I am an Associate Professor of Radiation Oncology with the Medical Center Line at the Stanford University School of Medicine and a medical physicist certified by the Canadian College of Physicists in Medicine. The main focus of my research effort is the the development of novel imaging and image-guidance techniques for cancer related investigations and interventions. As a Medical Physics Faculty at McGill University, I conducted research on free-hand 3D ultrasound-image guidance for radiotherapy simulation and pre-treatment verification. This research resulted in technology licensed and commercialized by Resonant Medical Incorporated, Montreal, CA (currently marketed by Elekta Ltd). Later on as a Senior Physicist with the System Concepts and Innovation team at Siemens Oncology, I contributed to the development of Megavoltage Cone-Beam CT which became a commercial product. At Stanford, I have initiated and led a project on 2D/3D angiography guidance for frameless stereotactic radiosurgery of arteriovenous malformations. This project resulted in clinically used simulation and planning system. I also led a multi-disciplinary research effort (robotics, computer science and medical physics) in collaboration with Philips Ultrasound Investigations on tele-robotic 3D ultrasound for real-time soft tissue guidance concurrent with radiation beam delivery. The expertise and technology that we have developed for 4D ultrasound imaging and analysis have been instrumental in enabling the data acquisition and analysis for an ongoing NIH-R01 funded patient study and other 4D CEUS studies currently ongoing at Stanford.

Academic Appointments

Honors & Awards

  • Member, Canadian College of Physicists in Medicine (CCPM) (2000)

Professional Education

  • M.Sc., Bulgarian National University, Physics (1992)
  • PhD, McGill University, Medical Physics (1998)


  • Schlosser, Hristov, Salisbury. "United States Patent 10,232,194 Manipulation of imaging probe during medical procedure", Leland Stanford Junior University, Mar 19, 2019
  • Maltz and Hristov. "United States Patent 7,697,662 Online verification of radiation field, collimator position and/or leakage", Siemens Medical Solution, Apr 13, 2010
  • Falco, Hristov. "United States Patent 7,634,304 Method and apparatus for lesion localization, definition and verification", McGill University, Dec 9, 2009
  • Hristov, Gangadharan. "United States Patent 7,551,759 Target identification using time-based data sets", Siemens Medical Solutions, Jun 23, 2009
  • Hristov. "United States Patent 7,388,976 Time-based system to link periodic X-ray images", Siemens Medical Solutions, Jun 17, 2008
  • Hristov. "United States Patent 7,366,336 System to link periodic X-ray images", Siemens Medical Solutions, Apr 29, 2008

Current Research and Scholarly Interests

Development and integration of X-ray, MRI and US imaging technologies for radiation therapy guidance; Design of synergistic approaches to radiation therapy delivery; Treatment planning optimization and modeling.

Clinical Trials

  • Feasibility 3D Perfusion Ultrasound for Liver Cancer SABR Planning and Response Evaluation Not Recruiting

    The purpose of this study is to prospectively analyze the value of 3D ultrasound perfusion imaging for treatment planning, the prediction of therapy success, and to monitor the treatment response in patients with a primary or metastatic liver tumor undergoing radiation treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jen-Yeu Wang, 650-723-3110.

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  • Pilot 3D Contrast-Enhanced Ultrasound Imaging to Predict Treatment Response in Liver Metastases Not Recruiting

    Patients are invited to participate in a research study of liver perfusion (how blood flows to the liver over time). Researchers hope to learn whether perfusion characteristics of liver metastases may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment. Patients were selected as a possible participant in this study because they are identified as having liver metastases

    Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.

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2023-24 Courses

Stanford Advisees

All Publications

  • Dynamic Contrast-Enhanced Ultrasound Modeling of an Analog to Pseudo-Diffusivity in Intravoxel Incoherent Motion Magnetic Resonance Imaging IEEE TRANSACTIONS ON MEDICAL IMAGING Hristov, D., Mustonen, L., von Eyben, R., Gotschel, S., Minion, M., El Kaffas, A. 2022; 41 (12): 3824-3834


    Tumor perfusion and vascular properties are important determinants of cancer response to therapy and thus various approaches for imaging perfusion are being explored. In particular, Intravoxel Incoherent Motion (IVIM) MRI has been actively researched as an alternative to Dynamic-Contrast-Enhanced (DCE) CT and DCE-MRI as it offers non-ionizing, non-contrast-based perfusion imaging. However, for repetitive treatment assessment in a short time period, high cost, limited access, and inability to scan at the bedside remain disadvantages of IVIM MRI. We propose an analysis framework that may enable 3D DCE Ultrasound (DCE-US) - low cost, bedside imaging with excellent safety record - as an alternative modality to IVIM MRI for the generation of DCE-US based pseudo-diffusivity maps in acoustically accessible anatomy and tumors. Modelling intravascular contrast propagation as a convective-diffusive process, we reconstruct parametric maps of pseudo-diffusivity by solving a large-scale fully coupled inverse problem without any assumptions regarding local constancy of the reconstructed parameters. In a mouse tumor model, we demonstrate that the 3D DCE-US pseudo-diffusivity is repeatable, sensitive to treatment with an antiangiogenic agent, and moderately correlated to histological measures of perfusion and angiogenesis.

    View details for DOI 10.1109/TMI.2022.3197363

    View details for Web of Science ID 000907324600029

    View details for PubMedID 35939460

  • Dose Prediction for Cervical Cancer Brachytherapy Using 3-D Deep Convolutional Neural Network IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES Ma, M., Kidd, E., Fahimian, B. P., Han, B., Niedermayr, T. R., Hristov, D., Xing, L., Yang, Y. 2022; 6 (2): 214-221
  • Evaluating dosimetric parameters predictive of hematologic toxicity in cervical cancer patients undergoing definitive pelvic chemoradiotherapy. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] Rahimy, E., von Eyben, R., Lewis, J., Hristov, D., Kidd, E. 1800


    PURPOSE: We performed aretrospective study of cervical cancer pelvic radiotherapy plans to explore dosimetric parameters predictive of hematologic toxicity (HT), with specific interest in evaluating metabolic parameters and identifying the best predictive model.METHODS: Active marrow was retroactively contoured as pelvic bone with SUV >mean on 18F-FDG-PET. "Highly active" marrow was contoured as the hottest 10-14% volume of active marrow. Pelvic bone contour was segmented into lumbosacral, iliac crest, and lower pelvis. Predictors of HT were evaluated using logistic regression and repeated measures modeling.RESULTS: One hundred women were evaluated from 2009 to 2020. The plurality/majority had stage IIIC1 disease (38%) and underwent IMRT (88%) with pelvic field alone (72%). The majority received weekly cisplatin (78%), and 82% completed at least five cycles. The most common HT was leukopenia (grade2+: 68%). Predictors of grade2+ and3+ HT were baseline WBC (p <0.001), and 10-and 20-Gy dosimetric parameters to the active marrow, highly active marrow, and pelvic bone. The best predictive model of leukocyte trajectory included baseline WBC (p <0.001), highly active marrow V20 (p <0.001), and interactions of baseline WBC with time (p <0.001) and highly active marrow V20 (p <0.001), such that those with low baseline WBC experienced the greatest impact of highly active marrow V20.CONCLUSION: Baseline WBC was highly predictive of HT; dosimetric predictors included dose to the active marrow, highly active marrow, and pelvic bone, with the greatest impact from V20 to the highly active marrow, particularly in women with low baseline WBC. Future studies should consider incorporating baseline WBC and limiting dose to the most highly active marrow.

    View details for DOI 10.1007/s00066-021-01885-z

    View details for PubMedID 35059758

  • Human-level comparable control volume mapping with a deep unsupervised-learning model for image-guided radiation therapy. Computers in biology and medicine Liang, X., Bassenne, M., Hristov, D. H., Islam, M. T., Zhao, W., Jia, M., Zhang, Z., Gensheimer, M., Beadle, B., Le, Q., Xing, L. 1800; 141: 105139


    PURPOSE: To develop a deep unsupervised learning method with control volume (CV) mapping from patient positioning daily CT (dCT) to planning computed tomography (pCT) for precise patient positioning.METHODS: We propose an unsupervised learning framework, which maps CVs from dCT to pCT to automatically generate the couch shifts, including translation and rotation dimensions. The network inputs are dCT, pCT and CV positions in the pCT. The output is the transformation parameter of the dCT used to setup the head and neck cancer (HNC) patients. The network is trained to maximize image similarity between the CV in the pCT and the CV in the dCT. A total of 554 CT scans from 158 HNC patients were used for the evaluation of the proposed model. At different points in time, each patient had many CT scans. Couch shifts are calculated for the testing by averaging the translation and rotation from the CVs. The ground-truth of the shifts come from bone landmarks determined by an experienced radiation oncologist.RESULTS: The system positioning errors of translation and rotation are less than 0.47mm and 0.17°, respectively. The random positioning errors of translation and rotation are less than 1.13mm and 0.29°, respectively. The proposed method enhanced the proportion of cases registered within a preset tolerance (2.0mm/1.0°) from 66.67% to 90.91% as compared to standard registrations.CONCLUSIONS: We proposed a deep unsupervised learning architecture for patient positioning with inclusion of CVs mapping, which weights the CVs regions differently to mitigate any potential adverse influence of image artifacts on the registration. Our experimental results show that the proposed method achieved efficient and effective HNC patient positioning.

    View details for DOI 10.1016/j.compbiomed.2021.105139

    View details for PubMedID 34942395

  • Technical Note: Extended field-of-view (FOV) MRI distortion determination through multi-positional phantom imaging. Journal of applied clinical medical physics Schuler, E., Mallozzi, R., Levy, J., Hristov, D. 2020


    Comprehensive characterization of geometric distortions for MRI simulators and MRI-guided treatment delivery systems is typically performed with large phantoms that are costly and unwieldy to handle. Here we propose an easily implementable methodology for MR distortion determination of the entire imaging space of the scanner through the use of a compact commercially available distortion phantom. The MagphanRT phantom was scanned at several locations within a MR scanner. From each scan, an approximate location of the phantom was determined from a subset of the fiducial spheres. The fiducial displacements were determined, and a displacement field was fitted to the displacement data using the entire multi-scan data set. An orthogonal polynomial expansion fitting function was used that had been augmented to include independent rigid-body transformations for each scan. The rigid-body portions of the displacement field were thereafter discarded, and the resultant fit then represented the distortion field. Multi-positional scans of the phantom were used successfully to determine the distortion field with extended coverage. A single scan of the phantom covered 20cm in its smallest dimension. By stitching together overlapping scans we extended the distortion measurements to 30cm. No information about the absolute location or orientation of each scan was required. The method, termed the Multi-Scan Expansion (MSE) method, can be easily applied for larger field-of-views (FOVs) by using a combination of larger phantom displacements and more scans. The implementation of the MSE method allows for distortion determination beyond the physical limitations of the phantom. The method is scalable to the user's needs and does not require any specialized equipment. This approach could open up for easier determination of the distortion magnitude at distances further from the scanner's isocenter. This is especially important in the newly proposed methodologies of MR-only simulation in RT and in adaptive replanning in MR linac systems.

    View details for DOI 10.1002/acm2.13065

    View details for PubMedID 33073909

  • Increased local tumor control through nanoparticle-mediated, radiation-triggered release of nitrite, an important precursor for reactive nitrogen species. Physics in medicine and biology Kim, A. S., Melemenidis, S., Gustavsson, A. K., Abid, D., Wu, Y., Liu, F., Hristov, D., Schuler, E. 2020


    The efficacy of dose-enhancing gold nanoparticles (AuNPs) is negatively impacted by low tumor uptake, low cell membrane penetration, limited diffusion distance, and short lifetime of radiation-induced secondary particles. To overcome these limitations, we have developed a novel AuNP system capable of radiation-triggered release of nitrite, a precursor of reactive nitrogen species (RNS), and report here on the in vivo characterization of this system. AuNPs were functionalized through PEGylation, cell-penetrating peptides (CPP; AuNP@CPP), and nitroimidazole (nIm; AuNP@nIm-CPP). Mice with subcutaneous 4T1 tumors received either AuNP@nIm-CPP or AuNP@CPP intraperitoneally. Tumor and normal tissue uptake were evaluated 24 hours post AuNP administration. A separate cohort of mice was injected and irradiated to a single-fraction dose of 18Gy in a 225 kVp small animal irradiator 24 hours post NP administration. The mice were followed for two weeks to evaluate tumor response. The mean physical and hydrodynamic size of both NP systems were 5nm and 13nm, respectively. NP nIm-loading of 1wt% was determined. Tumor accumulation of AuNP@nIm-CPP was significantly lower than that of AuNP@CPP (0.2% vs 1.2%, respectively). In contrast, AuNP@nIm-CPP showed higher accumulation compared to AuNP@CPP in liver (16.5% vs 6.6%, respectively) and spleen (10.8% vs 3.1%, respectively). With respect to tumor response, no differential response was found between non-irradiated mice receiving either saline or AuNP@nIm-CPP alone. The combination of AuNP@CPP+radiation showed no differential response from radiation alone. In contrast, a significant delay in tumor regrowth was observed in mice receiving AuNP@nIm-CPP+radiation compared to radiation alone. AuNP functionalized with both CPP and nIm exhibited an order of magnitude less tumor accumulation compared to the NP system without nIm yet resulted in a significantly higher therapeutic response. Our data suggest that by improving the biokinetics of AuNP@nIm-CPP, this novel NP system could be a promising radiosensitizer for enhanced therapeutic response following radiation therapy.

    View details for DOI 10.1088/1361-6560/abaa27

    View details for PubMedID 32721936

  • Parametric Response Mapping of Co-registered Positron Emission Tomography and Dynamic Contrast Enhanced Computed Tomography to Identify Radio-resistant Sub-volumes in Locally Advanced Cervical Cancer. International journal of radiation oncology, biology, physics Capaldi, D. P., Hristov, D. H., Kidd, E. A. 2020


    PURPOSE: To identify sub-volumes that may predict treatment response to definitive concurrent chemoradiation therapy (CCRT) using parametric-response-mapping (PRM) of co-registered positron-emission-tomography (PET) and dynamic-contrast-enhanced (DCE) computed-tomography (CT) in locally advanced cervical carcinoma.METHODS AND MATERIALS: Pre- and mid-treatment (after 23±4days of CCRT) DCE CT and PET imaging were performed on 21 cervical cancer patients who were enrolled in a pilot study to evaluate the prognostic-value of CT perfusion for primary cervical cancer (NCT01805141). Three-dimensional co-registered maps of PET/CT standardized-uptake-value (SUV) and DCE CT blood-flow (BF) were generated. PRM was performed using voxel-wise joint histogram analysis to classify voxels within the tumor as highly-metabolic and perfused (SUVhiBFhi), highly-metabolic and hypoxic (SUVhiBFlo), low-metabolically active and hypoxic (SUVloBFlo), or low-metabolically active and perfused (SUVloBFhi) tissue based on thresholds determined from population means of pre-treatment PET SUV and DCE CT BF. Relationships between baseline pre-treatment imaging metrics and relative changes in metabolic-tumor-volume (DeltaMTV), calculated from pre- and during-treatment imaging, were determined using univariable and multivariable linear regression models.RESULTS: The relative volume of three PRM sub-volumes significantly changed during treatment (SUVhiBFhi: p=.04; SUVhiBFlo: p=.0008; SUVloBFhi: p=.02), while SUVloBFlo did not (p=.9). Pre-treatment PET SUVmax (r=-.58,p=.006), PET SUVmean (rho=-.59,p=.005), DCE CT BFmean (r=-.50,p=.02), tumor-volume (rho=-.65,p=.001) and PRM SUVhiBFhi (rho=-.59,p=.004) were negatively correlated with DeltaMTV, while PRM SUVloBFlo was positively-related with DeltaMTV (r=.77,p<.0001). In a multivariable model that predicted DeltaMTV, PRM SUVloBFlo, which combines both PET/CT and DCE CT, was the only significant variable (beta=1.825,p=.03), over both imaging modalities independently.CONCLUSIONS: PRM was applied in locally advanced cervical carcinoma treated definitively with chemoradiation and radioresistant sub-volumes were identified which correlated with changes in MTV and predict treatment-response. Identification of these sub-volumes may assist in clinical decision-making to tailor therapies, such as brachytherapy, in an effort to improve patient outcomes.

    View details for DOI 10.1016/j.ijrobp.2020.03.023

    View details for PubMedID 32251757

  • Spatial Characterization of Tumor Perfusion Properties from 3D DCE-US Perfusion Maps are Early Predictors of Cancer Treatment Response. Scientific reports El Kaffas, A. n., Hoogi, A. n., Zhou, J. n., Durot, I. n., Wang, H. n., Rosenberg, J. n., Tseng, A. n., Sagreiya, H. n., Akhbardeh, A. n., Rubin, D. L., Kamaya, A. n., Hristov, D. n., Willmann, J. K. 2020; 10 (1): 6996


    There is a need for noninvasive repeatable biomarkers to detect early cancer treatment response and spare non-responders unnecessary morbidities and costs. Here, we introduce three-dimensional (3D) dynamic contrast enhanced ultrasound (DCE-US) perfusion map characterization as inexpensive, bedside and longitudinal indicator of tumor perfusion for prediction of vascular changes and therapy response. More specifically, we developed computational tools to generate perfusion maps in 3D of tumor blood flow, and identified repeatable quantitative features to use in machine-learning models to capture subtle multi-parametric perfusion properties, including heterogeneity. Models were developed and trained in mice data and tested in a separate mouse cohort, as well as early validation clinical data consisting of patients receiving therapy for liver metastases. Models had excellent (ROC-AUC > 0.9) prediction of response in pre-clinical data, as well as proof-of-concept clinical data. Significant correlations with histological assessments of tumor vasculature were noted (Spearman R > 0.70) in pre-clinical data. Our approach can identify responders based on early perfusion changes, using perfusion properties correlated to gold-standard vascular properties.

    View details for DOI 10.1038/s41598-020-63810-1

    View details for PubMedID 32332790

    View details for PubMedCentralID PMC7181711

  • Feasibility of Image Registration for Ultrasound-Guided Prostate Radiotherapy Based on Similarity Measurement by a Convolutional Neural Network. Technology in cancer research & treatment Zhu, N., Najafi, M., Han, B., Hancock, S., Hristov, D. 2019; 18: 1533033818821964


    PURPOSE:: Registration of 3-dimensional ultrasound images poses a challenge for ultrasound-guided radiation therapy of the prostate since ultrasound image content changes significantly with anatomic motion and ultrasound probe position. The purpose of this work is to investigate the feasibility of using a pretrained deep convolutional neural network for similarity measurement in image registration of 3-dimensional transperineal ultrasound prostate images.METHODS:: We propose convolutional neural network-based registration that maximizes a similarity score between 2 identical in size 3-dimensional regions of interest: one encompassing the prostate within a simulation (reference) 3-dimensional ultrasound image and another that sweeps different spatial locations around the expected prostate position within a pretreatment 3-dimensional ultrasound image. The similarity score is calculated by (1) extracting pairs of corresponding 2-dimensional slices (patches) from the regions of interest, (2) providing these pairs as an input to a pretrained convolutional neural network which assigns a similarity score to each pair, and (3) calculating an overall similarity by summing all pairwise scores. The convolutional neural network method was evaluated against ground truth registrations determined by matching implanted fiducial markers visualized in a pretreatment orthogonal pair of x-ray images. The convolutional neural network method was further compared to manual registration and a standard commonly used intensity-based automatic registration approach based on advanced normalized correlation.RESULTS:: For 83 image pairs from 5 patients, convolutional neural network registration errors were smaller than 5 mm in 81% of the cases. In comparison, manual registration errors were smaller than 5 mm in 61% of the cases and advanced normalized correlation registration errors were smaller than 5 mm only in 25% of the cases.CONCLUSION:: Convolutional neural network evaluation against manual registration and an advanced normalized correlation -based registration demonstrated better accuracy and reliability of the convolutional neural network. This suggests that with training on a large data set of transperineal ultrasound prostate images, the convolutional neural network method has potential for robust ultrasound-to-ultrasound registration.

    View details for PubMedID 30803364

  • Evaluation of transperineal ultrasound imaging as a potential solution for target tracking during hypofractionated radiotherapy for prostate cancer. Radiation oncology (London, England) Han, B., Najafi, M., Cooper, D. T., Lachaine, M., von Eyben, R., Hancock, S., Hristov, D. 2018; 13 (1): 151


    BACKGROUND: Emerging hypofractionated prostate radiotherapy regimens require solutions for accurate target tracking during beam delivery. The goal of this study is to evaluate the performance of the Clarity ultrasound monitoring system for prostate motion tracking.METHODS: Five prostate patients underwent continuous perineum ultrasound imaging during their daily treatments. Initial absolute 3D positions of fiducials implanted in the prostate were estimated from the KV images. Fiducial positions in MV images acquired during beam delivery were compared with predicted positions based on Clarity 3D tracking. The uncertainty in the comparison results was evaluated in a phantom validation study.RESULTS: Continuous real-time ultrasound motion tracking was recorded in 5 patients and 167 fractions for overall of 39.7h. Phantom validation of the proposed procedure demonstrated that predicted and observed fiducial positions agree within 1.1mm. In patients agreement between predicted and actual fiducial positions varied between 1.3mm and 3.3mm. On average ultrasound tracking reduced the maximum localization error in patients by 20% on average. With the motion corrected, the duration prostate beyond 1mm from its initial treatment position can be reduced from 37 to 22% of the total treatment time.CONCLUSION: Real-time ultrasound tracking reduces uncertainty in prostate position due to intra-fractional motion.TRIAL REGISTRATION: IRB Protocol #27372 . Date of registration of trial: 12/17/2013.

    View details for PubMedID 30126434

  • Pilot study of combined FDG-PET and dynamic contrast-enhanced CT of locally advanced cervical carcinoma before and during concurrent chemoradiotherapy suggests association between changes in tumor blood volume and treatment response. Cancer medicine Banks, T. I., von Eyben, R., Hristov, D., Kidd, E. A. 2018


    Modern PET/CT radiotherapy simulators offer FDG-PET and dynamic contrast-enhanced (DCE) CT imaging for combined volumetric assessment of tumor metabolism and perfusion. However, the clinical utility of such assessment has not been clearly defined. Thus, in a prospective longitudinal study of primary cervical tumors treated with concurrent chemoradiotherapy (CCRT) we evaluated: (1) whether PET and perfusion parameters correlate or provide complementary information; (2) what imaging changes occur during CCRT; and (3) whether any parameters are predictive of treatment response as assessed by PET/CT 3months posttherapy. FDG-PET/CT and DCE-CT scans were performed on 21 patients prior to and during CCRT. Coregistered volumetric parametric maps of standardized uptake value (SUV) measures and perfusion parameters blood flow (BF), blood volume (BV), and permeability were generated. Summary statistics for these parameters and their changes were calculated within the metabolic tumor volume (MTV). Correlations between SUV and BF/BV/permeability on local and global bases were assessed with Pearson's coefficient r. MTV, maximum SUV, and mean SUV decreased significantly between the pre- and during-treatment time points, while mean BV and permeability increased significantly. Global correlations between mean BF/BV/permeability and mean SUV values (-.15

    View details for PubMedID 29963760

  • Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging ANGIOGENESIS Zhou, J., Zhang, H., Wang, H., Lutz, A. M., El Kaffas, A., Tian, L., Hristov, D., Willmann, J. K. 2017; 20 (4): 547–55


    Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment (P = 0.005), but not in CT26 tumors (P > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors (P < 0.001), but not in treated versus control CT26 tumors (P = 0.796). Early decrease in both PE and AUC by 45-50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.

    View details for PubMedID 28721500

    View details for PubMedCentralID PMC5660665

  • X-Ray responsive nanoparticles with triggered release of nitrite, a precursor of reactive nitrogen species, for enhanced cancer radiosensitization NANOSCALE Liu, F., Lou, J., Hristov, D. 2017; 9 (38): 14627–34


    Remotely and locally triggered release of therapeutic species by X-ray irradiation is highly desired to enhance the efficacy of radiotherapy. However, the development of such X-ray responsive nanosystems remains a challenge, especially in response to high energy clinically relevant X-ray radiation. Herein, we report novel nitroimidazole ligated gold nanoparticles (AuNPs) that synergistically function to release nitrite, an important precursor for nitric oxide and reactive nitrogen species that sensitize cancer cells, upon radiation with clinically used 6 MeV X-rays, while no release was detected without radiation. These functional AuNPs were prepared with surface-grafted nitroimidazole as the nitrite-releasing agent, cell-penetrating peptide (CPP) to induce nucleus localization, and poly(ethylene glycol) for water solubility. In vitro radiotherapy using such nanoparticles showed enhanced sensitivity of hypoxic cancer cells to X-ray radiation, presumably due to the generation of both reactive oxygen and nitrogen species. The dose modifying factor (DMF) was found to be 0.71 for the dual-functionalized nanoparticle, which indicates that significant lower X-ray doses are required to achieve the same therapeutic effects. Thus, X-ray triggered nitrite release from gold-nitroimidazole nanosystems offers a novel strategy to sensitize cancer cells for improved radiotherapy.

    View details for PubMedID 28936509

  • Molecular Contrast-Enhanced Ultrasound Imaging of Radiation-Induced P-Selectin Expression in Healthy Mice Colon. International journal of radiation oncology, biology, physics El Kaffas, A., Smith, K., Pradhan, P., Machtaler, S., Wang, H., von Eyben, R., Willmann, J. K., Hristov, D. 2017; 97 (3): 581-585


    To evaluate the feasibility of using molecular contrast-enhanced ultrasound (mCEUS) to image radiation (XRT)-induced expression of cell adhesion molecules that mediate inflammatory response to XRT in healthy mouse colon tissue.The colons of male BALB/c mice (aged 6-8 weeks, n=9) were irradiated with 14 Gy using a Kimtron IC-225 x-ray irradiator operating at 225 kV/13.0 mA at a dose rate of 0.985 Gy/min. The head and thorax regions were shielded during irradiation. A second control cohort of mice was left untreated (n=6). Molecular CEUS was carried out before and 24 hours after irradiation using a VEVO2100 system and MS250 21-MHz center frequency transducer. Each imaging session comprised mCEUS imaging with P-selectin targeted microbubbles and control microbubbles targeted with an isotype control IgG. Quantification of mCEUS was carried out by measuring the differential targeted enhancement (dTE) parameter. The perfusion parameters peak enhancement and area under the curve were also extracted from the initial injection bolus. Animals were sacrificed at 24 hours and the colon was resected for immunohistochemistry analysis (P-selectin/CD31-stained vessel).For P-selectin targeted microbubble, a significant increase (40 a.u.; P=.013) in dTE (P-dTE) was observed in irradiated mice over 24 hours. In contrast, a nonsignificant change in P-selectin dTE was observed in control mice. For control microbubbles, no significant difference in the IgG dTE parameter was noted in treated and control animals over 24 hours. A nonsignificant increase in the peak enhancement and area under the curve perfusion parameters associated with blood volume was noted in animals treated with radiation. Quantitative histology indicated significantly elevated P-selectin expression per blood vessel (36% in treated; 14% in control).Our results confirm the feasibility of using mCEUS for imaging of XRT-induced expression of P-selectin as a potential approach to monitoring healthy tissue inflammatory damage during radiation therapy.

    View details for DOI 10.1016/j.ijrobp.2016.10.037

    View details for PubMedID 28126307

  • Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. Radiology Wang, H., Lutz, A. M., Hristov, D., Tian, L., Willmann, J. K. 2017; 282 (2): 443-452


    Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. (©) RSNA, 2016 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2016160032

    View details for PubMedID 27490690

  • Intrafractional Tracking Accuracy of a Transperineal Ultrasound Image Guidance System for Prostate Radiotherapy Technology in Cancer Research & Treatment Yu, A. S., Najafi, M., Hristov, D. H., Phillips, T. 2017; 16 (6): 1067-1078


    The aim of this study is to evaluate the tracking accuracy of a commercial ultrasound system under relevant treatment conditions and demonstrate its clinical utility for detecting significant treatment deviations arising from inadvertent intrafractional target motion.A multimodality male pelvic phantom was used to simulate prostate image-guided radiotherapy with the system under evaluation. Target motion was simulated by placing the phantom on a motion platform. The tracking accuracy of the ultrasound system was evaluated using an independent optical tracking system under the conditions of beam-on, beam-off, poor image quality with an acoustic shadow introduced, and different phantom motion cycles. The time delay between the ultrasound-detected and actual phantom motion was investigated. A clinical case example of prostate treatment is presented as a demonstration of the utility of the system in practice.Time delay between the motion phantom and ultrasound tracking system is 223 ± 45.2 milliseconds including video and optical tracking system frame rates. The tracking accuracy and precision were better with a longer period. The precision of ultrasound tracking performance in the axial (superior-inferior) direction was better than that in the lateral (left-right) direction (root mean square errors are 0.18 and 0.25 mm, respectively). The accuracy of ultrasound tracking performance in the lateral direction was better than that in the axial direction (the mean position errors are 0.23 and 0.45 mm, respectively). Interference by radiation and image quality do not affect tracking ability significantly. Further, utilizing the tracking system as part of a clinical study for prostate treatment further verified the accuracy and clinical appropriateness.It is feasible to use transperineal ultrasound daily to monitor prostate motion during treatment. Our results verify the accuracy and precision of an ultrasound system under typical external beam treatment conditions and further demonstrate that the tracking system was able to identify important prostate shifts in a clinical case.

    View details for DOI 10.1177/1533034617728643

    View details for PubMedCentralID PMC5762073

  • Quantitative Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging: First-In-Human Pilot Study in Patients with Liver Metastases THERANOSTICS El Kaffas, A., Sigrist, R., Fisher, G., Bachawal, S., Liau, J., Wang, H., Karanany, A., Durot, I., Rosenberg, J., Hristov, D., Willmann, J. K. 2017; 7 (15): 3745–58


    Purpose: To perform a clinical assessment of quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) feasibility and repeatability in patients with liver metastasis, and to evaluate the extent of quantitative perfusion parameter sampling errors in 2D compared to 3D DCE-US imaging. Materials and Methods: Twenty consecutive 3D DCE-US scans of liver metastases were performed in 11 patients (45% women; mean age, 54.5 years; range, 48-60 years; 55% men; mean age, 57.6 years; range, 47-68 years). Pairs of repeated disruption-replenishment and bolus DCE-US images were acquired to determine repeatability of parameters. Disruption-replenishment was carried out by infusing 0.9 mL of microbubbles (Definity; Latheus Medical Imaging) diluted in 35.1 mL of saline over 8 min. Bolus consisted of intravenous injection of 0.2 mL microbubbles. Volumes-of-interest (VOI) and regions-or-interest (ROI) were segmented by two different readers in images to extract 3D and 2D perfusion parameters, respectively. Disruption-replenishment parameters were: relative blood volume (rBV), relative blood flow (rBF). Bolus parameters included: time-to-peak (TP), peak enhancement (PE), area-under-the-curve (AUC), and mean-transit-time (MTT). Results: Clinical feasibility and repeatability of 3D DCE-US using both the destruction-replenishment and bolus technique was demonstrated. The repeatability of 3D measurements between pairs of repeated acquisitions was assessed with the concordance correlation coefficient (CCC), and found to be excellent for all parameters (CCC > 0.80), except for the TP (0.74) and MTT (0.30) parameters. The CCC between readers was found to be excellent (CCC > 0.80) for all parameters except for TP (0.71) and MTT (0.52). There was a large Coefficient of Variation (COV) in intra-tumor measurements for 2D parameters (0.18-0.52). Same-tumor measurements made in 3D were significantly different (P = 0.001) than measurements made in 2D; a percent difference of up to 86% was observed between measurements made in 2D compared to 3D in the same tumor. Conclusions: 3D DCE-US imaging of liver metastases with a matrix array transducer is feasible and repeatable in the clinic. Results support 3D instead of 2D DCE US imaging to minimize sampling errors due to tumor heterogeneity.

    View details for PubMedID 29109773

  • Robotic intrafractional US guidance for liver SABR: System design, beam avoidance, and clinical imaging. Medical physics Schlosser, J., Gong, R. H., Bruder, R., Schweikard, A., Jang, S., Henrie, J., Kamaya, A., Koong, A., Chang, D. T., Hristov, D. 2016; 43 (11): 5951-?


    To present a system for robotic 4D ultrasound (US) imaging concurrent with radiotherapy beam delivery and estimate the proportion of liver stereotactic ablative body radiotherapy (SABR) cases in which robotic US image guidance can be deployed without interfering with clinically used VMAT beam configurations.The image guidance hardware comprises a 4D US machine, an optical tracking system for measuring US probe pose, and a custom-designed robot for acquiring hands-free US volumes. In software, a simulation environment incorporating the LINAC, couch, planning CT, and robotic US guidance hardware was developed. Placement of the robotic US hardware was guided by a target visibility map rendered on the CT surface by using the planning CT to simulate US propagation. The visibility map was validated in a prostate phantom and evaluated in patients by capturing live US from imaging positions suggested by the visibility map. In 20 liver SABR patients treated with VMAT, the simulation environment was used to virtually place the robotic hardware and US probe. Imaging targets were either planning target volumes (PTVs, range 5.9-679.5 ml) or gross tumor volumes (GTVs, range 0.9-343.4 ml). Presence or absence of mechanical interference with LINAC, couch, and patient body as well as interferences with treated beams was recorded.For PTV targets, robotic US guidance without mechanical interference was possible in 80% of the cases and guidance without beam interference was possible in 60% of the cases. For the smaller GTV targets, these proportions were 95% and 85%, respectively. GTV size (1/20), elongated shape (1/20), and depth (1/20) were the main factors limiting the availability of noninterfering imaging positions. The robotic US imaging system was deployed in two liver SABR patients during CT simulation with successful acquisition of 4D US sequences in different imaging positions.This study indicates that for VMAT liver SABR, robotic US imaging of a relevant internal target may be possible in 85% of the cases while using treatment plans currently deployed in the clinic. With beam replanning to account for the presence of robotic US guidance, intrafractional US may be an option for 95% of the liver SABR cases.

    View details for PubMedID 27806580

  • Radiolucent 4D Ultrasound Imaging: System Design and Application to Radiotherapy Guidance IEEE TRANSACTIONS ON MEDICAL IMAGING Schlosser, J., Hristov, D. 2016; 35 (10): 2292-2300


    Four-dimensional (4D) ultrasound (US) is an attractive modality for image guidance due to its real-time, non-ionizing, volumetric imaging capability with high soft tissue contrast. However, existing 4D US imaging systems contain large volumes of metal which interfere with diagnostic and therapeutic ionizing radiation in procedures such as CT imaging and radiation therapy. This study aimed to design and characterize a novel 4D Radiolucent Remotely-Actuated UltraSound Scanning (RRUSS) device that overcomes this limitation. In a phantom, we evaluated the imaging performance of the RRUSS device including frame rate, resolution, spatial integrity, and motion tracking accuracy. To evaluate compatibility with radiation therapy workflow, we evaluated device-induced CT imaging artifacts, US tracking performance during beam delivery, and device compatibility with commercial radiotherapy planning software. The RRUSS device produced 4D volumes at 0.1-3.0 Hz with 60° lateral field of view (FOV), 50° maximum elevational FOV, and 200 mm maximum depth. Imaging resolution (-3 dB point spread width) was 1.2-7.9 mm at depths up to 100 mm and motion tracking accuracy was ≤ 0.3±0.5 mm. No significant effect of the RRUSS device on CT image integrity was found, and RRUSS device performance was not affected by radiotherapy beam exposure. Agreement within ±3.0% / 2.0 mm was achieved between computed and measured radiotherapy dose delivered directly through the RRUSS device at 6 MV and 15 MV. In vivo liver, kidney, and prostate images were successfully acquired. Our investigations suggest that a RRUSS device can offer non-interfering 4D guidance for radiation therapy and other diagnostic and therapeutic procedures.

    View details for DOI 10.1109/TMI.2016.2559499

    View details for Web of Science ID 000385985200008

    View details for PubMedID 27164579

  • VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer. Cancer research Zhou, J., Wang, H., Zhang, H., Lutz, A. M., Tian, L., Hristov, D., Willmann, J. K. 2016; 76 (14): 4081-4089


    Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.

    View details for DOI 10.1158/0008-5472.CAN-15-3271

    View details for PubMedID 27206846

  • Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model RADIOLOGY Wang, H., Hristov, D., Qin, J., Tian, L., Willmann, J. K. 2015; 277 (2): 424-434


    To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis.Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images.Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

    View details for DOI 10.1148/radiol.2015142824

    View details for Web of Science ID 000368435100018

    View details for PubMedCentralID PMC4627439

  • Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model. Radiology Wang, H., Hristov, D., Qin, J., Tian, L., Willmann, J. K. 2015; 277 (2): 424-34


    To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis.Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images.Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

    View details for DOI 10.1148/radiol.2015142824

    View details for PubMedID 26020439

    View details for PubMedCentralID PMC4627439

  • Monte Carlo modeling of ultrasound probes for image guided radiotherapy. Medical physics Bazalova-Carter, M., Schlosser, J., Chen, J., Hristov, D. 2015; 42 (10): 5745-?


    To build Monte Carlo (MC) models of two ultrasound (US) probes and to quantify the effect of beam attenuation due to the US probes for radiation therapy delivered under real-time US image guidance.MC models of two Philips US probes, an X6-1 matrix-array transducer and a C5-2 curved-array transducer, were built based on their megavoltage (MV) CT images acquired in a Tomotherapy machine with a 3.5 MV beam in the EGSnrc, BEAMnrc, and DOSXYZnrc codes. Mass densities in the probes were assigned based on an electron density calibration phantom consisting of cylinders with mass densities between 0.2 and 8.0 g/cm(3). Beam attenuation due to the US probes in horizontal (for both probes) and vertical (for the X6-1 probe) orientation was measured in a solid water phantom for 6 and 15 MV (15 × 15) cm(2) beams with a 2D ionization chamber array and radiographic films at 5 cm depth. The MC models of the US probes were validated by comparison of the measured dose distributions and dose distributions predicted by MC. Attenuation of depth dose in the (15 × 15) cm(2) beams and small circular beams due to the presence of the probes was assessed by means of MC simulations.The 3.5 MV CT number to mass density calibration curve was found to be linear with R(2) > 0.99. The maximum mass densities in the X6-1 and C5-2 probes were found to be 4.8 and 5.2 g/cm(3), respectively. Dose profile differences between MC simulations and measurements of less than 3% for US probes in horizontal orientation were found, with the exception of the penumbra region. The largest 6% dose difference was observed in dose profiles of the X6-1 probe placed in vertical orientation, which was attributed to inadequate modeling of the probe cable. Gamma analysis of the simulated and measured doses showed that over 96% of measurement points passed the 3%/3 mm criteria for both probes placed in horizontal orientation and for the X6-1 probe in vertical orientation. The X6-1 probe in vertical orientation caused the highest attenuation of the 6 and 15 MV beams, which at 10 cm depth accounted for 33% and 43% decrease compared to the respective (15 × 15) cm(2) open fields. The C5-2 probe in horizontal orientation, on the other hand, caused a dose increase of 10% and 53% for the 6 and 15 MV beams, respectively, in the buildup region at 0.5 cm depth. For the X6-1 probe in vertical orientation, the dose at 5 cm depth for the 3-cm diameter 6 MV and 5-cm diameter 15 MV beams was attenuated compared to the corresponding open fields to a greater degree by 65% and 43%, respectively.MC models of two US probes used for real-time image guidance during radiotherapy have been built. Due to the high beam attenuation of the US probes, the authors generally recommend avoiding delivery of treatment beams that intersect the probe. However, the presented MC models can be effectively integrated into US-guided radiotherapy treatment planning in cases for which beam avoidance is not practical due to anatomy geometry.

    View details for DOI 10.1118/1.4929978

    View details for PubMedID 26429248

  • Trajectory Modulated Arc Therapy: A Fully Dynamic Delivery With Synchronized Couch and Gantry Motion Significantly Improves Dosimetric Indices Correlated With Poor Cosmesis in Accelerated Partial Breast Irradiation INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Liang, J., Atwood, T., von Eyben, R., Fahimian, B., Chin, E., Horst, K., Otto, K., Hristov, D. 2015; 92 (5): 1148-1156


    To develop planning and delivery capabilities for linear accelerator-based nonisocentric trajectory modulated arc therapy (TMAT) and to evaluate the benefit of TMAT for accelerated partial breast irradiation (APBI) with the patient in prone position.An optimization algorithm for volumetrically modulated arc therapy (VMAT) was generalized to allow for user-defined nonisocentric TMAT trajectories combining couch rotations and translations. After optimization, XML scripts were automatically generated to program and subsequently deliver the TMAT plans. For 10 breast patients in the prone position, TMAT and 6-field noncoplanar intensity modulated radiation therapy (IMRT) plans were generated under equivalent objectives and constraints. These plans were compared with regard to whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose.For TMAT APBI, nonisocentric collision-free horizontal arcs with large angular span (251.5 ± 7.9°) were optimized and delivered with delivery time of ∼4.5 minutes. Percentage changes of whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose for TMAT relative to IMRT were -10.81% ± 6.91%, -27.81% ± 7.39%, -14.82% ± 9.67%, and 39.40% ± 10.53% (P≤.01).This is a first demonstration of end-to-end planning and delivery implementation of a fully dynamic APBI TMAT. Compared with IMRT, TMAT resulted in marked reduction of the breast tissue volume irradiated at high doses.

    View details for DOI 10.1016/j.ijrobp.2015.04.034

    View details for Web of Science ID 000357900600037

    View details for PubMedID 26050608

  • Ultrasound Imaging in Radiation Therapy: From Interfractional to Intrafractional Guidance. Cureus Western, C., Hristov, D., Schlosser, J. 2015; 7 (6)


    External beam radiation therapy (EBRT) is included in the treatment regimen of the majority of cancer patients. With the proliferation of hypofractionated radiotherapy treatment regimens, such as stereotactic body radiation therapy (SBRT), interfractional and intrafractional imaging technologies are becoming increasingly critical to ensure safe and effective treatment delivery. Ultrasound (US)-based image guidance systems offer real-time, markerless, volumetric imaging with excellent soft tissue contrast, overcoming the limitations of traditional X-ray or computed tomography (CT)-based guidance for abdominal and pelvic cancer sites, such as the liver and prostate. Interfractional US guidance systems have been commercially adopted for patient positioning but suffer from systematic positioning errors induced by probe pressure. More recently, several research groups have introduced concepts for intrafractional US guidance systems leveraging robotic probe placement technology and real-time soft tissue tracking software. This paper reviews various commercial and research-level US guidance systems used in radiation therapy, with an emphasis on hardware and software technologies that enable the deployment of US imaging within the radiotherapy environment and workflow. Previously unpublished material on tissue tracking systems and robotic probe manipulators under development by our group is also included.

    View details for DOI 10.7759/cureus.280

    View details for PubMedID 26180704

    View details for PubMedCentralID PMC4494460

  • Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer. Investigative radiology Wang, H., Kaneko, O. F., Tian, L., Hristov, D., Willmann, J. K. 2015; 50 (5): 322-329


    We sought to assess the feasibility and reproducibility of 3-dimensional ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n = 33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) after intravenous injection of either clinical grade VEGFR2-targeted microbubbles or nontargeted control microbubbles. Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24 hours after treatment with either bevacizumab (n = 7) or saline only (n = 7). Three-dimensional USMI data sets were retrospectively reconstructed into multiple consecutive 1-mm-thick USMI data sets to simulate 2-dimensional imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence.Three-dimensional USMI was highly reproducible using both VEGFR2-targeted microbubbles and nontargeted control microbubbles (intraclass correlation coefficient, 0.83). The VEGFR2-targeted USMI signal significantly (P = 0.02) decreased by 57% after antiangiogenic treatment compared with the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (ρ = 0.93, P = 0.003). If only central 1-mm tumor planes were analyzed to assess antiangiogenic treatment response, the USMI signal change was significantly (P = 0.006) overestimated by an average of 27% (range, 2%-73%) compared with 3-dimensional USMI.Three-dimensional USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer.

    View details for DOI 10.1097/RLI.0000000000000128

    View details for PubMedID 25575176

  • Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy. Medical physics Axente, M., Paidi, A., von Eyben, R., Zeng, C., Bani-Hashemi, A., Krauss, A., Hristov, D. 2015; 42 (3): 1170-?


    To clinically evaluate an iterative metal artifact reduction (IMAR) algorithm prototype in the radiation oncology clinic setting by testing for accuracy in CT number retrieval, relative dosimetric changes in regions affected by artifacts, and improvements in anatomical and shape conspicuity of corrected images.A phantom with known material inserts was scanned in the presence/absence of metal with different configurations of placement and sizes. The relative change in CT numbers from the reference data (CT with no metal) was analyzed. The CT studies were also used for dosimetric tests where dose distributions from both photon and proton beams were calculated. Dose differences and gamma analysis were calculated to quantify the relative changes between doses calculated on the different CT studies. Data from eight patients (all different treatment sites) were also used to quantify the differences between dose distributions before and after correction with IMAR, with no reference standard. A ranking experiment was also conducted to analyze the relative confidence of physicians delineating anatomy in the near vicinity of the metal implants.IMAR corrected images proved to accurately retrieve CT numbers in the phantom study, independent of metal insert configuration, size of the metal, and acquisition energy. For plastic water, the mean difference between corrected images and reference images was -1.3 HU across all scenarios (N = 37) with a 90% confidence interval of [-2.4, -0.2] HU. While deviations were relatively higher in images with more metal content, IMAR was able to effectively correct the CT numbers independent of the quantity of metal. Residual errors in the CT numbers as well as some induced by the correction algorithm were found in the IMAR corrected images. However, the dose distributions calculated on IMAR corrected images were closer to the reference data in phantom studies. Relative spatial difference in the dose distributions in the regions affected by the metal artifacts was also observed in patient data. However, in absence of a reference ground truth (CT set without metal inserts), these differences should not be interpreted as improvement/deterioration of the accuracy of calculated dose. With limited data presented, it was observed that proton dosimetry was affected more than photons as expected. Physicians were significantly more confident contouring anatomy in the regions affected by artifacts. While site specific preferences were detected, all indicated that they would consistently use IMAR corrected images.IMAR correction algorithm could be readily implemented in an existing clinical workflow upon commercial release. While residual errors still exist in IMAR corrected images, these images present with better overall conspicuity of the patient/phantom geometry and offer more accurate CT numbers for improved local dosimetry. The variety of different scenarios included herein attest to the utility of the evaluated IMAR for a wide range of radiotherapy clinical scenarios.

    View details for DOI 10.1118/1.4906245

    View details for PubMedID 25735272

  • Quality control procedures for dynamic treatment delivery techniques involving couch motion MEDICAL PHYSICS Yu, V. Y., Fahinnian, B. R., Xing, L., Hristov, D. H. 2014; 41 (8): 164-170


    In this study, the authors introduce and demonstrate quality control procedures for evaluating the geometric and dosimetric fidelity of dynamic treatment delivery techniques involving treatment couch motion synchronous with gantry and multileaf collimator (MLC). Tests were designed to evaluate positional accuracy, velocity constancy and accuracy for dynamic couch motion under a realistic weight load. A test evaluating the geometric accuracy of the system in delivering treatments over complex dynamic trajectories was also devised. Custom XML scripts that control the Varian TrueBeam™ STx (Serial #3) axes in Developer Mode were written to implement the delivery sequences for the tests. Delivered dose patterns were captured with radiographic film or the electronic portal imaging device. The couch translational accuracy in dynamic treatment mode was 0.01 cm. Rotational accuracy was within 0.3°, with 0.04 cm displacement of the rotational axis. Dose intensity profiles capturing the velocity constancy and accuracy for translations and rotation exhibited standard deviation and maximum deviations below 3%. For complex delivery involving MLC and couch motions, the overall translational accuracy for reproducing programmed patterns was within 0.06 cm. The authors conclude that in Developer Mode, TrueBeam™ is capable of delivering dynamic treatment delivery techniques involving couch motion with good geometric and dosimetric fidelity.

    View details for DOI 10.1118/1.4886757

    View details for Web of Science ID 000341068100014

  • Imaging dose in variable pitch body perfusion CT scans: An analysis using TG111 formalism. Medical physics Axente, M., Hristov, D. 2014; 41 (6): 061912-?


    To investigate the variation of imaging dose with tube potential in variable pitch body CT perfusion (CTp) protocols using the TG111 dosimetric formalism.TG111 recommendations were followed in choosing the phantom, dosimetric equipment, and methodology. Specifically, equilibrium doses (D(eq)) were measured centrally and peripherally in a long PMMA phantom. Reference planar average equilibrium doses were determined for each tube potential, for a reference set of exposure parameters (collimation, pitch, filtration) on a Siemens Definition CT scanner. These reference values were utilized to predict the imaging dose during perfusion scans using interpretations of the TG111 formalism. As a gold reference, the midscan average planar perfusion doses (D(CTp)) were obtained directly from central and peripheral D(eq) measurements for body CTp scans (144 and 271 mm) using variable pitch acquisition. Measurement-based D(CTp) values obtained using a thimble chamber were compared to the TG111-predicted values, and to CTDI(vol) reported at the console.Reference planar average equilibrium dose values measured for reference uniform pitch helical scans were consistently higher than console-reported or measured values for CTDI(vol). The measurement-based perfusion dose D(CTp) was predicted accurately by the reported CTDI(vol) for the 144 mm scan. The 271 mm scans delivered systematically larger dose than reported. The TG111-based dose estimates were proven to be conservative, as they were systematically higher than both the measured and the reported imaging doses.Upon successful implementation of TG111 formalism, standard imaging dose was measured for a body CTp protocol using the variable pitch helical acquisition. The TG111 formalism is not directly applicable to this type of acquisition. Measurement of dose for all variable pitch protocols is strongly suggested.

    View details for DOI 10.1118/1.4876377

    View details for PubMedID 24877823

  • Interactive focus plus context medical data exploration and editing COMPUTER ANIMATION AND VIRTUAL WORLDS Kirmizibayrak, C., Wakid, M., Yim, Y., Hristov, D., Hahn, J. K. 2014; 25 (2): 129-141

    View details for DOI 10.1002/cav.1538

    View details for Web of Science ID 000334273500004

  • Trajectory modulated prone breast irradiation: A LINAC-based technique combining intensity modulated delivery and motion of the couch RADIOTHERAPY AND ONCOLOGY Fahimian, B., Yu, V., Horst, K., Xing, L., Hristov, D. 2013; 109 (3): 475-481


    External beam radiation therapy (EBRT) provides a non-invasive treatment alternative for accelerated partial breast irradiation (APBI), however, limitations in achievable dose conformity of current EBRT techniques have been correlated to reported toxicity. To enhance the conformity of EBRT APBI, a technique for conventional LINACs is developed, which through combined motion of the couch, intensity modulated delivery, and a prone breast setup, enables wide-angular coronal arc irradiation of the ipsilateral breast without irradiating through the thorax and contralateral breast.A couch trajectory optimization technique was developed to determine the trajectories that concurrently avoid collision with the LINAC and maintain the target within the MLC apertures. Inverse treatment planning was performed along the derived trajectory. The technique was experimentally implemented by programming the Varian TrueBeam™ STx in Developer Mode. The dosimetric accuracy of the delivery was evaluated by ion chamber and film measurements in phantom.The resulting optimized trajectory was shown to be necessarily non-isocentric, and contain both translation and rotations of the couch. Film measurements resulted in 93% of the points in the measured two-dimensional dose maps passing the 3%/3mm Gamma criterion. Preliminary treatment plan comparison to 5-field 3D-conformal, IMRT, and VMAT demonstrated enhancement in conformity, and reduction of the normal tissue V50% and V100% parameters that have been correlated with EBRT toxicity.The feasibility of wide-angular intensity modulated partial breast irradiation using motion of the couch has been demonstrated experimentally on a standard LINAC for the first time. For patients eligible for a prone setup, the technique may enable improvement of dose conformity and associated dose-volume parameters correlated with toxicity.

    View details for DOI 10.1016/j.radonc.2013.10.031

    View details for Web of Science ID 000329482000027

    View details for PubMedID 24231240

  • Automatic 3D ultrasound calibration for image guided therapy using intramodality image registration. Physics in medicine and biology Schlosser, J., Kirmizibayrak, C., Shamdasani, V., Metz, S., Hristov, D. 2013; 58 (21): 7481-7496


    Many real time ultrasound (US) guided therapies can benefit from management of motion-induced anatomical changes with respect to a previously acquired computerized anatomy model. Spatial calibration is a prerequisite to transforming US image information to the reference frame of the anatomy model. We present a new method for calibrating 3D US volumes using intramodality image registration, derived from the 'hand-eye' calibration technique. The method is fully automated by implementing data rejection based on sensor displacements, automatic registration over overlapping image regions, and a self-consistency error metric evaluated continuously during calibration. We also present a novel method for validating US calibrations based on measurement of physical phantom displacements within US images. Both calibration and validation can be performed on arbitrary phantoms. Results indicate that normalized mutual information and localized cross correlation produce the most accurate 3D US registrations for calibration. Volumetric image alignment is more accurate and reproducible than point selection for validating the calibrations, yielding <1.5 mm root mean square error, a significant improvement relative to previously reported hand-eye US calibration results. Comparison of two different phantoms for calibration and for validation revealed significant differences for validation (p = 0.003) but not for calibration (p = 0.795).

    View details for DOI 10.1088/0031-9155/58/21/7481

    View details for PubMedID 24099806

  • Count-Based Listmode Respiratory Motion Detection for Quantitative PET 60th IEEE Nuclear Science Symposium (NSS) / Medical Imaging Conference (MIC) / 20th International Workshop on Room-Temperature Semiconductor X-ray and Gamma-ray Detectors Lee, K. S., Hristov, D. H. IEEE. 2013
  • Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237


    Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

    View details for DOI 10.1016/j.ijrobp.2011.10.071

    View details for PubMedID 22381907

  • Online Image-based Monitoring of Soft-tissue Displacements for Radiation Therapy of the Prostate INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schlosser, J., Salisbury, K., Hristov, D. 2012; 83 (5): 1633-1640


    Emerging prolonged, hypofractionated radiotherapy regimens rely on high-dose conformality to minimize toxicity and thus can benefit from image guidance systems that continuously monitor target position during beam delivery. To address this need we previously developed, as a potential add-on device for existing linear accelerators, a novel telerobotic ultrasound system capable of real-time, soft-tissue imaging. Expanding on this capability, the aim of this work was to develop and characterize an image-based technique for real-time detection of prostate displacements.Image processing techniques were implemented on spatially localized ultrasound images to generate two parameters representing prostate displacements in real time. In a phantom and five volunteers, soft-tissue targets were continuously imaged with a customized robotic manipulator while recording the two tissue displacement parameters (TDPs). Variations of the TDPs in the absence of tissue displacements were evaluated, as was the sensitivity of the TDPs to prostate translations and rotations. Robustness of the approach to probe force was also investigated.With 95% confidence, the proposed method detected in vivo prostate displacements before they exceeded 2.3, 2.5, and 2.8 mm in anteroposterior, superoinferior, and mediolateral directions. Prostate pitch was detected before exceeding 4.7° at 95% confidence. Total system time lag averaged 173 ms, mostly limited by ultrasound acquisition rate. False positives (FPs) (FP) in the absence of displacements did not exceed 1.5 FP events per 10 min of continuous in vivo imaging time.The feasibility of using telerobotic ultrasound for real-time, soft-tissue-based monitoring of target displacements was confirmed in vivo. Such monitoring has the potential to detect small clinically relevant intrafractional variations of the prostate position during beam delivery.

    View details for DOI 10.1016/j.ijrobp.2011.10.049

    View details for Web of Science ID 000306128100062

    View details for PubMedID 22285664

  • SU-D-213CD-01: 4D Ultrasound Calibration for Radiotherapy Guidance Using Automatic Intramodality Image Registration. Medical physics Schlosser, J., Kirmizibayrak, C., Shamdasani, V., Metz, S., Hristov, D. 2012; 39 (6): 3617-?


    In prior work we developed a robotic system providing real-time soft-tissue ultrasound (US) volumes during radiotherapy beam delivery. for image guidance, the US volumes must be transformed to the linear accelerator reference frame. In this work we propose and characterize a new method of calibrating 4D US volumes based on automatic intramodality image registration.A dynamic navigation link was used to port 3D US volumes from a Philips iU22 xMatrix machine to a PC in real-time. Sixty volumetric (3D) US images of a pelvic phantom were collected from various probe positions while the transducer's pose was monitored by an optical tracking system. US volumes were automatically registered to the first US volume using normalized mutual information. A system of equations was formulated and solved for the US probe-to-image transformation using the registration transformations and the optical tracking information. Accuracy of the US calibration was assessed on eight additional US volumes with two separate methods. In the first method, a set of three fiducial markers implanted in the phantom was manually selected in each volume by three individual readers. Selected marker locations were reconstructed in the stationary camera frame, and for each marker, mean distance to the reconstructed centroid was measured. In the second method, a bladder structure was semi-automatically segmented in each image volume. Mean distance between bladders segmented in a reference volume and the other seven volumes was computed. Calibration accuracy was also investigated as a function of the number of calibration images used.Mean error for the fiducial marker reconstruction was 2.3 mm. Mean distance error between segmented structures was 1.1 mm. The proposed calibration method typically converged with less than 20 images.Automatic image registration facilitates fast and simple US spatial calibration with accuracy under 2.3 mm using any US phantom. This work is supported in part by the Stanford University BioX program and by Philips Medical. Two of the authors of the abstract are employed by Philips Medical.

    View details for DOI 10.1118/1.4734685

    View details for PubMedID 28517382

  • Feasibility of low-dose single-view 3D fiducial tracking concurrent with external beam delivery MEDICAL PHYSICS Speidel, M. A., Wilfley, B. P., Hsu, A., Hristov, D. 2012; 39 (4): 2163-2169


    In external-beam radiation therapy, existing on-board x-ray imaging chains orthogonal to the delivery beam cannot recover 3D target trajectories from a single view in real-time. This limits their utility for real-time motion management concurrent with beam delivery. To address this limitation, the authors propose a novel concept for on-board imaging based on the inverse-geometry Scanning-Beam Digital X-ray (SBDX) system and evaluate its feasibility for single-view 3D intradelivery fiducial tracking.A chest phantom comprising a posterior wall, a central lung volume, and an anterior wall was constructed. Two fiducials were placed along the mediastinal ridge between the lung cavities: a 1.5 mm diameter steel sphere superiorly and a gold cylinder (2.6 mm length × 0.9 mm diameter) inferiorly. The phantom was placed on a linear motion stage that moved sinusoidally. Fiducial motion was along the source-detector (z) axis of the SBDX system with ±10 mm amplitude and a programmed period of either 3.5 s or 5 s. The SBDX system was operated at 15 frames per second, 100 kVp, providing good apparent conspicuity of the fiducials. With the stage moving, detector data were acquired and subsequently reconstructed into 15 planes with a 12 mm plane-to-plane spacing using digital tomosynthesis. A tracking algorithm was applied to the image planes for each temporal frame to determine the position of each fiducial in (x,y,z)-space versus time. A 3D time-sinusoidal motion model was fit to the measured 3D coordinates and root mean square (RMS) deviations about the fitted trajectory were calculated.Tracked motion was sinusoidal and primarily along the source-detector (z) axis. The RMS deviation of the tracked z-coordinate ranged from 0.53 to 0.71 mm. The motion amplitude derived from the model fit agreed with the programmed amplitude to within 0.28 mm for the steel sphere and within -0.77 mm for the gold seed. The model fit periods agreed with the programmed periods to within 7%.Three dimensional fiducial tracking with approximately 1 mm or better accuracy and precision appears to be feasible with SBDX, supporting its use to guide radiotherapy.

    View details for DOI 10.1118/1.3697529

    View details for Web of Science ID 000302371900045

    View details for PubMedID 22482637

    View details for PubMedCentralID PMC3326074

  • Evaluation of a metal artifact reduction technique in tonsillar cancer delineation. Practical radiation oncology Abelson, J. A., Murphy, J. D., Wiegner, E. A., Abelson, D., Sandman, D. N., Boas, F. E., Hristov, D., Fleischmann, D., Daly, M. E., Chang, D. T., Loo, B. W., Hara, W., Le, Q. 2012; 2 (1): 27-34


    Metal artifacts can degrade computed tomographic (CT) simulation imaging and impair accurate delineation of tumors for radiation treatment planning purposes. We investigated a Digital Imaging and Communications in Medicine-based metal artifact reduction technique in tonsillar cancer delineation.Eight patients with significant artifact and tonsil cancer were evaluated. Each patient had a positron emission tomography (PET)-CT and a contrast-enhanced CT obtained at the same setting during radiotherapy simulation. The CTs were corrected for artifact using the metal deletion technique (MDT). Two radiation oncologists independently delineated primary gross tumor volumes (GTVs) for each patient on native (CTnonMDT), metal corrected (CTMDT), and reference standard (CTPET/nonMDT) imaging, 1 week apart. Mixed effects models were used to determine if differences among GTVs were statistically significant. Two diagnostic radiologists and 2 radiation oncologists independently qualitatively evaluated CTs for each patient. Ratings were on an ordinal scale from -3 to +3, denoting that CTMDT was markedly, moderately, or slightly worse or better than CTnonMDT. Scores were compared with a Wilcoxon signed-rank test.The GTVPET/nonMDT were significantly smaller than GTVnonMDT (P = .004) and trended to be smaller than GTVMDT (P = .084). The GTVnonMDT and GTVMDT were not significantly different (P = .93). There was no significant difference in the extent to which GTVnonMDT or GTVMDT encompassed GTVPET/nonMDT (P = .33). In the subjective assessment of image quality, CTMDT did not significantly outperform CTnonMDT. In the majority of cases, the observer rated the CTMDT equivalent to (53%) or slightly superior (41%) to the corresponding CTnonMDT.The MTD modified images did not produce GTVMDT that more closely reproduced GTVPET/nonMDT than did GTVnonMDT. Moreover, the MTD modified images were not judged to be significantly superior when compared to the uncorrected images in terms of subjective ability to visualize the tonsilar tumors. This study failed to demonstrate value of the adjunctive use of a CT corrected for artifacts in the tumor delineation process. Artifacts do make tumor delineation challenging, and further investigation of other body sites is warranted.

    View details for DOI 10.1016/j.prro.2011.06.004

    View details for PubMedID 24674033

  • Multiparametric Imaging of Tumor Oxygenation, Redox Status, and Anatomical Structure Using Overhauser-Enhanced MRI-Prepolarized MRI System MAGNETIC RESONANCE IN MEDICINE Ahn, K., Scott, G., Stang, P., Conolly, S., Hristov, D. 2011; 65 (5): 1416-1422


    An integrated Overhauser-enhanced MRI-Prepolarized MRI system was developed to obtain radiobiological information that could be accurately coregistered with diagnostic quality anatomic images. EPR and NMR images were acquired through the double resonance technique and field cycling of the main magnetic field from 5 mT to 0.5 T. Dedicated EPR and NMR coils were devised to minimize radiofrequency power deposition with high signal-to-noise ratio. Trityl and nitroxide radicals were used to characterize oxygen and redox sensitivities of multispin echo Overhauser-enhanced MRI. Oxygen resolution of 3 mmHg was obtained from 2 mM deoxygenated trityl phantoms. Trityl radicals were stable in reducing environments and did not alter the redox-sensitive decaying rate of the nitroxide signals. Nitroxide radicals had a compounding effect for the trityl oximetry. Tumor oxygenation and redox status were acquired with anatomical images by injecting trityl and nitroxide probes subsequently in murine tumors. The Overhauser-enhanced MRI-Prepolarized MRI system is ready for quantitative longitudinal imaging studies of tumor hypoxia and redox status as radiotherapy prognostic factors.

    View details for DOI 10.1002/mrm.22732

    View details for Web of Science ID 000289760800027

    View details for PubMedID 21500268



    To integrate three-dimensional (3D) digital rotation angiography (DRA) and two-dimensional (2D) digital subtraction angiography (DSA) imaging into a targeting methodology enabling comprehensive image-guided robotic radiosurgery of arteriovenous malformations (AVMs).DRA geometric integrity was evaluated by imaging a phantom with embedded markers. Dedicated DSA acquisition modes with preset C-arm positions were configured. The geometric reproducibility of the presets was determined, and its impact on localization accuracy was evaluated. An imaging protocol composed of anterior-posterior and lateral DSA series in combination with a DRA run without couch displacement between acquisitions was introduced. Software was developed for registration of DSA and DRA (2D-3D) images to correct for: (a) small misalignments of the C-arm with respect to the estimated geometry of the set positions and (b) potential patient motion between image series. Within the software, correlated navigation of registered DRA and DSA images was incorporated to localize AVMs within a 3D image coordinate space. Subsequent treatment planning and delivery followed a standard image-guided robotic radiosurgery process.DRA spatial distortions were typically smaller than 0.3 mm throughout a 145-mm × 145-mm × 145-mm volume. With 2D-3D image registration, localization uncertainties resulting from the achievable reproducibility of the C-arm set positions could be reduced to about 0.2 mm. Overall system-related localization uncertainty within the DRA coordinate space was 0.4 mm. Image-guided frameless robotic radiosurgical treatments with this technique were initiated.The integration of DRA and DSA into the process of nidus localization increases the confidence with which radiosurgical ablation of AVMs can be performed when using only an image-guided technique. Such an approach can increase patient comfort, decrease time pressure on clinical and technical staff, and possibly reduce the number of cerebral angiograms needed for a particular patient.

    View details for DOI 10.1016/j.ijrobp.2010.05.015

    View details for PubMedID 20801584

  • Telerobotic system concept for real-time soft-tissue imaging during radiotherapy beam delivery MEDICAL PHYSICS Schlosser, J., Salisbury, K., Hristov, D. 2010; 37 (12): 6357-6367


    The curative potential of external beam radiation therapy is critically dependent on having the ability to accurately aim radiation beams at intended targets while avoiding surrounding healthy tissues. However, existing technologies are incapable of real-time, volumetric, soft-tissue imaging during radiation beam delivery, when accurate target tracking is most critical. The authors address this challenge in the development and evaluation of a novel, minimally interfering, telerobotic ultrasound (U.S.) imaging system that can be integrated with existing medical linear accelerators (LINACs) for therapy guidance.A customized human-safe robotic manipulator was designed and built to control the pressure and pitch of an abdominal U.S. transducer while avoiding LINAC gantry collisions. A haptic device was integrated to remotely control the robotic manipulator motion and U.S. image acquisition outside the LINAC room. The ability of the system to continuously maintain high quality prostate images was evaluated in volunteers over extended time periods. Treatment feasibility was assessed by comparing a clinically deployed prostate treatment plan to an alternative plan in which beam directions were restricted to sectors that did not interfere with the transabdominal U.S. transducer. To demonstrate imaging capability concurrent with delivery, robot performance and U.S. target tracking in a phantom were tested with a 15 MV radiation beam active.Remote image acquisition and maintenance of image quality with the haptic interface was successfully demonstrated over 10 min periods in representative treatment setups of volunteers. Furthermore, the robot's ability to maintain a constant probe force and desired pitch angle was unaffected by the LINAC beam. For a representative prostate patient, the dose-volume histogram (DVH) for a plan with restricted sectors remained virtually identical to the DVH of a clinically deployed plan. With reduced margins, as would be enabled by real-time imaging, gross tumor volume coverage was identical while notable reductions of bladder and rectal volumes exposed to large doses were possible. The quality of U.S. images obtained during beam operation was not appreciably degraded by radiofrequency interference and 2D tracking of a phantom object in U.S. images obtained with the beam on/off yielded no significant differences.Remotely controlled robotic U.S. imaging is feasible in the radiotherapy environment and for the first time may offer real-time volumetric soft-tissue guidance concurrent with radiotherapy delivery.

    View details for DOI 10.1118/1.3515457

    View details for Web of Science ID 000285849400027

    View details for PubMedID 21302793

  • Frameless image guided robotic radiosurgery of arteriovenous malformation localized on spatially correlated digital subtraction and C-arm CT angiography images JOURNAL OF NEUROINTERVENTIONAL SURGERY Hristov, D., Adler, J. R., Gibbs, I. C., Dodd, R., Marks, M., Chang, S. D., Do, H. M. 2010; 2 (3): 252-254


    A case is reported of frameless image guided robotic radiosurgery for an arteriovenous malformation (AVM). C-arm CT (CACT) and concurrent digital subtraction angiography images were used for AVM localization within the CACT volume. Treatment planning was performed on CT images registered with the CACT dataset. During delivery, a robotic linear accelerator tracked the target based on localization with frequent stereoscopic x-ray imaging. This case demonstrates that a frameless approach to AVM radiosurgery is possible.

    View details for DOI 10.1136/jnis.2009.001941

    View details for PubMedID 21990637

  • MRI GUIDANCE FOR ACCELERATED PARTIAL BREAST IRRADIATION IN PRONE POSITION: IMAGING PROTOCOL DESIGN AND EVALUATION 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Ahn, K., Hargreaves, B. A., Alley, M. T., Horst, K. C., Luxton, G., Daniel, B. L., Hristov, D. ELSEVIER SCIENCE INC. 2009: 285–93


    To design and evaluate a magnetic resonance imaging (MRI) protocol to be incorporated in the simulation process for external beam accelerated partial breast irradiation.An imaging protocol was developed based on an existing breast MRI technique with the patient in the prone position on a dedicated coil. Pulse sequences were customized to exploit T1 and T2 contrast mechanisms characteristic of lumpectomy cavities. A three-dimensional image warping algorithm was included to correct for geometric distortions related to nonlinearity of spatially encoding gradients. Respiratory motion, image distortions, and susceptibility artifacts of 3.5-mm titanium surgical clips were examined. Magnetic resonance images of volunteers were acquired repeatedly to analyze residual setup deviations resulting from breast tissue deformation.The customized sequences generated high-resolution magnetic resonance images emphasizing lumpectomy cavity morphology. Respiratory motion was negligible with the subject in the prone position. The gradient-induced nonlinearity was reduced to less than 1 mm in a region 15 cm away from the isocenter of the magnet. Signal-void regions of surgical clips were 4 mm and 8 mm for spin echo and gradient echo images, respectively. Typical residual repositioning errors resulting from breast deformation were estimated to be 3 mm or less.MRI guidance for accelerated partial breast irradiation with the patient in the prone position with adequate contrast, spatial fidelity, and resolution is possible.

    View details for DOI 10.1016/j.ijrobp.2009.03.063

    View details for Web of Science ID 000269328700045

    View details for PubMedID 19632067

  • Algorithm for X-ray Scatter, Beam-Hardening, and Beam Profile Correction in Diagnostic (Kilovoltage) and Treatment (Megavoltage) Cone Beam CT IEEE TRANSACTIONS ON MEDICAL IMAGING Maltz, J. S., Gangadharan, B., Bose, S., Hristov, D. H., Faddegon, B. A., Paidi, A., Bani-Hashemi, A. R. 2008; 27 (12): 1791-1810


    Quantitative reconstruction of cone beam X-ray computed tomography (CT) datasets requires accurate modeling of scatter, beam-hardening, beam profile, and detector response. Typically, commercial imaging systems use fast empirical corrections that are designed to reduce visible artifacts due to incomplete modeling of the image formation process. In contrast, Monte Carlo (MC) methods are much more accurate but are relatively slow. Scatter kernel superposition (SKS) methods offer a balance between accuracy and computational practicality. We show how a single SKS algorithm can be employed to correct both kilovoltage (kV) energy (diagnostic) and megavoltage (MV) energy (treatment) X-ray images. Using MC models of kV and MV imaging systems, we map intensities recorded on an amorphous silicon flat panel detector to water-equivalent thicknesses (WETs). Scattergrams are derived from acquired projection images using scatter kernels indexed by the local WET values and are then iteratively refined using a scatter magnitude bounding scheme that allows the algorithm to accommodate the very high scatter-to-primary ratios encountered in kV imaging. The algorithm recovers radiological thicknesses to within 9% of the true value at both kV and megavolt energies. Nonuniformity in CT reconstructions of homogeneous phantoms is reduced by an average of 76% over a wide range of beam energies and phantom geometries.

    View details for DOI 10.1109/TMI.2008.928922

    View details for Web of Science ID 000261364900011

    View details for PubMedID 19033095

  • A calculation model for primary intensity distributions from cylindrically symmetric x-ray lenses PHYSICS IN MEDICINE AND BIOLOGY Hristov, D., Maltz, J. 2008; 53 (3): 515-527


    A calculation model for the quantitative prediction of primary intensity fluence distributions obtained by the Bragg diffraction focusing of kilovoltage radiation by cylindrical x-ray lenses is presented. The mathematical formalism describes primary intensity distributions from cylindrically-symmetric x-ray lenses, with a planar isotropic radiation source located in a plane perpendicular to the lens axis. The presence of attenuating medium inserted between the lens and the lens focus is accounted for by energy-dependent attenuation. The influence of radiation scattered within the media is ignored. Intensity patterns are modeled under the assumption that photons that are not interacting with the lens are blocked out at any point of interest. The main characteristics of the proposed calculation procedure are that (i) the application of vector formalism allows universal treatment of all cylindrical lenses without the need of explicit geometric constructs; (ii) intensity distributions resulting from x-ray diffraction are described by a 3D generalization of the mosaic spread concept; (iii) the calculation model can be immediately coupled to x-ray diffraction simulation packages such as XOP and Shadow. Numerical simulations based on this model are to facilitate the design of focused orthovoltage treatment (FOT) systems employing cylindrical x-ray lenses, by providing insight about the influence of the x-ray source and lens parameters on quantities of dosimetric interest to radiation therapy.

    View details for DOI 10.1088/0031-9155/53/3/001

    View details for Web of Science ID 000252792700001

    View details for PubMedID 18199899

  • Design of magnetic resonance imaging protocol for accelerated partial breast irradiation in prone position and estimation of treatment margin 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Ahn, K., Hargreaves, B. A., Alley, M. T., Horst, K. C., Daniel, B. L., Hristov, D. ELSEVIER SCIENCE INC. 2008: S510–S510
  • Adapting radiotherapy to hypoxic tumours PHYSICS IN MEDICINE AND BIOLOGY Malinen, E., Sovik, A., Hristov, D., Bruland, O. S., Olsen, D. R. 2006; 51 (19): 4903-4921


    In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO(2)-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO(2)-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO(2) Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO(2) values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields and step-and-shoot intensity levels). Simulated random and systematic errors in the pO(2)-related images reduced the TCP for the non-uniform dose prescription. In conclusion, improved tumour control of hypoxic tumours by dose redistribution may be expected following hypoxia imaging, tumour control predictions, inverse treatment planning and IMRT.

    View details for DOI 10.1088/0031-9155/51/19/012

    View details for Web of Science ID 000241083800012

    View details for PubMedID 16985278

  • A multi-platform approach to image guided radiation therapy (IGRT) MEDICAL DOSIMETRY Amies, C., Bani-Hashemi, A., Celi, J. C., Grousset, G., Ghelmansarai, F., Hristov, D., Lane, D., Mitschke, M., Singh, A., Shukla, H., Stein, J., Wofford, M. 2006; 31 (1): 12-19


    Siemens Medical Solutions, Oncology Care Systems Group (SMSOCSG) is supporting the development of several technologies that enable image acquisition and decision making processes required for IGRT in various clinical settings. Four such technologies are presented including: (i) the integration of a traditional multi-slice computed tomography (CT) scanner "on rails" with a C-arm gantry linear accelerator; (ii) the development of a high sensitivity, fast, megavoltage (MV) electronic portal imaging device capable of clinical MV Conebeam CT (MVCBCT) reconstruction and fluoroscopy mounted on a C-arm gantry linear accelerator; (iii) the modification of a mobile C-arm with flat panel kilovoltage (kV) diagnostic imager; and (iv) the development of an in-line megavoltage and kilovoltage flat panel imaging system that has the potential to image both anatomical and dosimetric information in "real-time" utilizing the traditional C-arm gantry linear accelerator geometry. Each method of IGRT has unique as well as complementary qualities which are discussed from both a clinical and technical perspective.

    View details for DOI 10.1016/j.meddos.2005.12.013

    View details for Web of Science ID 000236687500003

    View details for PubMedID 16551525

  • Dosimetric and microdosimetric study of contrast-enhanced radiotherapy with kilovolt x-rays PHYSICS IN MEDICINE AND BIOLOGY Verhaegen, F., Reniers, B., Deblois, F. O., Devic, S., Seuntjens, J., Hristov, D. 2005; 50 (15): 3555-3569


    Kilovolt x-rays are clearly suboptimal compared to MV photon beams for radiotherapy of deep-seated tumours because of the increased attenuation in tissue, causing a rapid dose fall-off. This picture could change drastically when tumours can be labelled with contrast medium, containing high atomic number elements. This causes a significant dose enhancement to the tumour by exploiting the high cross sections for the photo-electric effect for kV x-rays. In this work, we have investigated the dosimetric and microdosimetric characteristics of kV contrast-enhanced radiation therapy (CERT) for different photon energies, contrast-medium concentrations and types (I and Gd). Two idealized patient treatment plans (head and lung) for irradiation with CT-arc beams were calculated. It is shown that the dose enhancement in tumours can be highly significant (up to about sixfold for realistic 80-120 kVp x-ray spectra and an iodine concentration of 50 mg ml-1) but that dose homogeneity in the tumour depends on photon energy, contrast-medium concentration and type, and irradiation scheme. An attempt to optimize the irradiation scheme is discussed. The microdosimetric study of the dose mean lineal energy shows that radiation quality changes in the contrast-medium-labelled region compared to homogeneous tissue are fairly small and limited to 10%. It is concluded that kV-CERT is a promising radiotherapy technique, provided contrast medium can be delivered reliably to tumours.

    View details for DOI 10.1088/0031-9155/50/15/005

    View details for Web of Science ID 000231321600005

    View details for PubMedID 16030382

  • Monte Carlo based modulated electron beam treatment planning using a few-leaf electron collimator - feasibility study International Workshop on Current Topics in Monte Carlo Treatment Planning Al-Yahya, K., Hristov, D., Verhaegen, F., Seuntjens, J. IOP PUBLISHING LTD. 2005: 847–57


    Energy modulated electron beam therapy with conventional clinical accelerators has lagged behind photon IMRT despite its potential to achieve highly conformal dose distributions in superficial targets. One of the reasons for this is the absence of an automated collimating device that allows for the flexible delivery of a series of variable field openings. Electron-specific multileaf collimators attached to the bottom of the applicator require the use of a large number of motors and suffer from being relatively bulky and impractical for head and neck sites. In this work, we investigate the treatment planning aspects of a proposed 'few-leaf' electron collimator (FLEC) that consists of four motor-driven trimmer bars at the end of the applicator. The device is designed to serve as an accessory to standard equipment and allows for the shaping of any irregular field by combination of rectangular fieldlets. Using a Monte Carlo model of the FLEC, dose distributions are optimized using a simulated annealing (SA) inverse planning algorithm based on a limited number of Monte Carlo pre-generated, realistic phantom-specific dose kernels and user-specified dose-volume constraints. Using a phantom setup with an artificial target enclosed by organs at risk (OAR) as well as using a realistic patient case, we demonstrate that highly conformal distributions can be generated. Estimates of delivery times are made and show that a full treatment fraction can be kept to 15 min or less.

    View details for DOI 10.1088/0031-9155/50/5/009

    View details for Web of Science ID 000227886900010

    View details for PubMedID 15798259

  • Low-dose megavoltage cone-beam CT for radiation therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pouliot, J., Bani-Hashemi, A., Chen, J., Svatos, M., Ghelmansarai, F., Mitschke, M., Aubin, M., Xia, P., Morin, O., Bucci, K., Roach, M., Hernandez, P., Zheng, Z. R., Hristov, D., Verhey, L. 2005; 61 (2): 552-560


    The objective of this work was to demonstrate the feasibility of acquiring low-exposure megavoltage cone-beam CT (MV CBCT) three-dimensional (3D) image data of sufficient quality to register the CBCT images to kilovoltage planning CT images for patient alignment and dose verification purposes.A standard clinical 6-MV Primus linear accelerator, operating in arc therapy mode, and an amorphous-silicon (a-Si) flat-panel electronic portal-imaging device (EPID) were employed. The dose-pulse rate of 6-MV Primus accelerator beam was windowed to expose an a-Si flat panel by using only 0.02 to 0.08 monitor unit (MUs) per image. A triggered image-acquisition mode was designed to produce a high signal-to-noise ratio without pulsing artifacts. Several data sets were acquired for an anthropomorphic head phantom and frozen sheep and pig cadaver head, as well as for a head-and-neck cancer patient on intensity-modulated radiotherapy (IMRT). For each CBCT image, a set of 90 to 180 projection images incremented by 1 degree to 2 degrees was acquired. The two-dimensional (2D) projection images were then synthesized into a 3D image by use of cone-beam CT reconstruction. The resulting MV CBCT image set was used to visualize the 3D bony anatomy and some soft-tissue details. The 3D image registration with the kV planning CT was performed either automatically by application of a maximization of mutual information (MMI) algorithm or manually by aligning multiple 1D slices.Low-noise 3D MV CBCT images without pulsing artifacts were acquired with a total delivered dose that ranged from 5 to 15 cGy. Acquisition times, including image readout, were on the order of 90 seconds for 180 projection images taken through a continuous gantry rotation of 180 degrees. The processing time of the data required an additional 90 seconds for the reconstruction of a 256(3) cube with 1.0-mm voxel size. Implanted gold markers (1 mm x 3 mm) were easily visible or all exposure levels without artifacts. In general, the presence of high Z materials such as tooth fillings or implanted markers did not result in visible streak artifacts. The registration of structures such as the spinal canal and the nasopharynx in the MV CBCT and kV CT data sets was possible with millimeter and degree accuracy as assessed by displacement simulations and subsequent visual evaluation.We believe that the quality of these images, along with the rapid acquisition and reconstruction times, demonstrates that MV CBCT performed by use of a standard linear accelerator equipped with a flat-panel imager can be applied clinically for patient alignment.

    View details for DOI 10.1016/j.ijrobp.2004.10.011

    View details for Web of Science ID 000226700200032

    View details for PubMedID 15736320

  • Cone beam X-ray scatter removal via image frequency modulation and filtering 27th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society Maltz, J. S., Blanz, W., Hristov, D., Bani-Hashemi, A. IEEE. 2005: 1854–1857


    We present a novel method for rapid removal of patient scatter from cone beam (CB) projection images that requires no scatter measurement, physical modeling or strong assumptions regarding the spatial smoothness of the scatter distribution. Method: A modulator grid is placed between the imaged distribution and the detector that differentially frequency modulates primary and scattered photons. When photons travel through the grid, photons that originate directly from the CB source are modulated by a higher frequency than scattered photons that have more proximal, diffusely distributed sources. We employ non-linear Fourier domain filtering to attenuate the contribution of scatter to the image spectrum. The theoretical validity of the method is verified using linear analysis of planar sources and its performance is evaluated using a simulator based on this analytical model. Results: Simulation experiments with an ideal modulator indicate that even unrealistically large amounts of scatter are almost entirely removed by this method. The recovered images are devoid of major artifacts and exhibit an RMS error of 10%. Conclusions: We have verified the theoretical validity of scatter removal via spatial frequency modulation. A disadvantage of the technique is that it will always produce a filtered image having at best 0.41 of the maximum detector resolution when maximum scatter rejection is desired. This is not a major consideration in most medical X-ray CB imaging applications using contemporary detector technology, especially since scatter often significantly reduces useful resolution.

    View details for Web of Science ID 000238998401210

    View details for PubMedID 17282580

  • Inverse treatment planning by physically constrained minimization of a biological objective function MEDICAL PHYSICS Stavrev, P., Hristov, D., Warkentin, B., Sham, E., Stavreva, N., Fallone, B. G. 2003; 30 (11): 2948-2958


    In the current state-of-the art of clinical inverse planning, the design of clinically acceptable IMRT plans is predominantly based on the optimization of physical rather than biological objective functions. A major impetus for this trend is the unproven predictive power of radiobiological models, which is largely due to the scarcity of data sets for an accurate evaluation of the model parameters. On the other hand, these models do capture the currently known dose-volume effects in tissue dose-response, which should be accounted for in the process of optimization. In order to incorporate radiobiological information in clinical treatment planning optimization, we propose a hybrid physico-biological approach to inverse treatment planning based on the application of a continuous penalty function method to the constrained minimization of a biological objective. The objective is defined as the weighted sum of normal tissue complication probabilities evaluated with the Lyman normal-tissue complication probability model. Physical constraints specify the admissible minimum and maximum target dose. The continuous penalty function method is then used to find an approximate solution of the resulting large-scale constrained minimization problem. Plans generated by our approach are compared to ones produced by a commercial planning system incorporating physical optimization. The comparisons show clinically negligible differences, with the advantage that the hybrid technique does not require specifications of any dose-volume constraints to the normal tissues. This indicates that the proposed hybrid physico-biological method can be used for the generation of clinically acceptable plans.

    View details for DOI 10.1118/1.1617411

    View details for Web of Science ID 000186596900012

    View details for PubMedID 14655942

  • On the selection of optimization parameters for an inverse treatment planning replacement of a forward planning technique for prostate cancer. Journal of applied clinical medical physics Hristov, D. H., Moftah, B. A., Charrois, C., Parker, W., Souhami, L., Podgorsak, E. B. 2002; 3 (3): 200-211


    The influence of organ volume sampling, lateral scatter inclusion, and the selection of objectives and constraints on the inverse treatment planning process with a commercial treatment planning system is investigated and suitable parameters are identified for an inverse treatment planning replacement of a clinical forward planning technique for prostate cancer. For the beam geometries of the forward technique, a variable set of parameters is used for the calculation of dose from pencil beams. An optimal set is identified after the evaluation of optimized plans that correspond to different sets of pencil-beam parameters. This set along with a single, optimized set of objectives and constraints is used to perform inverse planning on ten randomly selected patients. The acceptability of the resulting plans is verified by comparisons to the clinical ones calculated with the forward techniques. For the particular commercial treatment planning system, the default values of the pencil beam parameters are found adequate for inverse treatment planning. For all ten patients, the optimized, single set of objectives and constraints results in plans with target coverage comparable to that of the forward plans. Furthermore inverse treatment planning reduces the overall mean rectal and bladder doses by 4.8% and 5.8% of the prescription dose respectively. The study indicates that (i) inverse treatment planning results depend implicitly on the sampling of the dose distribution, (ii) inverse treatment planning results depend on the method used by the dose calculation model to account for scatter, and (iii) for certain sites, a single set of optimization parameters can be used for all patient plans.

    View details for PubMedID 12132941

  • On the implementation of dose-volume objectives in gradient algorithms for inverse treatment planning MEDICAL PHYSICS Hristov, D., Stavrev, P., Sham, E., Fallone, B. G. 2002; 29 (5): 848-856


    A method that allows a straightforward implementation of dose-volume constraints in gradient algorithms for inverse treatment planning is presented. The method is consistent with the penalty function approach, which requires the formulation of an objective function with penalty terms proportional to the magnitudes of constraint violations. Dose constraints with respect to minimum and maximum target dose levels are incorporated in quadratic, dose-penalty terms. Analogously, quadratic volume-penalty terms in the objective function reflect the violation of dose-volume constraints imposing limits on the fractions of healthy organ volumes that can be irradiated above specified dose levels. It has been demonstrated that within the framework of this formulation neither modified objective functions nor finite difference gradient calculations are necessary for the incorporation of gradient minimization algorithms. As an example, a simple steepest descent algorithm is presented along with its application to illustrate prostate and lung cases.

    View details for DOI 10.1118/1.1469629

    View details for Web of Science ID 000175675000023

    View details for PubMedID 12033581

  • On the consistent use of organ definitions and radiobiological models for the evaluation of complication probabilities of "tubular" organs INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Stavrev, P. V., Hristov, D. H., Seuntjens, J. P. 2002; 52 (4): 1150-1152

    View details for Web of Science ID 000174318500049

    View details for PubMedID 11958926

  • Intensity modulated radiation therapy for thyroid malignancies 22nd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society Parker, W., Hristov, D., Moftah, B. A., Vuong, T., Tsien, C., Podgorsak, E. B. IEEE. 2000: 1538–1541
  • Three-dimensional anatomy setup verification by correlation of orthogonal portal images and digitally reconstructed radiographs MEDICAL PHYSICS Sirois, L. M., Hristov, D. H., Fallone, B. G. 1999; 26 (11): 2422-2428


    A method for three-dimensional verification of anatomy setup that uses the correlation of portal images and reference megavoltage digitally reconstructed radiographs (MDRRs) is presented. Prior to a treatment, an orthogonal pair of portal images is acquired from which subimages containing anatomical features are selected. These subimages are consequently matched to MDRRs that represent different rotations of the anatomy around axes going through the treatment isocenter. The Pearson correlation coefficient is employed for the matching since it is invariant with respect to global scaling and shifting of the image intensities. Furthermore, it does not require feature extraction or point-pair identification. The greatest value of the correlation coefficient corresponds to the proper rotational alignment of the anatomy and the location of the correlation maximum in each view indicates the translational shifts of the anatomy. The mean accuracy of translation and rotation registrations tests were a fraction of a millimeter and a fraction of a degree, respectively, for MDRR-to-MDRR matching. For portal-to-MDRR matching, the mean translation registration error is on the order of 1 mm and the mean error in radial displacement is of the order of 2.7 mm.

    View details for Web of Science ID 000083775800030

    View details for PubMedID 10587227

  • A continuous penalty function method for inverse treatment planning MEDICAL PHYSICS Hristov, D. H., Fallone, B. G. 1998; 25 (2): 208-223


    Conventional inverse treatment planning attempts to calculate dose distributions that may not be feasible given the specified dose levels to various anatomical structures. A technique for inverse treatment planning has been developed that uses only target dose levels which are easily selectable to be feasible. A nonlinear constrained minimization problem is formulated to reflect the goal of sparing critical organs as much as possible while delivering a certain target dose within specified uniformity. The objective function is the squared dose delivered to critical organs. The constraints require the delivery of certain target dose within specified uniformity and non-negative pencil beam weights. A continuous penalty function method is introduced as a method for solving the large-scale constrained minimization problem. The performance of the continuous penalty function method is optimized by numerical investigation of few numerical integration schemes and a pair of weighting functions which influence the utility of the method. Clinical examples are presented that illustrate several features of the technique. The properties of the continuous penalty function method suggest that it may be a viable alternative to conventional inverse treatment planning.

    View details for Web of Science ID 000072063400010

    View details for PubMedID 9507482

  • An active set algorithm for treatment planning optimization MEDICAL PHYSICS Hristov, D. H., Fallone, B. G. 1997; 24 (9): 1455-1464


    An active set algorithm for optimization of radiation therapy dose planning by intensity modulated beams has been developed. The algorithm employs a conjugate-gradient routine for subspace minimization in order to achieve a higher rate of convergence than the widely used constrained steepest-descent method at the expense of a negligible amount of overhead calculations. The performance of the new algorithm has been compared to that of the constrained steepest-descent method for various treatment geometries and two different objectives. The active set algorithm is found to be superior to the constrained steepest descent, both in terms of its convergence properties and the residual value of the cost functions at termination. Its use can significantly accelerate the design of conformal plans with intensity modulated beams by decreasing the number of time-consuming dose calculations.

    View details for Web of Science ID A1997XV90400010

    View details for PubMedID 9304574

  • A grey-level image alignment algorithm for registration of portal images and digitally reconstructed radiographs MEDICAL PHYSICS Hristov, D. H., Fallone, B. G. 1996; 23 (1): 75-84


    An algorithm for automatic registration of pairs of portal images based on image correlation is presented. It uses a fast-Fourier-transform-based cross-correlation operator to find the optimal registration, accounting for both in-plane translations and rotations. Different cross-correlation operators have been tested: the Pearson linear correlation coefficient has been implemented by fast Fourier transform and its performance has been compared to that of the more conventional normalized cross-correlation. A sequential approach has been applied to speed up the registration considerably without degrading the performance of the algorithm. The algorithm has also been applied to the automatic registration of portal images to digitally reconstructed radiographs (DRRs), which have been modified to resemble megavoltage images. The results are indicative of the feasibility of this approach to the inspection of patient setup in radiation therapy.

    View details for Web of Science ID A1996TR49900009

    View details for PubMedID 8700035