Experimental validation of an innovative approach in biokinetics study for personalised dosimetry of molecular radiation therapy treatments.

One of today's main challenges in molecular radiation therapy is to assess an individual dosimetry that allows treatment to be tailored to the specific patient, in accordance with the current paradigm of 'personalized medicine'. The evaluation of the absorbed doses for tumor and organs at risk in molecular radiotherapy is typically based on MIRD schema acquiring few experimental points for the assessement of biokinetic parameters. WIDMApp, the wearable individual dose monitoring apparatus, is an innovative approach for internal dosimetry based on a wearable radiation detecting system for individual biokinetics sampling, a Monte Carlo simulation for particle interaction, and an unfolding algorithm for data analysis and integrated activity determination at organ level. A prototype of a WIDMApp detector element was used to record the photon emissions in a body phantom containing 3 spheres with liquid sources (18F,64Cu and99mTc) to simulate organs having different washout. Modelling the phantom geometry on the basis of a CT scan imaging, the Monte Carlo simulation computed the contribution of each emitting sphere to the signal detected in 3 positions on the phantoms surface. Combining the simulated results with the data acquired for 120 h, the unfolding algorithm deconvolved the detected signal and assessed the decay half-life (T1/2) and initial activity values (A(0)) that best reproduces the observed exponential decays. A 3%-18% level of agreement is found between the actualA(0) andT1/2values and those obtained by means of the minimization procedure based on the Monte Carlo simulation. That resulted in an estimation of the cumulated activity <15%. Moreover, WIDMApp data redundancy has been used to mitigate some experimental occurrences that happened during data taking. A first experimental test of the WIDMApp approach to internal radiation dosimetry is presented. Studies with patients are foreseen to validate the technique in a real environment.

Calculation of electron interaction models in N2 and O2.

Cosmic rays have the potential to significantly affect the atmospheric composition by increasing the rate and changing the types of chemical reactions through ion production. The amount and states of ionization, and the spatial distribution of ions produced are still open questions for atmospheric models. To precisely estimate these quantities, it is necessary to simulate particle-molecule interactions, down to very low energies. Models enabling such simulations require interaction probabilities over a broad energy range and for all energetically allowed scattering processes. In this paper, we focus on electron interaction with the two most abundant molecules in the atmosphere, i.e., N2 and O2, as an initial step. A set of elastic and inelastic cross section models for electron transportation in oxygen and nitrogen molecules valid in the energy range 10 eV - 1 MeV, is presented. Comparison is made with available theoretical and experimental data and a reasonable good agreement is observed. Stopping power is calculated and compared with published data to assess the general consistency and reliability of our results. Good overall agreement is observed, with relative differences lower than 6% with the ESTAR database.

Report on G4-Med, a Geant4 benchmarking system for medical physics applications developed by the Geant4 Medical Simulation Benchmarking Group.

BACKGROUND: Geant4 is a Monte Carlo code extensively used in medical physics for a wide range of applications, such as dosimetry, micro- and nanodosimetry, imaging, radiation protection, and nuclear medicine. Geant4 is continuously evolving, so it is crucial to have a system that benchmarks this Monte Carlo code for medical physics against reference data and to perform regression testing. AIMS: To respond to these needs, we developed G4-Med, a benchmarking and regression testing system of Geant4 for medical physics. MATERIALS AND METHODS: G4-Med currently includes 18 tests. They range from the benchmarking of fundamental physics quantities to the testing of Monte Carlo simulation setups typical of medical physics applications. Both electromagnetic and hadronic physics processes and models within the prebuilt Geant4 physics lists are tested. The tests included in G4-Med are executed on the CERN computing infrastructure via the use of the geant-val web application, developed at CERN for Geant4 testing. The physical observables can be compared to reference data for benchmarking and to results of previous Geant4 versions for regression testing purposes. RESULTS: This paper describes the tests included in G4-Med and shows the results derived from the benchmarking of Geant4 10.5 against reference data. DISCUSSION: Our results indicate that the Geant4 electromagnetic physics constructor G4EmStandardPhysics_option4 gives a good agreement with the reference data for all the tests. The QGSP_BIC_HP physics list provided an overall adequate description of the physics involved in hadron therapy, including proton and carbon ion therapy. New tests should be included in the next stage of the project to extend the benchmarking to other physical quantities and application scenarios of interest for medical physics. CONCLUSION: The results presented and discussed in this paper will aid users in tailoring physics lists to their particular application.

Inter-fractional monitoring of [Formula: see text]C ions treatments: results from a clinical trial at the CNAO facility.

The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.

Feasibility study on the use of CMOS sensors as detectors in radioguided surgery with ß-- emitters.

Radioguided surgery (RGS) is a medical practice which thanks to a radiopharmaceutical tracer and a probe allows the surgeon to identify tumor residuals up to a millimetric resolution in real-time. The employment of ß- emitters, instead of γ or ß+, reduces background from healthy tissues, administered activity to the patient, and medical exposure. In a previous work the possibility of using a CMOS Imager (Aptina MT9V011), initially designed for visible light imaging, to detect ß- from 90Y or 90Sr sources has been established. Because of its possible application as counting probe in RGS, the performances of MT9V011 in clinical-like conditions were studied.1 Through horizontal scans on a collimated 90Sr source of different sizes (1, 3, 5, 7 mm), we have determined relationships between scan fit parameters and the source dimension, namely A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter, are determined. Horizontal scan measurements on a source, interposing collimators of different size, aim to determine relationships or correlations between scan fit parameters and source dimension. A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter are determined. In order to get closer to clinical conditions, agar-agar phantoms containing 90Y with different dimensions and activities were prepared. A 90Y phantom is characterized by a central spot and a ring all around, for simulating both signal (tumor) and background (surrounding healthy tissue). The relationship found between scan maximum and 90Sr source diameter is then exploited to extract the concentration ratio between spot and external ring of the 90Y phantom. This observable, defined as the ratio between the tumor and the nearby healthy tissues uptake simulates the Tumor-to-Non-tumor Ratio (TNR). With the aim of evaluating the sensor's ability to discriminate signal from background relying on the significance parameter, a further 90Y phantom, featuring a well-known and clinical-like activity will mimic the signal only condition. This result is used to extrapolate to different source sizes, after having estimated the background for various TNR. The obtained significance values suggest that the MT9V011 sensor is capable of distinguishing a signal from an estimated background, depending on the interplay among TNR, acquisition time and tumor diameter.

Tumor-non-tumor discrimination by a ß- detector for Radio Guided Surgery on ex-vivo neuroendocrine tumors samples.

This paper provides a first insight of the potential of the ß- Radio Guided Surgery (ß--RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90Y-marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the ß--RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04 mL in that particular case.

Preliminary results in using Deep Learning to emulate BLOB, a nuclear interaction model.

PURPOSE: A reliable model to simulate nuclear interactions is fundamental for Ion-therapy. We already showed how BLOB ("Boltzmann-Langevin One Body"), a model developed to simulate heavy ion interactions up to few hundreds of MeV/u, could simulate also 12C reactions in the same energy domain. However, its computation time is too long for any medical application. For this reason we present the possibility of emulating it with a Deep Learning algorithm. METHODS: The BLOB final state is a Probability Density Function (PDF) of finding a nucleon in a position of the phase space. We discretised this PDF and trained a Variational Auto-Encoder (VAE) to reproduce such a discrete PDF. As a proof of concept, we developed and trained a VAE to emulate BLOB in simulating the interactions of 12C with 12C at 62 MeV/u. To have more control on the generation, we forced the VAE latent space to be organised with respect to the impact parameter (b) training a classifier of b jointly with the VAE. RESULTS: The distributions obtained from the VAE are similar to the input ones and the computation time needed to use the VAE as a generator is negligible. CONCLUSIONS: We show that it is possible to use a Deep Learning approach to emulate a model developed to simulate nuclear reactions in the energy range of interest for Ion-therapy. We foresee the implementation of the generation part in C++ and to interface it with the most used Monte Carlo toolkit: Geant4.

Characterisation of a ß detector on positron emitters for medical applications.

PURPOSE: Radio Guided Surgery (RGS) is a technique that helps the surgeon to achieve an as complete as possible tumor resection, thanks to the intraoperative detection of particles emitted by a radio tracer that bounds to tumoral cells. In the last years, a novel approach to this technique has been proposed that, exploiting ß- emitting radio tracers, overtakes some limitations of established γ-RGS. In this context, a first prototype of an intraoperative ß particle detector, based on a high light yield and low density organic scintillator, has been developed and characterised on pure ß- emitters, like 90Y. The demonstrated very high efficiency to ß- particles, together with the remarkable transparency to photons, suggested the possibility to use this detector also with ß+ emitting sources, that have plenty of applications in nuclear medicine. In this paper, we present upgrades and optimisations performed to the detector to reveal such particles. METHODS: Laboratory measurement have been performed on liquid Ga68 source, and were used to validate and tune a Monte Carlo simulation. RESULTS: The upgraded detector has an ~80% efficiency to electrons above ~110keV, reaching a plateau value of ~95%. At the same time, the probe is substantially transparent to photons below ~200keV, reaching a plateau value of ~3%. CONCLUSIONS: The new prototype seems to have promising characteristics to perform RGS also with ß+ emitting isotopes.

Preliminary results coupling "Stochastic Mean Field" and "Boltzmann-Langevin One Body" models with Geant4.

PURPOSE: Monte Carlo (MC) simulations are widely used for medical applications and nuclear reaction models are fundamental for the simulation of the particle interactions with patients in ion therapy. Therefore, it is of utmost importance to have reliable models in MC simulations for such interactions. Geant4 is one of the most used toolkits for MC simulation. However, its models showed severe limitations in reproducing the yields measured in the interaction of ion beams below 100 MeV/u with thin targets. For this reason, we interfaced two models, SMF ("Stochastic Mean Field") and BLOB ("Boltzmann-Langevin One Body"), dedicated to simulate such reactions, with Geant4. METHODS: Both SMF and BLOB are semi-classical, one-body approaches to solve the Boltzmann-Langevin equation. They include an identical treatment of the mean-field propagation, on the basis of the same effective interaction, but they differ in the way fluctuations are included. Furthermore, we tested a correction to the excitation energy calculated for the light fragments emerging from the simulations and a simple coalescence model. RESULTS: While both SMF and BLOB have been developed to simulate heavy ion interactions, they show very good results in reproducing the experimental yields of light fragments, up to alpha particles, obtained in the interaction of 12C with a thin carbon target at 62 MeV/u. CONCLUSIONS: BLOB in particular gives promising results and this stresses the importance of integrating it into the Geant4 toolkit.

Secondary radiation measurements for particle therapy applications: Charged secondaries produced by 16O ion beams in a PMMA target at large angles.

Particle therapy is a therapy technique that exploits protons or light ions to irradiate tumor targets with high accuracy. Protons and 12C ions are already used for irradiation in clinical routine, while new ions like 4He and 16O are currently being considered. Despite the indisputable physical and biological advantages of such ion beams, the planning of charged particle therapy treatments is challenged by range uncertainties, i.e. the uncertainty on the position of the maximal dose release (Bragg Peak - BP), during the treatment. To ensure correct 'in-treatment' dose deposition, range monitoring techniques, currently missing in light ion treatment techniques, are eagerly needed. The results presented in this manuscript indicate that charged secondary particles, mainly protons, produced by an 16O beam during target irradiation can be considered as candidates for 16O beam range monitoring. Hereafter, we report on the first yield measurements of protons, deuterons and tritons produced in the interaction of an 16O beam impinging on a PMMA target, as a function of detected energy and particle production position. Charged particles were detected at 90° and 60° with respect to incoming beam direction, and homogeneous and heterogeneous PMMA targets were used to probe the sensitivity of the technique to target inhomogeneities. The reported secondary particle yields provide essential information needed to assess the accuracy and resolution achievable in clinical conditions by range monitoring techniques based on secondary charged radiation.

MR-based artificial intelligence model to assess response to therapy in locally advanced rectal cancer.

PURPOSE: To develop and validate an Artificial Intelligence (AI) model based on texture analysis of high-resolution T2 weighted MR images able 1) to predict pathologic Complete Response (CR) and 2) to identify non-responders (NR) among patients with locally-advanced rectal cancer (LARC) after receiving neoadjuvant chemoradiotherapy (CRT). METHOD: Fifty-five consecutive patients with LARC were retrospectively enrolled in this study. Patients underwent 3 T Magnetic Resonance Imaging (MRI) acquiring T2-weighted images before, during and after CRT. All patients underwent complete surgical resection and histopathology was the gold standard. Textural features were automatically extracted using an open-source software. A sub-set of statistically significant textural features was selected and two AI models were built by training a Random Forest (RF) classifier on 28 patients (training cohort). Model performances were estimated on 27 patients (validation cohort) using a ROC curve and a decision curve analysis. RESULTS: Sixteen of 55 patients achieved CR. The AI model for CR classification showed good discrimination power with mean area under the receiver operating curve (AUC) of 0.86 (95% CI: 0.70, 0.94) in the validation cohort. The discriminatory power for the NR classification showed a mean AUC of 0.83 (95% CI: 0.71,0.92). Decision curve analysis confirmed higher net patient benefit when using AI models compared to standard-of-care. CONCLUSIONS: AI models based on textural features of MR images of patients with LARC may help to identify patients who will show CR at the end of treatment and those who will not respond to therapy (NR) at an early stage of the treatment.

Review and performance of the Dose Profiler, a particle therapy treatments online monitor.

Particle therapy (PT) can exploit heavy ions (such as He, C or O) to enhance the treatment efficacy, profiting from the increased Relative Biological Effectiveness and Oxygen Enhancement Ratio of these projectiles with respect to proton beams. To maximise the gain in tumor control probability a precise online monitoring of the dose release is needed, avoiding unnecessary large safety margins surroundings the tumor volume accounting for possible patient mispositioning or morphological changes with respect to the initial CT scan. The Dose Profiler (DP) detector, presented in this manuscript, is a scintillating fibres tracker of charged secondary particles (mainly protons) that will be operating during the treatment, allowing for an online range monitoring. Such monitoring technique is particularly promising in the context of heavy ions PT, in which the precision achievable by other techniques based on secondary photons detection is limited by the environmental background during the beam delivery. Developed and built at the SBAI department of "La Sapienza", within the INSIDE collaboration and as part of a Centro Fermi flagship project, the DP is a tracker detector specifically designed and planned for clinical applications inside a PT treatment room. The DP operation in clinical like conditions has been tested with the proton and carbon ions beams of Trento proton-therapy center and of the CNAO facility. In this contribution the detector performances are presented, in the context of the carbon ions monitoring clinical trial that is about to start at the CNAO centre.

The ß- radio-guided surgery: Method to estimate the minimum injectable activity from ex-vivo test.

PURPOSE: Radio-guided surgery with ß- decays is a novel technique under investigation. One of the main advantages is its capability to detect small (⩽0.1 ml) samples after injecting the patient with low activity of radiopharmaceutical. This paper presents an experimental method to quantify this feature based on ex-vivo tests on specimens from meningioma patients. METHODS: Patients were enrolled on the basis of the standard uptake value (SUV) and the tumour-to-non-tumour activity ratio (TNR) resulted from 68Ga-DOTATOC PET exams. After injecting the patients with 93-167 MBq of 90Y-DOTATOC, 26 samples excised during surgery were analyzed with a ß- probe. The radioactivity expected on the neoplastic specimens was estimated according to the SUV found in the PET scan and the correlation with the measured counts was studied. The doses to surgeon and medical personnel were also evaluated. RESULTS: Even injecting as low as 1.4 MBq/kg of radiotracer, tumour residuals of 0.1 ml can be detected. A negligible dose to the medical personnel was confirmed. CONCLUSIONS: Radio-guided surgery with ß- decays is a feasible technique with a low radiation dose for both personnel and patient, in particular if the patient is injected with the minimum required activity. A correlation greater than 80% was observed between the measured counts and the expected activity for the lesion samples based on the individual SUV and the TNR. This makes identifiable the minimum injectable radiotracer activity for cases where 90Y is the utilized radionuclide.

Secondary radiation measurements for particle therapy applications: charged particles produced by 4He and 12C ion beams in a PMMA target at large angle.

Proton and carbon ion beams are used in the clinical practice for external radiotherapy treatments achieving, for selected indications, promising and superior clinical results with respect to x-ray based radiotherapy. Other ions, like [Formula: see text] have recently been considered as projectiles in particle therapy centres and might represent a good compromise between the linear energy transfer and the radiobiological effectiveness of [Formula: see text] ion and proton beams, allowing improved tumour control probability and minimising normal tissue complication probability. All the currently used p, [Formula: see text] and [Formula: see text] ion beams allow achieving sharp dose gradients on the boundary of the target volume, however the accurate dose delivery is sensitive to the patient positioning and to anatomical variations with respect to photon therapy. This requires beam range and/or dose release measurement during patient irradiation and therefore the development of dedicated monitoring techniques. All the proposed methods make use of the secondary radiation created by the beam interaction with the patient and, in particular, in the case of [Formula: see text] ion beams are also able to exploit the significant charged radiation component. Measurements performed to characterise the charged secondary radiation created by [Formula: see text] and [Formula: see text] particle therapy beams are reported. Charged secondary yields, energy spectra and emission profiles produced in a poly-methyl methacrylate (PMMA) target by [Formula: see text] and [Formula: see text] beams of different therapeutic energies were measured at 60° and 90° with respect to the primary beam direction. The secondary yield of protons produced along the primary beam path in a PMMA target was obtained. The energy spectra of charged secondaries were obtained from time-of-flight information, whereas the emission profiles were reconstructed exploiting tracking detector information. The obtained measurements are in agreement with results reported in the literature and suggests the feasibility of range monitoring based on charged secondary particle detection: the implications for particle therapy monitoring applications are also discussed.

Secondary radiation measurements for particle therapy applications: prompt photons produced by 4He, 12C and 16O ion beams in a PMMA target.

Charged particle beams are used in particle therapy (PT) to treat oncological patients due to their selective dose deposition in tissues with respect to the photons and electrons used in conventional radiotherapy. Heavy (Z > 1) PT beams can additionally be exploited for their high biological effectiveness in killing cancer cells. Nowadays, protons and carbon ions are used in PT clinical routines. Recently, interest in the potential application of helium and oxygen beams has been growing. With respect to protons, such beams are characterized by their reduced multiple scattering inside the body, increased linear energy transfer, relative biological effectiveness and oxygen enhancement ratio. The precision of PT demands online dose monitoring techniques, crucial to improving the quality assurance of any treatment: possible patient mis-positioning and biological tissue changes with respect to the planning CT scan could negatively affect the outcome of the therapy. The beam range confined in the irradiated target can be monitored thanks to the neutral or charged secondary radiation emitted by the interactions of hadron beams with matter. Among these secondary products, prompt photons are produced by nuclear de-excitation processes, and at present, different dose monitoring and beam range verification techniques based on prompt-γ detection are being proposed. It is hence of importance to perform γ yield measurement in therapeutic-like conditions. In this paper we report on the yields of prompt photons produced by the interaction of helium, carbon and oxygen ion beams with a poly-methyl methacrylate (PMMA) beam stopping target. The measurements were performed at the Heidelberg Ion-Beam Therapy Center (HIT) with beams of different energies. An LYSO scintillator, placed at [Formula: see text] and [Formula: see text] with respect to the beam direction, was used as the photon detector. The obtained γ yields for the carbon ion beams are compared with results from the literature, while no other results from helium and oxygen beams have been published yet. A discussion on the expected resolution of a slit camera detector is presented, demonstrating the feasibility of a prompt-γ-based monitoring technique for PT treatments using helium, carbon and oxygen ion beams.

Secondary radiation measurements for particle therapy applications: nuclear fragmentation produced by 4He ion beams in a PMMA target.

Nowadays there is a growing interest in particle therapy treatments exploiting light ion beams against tumors due to their enhanced relative biological effectiveness and high space selectivity. In particular promising results are obtained by the use of 4He projectiles. Unlike the treatments performed using protons, the beam ions can undergo a fragmentation process when interacting with the atomic nuclei in the patient body. In this paper the results of measurements performed at the Heidelberg Ion-Beam Therapy center are reported. For the first time the absolute fluxes and the energy spectra of the fragments-protons, deuterons, and tritons-produced by 4He ion beams of 102, 125 and 145 MeV u-1 energies on a poly-methyl methacrylate target were evaluated at different angles. The obtained results are particularly relevant in view of the necessary optimization and review of the treatment planning software being developed for clinical use of 4He beams in clinical routine and the relative bench-marking of Monte Carlo algorithm predictions.

First ex vivo validation of a radioguided surgery technique with ß-radiation.

PURPOSE: A radio-guided surgery technique with ß(-)-emitting radio-tracers was suggested to overcome the effect of the large penetration of γ radiation. The feasibility studies in the case of brain tumors and abdominal neuro-endocrine tumors were based on simulations starting from PET images with several underlying assumptions. This paper reports, as proof-of-principle of this technique, an ex vivo test on a meningioma patient. This test allowed to validate the whole chain, from the evaluation of the SUV of the tumor, to the assumptions on the bio-distribution and the signal detection. METHODS: A patient affected by meningioma was administered 300MBq of (90)Y-DOTATOC. Several samples extracted from the meningioma and the nearby Dura Mater were analyzed with a ß(-) probe designed specifically for this radio-guided surgery technique. The observed signals were compared both with the evaluation from the histology and with the Monte Carlo simulation. RESULTS: we obtained a large signal on the bulk tumor (105cps) and a significant signal on residuals of ∼0.2ml (28cps). We also show that simulations predict correctly the observed yields and this allows us to estimate that the healthy tissues would return negligible signals (≈1cps). This test also demonstrated that the exposure of the medical staff is negligible and that among the biological wastes only urine has a significant activity. CONCLUSIONS: This proof-of-principle test on a patient assessed that the technique is feasible with negligible background to medical personnel and confirmed that the expectations obtained with Monte Carlo simulations starting from diagnostic PET images are correct.