PET are axially shifted little by little. We designed the small AS-SROP prototype for 4-layer depth-of-interaction detectors arranged in a ring diameter of 250 mm. The prototype had two modes: open and closed. The open mode formed the SROP with the open space of 139 mm and the closed mode formed a conventional cylindrical PET. The detectors were simultaneously moved by a rotation handle allowing them to be transformed between the two modes. We evaluated the basic performance of the developed prototype and carried out in-beam imaging tests in the HIMAC using (11)C radioactive beam irradiation. As a result, we found the open mode enabled in-beam PET imaging at a slight cost of imaging performance; the spatial resolution and sensitivity were 2.6 mm and 5.1% for the open mode and 2.1 mm and 7.3% for the closed mode. We concluded that the AS-SROP can minimize the decrease of resolution and sensitivity, for example, by transforming into the closed mode immediately after the irradiation while maintaining the open space only for the in-beam PET measurement.

Positron annihilation spectroscopy of biological tissue in 11C irradiation.

Positron annihilation spectroscopy (PAS) spectra of biological tissue in 11C irradiation are reported and spatial resolution coefficient of positron emission tomography (PET) obtained from the PAS spectrum is discussed for 11C irradiation. A PAS spectrum of the biological tissue with water is the same as that of the water pool phantom in 11C irradiation. However, a PAS spectrum of the biological tissue with less water differs from that of the water pool phantom. The PET spatial resolution coefficient depends on the kind of biological tissue. However, the PET spatial resolution coefficient, 0.00243±0.00014, can be used as a common value of maximum limit.

Performance evaluation of a depth-of-interaction detector by use of position-sensitive PMT with a super-bialkali photocathode.

Our purpose in this work was to evaluate the performance of a 4-layer depth-of-interaction (DOI) detector composed of GSO crystals by use of a position-sensitive photomultiplier tube (PMT) with a super-bialkali photocathode (SBA) by comparing it with a standard bialkali photocathode (BA) regarding the ability to identify the scintillating crystals, energy resolution, and timing resolution. The 4-layer DOI detector was composed of a 16 × 16 array of 2.9 × 2.9 × 7.5 mm(3) GSO crystals for each layer and an 8 × 8 multi-anode array type position-sensitive PMT. The DOI was achieved by a reflector control method, and the Anger method was used for calculating interacting points. The energy resolution in full width at half-maximum (FWHM) at 511 keV energy for the top layer (the farthest from the PMT) was improved and was 12.0% for the SBA compared with the energy resolution of 12.7% for the BA. As indicators of crystal identification ability, the peak-to-valley ratio and distance-to-width ratio were calculated; the latter was defined as the average of the distance between peaks per the average of the peak width. For both metrics, improvement of several percent was obtained; for example, the peak-to-valley ratio was increased from 1.78 (BA) to 1.86 (SBA), and the distance-to-width ratio was increased from 1.47 (BA) to 1.57 (SBA). The timing resolution (FWHM) in the bottom layer was improved slightly and was 2.4 ns (SBA) compared with 2.5 ns (BA). Better performance of the DOI detector is expected by use of a super bialkali photocathode.