Enhancing Safety in AI-Driven Cone Beam CT-based Online Adaptive Radiation Therapy: Development and Implementation of an Interdisciplinary Workflow.

Purpose: The emerging online adaptive radiation therapy (OART) treatment strategy based on cone beam computed tomography allows for real-time replanning according to a patient's current anatomy. However, implementing this procedure requires a new approach across the patient's care path and monitoring of the "black box" adaptation process. This study identifies high-risk failure modes (FMs) associated with AI-driven OART and proposes an interdisciplinary workflow to mitigate potential medical errors from highly automated processes, enhance treatment efficiency, and reduce the burden on clinicians. Methods and Materials: An interdisciplinary working group was formed to identify safety concerns in each process step using failure mode and effects analysis (FMEA). Based on the FMEA results, the team designed standardized procedures and safety checklists to prevent errors and ensure successful task completion. The Risk Priority Numbers (RPNs) for the top twenty FMs were calculated before and after implementing the proposed workflow to evaluate its effectiveness. Three hundred seventy-four adaptive sessions across 5 treatment sites were performed, and each session was evaluated for treatment safety and FMEA assessment. Results: The OART workflow has 4 components, each with 4, 8, 13, and 4 sequentially executed tasks and safety checklists. Site-specific template preparation, which includes disease-specific physician directives and Intelligent Optimization Engine template testing, is one of the new procedures introduced. The interdisciplinary workflow significantly reduced the RPNs of the high-risk FMs, with an average decrease of 110 (maximum reduction of 305.5 and minimum reduction of 27.4). Conclusions: This study underscores the importance of addressing high-risk FMs associated with AI-driven OART and emphasizes the significance of safety measures in its implementation. By proposing a structured interdisciplinary workflow and integrated checklists, the study provides valuable insights into ensuring the safe and efficient delivery of OART while facilitating its effective integration into clinical practice.

CT-guided online adaptive stereotactic body radiotherapy for pancreas ductal adenocarcinoma: Dosimetric and initial clinical experience.

Purpose/Objectives: Retrospective analysis suggests that dose escalation to a biologically effective dose of more than 70 Gy may improve overall survival in patients with pancreatic ductal adenocarcinoma (PDAC), but such treatments in practice are limited by proximity of organs at risk (OARs). We hypothesized that CT-guided online adaptive radiotherapy (OART) can account for interfraction movement of OARs and allow for safe delivery of ablative doses. Materials/Methods: This is a single institution retrospective analysis of patients with PDAC treated with OART on the Ethos platform (Varian Medical Systems, a Siemens Healthineers Company, Palo Alto). All patients were treated to 40 Gy in 5 fractions. PTV overlapping with a 5 mm planning risk volume expansion on the stomach, duodenum and bowel received 25 Gy. Initial treatment plans were created conventionally. For each fraction, PTV and OAR volumes were recontoured with AI assistance after initial cone beam CT (CBCT). The adapted plan was calculated, underwent QA, and then compared to the scheduled plan. A second CBCT was obtained prior to delivery of the selected plan. Total treatment time (first CBCT to end of radiation delivery) and active physician time (first to second CBCT) were recorded. PTV_4000 V95 %, PTV_2500 V9 5%, and D0.03 cc to stomach, duodenum and bowel were reported for scheduled (S) and adapted (A) plans. CTCAEv5.0 toxicities were recorded. Statistical analysis was performed using a two-sided T test and α of 0.05. Results: 21 patients with unresectable or locally-recurrent PDAC were analyzed, with a total of 105 fractions. Average total time was 29 min and 16 s (16:36-49:40) and average active physician time was 19:41 min (9:25-39:34). All fractions were treated with adapted plans. 97 % of adapted plans met PTV_4000 V95.0 % >95.0 % coverage goal and 100 % of adapted plans met OAR dose constraints. Median follow up was 6.6 months. Only 1 patient experienced acute grade 3+ toxicity directly attributable to radiation. Only 1 patient experienced late grade 3+ toxicity directly attributable to radiation. Conclusions: Daily CT-based OART was associated with significantly reduced dose OARs while achieving superior PTV coverage. Given the relatively quick total treatment time, radiation delivery was generally well tolerated and easily incorporated into the clinic workflow. Our initial clinical experience demonstrates OART allows for safe dose escalation in the treatment of PDAC.

Adaptive Radiation Therapy: A Review of CT-based Techniques.

Adaptive radiation therapy is a feedback process by which imaging information acquired over the course of treatment, such as changes in patient anatomy, can be used to reoptimize the treatment plan, with the end goal of improving target coverage and reducing treatment toxicity. This review describes different types of adaptive radiation therapy and their clinical implementation with a focus on CT-guided online adaptive radiation therapy. Depending on local anatomic changes and clinical context, different anatomic sites and/or disease stages and presentations benefit from different adaptation strategies. Online adaptive radiation therapy, where images acquired in-room before each fraction are used to adjust the treatment plan while the patient remains on the treatment table, has emerged to address unpredictable anatomic changes between treatment fractions. Online treatment adaptation places unique pressures on the radiation therapy workflow, requiring high-quality daily imaging and rapid recontouring, replanning, plan review, and quality assurance. Generating a new plan with every fraction is resource intensive and time sensitive, emphasizing the need for workflow efficiency and clinical resource allocation. Cone-beam CT is widely used for image-guided radiation therapy, so implementing cone-beam CT-guided online adaptive radiation therapy can be easily integrated into the radiation therapy workflow and potentially allow for rapid imaging and replanning. The major challenge of this approach is the reduced image quality due to poor resolution, scatter, and artifacts. Keywords: Adaptive Radiation Therapy, Cone-Beam CT, Organs at Risk, Oncology © RSNA, 2023.

Breast radiotherapy in the prone position primarily reduces the maximum out-of-field measured dose to the ipsilateral lung.

PURPOSE: To quantify the potential advantages of prone position breast radiotherapy in terms of the radiation exposure to out-of-field organs, particularly, the breast or the lung. Several dosimetric studies have been reported, based on commercial treatment planning software (TPS). These TPS approaches are not, however, adequate for characterizing out-of-field doses. In this work, relevant out-of-field organ doses have been directly measured. METHODS: The authors utilized an adult anthropomorphic phantom to conduct measurements of out-of-field doses in prone and supine position, using 50 Gy prescription dose intensity modulated radiation therapy (IMRT) and 3D-CRT plans. Measurements were made using multiple MOSFET dosimeters in various locations in the ipsilateral lung, the contralateral lung and in the contralateral breast. RESULTS: The closer the organ (or organ segment) was to the treatment volume, the more dose sparing was seen for prone vs supine positioning. Breast radiotherapy in the prone position results in a marked reduction in the dose to the proximal part of the ipsilateral lung, compared with treatment in the conventional supine position. This is true both for 3D-CRT and for IMRT. For IMRT, the maximum measured dose to the lung was reduced from 4 to 1.6 Gy, while for 3D-CRT, the maximum measured lung dose was reduced from 5 to 1.7 Gy. For the proximal part of the ipsilateral lung, as well as for the contralateral lung and the contralateral breast, there is little difference in the measured organ doses whether the treatment is given in the prone or the supine-position. CONCLUSIONS: The decrease in the maximum dose to the proximal part of the ipsilateral lung produced by prone position radiotherapy is of potentially considerable significance. The dose-response relation for radiation-induced lung cancer increases monotonically in the zero to 5-Gy dose range, implying that a major decrease in the maximum lung dose may result in a significant decrease in the radiation-induced lung cancer risk.

Effect of bismuth breast shielding on radiation dose and image quality in coronary CT angiography.

BACKGROUND: Coronary computed tomographic angiography (CCTA) is associated with high radiation dose to the female breasts. Bismuth breast shielding offers the potential to significantly reduce dose to the breasts and nearby organs, but the magnitude of this reduction and its impact on image quality and radiation dose have not been evaluated. METHODS: Radiation doses from CCTA to critical organs were determined using metal-oxide-semiconductor field-effect transistors positioned in a customized anthropomorphic whole-body dosimetry verification phantom. Image noise and signal were measured in regions of interest (ROIs) including the coronary arteries. RESULTS: With bismuth shielding, breast radiation dose was reduced 46%-57% depending on breast size and scanning technique, with more moderate dose reduction to the heart, lungs, and esophagus. However, shielding significantly decreased image signal (by 14.6 HU) and contrast (by 28.4 HU), modestly but significantly increased image noise in ROIs in locations of coronary arteries, and decreased contrast-to-noise ratio by 20.9%. CONCLUSIONS: While bismuth breast shielding can significantly decrease radiation dose to critical organs, it is associated with an increase in image noise, decrease in contrast-to-noise, and changes tissue attenuation characteristics in the location of the coronary arteries.

Dosimetric feasibility of neurovascular bundle-sparing stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer to preserve erectile function.

OBJECTIVE: We aim to test the hypothesis that neurovascular bundle (NVB) displacement by rectal hydrogel spacer combined with NVB delineation as an organ at risk (OAR) is a feasible method for NVB-sparing stereotactic body radiotherapy. METHODS: Thirty-five men with low- and intermediate-risk prostate cancer who underwent rectal hydrogel spacer placement and pre-, post-spacer prostate MRI studies were treated with prostate SBRT (36.25 Gy in five fractions). A prostate radiologist contoured the NVB on both the pre- and post-spacer T2W MRI sequences that were then registered to the CT simulation scan for NVB-sparing radiation treatment planning. Three SBRT treatment plans were developed for each patient: (1) no NVB sparing, (2) NVB-sparing using pre-spacer MRI, and (3) NVB-sparing using post-spacer MRI. NVB dose constraints include maximum dose 36.25 Gy (100%), V34.4 Gy (95% of dose) <60%, V32Gy <70%, V28Gy <90%. RESULTS: Rectal hydrogel spacer placement shifted NVB contours an average of 3.1 ± 3.4 mm away from the prostate, resulting in a 10% decrease in NVB V34.4 Gy in non-NVB-sparing plans (p < 0.01). NVB-sparing treatment planning reduced the NVB V34.4 by 16% without the spacer (p < 0.01) and 25% with spacer (p < 0.001). NVB-sparing did not compromise PTV coverage and OAR endpoints. CONCLUSIONS: NVB-sparing SBRT with rectal hydrogel spacer significantly reduces the volume of NVB treated with high-dose radiation. Rectal spacer contributes to this effect through a dosimetrically meaningful displacement of the NVB that may significantly reduce RiED. These results suggest that NVB-sparing SBRT warrants further clinical evaluation. ADVANCES IN KNOWLEDGE: This is a feasibility study showing that the periprostatic NVBs can be spared high doses of radiation during prostate SBRT using a hydrogel spacer and nerve-sparing treatment planning.

Radiation dose from single-heartbeat coronary CT angiography performed with a 320-detector row volume scanner.

PURPOSE: To determine radiation doses from coronary computed tomographic (CT) angiography performed by using a 320-detector row volume scanner and evaluate how the effective dose depends on scan mode and the calculation method used. MATERIALS AND METHODS: Radiation doses from coronary CT angiography performed by using a volume scanner were determined by using metal-oxide-semiconductor field-effect transistor detectors positioned in an anthropomorphic phantom physically and radiographically simulating a male or female human. Organ and effective doses were determined for six scan modes, including both 64-row helical and 280-row volume scans. Effective doses were compared with estimates based on the method most commonly used in clinical literature: multiplying dose-length product (DLP) by a general conversion coefficient (0.017 or 0.014 mSv.mGy(-1).cm(-1)), determined from Monte Carlo simulations of chest CT by using single-section scanners and previous tissue-weighting factors. RESULTS: Effective dose was reduced by up to 91% with volume scanning relative to helical scanning, with similar image noise. Effective dose, determined by using International Commission on Radiological Protection publication 103 tissue-weighting factors, was 8.2 mSv, using volume scanning with exposure permitting a wide reconstruction window, 5.8 mSv with optimized exposure and 4.4 mSv for optimized 100-kVp scanning. Estimating effective dose with a chest conversion coefficient resulted in a dose as low as 1.8 mSv, substantially underestimating effective dose for both volume and helical coronary CT angiography. CONCLUSION: Volume scanning markedly decreases coronary CT angiography radiation doses compared with those at helical scanning. When conversion coefficients are used to estimate effective dose from DLP, they should be appropriate for the scanner and scan mode used and reflect current tissue-weighting factors. (c) RSNA, 2010.

Frameless Stereotactic Radiosurgery on the Gamma Knife Icon: Early Experience From 100 Patients.

BACKGROUND: The Gamma Knife (GK) Icon (Elekta AB) uses a cone-beam computed tomography (CBCT) scanner and an infrared camera system to support the delivery of frameless stereotactic radiosurgery (SRS). There are limited data on patients treated with frameless GK radiosurgery (GKRS). OBJECTIVE: To describe the early experience, process, technical details, and short-term outcomes with frameless GKRS at our institution. METHODS: We reviewed our patient selection and described the workflow in detail, including image acquisition, treatment planning, mask-based immobilization, stereotactic CBCT localization, registration, treatment, and intrafraction monitoring. Because of the short interval of follow-up, we provide crude rates of local control. RESULTS: Data from 100 patients are reported. Median age is 67 yr old. 56 patients were treated definitively, 21 postoperatively, and 23 had salvage GKRS for recurrence after surgery. Forty-two patients had brain metastases, 26 meningiomas, 16 vestibular schwannomas, 9 high-grade gliomas, and 7 other histologies. Median doses to metastases were 20 Gy in 1 fraction (range: 14-21), 24 Gy in 3 fractions (range: 19.5-27), and 25 Gy in 5 fractions (range: 25-30 Gy). Thirteen patients underwent repeat SRS to the same area. Median treatment time was 17.7 min (range: 5.8-61.7). We found an improvement in our workflow and a greater number of patients eligible for GKRS because of the ability to fractionate treatments. CONCLUSION: We report a large cohort of consecutive patients treated with frameless GKRS. We look forward to studies with longer follow-up to provide valuable data on clinical outcomes and to further our understanding of the radiobiology of hypofractionation in the brain.

Performance of the cone beam computed tomography-based patient positioning system on the Gamma Knife Icon™.

PURPOSE: Cone beam computed tomography (CBCT) imaging has been implemented on the Leksell Gamma Knife® Icon™ for assessing patient positioning in mask-based Gamma Knife radiosurgery. The purpose of this study was to evaluate the performance of the CBCT-based patient positioning system as a tool for frameless Gamma Knife radiosurgery. METHODS: Daily quality assurance (QA) CBCT precision test results from a 12-month period were analyzed for the geometric accuracy and the stability of the imager. The performance of the image acquisition module and the image registration algorithm was evaluated using an anthropomorphic head phantom (CIRS Inc., Norfolk, VA) and a XYZR axis manual positioning stage (TOAUTO Inc., Guangdong, China). The head phantom was fixed on a mask adaptor and manually translated in the X, Y, Z directions or rotated around the X, Y, Z axes in the range of ±10 mm or ±10º. A CBCT scan was performed after each manual position setup followed by an image registration to the reference scan. To assess the overall setup uncertainties in fractionated treatment, two cylindrical Presage phantoms (Heuris Inc., Skillman, NJ) of 15 cm diameter and 10 cm height were irradiated with identical prescription dose and shot placement following standard mask-based treatment workflow according to two different fraction schedules: a single fraction treatment of 7.5 Gy and a 5-fraction treatment with 1.5 Gy per fraction. RESULTS: The averaged vector deviations of the four marks from their preset values are 0.087, 0.085, 0.095, and 0.079 mm from the 212 daily QA tests. The averaged displacements in the X, Y, Z coordinates and the pitch, yaw, roll angles from the image registration tests are 0.23, 0.27, 0.14, 0.32º, 0.19º, 0.31º from the manual setup. The corresponding maximum differences are 0.41, 0.33, 0.29 mm, 0.45º, 0.31º, and 0.43º, respectively. Compared to the treatment plan using the 2% & 1 mm criteria, the averaged 2D Gamma passing rate is 98.25% for the measured dose distribution from the Presage phantom with 1-fraction irradiation and 95.12% for the 5-fraction irradiation. The averaged Gamma passing rates are 99.53% and 98.16% for the 1-fraction and 5-fraction irradiations using the 2% & 2 mm criteria. CONCLUSIONS: The CBCT imager and the image registration algorithm can reproduce phantom position with <0.5 mm/0.5º uncertainty. A systematic contribution from the interfraction phantom repositioning procedure was observed in the Gamma analysis over the irradiated volumes of two end-to-end test phantoms.

Stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer: toxicity profile and early oncologic outcomes.

BACKGROUND: Multiple phase I-II clinical trials have reported on the efficacy and safety of prostate stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer. However, few have reported outcomes for prostate SBRT using periprostatic hydrogel spacer (SpaceOAR; Augmenix). Herein, we report safety and efficacy outcomes from our institutional prostate SBRT experience with SpaceOAR placement. METHODS: Fifty men with low- or intermediate-risk prostate cancer treated at a single institution with linear accelerator-based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) were included. All patients underwent SpaceOAR and fiducial marker placement followed by pre-treatment MRI. Toxicity assessments were conducted at least weekly while on treatment, 1 month after treatment, and every follow-up visit thereafter. Post-treatment PSA measurements were obtained 4 months after SBRT, followed by every 3-6 months thereafter. Acute toxicity was documented per RTOG criteria. RESULTS: Median follow up time was 20 (range 4-44) months. Median PSA at time of diagnosis was 7.4 (2.7-19.5) ng/ml. Eighteen men received 6 months of ADT for unfavorable intermediate risk disease. No PSA failures were recorded. Median PSA was 0.9 ng/mL at 20 months; 0.08 and 1.32 ng/mL in men who did and did not receive ADT, respectively. Mean prostate-rectum separation achieved with SpaceOAR was 9.6 ± 4 mm at the prostate midgland. No grade ≥ 3 GU or GI toxicity was recorded. During treatment, 30% of men developed new grade 2 GU toxicity (urgency or dysuria). These symptoms were present in 30% of men at 1 month and in 12% of men at 1 year post-treatment. During treatment, GI toxicity was limited to grade 1 symptoms (16%), although 4% of men developed grade 2 symptoms during the first 4 weeks after SBRT. All GI symptoms were resolving by the 1 month post-treatment assessment and no acute or late rectal toxicity was reported > 1 month after treatment. CONCLUSIONS: Periprostatic hydrogel placement followed by prostate SBRT resulted in minimal GI toxicity, and favorable early oncologic outcomes. These results indicate that SBRT with periprostatic spacer is a well-tolerated, safe, and convenient treatment option for localized prostate cancer.

A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy.

BACKGROUND: The SpaceOAR hydrogel is employed to limit rectal radiation dose during prostate radiotherapy. We identified a novel parameter - the product of angle θ and hydrogel volume - to quantify hydrogel placement. This parameter predicted rectum dosimetry and acute rectal toxicity in prostate cancer patients treated with stereotactic body radiotherapy to 36.25 Gy in 5 fractions. METHODS: Twenty men with low- and intermediate-risk prostate cancer underwent hydrogel placement from 2015 to 2017. Hydrogel symmetry was assessed on the CT simulation scan in 3 axial slices (midgland, 1 cm above midgland, 1 cm below midgland). Two novel parameters quantifying hydrogel placement - hydrogel volume and angle θ formed by the prostate, hydrogel, and rectum - were measured, and the normalized product of θ and hydrogel volume calculated. These were then correlated with perirectal distance, rectum maximum 1-3 cc point doses (rDmax 1-3 cc), and rectum volumes receiving 80-95% of the prescription dose (rV80-95%). Acute rectal toxicity was recorded per RTOG criteria. RESULTS: In 50% of patients, hydrogel placement was symmetric bilaterally to within 1 cm of midline in all three CT simulation scan axial slices. Lateral hydrogel asymmetry < 2 cm in any one axial slice did not affect rectum dosimetry, but absence of hydrogel in the inferior axial slice resulted in a mean increase of 171 cGy in the rDmax 1 cc (p < 0.005). The perirectal distance measured at prostate midgland, midline (mean 9.1 ± 4.3 mm) correlated strongly with rV95 (R2 0.6, p < 0.001). The mean hydrogel volume and θ were 10.3 ± 4.5 cc and 70 ± 49°, respectively. Perirectal distance, rV95 and rDmax 1 cc correlated with hydrogel angle θ (p < 0.01), and yet more strongly with the novel metric θ*hydrogel volume (p < 0.001). With a median follow up of 14 months, no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved within 1 month of SBRT. Men who had these symptoms had higher rDmax 1 cc and smaller θ*hydrogel volume measurements. CONCLUSIONS: Optimal hydrogel placement occurs at prostate midgland, midline. The novel parameter θ*hydrogel volume describes a large proportion of rectum dosimetric benefit derived from hydrogel placement, and can be used to assess the learning curve phenomenon for hydrogel placement.

Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice.

Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice. Posterior subcapsular cataracts, characteristic of radiation exposure, developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and are the first to demonstrate the impact of multiple haploinsufficiency on radiation effects in an intact mammal. These observations may help explain observed interindividual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut corps. These findings demonstrate that Mrad9 and Atm are important determinants of lens opacification and, given the roles of Atm and Rad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis.

Mice and the A-Bomb: Irradiation Systems for Realistic Exposure Scenarios.

Validation of biodosimetry assays is normally performed with acute exposures to uniform external photon fields. Realistically, exposure to a radiological dispersal device or reactor leak will include exposure to low dose rates and likely exposure to ingested radionuclides. An improvised nuclear device will likely include a significant neutron component in addition to a mixture of high- and low-dose-rate photons and ingested radionuclides. We present here several novel irradiation systems developed at the Center for High Throughput Minimally Invasive Radiation Biodosimetry to provide more realistic exposures for testing of novel biodosimetric assays. These irradiators provide a wide range of dose rates (from Gy/s to Gy/week) as well as mixed neutron/photon fields mimicking an improvised nuclear device.

Radiation Dose-Rate Effects on Gene Expression in a Mouse Biodosimetry Model.

In the event of a nuclear accident or radiological terrorist attack, there will be a pressing need for biodosimetry to triage a large, potentially exposed population and to assign individuals to appropriate treatment. Exposures from fallout are likely, resulting in protracted dose delivery that would, in turn, impact the extent of injury. Biodosimetry approaches that can distinguish such low-dose-rate (LDR) exposures from acute exposures have not yet been developed. In this study, we used the C57BL/6 mouse model in an initial investigation of the impact of low-dose-rate delivery on the transcriptomic response in blood. While a large number of the same genes responded to LDR and acute radiation exposures, for many genes the magnitude of response was lower after LDR exposures. Some genes, however, were differentially expressed (P < 0.001, false discovery rate <5%) in mice exposed to LDR compared with mice exposed to acute radiation. We identified a set of 164 genes that correctly classified 97% of the samples in this experiment as exposed to acute or LDR radiation using a support vector machine algorithm. Gene expression is a promising approach to radiation biodosimetry, enhanced greatly by this first demonstration of its potential for distinguishing between acute and LDR exposures. Further development of this aspect of radiation biodosimetry, either as part of a complete gene expression biodosimetry test or as an adjunct to other methods, could provide vital triage information in a mass radiological casualty event.

Radiation dose-rate effects on gene expression for human biodosimetry.

BACKGROUND: The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose, but a realistic scenario would include exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate damage from low-dose rate exposures and propose appropriate clinical treatment. METHODS: We irradiated human whole blood ex vivo to three doses, 0.56 Gy, 2.23 Gy and 4.45 Gy, using two dose rates: acute, 1.03 Gy/min and a low dose-rate, 3.1 mGy/min. After 24 h, we isolated RNA from blood cells and these were hybridized to Agilent Whole Human genome microarrays. We validated the microarray results using qRT-PCR. RESULTS: Microarray results showed that there were 454 significantly differentially expressed genes after prolonged exposure to all doses. After acute exposure, 598 genes were differentially expressed in response to all doses. Gene ontology terms enriched in both sets of genes were related to immune processes and B-cell mediated immunity. Genes responding to acute exposure were also enriched in functions related to natural killer cell activation and cell-to-cell signaling. As expected, the p53 pathway was found to be significantly enriched at all doses and by both dose-rates of radiation. A support vectors machine classifier was able to distinguish between dose-rates with 100 % accuracy using leave-one-out cross-validation. CONCLUSIONS: In this study we found that low dose-rate exposure can result in distinctive gene expression patterns compared with acute exposures. We were able to successfully distinguish low dose-rate exposed samples from acute dose exposed samples at 24 h, using a gene expression-based classifier. These genes are candidates for further testing as markers to classify exposure based on dose-rate.

Reduction of the secondary neutron dose in passively scattered proton radiotherapy, using an optimized pre-collimator/collimator.

Proton radiotherapy represents a potential major advance in cancer therapy. Most current proton beams are spread out to cover the tumor using passive scattering and collimation, resulting in an extra whole-body high-energy neutron dose, primarily from proton interactions with the final collimator. There is considerable uncertainty as to the carcinogenic potential of low doses of high-energy neutrons, and thus we investigate whether this neutron dose can be significantly reduced without major modifications to passively scattered proton beam lines. Our goal is to optimize the design features of a patient-specific collimator or pre-collimator/collimator assembly. There are a number of often contradictory design features, in terms of geometry and material, involved in an optimal design. For example, plastic or hybrid plastic/metal collimators have a number of advantages. We quantify these design issues, and investigate the practical balances that can be achieved to significantly reduce the neutron dose without major alterations to the beamline design or function. Given that the majority of proton therapy treatments, at least for the next few years, will use passive scattering techniques, reducing the associated neutron-related risks by simple modifications of the collimator assembly design is a desirable goal.

The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene.

The accelerated appearance of ocular cataracts at younger ages has been recorded in both astronauts and airline pilots, and is usually attributed to high-energy heavy ions in galactic cosmic ray radiation. We have previously shown that high-LET 1-GeV/nucleon (56)Fe ions are significantly more effective than X-rays in producing cataracts in mice. We have also shown that mice haploinsufficient for ATM develop cataracts earlier than wild-type animals, when exposed to either low-LET X-rays or high-LET (56)Fe ions. In this paper we derive quantitative estimates for the relative biological effectiveness (RBE) of high energy (56)Fe ions compared with X-rays, both for wild type and for mice haploinsufficient for ATM. There is a clear trend toward higher RBE's in haploinsufficient animals, both for low- and high-grade cataracts. Haploinsufficiency for ATM results in an enhanced sensitivity to X-rays compared with the wild type, and this enhancement appears even larger after exposure to high-LET heavy ions.

Estimated radiation risks potentially associated with full-body CT screening.

PURPOSE: To estimate the radiation-related cancer mortality risks associated with single or repeated full-body computed tomographic (CT) examinations by using standard radiation risk estimation methods. MATERIALS AND METHODS: The estimated dose to the lung or stomach from a single full-body CT examination is 14-21 mGy, which corresponds to a dose region for which there is direct evidence of increased cancer mortality in atomic bomb survivors. Total doses for repeated examinations are correspondingly higher. The authors used estimated cancer risks in a U.S. population derived from atomic bomb-associated cancer mortality data, together with calculated organ doses from a full-body CT examination, to estimate the radiation risks associated with single and multiple full-body CT examinations. RESULTS: A single full-body CT examination in a 45-year-old adult would result in an estimated lifetime attributable cancer mortality risk of around 0.08%, with the 95% credibility limits being a factor of 3.2 in either direction. A 45-year-old adult who plans to undergo annual full-body CT examinations up to age 75 (30 examinations) would accrue an overall estimated lifetime attributable risk of cancer mortality of about 1.9%, with the 95% credibility limits being a factor of 2 in either direction. CONCLUSION: The authors provide estimates of lifetime cancer mortality risks from both single and annual full-body CT examinations. These risk estimates are needed to assess the utility of full-body CT examinations from both an individual and a public health perspective.