An investigation of image guidance dose for breast radiotherapy.

Cone-beam computed tomography (CBCT) is used for external-beam radiation therapy setup and target localization. As with all medical applications of ionizing radiation, radiation exposure should be managed safely and optimized to achieve the necessary image quality using the lowest possible dose. The present study investigates doses from standard kilovoltage kV radiographic and CBCT imaging protocol, and proposes two novel reduced dose CBCT protocols for the setup of breast cancer patients undergoing external beam radiotherapy. The standard thorax kV and low-dose thorax CBCT protocols available on Varian's On-Board Imaging system was chosen as the reference technique for breast imaging. Two new CBCT protocols were created by modifying the low-dose thorax protocol, one with a reduced gantry rotation range ("Under breast" protocol) and the other with a reduced tube current-time product setting ("Low dose thorax 10ms" protocol). The absorbed doses to lungs, heart, breasts, and skin were measured using XRQA2 radiochromic film in an anthropomorphic female phantom. The absorbed doses to lungs, heart, and breasts were also calculated using the PCXMC Monte Carlo simulation software. The effective dose was calculated using the measured doses to the included organs and the ICRP 103 tissue weighting factors. The deviation between measured and simulated organ doses was between 3% and 24%. Reducing the protocol exposure time to half of its original value resulted in a reduction in the absorbed doses of the organs of 50%, while the reduced rotation range resulted in a dose reduction of at least 60%. Absorbed doses obtained from "Low dose thorax 10ms" protocol were higher than the doses from our departments orthogonal kV-kV imaging protocol. Doses acquired from "Under breast" protocol were comparable to the doses measured from the orthogonal kV-kV imaging protocol. The effective dose per fraction using the CBCT for standard low-dose thorax protocol was 5.00 ± 0.30 mSv; for the "Low dose thorax 10ms" protocol it was 2.44 ± 0.21 mSv; and for the "Under breast" protocol it was 1.23 ± 0.25 mSv when the image isocenter was positioned at the phantom center and 1.17 ± 0.30 mSv when the image isocenter was positioned in the middle of right breast. The effective dose per fraction using the orthogonal kV-kV protocol was 1.14 ± 0.16 mSv. The reduction of the scan exposure time or beam rotation range of the CBCT imaging significantly reduced the dose to the organs investigated. The doses from the "Under breast" protocol and orthogonal kV-kV imaging protocol were comparable. Simulated organ doses correlated well with measured doses. Effective doses from imaging techniques should be considered with the increase use of kV imaging protocols in order to support the use of IGRT.

Modelling the dynamic dose response of an nMAG polymer gel dosimeter.

Gel dosimetry measures the absorbed radiation dose with high spatial resolution in 3D. However, recently published data show that the response of metacrylic-based polymer gels depends on the segmented delivery pattern, which could potentially be a considerable disadvantage for measurements of modern dynamic radiotherapy techniques. The aim of this study is to design a dynamic compartment model for the response of a gel dosimeter, exposed to an arbitrary irradiation pattern (segmented delivery and intensity modulation), in order to evaluate the associated effects on absorbed dose measurements. The model is based on the separation of the protons affecting the magnetic resonance signal (i.e. the R2 value) into six compartments, described by a set of differential equations. The model is used to calculate R2 values for a number of different segmented delivery patterns between 0-4 Gy over 1-33 fractions. Very good agreement is found between calculated and measured R2 values, with an average difference of 0.3 ± 1.1% (1 SD). The model is also used to predict the behaviour of a gel dosimeter exposed to irradiation according to typical IMRT, VMAT and respiratory gating scenarios. The calculated R2 values are approximately independent of the segmented delivery, given that the same total dose is delivered during the same total time. It is concluded that this study helps to improve the theoretical understanding of the dependence of metacrylic-based polymer gel response to segmented radiation delivery.

Direct dose to water dosimetry for pretreatment IMRT verification using a modified EPID.

PURPOSE: Electronic portal imaging devices (EPIDs) are high resolution systems that produce electronic dose maps with minimal time required for equipment setup, and therefore potentially present a time-saving alternative for intensity modulated radiation therapy (IMRT) pretreatment verification. A modified commercial EPID was investigated operated with an opaque sheet blocking the optical signal produced in the phosphor layer as a precursor to a switched mode dual dosimetry-imaging EPID system. The purpose of this study was to investigate the feasibility of using this system for direct dose to water dosimetry for pretreatment IMRT verification. METHODS: A Varian amorphous silicon EPID was modified by placing an opaque sheet between the Gd(2)S(2)O:Tb phosphor layer and the photodiode array to block the optical photons. The EPID was thus converted to a direct-detecting system (dEPID), in which the high energy radiation deposits energy directly in the photodiode array. The copper build-up was replaced with d(max) solid water. Sixty-one IMRT beams of varying complexity were delivered to the EPID, to EDR2 dosimetric film and to a 2D ion chamber array (MapCheck). EPID data was compared to film and MapCheck data using gamma analysis with 3%, 3mm pass criteria. RESULTS: The fraction of points that passed the gamma test was on average 98.1% and 98.6%, for the EPID versus film and EPID versus MapCheck comparisons, respectively. In the case of comparison with film, the majority of observed discrepancies were associated with problems related to film sensitivity or processing. CONCLUSIONS: The very close agreement between EPID and both film and MapCheck data demonstrates that the modified EPID is suitable for direct dose to water measurement for pretreatment IMRT verification. These results suggest a reconfigured EPID could be an efficient and accurate dosimeter. Alternatively, optical switching methods could be developed to produce a dual-mode EPID with both dosimetry and imaging capabilities.

RapidArc treatment verification in 3D using polymer gel dosimetry and Monte Carlo simulation.

The aim of this study was to verify the advanced inhomogeneous dose distribution produced by a volumetric arc therapy technique (RapidArc) using 3D gel measurements and Monte Carlo (MC) simulations. The TPS (treatment planning system)-calculated dose distribution was compared with gel measurements and MC simulations, thus investigating any discrepancy between the planned dose delivery and the actual delivery. Additionally, the reproducibility of the delivery was investigated using repeated gel measurements. A prostate treatment plan was delivered to a 1.3 liter nPAG gel phantom using one single arc rotation and a target dose of 3.3 Gy. Magnetic resonance imaging of the gel was carried out using a 1.5 T scanner. The MC dose distributions were calculated using the VIMC-Arc code. The relative absorbed dose differences were calculated voxel-by-voxel, within the volume enclosed by the 90% isodose surface (VOI(90)), for the TPS versus gel and TPS versus MC. The differences between the verification methods, MC versus gel, and between two repeated gel measurements were investigated in the same way. For all volume comparisons, the mean value was within 1% and the standard deviation of the differences was within 2.5% (1SD). A 3D gamma analysis between the dose matrices were carried out using gamma criteria 3%/3 mm and 5%/5 mm (% dose difference and mm distance to agreement) within the volume enclosed by the 50% isodose surface (VOI(50)) and the 90% isodose surface (VOI(90)), respectively. All comparisons resulted in very high pass rates. More than 95% of the TPS points were within 3%/3 mm of both the gel measurement and MC simulation, both inside VOI(50) and VOI(90). Additionally, the repeated gel measurements showed excellent consistency, indicating reproducible delivery. Using MC simulations and gel measurements, this verification study successfully demonstrated that the RapidArc plan was both accurately calculated and delivered as planned.

Sperm DNA integrity in men treated for childhood cancer.

PURPOSE: It is not known whether childhood cancer and its treatment are associated with sperm DNA damage, which subsequently affects fertility and might be transmitted to the offspring. The aim of this study is to assess DNA fragmentation index (DFI) as an indicator of sperm DNA integrity in childhood cancer survivors (CCS), with treatment regimen taken into account. EXPERIMENTAL DESIGN: In 99 CCS and 193 age-matched healthy controls, DFI was assessed by using sperm chromatin structure assay. RESULTS: In the whole group of CCS, DFI was increased compared with the controls, with borderline statistical significance [mean difference, 1.8%; 95% confidence interval (95% CI), -0.0088%-3.7%]. Those treated with radiotherapy only (mean difference, 6.0%; 95% CI, 1.6-10%) or surgery only (mean difference, 2.9%; 95% CI, 0.083-5.8%) had statistically significantly higher DFI than the controls. The odds ratio (OR) for having DFI >20%, which is associated with reduced fertility, was significantly increased in CCS compared with the control group (OR, 2.2; 95% CI, 1.1-4.4). For the radiotherapy-only group, the OR was even higher (OR, 4.9; 95% CI, 1.3-18). DFI was not associated with dose of scattered testicular irradiation or type of chemotherapy given. CONCLUSIONS: DFI was increased in CCS, with those treated with chemotherapy being the only exception. This sperm DNA impairment may be associated with the disease per se rather than due to the treatment, and may have negative consequences in terms of fertility and risk of transmission to the offspring.

Direct-detection EPID dosimetry: investigation of a potential clinical configuration for IMRT verification.

The routine use of electronic portal imaging devices (EPIDs) as dosimeters for radiotherapy quality assurance is complicated by the non-water equivalence of the EPID's dose response. A commercial EPID modified to a direct-detection configuration was previously demonstrated to provide water-equivalent dose response with d(max) solid water build-up and 10 cm solid water backscatter. Clinical implementation of the direct EPID (dEPID) requires a design that maintains the water-equivalent dose response, can be incorporated onto existing EPID support arms and maintains sufficient image quality for clinical imaging. This study investigated the dEPID dose response with different configurations of build-up and backscatter using varying thickness of solid water and copper. Field size output factors and beam profiles measured with the dEPID were compared with ionization chamber measurements of dose in water for both 6 MV and 18 MV. The dEPID configured with d(max) solid water build-up and no backscatter (except for the support arm) was within 1.5% of dose in water data for both energies. The dEPID was maintained in this configuration for clinical dosimetry and image quality studies. Close agreement between the dEPID and treatment planning system was obtained for an IMRT field with 98.4% of pixels within the field meeting a gamma criterion of 3% and 3 mm. The reduced sensitivity of the dEPID resulted in a poorer image quality based on quantitative (contrast-to-noise ratio) and qualitative (anthropomorphic phantom) studies. However, clinically useful images were obtained with the dEPID using typical treatment field doses. The dEPID is a water-equivalent dosimeter that can be implemented with minimal modifications to the standard commercial EPID design. The proposed dEPID design greatly simplifies the verification of IMRT dose delivery.

EPID dosimetry: effect of different layers of materials on absorbed dose response.

PURPOSE: Commercial EPIDs are normally used in indirect detection mode (iEPID) where incident x-ray photons are converted to optical photons in a phosphor scintillator, which are then detected by a photodiode array. The EPIDs are constructed from a number of nonwater equivalent materials which affect the dose response of the detector. The so-called direct detection EPIDs (dEPIDs), operating without the phosphor layer, have been reported to display dose response close to in-water data. In this study, the effect that different layers of materials in the EPID have on the dose response was experimentally investigated and evaluated with respect to changes in field size response and beam profiles. METHODS: An iEPID was disassembled and the different layers of materials were removed or replaced with other materials. Data were also obtained on and off the support arm and with a sheet of opaque paper blocking the optical photons from the gadolinium oxysulfide (Gd2S2O:Tb) phosphor layer. Field size response was measured for field sizes ranging from 2 x 2 to 25 x 25 cm2, and profiles for the 25 x 25 cm2 beams were extracted from the data. RESULTS: The iEPID configuration was found to be very sensitive to backscatter. The increases in output with solid water backscatter compared to the no backscatter case were 14.7% and 6.6% at the largest field size investigated for the 6 and 18 MV beams, respectively. The Gd2S2O:Tb phosphor layer had a large influence on field size response as well as beam profiles for 6 MV photons, while no major effects were observed for the 18 MV beam. For 18 MV large differences in dose response were found when the standard 1 mm Cu buildup was changed for dmax equivalent Cu or solid water buildup, indicating that head scatter largely influences dose response for this energy. When the optical photons originating in the Gd2S2O:Tb layer were blocked from reaching the photodiodes, both field size output data and beam profiles corresponded well with data obtained in the dEPID configuration as well as reference ion chamber data for both energies. CONCLUSIONS: As expected, changing the layers of material in the EPID had a dramatic effect on dose response, which was often quite complex. For 6 MV, the complex dose response is mainly caused by the optical photons from the Gd2S2O:Tb layer, while insufficient filtering of scattered radiation largely affects the dose response for the 18 MV beam. The iEPID was also found to be very sensitive to backscatter for both energies. Blocking the optical photons created in the Gd2S2O:Tb layer essentially changed the iEPID configuration into the dEPID configuration, thus demonstrating great potential for a system that can be optimized for both imaging and dosimetry.

Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils.

Staphylococcus epidermidis often causes foreign-body infections such as those associated with hip prostheses, but the underlying pathogenic mechanisms are not fully understood. We performed spectrophotometry to study the ability of S. epidermidis to bind to immobilised fibrinogen, fibronectin, vitronectin, and collagen. The strains were isolated from infected hip prostheses or from normal flora and the well-known protein-binding strain Staphylococcus aureus Cowan was used as positive control. We also analysed the interaction between neutrophils and a fibrinogen-bound prosthesis-derived strain of S. epidermidisby measuring chemiluminescence to determine the neutrophil oxidative response and binding of annexin V to indicate neutrophil apoptosis. We found that binding of S. epidermidis to extracellular matrix proteins varied under different growth conditions, and that prosthesis isolates adhered better to vitronectin than did strains from normal flora. The oxidative response caused by fibrinogen-bound S. epidermidis was not above the background level, which was in marked contrast to the distinct response induced by fibrinogen-associated S. aureus Cowan. Furthermore, fibrinogen-adhering S. epidermidis retarded neutrophil apoptosis. We conclude that surface-bound S. epidermidis induces only a weak inflammatory response, which in combination with the ability of the adherent bacteria to retard neutrophil apoptosis may contribute to low-grade inflammation and loosening of prostheses.

Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils.

S. epidermidis is the most common isolate in foreign body infections. The aim of this study was to understand why S. epidermidis causes silent biomaterial infections. In view of the divergent inflammatory responses S. epidermidis and S. aureus cause in patients, we analyzed how they differ when interacting with human neutrophils. Neutrophils interacting with S. epidermidis strains isolated either from granulation tissue covering infected hip prostheses or from normal skin flora were tested by measuring the oxidative response as chemiluminescence and apoptosis as annexin V binding. Different S. aureus strains were tested in parallel. All S. epidermidis tested were unable to modulate the oxidative reaction in response to formyl-methionyl-leucyl-phenylalanine (fMLP) and did not provoke, but rather inhibited, apoptosis. In contrast, some S. aureus strains enhanced the oxidative reaction, and this priming capacity was linked to p38-mitogen-activated-protein-kinase (p38-MAPK) activation and induction of apoptosis. Our results may explain why S. epidermidis is a weak inducer of inflammation compared to S. aureus, and therefore responsible for the indolent and chronic course of S. epidermidis biomaterial infections.

Anti-inflammatory effects of a titanium-peroxy gel: role of oxygen metabolites and apoptosis.

Polymorphonuclear neutrophils (PMN) are among the first inflammatory cells to arrive at an implant interface, where they encounter with the foreign material and may produce reactive oxygen species (ROS). During the interaction between titanium and ROS, titanium-peroxy (Ti-peroxy) compounds may be formed. We used a Ti-peroxy gel, made from titanium and hydrogen peroxide, to study the effects of Ti-peroxy compounds on PMN. In the absence of serum, the Ti-peroxy gel decreased the oxidative response of PMN to yeast and PMA and reduced PMN apoptosis without inducing necrosis. These effects could not be ascribed to the release of hydrogen peroxide from the Ti-peroxy gel, because a steady-state hydrogen peroxide producing system failed to mimic the effects of the gel. The effects were similarly unaffected when PMN were preincubated with beta(2)-integrin antibodies, questioning the involvement of adhesion molecules. Nevertheless, when a filter was used to separate the Ti-peroxy gel from the cells, the gel effect on PMN life span was abolished, pointing to a contact-dependent mechanism. In the presence of serum, the Ti-peroxy gel had no effect on the PMN oxidative response and life span, but appeared rather inert. In summary, this study demonstrates that the Ti-peroxy gel has potentially anti-inflammatory properties through a combined peroxide and physical contact effect, supporting the notion that interactions between titanium and inflammatory cells are responsible for the good performance of titanium in vivo.