Proton Treatment Research Articles

FLIP: a novel method for patient-specific dose quantification in circulating blood in large vessels during proton or photon external beam radiotherapy treatments.

To provide a novel and personalized method (FLIP, FLowandIrradiation Personalized) using patient-specific circulating blood flows and individualized time-dependent irradiation distributions, to quantify the dose delivered to blood in large vessels during proton or photon external beam radiotherapy. Patient-specific data were obtained from ten cancer patients undergoing radiotherapy, including the blood velocity field in large vessels and the temporal irradiation scheme using photons or protons. The large vessels and the corresponding blood flow velocities are obtained from phase-contrast MRI sequences. The blood dose is obtained discretizing the fluid into individual blood particles (BPs). A Lagrangian approach was applied to simulate the BPs trajectories along the vascular velocity field flowlines. Beam delivery dynamics was obtained from beam delivery machine measurements. The whole irradiation sequence is split into a sequence of successive irradiation elements, each one with its constant dose rate, as well as its corresponding initial and final time. Calculating the dose rate and knowing the spatiotemporal distribution of BPs, the dose is computed by accumulating the energy received by each BP as the time-dependent irradiation beams take place during the treatment. Blood Dose Volume Histograms (DVHs) from proton therapy and photon radiotherapy (RT) patients were assessed. The irradiation times distribution is obtained for BPs in both modalities. Two dosimetric parameters are presented: (i) D3%, representing the minimum dose received by the 3% of BPs receiving the highest doses, and (ii) V0.5Gy, denoting the blood volume percentage that has received at least 0.5 Gy. A novel methodology is proposed for quantifying the circulating blood dose along large vessels. This methodology involves the use of patient-specific vasculature, blood flow velocity field, and dose delivery dynamics recovered from the irradiation machine. Relevant parameters that affect the dose received, as the distance between large vessels and CTV, are identified.

A simulation framework for preclinical proton irradiation workflow

Objective.The integration of proton beamlines with x-ray imaging/irradiation platforms has opened up possibilities for image-guided Bragg peak irradiations in small animals. Such irradiations allow selective targeting of normal tissue substructures and tumours. However, their small size and location pose challenges in designing experiments. This work presents a simulation framework useful for optimizing beamlines, imaging protocols, and design of animal experiments. The usage of the framework is demonstrated, mainly focusing on the imaging part.Approach.The fastCAT toolkit was modified with Monte Carlo (MC)-calculated primary and scatter data of a small animal imager for the simulation of micro-CT scans. The simulated CT of a mini-calibration phantom from fastCAT was validated against a full MC TOPAS CT simulation. A realistic beam model of a preclinical proton facility was obtained from beam transport simulations to create irradiation plans in matRad. Simulated CT images of a digital mouse phantom were generated using single-energy CT (SECT) and dual-energy CT (DECT) protocols and their accuracy in proton stopping power ratio (SPR) estimation and their impact on calculated proton dose distributions in a mouse were evaluated.Main results.The CT numbers from fastCAT agree within 11 HU with TOPAS except for materials at the centre of the phantom. Discrepancies for central inserts are caused by beam hardening issues. The root mean square deviation in the SPR for the best SECT (90 kV/Cu) and DECT (50 kV/Al-90 kV/Al) protocols are 3.7% and 1.0%, respectively. Dose distributions calculated for SECT and DECT datasets revealed range shifts <0.1 mm, gamma pass rates (3%/0.1 mm) greater than 99%, and no substantial dosimetric differences for all structures. The outcomes suggest that SECT is sufficient for proton treatment planning in animals.Significance.The framework is a useful tool for the development of an optimized experimental configuration without using animals and beam time.

Proton bunch monitors for the clinical translation of prompt gamma-ray timing

Abstract Objective: Prompt gamma-ray timing is an emerging technology in the field of particle therapy treatment verification. This system measures the arrival times of gamma rays produced in the patient body and uses the cyclotron radio frequency signal as time reference for the beam micro-bunches. Its translation into clinical practice is currently hindered by observed instabilities in the phase relation between the cyclotron radio frequency and the measured arrival time of prompt gamma rays. To counteract this, two proton bunch monitors are presented, integrated into the prompt gamma-ray timing workflow and evaluated. Approach: The two monitors are (a) a diamond detector placed at the beam energy degrader, and (b) a cyclotron monitor signal measuring the phase difference between dee current and voltage. First, the two proton bunch monitors as well as their mutual correlation were characterized. Then, a prompt gamma-ray timing measurement was performed aiming to quantify the present magnitude of the phase instabilities and to evaluate the ability of the proton bunch monitors to correct for these instabilities. Main results: It was found that the two new monitors showed a very high correlation for intermediate proton energies after the first second of irradiation, and that they were able to reduce fluctuations in the detected phase of prompt gamma rays. Furthermore, the amplitude of the phase instabilities had intrinsically decreased from about 700 ps to below 100 ps due to cyclotron upgrades. Significance: The uncertainty of the prompt gamma-ray timing method for proton treatment verification was reduced. For routine clinical application, challenges remain in accounting for detector load effects, temperature drifts and throughput limitations.

Cardiac motion in patients with ventricular tachycardia: potential implications for the treatment of patients candidates to stereotactic arrhythmia radio-ablation (STAR)

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has proven to be a valid alternative treatment for refractory ventricular tachycardia (VT) in patients who are unsuitable to undergo standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. There is increased research activity on better understanding the complex and fast motion of the heart and on reducing radiation toxicity. Purpose In the context of an in silico study to evaluate the feasibility of STAR with protons in patients with VT, the initial findings related to cardiac motion on the first 10 patients are here presented. Methods Prior to CA, each patient underwent ECG gated CT scans in expiratory breath-hold, with and without contrast and reconstructed at 30% (systole) and 80% (diastole) of the cardiac R-R cycle. Contouring of the ablation target as a clinical target volume (CTV) for proton treatment planning was performed based on a standard electrophysiological study with 3D eletroanatomical mapping. Two different treatment plans were created: the first with only the diastolic CTV as target (gated treatment), the second including both diastolic and systolic CTVs to create an Internal Target Volume (ITV) in the hypothesis of non-gated treatment. Robust optimization was used to create the Planning Target Volume (PTV). Results The target volumes used for treatment planning are given in Table 1. The median CTV was 10.90 (2.93-36.94) cm3 for diastole and 14.26 (1.73-36.31) cm3 for systole. These volumes are somewhat smaller than those reported in patients treated previously with STAR: this difference may be due to the fact that no respiratory motion was included in the target contour and that the study population includes many patients referred for ventricular ectopic beats without structural heart disease, where the ablation target is expected to be smaller as compared to patients with VT in structural heart disease. Despite a small median difference between the diastolic and systolic CTV of 0.53 (0.03-9.61) cm3, the ITV approach resulted in a median increase in volume compared to the largest of the two CTVs of 29 % (1%-44%). When considering the proton range uncertainty and potential errors in patient positioning (PTV), the target is this time enlarged by a factor 2.9 (1.9-3.9). This data indicates that both cardiac motion and uncertainties in patient positioning before treatment will have a large impact on the treatment volume thus affecting the amount of surrounding tissue exposed to radiation. Conclusion The ablation target contour at systole and diastole are of similar magnitude but their non-overlap results in a large increase in treated volume when radiation delivery is not gated for cardiac motion. Further analysis shall investigate on a case-by-case basis the potential reduction in risk of healthy tissue toxicity with cardiac-gated proton delivery.Table 1

First experimental verification of prompt gamma imaging with carbon ion irradiation

Prompt Gamma Imaging (PGI) is a promising technique for range verification in Particle Therapy. This technique was already tested in clinical environment with a knife-edge-collimator camera for proton treatments but remains relatively unexplored for Carbon Ion Radiation Therapy (CIRT). Previous FLUKA simulations suggested that PG profile shifts could be detected in CIRT with a precision of \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 4 mm (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2 \\sigma$$\\end{document}) for a particle statistic equal to \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$5 \\cdot 10^{7}$$\\end{document} C-ions using a 10 × 10 cm2 camera. An experimental campaign was carried out at CNAO (Pavia, Italy) to verify these results, using a knife-edge-collimator camera prototype based on a 5 × 5 cm2 pixelated LYSO crystal. PG profiles were measured irradiating a plastic phantom with a C-ion pencil beam at clinical energies and intensities, also moving the detector to extend the FOV to 13 × 5 cm2. The prototype detected Bragg-peak shifts with \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 4 mm precision for a statistic of \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim 4 \\cdot 10^{8}$$\\end{document} C-ions (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$3 \\cdot 10^{8}$$\\end{document} for the extended FOV), slightly larger than expected. Nevertheless, the detector demonstrated significant potential for verifying the precision in dose delivery following a treatment fraction, which remains fundamental in the clinical environment. For the first time to our knowledge, range verification based on PGI was applied to a C-ion beam at clinical energy and intensities.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

A comparison of the acoustic waves generated in proton and carbon ion therapy

Hadron therapy, which employs particles such as protons and carbon-ions, is a promising method of cancer treatment due to its unique ability to deliver maximum energy at the Bragg peak near the tumor, sparing surrounding healthy tissue. Ionoacoustic waves, generated by thermal expansion from electronic collisions and localized heating, can be detected to optimize dose delivery and verify particle range, thus improving treatment precision. These waves offer a unique opportunity for comparative studies of different particle therapies. In this study, a mathematical model and computational simulations are used to compare the characteristics of ionoacoustic waves generated in tissue by proton and carbon-ion beams. In particular, we assess the impact of the nuclear fragmentation tail on the ionoacoustic signals generated in carbon-ion therapy. Our approach will allow us to make some important observations to study the comparative effects of proton and carbon-ion therapy. The aim of this work is to perform a comprehensive comparative analysis of ionoacoustic waves from proton and carbon-ion treatments, focusing on their potential for in-vivo range verification. This research addresses the current gap in understanding the use of ionoacoustic signals for range verification in ion beam therapy, which is critical given the growing clinical application of carbon ion therapy and its under-explored acoustic properties. This study pioneers the feasibility of using acoustic imaging from carbon-ion beams to detect the Bragg peak position and measure tumor dose in real-time. Carbon-ion dose mapping and relative biological effectiveness (RBE) assessment can be facilitated by real-time signal monitoring. Our study aims to significantly advance the field by addressing the lack of a verification technique for carbon-ion beams, focusing on the considerable impact of the nuclear fragmentation tail on ionoacoustic signal waveforms, which provides crucial insights into the unique energy deposition properties of carbon-ions.

Acute toxicities in proton therapy for head and neck cancer – A matched analysis of the DAHANCA 35 feasibility study

Background and purposeAs preparation for a national randomized study comparing proton radiotherapy to photon radiotherapy, DAHANCA 35, we performed a non-randomized pilot study to investigate patient selection, logistics, planning, and treatment delivery. With the present study, as a comprehensive safety analysis, we want to compare toxicity during and up to two months after therapy to a historically matched group of patients treated with photon radiotherapy. Materials and methods62 patients treated with protons were matched to 124 patients who received photon treatment outside a protocol. Available data were retrieved from the DAHANCA database. Patients were matched on treatment centre, concurrent chemotherapy, tumour site, stage, p16 status for oropharynx cancers. Selection of patients for proton therapy was based on comparative treatment plans with a NTCP reduction for dysphagia and xerostomia at six months. ResultsBaseline characteristics between groups were well balanced, except for the type of drug used concurrently; more photon patients received Carboplatin (21.2 % vs 5.8 %, p = 0.01). Proton therapy was associated with significantly less weight loss at the end of treatment, mean weight loss of 3 % for protons and 5 % for photons (p < 0.001). There were more grade 3 skin reactions and grade 3 mucositis after proton treatment compared with photons at the end of treatment, Risk Ratio (RR) 1.9 (95 % CI: 1.01–3.5, p = 0.04) and RR 1.5 (95 % CI: 1.3–1.7, p < 0.001), respectively. All differences resolved at follow up two months after treatment. There were no significant differences between groups on opioid use, use of feeding tubes, or hospitalization during the observation period. ConclusionProton treatment resulted in excess objective mucositis and dermatitis, which was transient and did not seem to negatively influence weight or treatment compliance and intensity. Selection bias was likely especially since NTCP models were used for selection of proton treatment and photon treated patients were matched manually. We are currently including patients in a randomized controlled trial.

Ab initio density response and local field factor of warm dense hydrogen

We present quasi-exact ab initio path integral Monte Carlo (PIMC) results for the partial static density responses and local field factors of hydrogen in the warm dense matter regime, from solid density conditions to the strongly compressed case. The full dynamic treatment of electrons and protons on the same footing allows us to rigorously quantify both electronic and ionic exchange–correlation effects in the system, and to compare the results with those of earlier incomplete models such as the archetypal uniform electron gas or electrons in a fixed ion snapshot potential that do not take into account the interplay between the two constituents. The full electronic density response is highly sensitive to electronic localization around the ions, and our results constitute unambiguous predictions for upcoming X-ray Thomson scattering experiments with hydrogen jets and fusion plasmas. All PIMC results are made freely available and can be used directly for a gamut of applications, including inertial confinement fusion calculations and the modeling of dense astrophysical objects. Moreover, they constitute invaluable benchmark data for approximate but computationally less demanding approaches such as density functional theory or PIMC within the fixed-node approximation.

An experimental validation of a filtering approach for prompt gamma prediction in a research proton treatment planning system

Objective. Prompt gamma (PG) radiation generated from nuclear reactions between protons and tissue nuclei can be employed for range verification in proton therapy. A typical clinical workflow for PG range verification compares the detected PG profile with a predicted one. Recently, a novel analytical PG prediction algorithm based on the so-called filtering formalism has been proposed and implemented in a research version of RayStation (RaySearch Laboratories AB), which is a widely adopted treatment planning system. This work validates the performance of the filtering PG prediction approach. Approach. The said algorithm is validated against experimental data and benchmarked with another well-established PG prediction algorithm implemented in a MATLAB-based software REGGUI. Furthermore, a new workflow based on several PG profile quality criteria and analytical methods is proposed for data selection. The workflow also calculates sensitivity and specificity information, which can help practitioners to decide on irradiation course interruption during treatment and monitor spot selection at the treatment planning stage. With the proposed workflow, the comparison can be performed on a limited number of selected high-quality irradiation spots without neighbouring-spot aggregation. Main results. The mean shifts between the experimental data and the predicted PG detection (PGD) profiles (ΔPGD) by the two algorithms are estimated to be 1.5±2.1 mm and −0.6±2.2 mm for the filtering and REGGUI prediction methods, respectively. The ΔPGD difference between two algorithms is observed to be consistent with the beam model difference within uncertainty. However, the filtering approach requires a much shorter computation time compared to the REGGUI approach. Significance. The novel filtering approach is successfully validated against experimental data and another widely used PG prediction algorithm. The workflow designed in this work selects spots with high-quality PGD shift calculation results, and performs sensitivity and specificity analyses to assist clinical decisions.

Protonated Z-scheme CdS-covalent organic framework heterojunction with highly efficient photocatalytic hydrogen evolution

The low efficiency of photocatalytic hydrogen production from water is mainly suffer from limited light absorption, charge separation and water delivery to the active centers. Herein, an inorganic–organic Z-scheme heterojunction (CdS-COF-Ni) is constructed by in-situ growth of CdS nanosheets on the porphyrin-based covalent organic framework with nickel ions (COF-Ni) in the porphyrin centers. A built-in electric field is formed at the interface, which accelerates the separation and transfer of photogenerated charges. Moreover, through the surface protonation treatment in ascorbic acid (AC) solution, the hydrophilicity of the obtained composite is obviously increased and facilitates the transport of water molecules to the photocatalytic centers. Under the synergistic effect of the interfacial interaction and surface protonation treatment, the photocatalytic hydrogen production rate is optimized to be 18.23 mmol h−1 g−1 without adding any cocatalysts, which is 21 times that of CdS. After a series of photoelectrochemical measurements, in situ X-ray photoelectron spectroscopy (XPS) analysis, and density functional theory (DFT) calculations, it is found that the photocatalytic charge transfer pathway conforms to the Z-scheme mechanism, which not only greatly accelerates the separation and transfer of photogenerated charges, but also retains a high reduction capacity for water splitting. This work offers a good strategy for constructing highly efficient organic–inorganic heterojunctions for water splitting.

Dosimetric evaluation of intensity modulated photon versus proton reirradiation of head and neck cancer

BackgroundReirradiation of head and neck cancer (HNC) became more accessible in the last decade, owing to modern irradiation techniques which offer a reduction in treatment related toxicities. The aim of this paper was to comparatively evaluate the dosimetric aspects derived from intensity modulated photon vs. proton treatment planning in reirradiated HNC patients. MethodsSix recurrent HNC patients were enrolled in this retrospective study. For each patient two treatment plans were created: one IMRT/VMAT and one IMPT plan. The prescribed dose for the second irradiation was between 50 and 70 Gy RBE. The study comparatively analyzed the CTV coverage, doses to organs at risk (OARs) and low doses received by the healthy tissue (other than OAR). ResultsSimilar CTV coverage was achieved for photon vs proton plans, with the latter presenting better homogeneity in four cases. Maximum dose to CTV was generally higher for photon plans, with differences ranging from 0.3 to 1.9%. For parotid glands and body, the mean dose was lower for proton plans. A notable reduction of low dose to healthy tissue (other than OARs) could be achieved with protons, with an average of 60% and 64% for D10% and Dmean, respectively. ConclusionThe dosimetric comparison between photon and proton reirradiation of HNC showed a great need for treatment individualization, concluding that protons should be considered for reirradiation on an individual basis.

Motion-induced dose perturbations in photon radiotherapy and proton therapy measured by deformable liver-shaped 3D dosimeters in an anthropomorphic phantom

Background and purposeThe impact of intrafractional motion and deformations on clinical radiotherapy delivery has so far only been investigated by simulations as well as point and planar dose measurements. The aim of this study was to combine anthropomorphic 3D dosimetry with a deformable abdominal phantom to measure the influence of intra-fractional motion and gating in photon radiotherapy and evaluate the applicability in proton therapy. Material and methodsAn abdominal phantom was modified to hold a deformable anthropomorphic 3D dosimeter shaped as a human liver. A liver-specific photon radiotherapy and a proton pencil beam scanning therapy plan were delivered to the phantom without motion as well as with 12 mm sinusoidal motion while using either no respiratory gating or respiratory gating. ResultsUsing the stationary irradiation as reference the local 3 %/2 mm 3D gamma index pass rate of the motion experiments in the planning target volume (PTV) was above 97 % (photon) and 78 % (proton) with gating whereas it was below 74 % (photon) and 45 % (proton) without gating. ConclusionsFor the first time a high-resolution deformable anthropomorphic 3D dosimeter embedded in a deformable abdominal phantom was applied for experimental validation of both photon and proton treatments of targets exhibiting respiratory motion. It was experimentally shown that gating improves dose coverage and the geometrical accuracy for both photon radiotherapy and proton therapy.

Validation and reproducibility of in vivo dosimetry for pencil beam scanned FLASH proton treatment in mice

PurposeTo investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber. Methods and Materials227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector. ResultsCalibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose. ConclusionIn vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose.

Proton CT on biological phantoms for x-ray CT calibration in proton treatment planning

Objective. To present and characterize a novel method for x-ray computed tomography (xCT) calibration in proton treatment planning, based on proton CT (pCT) measurements on biological phantoms. Approach. A pCT apparatus was used to perform direct measurements of 3D stopping power relative to water (SPR) maps on stabilized, biological phantoms. Two single-energy xCT calibration curves—i.e. tissue substitutes and stoichiometric—were compared to pCT data. Moreover, a new calibration method based on these data was proposed, and verified against intra- and inter-species variability, dependence on stabilization, beam-hardening conditions, and analysis procedures. Main results. Biological phantoms were verified to be stable in time, with a dependence on temperature conditions, especially in the fat region: (−2.5 土 0.5) HU °C−1. The pCT measurements were compared with standard xCT calibrations, revealing an average SPR discrepancy within ±1.60% for both fat and muscle regions. In the bone region the xCT calibrations overestimated the pCT-measured SPR of the phantom, with a maximum discrepancy of about +3%. As a result, a new cross-calibration curve was directly extracted from the pCT data. Overall, the SPR uncertainty margin associated with this curve was below 3%; fluctuations in the uncertainty values were observed across the HU range. Cross-calibration curves obtained with phantoms made of different animal species and anatomical parts were reproducible with SPR discrepancies within 3%. Moreover, the stabilization procedure did not affect the resulting curve within a 2.2% SPR deviation. Finally, the cross-calibration curve was affected by the beam-hardening conditions on xCTs, especially in the bone region, while dependencies below 2% resulted from the image registration procedure. Significance. Our results showed that pCT measurements on biological phantoms may provide an accurate method for the verification of current xCT calibrations and may represent a tool for the implementation of a new calibration method for proton treatment planning.

Robustness of intensity modulated proton treatment of esophageal cancer for anatomical changes and breathing motion

Background and purposeIn this study, we assessed the robustness of intensity modulated proton therapy (IMPT) in esophageal cancer for anatomical variations during treatment. MethodsThe first sixty esophageal cancer patients, treated clinically with chemoradiotherapy were included. The treatment planning strategy was based on an internal target volume (ITV) approach, where the ITV was created from the clinical target volumes (CTVs) delineated on all phases of a 4DCT. For optimization, a 3 mm isotropic margin was added to the ITV, combined with robust optimization using 5 mm setup and 3 % range uncertainty. Each patient received weekly repeat CTs (reCTs). Robust plan re-evaluation on all reCTs, and a robust dose summation was performed. To assess the factors influencing ITV coverage, a multivariate linear regression analysis was performed. Additionally, clinical adaptations were evaluated. ResultsThe target coverage was adequate (ITV V94%>98 % on the robust voxel-wise minimum dose) on most reCTs (91 %), and on the summed dose in 92 % of patients. Significant predictors for ITV coverage in the multivariate analysis were diaphragm baseline shift and water equivalent depth (WED) of the ITV in the beam direction. Underdosage of the ITV mainly occurred in week 1 and 4, leading to treatment adaptation of eight patients, all on the first reCT. ConclusionOur IMPT treatment of esophageal cancer is robust for anatomical variations. Adaptation appears to be most effective in the first week of treatment. Diaphragm baseline shifts and WED are predictive factors for ITV underdosage, and should be incorporated in an adaptation protocol.

Fetal dose assessment in a pregnant patient with brain tumor: A comparative study of proton PBS and 3DCRT/VMAT radiation therapy techniques.

The treatment of brain tumors in pregnant patients poses challenges, as the out-of-field dose exposure to the fetus can potentially be harmful. A pregnant patient with prior radiation treatment was presented with a brain tumor at our clinic. This work reports on our pre-treatment study that compared fetal dose exposure between intensity-modulated proton therapy (IMPT) using pencil beam scanning (PBS) and conventional photon 3D conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT), and the subsequent pregnant patient's radiation treatment. Pre-treatment measurements of clinical plans, 3DCRT, VMAT, and IMPT, were conducted on a phantom. Measurements were performed using a device capable of neutron detections, closely following AAPM guidelines, TG158. For photon measurements, fetus shielding was utilized. On patient treatment days, which was determined to be proton treatment, shielding was used only during daily imaging for patient setup. Additionally, an in vivo measurement was conducted on the patient. Measurements showed that IMPT delivered the lowest fetal dose, considering both photon and neutron out-of-field doses to the fetus, even when shielding was implemented for photon measurements. Additionally, the proton plans demonstrated superior treatment for the mother, a reirradiation case. The patient was treated with proton therapy, and the baby was subsequently delivered at full term with no complications. This case study supports previous clinical findings and advocates for the expanded use of proton therapy in this patient population.

The impact of the titanium cranial hardware in proton single-field uniform dose plans.

Neurosurgical cranial titanium mesh and screws are commonly encountered in postoperative radiation therapy. However, only a limited number of reports are available in the context of proton therapy, resulting in a lack of consensus among the proton centers regarding the protocol for handling the hardware. This study is to examine the impact of the hardware in proton plans. The results serve as evidence for proton centers to generate standard operating procedures to manage the hardware in proton treatment. Plans with different gantry angles and material overrides are generated on the CT images of a phantom made of the hardware. The dose distributions of the plans with and without material override, at different depths are compared. Films and ionization chambers are used to measure the plans and the measurements are compared to the treatment planning system (TPS) calculations by gamma analysis. There are some overdose and underdose regions downstream of the hardware. The overdose and underdose values are within a few percent of the prescribed dose when multiple fields with large hinge angles are used. The gamma analysis results show that the measurements agree with the TPS calculations within limits that are clinically relevant. The study has demonstrated the influence of the hardware on proton plans. Based on the result of this study, a standard operating procedure of managing the hardware has been implemented in our clinic.

A reference-point-method-based online proton treatment plan re-optimization strategy and a novel solution to planning constraint infeasibility problem

Objective. Propose a highly automated treatment plan re-optimization strategy suitable for online adaptive proton therapy. The strategy includes a rapid re-optimization method that generates quality replans and a novel solution that efficiently addresses the planning constraint infeasibility issue that can significantly prolong the re-optimization process. Approach. We propose a systematic reference point method (RPM) model that minimizes the l-infinity norm from the initial treatment plan in the daily objective space for online re-optimization. This model minimizes the largest objective value deviation among the objectives of the daily replan from their reference values, leading to a daily replan similar to the initial plan. Whether a set of planning constraints is feasible with respect to the daily anatomy cannot be known before solving the corresponding optimization problem. The conventional trial-and-error-based relaxation process can cost a significant amount of time. To that end, we propose an optimization problem that first estimates the magnitude of daily violation of each planning constraint. Guided by the violation magnitude and clinical importance of the constraints, the constraints are then iteratively converted into objectives based on their priority until the infeasibility issue is solved. Main results. The proposed RPM-based strategy generated replans similar to the offline manual replans within the online time requirement for six head and neck and four breast patients. The average target D 95 and relevant organ at risk sparing parameter differences between the RPM replans and clinical offline replans were −0.23, −1.62 Gy for head and neck cases and 0.29, −0.39 Gy for breast cases. The proposed constraint relaxation solution made the RPM problem feasible after one round of relaxation for all four patients who encountered the infeasibility issue. Significance. We proposed a novel RPM-based re-optimization strategy and demonstrated its effectiveness on complex cases, regardless of whether constraint infeasibility is encountered.

Exploring flavor separation in soy protein enzymatic hydrolysates via resin adsorption/desorption: A study on physicochemical characteristics and mass transfer dynamics

The green separation of soy protein enzymatic hydrolysates (SPEH) with different flavors can enhance the application of SPEH in the food industry. This study investigated the detailed process of separating and purifying SPEH by utilising the interaction between SPEH and adsorptive resins, and the mass transfer behaviour of SPEH in the adsorptive resin was explored by a mathematical model. Initially, soybean meal underwent hydrolysis by papain. Subsequently, the resulting SPEH was adsorbed onto the resin under various pH conditions and then desorbed. In general, SPEH exhibited a greater ability to bind with the resin under protonation treatment (pH 3.0) compared to deprotonation treatment (pH 9.0). The equilibrium adsorption capacity at pH 3.0 and 9.0 was 33.1 ± 1.7 mg g−1 and 24.1 ± 0.9 mg g−1, respectively. At the same time, SPEH exhibited greater surface diffusivity within the resin during adsorption at pH 3.0 (2.83 × 10−8 cm2 s−1) compared to pH 9.0 (2.41 × 10−8 cm2 s−1). Due to the robust binding affinity of SPEH with the resin in the acidic environment, a smaller quantity of SPEH was released from the resin during the subsequent desorption process. Furthermore, the bitter SPEH, characterised by an abundance of random coil and β-turn structures, demonstrated greater affinity for binding with the adsorptive resin compared to the salty and umami SPEH, which exhibited a higher proportion of β-sheet structure. After adsorption at pH levels ranging from 3.0 to 9.0 and subsequent desorption, the recovery of SPEH ranged from 30.4 % to 35.7 %, with purities between 57.5 % and 62.3 %. Overall, this study offers valuable insights into the targeted separation of various flavor components from SPEH, shedding light on the intricate dynamics of adsorption and desorption processes under different pH conditions.