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PDF file, 40K, Dose given to MCa4 tumors vs HF10 before the radiation. MCa4 tumors of approximately the same size were treated with a range of 60-80 Gy, which is a narrow range around TCD50 value of 69 Gy consistent with the literature (Stone, 1975).

PURPOSE: Preclinical radiation replicating clinical intensity modulated radiation therapy (IMRT) techniques can provide data translatable to clinical practice. For this work, treatment plans were created for oxygen-guided dose-painting in small animals using inverse-planned IMRT. Spatially varying beam intensities were achieved using 3-dimensional (3D)-printed compensators. METHODS AND MATERIALS: Optimized beam fluence from arbitrary gantry angles was determined using a verified model of the XRAD225Cx treatment beam. Compensators were 3D-printed with varied thickness to provide desired attenuation using copper/polylactic-acid. Spatial resolution capabilities were investigated using printed test-patterns. Following American Association of Physicists in Medicine TG119, a 5-beam IMRT plan was created for a miniaturized (~1/8th scale) C-shape target. Electron paramagnetic resonance imaging of murine tumor oxygenation guided simultaneous integrated boost (SIB) plans conformally treating tumor to a base dose (Rx(1)) with boost (Rx(2)) based on tumor oxygenation. The 3D-printed compensator intensity modulation accuracy and precision was evaluated by individually delivering each field to a phantom containing radiochromic film and subsequent per-field gamma analysis. The methodology was validated end-to-end with composite delivery (incorporating 3D-printed tungsten/polylactic-acid beam trimmers to reduce out-of-field leakage) of the oxygen-guided SIB plan to a phantom containing film and subsequent gamma analysis. RESULTS: Resolution test-patterns demonstrate practical printer resolution of ~0.7 mm, corresponding to 1.0 mm bixels at the isocenter. The miniaturized C-shape plan provides planning target volume coverage (V(95%) = 95%) with organ sparing (organs at risk D(max) < 50%). The SIB plan to hypoxic tumor demonstrates the utility of this approach (hypoxic tumor V(95%,Rx2) = 91.6%, normoxic tumor V(95%,Rx1) = 95.7%, normal tissue V(100%,Rx1) = 7.1%). The more challenging SIB plan to boost the normoxic tumor rim achieved normoxic tumor V(95%,Rx2) = 90.9%, hypoxic tumor V(95%,Rx1) = 62.7%, and normal tissue V(100%,Rx2) = 5.3%. Average per-field gamma passing rates using 3%/1.0 mm, 3%/0.7 mm, and 3%/0.5 mm criteria were 98.8% ± 2.8%, 96.6% ± 4.1%, and 90.6% ± 5.9%, respectively. Composite delivery of the hypoxia boost plan and gamma analysis (3%/1 mm) gave passing results of 95.3% and 98.1% for the 2 measured orthogonal dose planes. CONCLUSIONS: This simple and cost-effective approach using 3D-printed compensators for small-animal IMRT provides a methodology enabling preclinical studies that can be readily translated into the clinic. The presented oxygen-guided dose-painting demonstrates that this methodology will facilitate studies driving much needed biologic personalization of radiation therapy for improvements in patient outcomes.

Purpose Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. Methods and materials 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. Results With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. Conclusions More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO2 resolution at low oxygen levels. The difficulty of using mouse models is their small size and that of their tumors. To overcome this we used XRAD225Cx micro-CT/ therapy system and 3D printed conformal blocks. Radiation is delivered first to a uniform 15% tumor control dose for the whole tumor and then a boost dose to either hypoxic tumor regions or equal volumes of well oxygenated tumor. Delivery of the booster dose used a multiple beam angles to deliver radiation beams whose shape conforms to that of all hypoxic regions or fully avoids those regions. To treat/avoid all hypoxic regions we used individual radiation blocks 3D-printed from acrylonitrile butadiene styrene polymer infused with tungsten particles fabricated immediately after imaging to determine regions with pO2 less than 10 torr. Preliminary results demonstrate the efficacy of the radiation treatment with hypoxic boosts with syngeneic FSa fibrosarcoma tumors in the legs of C3H mice.

Purpose X-ray induced luminescence (XIL) is a hybrid X-ray/optical imaging modality that employs nanophosphors that luminescence in response to X-ray irradiation. X-ray-activated phosphorescent nanoparticles have potential applications in radiation therapy as theranostics, nanodosimeters, or radiosensitizers. Extracting clinically relevant information from the luminescent signal requires the development of a robust imaging model that can determine nanophosphor distributions at depth in an optically scattering environment from surface radiance measurements. The applications of XIL in radiotherapy will be limited by the dose-dependent sensitivity at depth in tissue. We propose a novel geometry called selective plane XIL (SPXIL), and apply it to experimental measurements in optical gel phantoms and sensitivity simulations. Methods An imaging model is presented based on the selective plane geometry which can determine the detected diffuse optical signal for a given X-ray dose and nanophosphor distribution at depth in a semi-infinite, optically homogenous material. The surface radiance in the model is calculated using an analytical solution to the extrapolated boundary condition. Y2O3:Eu3+ nanoparticles are synthesized and inserted into various optical phantom in order to measure the luminescent output per unit dose for a given concentration of nanophosphors and calibrate an imaging model for XIL sensitivity simulations. SPXIL imaging with a dual-source optical gel phantom is performed, and an iterative Richardson-Lucy deconvolution using a shifted Poisson noise model is applied to the measurements in order to reconstruct the nanophosphor distribution. Results Nanophosphor characterizations showed a peak emission at 611 nm, a linear luminescent response to tube current and nanoparticle concentration, and a quadratic luminescent response to tube voltage. The luminescent efficiency calculation accomplished with calibrated bioluminescence mouse phantoms determines 1.06 photons were emitted per keV of X-ray radiation absorbed per g/mL of nanophosphor concentration. Sensitivity simulations determined XIL could detect a concentration of 1 mg/mL of nanophosphors with a dose of 1 cGy at a depth ranging from 2 to 4 cm, depending on the optical parameters of the homogeneous diffuse optical environment. The deconvolution applied to the SPXIL measurements could resolve two sources 1 cm apart up to a depth of 1.75 cm in the diffuse phantom. Conclusions We present a novel imaging geometry for XIL in a homogenous, diffuse optical environment. Basic characterization of Y2O3:Eu3+ nanophosphors are presented along with XIL/SPXIL measurements in optical gel phantoms. The diffuse optical imaging model is validated using these measurements and then calibrated in order to execute initial sensitivity simulations for the dose-depth limitations of XIL imaging. The SPXIL imaging model is used to perform a deconvolution on a dual-source phantom, which successfully reconstructs the nanophosphor distributions. This article is protected by copyright. All rights reserved.

PURPOSE Most radiation therapy optimization problems can be formulated as an unconstrained problem and solved efficiently by quasi-Newton methods such as the Limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) algorithm. However, several next generation planning techniques such as total variation regularization- based optimization and MV+kV optimization, involve constrained or mixed-norm optimization, and cannot be solved by quasi-Newton methods. Using standard optimization algorithms on such problems often leads to prohibitively long optimization times and large memory requirements. This work investigates the use of a recently developed proximal operator graph solver (POGS) in solving such radiation therapy optimization problems. METHODS Radiation therapy inverse treatment planning was formulated as a graph form problem, and the proximal operators of POGS for quadratic optimization were derived. POGS was exploited for the first time to impose hard dose constraints along with soft constraints in the objective function. The solver was applied to several clinical treatment sites (TG119, liver, prostate, and head&neck), and the results were compared to the solutions obtained by other commercial and non-commercial optimizers. RESULTS For inverse planning optimization with nonnegativity box constraints on beamlet intensity, the speed of POGS can compete with that of LBFGSB in some situations. For constrained and mixed-norm optimization, POGS is about one or two orders of magnitude faster than the other solvers while requiring less computer memory. CONCLUSIONS POGS was used for solving inverse treatment planning problems involving constrained or mixed-norm formulation on several example sites. This approach was found to improve upon standard solvers in terms of computation speed and memory usage, and is capable of solving traditionally difficult problems, such as total variation regularization-based optimization and combined MV+kV optimization.

Purpose Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity. Methods and Materials Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs. Results Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P =.02), grade 3+ neutropenia (33% vs 8%, P =.04), and grade 2+ thrombocytopenia (32% vs 7%, P =.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 ( P Conclusions Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.

Urinary incontinence is a potential side effect of prostatectomy and intensity modulated radiation therapy (IMRT) for prostate cancer. There are limited data on dosimetric parameters that may predict for poor continence recovery in men who receive postoperative IMRT.Eighty-seven men with nonmetastatic prostate cancer who underwent prostatectomy followed by adjuvant (13%) or salvage (87%) IMRT were identified. The Expanded Prostate Cancer Index composite questionnaire was prospectively collected at baseline, 6 weeks, and 6, 12, 18, 24, 36, and 48 months post-IMRT. Relevant critical structures were contoured and dose-volume metrics collected. The primary endpoint was urinary continence global score. Longitudinal analysis using a generalized estimating equation model was performed.There was no statistically significant change in Expanded Prostate Cancer Index composite urinary continence global scores over time as compared with baseline (all P.05). In univariate analysis, bladder volume receiving 70 Gy (V70 Gy) and penile bulb V70 Gy were associated with urinary continence (odds ratio, 0.82; P.05). In a multivariable model that included body mass index, distance between vesicourethral junction and genitourinary diaphragm, time from surgery, use of antihypertensive medications, age, diabetes, and bladder V70 Gy, only bladder V70 Gy (odds ratio, 0.82; P = .03) was associated with outcome. After 2 years, there was a significant difference in global score for those with V70 Gy42.27 versus ≥42.27 mL (all P.05 at 2 and 3 years post-IMRT).There was no significant change in patient-reported urinary continence scores after postprostatectomy IMRT. Bladder V70 Gy was independently associated with a decrease in urinary continence scores. Further evaluation is necessary to optimize quality of life in these men.

BACKGROUND Patient dose from image guidance in radiotherapy is small compared to the treatment dose. However, the imaging beam is untargeted and deposits dose equally in tumor and healthy tissues. It is desirable to minimize imaging dose while maintaining efficacy. OBJECTIVE Image guidance typically does not require full image quality throughout the patient. Dynamic filtration of the kV beam allows local control of CT image noise for high quality around the target volume and lower quality elsewhere, with substantial dose sparing and reduced scatter fluence on the detector. METHODS The dynamic Intensity-Weighted Region of Interest (dIWROI) technique spatially varies beam intensity during acquisition with copper filter collimation. Fluence is reduced by 95% under the filters with the aperture conformed dynamically to the ROI during cone-beam CT scanning. Preprocessing to account for physical effects of the collimator before reconstruction is described. RESULTS Reconstructions show image quality comparable to a standard scan in the ROI, with higher noise and streak artifacts in the outer region but still adequate quality for patient localization. Monte Carlo modeling shows dose reduction by 10-15% in the ROI due to reduced scatter, and up to 75% outside. CONCLUSIONS The presented technique offers a method to reduce imaging dose by accepting increased image noise outside the ROI, while maintaining full image quality inside the ROI.

Introduction: It has been known for over a century that all living systems develop radiation resistance under hypoxic conditions - low pO2. But giving extra radiation - dose painting - or boosting hypoxic tumors regions has not shown enhanced control in mammalian tumors. Pulse EPR quantitative pO2 values can be tomographically imaged as a magnetic resonance measurement with fixed stepped gradients. If there are distinct hypoxic regions, their images can then be extra radiation dose boosts. An isocentric animal irradiation system allowed conformal boosts to tiny resistant tumor subvolumes with 3D printed tungsten loaded plastic blocks. A randomized trial compared radiation boosts to hypoxic tumor vs well oxygenated tumor to determine hypoxic boost control advantage. Methods: Carcinomas (MCa4) and fibrosarcomas (FSa) in mouse legs with mean volume of 350 μl were treated with an XRAD225Cx animal irradiator to a dose that controlled 15% of tumors (TCD15), determined in separate experiments. Pulse electron paramagnetic resonance (EPR) using Spin Lattice Relaxation (SLR) and a soluble trityl spin probe has been shown to quantitatively image solution and tumor pO2. This and boost treatments were given after EPR pO2 imaging, reconstruction, registration with tumor defining T2 MRI, determination of all tumor hypoxic regions (pO2 ≤10 torr) and 3D printed tungsten loaded plastic aperture fabrication to radiate either well oxygenated or hypoxic tumor regions. Mice were followed for either 180 days (MCa4) or 90 days (FSa) sufficient for 99% of local failures to occur. Treatment of 3D hypoxic volumes was also analyzed for control dependence on surface to volume ratio (SVR). Results: Tumor control was doubled by radiating hypoxic tumor relative to well oxygenated tumor in 48 MCa4 tumors (p=0.013) and 54 FSa tumors (p=0.04). This was the first demonstration in mammalian tumors of an advantage to targeting hypoxic regions in tumors. It provides the first evidence of image based dose painting within the volume of the tumor. For MCa4 tumors, SVR values below median had significant increased survival (p=0.003) while for FSa tumors below median SVR tumors trended to increased survival (p=0.3). Clinical Relevance: Modern radiation delivery used intensity modulated radiation therapy (IMRT) for dose gradients outside the tumor volume to reduce doses to critical structures. Dose within the tumor have strict inhomogeneity limits. Allowance of higher dose variation within the tumor volume allows “hot spots” to resistant tumor volumes, sharper gradients outside the volume to protect critical structures. This will enhance the therapeutic ratio. Citation Format: Howard Halpern, Matthew Maggio, Eugene Barth, Darwin Bodero, Richard C. Miller, Charles A. Pelizzari, Martyna Krzykawska-Serda, Subramanian V. Sundramoorthy, Bulent Aydogan, Ralph R. Weichselbaum, Victor M. Tormyshev, Inna Gertsenshteyn, Boris Epel. Increased tumor control boosting hypoxic regions identified with EPR pO2 imaging in 2 tumor types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2773.

Background Some patients cannot be imaged with cone-beam CT for image-guided radiation therapy because their size, pose, or fixation devices cause collisions with the machine. Objective To investigate imaging trajectories that avoid such collisions by using virtual isocenter and variable magnification during acquisition while yielding comparable image quality. Methods The machine components most likely to collide are the gantry and kV detector. A virtual isocenter trajectory continuously moves the patient during gantry rotation to maintain an increased separation between the two. With dynamic magnification, the kV detector is dynamically moved to increase clearance for an angular range around the potential collision point while acquiring sufficient data to maintain the field-of-view. Both strategies were used independently and jointly with the resultant image quality evaluated against the standard circular acquisition. Results Collision avoiding trajectories show comparable contrast and resolution to standard techniques. For an anthropomorphic phantom, the RMSE is 0.97, and visual image fidelity is >0.96 for all trajectories when compared to a standard circular scan. Conclusions The proposed trajectories avoid machine-patient collisions while providing comparable image quality to the current standard thereby enabling CBCT imaging for patients that could not otherwise be scanned.

Purpose: This work presents a method of collision predictions for external beam radiotherapy using surface imaging. The present methodology focuses on collision prediction during treatment simulation to evaluate the clearance of a patient’s treatment position and allow for its modification if necessary. Methods: A Kinect camera (Microsoft, Redmond, WA) is used to scan the patient and immobilization devices in the treatment position at the simulator. The surface is reconstructed using the skanect software (Occipital, Inc., San Francisco, CA). The treatment isocenter is marked using simulated orthogonal lasers projected on the surface scan. The point cloud of this surface is then shifted to isocenter and converted from Cartesian to cylindrical coordinates. A slab models the treatment couch. A cylinder with a radius equal to the normal distance from isocenter to the collimator plate, and a height defined by the collimator diameter is used to estimate collisions. Points within the cylinder clear through a full gantry rotation with the treatment couch at 0° , while points outside of it collide. The angles of collision are reported. This methodology was experimentally verified using a mannequin positioned in an alpha cradle with both arms up. A planning CT scan of the mannequin was performed, two isocenters were marked in pinnacle, and this information was exported to AlignRT (VisionRT, London, UK)—a surface imaging system for patient positioning. This was used to ensure accurate positioning of the mannequin in the treatment room, when available. Collision calculations were performed for the two treatment isocenters and the results compared to the collisions detected the room. The accuracy of the Kinect-Skanect surface was evaluated by comparing it to the external surface of the planning CT scan. Results: Experimental verification results showed that the predicted angles of collision matched those recorded in the room within 0.5°, in most cases (largest deviation −1.2°). The accuracy study for the Kinect-Skanect surface showed an average discrepancy between the CT external contour and the surface scan of 2.2 mm. Conclusions: This methodology provides fast and reliable collision predictions using surface imaging. The use of the Kinect-Skanect system allows for a comprehensive modeling of the patient topography including all the relevant anatomy and immobilization devices that may lead to collisions. The use of this tool at the treatment simulation stage may allow therapists to evaluate the clearance of a patient’s treatment position and optimize it before the planning CT scan is performed. This can allow for safer treatments for the patients due to better collision predictions and improved clinical workflow by minimizing replanning and resimulations due to unforeseen clearance issues.

Checkpoint blockade immunotherapy relies on energized cytotoxic T cells attacking tumour tissue systemically. However, for many cancers, the reliance on T cell infiltration leads to low response rates. Conversely, radiotherapy has served as a powerful therapy for local tumours over the past 100 years, yet is rarely sufficient to cause systemic tumour rejection. Here, we describe a treatment strategy that combines nanoscale metal–organic framework (nMOF)-enabled radiotherapy–radiodynamic therapy with checkpoint blockade immunotherapy for both local and systemic tumour elimination. In mouse models of breast and colorectal cancer, intratumorally injected nMOFs treated with low doses of X-ray irradiation led to the eradication of local tumours and, when loaded with an inhibitor of the immune checkpoint molecule indoleamine 2,3-dioxygenase, the irradiated nMOFs led to consistent abscopal responses that rejected distal tumours. By combining the advantages of local radiotherapy and systemic tumour rejection via synergistic X-ray-induced in situ vaccination and indoleamine 2,3-dioxygenase inhibition, nMOFs may overcome some of the limitations of checkpoint blockade in cancer treatment.

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO

Modern standards for radiation treatment do not take into account tumor oxygenation for radiation treatment planning. Strong correlation between tumor oxygenation and radiation treatment success suggests that oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. We have developed an OGRT protocol for rodents. Electron paramagnetic resonance (EPR) imaging is used for recording oxygen maps with high spatial resolution and excellent accuracy better than 1 torr. Radiation is delivered with an animal intensity modulated radiation therapy (IMRT) XRAD225Cx micro-CT/ therapy system. The radiation plan is delivered in two steps. First, a uniform 15% tumor control dose (TCD15) is delivered to the whole tumor. In the second step, an additional booster dose amounting to the difference between TCD98 and TCD15 is delivered to radio-resistant, hypoxic tumor regions. Delivery of the booster dose is performed using a multiport conformal beam protocol. For radiation beam shaping we used individual radiation blocks 3D-printed from tungsten infused ABS polymer. Calculation of beam geometry and the production of blocks is performed next to the EPR imager, immediately after oxygen imaging. Preliminary results demonstrate the sub-millimeter precision of the radiation delivery and high dose accuracy. The efficacy of the radiation treatment is currently being tested on syngeneic FSa fibrosarcoma tumors grown in the legs of C3H mice.

This pilot study compared the detectability of internal thermal marks produced with MRI-guided focused ultrasound (MRgFUS) on MRI, computed tomography (CT), ultrasonography (US), and color images from digital scanning. Internal marks made using MRgFUS could potentially guide surgical, biopsy or radiotherapy procedures. New Zealand White rabbits (n = 6) thigh muscle were marked using a Philips MRgFUS system. Before and after sonications, rabbits were imaged using T1- and T2-weighted MRI. Then rabbits were sacrificed and imaging was performed using CT and US. After surgical excision specimens were scanned for color conspicuity analysis. Images were read by a radiologist and quantitative analysis of signal intensity was calculated for marks and normal muscle. Of a total of 19 excised marks, approximately 79%, 63%, and 62% were visible on MRI, CT, and US, respectively. The average maximum temperature elevation in the marks during MRgFUS was 39.7 ± 10.1 °C, and average dose diameter (i.e., the diameter of the area that achieved a thermal dose greater than 240 cumulative equivalent minutes at 43 °C) of the mark at the focal plane was 7.3 ± 2.1 mm. On MRI the average normalized signal intensities were significantly higher in marks compared to normal muscle (p < 0.05). On CT, the marked regions were approximately 10 HU lower than normal muscle (p < 0.05). The results demonstrate that MRgFUS can be used to create internal marks that are visible on MRI, CT and US.

The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinct molecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenic mice containing the iHPV-Luc, K14-CreERtam, and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 and MCM7, two biomarkers associated with HPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques. Cancer Res; 74(7); 2073–81. ©2014 AACR.

Purpose To perform validation of risk predictions for late rectal toxicity (LRT) in prostate cancer obtained using a new approach to synthesize published normal tissue complication data. Methods and Materials A published study survey was performed to identify the dose-response relationships for LRT derived from nonoverlapping patient populations. To avoid mixing models based on different symptoms, the emphasis was placed on rectal bleeding. The selected models were used to compute the risk estimates of grade 2+ and grade 3+ LRT for an independent validation cohort composed of 269 prostate cancer patients with known toxicity outcomes. Risk estimates from single studies were combined to produce consolidated risk estimates. An agreement between the actuarial toxicity incidence 3 years after radiation therapy completion and single-study or consolidated risk estimates was evaluated using the concordance correlation coefficient. Goodness of fit for the consolidated risk estimates was assessed using the Hosmer-Lemeshow test. Results A total of 16 studies of grade 2+ and 5 studies of grade 3+ LRT met the inclusion criteria. The consolidated risk estimates of grade 2+ and 3+ LRT were constructed using 3 studies each. For grade 2+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.537 compared with 0.431 for the best-fit single study. For grade 3+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.477 compared with 0.448 for the best-fit single study. No evidence was found for a lack of fit for the consolidated risk estimates using the Hosmer-Lemeshow test ( P =.531 and P =.397 for grade 2+ and 3+ LRT, respectively). Conclusions In a large cohort of prostate cancer patients, selected sets of consolidated risk estimates were found to be more accurate predictors of LRT than risk estimates derived from any single study.

Purpose To summarize the results of a 4-year period in which endorectal magnetic resonance imaging (MRI) was considered for all men referred for salvage radiation therapy (RT) at a single academic center; to describe the incidence and location of locally recurrent disease in a contemporary cohort of men with biochemical failure after radical prostatectomy (RP), and to identify prognostic variables associated with MRI findings in order to define which patients may have the highest yield of the study. Methods and Materials Between 2007 and 2011, 88 men without clinically palpable disease underwent eMRI for detectable prostate-specific antigen (PSA) after RP. The median interval between RP and eMRI was 32 months (interquartile range, 14-57 months), and the median PSA level was 0.30 ng/mL (interquartile range, 0.19-0.72 ng/mL). Magnetic resonance imaging scans consisting of T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging were evaluated for features consistent with local recurrence. The prostate bed was scored from 0-4, whereby 0 was definitely normal, 1 probably normal, 2 indeterminate, 3 probably abnormal, and 4 definitely abnormal. Local recurrence was defined as having a score of 3-4. Results Local recurrence was identified in 21 men (24%). Abnormalities were best appreciated on T2-weighted axial images (90%) as focal hypointense lesions. Recurrence locations were perianastomotic (67%) or retrovesical (33%). The only risk factor associated with local recurrence was PSA; recurrence was seen in 37% of men with PSA >0.3 ng/mL vs 13% if PSA ≤0.3 ng/mL ( P 3 and was directly associated with PSA ( r =0.5, P =.02). The correlation between MRI-based tumor volume and PSA was even stronger in men with positive margins ( r =0.8, P Conclusions Endorectal MRI can define areas of local recurrence after RP in a minority of men without clinical evidence of disease, with yield related to PSA. Further study is necessary to determine whether eMRI can improve patient selection and success of salvage RT.

In image guided radiation therapy (IGRT), certain patient treatment positions can lead to collisions of the patient with the linac gantry. When such collisions arise, it prevents the gantry from rotating around the patient and acquiring sufficient projection information for current analytic-based reconstruction methods such as FDK. One way to alleviate such a collision would be to move the patient or imaging arms at the offending gantry position changing the magnification. In this work, we investigate if optimization-based reconstruction methods can reconstruct from data acquired from such dynamic-magnification trajectories. Using real data from Varian's TrueBeam 2.0 kV imaging system, we found that these methods can reconstruct from trajectories where different magnifications are used in a single scan. This suggests these optimization-based reconstruction methods have the potential to enable collision avoiding imaging trajectories, improving patient comfort and reducing the costly clinical delays that currently arise from these collisions.

Current strategies to target tumors with nanomedicines rely on passive delivery via the enhanced permeability and retention effect, leveraging the disorganized tumor microvasculature to promote macromolecule extravasation and the reduced lymphatic and venous drainage that favor retention. Nonetheless, FDA approvals and clinical use of nanomedicines have lagged, reflecting failure to display superiority over conventional formulations. Here, we have exploited image-guided X-irradiation to augment nanoparticle accumulation in tumors. A single 5 Gy dose of radiation, below that required to significantly delay tumor growth, can markedly enhance delivery of macromolecules and nanoparticles. The radiation effect was independent of endothelial cell integrity, suggesting a primary role for damage to microvascular pericytes and/or interstitial extracellular matrix. Significantly, radiation-guided delivery potentiated the therapeutic effects of PEGylated liposomal doxorubicin on experimental tumors. Applied to patients, these results suggest repurposing image-guided radiotherapy as a tool to guide cancer nanomedicine delivery, enhancing local control for primary tumors and metastatic disease while limiting systemic toxicity.

Increasing interest in optimization-based reconstruction in research on, and applications of, cone-beam computed tomography (CBCT) exists because it has been shown to have to potential to reduce artifacts observed in reconstructions obtained with the Feldkamp-Davis-Kress (FDK) algorithm (or its variants), which is used extensively for image reconstruction in current CBCT applications. In this work, we carried out a study on optimization-based reconstruction for possible reduction of artifacts in FDK reconstruction specifically from short-scan CBCT data. The investigation includes a set of optimization programs such as the image-total-variation (TV)-constrained data-divergency minimization, data-weighting matrices such as the Parker weighting matrix, and objects of practical interest for demonstrating and assessing the degree of artifact reduction. Results of investigative work reveal that appropriately designed optimization-based reconstruction, including the image-TV-constrained reconstruction, can reduce significant artifacts observed in FDK reconstruction in CBCT with a short-scan configuration.

Kilo-voltage cone-beam computed tomography (CBCT) plays an important role in image guided radiation therapy (IGRT) by providing 3D spatial information of tumor potentially useful for optimizing treatment planning. In current IGRT CBCT system, reconstructed images obtained with analytic algorithms, such as FDK algorithm and its variants, may contain artifacts. In an attempt to compensate for the artifacts, we investigate optimization-based reconstruction algorithms such as the ASD-POCS algorithm for potentially reducing arti- facts in IGRT CBCT images. In this study, using data acquired with a physical phantom and a patient subject, we demonstrate that the ASD-POCS reconstruction can significantly reduce artifacts observed in clinical re- constructions. Moreover, patient images reconstructed by use of the ASD-POCS algorithm indicate a contrast level of soft-tissue improved over that of the clinical reconstruction. We have also performed reconstructions from sparse-view data, and observe that, for current clinical imaging conditions, ASD-POCS reconstructions from data collected at one half of the current clinical projection views appear to show image quality, in terms of spatial and soft-tissue-contrast resolution, higher than that of the corresponding clinical reconstructions.

The outcome of cancer radiation treatment is strongly correlated with tumor oxygenation. The aim of this study is to use oxygen tension distributions in tumors obtained using Electron Paramagnetic Resonance (EPR) imaging to devise better tumor radiation treatment. The proposed radiation plan is delivered in two steps. In the first step, a uniform 50 % tumor control dose (TCD50) is delivered to the whole tumor. For the second step an additional dose boost is delivered to radioresistant, hypoxic tumor regions. FSa fibrosarcomas grown in the gastrocnemius of the legs of C3H mice were used. Oxygen tension images were obtained using a 250 MHz pulse imager and injectable partially deuterated trityl OX63 (OX71) spin probe. Radiation was delivered with a novel animal intensity modulated radiation therapy (IMRT) XRAD225Cx microCT/radiation therapy delivery system. In a simplified scheme for boost dose delivery, the boost area is approximated by a sphere, whose radius and position are determined using an EPR O2 image. The sphere that irradiates the largest fraction of hypoxic voxels in the tumor was chosen using an algorithm based on Receiver Operator Characteristic (ROC) analysis. We used the fraction of irradiated hypoxic volume as the true positive determinant and the fraction of irradiated normoxic volume as the false positive determinant in the terms of that analysis. The most efficient treatment is the one that demonstrates the shortest distance from the ROC curve to the upper left corner of the ROC plot. The boost dose corresponds to the difference between TCD90 and TCD50 values. For the control experiment an identical radiation dose to the normoxic tumor area is delivered.

Purpose: The aim of this study was to quantify the effect of four image registration methods on lung texture features extracted from serial computed tomography(CT) scans obtained from healthy human subjects. Methods: Two chest CT scans acquired at different time points were collected retrospectively for each of 27 patients. Following automated lung segmentation, each follow-up CT scan was registered to the baseline scan using four algorithms: (1) rigid, (2) affine, (3) B-splines deformable, and (4) demons deformable. The registration accuracy for each scan pair was evaluated by measuring the Euclidean distance between 150 identified landmarks. On average, 1432 spatially matched 32 × 32-pixel region-of-interest (ROI) pairs were automatically extracted from each scan pair. First-order, fractal, Fourier, Laws’ filter, and gray-level co-occurrence matrix texture features were calculated in each ROI, for a total of 140 features. Agreement between baseline and follow-up scan ROI feature values was assessed by Bland–Altman analysis for each feature; the range spanned by the 95% limits of agreement of feature value differences was calculated and normalized by the average feature value to obtain the normalized range of agreement (nRoA). Features with small nRoA were considered “registration-stable.” The normalized bias for each feature was calculated from the feature value differences between baseline and follow-up scans averaged across all ROIs in every patient. Because patients had “normal” chest CT scans, minimal change in texture feature values between scan pairs was anticipated, with the expectation of small bias and narrow limits of agreement. Results: Registration with demons reduced the Euclidean distance between landmarks such that only 9% of landmarks were separated by ≥1 mm, compared with rigid (98%), affine (95%), and B-splines (90%). Ninety-nine of the 140 (71%) features analyzed yielded nRoA > 50% for all registration methods, indicating that the majority of feature values were perturbed following registration. Nineteen of the features (14%) had nRoA < 15% following demons registration, indicating relative feature value stability. Student'st-tests showed that the nRoA of these 19 features was significantly larger when rigid, affine, or B-splines registration methods were used compared with demons registration. Demons registration yielded greater normalized bias in feature value change than B-splines registration, though this difference was not significant (p = 0.15). Conclusions: Demons registration provided higher spatial accuracy between matched anatomic landmarks in serial CT scans than rigid, affine, or B-splines algorithms. Texture feature changes calculated in healthy lung tissue from serial CT scans were smaller following demons registration compared with all other algorithms. Though registration altered the values of the majority of texture features, 19 features remained relatively stable after demons registration, indicating their potential for detecting pathologic change in serial CT scans. Combined use of accurate deformable registration using demons and texture analysis may allow for quantitative evaluation of local changes in lung tissue due to disease progression or treatment response.

Purpose To characterize the late genitourinary (GU) and gastrointestinal (GI) toxicity for prostate cancer patients treated with intensity-modulated radiation therapy (IMRT) and propose dose–volume histogram (DVH) guidelines to limit late treatment-related toxicity. Methods and Materials In this study 296 consecutive men were treated with IMRT for adenocarcinoma of the prostate. Most patients received treatment to the prostate with or without proximal seminal vesicles (90%), to a median dose of 76 Gy. Concurrent androgen deprivation therapy was given to 150 men (51%) for a median of 4 months. Late toxicity was defined by Common Toxicity Criteria version 3.0 as greater than 3 months after radiation therapy completion. Four groupings of DVH parameters were defined, based on the percentage of rectal or bladder tissue receiving 70 Gy (V 70 ), 65 Gy (V 65 ), and 40 Gy (V 40 ). These DVH groupings, as well as clinical and treatment characteristics, were correlated to maximal Grade 2+ GU and GI toxicity. Results With a median follow-up of 41 months, the 4-year freedom from maximal Grade 2+ late toxicity was 81% and 91% for GU and GI systems, respectively, and by last follow-up, the rates of Grade 2+ GU and GI toxicity were 9% and 5%, respectively. On multivariate analysis, whole-pelvic IMRT was associated with Grade 2+ GU toxicity and age was associated with Grade 2+ GI toxicity. Freedom from Grade 2+ GI toxicity at 4 years was 100% for men with rectal V 70 ≤10%, V 65 ≤20%, and V 40 ≤40%; 92% for men with rectal V 70 ≤20%, V 65 ≤40%, and V 40 ≤80%; and 85% for men exceeding these criteria ( p = 0.13). These criteria were more highly associated with GI toxicity in men aged ≥70 years ( p = 0.07). No bladder dose–volume relationships were associated with the risk of GU toxicity. Conclusions IMRT is associated with low rates of severe GU or GI toxicity after treatment for prostate cancer. Rectal dose constraints may help limit late GI morbidity.

Flat-panel-detector X-ray cone-beam computed tomography (CBCT) is used in a rapidly increasing host of imaging applications, including image-guided surgery and radiotherapy. The purpose of the work is to investigate and evaluate image reconstruction from data collected at projection views significantly fewer than what is used in current CBCT imaging. Specifically, we carried out imaging experiments by use of a bench-top CBCT system that was designed to mimic imaging conditions in image-guided surgery and radiotherapy; we applied an image reconstruction algorithm based on constrained total-variation (TV)-minimization to data acquired with sparsely sampled view-angles; and we conducted extensive evaluation of algorithm performance. Results of the evaluation studies demonstrate that, depending upon scanning conditions and imaging tasks, algorithms based on constrained TV-minimization can reconstruct images of potential utility from a small fraction of the data used in typical, current CBCT applications. A practical implication of the study is that the optimization of algorithm design and implementation can be exploited for considerably reducing imaging effort and radiation dose in CBCT.

To study the feasibility of using 2-deoxy-D-glucose (2-DG)-labeled gold nanoparticle (AuNP-DG) as a computed tomography (CT) contrast agent with tumor targeting capability through in vitro experiments.Gold nanoparticles (AuNP) were fabricated and were conjugated with 2-deoxy-D-glucose. The human alveolar epithelial cancer cell line, A-549, was chosen for the in vitro cellular uptake assay. Two groups of cell samples were incubated with the AuNP-DG and the unlabeled AuNP, respectively. Following the incubation, the cells were washed with sterile PBS to remove the excess gold nanoparticles and spun to cell pellets using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifugation. The reconstructed CT images were analyzed using a commercial software package.Significant contrast enhancement in the cell samples incubated with the AuNP-DG with respect to the cell samples incubated with the unlabeled AuNP was observed in multiple CT slices.Results from this study demonstrate enhanced uptake of 2-DG-labeled gold nanoparticle by cancer cells in vitro and warrant further experiments to study the exact molecular mechanism by which the AuNP-DG is internalized and retained in the tumor cells.