[Safety Analysis Using Event Tree Analysis for Multi-Ion Therapy].

At the National Institutes for Quantum Science and Technology (QST), a multi-ion therapy using helium, carbon, oxygen, and neon ions has been studied for charged particle therapy with more optimal biological effects. To make multi-ion therapy clinically feasible, a new treatment system was developed to realize the changes of the ion species in each irradiation using the Heavy Ion Medial Accelerator in Chiba (HIMAC). Since radiation therapy is safety-critical, it is necessary to construct a safety system that includes multiple safety barriers in the new treatment system for multi-ion therapy and to perform a safety analysis for the prevention of serious accidents. In this study, we conducted a safety analysis using event tree analysis (ETA) for newly introduced processes in the treatment planning, accelerator, and irradiation system of the multi-ion therapy. ETA is an optimal method to verify multiple safety barriers that are essential for medical safety and to shorten the time for safety analysis by focusing only on the new processes. Through ETA, we clarified the types of malfunctions and human errors that may lead to serious accidents in the new system for multi-ion therapy, and verified whether safety barriers such as interlock systems and human check procedures are sufficient to prevent such malfunctions and human errors. As a result, 6 initial events which may lead to serious accidents were listed in the treatment planning process, 16 initial events were listed in the accelerator system, and 13 initial events were listed in the irradiation system. Among these 35 initial events, 5 cautionary initial events were identified that could lead to serious final events and they had a probability of occurrence higher than 10-4. Meanwhile, the others were all initial events that do not lead to serious accidents, or the initial events that can lead to serious accidents but were considered to have sufficient safety barriers. The safety analysis using ETA successfully identified the system malfunctions and the human errors that can lead to serious accidents, and the multiple safety barriers against them were systematically analyzed. It became clear that the multiple safety barriers were not sufficient for some initial events. We plan to improve the safety barriers for the five cautionary initial events before the start of the clinical trial. Based on these findings, we achieved our objective to conduct a safety analysis for a new treatment system for multi-ion therapy. The safety analysis procedure using ETA proposed by this study will be effective when new systems for radiotherapy are established at QST and other facilities in the future as well.

Effects of cellular radioresponse on therapeutic helium-, carbon-, oxygen-, and neon-ion beams: a simulation study.

Objective. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges.Approach. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams.Main results. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases.Significance.From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.

Stopping-power ratio of body tissues with updated effective energies and elemental I values for treatment planning of proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions.

The stopping-power ratio (SPR) of body tissues relative to water depends on the particle energy and mean excitation energy (I value) of the tissues. Effective energies to minimize the range error in proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions and elemental I values have been updated in recent studies. We investigated the effects of these updates on SPR estimation for computed tomography-based treatment planning. The updates led to an increase of up to 0.5% in the SPRs of soft tissues, whereas they led to a decrease of up to 1.9% in the SPRs of bone tissues compared with the current clinical settings. For 44 proton beams planned for 15 randomly sampled patients, the mean water-equivalent target depth change was - 0.2 mm with a standard deviation of 0.2 mm. The maximum change was - 0.6 mm, which we consider to be insignificant in clinical practice.

Denoising PET images for proton therapy using a residual U-net.

The use of proton therapy has the advantage of high dose concentration as it is possible to concentrate the dose on the tumor while suppressing damage to the surrounding normal organs. However, the range uncertainty significantly affects the actual dose distribution in the vicinity of the proton range, limiting the benefit of proton therapy for reducing the dose to normal organs. By measuring the annihilation gamma rays from the produced positron emitters, it is possible to obtain a proton induced positron emission tomography (pPET) image according to the irradiation region of the proton beam. Smoothing with a Gaussian filter is generally used to denoise PET images; however, this approach lowers the spatial resolution. Furthermore, other conventional smoothing processing methods may deteriorate the steep region of the pPET images. In this study, we proposed a denoising method based on a Residual U-Net for pPET images. We conducted the Monte Carlo simulation and irradiation experiment on a human phantom to obtain pPET data. The accuracy of the range estimation and the image similarity were evaluated for pPET images using the Residual U-Net, a Gaussian filter, a median filter, the block-matching and 3D-filtering (BM3D), and a total variation (TV) filter. Usage of the Residual U-Net yielded effective results corresponding to the range estimation; however, the results of peak-signal-to-noise ratio were identical to those for the Gaussian filter, median filter, BM3D, and TV filter. The proposed method can contribute to improving the accuracy of treatment verification and shortening the PET measurement time.

Extension of the ML-EM algorithm for dose estimation using PET in proton therapy: application to an inhomogeneous target.

Positron emission tomography (PET) has been used for in vivo treatment verification, mainly for range verification, in proton therapy. Evaluating the direct dose from PET measurements remains challenging; however, it is highly desirable from a clinical perspective. In this study, a method for estimating the dose distribution from the positron emitter distributions was developed using the maximum likelihood expectation maximization algorithm. The 1D spatial relationship between positron emitter distributions and a dose distribution in an inhomogeneous target was inputted into the system matrix based on a filter framework. In contrast, spatial resolution of the PET system and total variation regularization (as prior knowledge for dose distribution) were considered in the 3D image-space. The dose estimation was demonstrated using Monte Carlo simulated PET activity distributions with substantial noise in a head and neck phantom. This mimicked the single field irradiation of the spread-out Bragg peak beams at clinical dose levels. Besides the simple implementation of the algorithm, this strategy achieved a high-speed calculation (30 s for a 3D dose estimation) and accurate dose and range estimations (less than 10% and 2 mm errors at 1-σ values, respectively). The proposed method could be key for using PET for in vivo dose monitoring.

Clinical investigation of the utility of a pair of coagulation-fibrinolysis markers for definite diagnosis of sepsis-induced disseminated intravascular coagulation: A single-center, diagnostic, prospective, observational study.

BACKGROUND: Disseminated intravascular coagulation (DIC) often occurs with sepsis. A scoring system has been used for the diagnosis of DIC, but the system included at least 4 parameters. The purpose of this study was to propose a simple set of DIC criteria with coagulation-fibrinolysis markers (CFMs). METHODS: Patients with ≥2 signs of systemic inflammatory response syndrome and a quick Sequential Organ Failure Assessment score ≥ 2 points were investigated. All blood samples were collected on Days 0, 1, 3, and 7. Cutoff values of CFMs were calculated by receiver operating curve analysis. Positive predictive values (PPVs) and negative predictive values (NPVs) for the Japanese Association for Acute Medicine (JAAM) DIC criteria were evaluated by pairing the markers. Differences were analyzed by the Mann-Whitney U test, Kruskal-Wallis test, and the log-rank test. RESULTS: A total of 107 patients were enrolled. The cutoff values of soluble fibrin (SF), protein C (PC), and plasminogen activator inhibitor (PAI)-1 were 48 µg/mL, 42%, and 71 ng/mL according to the International Society of Thrombosis and Hemostasis DIC criteria. The PPV of the severe SFxPC group was 100% for the JAAM DIC criteria, excluding Day 0. CONCLUSION: Cutoff values of SF over 48 µg/mL and PC <42% could almost definitely identify JAAM DIC.

ML-EM algorithm for dose estimation using PET in proton therapy.

Positron emission tomography (PET) has been extensively studied and clinically investigated for dose verification in proton therapy. However, the production distributions of positron emitters are not proportional to the dose distribution. Thus, direct dose evaluation is limited when using the conventional PET-based approach. We propose a method for estimating the dose distribution from the positron emitter distributions using the maximum likelihood (ML) expectation maximization (EM) algorithm combined with filtering. In experiments to verify the effectiveness of the proposed method, mono-energetic and spread-out Bragg-peak proton beams were delivered by a synchrotron, and a water target was irradiated at clinical dose levels. Planar PET measurements were performed during beam pauses and after irradiation over a total period of 200 s. In addition, we conducted a Monte Carlo simulation to obtain the required filter functions and analyze the influence of the number of algorithm iterations on estimation. We successfully estimated the 2D dose distributions even under statistical noise in the PET images. The accuracy of the 2D dose estimation was about 10% for both beams at the 1-[Formula: see text] values of relative error. This value is comparable to the deviations in the measured PET activity distributions. For the laterally integrated profile along the beam direction, a low error within 5% was obtained per irradiation value. Moreover, the difference of estimated proton ranges was within 1 mm, and 2D estimation from the PET images was completed in 21 ms. Hence, the proposed algorithm may be applied to real-time dose monitoring. Although this is the first attempt to use the ML-EM algorithm for dose estimation, the proposed method showed high accuracy and speed in the estimation of proton dose distribution from PET data. The proposed method is thus a step forward to exploit the full potential of PET for in vivo dose verification.

Veno-Arterial Extracorporeal Membrane Oxygenation for Septic Cardiomyopathy due to Legionella Pneumonia after Influenza Virus Infection.

A 57-year-old man presented to the emergency department with fever and progressive altered level of consciousness of 5 days' duration. Three days before admission, influenza A was diagnosed at a clinic. On admission, his vital signs were unstable. Pneumonia was diagnosed through chest computed tomography, and urinary Legionella antigen test was positive. A diagnosis of septic shock due to Legionella and influenza pneumonia was made, and critical care management was initiated, including mechanical ventilation and vasopressors. However, tachycardia did not improve, left ventricular ejection fraction was 20%, and circulatory insufficiency progressed. Therefore, considering the involvement of septic cardiomyopathy and cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated for circulation assistance on day 3 since admission. Tachycardia and myocardial dysfunction improved by day 8, and VA-ECMO was withdrawn. Subsequently, nutrition management and rehabilitation were performed, and the patient was transferred to a recovery hospital on day 108. VA-ECMO may be beneficial when concomitant with circulatory assistance in uncontrollable cases of septic cardiomyopathy using catecholamines and ß-blockers. It may be necessary to adopt VA-ECMO at an appropriate time before the patient progresses to cardiopulmonary arrest.

Precision imaging of 4.4 MeV gamma rays using a 3-D position sensitive Compton camera.

Imaging of nuclear gamma-ray lines in the 1-10 MeV range is far from being established in both medical and physical applications. In proton therapy, 4.4 MeV gamma rays are emitted from the excited nucleus of either 12C* or 11B* and are considered good indicators of dose delivery and/or range verification. Further, in gamma-ray astronomy, 4.4 MeV gamma rays are produced by cosmic ray interactions in the interstellar medium, and can thus be used to probe nucleothynthesis in the universe. In this paper, we present a high-precision image of 4.4 MeV gamma rays taken by newly developed 3-D position sensitive Compton camera (3D-PSCC). To mimic the situation in proton therapy, we first irradiated water, PMMA and Ca(OH)2 with a 70 MeV proton beam, then we identified various nuclear lines with the HPGe detector. The 4.4 MeV gamma rays constitute a broad peak, including single and double escape peaks. Thus, by setting an energy window of 3D-PSCC from 3 to 5 MeV, we show that a gamma ray image sharply concentrates near the Bragg peak, as expected from the minimum energy threshold and sharp peak profile in the cross section of 12C(p,p)12C*.

Clinical Investigation of Coagulation Markers for Early Detection of Sepsis-Induced Disseminated Intravascular Coagulation: A Single-Center, Prospective Observational Study.

Disseminated intravascular coagulation (DIC) often complicates sepsis, and its early treatment is crucial for improving patient outcomes. Coagulation markers may enable earlier diagnosis of DIC. The purpose of this study was to evaluate whether the risk of DIC onset can be predicted using coagulation markers. Patients who showed symptoms of systemic inflammatory response syndrome ≥2 and the quick Sequential Organ Failure Assessment score ≥2 points were investigated. All blood samples collected from the time of hospital admission to 7 days postadmission were investigated. Patients were classified according to time of DIC onset (1) no DIC group (not DIC developed), (2) pre-DIC group (DIC onset >24 hours after admission), (3) DIC group (DIC onset at time of the admission) and according to cutoff values of coagulation markers, High group and Low group. Statistical differences were analyzed by log-rank test, Kruskal-Wallis rank test, and Friedman test. A total of 107 patients were enrolled in the study. Soluble fibrin (SF), plasminogen activator inhibitor (PAI)-1, and d-dimer levels were significantly increased even under pre-DIC conditions. Japanese Association for Acute Medicine (JAAM) DIC scores increased significantly over time in the High SF group (≥31.0 µg/mL) and High PAI-1 group (≥49.0 ng/mL), while JAAM DIC scores in the Low SF group remained ≤3 until day 7. We proposed the cutoff values of SF as 31 µg/mL to detect early phase of DIC. Soluble fibrin might be useful not only to predict DIC but also to exclude a diagnosis of DIC.

Measurement of nuclear reaction cross sections by using Cherenkov radiation toward high-precision proton therapy.

Monitoring the in vivo dose distribution in proton therapy is desirable for the accurate irradiation of a tumor. Although positron emission tomography (PET) is widely used for confirmation, the obtained distribution of positron emitters produced by the protons does not trace the dose distribution due to the different physical processes. To estimate the accurate dose from the PET image, the cross sections of nuclear reactions that produce positron emitters are important yet far from being sufficient. In this study, we measured the cross sections of 16O(p,x)15O, 16O(p,x)13N, and 16O(p,x)11C with a wide-energy range (approximately 5-70 MeV) by observing the temporal evolution of the Cherenkov radiation emitted from positrons generated via ß+ decay along the proton path. Furthermore, we implemented the new cross sectional data into a conventional Monte Carlo (MC) simulation, so that a direct comparison was possible with the PET measurement. We confirmed that our MC results showed good agreement with the experimental data, both in terms of the spatial distributions and temporal evolutions. Although this is the first attempt at using the Cherenkov radiation in the measurements of nuclear cross sections, the obtained results suggest the method is convenient and widely applicable for high precision proton therapy.