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This paper reports on the design of an open source treatment planning system for optimal multi-ion irradiation of a heterogeneous target with arbitrary spatial dose distributions. The developed TPS features controllable avoidance of dose in organs at risk and optional linear energy transfer enhancement in hypoxic target sub-volumes. The performance of the treatment planning system is evaluated under a variety of conditions in a heterogeneous target to demonstrate the dose uniformity and conformance benefits of treatment achievable with manifold multi-ion therapy versus single-ion or dual-ion therapy.

Objective. We aim to evaluate a method for estimating 1D physical dose deposition profiles in carbon ion therapy via analysis of dynamic PET images using a deep residual learning convolutional neural network (CNN). The method is validated using Monte Carlo simulations of 12C ion spread-out Bragg peak (SOBP) profiles, and demonstrated with an experimental PET image. Approach. A set of dose deposition and positron annihilation profiles for monoenergetic 12C ion pencil beams in PMMA are first generated using Monte Carlo simulations. From these, a set of random polyenergetic dose and positron annihilation profiles are synthesised and used to train the CNN. Performance is evaluated by generating a second set of simulated 12C ion SOBP profiles (one 116 mm SOBP profile and ten 60 mm SOBP profiles), and using the trained neural network to estimate the dose profile deposited by each beam and the position of the distal edge of the SOBP. Next, the same methods are used to evaluate the network using an experimental PET image, obtained after irradiating a PMMA phantom with a 12C ion beam at QST’s Heavy Ion Medical Accelerator in Chiba facility in Chiba, Japan. The performance of the CNN is compared to that of a recently published iterative technique using the same simulated and experimental 12C SOBP profiles. Main results. The CNN estimated the simulated dose profiles with a mean relative error (MRE) of 0.7% ± 1.0% and the distal edge position with an accuracy of 0.1 mm ± 0.2 mm, and estimate the dose delivered by the experimental 12C ion beam with a MRE of 3.7%, and the distal edge with an accuracy of 1.7 mm. Significance. The CNN was able to produce estimates of the dose distribution with comparable or improved accuracy and computational efficiency compared to the iterative method and other similar PET-based direct dose quantification techniques.

Neutron Capture Enhanced Particle Therapy (NCEPT) boosts the effectiveness of particle therapy by capturing thermal neutrons produced by beam-target nuclear interactions in and around the treatment site, using tumour-specific 10B or 157Gd-based neutron capture agents. Neutron captures release high-LET secondary particles together with prompt gamma photons with energies of 478 keV (10B) or 7.94 MeV (157Gd). A key requirement for NCEPT’s translation is the development of in vivo dosimetry techniques which can measure both the direct ion dose and the dose due to neutron capture. In this work, we report signatures which can be used to discriminate between photons resulting from neutron capture and those originating from other processes. A Geant4 Monte Carlo simulation study into timing and energy thresholds for discrimination of prompt gamma photons resulting from thermal neutron capture during NCEPT was conducted. Three simulated 300×300×300 mm3 cubic PMMA targets were irradiated by 4He or 12C ion beams with a spread out Bragg peak (SOBP) depth range of 60 mm; one target is homogeneous while the others include 10×10×10 mm3 neutron capture inserts (NCIs) of pure 10B or 157Gd located at the distal edge of the SOBP. The arrival times of photons and neutrons entering a simulated 50×50×50 mm3 ideal detector were recorded. The majority of photons resulting from neutron capture were found to arrive at the detector at least 60 ns later than photons created by other processes. A range of candidate detector and thermal neutron shielding materials were simulated, and detections meeting the proposed acceptance criteria (i.e. falling within the target energy window and arriving 60 ns post beam-off) were classified as true or false positives, depending on their origin. The ratio of true / false positives (RTF) was calculated; for targets with 10B and 157Gd NCIs, the detector materials which resulted in the highest RTF were cadmium-shielded CdTe and boron-shielded LSO, respectively. The optimal irradiation period for both carbon and helium ions was 1 µs for the 10B NCI and 1 ms for the 157Gd NCI.

This work presents a simulation study evaluating relative biological effectiveness at 10% survival fraction (RBE10) of several different positron-emitting radionuclides in heavy ion treatment systems, and comparing these to the RBE10s of their non-radioactive counterparts. RBE10 is evaluated as a function of depth for three positron-emitting radioactive ion beams (10C, 11C and 15O) and two stable ion beams (12C and 16O) using the modified microdosimetric kinetic model (MKM) in a heterogeneous skull phantom subject to a rectangular 50 mm × 50 mm × 60 mm spread out Bragg peak. We demonstrate that the RBE10 of the positron-emitting radioactive beams is almost identical to the corresponding stable isotopes. The potential improvement in PET quality assurance image quality which is obtained when using radioactive beams is evaluated by comparing the signal to background ratios of positron annihilations at different intra- and post-irradiation time points. Finally, the incidental dose to the patient resulting from the use of radioactive beams is also quantified and shown to be negligible.

This work presents an iterative method for the estimation of the absolute dose distribution in patients undergoing carbon ion therapy, via analysis of the distribution of positron annihilations resulting from the decay of positron-emitting fragments created in the target volume. The proposed method relies on the decomposition of the total positron-annihilation distributions into profiles of the three principal positron-emitting fragment species - 11C, 10C and 15O. A library of basis functions is constructed by simulating a range of monoenergetic 12C ion irradiations of a homogeneous polymethyl methacrylate phantom and measuring the resulting one-dimensional positron-emitting fragment profiles and dose distributions. To estimate the dose delivered during an arbitrary polyenergetic irradiation, a linear combination of factors from the fragment profile library is iteratively fitted to the decomposed positron annihilation profile acquired during the irradiation, and the resulting weights combined with the corresponding monoenergetic dose profiles to estimate the total dose distribution. A total variation regularisation term is incorporated into the fitting process to suppress high-frequency noise. The method was evaluated with 14 different polyenergetic 12C dose profiles in a polymethyl methacrylate target: one which produces a flat biological dose, 10 with randomised energy weighting factors, and three with distinct dose maxima or minima within the spread-out Bragg peak region. The proposed method is able to calculate the dose profile with mean relative errors of 0.8%, 1.0% and 1.6% from the 11C, 10C, 15O fragment profiles, respectively, and estimate the position of the distal edge of the SOBP to within an average of 0.7 mm, 1.9 mm and 1.2 mm of its true location.

Purpose This work has two related objectives. The first is to estimate the relative biological effectiveness of two radioactive heavy ion beams based on experimental measurements, and compare these to the relative biological effectiveness of corresponding stable isotopes to determine whether they are therapeutically equivalent. The second aim is to quantitatively compare the quality of images acquired postirradiation using an in-beam whole-body positron emission tomography scanner for range verification quality assurance. Methods The energy deposited by monoenergetic beams of 11 C at 350 MeV/u, 15 O at 250 MeV/u, 12 C at 350 MeV/u, and 16 O at 430 MeV/u was measured using a cruciform transmission ionization chamber in a water phantom at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Dose-mean lineal energy was measured at various depths along the path of each beam in a water phantom using a silicon-on-insulator mushroom microdosimeter. Using the modified microdosimetric kinetic model, the relative biological effectiveness at 10% survival fraction of the radioactive ion beams was evaluated and compared to that of the corresponding stable ions along the path of the beam. Finally, the postirradiation distributions of positron annihilations resulting from the decay of positron-emitting nuclei were measured for each beam in a gelatin phantom using the in-beam whole-body positron emission tomography scanner at HIMAC. The depth of maximum positron-annihilation density was compared with the depth of maximum dose deposition and the signal-to-background ratios were calculated and compared for images acquired over 5 and 20 min postirradiation of the phantom. Results In the entrance region, the h b o x RBE 10 was 1.2 ± 0.1 for both 11 C and 12 C beams, while for 15 O and 16 O it was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. At the Bragg peak, the RBE 10 was 2.7 ± 0.4 for 11 C and 2.9 ± 0.4 for 12 C, while for 15 O and 16 O it was 2.7 ± 0.4 and 2.8 ± 0.4, respectively. In the tail region, RBE 10 could only be evaluated for carbon; the RBE 10 was 1.6 ± 0.2 and 1.5 ± 0.1 for 11 C and 12 C, respectively. Positron emission tomography images obtained from gelatin targets irradiated by radioactive ion beams exhibit markedly improved signal-to-background ratios compared to those obtained from targets irradiated by nonradioactive ion beams, with 5-fold and 11-fold increases in the ratios calculated for the 15 O and 11 C images compared with the values obtained for 16 O and 12 C, respectively. The difference between the depth of maximum dose and the depth of maximum positron annihilation density is 2.4 ± 0.8 mm for 11 C, compared to -5.6 ± 0.8 mm for 12 C and 0.9 ± 0.8 mm for 15 O vs -6.6 ± 0.8 mm for 16 O. Conclusions The RBE 10 values for 11 C and 15 O were found to be within the 95% confidence interval of the RBEs estimated for their corresponding stable isotopes across each of the regions in which it was evaluated. Furthermore, for a given dose, 11 C and 15 O beams produce much better quality images for range verification compared with 12 C and 16 O, in particular with regard to estimating the location of the Bragg peak.

In heavy-ion therapy, the stopping position of primary ions in tumours needs to be monitored for effective treatment and to prevent overdose exposure to normal tissues. Positron-emitting ion beams, such as

Dose and range verification have become important tools to bring carbon ion therapy to a higher level of confidence in clinical applications. Positron emission tomography is among the most commonly used approaches for this purpose and relies on the creation of positron emitting nuclei in nuclear interactions of the primary ions with tissue. Predictions of these positron emitter distributions are usually obtained from time-consuming Monte Carlo simulations or measurements from previous treatment fractions, and their comparison to the current, measured image allows for treatment verification. Still, a direct comparison of planned and delivered dose would be highly desirable, since the dose is the quantity of interest in radiation therapy and its confirmation improves quality assurance in carbon ion therapy. In this work, we present a deconvolution approach to predict dose distributions from PET images in carbon ion therapy. Under the assumption that the one-dimensional PET distribution is described by a convolution of the depth dose distribution and a filter kernel, an evolutionary algorithm is introduced to perform the reverse step and predict the depth dose distribution from a measured PET distribution. Filter kernels are obtained from either a library or are created for any given situation on-the-fly, using predictions of the [Formula: see text]-decay and depth dose distributions, and the very same evolutionary algorithm. The applicability of this approach is demonstrated for monoenergetic and polyenergetic carbon ion irradiation of homogeneous and heterogeneous solid phantoms as well as a patient computed tomography image, using Monte Carlo simulated distributions and measured in-beam PET data. Carbon ion ranges are predicted within less than 0.5 mm and 1 mm deviation for simulated and measured distributions, respectively.

The purpose of this work is to develop a validated Geant4 simulation model of a whole-body prototype PET scanner constructed from the four-layer depth-of-interaction detectors developed at the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Japan. The simulation model emulates the behaviour of the unique depth of interaction sensing capability of the scanner without needing to directly simulate optical photon transport in the scintillator and photodetector modules. The model was validated by evaluating and comparing performance metrics from the NEMA NU 2-2012 protocol on both the simulated and physical scanner, including spatial resolution, sensitivity, scatter fraction, noise equivalent count rates and image quality. The results show that the average sensitivities of the scanner in the field-of-view were 5.9 cps kBq−1 and 6.0 cps kBq−1 for experiment and simulation, respectively. The average spatial resolutions measured for point sources placed at several radial offsets were 5.2± 0.7 mm and 5.0± 0.8 mm FWHM for experiment and simulation, respectively. The peak NECR was 22.9 kcps at 7.4 kBq ml−1 for the experiment, while the NECR obtained via simulation was 23.3 kcps at the same activity. The scatter fractions were 44% and 41.3% for the experiment and simulation, respectively. Contrast recovery estimates performed in different regions of a simulated image quality phantom matched the experimental results with an average error of -8.7% and +3.4% for hot and cold lesions, respectively. The results demonstrate that the developed Geant4 model reliably reproduces the key NEMA NU 2-2012 performance metrics evaluated on the prototype PET scanner. A simplified version of the model is included as an advanced example in Geant4 version 10.5.

In heavy-ion therapy, the stopping position of primary ions in tumours needs to be monitored for effective treatment and to prevent overdose exposure to normal tissues. Positron-emitting ion beams, such as 11C and 15O, have been suggested for range verification in heavy-ion therapy using in-beam positron emission tomography (PET) imaging, which offers the capability of visualizing the ion stopping position with a high signal-to-noise ratio. We have previously demonstrated the feasibility of in-beam PET imaging for the range verification of 11C and 15O ion beams and observed a slight shift between the beam stopping position and the dose peak position in simulations, depending on the initial beam energy spread. In this study, we focused on the experimental confirmation of the shift between the Bragg peak position and the position of the maximum detected positron-emitting fragments via a PET system for positron-emitting ion beams of 11C (210 MeV u-1) and 15O (312 MeV u-1) with momentum acceptances of 5% and 0.5%. For this purpose, we measured the depth doses and performed in-beam PET imaging using a polymethyl methacrylate (PMMA) phantom for both beams with different momentum acceptances. The shifts between the Bragg peak position and the PET peak position in an irradiated PMMA phantom for the 15O ion beams were 1.8 mm and 0.3 mm for momentum acceptances of 5% and 0.5%, respectively. The shifts between the positions of two peaks for the 11C ion beam were 2.1 mm and 0.1 mm for momentum acceptances of 5% and 0.5%, respectively. We observed larger shifts between the Bragg peak and the PET peak positions for a momentum acceptance of 5% for both beams, which is consistent with the simulation results reported in our previous study. The biological doses were also estimated from the calculated relative biological effectiveness (RBE) values using a modified microdosimetric kinetic model (mMKM) and Monte Carlo simulation. Beams with a momentum acceptance of 5% should be used with caution for therapeutic applications to avoid extra dose to normal tissues beyond the tumour when the dose distal fall-off is located beyond the treatment volume.

This paper presents Neutron Capture Enhanced Particle Therapy (NCEPT), a method for enhancing the radiation dose delivered to a tumour relative to surrounding healthy tissues during proton and carbon ion therapy by capturing thermal neutrons produced inside the treatment volume during irradiation. NCEPT utilises extant and in-development boron-10 and gadolinium-157-based drugs from the related field of neutron capture therapy. Using Monte Carlo simulations, we demonstrate that a typical proton or carbon ion therapy treatment plan generates an approximately uniform thermal neutron field within the target volume, centred around the beam path. The tissue concentrations of neutron capture agents required to obtain an arbitrary 10% increase in biological effective dose are estimated for realistic treatment plans, and compared to concentrations previously reported in the literature. We conclude that the proposed method is theoretically feasible, and can provide a worthwhile improvement in the dose delivered to the tumour relative to healthy tissue with readily achievable concentrations of neutron capture enhancement drugs.

Dose monitoring and range verification are important tools in carbon ion therapy. For their implementation, positron emission tomography (PET) can be used to image the $\beta^{+}$-activation of tissue during treatment. Predictions of these $\beta^{+}$-activity distributions are usually obtained from Monte Carlo simulations, which demands high computational time and thus limits the applicability of this technique in clinical scenario. Nevertheless, it is desirable to explore faster approaches able to give such a prediction, since only its comparison with the measured distributions allows a definite assessment of potential range deviations from the planned treatment. For the first time, we present an approach to perform deconvolution from PET data in carbon ion therapy and reconstruct the dose. A filtering method is used to predict positron emitter profiles from dose profiles in short time. In order to reverse the convolution and estimate a dose distribution from a positron emitter distribution, we apply an evolutionary algorithm. Filters are obtained from either a library or are created in advance for a specific problem, assuming that a prediction of the positron emitter distribution is available. To perform the latter method and find the best filter for a specific problem, we use another evolutionary algorithm, hence optimizing the filter on-the-fly for the given treatment scheme. The application of our method is shown for dose and positron emitter distributions in homogeneous phantoms using simulated and newly measured online PET data. Carbon ion ranges can be predicted within 2 mm and the shape of the dose distribution is reconstructed with an overall promising agreement.

© 2019 Commonwealth of Australia, Australian Nuclear Science and Technology Organisation, ANSTO.. 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.

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.

The management of benign prostatic hyperplasia has undergone a rapid evolution over the past decade from a surgical emphasis to a medical emphasis. Great strides in the development of α-adrenergic blockers, 5α-reductase inhibitors and a variety of phytotherapeutics have fueled this evolution. This article reviews the past, present and future of the medical management of benign prostatic hyperplasia.