Person: Berbeco, Ross
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Berbeco
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Ross
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Berbeco, Ross
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Publication AGuIX nanoparticles as a promising platform for image-guided radiation therapy(Springer Vienna, 2015) Detappe, Alexandre; Kunjachan, Sijumon; Rottmann, Joerg; Robar, James; Tsiamas, Panagiotis; Korideck, Houari; Tillement, Olivier; Berbeco, RossAGuIX are gadolinium-based nanoparticles developed mainly for imaging due to their MR contrast properties. They also have a potential role in radiation therapy as a radiosensitizer. We used MRI to quantify the uptake of AGuIX in pancreatic cancer cells, and TEM for intracellular localization. We measured the radiosensitization of a pancreatic cancer cell line in a low-energy (220 kVp) beam, a standard 6 MV beam (STD) and a flattening filter free 6 MV beam (FFF). We demonstrated that the presence of nanoparticles significantly decreases cell survival when combined with an X-ray beam with a large proportion of low-energy photons (close to the k-edge of the nanoparticles). The concentration of nanoparticles in the cell achieves its highest level after 15 min and then reaches a plateau. The accumulated nanoparticles are mainly localized in the cytoplasm, inside vesicles. We found that the 6 MV FFF beams offer the best trade-off between penetration depth and proportion of low-energy photons. At 10 cm depth, we measured a DEF20 % of 1.30 ± 0.47 for the 6 MV FFF beam, compared to 1.23 ± 0.26 for the 6 MV STD beam. Additional measurements with un-incubated nanoparticles provide evidence that chemical processes might also be contributing to the dose enhancement effect.Publication Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models(2014) Herter-Sprie, Grit S.; Korideck, Houari; Christensen, Camilla L.; Herter, Jan M.; Rhee, Kevin; Berbeco, Ross; Bennett, David G.; Akbay, Esra A.; Kozono, David; Mak, Raymond; Makrigiorgos, Gerassimos; Kimmelman, Alec C.; Wong, Kwok-KinClose resemblance of murine and human trials is essential to achieve the best predictive value of animal-based translational cancer research. Kras-driven genetically engineered mouse models of non-small cell lung cancer faithfully predict the response of human lung cancers to systemic chemotherapy. Due to development of multifocal disease, however, these models have not been usable in studies of outcomes following focal radiotherapy (RT). We report the development of a preclinical platform to deliver state-of-the-art image-guided RT in these models. Presence of a single tumour as usually diagnosed in patients is modelled by confined injection of adenoviral Cre recombinase. Furthermore, three-dimensional conformal planning and state-of-the-art image-guided dose delivery are performed as in humans. We evaluate treatment efficacies of two different radiation regimens and find that Kras-driven tumours can temporarily be stabilized upon RT, whereas additional loss of either Lkb1 or p53 renders these lesions less responsive to RT.Publication Measurement of the interplay effect in lung IMRT treatment using EDR2 films(John Wiley and Sons Inc., 2006) Berbeco, Ross; Pope, Cynthia J.; Jiang, Steve B.Intrafraction organ motion during the dynamic delivery of intensity‐modulated radiation therapy (IMRT) treatment of lung tumors may cause unexpected hot/cold spots within the target volume, due to the interplay effect between tumor motion and multileaf collimator (MLC) leaf motion. In the past, this has been investigated through theoretical analysis, computer simulation, and experimental measurement using an ionization chamber dosimeter. In the work presented here, the interplay effect was studied experimentally in 2D, using Kodak EDR2 films. A five‐field lung IMRT plan was delivered to a solid water phantom with embedded film. The phantom was placed on a motor‐driven platform with a sinusoidal motion to simulate the respiration‐induced tumor motion. The delivery of each field began at one of eight equally spaced initial breathing phases. The dose distribution for each treatment fraction was estimated by combining the dose distributions for all fields with randomly sampled initial breathing phases. The dose variation caused by the interplay effect was estimated by looking at the dose values from 1000 trials of 30 fractions. It was found that, on a day‐to‐day basis, the standard deviation of the dose to a given pixel in the high‐dose region could be as high as 2% to 4% due to the motion interplay effect. After 30 fractions, the standard deviation in the dose to each pixel is reduced to 0.4% to 0.7%. However, compared to the static delivery, the dose distribution from a 30‐fraction case in the presence of motion shows some underdosing in the region of interest. We found that the maximum dose in the target remains within 1% of the maximum dose in the static case, but the minimum dose in the target is most likely to be about 6% lower than the static case. Our results indicate that there can be some underdosing of the tumor due to the interplay effect in lung IMRT delivery over the entire course of a 30‐fraction treatment. PACS number: 87.53.MrPublication Evaluation of the need for simultaneous orthogonal gated setup imaging(John Wiley and Sons Inc., 2010) Berbeco, Ross; Nishioka, Seiko; Shirato, HirokiImage‐guided patient setup for respiratory‐gated radiotherapy often relies on a pair of respiratory‐gated orthogonal radiographs, acquired one after the other. This study quantifies the error due to changes in the internal/external correlation which may affect asynchronous (non‐simultaneous) imaging. The dataset from eight patients includes internal and external coordinates acquired at 30Hz during multi‐fraction SBRT treatments using the Mitsubishi RTRT system coupled with an external surrogate gating device. We performed a computational simulation of the position of an implanted fiducial marker in an asynchronous orthogonal image set. A comparison is made to the reference position, the actual 3D fiducial location at the initial time point, as would be obtainable by simultaneous orthogonal setup imaging at that time point. The time interval between the two simulated radiographic acquisitions was set to a minimum of 30, 60 or 90 seconds, based on our clinical experience. The setup position is derived from a combination of both the initial (AP) and the final (LR) simulated 2D images in the following way: LRsetup=LRinitial,SIsetup=SIinitial+(SIfinal−SIinitial)/2,APsetup=APfinal. The 3D error is then the magnitude of the vector from the initial (reference) position to the setup position. The calculation was done for every exhale phase in the data for which there was another one at least 30, 60 or 90 seconds later, at an amplitude within 0.5 mm from the first. A correlation between the time interval and the 3D error was also sought. The mean 3D error is found to be roughly equivalent for time intervals (tinterval) of 30, 60 and 90 seconds between the orthogonal simulated images (0.8 mm, 0.8 mm, 0.6 mm, respectively). The 3D error is less than 1, 2 and 3 mm for 77%, 89% and 98% of the data points, respectively. The actual time between simulated images turned out to be very close to tinterval, with 90% of the second simulated image acquisitions being completed within 38, 68 and 95 seconds of the first simulated image for tinterval of 30, 60 and 90 seconds, respectively. No correlation was found between the length of the time interval and the 3D error. When acquiring respiratory‐gated radiographs for patient setup, only small errors should be expected if those images are not taken simultaneously. PACS number: 87.55.nePublication Comparison of Texture Features Derived from Static and Respiratory-Gated PET Images in Non-Small Cell Lung Cancer(Public Library of Science, 2014) Yip, Stephen; McCall, Keisha; Aristophanous, Michalis; Chen, Aileen; Aerts, Hugo; Berbeco, RossBackground: PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging. Methods: Twenty-six patients (34 lesions) received 3D and 4D [18F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (δ3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and δ3D-4D were also assessed. Results: 4D-PET increased LRLG ( = 1%–2%, p<0.02), Busyness ( = 7%–19%, p<0.01), and decreased MCC ( = 1%–2%, p<7.5×10−3), Coarseness ( = 5%–10%, p<0.05) and Contrast ( = 4%–6%, p>0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV<5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and δ3D-4D for the texture features. Motion amplitude had moderate impact on δ for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast. Conclusions: Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion.Publication Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial(Ivyspring International Publisher, 2016) Kotb, Shady; Detappe, Alexandre; Lux, François; Appaix, Florence; Barbier, Emmanuel L.; Tran, Vu-Long; Plissonneau, Marie; Gehan, Hélène; Lefranc, Florence; Rodriguez-Lafrasse, Claire; Verry, Camille; Berbeco, Ross; Tillement, Olivier; Sancey, LucieNanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial.Publication Relationship between the Temporal Changes in Positron-Emission-Tomography-Imaging-Based Textural Features and Pathologic Response and Survival in Esophageal Cancer Patients(Frontiers Media S.A., 2016) Yip, Stephen; Coroller, Thibaud; Niu, Nina; Mamon, Harvey; Aerts, Hugo; Berbeco, RossPurpose Although change in standardized uptake value (SUV) measures and PET-based textural features during treatment have shown promise in tumor response prediction, it is unclear which quantitative measure is the most predictive. We compared the relationship between PET-based features and pathologic response and overall survival with the SUV measures in esophageal cancer. Methods: Fifty-four esophageal cancer patients received PET/CT scans before and after chemoradiotherapy. Of these, 45 patients underwent surgery and were classified into complete, partial, and non-responders to the preoperative chemoradiation. SUVmax and SUVmean, two cooccurrence matrix (Entropy and Homogeneity), two run-length matrix (RLM) (high-gray-run emphasis and Short-run high-gray-run emphasis), and two size-zone matrix (high-gray-zone emphasis and short-zone high-gray emphasis) textures were computed. The relationship between the relative difference of each measure at different treatment time points and the pathologic response and overall survival was assessed using the area under the receiver-operating-characteristic curve (AUC) and Kaplan–Meier statistics, respectively. Results: All Textures, except Homogeneity, were better related to pathologic response than SUVmax and SUVmean. Entropy was found to significantly distinguish non-responders from the complete (AUC = 0.79, p = 1.7 × 10−4) and partial (AUC = 0.71, p = 0.01) responders. Non-responders can also be significantly differentiated from partial and complete responders by the change in the run-length and size-zone matrix textures (AUC = 0.71–0.76, p ≤ 0.02). Homogeneity, SUVmax, and SUVmean failed to differentiate between any of the responders (AUC = 0.50–0.57, p ≥ 0.46). However, none of the measures were found to significantly distinguish between complete and partial responders with AUC <0.60 (p = 0.37). Median Entropy and RLM textures significantly discriminated patients with good and poor survival (log-rank p < 0.02), while all other textures and survival were poorly related (log-rank p > 0.25). Conclusion: For the patients studied, temporal changes in Entropy and all RLM were better correlated with pathological response and survival than the SUV measures. The hypothesis that these metrics can be used as clinical predictors of better patient outcomes will be tested in a larger patient dataset in the future.Publication Evaluation of 3D fluoroscopic image generation from a single planar treatment image on patient data with a modified XCAT phantom(IOP Publishing, 2013) Mishra, Pankaj; Li, Ruijiang; James, Sara St; Mak, Raymond; Williams, Christopher; Yue, Yong; Berbeco, Ross; Lewis, JohnAccurate understanding and modeling of respiration-induced uncertainties is essential in image-guided radiotherapy. Explicit modeling of overall lung motion and interaction among different organs promises to be a useful approach. Recently, preliminary studies on 3D fluoroscopic treatment imaging and tumor localization based on Principal Component Analysis (PCA) motion models and cost function optimization have shown encouraging results. However, the performance of this technique for varying breathing parameters and under realistic conditions remains unclear and thus warrants further investigation. In this work, we present a systematic evaluation of a 3D fluoroscopic image generation algorithm via two different approaches. In the first approach the model’s accuracy is tested for changing parameters for sinusoidal breathing. These parameters included changing respiratory motion amplitude, period, and baseline shift. The effects of setup error, imaging noise and different tumor sizes are also examined. In the second approach, we test the model for anthropomorphic images obtained from a modified XCAT phantom. This set of experiments is important as all the underlying breathing parameters are simultaneously tested, as in realistic clinical conditions. Based on our simulation results for more than 250 seconds of breathing data for 8 different lung patients, the overall tumor localization accuracy of the model in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions are 0.1 ± 0.1 mm, 0.5 ± 0.5 mm and 0.8 ± 0.8 mm respectively. 3D tumor centroid localization accuracy is 1.0 ± 0.9 mm.Publication Key clinical beam parameters for nanoparticle-mediated radiation dose amplification(Nature Publishing Group, 2016) Detappe, Alexandre; Kunjachan, Sijumon; Drané, Pascal; Kotb, Shady; Myronakis, Marios; Biancur, Douglas E.; Ireland, Thomas; Wagar, Matthew; Lux, Francois; Tillement, Olivier; Berbeco, RossAs nanoparticle solutions move towards human clinical trials in radiation therapy, the influence of key clinical beam parameters on therapeutic efficacy must be considered. In this study, we have investigated the clinical radiation therapy delivery variables that may significantly affect nanoparticle-mediated radiation dose amplification. We found a benefit for situations which increased the proportion of low energy photons in the incident beam. Most notably, “unflattened” photon beams from a clinical linear accelerator results in improved outcomes relative to conventional “flat” beams. This is measured by significant DNA damage, tumor growth suppression, and overall improvement in survival in a pancreatic tumor model. These results, obtained in a clinical setting, clearly demonstrate the influence and importance of radiation therapy parameters that will impact clinical radiation dose amplification with nanoparticles.Publication Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy(American Chemical Society (ACS), 2015) Kunjachan, Sijumon; Detappe, Alexandre; Kumar, Rajiv; Ireland, Thomas; Cameron, Lisa; Biancur, Douglas; Motto-Ros, Vincent; Sancey, Lucie; Sridhar, Srinivas; Makrigiorgos, Gerassimos; Berbeco, RossMore than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.