The purpose of the current study was to characterize the effects of simulated microgravity and radiation-induced changes in retina and retinal vasculature, and to assess the accompanying early changes in immune cells and hematological parameters. To better understand the effects of spaceflight, we used a combination of treatments designed to simulate both the radiation and low-gravity aspects of space conditions. To simulate the broad energy spectrum of a large solar particle event (SPE) and galactic cosmic ray (GCR) radiation, male C57BL/6J mice were exposed to whole-body irradiation using fully modulated beams of 150-MeV protons containing particles of energy from 0 to 150 MeV and a uniform dose-vs.-depth profile. The mice were also hindlimb-unloaded (HLU) by tail suspension. Mice were unloaded for 7 days, exposed to 50 cGy, unloaded for an additional 7 days and then sacrificed for tissue isolation at days 4 and 30 after the combined treatments. Increases in the number of apoptotic cells were observed in the endothelial cells of mice that received radiation alone or with HLU compared to controls at both days 4 and 30 (P < 0.05). Endothelial nitric oxide synthase (eNOS) levels were significantly elevated in the retina after irradiation only or combined with HLU compared to controls at the 30-day time point (P < 0.05). The most robust changes were observed in the combination group, suggesting a synergistic response to radiation and unloading. For hematopoietic parameters, our analysis indicated the main effects for time and radiation at day 4 after treatments (day 11 postirradiation) (P < 0.05), but a smaller influence of HLU for both white blood cell and lymphocyte counts. The group treated with both radiation and HLU showed greater than 50% reduction in lymphocyte counts compared to controls. Radiation-dependent differences were also noted in specific lymphocyte subpopulations (T, B, natural killer cells). This study shows indications of an early effect of low-dose radiation and spaceflight conditions on retina and immune populations.

Background: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. Methods: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1-3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive <15. Dose-limiting toxicity (DLT) included acute grade 3 liver, intestinal or spinal cord toxicity or any grade 4 toxicity. The MTD is defined as the dose level below that which results in DLT in 2 or more of the 6 patients in the highest dose level cohort. Results: Nine patients were enrolled (6 male, 3 female): median age 64 years (range, 33-77 years); median gross tumor volume (GTV) 11.1 mL (range, 2.14-89.3 mL); most common primary site, colorectal (5 patients). Four patients had multiple tumors. No patient experienced a DLT and dose was escalated to 60 in 3 fractions without reaching MTD. The only toxicity within 90 days of completion of treatment was one patient with a grade 1 skin hyperpigmentation without tenderness or desquamation. Two patients in the low dose cohort had local recurrence and repeat SBRT was done to previously treated lesions without any toxicities. Conclusions: Biologically ablative Proton SBRT doses are well tolerated in patients with limited liver metastases with no patients experiencing any grade 2+ acute toxicity. Results from this trial provide the grounds for an ongoing phase II Proton SBRT study of 60 over 3 fractions for liver metastases.

There is concern that degradation of vision as a result of space flight may compromise both mission goals and long-term quality of life after space travel. The visual disturbances may be due to a combination of intracerebral pressure changes and exposure to ionizing radiation. The retina and the retinal vasculature play important roles in vision, yet have not been studied extensively in relationship to space travel and space radiation. The goal of the current study was to characterize oxidative damage and apoptosis in retinal endothelial cells after whole-body gamma-ray, proton and oxygen (16O) ion radiation exposure at 0.1 to 1 Gy. Six-month-old male C57Bl/6J mice were whole-body irradiated with 600 MeV/n 16O ions (0, 0.1, 0.25, 1 Gy), solar particle event (SPE)-like protons (0, 0.1, 0.25, 0.5 Gy) or 60Co gamma rays (0, 0.1, 0.25, 0.5 Gy). Eyes were isolated for examining endothelial nitric oxide synthase (eNOS) expression and characterization of apoptosis in retina and retinal endothelial cells at two weeks postirradiation. The expression of eNOS was significantly increased in the retina after proton and 16O ion exposure. 16O ions induced over twofold increase in eNOS expression compared to proton exposure at two weeks postirradiation (P < 0.05). TUNEL assays showed dose-dependent increases in apoptosis in the retina after irradiation. Low doses of 16O ions elicited apoptosis in the mouse retinal endothelial cells with the most robust changes observed after 0.1 Gy irradiation (P < 0.05) compared to controls. Data also showed that 16O ions induced a higher frequency of apoptosis in retinal endothelial cells compared to protons (P < 0.05). In summary, our study revealed that exposure to low-dose ionizing radiation induced oxidative damage and apoptosis in the retina. Significant changes in retinal endothelial cells occur at doses as low as 0.1 Gy. There were significant differences in the responses of endothelial cells among the radiation types examined here.

Passively scattered proton therapy (PSPT) has been used for stereotactic body radiation therapy (SBRT) of various sites, including the lung and liver. To our knowledge there is no data for PSPT for spinal SBRT. Therefore, we undertook a dosimetric analysis to evaluate the feasibility of using PSPT with minimal beams for SBRT to treat spine metastases per the ongoing clinical trial RTOG 0631. In 2 model patient simulations, vertebral levels were selected in the cervical, thoracic, and lumbar spine, and clinical target volumes (CTVs) were generated according to the guidelines described in RTOG 0631 to a dose of 18 CGE in 1 fraction. Multiple plans were generated for each CTV using passively scattered proton beams. Plans were evaluated based on the dose coverage of the target volume, the ability to meet dose constraints to surrounding organs at risk, as well as dose homogeneity. RTOG 0631 criteria for target coverage and normal tissue constraints were met for each of the target volumes in the cervical, thoracic, and lumbar spine levels. For upper cervical vertebra, 2 opposed lateral beams were sufficient to achieve dose coverage and meet constraints. The spinal cord received a maximum dose of 13.8 CGE with 0.22 mL receiving 10 CGE, and 2.24 mL of the pharynx received a dose of 10.5 CGE. In the lower cervical, thoracic, and lumbar spine, the shoulders, lungs, and bowel, respectively, impeded the use of lateral beams, and instead 5 beams were required to meet homogeneity and conformity constraints. The 5-beam arrangement included a posterior beam, 2 posterior oblique beams, and 2 posterior oblique patches. For the thoracic target, the spinal cord received a maximum dose of 11.3 CGE with 0.36 mL receiving 10 CGE, and 0.03 mL of the esophagus received 16 CGE. In the lumbar spine, 0.05 mL of the cauda equina received 16 CGE. Distant anterior structures, such as the heart, stomach, and bowel received negligible dose. The treatment of spine metastases per the RTOG 0631 protocol using PSPT is feasible at each spinal level with negligible distant anterior structure dose. For the superior cervical spine we recommend the use of 2 opposed lateral beams, and in the lower cervical, thoracic, and lumbar spine we recommend a 5-beam patch plan using posterior and posterior oblique beams.

Purpose:Stereotactic radiosurgery is an effective and noninvasive treatment for intracranial lesions that uses highly focused radiation beams in a single treatment fraction. The purpose of this study is to investigate the dosimetric differences between the treatment brain metastasis with a proton beam vs. intensity modulated radiation therapy (IMRT).Methods:Ten separate brain metastasis targets where chosen and treatment plans were created for each, using three different strategies: custom proton beam shaping devices, standardized proton beam shaping devices, and IMRT. Each plan was required to satisfy set parameters for providing adequate coverage and minimizing risk to adjacent tissues. The effectiveness of each plan was calculated by comparing the homogeneity index, conformity index, and V12 for each target using a paired one tailed T‐test (α=0.05). Specific comparison of the conformity indices was also made using a subcategory containing targets with volume>1cc.Results:There was no significant difference between the homogeneity indices of the three plans (p>0.05), showing that each plan has the capability of adequately covering the targets. There was a statistically significant difference (p<0.01) between the conformity indices of the custom and the standard proton plan, as with the custom proton and IMRT (p<0.01), with custom proton showing stronger conformity to the target in both cases. There was also a statistical difference between the V12 of all three plans (Custom v. Standardized: p=0.02, Custom v. IMRT: p<0.01, Standardized v. IMRT: p<0.01) with custom proton supplying the lowest dose to surrounding tissues. For large targets (volume>1cc) there was no statistical difference between the proton plans and the IMRT treatment for the conformity index.Conclusion:A custom proton plan is the recommended treatment explored in this study as it is the most reliable way of effectively treating the target while sparing the maximum amount of normal tissue.

Purpose: To investigate magnetic focusing for small volume proton targets using a doublet combination of quadrupole rare earth permanent magnet Halbach cylinder assemblies Methods: Monte Carlo computer simulations were performed using the Geant4 toolkit to compare dose depositions of proton beams transported through two focusing magnets or in their absence. Proton beams with energies of 127 MeV and initial diameters of 5, 8 and 10 mm were delivered through two identical focusing magnets similar to those currently in experimental use at Loma Linda University Medical Center. Analogous experiments used optimized configurations based on the simulation results. Dose was measured by a diode detector and Gafchromic EBT3 film and compared to simulation data. Based on results from the experimental data, an additional set of simulations was performed with an initial beam diameter of 18 mm and a two differing length magnets (40mm & 68mm). Results: Experimental data matched well with Monte Carlo simulations. However, under conditions necessary to produce circular beam spots at target depth, magnetically focused beams using two identical 40 mm length magnets did not meet all of our performance criteria of circular beam spots, improved peak to entrance (P/E) dose ratios and dose delivery efficiencies. The simulations using the longer 68 mm 2nd magnet yielded better results with 34% better P/E dose ratio and 20–50% better dose delivery efficiencies when compared to unfocused 10 mm beams. Conclusion: While magnetic focusing using two magnets with identical focusing power did not yield desired results, ongoing Monte Carlo simulations suggest that increasing the length of the 2nd magnet to 68 mm could improve P/E dose ratios and dose efficiencies. Future work includes additional experimental validation of the longer 2nd magnet setup as well as experiments with triplet magnet systems. This project was sponsored with funding from the Department of Defense (DOD# W81XWH‐BAA‐10‐1).

Purpose: To evaluate the impact of titanium and surgical stainless steel implants on the microscopic dose distribution in proton treatment plans Methods: Geant4 Monte Carlo simulations were used to analyze the microdosimetric distribution of proton radiation in the vicinity of 3.1 mm thick CP Grade 4 titanium (Ti) or 316 stainless steel (SS316) plates in a water phantom. Additional simulations were performed using either water, or water with a density equivalent to the respective metals (Tiwater, SS316water) (to reflect common practice in treatment planning). Implants were placed at the COM of SOBPs of 157 MeV (range of ∼15 cm in water) protons with 30 or 60 mm modulation. Primary and secondary particle dose and fluence, frequency‐weighted and dose‐weighted average lineal energy, average radiation quality factor, dose equivalent and energy deposition histograms in the plate vicinity were compared. Results: Preliminary results show frequency‐weighted (yf) and dose‐weighted lineal energy (yd) was increased downstream of the Ti plate (yf = 3.1 keV/µm; yd = 5.5 keV/µm) and Tiwater (yf = 4.1 keV/µm; yd = 6.8 keV/µm) compared to that of water (ie, the absence of a plate) (yf = 2.5 keV/µm; yd = 4.5 keV/µm). In addition, downstream proton dose deposition was also elevated due to the presence of the Ti plate or Tiwater. The additional dose deposited at higher lineal energy implies that tissues downstream of the plate will receive a higher dose equivalent. Detailed analyses of the Ti, Tiwater, SS316, and SS316 water simulations will be presented. Conclusion: The presence of high‐density materials introduces changes in the spatial distribution of radiation in the vicinity of an implant. Further work quantifying these effects could be incorporated into future treatment planning systems resulting in more accurate treatment plans. This project was sponsored with funding from the Department of Defense (DOD # W81XWH‐10‐2‐0192).

Purpose:To design, implement and evaluate a shielding system that will reduce out‐of‐field dose experienced by the patient and associated electronic systems in passively scattered proton therapy treatment.Methods:A multi‐stage neutron shielding system was retrofitted to the Gantry 1 treatment nozzle at Loma Linda University Medical Center. The system uses multiple borated polyethylene plates staged after the primary beam modifying devices to attenuate and absorb neutrons produced by such devices. This arrangement locates increasing levels of shielding between the sources of secondary particles in the nozzle and the patient. Additionally, the design of this shielding structure allows it to be easily retrofitted to an existing proton nozzle system without impacting design or treatment beam characteristics. The effectiveness of the shielding was evaluated both through experimental measurements and Geant4 Monte Carlo simulations.Results:Measurements were completed with Landauer Luxel+ dosimeters that use optically stimulated luminescence and CR‐39 to detect fast neutrons, thermal neutrons, protons, photons and beta particles. Measurements of a 250 MeV proton beam indicated that the shielding system reduced out‐of‐field dose to the patient by almost half with dose equivalent values at 50 and 40 cm from the field edge decreasing from 0.965 and 1.262 mSv/Gy to 0.596 and 0.777 mSv/Gy respectively. The installation of the multi‐stage shielding system also reduced dose equivalent experienced by electronic systems installed in the treatment room by up to 80%. Geant4 simulations were also used to evaluate the neutron fluence at various positions in the treatment room as well as provide information on microdosimetry spectra within the patient and treatment room.Conclusion:The shielding system described above proved to be an effective an inexpensive method of reducing out‐of‐field doses to the patient and electronic systems and can be easily retrofitted to existing passive scattering nozzles.

The small fields and sharp gradients typically encountered in proton radiosurgery require high spatial resolution dosimetric measurements, especially below 1-2 cm diameters. Radiochromic film provides high resolution, but requires postprocessing and special handling. Promising alternatives are diode detectors with small sensitive volumes (SV) that are capable of high resolution and real-time dose acquisition. In this study we evaluated the PTW PR60020 proton dosimetry diode using radiation fields and beam energies relevant to radiosurgery applications. Energies of 127 and 157 MeV (9.7 to 15 cm range) and initial diameters of 8, 10, 12, and 20mm were delivered using single-stage scattering and four modulations (0, 15, 30, and 60mm) to a water tank in our treatment room. Depth dose and beam profile data were compared with PTW Markus N23343 ionization chamber, EBT2 Gafchromic film, and Monte Carlo simulations. Transverse dose profiles were measured using the diode in "edge-on" orientation or EBT2 film. Diode response was linear with respect to dose, uniform with dose rate, and showed an orientation-dependent (i.e., beam parallel to, or perpendicular to, detector axis) response of less than 1%. Diodevs. Markus depth-dose profiles, as well as Markus relative dose ratio vs. simulated dose-weighted average lineal energy plots, suggest that any LET-dependent diode response is negligible from particle entrance up to the very distal portion of the SOBP for the energies tested. Finally, while not possible with the ionization chamber due to partial volume effects, accurate diode depth-dose measurements of 8, 10, and 12 mm diameter beams were obtained compared to Monte Carlo simulations. Because of the small SV that allows measurements without partial volume effects and the capability of submillimeter resolution (in edge-on orientation) that is crucial for small fields and high-dose gradients (e.g., penumbra, distal edge), as well as negligible LET dependence over nearly the full the SOBP, the PTW proton diode proved to be a useful high-resolution, real-time metrology device for small proton field radiation measurements such as would be encountered in radiosurgery applications.

Purpose: To evaluate the maco and micro-dosimetric impact of metal inhomogeneities (as seen in patients who have undergone reconstructive surgery) in proton therapy Methods: Monte Carlo simulations were performed of 3.1mm CP Grade 4 titanium and 3.4mm thick 316 stainless steel plates in a water phantom. Analogous experimental proton dose data was collected in a water phantom using GAFCHROMIC EBT2 radiochromic film (Ashland, Wayne, NJ) and a PTW Markus Ionization Chamber. Beam energy (157 and 225 MeV) and plate placement (eg, at center of modulation) were chosen to be clinically relevant to para spinal and prostate irradiations in the presence of spinal and hip implants, respectively. Film was scanned on an Epson 10000XL scanner and dose maps were calculated from three channel data using FilmQAPro software (Wayne, NJ). Macroscopic dose around the implant was evaluated and impact on proton range was determined and compared to clinical treatment planning system parameters. Dose equivalent and average quality factor distributions around the implant were also studied using Monte Carlo and microdosimetric methods. Results: Ion chamber data revealed range shifts due to titanium (316 stainless steel) plates of 6.4 to 6.9mm (15.0 to 15.5mm) corresponding to an effective relative density of 3.03 to 3.21 (5.46 to 5.59). Ion chamber data did not show small scale dose redistribution upstream of plates. However, dose data collection and analysis using film (which has higher spatial resolution) is ongoing. In addition, analysis of Monte Carlo simulations will investigate microdosimetric changes and corresponding fluctuations of RBE in plate vicinity. Conclusion: The presence of high-density materials can introduce changes in the spatial distribution of dose in the vicinity of an implant. This can introduce uncertainty in the dose distribution predicted by proton treatment planning software directly, or due to more subtle consequences of changes in RBE near the material. Department of Defense (DOD# W81XWH-BAA-10-1)

Purpose: To investigate the effect of initial proton beam source placement, distribution and angle on the proton dose distribution in a therapeutic nozzle using Geant4. Methods: We performed Geant4 Monte Carlo simulations of a passively scattered proton treatment nozzle. Accurate geometry including all elements in the treatment room was used. Protons were generated just inside the vacuum pipe using one of two models. First, a standard two dimensional Gaussian distribution of proton starting position was used with a small random angle added to the initial direction. The size of the Gaussian distribution and the random angle were set to match measured beam spot size and angular spread at the exit window. Second, a point source of protons further back in the vacuum pipe with a small random angle was used. The distance of the point source to exit window and the random angle were set to match the spot size and angular deviation used for the Gaussian distribution. Depth dose curves and orthogonal beam profiles were examined to determine changes between the two models. Results: Orthogonal beam profiles for large apertures showed changes of up to 6.5% between the two models with the point source showing much better agreement with measured data. Depth dose curves and orthogonal profiles for small apertures were unaffected. For large apertures, the average difference compared to measured data was of 1.9% and 0.7% and the max difference was 5.0% and 1.6% for Gaussian and point sources, respectively. Conclusions: The point source more realistically models the proton distribution in the vacuum pipe by correlating the proton position with the direction. For certain scattering setups and large apertures point source modeling is necessary to accurate match measured data with Monte Carlo simulations.

The use of proton patch fields that are stopped on the lateral boundary of a master field is common practice in passively deliveredprotonradiation therapy, as it allows for effective coverage of target volumes in close proximity to critical structures, e.g., the spinal cord. In a typical patient setup scenario, initial orthogonal radiographs are taken to align the patient in three dimensions relative to the proton beam isocenter and a beam's eye view (BEV) x‐ray image of the master field is taken to verify correct alignment and to perform final corrections. As part of these corrections, frequently an aperture rotation is required to account for rotational misalignment of the patient relative to the beam profile. Similarly, subsequent fields patching on the master field are verified with BEV x‐ray images prior to treatment and appropriate corrective moves and aperture rotations are made. To date, no studies of the influence of aperture rotations on the deliveredproton treatment across various clinical configurations have been published. We are currently performing a systematic study of clinical proton patch‐field combinations using our protontreatment planning software (Odyssey, Permedics). Performing incremental rotations of both the master and patch fields in the treatment plan, will determine the effect on the DVH for both the gross tumor volume (GTV) and organs at risk (OAR). Study endpoints include deviations from the maximum, minimum and mean dosedelivered to GTV and OAR prescribed by the clinician. This study covers a range of clinical scenarios, including tumors of the cervical spine, tumors of the paranasal sinus, frontal lobe gliomas, and parasacral tumors. It is expected that the results of this study will result in practical guidelines for the setup of proton patch‐field combinations.

Purpose: One of the uncertainties in proton therapy is the depth dependence of cell survival RBE. Nanodosimetry is an experimental gas‐based technique that can also be simulated with Monte Carloradiation transportation codes. Agreement between experimental and simulated nanodosimetric data has previously been presented. Here we explore the use of simulated nanodosimetric distributions for prediction of RBE in a spread‐out Bragg peak (SOBP) of 200 MeV protons.Method and Materials: A previously published model converting nanodosimetric data to frequency distributions of double strand breaks (DSBs) of different complexity (number of associated breaks) was used as the starting point. A radiobiological model of cell survival using these frequency distributions and assigning different relative lethality to simple and complex DSBs was developed and model parameters were chosen to reproduce the characteristics of LET‐dependent RBE for V79 cell survival. GEANT4 was used to calculate proton spectra at 8 different depths within a 200 MeV SOBP (3 cm width), serving as input to a dedicated Monte Carlo simulation code for nanodosimetry. Cell survival RBE values as a function of protondose were determined at each SOBP depth. Results: With an SOPB protondose of 1.63 Gy (corresponding to a dose of 1.8 GyE for an assumed RBE of 1.1), the predicted RBE for V79 cell survival had an entry value of 1.23, decreasing to a minimum of 1.17 in the SOBP plateau, and then increasing to about 1.25 in the proximal SOBP, followed by an avalanche‐type increase to a value of 1.39 at the distal SOPB end. Conclusions: The depth dependence of V79 survival RBE was predicted using simulated nanodosimetric data within a proton SOBP. We found that the predicted RBE decreased slightly in the SOBP plateau, increased by about 10% in the proximal SOBP, and increased steeply by 20% in the distal SOPB.