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PURPOSE In-beam Positron Emission Tomography (PET) is one of the modalities that can be used for in-vivo non-invasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy to interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify and visualize regions with possible morphological changes occurring over the course of treatment. MATERIALS AND METHODS We selected a patient treated for Squamous Cell Carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the Voxel-Based Morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify inter-fractional morphological changes and to visualize them superimposed on the Computed Tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal inter-fractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments. This article is protected by copyright. All rights reserved.

Open physics 19(1), 383 - 394 (2021). doi:10.1515/phys-2021-0032, Published by de Gruyter, Berlin

To compare unassisted and CAD-assisted detection and time efficiency of radiologists in reporting lung nodules on CT scans taken from patients with extra-thoracic malignancies using a Cloud-based system. Three radiologists searched for pulmonary nodules in patients with extra-thoracic malignancy who underwent CT (slice thickness/spacing 2 mm/1.7 mm) between September 2015 and March 2016. All nodules detected by unassisted reading were measured and coordinates were uploaded on a cloud-based system. CAD marks were then reviewed by the same readers using the cloud-based interface. To establish the reference standard all nodules ≥ 3 mm detected by at least one radiologist were validated by two additional experienced radiologists in consensus. Reader detection rate and reporting time with and without CAD were compared. The study was approved by the local ethics committee. All patients signed written informed consent. The series included 225 patients (age range 21–90 years, mean 62 years), including 75 patients having at least one nodule, for a total of 215 nodules. Stand-alone CAD sensitivity for lesions ≥ 3 mm was 85% (183/215, 95% CI: 82–91); mean false-positive rate per scan was 3.8. Sensitivity across readers in detecting lesions ≥ 3 mm was statistically higher using CAD: 65% (95% CI: 61–69) versus 88% (95% CI: 86–91, p

Positron emission tomography (PET) is a well established imaging technique for range monitoring in hadrontherapy. Multiple fields are standard protocol in treatments, but because of washout and residual activity background from previous irradiation plans, to this date quantitative verification of the particle range for each beam field is still an open issue. In this paper, a new method for the evaluation with a PET detector of the activity range of the second field of a treatment is discussed. Two treatment plans with two parallel-opposed beam fields, one using protons and one using carbon ions, were delivered on PMMA phantoms. In both cases, the second beam field was extracted from the first irradiation residual activity and compared with a reference image, obtained from the experimental acquisition of the second field alone. Results demonstrate good agreement between the extracted second field and the reference image, with average difference in the activity range along the preferential direction of the beam less than 0.5 mm for protons, and 1.5 mm for carbon ions. Without taking into account any preferential direction, differences within 0.5 mm were found for both cases. The method will soon be tested with nonhomogeneous phantoms and, subsequently, with in-vivo clinical data.

Simultaneous PET/MR/EEG (Positron Emission Tomography – Magnetic Resonance – Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm.It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

The 4D GRAPH-X (Dynamic GRAting-based PHase contrast x-ray imaging) project aims at developing a prototype of an x-ray grating-based phase-contrast imaging scanner in a laboratory setting, which is based on the Moirè single-shot acquisition method in order to be optimized for analysing moving objects (in the specific case, a dynamic thorax phantom), that could evolve into a suitable tool for biomedical applications although it can be extended to other application fields. When designing an x-ray Talbot-Lau interferometer, high visibility and sensitivity are two important figures of merit, strictly related to the performance of the system in obtaining high quality phase contrast and dark-field images. Wave field simulations are performed to optimize the setup specifications and construct a high-resolution and high-sensitivity imaging system. In this work, the design of a dynamic imaging setup using a conventional milli-focus x-ray source is presented. Optimization by wave front simulations leads to a symmetric configuration with 5.25 μm pitch at third Talbot order and 45 keV design energy. The simulated visibility is about 22%. Results from GATE based Monte Carlo simulations show a 19% transmission percentage of the incoming beam into the detector after passing through all the gratings and the sample. Such results are promising in view of building a system optimized for dynamic imaging.

This paper focuses on the design and the characterization of a frequency-selective shield for positron emission tomography (PET) detector modules of hybrid magnetic resonance-PET scanners, where the shielding of the PET cassettes is located close to the observed object. The proposed shielding configuration is designed and optimized to guarantee a high shielding effectiveness (SE) of up to 60 dB for ${B} _{1}$ -fields at the Larmor frequency of 64 MHz, thus preventing interactions between the radio-frequency (RF) coil and PET electronics. On the other hand, the shield is transparent to the gradient fields with the consequence that eddy-current artifacts in the acquired EPI images are significantly reduced with respect to the standard solid-shield configuration. The frequency-selective behavior of the shield is characterized and validated via simulation studies with CST MICROWAVE STUDIO in the megahertz and kilohertz range. Bench measurements with an RF coil built in-house demonstrated the high SE at the Larmor frequency. Moreover, measurements on a 4-T human scanner confirmed the abolishment of eddy current artifact and also provided an understanding of where the eddy currents occur with respect to the sequence parameters. Simulations and measurements for the proposed shielding concept were compared with a solid copper shielding configuration.

Purpose In recent years, there has been growing interest in the use of gold nanoparticles (GNPs) combined with radiotherapy to improve tumor control. However, the complex interplay between GNP uptake and dose distribution in realistic clinical treatment are still somewhat unknown. Methods The effects of different concentrations of 2 nm diameter GNP, ranging from 0 to 5×105 nanoparticles per tumoral cell, were theoretically investigated. A parametrization of the GNP distribution outside the target was carried out using a Gaussian standard deviation σ, from a zero value, relative to a selective concentration of GNPs inside the tumor volume alone, to 50mm, when GNPs are spatially distributed also in the healthy tissues surrounding the tumor. Treatment simulations of five patients with breast cancer were performed with 6 and 15 MV photons assuming a partial breast irradiation. A closed analytical reformulation of the Local Effect Model coupled with the estimation of local dose deposited around a GNP was validated using an in vitro study for MDA-MB-231 tumoral cells. The expected treatment outcome was quantified in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP) as a function of the spatially varying gold uptake. Results Breast cancer treatment planning simulations show improved treatment outcomes when GNPs are selectively concentrated in the tumor volume (i.e., σ = 0 mm). In particular, the TCP increases up to 18% for 5×105 nanoparticles per cell in the tumor region depending on the treatment schedules, whereas an improvement of the therapeutic index is observed only for concentrations of about 105 GNPs per tumoral cell and limited spatial distribution in the normal tissue. Conclusions The model provides a useful framework to estimate the nanoparticle-driven radiosensitivity in breast cancer treatment irradiation, accounting for the complex interplay between dose and GNP uptake distributions.

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.

In-beam positron emission tomography (PET) monitoring can provide early treatment assessment in proton therapy. However, open ring configurations and low positron emitter production yields degrade image quality, hampering the assessment accuracy. To achieve the highest precision for range monitoring, it is compulsory to mitigate image noise and compensate for data truncation. The goal of this article is to study the performance of state-of-the-art algorithms for in-beam PET image reconstruction, by evaluating the impact of the system response model and assessing the accuracy of range measurements. The approaches investigated here were maximum- a-posteriori algorithms combined with total-variation and median-root priors. Maximum-likelihood-expectation-maximization was used as reference. To compute the system matrix, different models were compared: a precise Monte Carlo model, and single-ray tracing with and without Gaussian blurring in image space. The proposed methods were tested on simulations of spread-out-bragg-peaks delivered on phantoms. The in-beam PET innovative imaging scanner geometry was used as a case study. After image post-processing, the explored methods delivered similar results. This article demonstrates the feasibility and reliability of using a simple and fast reconstruction method to perform range evaluations, given the correct image post-processing.

Summary: Charged particle therapy exploits proton or 12C beams to treat deep-seated solid tumors. Due to the advantageous characteristics of charged particles energy deposition in matter, the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However, the beam nuclear interactions with the patient tissues induces fragmentation both of projectile and target nuclei and needs to be carefully taken into account. In proton treatments, target fragmentation produces low energy, short range fragments along all the beam range, which deposit a non negligible dose in the entry channel. In 12C treatments the main concern is represented by long range fragments due to beam fragmentation that release their dose in the healthy tissues beyond the tumor. The FOOT experiment (FragmentatiOn Of Target) of INFN is designed to study these processes, in order to improve the nuclear fragmentation description in next generation Treatment Planning Systems and the treatment plans quality. Target (16O and 12C nuclei) fragmentation induced by –proton beams at therapeutic energies will be studied via an inverse kinematic approach, where 16O and 12C therapeutic beams impinge on graphite and hydrocarbon targets to provide the nuclear fragmentation cross section on hydrogen. Projectile fragmentation of 16O and 12C beams will be explored as well. The FOOT detector includes a magnetic spectrometer for the fragments momentum measurement, a plastic scintillator for ΔE and time of flight measurements and a crystal calorimeter to measure the fragments kinetic energy. These measurements will be combined in order to make an accurate fragment charge and isotopic identification. Keywords: Hadrontherapy, Nuclear fragmentation cross sections, Tracking detectors, Scintillating detectors

Treatment quality assessment is a crucial feature for both present and next-generation ion therapy facilities. Several approaches are being explored, based on prompt radiation emission or on PET signals by [Formula: see text]-decaying isotopes generated by beam interactions with the body. In-beam PET monitoring at synchrotron-based ion therapy facilities has already been performed, either based on inter-spill data only, to avoid the influence of the prompt radiation, or including both in-spill and inter-spill data. However, the PET images either suffer of poor statistics (inter-spill) or are more influenced by the background induced by prompt radiation (in-spill). Both those problems are expected to worsen for accelerators with improved duty cycle where the inter-spill interval is reduced to shorten the treatment time. With the aim of assessing the detector performance and developing techniques for background reduction, a test of an in-beam PET detector prototype was performed at the CNAO synchrotron-based ion therapy facility in full-beam acquisition modality. Data taken with proton beams impinging on PMMA phantoms showed the system acquisition capability and the resulting activity distribution, separately reconstructed for the in-spill and the inter-spill data. The coincidence time resolution for in-spill and inter-spill data shows a good agreement, with a slight deterioration during the spill. The data selection technique allows the identification and rejection of most of the background originated during the beam delivery. The activity range difference between two different proton beam energies (68 and 72 MeV) was measured and found to be in sub-millimeter agreement with the expected result. However, a slightly longer (2 mm) absolute profile length is obtained for in-spill data when compared to inter-spill data.

This paper describes the development and characterization of a Δ E-TOF detector composed of a plastic scintillator bar coupled at both ends to silicon photomultipliers. This detector is a prototype of a larger version which will be used in the FOOT (FragmentatiOn Of Target) experiment to identify the fragments produced by ion beams accelerated onto a hydrogen-enriched target. The final Δ E-TOF detector will be composed of two layers of plastic scintillator bars with orthogonal orientation and will measure, for each crossing fragment, the energy deposited in the plastic scintillator ( Δ E), the time of flight (TOF), and the coordinates of the interaction position in the scintillator. To meet the FOOT experimental requirements, the detector should have energy resolution of a few percents and time resolution of 70 ps, and it should allow to discriminate multiple fragments belonging to the same event. To evaluate the achievable performances, the detector prototype was irradiated with protons of kinetic energy in the 70–230 MeV range and interacting at several positions along the bar. The measured energy resolution σ Δ E ∕ Δ E was 6–14%, after subtracting the fluctuations of the deposited energy. A time resolution σ between 120 and 180 ps was obtained with respect to a trigger detector. A spatial resolution σ of 1.9 cm was obtained for protons interacting at the center of the bar.

In hadron therapy, the accelerated ions, interacting with the body of the patient, cause the fragmentation of both projectile and target nuclei. The fragments interact with the human tissues depositing energy both in the entrance channel and in the volume surrounding the tumor. The knowledge of the fragments features is crucial to determine the energy amount deposited in the human body, and - hence - the damage to the organs and to the tissues around the tumor target. The FOOT (FragmentatiOn Of Target) experiment aims at studying the fragmentation induced by the interaction of a proton beam (150-250 MeV/n) inside the human body. The FOOT detector includes an electronic setup for the identification of Z ≥ 3 fragments integrated with an emulsion spectrometer to measure Z ≤ 3 fragments. Charge identification by nuclear emulsions is based on the development of techniques of controlled fading of the particle tracks inside the nuclear emulsion, that extend the dynamical range of the films developed for the tracking of minimum ionising particles. The controlled fading strongly depends on temperature, relative humidity and treatment duration. In this study the performances in terms of charge separation of proton, helium and carbon particles, obtained on a batch of new emulsion films produced in Japan are reported.

The TRIMAGE project aims at developing a brain-dedicated PET/MR/EEG system able to perform simultaneous PET, MR, and EEG acquisitions for application in schizophrenia. Both PET and MR components have been designed in this project. The PET component consists of a full ring with 18 sectors each comprising three square detector modules. The modules are based on dual-layer staggered matrices of LYSO crystals read out by silicon photomultipliers. This paper describes in full detail the final version of the PET detectors and the related electronics. It also reports on the preliminary performance of a pair of sectors in terms of pixel resolvability index (RI), energy resolution, singles count rate capability, and coincidence time resolution (CTR). The procedures used for the optimization and calibration of PET detector are described. Results demonstrate the pixel/layer identification performance with an RI of about 0.2 while the energy resolution resulted in 20% and 22% FWHM for the bottom and top layer, respectively. The maximum singles count rate of a PET detector is about 700 kcps and the CTR of two sectors is 515 ps.

Quality assurance in particle therapy is an open issue that can be addressed with reliable monitoring techniques, such as in-beam PET and prompt-gamma-timing (PGT). In-beam PET is able to provide online feedback on the particle range by detecting the radiation related to the β + activity, while PGT relies on the time-of-flight (TOF) of prompt photons . The I3PET (In-beam PET Innovative Imaging) project is developing a novel scanner demonstrator that combines in-beam PET and PGT within the same detector, exploiting the potential synergy of these two techniques.

Purpose: M5L, a fully automated computer-aided detection (CAD) system for the detection and segmentation of lung nodules in thoracic computed tomography (CT), is presented and validated on several image datasets. Methods: M5L is the combination of two independent subsystems, based on the Channeler Ant Model as a segmentation tool [lung channeler ant model (lungCAM)] and on the voxel-based neural approach. The lungCAM was upgraded with a scan equalization module and a new procedure to recover the nodules connected to other lung structures; its classification module, which makes use of a feed-forward neural network, is based of a small number of features (13), so as to minimize the risk of lacking generalization, which could be possible given the large difference between the size of the training and testing datasets, which contain 94 and 1019 CTs, respectively. The lungCAM (standalone) and M5L (combined) performance was extensively tested on 1043 CT scans from three independent datasets, including a detailed analysis of the full Lung Image Database Consortium/Image Database Resource Initiative database, which is not yet found in literature. Results: The lungCAM and M5L performance is consistent across the databases, with a sensitivity of about 70% and 80%, respectively, at eight false positive findings per scan, despite the variable annotation criteria and acquisition and reconstruction conditions. A reduced sensitivity is found for subtle nodules and ground glass opacities (GGO) structures. A comparison with other CAD systems is also presented. Conclusions: The M5L performance on a large and heterogeneous dataset is stable and satisfactory, although the development of a dedicated module for GGOs detection could further improve it, as well as an iterative optimization of the training procedure. The main aim of the present study was accomplished: M5L results do not deteriorate when increasing the dataset size, making it a candidate for supporting radiologists on large scale screenings and clinical programs.

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment. The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model. The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found. In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images.

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the β+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

In vivo range monitoring techniques are necessary in order to fully take advantage of the high dose gradients deliverable in hadrontherapy treatments. Positron emission tomography (PET) scanners can be used to monitor beam-induced activation in tissues and hence measure the range. The INSIDE (Innovative Solutions for In-beam DosimEtry in Hadrontherapy) in-beam PET scanner, installed at the Italian National Center of Oncological Hadrontherapy (CNAO, Pavia, Italy) synchrotron facility, has already been successfully tested in vivo during a proton therapy treatment. We discuss here the system performance evaluation with carbon ion beams, in view of future in vivo tests. The work is focused on the analysis of activity images obtained with therapeutic treatments delivered to polymethyl methacrylate (PMMA) phantoms, as well as on the test of an innovative and robust Monte Carlo simulation technique for the production of reliable prior activity maps. Images are reconstructed using different integration intervals, so as to monitor the activity evolution during and after the treatment. Three procedures to compare activity images are presented, namely Pearson correlation coefficient, Beam's eye view and overall view. Images of repeated irradiations of the same treatments are compared to assess the integration time necessary to provide reproducible images. The range agreement between simulated and experimental images is also evaluated, so as to validate the simulation capability to provide sound prior information. The results indicate that at treatment end, or at most 20 s afterwards, the range measurement is reliable within 1-2 mm, when comparing both different experimental sessions and data with simulations. In conclusion, this work shows that the INSIDE in-beam PET scanner performance is promising towards its in vivo test with carbon ions.

Background and objective: Standardised Uptake Value (SUV), in clinical research and practice, is a marker of tumour avidity in Positron Emission Tomography/Computed Tomography (PET/CT). Since many technical, physical and physiological factors affect the SUV absolute measurement, the liver uptake is often used as reference value both in quantitative and semi-quantitative evaluation. The purpose of this investigation was to automatically detect the liver position in whole-body PET/CT scans and extract its average SUV value. Methods: We developed an algorithm, called LIver DEtection Algorithm (LIDEA), that analyses PET/CT scans, and under the assumption that the liver is a large homogeneous volume near the centre of mass of the patient, finds its position and automatically places a region of interest (ROI) in the liver, which is used to calculate the average SUV. The algorithm was validated on a population of 630 PET/CT scans coming from more than 60 different scanners. The SUV was also calculated by manually placing a large ROI in the liver. Results: LIDEA identified the liver with a 97.3% sensitivity with PET/CT images only and reached a 98.9% correct detection rate when using the co-registered CT scan to avoid liver misidentification in the right lung. The average liver SUV obtained with LIDEA was successfully validated against its manual assessment, with no systematic difference (0.11 ± 0.36 SUV units) and a R 2 = 0.89 correlation coefficient. Conclusions: LIDEA proved to be a reliable tool to automatically identify and extract the average SUV of the liver in oncological whole-body PET/CT scans.