Breathing-Adapted Imaging Techniques for Rapid 4-Dimensional Lung Tomosynthesis.

Purpose: This article presents enhancements to a 4-dimensional (4D) lung digital tomosynthesis (DTS) model introduced in a 2018 paper. That model was proposed as an adjunct to 4D computed tomography (4DCT) to improve tumor localization through artifact reduction achieved by imaging the entire lung in all projections, reducing the projection collection time duration for each phase compared with 4DCT, and requiring only a single-breath cycle to capture all phases. This is applicable to SABR treatment planning. Enhancements comprise customized patient 4D-DTS x-ray scanning parameters. Methods and Materials: Imaging parameters derived with the 4D-DTS model were arc duration, frames per second, pulse duration, and tube current normalized to single-chest radiographic milliampere-seconds (mA/mAsAEC). Optimized phase-specific DTS projections imaging parameters were derived for volunteer respiration-tracking surrogate waveforms and for sinusoidal waveforms. These parameters are temporally matched to the respiratory surrogate waveform and presented as continuous data plots during a period of 20 seconds. Comparison is made between surrogate excursions during a single-phase CT and 4D-DTS reconstructions. Results: 4D-DTS imaging techniques were customized to volunteer respiratory waveforms and sinusoidal waveforms. Technique settings at the highest velocity portions of the volunteer waveforms were arc duration 0.066 seconds, frame rate 921 Hz, pulse duration 1.076 ms, and normalized tube current 76.2 s-1. Technique settings at the highest velocity portions of the sinusoidal waveforms were arc duration 0.029 seconds, frame rate 2074 Hz, pulse duration 0.472 ms, and normalized tube current 173.6 s-1. Sinusoidal surrogate excursion distance at the highest velocity portion of the waveform during a CT rotation of 0.5 seconds ranged from 2.68 to 21.09 mm, all greater than the limiting excursion distance chosen in the 4D-DTS model. Conclusions: 4D-DTS image technique settings can be customized to individual patient breathing patterns so that captured range of motion satisfies an operator-selected value.

Isoflavone-mediated radioprotection involves regulation of early endothelial cell death and inflammatory signaling in Radiation-Induced lung injury.

Purpose: Vascular damage and inflammation are limiting toxic effects of lung cancer radiotherapy, which lead to pneumonitis and pulmonary fibrosis. We have demonstrated that soy isoflavones (SIF) mitigate these toxic effects at late time points after radiation. However, the process by which SIF impacts the onset of radiation-induced inflammation remains to be elucidated. We have now investigated early events of radiation-induced inflammation and identified cellular and molecular signaling patterns by endothelial cells that could be modified by SIF to control vascular damage and the initiation of lung inflammation.Materials and methods: Histopathological, cellular and molecular studies were performed on mouse lungs from C57Bl/6 mice treated with 10 Gy of thoracic radiation (XRT) in conjunction with daily oral SIF treatment given prior and after radiation. Parallel studies were performed in-vitro using EA.hy926 endothelial cell line with SIF and radiation. Immunohistochemistry, western blots analysis, and flow cytometry were performed on lung tissue or EA.hy926 cells to analyze endothelial cells, their patterns of cell death or survival, and signaling molecules involved in inflammatory events.Results: Histopathological differences in inflammatory infiltrates and vascular injury in lungs, including vascular endothelial cells, were observed with SIF treatment at early time points post-XRT. XRT-induced expression of proinflammatory adhesion molecule ICAM-1 cells was reduced by SIF in-vitro and in-vivo in endothelial cells. Molecular changes in endothelial cells with SIF treatment in conjunction with XRT included increased DNA damage, reduced cell viability and cyclin B1, and inhibition of nuclear translocation of NF-κB. Analysis of cell death showed that SIF treatment promoted apoptotic endothelial cell death and decreased XRT-induced type III cell death. In-vitro molecular studies indicated that SIF + XRT increased apoptotic caspase-9 activation and production of IFNß while reducing the release of inflammatory HMGB-1 and IL-1α, the cleavage of pyroptotic gasdermin D, and the release of active IL-1ß, which are all events associated with type III cell death.Conclusions: SIF + XRT caused changes in patterns of endothelial cell death and survival, proinflammatory molecule release, and adhesion molecule expression at early time points post-XRT associated with early reduction of immune cell recruitment. These findings suggest that SIF could mediate its radioprotective effects in irradiated lungs by limiting excessive immune cell homing via vascular endothelium into damaged lung tissue and curtailing the overall inflammatory response to radiation.

Model evaluation of rapid 4-dimensional lung tomosynthesis.

PURPOSE: This is an investigation of a lung motion digital tomosynthesis (DTS) model using combined stationary detector and stationary cold cathode x-ray sources at projection acquisition rates that exceed the present norms. The intent is to reduce anatomical uncertainties from artifacts inherent in thoracic 4-dimensional computed tomography (CT). METHODS AND MATERIALS: Parameters necessary to perform rapid lung 4-dimensional DTS were studied using a conventional radiographic system with linear motion of the x-ray source and a simple hypothetical hardware performance model. Hypothetical rapid imaging parameters of sweep duration, projections per second, pulse duration, and tube current (mA) were derived on the basis of 0.5 mm and 1 mm motion captures per phase, 10 and 15 breaths per minute (bpm), 10 to 40 mm breathing amplitude, and 2 signal-to-noise ratio (SNR) levels. Anterior-posterior and lateral projection images of a normal size anthropomorphic thorax phantom with iodine contrast inserts were collected and reconstructed with an algebraic algorithm to study the effects of reduced x-ray output associated with field emission cold cathodes composed of carbon nanotubes or metal Spindt-type. Radiographic projections were collected at 3 SNR levels that were set at standard clinical DTS milliampere-seconds (mAs) and reduced corresponding to 50% and 25% standard DTS mAs to simulate a reduced x-ray output. RESULTS: The DTS SNR of the inserts was superior in all reconstructions at clinical mAs versus automatic exposure-control radiographs and superior in 3 of 4 at the 50% and 25% mAs levels. The most demanding performance parameters corresponding to 40 mm amplitude, 15 bpm, 0.5 mm motion capture limit, and 61 projections were sweep duration (10.4 msec), projection rate (5862 projections per second), pulse duration (0.161 msec), current 189 mA anterior-posterior, and 653 mA lateral. CONCLUSIONS: Feasibility depends on the output performance of stationary cold cathode hardware being developed for DTS. Present image receptor technology can accommodate frame acquisition rates.

Percent depth doses and X-ray beam characterizations of a fluoroscopic system incorporating copper filtration.

PURPOSE: In this investigation, we sought to characterize X-ray beam qualities and quantitate percent depth dose (PDD) curves for fluoroscopic X-ray beams incorporating added copper (Cu) filtration, such as those commonly used in fluoroscopically guided interventions (FGI). The intended application of this research is for dosimetry in soft tissue from FGI procedures using these data. METHODS: All measurements in this study were acquired on a Siemens (Erlangen, Germany) Artis zeego fluoroscope. X-ray beam characteristics of first half-value layer (HVL), second HVL, homogeneity coefficients (HCs), backscatter factors (BSFs) and kVp accuracy and precision were determined to characterize the X-ray beams used for the PDD measurements. A scanning water tank was used to measure PDD curves for 60, 80, 100, and 120 kVp X-ray beams with Cu filtration thicknesses of 0.0, 0.1, 0.3, 0.6, and 0.9 mm at 11 cm, 22 cm, and 42 cm nominal fields of view, in water depths of 0 to 150 mm. RESULTS: X-ray beam characteristics of first HVLs and HCs differed from previous published research of fluoroscopic X-ray beam qualities without Cu filtration. PDDs for 60, 80, 100, and 120 kVp with 0 mm of Cu filtration were comparable to previous published research, accounting for differences in fluoroscopes, geometric orientation, type of ionization chamber, X-ray beam quality, and the water tank used for data collection. PDDs and X-ray beam characteristics for beam qualities with Cu filtration are presented, which have not been previously reported. CONCLUSIONS: The data sets of X-ray beam characteristics and PDDs presented in this study can be used to estimate organ or soft tissue doses at depth involving similar beam qualities or to compare with mathematical models.

Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen.

BACKGROUND: We previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. To investigate whether tumor irradiation augments the immune response to MUC1 tumor antigen, we have tested the efficacy of tumor irradiation combined with an MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for murine renal adenocarcinoma (Renca) cells transfected with MUC1. METHODS: Established subcutaneous Renca-MUC1 tumors were treated with 8 Gy radiation on day 11 and peritumoral injections of MVA-MUC1-IL2 vector on day 12 and 17, or using a reverse sequence of vaccine followed by radiation. Growth delays were monitored by tumor measurements and histological responses were evaluated by immunohistochemistry. Specific immunity was assessed by challenge with Renca-MUC1 cells. Generation of tumor-specific T cells was detected by IFN-γ production from splenocytes stimulated in vitro with tumor lysates using ELISPOT assays. RESULTS: Tumor growth delays observed by tumor irradiation combined with MVA-MUC1-IL-2 vaccine were significantly more prolonged than those observed by vaccine, radiation, or radiation with MVA empty vector. The sequence of cancer vaccine followed by radiation two days later resulted in 55-58% complete responders and 60% mouse long-term survival. This sequence was more effective than that of radiation followed by vaccine leading to 24-30% complete responders and 30% mouse survival. Responding mice were immune to challenge with Renca-MUC1 cells, indicating the induction of specific tumor immunity. Histology studies of regressing tumors at 1 week after therapy, revealed extensive tumor destruction and a heavy infiltration of CD45+ leukocytes including F4/80+ macrophages, CD8+ cytotoxic T cells and CD4+ helper T cells. The generation of tumor-specific T cells by combined therapy was confirmed by IFN-γ secretion in tumor-stimulated splenocytes. An abscopal effect was measured by rejection of an untreated tumor on the contralateral flank to the tumor treated with radiation and vaccine. CONCLUSIONS: These findings suggest that cancer vaccine given prior to local tumor irradiation augments an immune response targeted at tumor antigens that results in specific anti-tumor immunity. These findings support further exploration of the combination of radiotherapy with cancer vaccines for the treatment of cancer.

Extrapolation Ionization Chamber Dosimetry of Fluorescent X-Ray Energies from 4.5 to 19.6 keV.

Characteristic X rays of energies less than approximately 20 keV are of interest in radiobiology and radiation oncology. There is evidence that these low-energy photons produce higher relative biological effectiveness (RBE) and lower oxygen enhancement ratio (OER) relative to higher energies. Lower energy X rays also offer the advantage of healthy tissue sparing beyond the target treatment depth. Electronic brachytherapy systems that can deliver characteristic and bremsstrahlung X rays of varying energy are in clinical use as well as under development. We performed low-energy extrapolation ionization chamber dosimetry using two methods: 1. the exposure-to-dose method; and 2. the Burlin theory method combined with the extrapolation chamber method of Klevenhagen. We investigated fluorescent X rays emitted from seven metals: titanium (Ti, Z = 22); chromium (Cr, Z = 24); iron (Fe, Z = 26); cobalt (Co, Z = 27); copper (Cu, Z = 29); zinc (Zn, Z = 30); and molybdenum (Mo, Z = 42). X rays were produced by irradiation of the metals with a 55 kVp, 45 mA silver anode spectrum. The data obtained were air kerma rate (cGy/min), and radiation dose rate (cGy/min) in phosphate-buffered saline (PBS) solution and water. Air kerma rates ranged from 3.55 ± 0.10 to 14.36 ± 0.39 cGy/min. Dose rates ranged from 3.85 ± 0.10 to 16.96 ± 0.46 cGy/min in PBS and 3.59 ± 0.10 to 16.06 ± 0.43 cGy/min in water. Dose-rate energy dependence of both models was examined by taking a ratio of measured to Monte Carlo calculated dose rates. Dosimetry method 1 exhibited a linear relationship across all energies with a slope of 0.0127 keV(-1) and R(2) of 0.9276. Method 2 exhibited a linear relationship across all energies with a slope of 0.0467 keV(-1) and R(2) of 0.9933. Method 1 or 2 may be used as a relative dosimetry system to derive dose rates to water by using a second reference ion chamber with a NIST-traceable calibration for the molybdenum spectrum.

Investigating ion recombination effects in a liquid-filled ionization chamber array used for IMRT QA measurements.

PURPOSE: PTW's Octavius 1000 SRS array performs IMRT quality assurance (QA) measurements with liquid-filled ionization chambers (LICs) to allow closer detector spacing and higher resolution, compared to air-filled QA devices. However, reduced ion mobility in LICs relative to air leads to increased ion recombination effects and reduced collection efficiencies that are dependent on Linac pulse frequency and pulse dose. These pulse parameters are variable during an IMRT delivery, which affects QA results. In this study, (1) 1000 SRS collection efficiencies were measured as a function of pulse frequency and pulse dose, (2) two methods were developed to correct changes in collection efficiencies during IMRT QA measurements, and the effects of these corrections on QA pass rates were compared. METHODS: To obtain collection efficiencies, the OCTAVIUS 1000 SRS was used to measure open fields of varying pulse frequency, pulse dose, and beam energy with results normalized to air-filled chamber measurements. Changes in ratios of 1000 SRS to chamber measured dose were attributed to changing collection efficiencies, which were then correlated to pulse parameters using regression analysis. The usefulness of the derived corrections was then evaluated using 6 MV and 10FFF SBRT RapidArc plans delivered to the OCTAVIUS 4D system using a TrueBeam (Varian Medical Systems) linear accelerator equipped with a high definition multileaf collimator. For the first correction, matlab software was developed that calculates pulse frequency and pulse dose for each detector, using measurement and DICOM RT Plan files. Pulse information is converted to collection efficiency, and measurements are corrected by multiplying detector dose by ratios of calibration to measured collection efficiencies. For the second correction the MU/min in the daily 1000 SRS calibration was chosen to match the average MU/min of the volumetric modulated arc therapy plan. Effects of the two corrections on QA results were examined by performing 3D gamma analysis comparing predicted to measured dose, with and without corrections. RESULTS: Collection efficiencies correlated linearly to pulse dose, while correlations with pulse frequency were less defined, generally increasing as pulse frequency decreased. After complex matlab corrections, average 3D gamma pass rates improved by [0.07%,0.40%,1.17%] for 6 MV and [0.29%,1.40%,4.57%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. Maximum changes in gamma pass rates were [0.43%,1.63%,3.05%] for 6 MV and [1.00%,4.80%,11.2%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. On average, pass rates of simple daily calibration corrections were within 1% of complex matlab corrections. CONCLUSIONS: OCTAVIUS 1000 SRS ion recombination effects have little effect on 6 MV measurements. However, the effect could potentially be clinically significant for higher pulse dose unflattened beams when using tighter gamma tolerances, especially when small aperture sizes are used, as is common for SRS/SBRT. In addition, ion recombination effects are strongly correlated to changing MU/min, therefore MU/min used in daily 1000 SRS calibrations should be matched to the expected average MU/min of the IMRT plan.

Effect of fluoroscopic X-ray beam spectrum on air-kerma measurement accuracy: implications for establishing correction coefficients on interventional fluoroscopes with KAP meters.

The first goal of this study was to investigate the accuracy of the displayed reference plane air kerma (Ka,r) or air kerma-area product (Pk,a) over a broad spectrum of X-ray beam qualities on clinically used interventional fluoroscopes incorporating air kerma-area product meters (KAP meters) to measure X-ray output. The second goal was to investigate the accuracy of a correction coefficient (CC) determined at a single beam quality and applied to the measured Ka,r over a broad spectrum of beam qualities. Eleven state-of-the-art interventional fluoroscopes were evaluated, consisting of eight Siemens Artis zee and Artis Q systems and three Philips Allura FD systems. A separate calibrated 60 cc ionization chamber (external chamber) was used to determine the accuracy of the KAP meter over a broad range of clinically used beam qualities. For typical adult beam qualities, applying a single CC deter-mined at 100 kVp with copper (Cu) in the beam resulted in a deviation of < 5% due to beam quality variation. This result indicates that applying a CC determined using The American Association of Physicists in Medicine Task Group 190 protocol or a similar protocol provides very good accuracy as compared to the allowed ± 35% deviation of the KAP meter in this limited beam quality range. For interventional fluoroscopes dedicated to or routinely used to perform pediatric interventions, using a CC established with a low kVp (~ 55-60 kVp) and large amount of Cu filtration (~ 0.6-0.9 mm) may result in greater accuracy as compared to using the 100 kVp values. KAP meter responses indicate that fluoroscope vendors are likely normalizing or otherwise influencing the KAP meter output data. Although this may provide improved accuracy in some instances, there is the potential for large discrete errors to occur, and these errors may be difficult to identify.

Development and evaluation of an end-to-end test for head and neck IMRT with a novel multiple-dosimetric modality phantom.

A comprehensive end-to-end test for head and neck IMRT treatments was developed using a custom phantom designed to utilize multiple dosimetry devices. Initial end-to-end test and custom H&N phantom were designed to yield maximum information in anatomical regions significant to H&N plans with respect to: (i) geometric accuracy, (ii) dosimetric accuracy, and (iii) treatment reproducibility. The phantom was designed in collaboration with Integrated Medical Technologies. The phantom was imaged on a CT simulator and the CT was reconstructed with 1 mm slice thickness and imported into Varian's Eclipse treatment planning system. OARs and the PTV were contoured with the aid of Smart Segmentation. A clinical template was used to create an eight-field IMRT plan and dose was calculated with heterogeneity correction on. Plans were delivered with a TrueBeam equipped with a high definition MLC. Preliminary end-to-end results were measured using film, ion chambers, and optically stimulated luminescent dosimeters (OSLDs). Ion chamber dose measurements were compared to the treatment planning system. Films were analyzed with FilmQA Pro using composite gamma index. OSLDs were read with a MicroStar reader using a custom calibration curve. Final phantom design incorporated two axial and one coronal film planes with 18 OSLD locations adjacent to those planes as well as four locations for IMRT ionization chambers below inferior film plane. The end-to-end test was consistently reproducible, resulting in average gamma pass rate greater than 99% using 3%/3 mm analysis criteria, and average OSLD and ion chamber measurements within 1% of planned dose. After initial calibration of OSLD and film systems, the end-to-end test provides next-day results, allowing for integration in routine clinical QA. Preliminary trials have demonstrated that our end-to-end is a reproducible QA tool that enables the ongoing evaluation of dosimetric and geometric accuracy of clinical head and neck treatments.

Approaches to interventional fluoroscopic dose curves.

Modern fluoroscopes used for image-based guidance in interventional procedures are complex X-ray machines, with advanced image acquisition and processing systems capable of automatically controlling numerous parameters based on defined protocol settings. This study evaluated and compared approaches to technique factor modulation and air kerma rates in response to simulated patient thickness variations for four state-of-the-art and one previous-generation interventional fluoroscopes. A polymethyl methacrylate (PMMA) phantom was used as a tissue surrogate for the purposes of determining fluoroscopic reference plane air kerma rates, kVp, mA, and variable copper filter thickness over a wide range of simulated tissue thicknesses. Data were acquired for each fluoroscopic and acquisition dose curve within each vendor's default abdomen or body imaging protocol. The data obtained indicated vendor- and model-specific variations in the approach to technique factor modulation and reference plane air kerma rates across a range of tissue thicknesses. However, in the imaging protocol evaluated, all of the state-of-the-art systems had relatively low air kerma rates in the fluoroscopic low-dose imaging mode as compared to the previous-generation unit. Each of the newest-generation systems also employ Cu filtration within the selected protocol in the acquisition mode of imaging; this is a substantial benefit, reducing the skin entrance dose to the patient in the highest dose-rate mode of fluoroscope operation. Some vendors have also enhanced the radiation output capabilities of their fluoroscopes which, under specific conditions, may be beneficial; however, these increased output capabilities also have the potential to lead to unnecessarily high dose rates. Understanding how fluoroscopic technique factors are modulated provides insight into the vendor-specific image acquisition approach and may provide opportunities to optimize the imaging protocols for clinical practice.

Sensitivity and variability of Presage dosimeter formulations in sheet form with application to SBRT and SRS QA.

PURPOSE: To measure sensitivity and stability of the Presage dosimeter in sheet form for various chemical concentrations over a range of clinical photon energies and examine its use for stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) QA. METHODS: Presage polymer dosimeters were formulated to investigate and optimize their sensitivity and stability. The dosimeter is composed of clear polyurethane base, leucomalachite green (LMG) reporting dye, and bromoform radical initiator in 0.9-1.0 mm thick sheets. The chemicals are mixed together for 2 min, cast in an aluminum mold, and left to cure at 60 psi for a minimum of two days. Dosimeter response was characterized at energies Co-60, 6 MV, 10 MV flattening-filter free, 15 MV, 50 kVp (mean 19.2 keV), and Ir-192. The dosimeters were scanned by a Microtek Scanmaker i800 at 300 dpi, 2(16) bit depth per color channel. Red component images were analyzed with ImageJ and rit. SBRT QA was done with gamma analysis tolerances of 2% and 2 mm DTA. RESULTS: The sensitivity of the Presage dosimeter increased with increasing concentration of bromoform. Addition of tin catalyst decreased curing time and had negligible effect on sensitivity. LMG concentration should be at least as high as the bromoform, with ideal concentration being 2% wt. Gamma Knife SRS QA measurements of relative output and profile widths were within 2% of manufacturer's values validated at commissioning, except the 4 mm collimator relative output which was within 3%. The gamma pass rate of Presage with SBRT was 73.7%, compared to 93.1% for EBT2 Gafchromic film. CONCLUSIONS: The Presage dosimeter in sheet form was capable of detecting radiation over all tested photon energies and chemical concentrations. The best sensitivity and photostability of the dosimeter were achieved with 2.5% wt. LMG and 8.2% wt. bromoform. Scanner used should not emit any UV radiation as it will expose the dosimeter, as with the Epson 10000 XL scanner. Presage dosimeter in this form was sensitive enough for use in SRS and SBRT QA. The lower gamma pass rate for Presage compared to Gafchromic film can be attributed to the simple equipment used in the fabrication process, which limited the dosimeter's sensitivity uniformity by agglomeration of air bubbles in the material, nonuniform concentration of chemicals throughout the material, and thickness variations. This demands improvements in mixing tools and molds.

Measurement of gold nanofilm dose enhancement using unlaminated radiochromic film.

PURPOSE: Bombarding high-Z material with x-ray radiation releases Auger electrons and Coster-Kronig electrons, along with deeper penetrating fluorescent x-rays and photoelectrons. The Auger and Coster-Kronig electron penetration distance is on the order of nanometers to micrometers in water or tissue, creating a large dose enhancement accompanied by a RBE greater than 1 at the cellular level. The authors' aim is to measure the gold nanofilm dose enhancement factor (DEF) at the cellular level with unlaminated radiochromic film via primary 50 kVp tungsten x-ray spectrum interaction, similar to an electronic brachytherapy spectrum. METHODS: Unlaminated Gafchromic(®) EBT2 film and Monte Carlo modeling were combined to derive DEF models. Gold film of thickness 23.1 ± 4.3 nm and surface roughness of 1.2 ± 0.2 nm was placed in contact with unlaminated radiochromic film in a downstream orientation and exposed to a 50 kVp tungsten bremsstrahlung, mean energy 19.2 keV. Film response correction factors were derived by Monte Carlo modeling of electron energy deposition in the film's active layer, and by measuring film energy dependence from 4.5 keV to 50 kVp. RESULTS: The measured DEF within a 13.6 µm thick water layer was 0.29 with a mean dose of 94 ± 9.4 cGy from Au emissions and 324 ± 32.4 cGy from the 50 kVp primary beam. Monte Carlo derived correction factors allowed determination of Au contributed dose in shallower depths at 0.25 µm intervals. Maximum DEF of 18.31 was found in the first 0.25 µm water depth. CONCLUSIONS: Dose enhancement from Au nanofilm can be measured at the cellular level using unlaminated radiochromic film. Complementing the measured dose value with Monte Carlo calculations allows estimation of dose enhancement at depth increments within the cellular range.

Gamma Knife radiosurgery in the management of brainstem metastases.

BACKGROUND: Metastases to the brainstem portend a poor prognosis and present a challenge in clinical management. Surgical resection is rarely a viable option. METHODS: Post-treatment MRI scans of patients with brainstem metastases treated with radiosurgery were used to determine local control and disease progression. Median survival was calculated using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using log-rank test and Cox proportional hazards model, respectively. RESULTS: Thirty-two consecutive patients with brainstem metastasis underwent Gamma Knife radiosurgery. Median age was 50 years. Median tumor volume was 0.71 cm3 and median tumor margin dose was 13 Gy. Seventeen of 32 patients received WBRT prior to stereotactic radiosurgery. Median survival was 5.2 months. There was a statistically significant difference in survival based on RTOG recursive partition analysis (RPA) class. Median survival of patients categorized as RPA class I was 19.2 months, RPA class II was 8.4 months, and RPA class III was 1.9 months. The overall local tumor control rate was 87.5%. There were no acute complications following stereotactic radiosurgery and no evidence of radiation necrosis noted on post-treatment MRI scans. CONCLUSION: Stereotactic radiosurgery is an effective treatment for brainstem metastases and should be considered especially for patients with good performance status.

Fast Monte Carlo simulation for total body irradiation using a (60)Co teletherapy unit.

Our institution delivers TBI using a modified Theratron 780 60Co unit. Due to limitations of our treatment planning system in calculating dose for this treatment, we have developed a fast Monte Carlo code to calculate dose distributions within the patient. The algorithm is written in C and uses voxel density information from CT images to calculate dose in heterogeneous media. To test the algorithm, film-based dose measurements were made separately in a simple water phantom with a high-density insert and a RANDO phantom and then compared to doses calculated by the Monte Carlo algorithm. In addition, a separate simulation in GEANT4 was run for the RANDO phantom and compared to both film and the in-house simulation. All results were analyzed using RIT113 film analysis software. Simulations in the water phantom accurately predict the depth of maximum dose in the phantom at 0.5 cm. The measured PDD along the central axis of the beam closely matches the PDD generated from the Monte Carlo code, deviating on average by only 3% along the depth of the water phantom. Dose measured at planes inside the high-density insert had a mean difference of 4.9% on cross-profile measurement. In the RANDO phantom, gamma pass rates vary between 91% and 99% at 3 mm, 3%, and were >99% at 5 mm, 5% for the four film planes measured. Profiles taken across the film and both simulations resulted in mean relative differences of < 2% for all profiles in each slice measured. The Monte Carlo algorithm presented here is potentially a viable method for calculating dose distributions delivered in TBI treatments at our center. While not yet refined enough to be the primary method of treatment planning, the algorithm at its current resolution determines the dose distribution for one patient within a few hours, and provides clinically useful information in planning TBI. With appropriate optimization, the Monte Carlo method presented here could potentially be implemented as a first-line treatment planning option for 60Co TBI.

Effects of titanium mesh implant on dosimetry during Gamma Knife radiosurgery.

Calvarial reconstruction following resection of tumors involving the skull is often followed by stereotactic radiosurgery. Prior studies have addressed the effects of various cranioplasty materials on dose distributions in linac-based radiosurgery. We aim to determine the effects of titanium mesh implants on Gamma Knife dose. Radiation backscatter and transmission were measured for eight types of titanium mesh using film, ion chamber, and Theratron Co-60 teletherapy device. A single mesh was selected for Gamma Knife irradiation using a CaSO(4) skull filled with ballistics gel. Dose profiles for reconstructed and intact skulls were compared with the planning system prediction at 2.5 and 5.5 cm depth. Titanium contact backscatter and transmission dose perturbations ranged from -18% to 23%. Radiation dose measured at 1.5 cm below the calvarial implant increased by 0.5% to 3.3% relative to bone. Measured Gamma Knife dose profile diameters agreed with expected profiles. Maximum dose within the intact phantom was 3% less than planned due to skull attenuation. Maximum dose within the reconstructed phantom was between the intact phantom and planned doses. Titanium mesh implants and hydroxyapatite cranioplasty result in minimal alteration (< 3%) in the delivered Gamma Knife dose.

B-DIM impairs radiation-induced survival pathways independently of androgen receptor expression and augments radiation efficacy in prostate cancer.

Increased consumption of cruciferous vegetables is associated with decreased risk in prostate cancer (PCa). The active compound in cruciferous vegetables appears to be the self dimerized product [3,3'-diindolylmethane (DIM)] of indole-3-carbinol (I3C). Nutritional grade B-DIM (absorption-enhanced) has proven safe in a Phase I trial in PCa. We investigated the anti-cancer activity of B-DIM as a new biological approach to improve the effects of radiotherapy for hormone refractory prostate cancer cells, which were either positive or negative for androgen receptor (AR) expression. B-DIM inhibited cell growth in a dose-dependent manner in both PC-3 (AR-) and C4-2B (AR+) cell lines. B-DIM was effective at increasing radiation-induced cell killing in both cell lines, independently of AR expression. B-DIM inhibited NF-κB and HIF-1α DNA activities and blocked radiation-induced activation of these transcription factors in both PC-3 and C4-2B cells. In C4-2B (AR+) cells, AR expression and nuclear localization were significantly increased by radiation. However, B-DIM abrogated the radiation-induced AR increased expression and trafficking to the nucleus, which was consistent with decreased PSA secretion. In vivo, treatment of PC-3 prostate tumors in nude mice with B-DIM and radiation resulted in significant primary tumor growth inhibition and control of metastasis to para-aortic lymph nodes. These studies demonstrate that B-DIM augments radiation-induced cell killing and tumor growth inhibition. B-DIM impairs critical survival signaling pathways activated by radiation, leading to enhanced cell killing. These novel observations suggest that B-DIM could be used as a safe compound to enhance the efficacy of radiotherapy for castrate-resistant PCa.

Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury.

BACKGROUND: We have demonstrated that soy isoflavones radiosensitize cancer cells. Prostate cancer patients receiving radiotherapy (RT) and soy tablets had reduced radiation toxicity to surrounding organs. We have now investigated the combination of soy with RT in lung cancer (NSCLC), for which RT is limited by radiation-induced pneumonitis. METHODS: Human A549 NSCLC cells were injected i.v. in nude mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with left lung RT at 12 Gy and with oral soy treatments at 1mg/day for 30 days. Lung tissues were processed for histology. RESULTS: Compared to lung tumor nodules treated with soy isoflavones or radiation, lung tissues from mice treated with both modalities showed that soy isoflavones augmented radiation-induced destruction of A549 lung tumor nodules leading to small residual tumor nodules containing degenerating tumor cells with large vacuoles. Soy isoflavones decreased the hemorrhages, inflammation and fibrosis caused by radiation in lung tissue, suggesting protection of normal lung tissue. CONCLUSIONS: Soy isoflavones augment destruction of A549 lung tumor nodules by radiation, and also mitigate vascular damage, inflammation and fibrosis caused by radiation injury to normal lung tissue. Soy could be used as a non-toxic complementary approach to improve RT in NSCLC.

A comparison of reconstruction algorithms for C-arm mammography tomosynthesis.

Digital tomosynthesis is an imaging technique to produce a tomographic image from a series of angular digital images in a manner similar to conventional focal plane tomography. Unlike film focal plane tomography, the acquisition of the data in a C-arm geometry causes the image receptor to be positioned at various angles to the reconstruction tomogram. The digital nature of the data allows for input images to be combined into the desired plane with the flexibility of generating tomograms of many separate planes from a single set of input data. Angular datasets were obtained of a low contrast detectability (LCD) phantom and cadaver breast utilizing a Lorad stereotactic biopsy unit with a coupled source and digital detector in a C-arm configuration. Datasets of 9 and 41 low-dose projections were collected over a 30 degrees angular range. Tomographic images were reconstructed using a Backprojection (BP) algorithm, an Iterative Subtraction (IS) algorithm that allows the partial subtraction of out-of-focus planes, and an Algebraic Reconstruction (AR) algorithm. These were compared with single view digital radiographs. The methods' effectiveness at enhancing visibility of an obscured LCD phantom was quantified in terms of the Signal to Noise Ratio (SNR), and Signal to Background Ratio (SBR), all normalized to the metric value for the single projection image. The methods' effectiveness at removing ghosting artifacts in a cadaver breast was quantified in terms of the Artifact Spread Function (ASF). The technology proved effective at partially removing out of focus structures and enhancing SNR and SBR. The normalized SNR was highest at 4.85 for the obscured LCD phantom, using nine projections and IS algorithm. The normalized SBR was highest at 23.2 for the obscured LCD phantom, using 41 projections and an AR algorithm. The highest normalized metric values occurred with the obscured phantom. This supports the assertion that the greatest value of tomosynthesis is in imaging fibroglandular breasts. The ASF performance was best with the AR technique and nine projections.