Poster - Thurs Eve-01: Comparison of clinical IMRT plan quality and delivery accuracy: Few large segments vs many small segments.

Commercial radiation treatment planning systems for intensity modulation use optimization algorithms that can vary multi-leaf collimator (MLC) segment sizes, segment number and the minimum number of monitor units (MU) per segment. These parameters are varied according to the treatment site, size, location, and proximity to the organs at risk. This study compares the utility of optimization using (Case A) few large segments and a higher minimum MU per segment to that of (case B) using many smaller segments with a lower minimum MU per segment. For Case A, the patient benefits from a reduced treatment time associated with fewer MUs and fewer MLC movements and an increased accuracy in dose delivery. Also, shorter treatment times may lead to fewer patient movement uncertainties. The accumulated MLC leakage dose is reduced, the patient specific quality assurance (QA) is more manageable and small field modeling inaccuracies are reduced. Pinnacle-3 (v8) plans are generated with direct machine parameter optimization (DMPO) for both scenarios. Three dimensional dose distributions and dose volume histograms are used to compare plan quality. We compare plans using few large MLC segments with those using many small MLC segments for some clinical cases. Improved plan quality is demonstrated using fewer MLC segments. Dose QAs are performed and compared for each scenario using MapCheck and film. When comparing dose delivery accuracy between different MU per segment settings, a decrease in delivery errors with minimum MU size is observed. In conclusion, few large MLC segments with larger area should be used when possible.

Poster - Thurs Eve-43: Verification of dose calculation with tissue inhomogeneity using MapCHECK.

MapCHECK (Sun Nuclear, Melbourne, FL) with 445 diode detectors has been used widely for routine IMRT quality assurance (QA)1 . However, routine IMRT QA has not included the verification of inhomogeneity effects. The objective of this study is to use MapCHECK and a phantom to verify dose calculation and IMRT delivery with tissue inhomogeneity. A phantom with tissue inhomogeneities was placed on top of MapCHECK to measure the planar dose for an anterior beam with photon energy 6 MV or 18 MV. The phantom was composed of a 3.5 cm thick block of lung equivalent material and solid water arranged side by side with a 0.5 cm slab of solid water on the top of the phantom. The phantom setup including MapCHECK was CT scanned and imported into Pinnacle 8.0d for dose calculation. Absolute dose distributions were compared with gamma criteria 3% for dose difference and 3 mm for distance-to-agreement. The results are in good agreement between the measured and calculated planar dose with 88% pass rate based on the gamma analysis. The major dose difference was at the lung-water interface. Further investigation will be performed on a custom designed inhomogeneity phantom with inserts of varying densities and effective depth to create various dose gradients at the interface for dose calculation and delivery verification. In conclusion, a phantom with tissue inhomogeneities can be used with MapCHECK for verification of dose calculation and delivery with tissue inhomogeneity.

Monte Carlo simulations of DNA damage from incorporated cold iodine following photoelectrically induced Auger electron cascades.

Radiation-induced damage in nucleosomal DNA from Auger electron cascades due to incorporated cold IUdR has been modelled through Monte Carlo simulations. Probabilities of DNA double strand break (DSB) production following a vacancy in the K, L, M and N shells of iodine are estimated. DSB complexity from the base damage accompanying a break was also estimated. Multiple DSB events were analysed for correlated breaks due to nucleosome periodicity. The probability of an Auger cascade causing at least one DSB strongly depended on the shell in which the initial vacancy was produced. This probability was approximately 0.35 for K and L shells and fell to 0.02 for the N shell. As expected, DSBs were predominantly induced in a nucleosome containing incorporated iodine and were accompanied with extensive base damage. Analysis of multiple DSB events showed that approximately 14% of the DSBs produced following a vacancy in the L1 orbital can be interpreted as correlated with base pair separation attributable to the nucleosome periodicity. The data generated in this work provide a basis for the development of photon-activation therapy using kilovoltage X rays incident upon IUdR sensitised tumours.

Operational characteristics of a prototype x-ray needle device.

A prototype x-ray needle, which emits 62.5 kVp x-rays at the tip of a 20 cm long, 4 mm diameter steel needle, has been developed by Titan Pulse Sciences Incorporated (PSI) (Albuquerque, NM) and was tested for its suitability in brachytherapy applications in comparison with a similar device by the Photoelectron Corporation. The depth dose profiles were also compared with those of two common brachytherapy sources (125I and 192Ir). The depth dose characteristics of the radiation were comparable with the two brachytherapy sources with a slightly reduced attenuation gradient. The dose rate from the x-ray needle tip was relatively isotropic at the needle tip and was continuously adjustable over the range of 0 cGy min(-1) to upwards of 62 cGy min(-1) at a reference distance of 1 cm in air. We detected a significant proportion of x-rays generated along the needle shaft, and not at the needle tip, as intended. The energy spectrum emitted from this device had a peak intensity at 21 keV and an average energy of 28 keV. The beam was attenuated in both aluminium (the first half-value layer being less than 0.1 mm) and in water (50% dose at approximately 2 mm). These studies confirm that although there is potential for a system similar to this one for clinical applications, the simplistic electron guidance used in this particular prototype device limits it to research applications. Further optimization is required in focusing and steering the electron beam to the target, improving x-ray production efficiency and using x-ray target cooling to achieve higher dose rates.

Monte Carlo simulations and measurement of DNA damage from x-ray-triggered auger cascades in iododeoxyuridine (IUdR).

We investigated the DNA damage from Auger electrons emitted from incorporated stable iodine (127I), following photoelectric absorption of external x-rays. The effectiveness of the Auger electrons in producing DNA double-strand breaks (DSB) was determined theoretically, using Monte Carlo simulations of the radiation physics and chemistry, and was shown to be in reasonable agreement with DNA damage measured using the comet assay. The DSB yields were measured in CHO cells for 60Co (as a non-Auger-promoting radiation) and for tungsten-filtered 100 kVp x-rays capable of producing Auger electron emission. The theoretical study showed that on average, 2.5 Auger electrons were emitted for N-shell orbital vacancies and up to 10 Auger electrons were emitted from L1-shell vacancies. These Auger bursts produced approximately 0.03 DSB per N-shell vacancy and 0.3 DSB per K-shell or L-shell vacancy. The calculated yield of DSB from Auger cascades per unit dose (1 Gy) in water was approximately 1.7 for tungsten-filtered 100 kVp x-rays, assuming 20% IUdR substitution of thymidine. The comet assay yielded an experimental value of 3.6+/-1.6 per 1 Gy for the same conditions. The Monte Carlo simulations also demonstrated a high complexity of DSB produced by Auger cascades with virtually all DSB from inner shell orbitals (i.e. K, L shells) accompanied by compounded strand breakage and base damage, indicating a difficult lesion to repair. This finding agrees well with comet assay results of DNA repair, where an increase in the DSB yield in IUdR-sensitized cells was shown to persist after a time of 24 h. We conclude that Auger cascades in iodine produce a modest increase in the number of initial strand breaks of the order of 10% but the complex nature of these DSB makes them very difficult to repair or potentially prone to misrepair. The accentuated DNA damage may have major consequences for cell survival and may be exploitable in kilovoltage photon activation therapy (PAT) of tumors sensitized with iodine.

Optimal photon energies for IUdR K-edge radiosensitization with filtered x-ray and radioisotope sources.

The purpose of this work is to determine the most physically effective radiation energy for K-edge absorption of x- or gamma-rays by iododeoxyuridine (IUdR) on Chinese hamster ovary (CHO) cells. Brachytherapy sources (Sm-145, I-125, Yb-169 and Am-241) and x-ray beams (30 kVp, 100 kVp and 100 kVp with gold, gadolinium, lead or tungsten filtration) were investigated for their preferential absorption qualities by IUdR sensitized DNA. The 30 kVp, 100 kVp and 100 kVp with tungsten filtration were then used to irradiate CHO cells, with or without IUdR incorporation (i.e. 10(-5) M of IUdR for 3 days). Radiation absorption calculations were performed to determine the increase in energy absorption in DNA with and without IUdR incorporated. In order to measure the in vitro biological effects of K-edge absorption, cell survival experiments were performed. The radiation physics calculations yielded an iodine dose enhancement ratio (DER) of 1.4+/-0.15. 1.8+/-0.15 and 2.7+/-0.15 for the 30 kVp, 100 kVp and tungsten filtered 100 kVp respectively, for 18% IUdR replacement of thymidine in DNA. The corresponding cell sensitization enhancement ratios (SER), determined from the cell survival assay, were determined to be 1.24+/-0.2, 1.8+/-0.2 and 2.3+/-0.3 for the 30 kVp, 100 kVp and tungsten filtered 100 kVp respectively, for cells with 18+/-2% IUdR incorporation. These SER values are in reasonable agreement with the DER values of 1.4, 1.8 and 2.7. From these radiation calculations and radiobiology experiments we confirm that using x-radiation energies above the K-edge of iodine (33.2 keV) can have a significant effect on cell survival. This effect is due mainly to the increase in the local dose to the DNA for IUdR-sensitized cells compared with the normal DNA which lacks the iodine contrast agent. Our results support the clinical application of IUdR and low-energy brachytherapy, perhaps using new technologies such as the x-ray needle or new isotopes such as Yb-169.

Function of the Greek key connection analysed using circular permutants of superoxide dismutase.

Human Cu,Zn superoxide dismutase (SOD) is a single domain all beta-sheet protein with its eight beta-strands arranged as a Greek key beta-barrel or immunoglobulin fold. Three circularly permuted variants of SOD were made by joining the native amino- and carboxy-termini, and introducing new termini at sites originally within connections between beta-strands. The locations of the new termini were chosen to interrupt beta-turns between the two N-terminal beta-hairpins and the short cross-barrel Greek key connection. Expression levels in the Escherichia coli periplasm were indistinguishable from that of native SOD. Reaction rates for the purified proteins were similar to those of the native enzyme, indicating that the permutants are correctly folded. Interrupting the covalent cross-bracing provided by the Greek key connection reduced the stability of the protein by approximately 1.0 kcal/mol, indicating only a slight contribution to conformational stability. The experiments test and eliminate two hypotheses for folding pathways for Greek key beta-barrels that require N-terminal beta-hairpins or covalent attachment across the short Greek key connection.