Impact of secondary particles on the magnetic field generated by a proton pencil beam: a finite-element analysis based on Geant4-DNA simulations.

PURPOSE: To investigate the static magnetic field generated by a proton pencil beam as a candidate for range verification by means of Monte Carlo simulations, thereby improving upon existing analytical calculations. We focus on the impact of statistical current fluctuations and secondary protons and electrons. METHODS: We considered a pulsed beam (10 µ ${\umu}$ s pulse duration) during the duty cycle with a peak beam current of 0.2 µ $\umu$ A and an initial energy of 100 MeV. We ran Geant4-DNA Monte Carlo simulations of a proton pencil beam in water and extracted independent particle phase spaces. We calculated longitudinal and radial current density of protons and electrons, serving as an input for a magnetic field estimation based on a finite element analysis in a cylindrical geometry. We made sure to allow for non-solenoidal current densities as is the case of a stopping proton beam. RESULTS: The rising proton charge density toward the range is not perturbed by energy straggling and only lowered through nuclear reactions by up to 15%, leading to an approximately constant longitudinal current. Their relative low density however (at most 0.37 protons/mm3 for the 0.2  µ ${\umu}$ A current and a beam cross-section of 2.5 mm), gives rise to considerable current density fluctuations. The radial proton current resulting from lateral scattering and being two orders of magnitude weaker than the longitudinal current is subject to even stronger fluctuations. Secondary electrons with energies above 10 eV, that far outnumber the primary protons, reduce the primary proton current by only 10% due to their largely isotropic flow. A small fraction of electrons (<1%), undergoing head-on collisions, constitutes the relevant electron current. In the far-field, both contributions to the magnetic field strength (longitudinal and lateral) are independent of the beam spot size. We also find that the nuclear reaction-related losses cause a shift of 1.3 mm to the magnetic field profile relative to the actual range, which is further enlarged to 2.4 mm by the electron current (at a distance of ρ = 50 $\rho =50$  mm away from the central beam axis). For ρ > 45 $\rho >45$  mm, the shift increases linearly. While the current density variations cause significant magnetic field uncertainty close to the central beam axis with a relative standard deviation (RSD) close to 100%, they average out at a distance of 10 cm, where the RSD of the total magnetic field drops below 2%. CONCLUSIONS: With the small influence of the secondary electrons together with the low RSD, our analysis encourages an experimental detection of the magnetic field through sensitive instrumentation, such as optical magnetometry or SQUIDs.

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: A voxel-based morphometry approach exploiting Monte Carlo simulations.

PURPOSE: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive 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. 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 interfractional 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 interfractional 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.

Improving the characterization of meningioma microstructure in proton therapy from conventional apparent diffusion coefficient measurements using Monte Carlo simulations of diffusion MRI.

PURPOSE: Proton therapy could benefit from noninvasively gaining tumor microstructure information, at both planning and monitoring stages. The anatomical location of brain tumors, such as meningiomas, often hinders the recovery of such information from histopathology, and conventional noninvasive imaging biomarkers, like the apparent diffusion coefficient (ADC) from diffusion-weighted MRI (DW-MRI), are nonspecific. The aim of this study was to retrieve discriminative microstructural markers from conventional ADC for meningiomas treated with proton therapy. These markers were employed for tumor grading and tumor response assessment. METHODS: DW-MRIs from patients affected by meningioma and enrolled in proton therapy were collected before (n = 35) and 3 months after (n = 25) treatment. For the latter group, the risk of an adverse outcome was inferred by their clinical history. Using Monte Carlo methods, DW-MRI signals were simulated from packings of synthetic cells built with well-defined geometrical and diffusion properties. Patients' ADC was modeled as a weighted sum of selected simulated signals. The weights that best described a patient's ADC were determined through an optimization procedure and used to estimate a set of markers of tumor microstructure: diffusion coefficient (D), volume fraction (vf), and radius (R). Apparent cellularity (ρapp ) was estimated from vf and R for an easier clinical interpretability. Differences between meningothelial and atypical subtypes, and low- and high-grade meningiomas were assessed with nonparametric statistical tests, whereas sensitivity and specificity with ROC analyses. Similar analyses were performed for patients showing low or high risk of an adverse outcome to preliminary evaluate response to treatment. RESULTS: Significant (P < 0.05) differences in median ADC, D, vf, R, and ρapp values were found when comparing meningiomas' subtypes and grades. ROC analyses showed that estimated microstructural parameters reached higher specificity than ADC for subtyping (0.93 for D and vf vs 0.80 for ADC) and grading (0.75 for R vs 0.67 for ADC). High- and low-risk patients showed significant differences in ADC and microstructural parameters. The skewness of ρapp was the parameter with highest AUC (0.90) and sensitivity (0.75). CONCLUSIONS: Matching measured with simulated ADC yielded a set of potential imaging markers for meningiomas grading and response monitoring in proton therapy, showing higher specificity than conventional ADC. These markers can provide discriminative information about spatial patterns of tumor microstructure implying important advantages for patient-specific proton therapy workflows.

Multi-parametric qualitative and quantitative MRI assessment as predictor of histological grading in previously treated meningiomas.

PURPOSE: Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading. METHODS: Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores. RESULTS: Univariate analysis showed different distributions (p < 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson's chi-square; Fisher's exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia. CONCLUSION: Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma.

Design and commissioning of the non-dedicated scanning proton beamline for ocular treatment at the synchrotron-based CNAO facility.

PURPOSE: Only few centers worldwide treat intraocular tumors with proton therapy, all of them with a dedicated beamline, except in one case in the USA. The Italian National Center for Oncological Hadrontherapy (CNAO) is a synchrotron-based hadrontherapy facility equipped with fixed beamlines and pencil beam scanning modality. Recently, a general-purpose horizontal proton beamline was adapted to treat also ocular diseases. In this work, the conceptual design and main dosimetric properties of this new proton eyeline are presented. METHODS: A 28 mm thick water-equivalent range shifter (RS) was placed along the proton beamline to shift the minimum beam penetration at shallower depths. FLUKA Monte Carlo (MC) simulations were performed to optimize the position of the RS and patient-specific collimator, in order to achieve sharp lateral dose gradients. Lateral dose profiles were then measured with radiochromic EBT3 films to evaluate the dose uniformity and lateral penumbra width at several depths. Different beam scanning patterns were tested. Discrete energy levels with 1 mm water-equivalent step within the whole ocular energy range (62.7-89.8 MeV) were used, while fine adjustment of beam range was achieved using thin polymethylmethacrylate additional sheets. Depth-dose distributions (DDDs) were measured with the Peakfinder system. Monoenergetic beam weights to achieve flat spread-out Bragg Peaks (SOBPs) were numerically determined. Absorbed dose to water under reference conditions was measured with an Advanced Markus chamber, following International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice. Neutron dose at the contralateral eye was evaluated with passive bubble dosimeters. RESULTS: Monte Carlo simulations and experimental results confirmed that maximizing the air gap between RS and aperture reduces the lateral dose penumbra width of the collimated beam and increases the field transversal dose homogeneity. Therefore, RS and brass collimator were placed at about 98 cm (upstream of the beam monitors) and 7 cm from the isocenter, respectively. The lateral 80%-20% penumbra at middle-SOBP ranged between 1.4 and 1.7 mm depending on field size, while 90%-10% distal fall-off of the DDDs ranged between 1.0 and 1.5 mm, as a function of range. Such values are comparable to those reported for most existing eye-dedicated facilities. Measured SOBP doses were in very good agreement with MC simulations. Mean neutron dose at the contralateral eye was 68 µSv/Gy. Beam delivery time, for 60 Gy relative biological effectiveness (RBE) prescription dose in four fractions, was around 3 min per session. CONCLUSIONS: Our adapted scanning proton beamline satisfied the requirements for intraocular tumor treatment. The first ocular treatment was delivered in August 2016 and more than 100 patients successfully completed their treatment in these 2 yr.

Dosimetric characterization of 3D printed bolus at different infill percentage for external photon beam radiotherapy.

BACKGROUND AND PURPOSE: 3D printing is rapidly evolving and further assessment of materials and technique is required for clinical applications. We evaluated 3D printed boluses with acrylonitrile butadiene styrene (ABS) and polylactide (PLA) at different infill percentage. MATERIAL AND METHODS: A low-cost 3D printer was used. The influence of the air inclusion within the 3D printed boluses was assessed thoroughly both with treatment planning system (TPS) and with physical measurements. For each bolus, two treatment plans were calculated with Monte Carlo algorithm, considering the computed tomography (CT) scan of the 3D printed bolus or modelling the 3D printed bolus as a virtual bolus structure with a homogeneous density. Depth dose measurements were performed with Gafchromic films. RESULTS: High infill percentage corresponds to high density and high homogeneity within bolus material. The approximation of the bolus in the TPS as a homogeneous material is satisfying for infill percentages greater than 20%. Measurements performed with PLA boluses are more comparable to the TPS calculated profiles. For boluses printed at 40% and 60% infill, the discrepancies between calculated and measured dose distribution are within 5%. CONCLUSIONS: 3D printing technology allows modulating the shift of the build-up region by tuning the infill percentage of the 3D printed bolus in order to improve superficial target coverage.

3D-printed applicators for high dose rate brachytherapy: Dosimetric assessment at different infill percentage.

PURPOSE: Dosimetric assessment of high dose rate (HDR) brachytherapy applicators, printed in 3D with acrylonitrile butadiene styrene (ABS) at different infill percentage. MATERIALS AND METHODS: A low-cost, desktop, 3D printer (Hamlet 3DX100, Hamlet, Dublin, IE) was used for manufacturing simple HDR applicators, reproducing typical geometries in brachytherapy: cylindrical (common in vaginal treatment) and flat configurations (generally used to treat superficial lesions). Printer accuracy was investigated through physical measurements. The dosimetric consequences of varying the applicator's density by tuning the printing infill percentage were analysed experimentally by measuring depth dose profiles and superficial dose distribution with Gafchromic EBT3 films (International Specialty Products, Wayne, NJ). Dose distributions were compared to those obtained with a commercial superficial applicator. RESULTS: Measured printing accuracy was within 0.5mm. Dose attenuation was not sensitive to the density of the material. Surface dose distribution comparison of the 3D printed flat applicators with respect to the commercial superficial applicator showed an overall passing rate greater than 94% for gamma analysis with 3% dose difference criteria, 3mm distance-to-agreement criteria and 10% dose threshold. CONCLUSION: Low-cost 3D printers are a promising solution for the customization of the HDR brachytherapy applicators. However, further assessment of 3D printing techniques and regulatory materials approval are required for clinical application.

Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats.

PURPOSE: Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. METHODS: The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity ΔSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal ΔR1 and transverse ΔR2(*) relaxation rates. RESULTS: An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the ΔR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of ΔR2(*) showed a larger average radio-sensitivity for the oxy rats with ΔR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one-out procedure yielded a radio-sensitivity error lower than 20% in both neural networks. CONCLUSIONS: While preliminary, these specific results suggest that subjects affected by the same pathology can benefit differently from the same irradiation modalities and support the usefulness of IBT in discriminating between different responses.

The impact of low-Z and high-Z metal implants in IMRT: a Monte Carlo study of dose inaccuracies in commercial dose algorithms.

PURPOSE: The aim of the study was to evaluate the dosimetric impact of low-Z and high-Z metallic implants on IMRT plans. METHODS: Computed tomography (CT) scans of three patients were analyzed to study effects due to the presence of Titanium (low-Z), Platinum and Gold (high-Z) inserts. To eliminate artifacts in CT images, a sinogram-based metal artifact reduction algorithm was applied. IMRT dose calculations were performed on both the uncorrected and corrected images using a commercial planning system (convolution/superposition algorithm) and an in-house Monte Carlo platform. Dose differences between uncorrected and corrected datasets were computed and analyzed using gamma index (Pγ<1) and setting 2 mm and 2% as distance to agreement and dose difference criteria, respectively. Beam specific depth dose profiles across the metal were also examined. RESULTS: Dose discrepancies between corrected and uncorrected datasets were not significant for low-Z material. High-Z materials caused under-dosage of 20%-25% in the region surrounding the metal and over dosage of 10%-15% downstream of the hardware. Gamma index test yielded Pγ<1>99% for all low-Z cases; while for high-Z cases it returned 91% < Pγ<1< 99%. Analysis of the depth dose curve of a single beam for low-Z cases revealed that, although the dose attenuation is altered inside the metal, it does not differ downstream of the insert. However, for high-Z metal implants the dose is increased up to 10%-12% around the insert. In addition, Monte Carlo method was more sensitive to the presence of metal inserts than superposition/convolution algorithm. CONCLUSIONS: The reduction in terms of dose of metal artifacts in CT images is relevant for high-Z implants. In this case, dose distribution should be calculated using Monte Carlo algorithms, given their superior accuracy in dose modeling in and around the metal. In addition, the knowledge of the composition of metal inserts improves the accuracy of the Monte Carlo dose calculation significantly.

Imaging dose assessment for IGRT in particle beam therapy.

INTRODUCTION: Image-guided advanced photon and particle beam treatments are promising options for improving lung treatments. Extensive use of imaging increases the overall patient dose. The aim of this study was to determine the imaging dose for different IGRT solutions used in photon and particle beam therapy. MATERIAL AND METHODS: Measurements were performed in an Alderson phantom with TLDs. Clinically applied protocols for orthogonal planar kV imaging, stereoscopic imaging, CT scout views, fluoroscopy, CT, 4D-CT and CBCT were investigated at five ion beam centers and one conventional radiotherapy department. The overall imaging dose was determined for a patient undergoing a lung tumor irradiation with institute specific protocols. RESULTS: OAR doses depended on imaging modality and OAR position. Dose values were in the order of 1 mGy for planar and stereoscopic imaging and 10-50 mGy for volumetric imaging, except for one CBCT device leading to lower doses. The highest dose per exam (up to 150 mGy to the skin) was recorded for a 3-min fluoroscopy. DISCUSSION: Modalities like planar kV or stereoscopic imaging result in very low doses (≈ 1 mGy) to the patient. Imaging a moving target during irradiation, low-dose protocols and protocol optimization can reduce the imaging dose to the patient substantially.

Dosimetric assessment of a novel metal artifact reduction method in CT images.

The aim of this study was to assess the ability of metal artifact reduction (MAR) algorithm in restoring the CT image quality while correcting the tissue density information for the accurate estimation of the absorbed dose. A phantom filled with titanium (low-Z metal) and Cerrobend (high-Z metal) inserts was used for this purpose. The MAR algorithm was applied to phantom's CT dataset. Static intensity-modulated radiation therapy (IMRT) plans, including five beam angles, were designed and optimized on the uncorrected images to deliver 10 Gy on the simulated target. Monte Carlo dose calculation was computed on uncorrected, corrected, and ground truth image datasets. It was firstly verified that MAR methodology was able to correct HU errors due to the metal presence. In the worst situation (high-Z phantom), the image difference, uncorrected ground truth and corrected ground truth, went from -4.4 ± 118.8 HU to 0.4 ± 10.8 HU, respectively. Secondly, it was observed that the impact of dose errors estimation depends on the atomic number of the metal: low-Z inserts do not produce significant dose inaccuracies, while high-Z implants substantially influence the computation of the absorbed dose. In this latter case, dose errors in the PTV region were up to 23.56% (9.72% mean value) when comparing the uncorrected vs. the ground truth dataset. After MAR correction, errors dropped to 0.11% (0.10% mean value). In conclusion, it was assessed that the new MAR algorithm is able to restore image quality without distorting mass density information, thus producing a more accurate dose estimation.

Comparative assessment of 3D surface scanning systems in breast plastic and reconstructive surgery.

In this work, we compared accuracy, repeatability, and usability in breast surface imaging of 2 commercial surface scanning systems and a hand-held laser surface scanner prototype coupled with a patient's motion acquisition and compensation methodology. The accuracy of the scanners was assessed on an anthropomorphic phantom, and to evaluate the usability of the scanners on humans, thorax surface images of 3 volunteers were acquired. Both the intrascanner repeatability and the interscanner comparative accuracy were assessed. The results showed surface-to-surface distance errors inferior to 1 mm and to 2 mm, respectively, for the 2 commercial scanners and for the prototypical one. Moreover, comparable performances of the 3 scanners were found when used for acquiring the breast surface. On the whole, this study demonstrated that handheld laser surface scanners coupled with subject motion compensation methods lend themselves as competitive technologies for human body surface modeling.

Scale invariant feature transform in adaptive radiation therapy: a tool for deformable image registration assessment and re-planning indication.

Adaptive radiation therapy (ART) aims at compensating for anatomic and pathological changes to improve delivery along a treatment fraction sequence. Current ART protocols require time-consuming manual updating of all volumes of interest on the images acquired during treatment. Deformable image registration (DIR) and contour propagation stand as a state of the ART method to automate the process, but the lack of DIR quality control methods hinder an introduction into clinical practice. We investigated the scale invariant feature transform (SIFT) method as a quantitative automated tool (1) for DIR evaluation and (2) for re-planning decision-making in the framework of ART treatments. As a preliminary test, SIFT invariance properties at shape-preserving and deformable transformations were studied on a computational phantom, granting residual matching errors below the voxel dimension. Then a clinical dataset composed of 19 head and neck ART patients was used to quantify the performance in ART treatments. For the goal (1) results demonstrated SIFT potential as an operator-independent DIR quality assessment metric. We measured DIR group systematic residual errors up to 0.66 mm against 1.35 mm provided by rigid registration. The group systematic errors of both bony and all other structures were also analyzed, attesting the presence of anatomical deformations. The correct automated identification of 18 patients who might benefit from ART out of the total 22 cases using SIFT demonstrated its capabilities toward goal (2) achievement.

New technologies for the assessment of breast surgical outcomes.

BACKGROUND: Although interest in objective and quantitative breast surgical outcome assessment is rapidly increasing, published reports have yet to make a real impact on everyday clinical practice. OBJECTIVE: The authors offer a preliminary report on an innovative methodology customized for breast shape evaluation that, in our opinion, could overcome most of the technical and conceptual limitations of previous studies. METHODS: Three-dimensional/four-dimensional breast scanning was performed using a breast-dedicated prototype laser scanner made up of a handheld device, including a charge-coupled device (CCD) camera coupled to a spot laser source. Two additional motion analyzer cameras were used for handheld device tracking and the acquisition of patient motion. RESULTS: Seven female volunteers, including both subjects who had undergone cosmetic or reconstructive breast surgery and those with no such history, underwent a dynamic breast shape survey. Curvature mapping on three-dimensional mesh warranted precise measurements of local geometric properties of the breast surface. Elaboration and representation of breast dynamic behavior during common motor tasks (eg, walking, running, sitting, and lying) was also possible. CONCLUSIONS: The scanning methodology reported here reliably describes the breast surface not only in a static position, but also at specific postures or during motion of the body. It also opens the door for quantitative static and dynamic assessment of surgical outcomes, the intraoperative assessment of breast shape, and other applications. Limitations include the relatively long amount of time required for each scan and the need for technical and clinical validation, particularly with respect to four-dimensional assessment.