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In order to integrate radiobiological modelling with clinical treatment planning for proton radiotherapy, we extended our in-house treatment planning system FoCa with a 3D analytical algorithm to calculate linear energy transfer (LET) in voxelized patient geometries. Both active scanning and passive scattering delivery modalities are supported. The analytical calculation is much faster than the Monte-Carlo (MC) method and it can be implemented in the inverse treatment planning optimization suite, allowing us to create LET-based objectives in inverse planning. The LET was calculated by combining a 1D analytical approach including a novel correction for secondary protons with pencil-beam type LET-kernels. Then, these LET kernels were inserted into the proton-convolution-superposition algorithm in FoCa. The analytical LET distributions were benchmarked against MC simulations carried out in Geant4. A cohort of simple phantom and patient plans representing a wide variety of sites (prostate, lung, brain, head and neck) was selected. The calculation algorithm was able to reproduce the MC LET to within 6% (1 standard deviation) for low-LET areas (under 1.7 keV µm(-1)) and within 22% for the high-LET areas above that threshold. The dose and LET distributions can be further extended, using radiobiological models, to include radiobiological effectiveness (RBE) calculations in the treatment planning system. This implementation also allows for radiobiological optimization of treatments by including RBE-weighted dose constraints in the inverse treatment planning process.

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Modern proton therapy affords control of the delivery of radiotherapeutic dose on fine length and temporal scales. The authors have developed a novel detector technology based on Micromesh Gaseous Structure (Micromegas) that is uniquely tailored for applications using therapeutic proton beams. An implementation of a prototype Micromegas detector for Monte Carlo using Geant4 is presented here. Comparison of simulation results with measurements demonstrates agreement in relative dose along the proton longitudinal dose profile to be 1%. The effect of a radioactive calibration source embedded in the chamber gas is demonstrated by measurements and reproduced by simulations, also at the 1% level. Our Monte Carlo simulations are shown to reproduce the time structure of ionization pulses produced by a double-scattering delivery system.

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In proton radiotherapy, the range of particles in the patient body is determined by the energy of the protons. For most systems, the energy selection time is on the order of a few seconds, which becomes a serious obstacle for continuous dose delivery techniques requiring adaptive range modulation. This work analyses the feasibility of using the range modulation wheel, an element in the beamline used to form the spread-out Bragg peak (SOBP), to produce near-instantaneous changes not only in the modulation, but also in the range of the beam. While delivering proton beams in double scattering mode, the beam current can be synchronized with the range modulation wheel rotation by defining a current modulation pattern. Different current modulation patterns were computed from Monte Carlo simulations of our double scattering nozzle to range shift an SOBP of initial range 15 cm by varying degrees of up to ∼9 cm. These patterns were passed to the treatment control system at our institution and the resulting measured depth-dose distributions were analysed in terms of flatness, distal penumbra and relative irradiation time per unit mid-SOBP dose. Suitable SOBPs were obtained in all cases, with the maximum range shift being limited only by the maximum thickness of the wheel. The distal dose fall-off (80% to 20%) of the shifted peaks was broadened to about 1 cm, from the original 0.5 cm, and the predicted overhead in delivery time showed a linear increase with the amount of the shift. By modulating the beam current in clinical scattered proton beams equipped with a modulation wheel, it is possible to dynamically modify the in-patient range of the SOBP without adding any specific hardware or compensators to the beamline. A compromise between sharper distal dose fall-off and lower delivery time can be achieved and is subject to optimization.

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The effectiveness of simulated solar particle event (SPE) proton radiation to induce retching and vomiting was evaluated in the ferret experimental animal model. The endpoints measured in the study included: (1) the fraction of animals that retched or vomited, (2) the number of retches or vomits observed, (3) the latency period before the first retch or vomit and (4) the duration between the first and last retching or vomiting events. The results demonstrated that γ ray and proton irradiation delivered at a high dose rate of 0.5 Gy/min induced dose-dependent changes in the endpoints related to retching and vomiting. The minimum radiation doses required to induce statistically significant changes in retching- and vomiting-related endpoints were 0.75 and 1.0 Gy, respectively, and the relative biological effectiveness (RBE) of proton radiation at the high dose rate did not significantly differ from 1. Similar but less consistent and smaller changes in the retching- and vomiting-related endpoints were observed for groups irradiated with γ rays and protons delivered at a low dose rate of 0.5 Gy/h. Since this low dose rate is similar to a radiation dose rate expected during a SPE, these results suggest that the risk of SPE radiation-induced vomiting is low and may reach statistical significance only when the radiation dose reaches 1 Gy or higher.

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PURPOSE: Radiotherapy planning for iliac pelvic nodes can be challenging due to the close proximity of sensitive healthy tissues such as the bowel and rectum. Modern treatment techniques like photon intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) offer improved healthy tissue sparing for similar target coverage. In this study we compare IMRT and IMPT plans for six post-cystectomy patients. METHODS: A dose of 50.4 Gy was prescribed to the planning target volume (PTV), which for IMRT is the clinical target volume (CTV) plus a 5 mm expansion for geometric uncertainties due to CTV and patient positioning errors, and for proton beams is the CTV plus the lateral 5 mm margin plus an additional longitudinal margin to allow for the proton range uncertainty. The optimization objectives are: 98% of the PTV receive at least 95% of the prescription, target maximum dose = 107% of prescription, rectum V[40Gy] < 30% and max = 105%, and bowel V[45Gy] < 125 cc and max = 107%. All IMRT and IMPT plans are made to achieve the target coverage objective. RESULTS: Using IMPT, the rectum would receive a mean dose of 9.0 Gy with an average (over the six patients) maximum dose of 38.1 Gy. Using IMRT, the rectum would receive a mean dose of 13.0 Gy and an average maximum dose of 37.6 Gy. The IMPT plans give a mean dose of 17.9 Gy and a maximum dose of 53.4 Gy for the bowel, whereas the IMRT plans give a mean dose of 23.8 Gy and a maximum dose of 53.2 Gy. Both the rectum and bowel show slightly lower mean doses for IMPT. CONCLUSIONS: Our results indicate that IMPT plans improve normal tissue sparing as compared to IMRT plans and provide adequate dose coverage of the target volume.

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PURPOSE: In the treatment of superficial lesions with proton Pencil Beam Scanning (PBS), spot size is dominated by the nozzle contribution. Accuracy of phase-space modeling is therefore paramount. IBA's Dedicated (DN) and Universal Nozzles (UN) have different designs and, consequently, characteristics. Here we report the phase spaces of these two nozzles, without and with a range shifter (RS). METHODS: In-air spot fluence measurements were made for five proton energies: 225, 210, 180, 150 and 115 MeV and at five distances from isocenter pertinent to SAD-type treatments: +33, +20, +10, 0 and -10 cm ('+' implies upstream), without and with a 7.5 cm water-equivalently-thick RS (sufficient to pull back the lowest energy Bragg peak to patient surface), fixed with its upstream side 41 cm from isocenter. Data collected on a fixed horizontal beam-line with a DN and a gantry-mounted UN were compared. The full-width-at-half-maximum (FWHM) of a Gaussian fit to each spot fluence profile was extracted along the two principal axes. RESULTS: With no RS, the proton spots are ∼20-70% larger at isocenter in the UN than in the DN. Spots are less asymmetric, and eccentricity increases more slowly with energy, in the UN than in the DN. Over the 33 cm in-air travel upstream of isocenter, the spot FWHM varies by less than ∼2 mm. However, spot asymmetry becomes more severe upstream (for 115 MeV spots, 30-40% compared to <20% at isocenter for DN, but similar and <10% for UN). With an RS, spot FWHM at isocenter increases by 12.7 mm from 8.3 mm (DN) and 10.7 mm from 13 mm (UN) for 150 MeV protons (typical for brain treatments). With no RS, relatively distance-independent spot size facilitates SAD-type treatments. For patients with superficial lesions, where an RS is required and the phase space varies rapidly with distance, the RS should be permitted at two additional locations. US Army Medical Research and Materiel Command under Contact Agreement No. DAMD17-W81XWH-04-2-0022.

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Alcohol dehydrogenase class IV (ADH4) participates in retinol metabolism and is expressed primarily in ocular, digestive, and reproductive tissues of the mouse. A naturally occurring genetic variant in C57BL/6J mice results in a faster migrating ADH4 enzyme during electrophoresis when compared to other non-C57BJ/6J strains. The C57BL/6 ADH4 gene coding sequence is found to have two nucleotide substitutions when compared to the gene from C3HeB/FeJ mice. The substitution in exon 5 encodes Arg120 instead of Cys120 in C57BL/6 ADH4 polypeptide; that would account for the protein electrophoretic phenotype. Arg120 is present in all published mammalian ADH4 sequences but is only in a limited number of mouse strains. The Arg120 residue is part of the outer loop of the substrate binding pocket and appears to have an effect on the affinity of the enzyme for several substrates.

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The ADH gene family in vertebrates is composed of at least seven distinct classes based upon sequence comparisons and enzyme properties. The Adh4 gene product may play an important role in differentiation and development because of its capacity to metabolize retinol to retinoic acid. Allelic gene differences exist among inbred mouse strains which control structure and tissue-specific regulation of Adh4. C57BL/6 mice are unique and have no detectable ADH4 enzyme activity in epididymis and low levels in seminal vesicle, ovary and uterus compared to other strains. C57BL/6 mice express Adh4 in stomach at levels similar to other strains. The goal of this research was to investigate this genetic variation at the molecular level. Northern analysis revealed that the content of ADH4 mRNA in tissues correlate with the enzyme expression pattern. Interestingly, C57BL/6 mice express an ADH4 mRNA in stomach which is smaller than expressed in C3H and other mice. An analysis of the 5'- and 3'-ends of the mRNA using RACE analysis determined that the ADH4 mRNA in C57BL/6 mice is truncated in the 3'-untranslated region. Sequence analysis of RACE products showed that the truncation is due to a single nucleotide mutation which produces an early polyadenylation signal. Additional RACE and Northern analysis revealed that at least five different polyadenylation sites are used in the Adh4 gene. Using 3'-end polymorphisms found between C57BL/6 and C3H strains and RT-PCR, it was shown that the lack of expression in epididymis in C57BL/6 mice is cis-acting in F(1) hybrid animals. The DNA sequence of the proximal promoter (-600/+42 nt) was determined in several mouse strains differing in tissue-specific expression patterns and did not reveal any nucleotide substitutions correlating with expression pattern suggesting further upstream or downstream sequences may be involved.

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