[Show abstract][Hide abstract] ABSTRACT: Our previous results with flight (FLT) mice showed abnormalities in thymuses and spleens that have potential to compromise immune defense mechanisms. In this study, the organs were further evaluated in C57BL/6 mice after Space Shuttle Atlantis returned from a 13-day mission. Thymuses and spleens were harvested from FLT mice and ground controls housed in similar animal enclosure modules (AEM). Organ and body mass, DNA fragmentation and expression of genes related to T cells and cancer were determined. Although significance was not obtained for thymus mass, DNA fragmentation was greater in the FLT group (P<0.01). Spleen mass alone and relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 6/84 T cell-related genes were affected versus the AEM control group (P<0.05; up: IL10, Il18bp, Il18r1, Spp1; down: Ccl7, IL6); 15/84 cancer-related genes had altered expression (P<0.05; up: Casp8, FGFR2, Figf, Hgf, IGF1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb; down: Cdc25a, E2F1, Mmp9, Myc). In the spleen, 8/84 cancer-related genes were affected in FLT mice compared to AEM controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, NFkB1, Pdgfa). Pathway analysis (apoptosis signaling and checkpoint regulation) was used to map relationships among the cancer-related genes. The results showed that a relatively short mission in space had a significant impact on both organs. The findings also indicate that immune system aberrations due to stressors associated with space travel should be included when estimating risk for pathologies such as cancer and infection and in designing appropriate countermeasures. Although this was the historic last flight of NASA's Space Shuttle Program, exploration of space will undoubtedly continue.
PLoS ONE 09/2013; 8(9):e75097. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare the prognostic value of the percentage of positive biopsy cores (PPBC), the percentage of cancer volume (PCV), and the maximum involvement of biopsy cores (MIBC) as a prognostic factor in low- and intermediate-risk patients with clinically localized prostate cancer who received proton or photon beam therapy. Four hundred and fifty-nine patients with clinically localized prostate carcinoma who were treated with proton or photon beam therapy at Loma Linda University Medical Center were used for this analysis. Patients were treated with a median dose of 74.0 Gy (range 70.2-79.2) proton or combined proton/photon beam radiotherapy. Pathology reports were reviewed and PPBC, PCV, and MIBC were recorded. Analysis of biochemical no evidence of disease (bNED) outcome was assessed using Kaplan-Meier analyses. Cox regression multivariate analyses were performed to assess the impact of the biopsy factors on survival. Results: 285, 291, and 291 patients had biopsy information available for analysis, respectively. Survival analysis showed that a higher PPBC, PCV, and MIBC were each individually associated with an increased risk of biochemical failure on univariate analysis (p < 0.01). Only PPBC and PCV were associated with an increased risk of biochemical failure on multivariate analysis, adjusting for age, NCCN risk group, and dose (p < 0.01). When isolating the intermediate-risk group, only PPBC and PCV were statistically significant on multivariate analysis. Multivariate analysis of the intermediate-risk group comparing PPBC and PCV showed that PPBC was not a significant predictor of biochemical failure, while PCV was a significant predictor of biochemical failure (p = 0.37 and p = 0.03, respectively). Conclusion: PPBC and PCV can potentially be used for additional risk stratification of intermediate-risk patients with PCV potentially being the most clinically relevant predictor bNED survival. MIBC was not found to have utility in the prognosis of low- and intermediate-risk patients.
Technology in cancer research & treatment 09/2013; · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To develop and test a method for optimizing and constructing a dual scattering system in passively scattered proton therapy.Methods: A beam optics optimization algorithm was developed to optimize the thickness of the first scatterer (S1) and the profile (of both the high-Z material and Lexan) of the second scatterer (S2) to deliver a proton beam matching a given set of parameters, including field diameter, fluence, flatness, and symmetry. A new manufacturing process was also tested that allows the contoured second scattering foil to be created much more economically and quickly using Cerrobend casting. Two application-specific scattering systems were developed and tested using both experimental and Monte Carlo techniques to validate the optimization process described.Results: A scattering system was optimized and constructed to deliver large uniform irradiations of radiobiology samples at low dose rates. This system was successfully built and tested using film and ionization chambers. The system delivered a uniform radiation field of 50 cm diameter (to a dose of ±7% of the central axis) while the depth dose profile could be tuned to match the specifications of the particular investigator using modulator wheels and range shifters. A second scattering system for intermediate field size (4 cm < diameter < 10 cm) stereotactic radiosurgery and radiation therapy (SRS and SRT) treatments was also developed and tested using GEANT4. This system improved beam efficiency by over 70% compared with existing scattering systems while maintaining field flatness and depth dose profile. In both cases the proton range uniformity across the radiation field was maintained, further indicating the accuracy of the energy loss formalism in the optimization algorithm.Conclusions: The methods described allow for rapid prototyping of scattering foils to meet the demands of both research and clinical beam delivery applications in proton therapy.
Medical Physics 04/2013; 40(4):041702. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present Monte Carlo simulations of magnetically focused proton beams shaped by a single quadrapole magnet. Such beams are narrowly focused in one longitudinal plane but fan out in the perpendicular plane producing elongated elliptical beam spots (a 'screwdriver' shape). The focused beams were compared to passively collimated beams (the current standard of delivery for small radiosurgery beams). Beam energies considered were relevant to functional radiosurgery and standard radiosurgery clinical applications. Three monoenergetic beams (100, 125, and 150 MeV) and a modulated beam were simulated. Monoenergetic magnetically focused beams demonstrated 28 to 32% lower entrance doses, 31 to 47% larger central peak to entrance depth dose ratios, 26 to 35% smaller integral dose, 25 to 32% smaller estimated therapeutic ratios, 19 to 37% smaller penumbra volumes, and 38 to 65% smaller vertical profile lateral penumbras at Bragg depth, compared to the collimated beams. Focused modulated beams showed 31% larger central peak to entrance dose ratio, and 62 to 65% smaller vertical lateral penumbras over the plateau of the spread out Bragg peak. These advantages can be attributed to the directional acceleration of protons in the transverse plane due to the magnetic field. Such beams can be produced using commercially available assemblies of permanent rare earth magnets that do not require electric power or cryrogenic cooling. Our simulations suggest that these magnets can be inexpensively incorporated into the beam line to deliver reduced dose to normal tissue, and enhanced dose to elongated elliptical targets with major and minor axes on the order of a few centimeters and millimeters, respectively. Such beams may find application in novel proton functional and standard radiosurgery treatments in and around critical structures.
Physics in Medicine and Biology 01/2013; 58(3):535-553. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Due to radiation-induced immune depression and development of pathologies such as cancer, there is increasing urgency to identify radiomitigators that are effective when administered after radiation exposure. The main goal of this study was to determine the radiomitigation capacity of MnTE-2-PyP[Mn(III) tetrakis (N-ethylpyridinium-2-yl) porphyrin], a superoxide dismutase (SOD) mimetic, and evaluate leukocyte parameters in spleen and blood. C57BL/6 mice were total-body exposed to 2 Gy γ-rays (Co-60), i.e., well below a lethal dose, followed by subcutaneous implantation of 5 3 10(5) RM-9 prostate tumor cells and initiation of MnTE-2-PyP treatment (day 0); interval between each procedure was 1-2 h. The drug was administered daily (12 times). Tumor progression was monitored and immunological analyses were performed on a subset per group on day 12. Animals treated with MnTE-2-PyP alone had significantly slower tumor growth compared to mice that did not receive the drug (P < 0.05), while radiation alone had no effect. Treatment of tumor-bearing mice with MnTE-2-PyP alone significantly increased spleen mass relative to body mass; the numbers of splenic white blood cells (WBC) and lymphocytes (B and T), as well as circulating WBC, granulocytes, and platelets, were high compared to one of more of the other groups (P < 0.05). The results show that MnTE-2-PyP slowed RM-9 tumor progression and up-regulated immune parameters, but mitigation of the effects of 2 Gy total-body irradiation were minimal. Key words: Ionizing radiation; Oxidative stress; Cancer; Leukocytes; Lymphocytes.
Technology in cancer research & treatment 03/2012; 11(5):447-57. · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Simulations of a clinical proton treatment nozzle with GEANT4 were performed and compared against measured data to assess simulation accuracy. Various parameters were then adjusted to examine their effect of accuracy and determine optimal values. This analysis included GEANT version (9.3 and 9.5), range cuts, step max, and initial beam model. GEANT4 version 9.5 was found to give better range accuracy than version 9.3. Simulation accuracy was found to not be very sensitive to range cuts and step max parameters, but recommended values for high accuracy simulations are 250 11m for range cuts and 0.1 mm for step max. Finally, the initial beam model was shown to change the lateral profile in the phantom, however, lateral profiles still show significantly higher error rates than depth profiles.
Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC), 2012 IEEE; 01/2012
[Show abstract][Hide abstract] ABSTRACT: The James M. Slater, M.D. Proton Therapy Treatment and Research Center of the Loma Linda University Medical Center (LLUMC) has treated more than 15,000 patients with proton beams since its inception in 1990, and it is responsible for the majority of patients treated with protons in a hospital setting. Moreover, it is one of only a few institutions with approval by the Federal Drug Administration to treat patients with dynamically scanned proton beams with such beams available presently for experimentation at LLUMC. These features place LLUMC in a unique position for determining improved estimates of outcomes and risks associated with proton therapy including more precise risk estimates for second cancers in patients treated with active or passive proton delivery systems An ancillary benefit in the context of establishing the risks of doses in medical applications is that it would provide a much more solid basis for the estimation of effective doses and the application of microdosimetric spectral analyses to such risk estimations. Such results are important as both the number of institutions treating with protons and the number of patients treated with protons will be increasing rapidly over the next few years.The LLUMC prostate cancer group is the largest and most homogeneously treated proton patient group at the facility and has the potential for yielding risk estimates of secondary cancers with reasonable uncertainty, as will be discussed in this presentation. The total dose and dose per fraction for all patients treated to date have a relatively restricted range from 74 Gy to 81 Gy. In addition, the primary treatment planning and delivery technique (opposing laterals with one field treated per day, proton energy range 225–250 MeV) has not been changed from inception. In particular, this group represents a single-institution homogeneous cohort in terms of treatment parameters important for, for example, secondary neutron dose outside the treatment volume. The potential clinical and epidemiological benefit from such treatments has provided the impetus for the development of a comprehensive patient database. A projected accrual has been calculated based upon the current number of proton patients already being followed, their observed survival, and the censoring rate because of loss to follow-up. The analysis is presented and discussed for a patient population restricted to those treated with protons only, i.e., not including those who received combined proton and X-ray treatments.
[Show abstract][Hide abstract] ABSTRACT: A comparison was made of three study arms delivering localized fractionated hyperthermia followed by irradiation for two weeks. The treatment results demonstrated 18-week survival and NED survival to be 35 per cent (7/20) and 30 per cent (6/20) respectively for heat and irradiation 5 days per week, 57.9 per cent (11/19) and 52.6 per cent (10/19) for combined treatment 3 days per week and 27.8 per cent (5/18) for heat 3 days per week and irradiation 5 days per week. It is felt that thermotolerance will account for the lack of difference between 24 h and 48 h irradiation schedules when irradiation is given daily. Irradiation fraction size, however, is suggested as a moderating variable as well.
International Journal of Hyperthermia 07/2009; 3(4):361-4. · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the efficacy of the antioxidant Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) in protecting ocular tissue and retinal microvasculature from radiation damage.
75 rats were treated with Mn TE-2-PyP at 2.5 micro g/injection into one eye an hour before proton irradiation. The radiation was delivered in a single fraction to total doses of 8 Gray (Gy) or 28 Gy; Rats were sacrificed 3 days and 3, 6, 9, and 12 months thereafter for histology and quantification of photoreceptor cell populations and retinal capillary changes.
By 6 months following radiation, there was significant loss of retinal outer and inner nuclear layers in eyes receiving radiation only (8 and 28 Gy) (p < 0.05) compared to their controls and to the eyes of rats treated with radiation plus metalloporphyrin. Retinal microvessel length density decreased significantly 6 months following 28 Gy (p < 0.05) compared to their controls and to MnTE-2-PyP treated rats. By 12 months following irradiation, irradiated eyes showed extensive damage to the photoreceptor layer, whereas the eyes of animals receiving radiation plus MnTE-2-PyP showed almost no morphological damage. MnTE-2-PyP treatment also suppressed radiation-induced apoptosis in our study.
These results demonstrated that MnTE-2-PyP protected both photoreceptors and retinal capillaries from radiation damage, suggesting that this metalloporphyrin antioxidant is effective in regulating the damage induced by proton radiation.
Current eye research 02/2009; 34(1):62-72. · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Replacement of current CT-based, three-dimensional (3D) treatment planning systems by newer versions capable of automated multi-modality image registration may be economically prohibitive for most radiation oncology clinics. We present a low-cost technique for MR-CT image registration on a "first generation" CT-based, 3D treatment planning system for intracranial tumors. The technique begins with fabrication of a standard treatment mask. A second truncated mask, the "minimask," is then made, using the standard mask as a mold. Two orthogonal leveling vials glued onto the minimask detect angular deviations in pitch and roll. Preservation of yaw is verified by referencing a line marked according to the CT laser on the craniocaudal axis. The treatment mask immobilizes the patient's head for CT. The minimask reproduces this CT-based angular treatment position, which is then maintained by taping the appropriately positioned head to the MR head coil for MR scanning. All CT and MR images, in DICOM 3.0 format, are entered into the treatment planning system via a computer network. Interactive registration of MR to CT images is controlled by real-time visual feedback on the computer monitor. Translational misalignments at the target are eliminated or minimized by iterative use of qualitative visual inspection. In this study, rotational errors were measured in a retrospective series of 20 consecutive patients who had undergone CT-MR image registration using this technique. Anatomic structures defined the three CT orthogonal axes from which angular errors on MR image were measured. Translational errors at the target isocenter were within pixel size, as judged by visual inspection. Clinical setup using the minimask resulted in overall average angular deviation of 3 degrees +/-2 degrees (mean +/- SD) and translational deviation within the edges of the target volume of typically less than 2 mm. The accuracy of this registration technique for target delineation of intracranial tumors is compatible with practice guidelines. This method, then, provides a cost-effective means to register MR and CT images for target delineation of intracranial tumors.
Technology in cancer research & treatment 07/2005; 4(3):275-81. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the effects on pulmonary function of irradiating lung cancer with protons alone or protons combined with photons.
Prospective phase I/II study.
University medical center.
Ten patients with stage I-II non-small cell lung cancer (NSCLC) and FEV(1) < or = 1.0 L were irradiated with protons to areas of gross disease only, using 51 cobalt gray equivalents (CGE) in 10 fractions (protocol 1). Fifteen patients with stage I-IIIA NSCLC and FEV(1) > 1.0 L received 45-Gy photon irradiation to the primary lung tumor and the mediastinum, plus a 28.8-CGE proton boost to the gross tumor volume (protocol 2).
Pulmonary function was evaluated prior to treatment and 1 month, 3 months, and 6 to 12 months following irradiation.
In patients receiving protocol 1, no significant changes in pulmonary function occurred. In patients receiving protocol 2, at 6 to 12 months, the diffusion capacity of the lung for carbon monoxide had declined from 61% of predicted to 45% of predicted (p < 0.05), total lung capacity had declined from 114% of predicted to 95% of predicted (p < 0.05), and residual volume had declined from 160% of predicted to 132% of predicted (p < 0.05). Airway resistance increased from 3.8 to 5.2 cm H(2)O/L/s (p < 0.05). No statistically significant changes occurred in vital capacity, FEV(1), or PaO(2).
Our observations indicate that it is feasible to apply higher-than-conventional doses of radiation at a higher-than-conventional dose per fraction without excess pulmonary toxicity when conformal radiation techniques with protons are used.
[Show abstract][Hide abstract] ABSTRACT: The Loma Linda University (LLU) Radiobiology Program coordinates basic research and proton beam service activities for the university and extramural communities. The current focus of the program is on the biological and physical properties of protons and the operation of radiobiology facilities for NASA-sponsored projects. The current accelerator, supporting facilities and operations are described along with a brief review of extramural research projects supported by the program. These include space craft electronic parts and shielding testing as well as tumorigenesis and animal behavior experiments. An overview of research projects currently underway at LLU is also described. These include: 1) acute responses of the C57Bl/6 mouse immune system, 2) modulation of gene expression in the nematode C. elegans and rat thyroid cells, 3) quantitation of dose tolerance in rat CNS microvasculature, 4) behavioral screening of whole body proton and iron ion-irradiated C57Bl/6 mice, and 5) investigation of the role of cell integration into epithelial structures on responses to radiation.
[Show abstract][Hide abstract] ABSTRACT: Calculation of normal tissue complication probabilities (NTCP) for proton radiation therapy (PRT) and two photon radiation therapy techniques for cranial irradiation of childhood optic nerve gliomas was made. Evaluation of usefulness of calculated NTCP values for comparison of treatment plans and clinical appropriateness of computed data was used. Three radiation plans were calculated on datasets of children treated previously for optic nerve gliomas with PRT. Dose-volume histograms (DVH) were computed and used to calculate NTCP. Evaluated complication endpoints were necrosis, blindness, and cognitive impairment. Calculated NTCP depended strongly on tumor volume and the normal tissue volume exposed to high radiation doses. Dose conformity and steeper dose-gradient correlated with reduced NTCP. Regarding the chosen complication endpoints, PRT was superior to 3D photons; conventional photons were calculated to have the highest NTCPs. Differences might reach clinical significance for cognitive impairment, a frequently observed toxicity. Calculated NTCP values were highly dependent on implemented clinical data. Calculation of NTCP can be used for ranking of treatment plans and modalities. Highly dependent on implemented clinical data, the calculated percentage of NTCP might be more of a figure of merit than a real predictive value and requires comparison to clinical experience. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 351-358 (2000).
International Journal of Cancer 01/2001; 90(6):351-8. · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation
The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls.
Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss.
The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.
International Journal of Radiation OncologyBiologyPhysics 12/2000; 48(4):1155-66. · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to determine the w-value of air for protons using the paired gas method. Several plastic- and magnesium-walled chambers were used with air, synthetic air, nitrogen, and argon flowing gases. Using argon as a reference gas, the w-value of air was measured and ranged from 32.7 to 34.5 J/C for protons with energies encountered in radiotherapy. Using nitrogen as a reference gas, the w-value of air ranged from 35.2 to 35.4 J/C over the same range of proton energies. The w-value was found, at a given energy, to be independent of the ion chamber used. The uncertainty in these measurements was estimated at 5.2% at the 2sigma level. This uncertainty was dominated by the 4.4% uncertainty in the w-value of the reference gas.
Medical Physics 11/2000; 27(10):2363-8. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The acute effects of proton whole-body irradiation on the distribution and function of leukocyte populations in the spleen and blood were examined and compared to the effects of photons derived from a (60)Co gamma-ray source. Adult female C57BL/6 mice were exposed to a single dose (3 Gy at 0.4 Gy/min) of protons at spread-out Bragg peak (SOBP), protons at the distal entry (E) region, or gamma rays and killed humanely at six different times thereafter. Specific differences were noted in the results, thereby suggesting that the kinetics of the response may be variable. However, the lack of significant differences in most assays at most times suggests that the RBE for both entry and peak regions of the Bragg curve was essentially 1.0 under the conditions of this study. The greatest immunodepression was observed at 4 days postexposure. Flow cytometry and mitogenic stimulation analyses of the spleen and peripheral blood demonstrated that lymphocyte populations differ in radiosensitivity, with B (CD19(+)) cells being most sensitive, T (CD3(+)) cells being moderately sensitive, and natural killer (NK1.1(+)) cells being most resistant. B lymphocytes showed the most rapid recovery. Comparison of the T-lymphocyte subsets showed that CD4(+) T helper/inducer cells were more radiosensitive than the CD8(+) T cytotoxic/suppressor cells. These findings should have an impact on future studies designed to maximize protection of normal tissue during and after proton-radiation exposure.
Radiation Research 06/2000; 153(5 Pt 1):587-94. · 2.45 Impact Factor