Wu Liu is an associate professor and clinical medical physicist at Department of Radiation Oncology, Stanford University, Stanford, CA, USA. He was born and raised in Beijing, China. He received B.S. degree in Astronomy from Nanjing University, Nanjing, China and M.S. degree in Astrophysics from Chinese Academy of Sciences, Beijing, China. He obtained his M.S. degree in Computer Science and Ph.D. degree in Medical Physics (2007) from University of Wisconsin-Madison, Madison, WI, USA. He then completed his postdoctoral training at Stanford University. Before re-joining Stanford, he was a medical physicist at Yale-New Haven hospital and an assistant professor at Yale University.

Academic Appointments

Professional Education

  • PhD, University of Wisconsin-Madison, Medical Physics
  • MS, University of Wisconsin-Madison, Computer Sciences
  • MS, Graduate School of Chinese Academy of Science, Beijing, China, Astrophysics
  • BS, Nanjing University, Nanjing, China, Astronomy

Current Research and Scholarly Interests

Theranostic nanoparticles for radiosensitization and medical imaging. Novel treatment technique for ocular disease radiotherapy. Radio-neuromodulation using focused kV x-rays. Use artificial intelligence in image and biological guided radiotherapy and medical image analysis (PET, x-ray, and CT images). Ultrasound parametric imaging.

Tumor-targeted delivery and cell internalization of theranostic gadolinium nanoparticles for image-guided nanoparticle-enhanced radiation therapy
The goal of this research is to develop gadolinium nanoparticles linked to pH-Low Insertion Peptides as a novel means for simultaneously imaging and radiosensitizing solid tumors and to develop a novel mechanistic biophysical model to predict radiosensitization by nanoparticles. Conjugation of pHLIP to gadolinium nanoparticles actively targets solid tumors’ acidic microenvironment and also delivers cell-impermeable, radiation sensitizing nanoparticles into cancer cells, which is critical for the nanoparticle-induced short-range Auger and photoelectrons to reach the vital cellular targets. The magnetic resonance imaging property of gadolinium can be used to examine in vivo nanoparticle distributions and facilitate enhanced quantitative treatment planning for radiation therapy.

Focused kV X-ray Modulated Conformal Radiotherapy for Small Targets
The proposed focused kV x-ray technique by polycapillary lens can deliver personalized highly-conformal radiation treatment to small targets a few millimeters in size, which is not possible by current radiation devices, and has numerous potential applications in medicine. It can treat neovascular age-related macular degeneration of different sizes with conformal lesion coverage in contrast to the current way of using collimated divergent beams to deliver a universal treatment to all patients resulting in incomplete dosimetric coverage and/or toxic treatment. The ability of conformally treating ultrasmall targets also enables a new set of preclinical small animal researches with target sizes comparable to the relative sizes in humans, such as radiation-based neuromodulation, which can alter local neuronal function without ablative nerve destruction.

2023-24 Courses

All Publications

  • Adaptive Region-Specific Loss for Improved Medical Image Segmentation. IEEE transactions on pattern analysis and machine intelligence Chen, Y., Yu, L., Wang, J., Panjwani, N., Obeid, J., Liu, W., Liu, L., Kovalchuk, N., Gensheimer, M. F., Vitzthum, L. K., Beadle, B. M., Chang, D. T., Le, Q., Han, B., Xing, L. 2023; PP


    Defining the loss function is an important part of neural network design and critically determines the success of deep learning modeling. A significant shortcoming of the conventional loss functions is that they weight all regions in the input image volume equally, despite the fact that the system is known to be heterogeneous (i.e., some regions can achieve high prediction performance more easily than others). Here, we introduce a region-specific loss to lift the implicit assumption of homogeneous weighting for better learning. We divide the entire volume into multiple sub-regions, each with an individualized loss constructed for optimal local performance. Effectively, this scheme imposes higher weightings on the sub-regions that are more difficult to segment, and vice versa. Furthermore, the regional false positive and false negative errors are computed for each input image during a training step and the regional penalty is adjusted accordingly to enhance the overall accuracy of the prediction. Using different public and in-house medical image datasets, we demonstrate that the proposed regionally adaptive loss paradigm outperforms conventional methods in the multi-organ segmentations, without any modification to the neural network architecture or additional data preparation.

    View details for DOI 10.1109/TPAMI.2023.3289667

    View details for PubMedID 37363838

  • High resolution imaging with focused kV x-rays for small animal radio-neuromodulation. Medical physics Shi, L., Bennett, N. R., Nguyen, E., MacDonald, C., Wang, A., Liu, W. 2023


    High precision radiotherapy with small irradiator size has potential in many treatment applications involving small shallow targets, with small animal radio-neuromodulation as an intriguing example. A focused kV technique based on novel usage of polycapillary x-ray lenses can focus x-ray beams to <0.2 mm in diameter, which is ideal for such uses.Such an application also requires high resolution CT images for treatment planning and setup. In this work, we demonstrate the feasibility of using a virtual focal spot generated with an x-ray lens to perform high-resolution CBCT acquisition.The experiment with x-ray lens was set up on an x-ray tabletop system to generate a virtual focal spot. The flood field images with and without the x-ray lens were first compared. A pinhole image was acquired for the virtual focal spot and compared with the one acquired with the conventional focal spot without the lens. The planar imaging resolution with and without the lens were evaluated using a line pair resolution phantom. The spatial resolution of the two settings were estimated by reconstructing a 0.15-mm wire phantom and comparing its full width half maximum (FWHM). A CBCT scan of a rodent head was also acquired to further demonstrate the improved resolution using the x-ray lens.The proposed imaging setup with x-ray lens had a limited exposure area of 5 cm by 5 cm on the detector, which was suitable for guiding radio-neuromodulation to a small target in rodent brain. Compared to conventional imaging acquisition with a measured x-ray focal spot of 0.395 mm FWHM, the virtual focal spot size was measured at 0.175 mm. The reduction in focal spot size with lens leads to an almost doubled planar imaging resolution and a 26% enhancement in 3D spatial resolution. A realistic CBCT acquisition of a rodent head mimicked the imaging acquisition step for radio-neuromodulation and further showed the improved visualization for fine structures.This work demonstrated that the focused kV x-ray technique was capable of generating small focal spot size of <0.2 mm, which substantially improved x-ray imaging resolution for small animal imaging.

    View details for DOI 10.1002/mp.16413

    View details for PubMedID 37060293

  • 3D printing in brachytherapy: A systematic review of gynecological applications. Brachytherapy Fahimian, B. P., Liu, W., Skinner, L., Yu, A. S., Phillips, T., Steers, J. M., DeMarco, J., Fraass, B. A., Kamrava, M. 2023


    PURPOSE: To provide a systematic review of the applications of 3D printing in gynecological brachytherapy.METHODS: Peer-reviewed articles relating to additive manufacturing (3D printing) from the 34 million plus biomedical citations in National Center for Biotechnology Information (NCBI/PubMed), and 53 million records in Web of Science (Clarivate) were queried for 3D printing applications. The results were narrowed sequentially to, (1) all literature in 3D printing with final publications prior to July 2022 (in English, and excluding books, proceedings, and reviews), and then to applications in, (2) radiotherapy, (3) brachytherapy, (4) gynecological brachytherapy. Brachytherapy applications were reviewed and grouped by disease site, with gynecological applications additionally grouped by study type, methodology, delivery modality, and device type.RESULTS: From 47,541 3D printing citations, 96 publications met the inclusion criteria for brachytherapy, with gynecological clinical applications compromising the highest percentage (32%), followed by skin and surface (19%), and head and neck (9%). The distribution of delivery modalities was 58% for HDR (Ir-192), 35% for LDR (I-125), and 7% for other modalities. In gynecological brachytherapy, studies included design of patient specific applicators and templates, novel applicator designs, applicator additions, quality assurance and dosimetry devices, anthropomorphic gynecological applicators, and in-human clinical trials. Plots of year-to-year growth demonstrate a rapid nonlinear trend since 2014 due to the improving accessibility of low-cost 3D printers. Based on these publications, considerations for clinical use are provided.CONCLUSIONS: 3D printing has emerged as an important clinical technology enabling customized applicator and template designs, representing a major advancement in the methodology for implantation and delivery in gynecological brachytherapy.

    View details for DOI 10.1016/j.brachy.2023.02.002

    View details for PubMedID 37024350

  • Radio-luminescent imaging for rapid, high resolution eye plaque loading verification. Medical physics Yan, H., De Jean, P., Grafil, E., Ashraf, R., Niedermayr, T., Astrahan, M., Mruthyunjaya, P., Beadle, B., Xing, L., Liu, W. 2022


    BACKGROUND: Eye plaque brachytherapy (EPB) is currently an optimal therapy for intraocular cancers. Due to the lack of an effective and practical technique to measure the seed radioactivity distribution, current quality assurance (QA) practice according to the AAPM TG129 only stipulates that the plaque assembly be visually inspected. Consequently, uniform seed activity is routinely adopted to avoid possible loading mistakes of differential seed loading. However, modulated dose delivery, which represents a general trend in radiotherapy to provide more personalized treatment for a given tumor and patient, requires differential activities in the loaded seeds.PURPOSE: In this study, a fast and low-cost radio-luminescent imaging and dose calculating system to verify the seed activity distribution for differential loading was developed.METHODS: A proof-of-concept system consisting of a thin scintillator sheet coupled to a camera/lens system was constructed. A seed-loaded plaque can be placed directly on the scintillator surface with the radioactive seeds facing the scintillator. The camera system collects the radioluminescent signal generated by the scintillator at its opposite side. The predicted dose distribution in the scintillator's sensitive layer was calculated using a Monte Carlo simulation with the planned plaque loading pattern of I-125 seeds. Quantitative comparisons of the distribution of relative measured signal intensity and that of the relative predicted dose in the sensitive layer were performed by gamma analysis, similar to IMRT QA.RESULTS: Data analyses showed high gamma (3%/0.3mm, global, 20% threshold) passing rates for correct seed loadings and low passing rates with distinguished high gamma value area for incorrect loadings, indicating that possible errors may be detected. The measurement and analysis only required a few extra minutes, significantly shorter than the time to assay the extra verification seeds the physicist already must perform as recommended by TG129.CONCLUSIONS: Radio-luminescent QA can be used to facilitate and assure the implementation of intensity modulated, customized plaque loading. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/mp.16003

    View details for PubMedID 36183146

  • Intravitreal brolucizumab as treatment of early onset radiation retinopathy secondary to plaque brachytherapy for choroidal melanoma. American journal of ophthalmology case reports Villegas, N. C., Mishra, K., Steinle, N., Liu, W., Beadle, B., Mruthyunjaya, P. 2022; 27: 101581


    Purpose: To describe the efficacy and safety of brolucizumab (Beovu, Novartis Pharmaceuticals) in a case of cystoid macular edema associated with radiation retinopathy as a result of iodine-125 plaque brachytherapy (PBT) for choroidal melanoma, resistant to treatment with other anti-vascular endothelial growth factor (VEGF) agents.Observations: A 67-year-old woman with choroidal melanoma in the right eye and best-corrected visual acuity (BCVA) of 20/20, underwent uncomplicated PBT. On post-operative month 7, the patient developed early onset radiation retinopathy. She failed to improve significantly with sub-tenon triamcinolone and 3 injections of intravitreal bevacizumab; BCVA was 20/200. Intravitreal brolucizumab was administered, and one month after, macular edema had resolved completely on optical coherence tomography, and BCVA improved to 20/50. At last follow up, 1 month after the third brolucizumab injection, BCVA was 20/60 and there was sustained resolution of intraretinal fluid. There were no signs of intraocular inflammation, progressive RR or optic neuropathy on exam or fluorescein angiography.Conclusions: This case suggests a positive effect of brolucizumab in the management of radiation retinopathy following PBT refractory to other anti-VEGF agents. However, one must consider the risk of severe vision loss associated with retinal vasculitis from use of brolucizumab.

    View details for DOI 10.1016/j.ajoc.2022.101581

    View details for PubMedID 35599950

  • Microdosimetric Investigation and a Novel Model of Radiosensitization in the Presence of Metallic Nanoparticles. Pharmaceutics Yan, H., Carlson, D. J., Abolfath, R., Liu, W. 1800; 13 (12)


    Auger cascades generated in high atomic number nanoparticles (NPs) following ionization were considered a potential mechanism for NP radiosensitization. In this work, we investigated the microdosimetric consequences of the Auger cascades using the theory of dual radiation action (TDRA), and we propose the novel Bomb model as a general framework for describing NP-related radiosensitization. When triggered by an ionization event, the Bomb model considers the NPs that are close to a radiation sensitive cellular target, generates dense secondary electrons and kills the cells according to a probability distribution, acting like a "bomb." TDRA plus a distance model were used as the theoretical basis for calculating the change in alpha of the linear-quadratic survival model and the relative biological effectiveness (RBE). We calculated these quantities for SQ20B and Hela human cancer cells under 250 kVp X-ray irradiation with the presence of gadolinium-based NPs (AGuIXTM), and 220 kVp X-ray irradiation with the presence of 50 nm gold NPs (AuNPs), respectively, and compared with existing experimental data. Geant4-based Monte Carlo (MC) simulations were used to (1) generate the electron spectrum and the phase space data of photons entering the NPs and (2) calculate the proximity functions and other related parameters for the TDRA and the Bomb model. The Auger cascade electrons had a greater proximity function than photoelectric and Compton electrons in water by up to 30%, but the resulting increases in alpha were smaller than those derived from experimental data. The calculated RBEs cannot explain the experimental findings. The relative increase in alpha predicted by TDRA was lower than the experimental result by a factor of at least 45 for SQ20B cells with AGuIX under 250 kVp X-ray irradiation, and at least four for Hela cells with AuNPs under 220 kVp X-ray irradiation. The application of the Bomb model to Hela cells with AuNPs under 220 kVp X-ray irradiation indicated that a single ionization event for NPs caused by higher energy photons has a higher probability of killing a cell. NPs that are closer to the cell nucleus are more effective for radiosensitization. Microdosimetric calculations of the RBE for cell death of the Auger electron cascade cannot explain the experimentally observed radiosensitization by AGuIX or AuNP, while the proposed Bomb model is a potential candidate for describing NP-related radiosensitization at low NP concentrations.

    View details for DOI 10.3390/pharmaceutics13122191

    View details for PubMedID 34959471

  • MR to Ultrasound Image Registration with Segmentation-Based Learning for HDR Prostate Brachytherapy Chen, Y., Xing, L., Yu, L., Liu, W., Fahimian, B., Niedermayr, T., Bagshaw, H., Buyyounouski, M., Han, B. WILEY. 2021
  • MR to ultrasound image registration with segmentation-based learning for HDR prostate brachytherapy. Medical physics Chen, Y. n., Xing, L. n., Yu, L. n., Liu, W. n., Fahimian, B. P., Niedermayr, T. n., Bagshaw, H. P., Buyyounouski, M. n., Han, B. n. 2021


    Propagation of contours from high-quality magnetic resonance (MR) images to treatment planning ultrasound (US) images with severe needle artifacts is a challenging task, which can greatly aid the organ contouring in high dose rate (HDR) prostate brachytherapy. In this study, a deep learning approach was developed to automatize this registration procedure for HDR brachytherapy practice.Because of the lack of training labels and difficulty of accurate registration from inferior image quality, a new segmentation-based registration framework was proposed for this multi-modality image registration problem. The framework consisted of two segmentation networks and a deformable registration network, based on the weakly-supervised registration strategy. Specifically, two 3D V-Nets were trained for the prostate segmentation on the MR and US images separately, to generate the weak supervision labels for the registration network training. Besides the image pair, the corresponding prostate probability maps from the segmentation were further fed to the registration network to predict the deformation matrix, and an augmentation method was designed to randomly scale the input and label probability maps during the registration network training. The overlap between the deformed and fixed prostate contours was analyzed to evaluate the registration accuracy. Three datasets were collected from our institution for the MR and US image segmentation networks, and the registration network learning, which contained 121, 104 and 63 patient cases, respectively.The mean Dice similarity coefficient (DSC) results of the two prostate segmentation networks are 0.86±0.05 and 0.90±0.03, for MR images and the US images after the needle insertion, respectively. The mean DSC, center-of-mass (COM) distance, Hausdorff distance (HD) and averaged symmetric surface distance (ASSD) results for the registration of manual prostate contours were 0.87±0.05, 1.70±0.89 mm, 7.21±2.07 mm, 1.61±0.64 mm, respectively. By providing the prostate probability map from the segmentation to the registration network, as well as applying the random map augmentation method, the evaluation results of the four metrics were all improved, such as an increase of DSC from 0.83±0.08 to 0.86±0.06 and from 0.86±0.06 to 0.87±0.05, respectively.A novel segmentation-based registration framework was proposed to automatically register prostate MR images to the treatment planning US images with metal artifacts, which not only largely saved the labor work on the data preparation, but also improved the registration accuracy. The evaluation results showed the potential of this approach in HDR prostate brachytherapy practice.

    View details for DOI 10.1002/mp.14901

    View details for PubMedID 33905566

  • Precision radiotherapy using monochromatic inverse Compton x-ray sources. Medical physics Simiele, E. A., Breitkreutz, D. Y., Capaldi, D. P., Liu, W., Bush, K. K., Skinner, L. B. 2020


    PURPOSE: The dosimetric properties of Inverse Compton (IC) x-ray sources were investigated to determine their utility for stereotactic radiation therapy.METHODS: Monte Carlo simulations were performed using the egs brachy user code of EGSnrc. Nominal IC source x-ray energies of 80 keV and 150 keV were considered in this work. Depth-dose and lateral dose-profiles in water were calculated, as was dose enhancement in bone. Further simulations were performed for brain and spine treatment sites. The impact of gold nanoparticle doping was also investigated for the brain treatment site. Analogous dose calculations were performed in a clinical treatment planning system using a clinical 6 MV photon beam model and were compared to the Monte Carlo simulations.RESULTS: Both 80 keV and 150 keV IC beams were observed to have sharp 80-20 penumbra (i.e., < 0.1 mm) with broad low-dose tails in water. For reference, the calculated penumbra for the 6 MV clinical beam was 3 mm. Maximum dose enhancement factors in bone of 3.1, 1.4, and 1.1 were observed for the 80 keV, 150keV, and clinical 6 MV beams, respectively. The plan quality for the single brain metastasis case was similar between the IC beams and the 6 MV beam without gold nanoparticles. As the concentration of gold within the target increased, the V12 Gy to the normal brain tissue and Dmax within the target volume significantly decreased and the conformity significantly improved, which resulted in superior plan quality over the clinical 6 MV beam plan. In the spine cases, the sharp penumbra and enhanced dose to bone of the IC beams produced superior plan quality (i.e., better conformity, normal tissue sparing, and spinal cord sparing) as compared to the clinical 6 MV beam plans.CONCLUSIONS: The findings from this work indicate that inverse Compton x-ray sources are well-suited for stereotactic radiotherapy treatments due to their sharp penumbra and dose enhancement around high atomic-number materials. Future work includes investigating the properties of intensity-modulated inverse Compton x-ray sources to improve the homogeneity within the target tissue.

    View details for DOI 10.1002/mp.14552

    View details for PubMedID 33107049

  • Practice Patterns for the Treatment of Uveal Melanoma with Iodine-125 Plaque Brachytherapy: Ocular Oncology Study Consortium Report 5. Ocular oncology and pathology Binder, C., Mruthyunjaya, P., Schefler, A. C., Seider, M. I., Crilly, R., Hung, A., Meltsner, S., Mowery, Y., Kirsch, D. G., Teh, B. S., Jennelle, R. L., Studenski, M. T., Liu, W., Lee, C., Hayman, J. A., Kastner, B., Hadsell, M., Skalet, A. H. 2020; 6 (3): 210-218


    Treatment planning for I-125 plaque therapy for uveal melanoma has advanced significantly since the Collaborative Ocular Melanoma Study trial, with more widely available image-guided planning and improved dosimetry.We evaluated real-world practice patterns for I-125 plaque brachytherapy in the United States by studying practice patterns at centers that comprise the Ocular Oncology Study Consortium (OOSC).The OOSC database and responses to a treatment practice survey were evaluated. The database contains treatment information from 9 institutions. Patients included in the database were treated between 2010 and 2014. The survey was conducted in 2018 and current treatment planning methods and prescriptions were queried.Examination of the OOSC database revealed that average doses to critical structures were highly consistent, with the exception of one institution. Survey responses indicated that most centers followed published guidelines regarding dose and prescription point. Dose rate ranged from 51 to 118 cGy/h. As of 2018, most institutions use pre-loaded plaques and fundus photographs and/or computed tomography or magnetic resonance imaging in planning.While there were differences in dosimetric practices, overall agreement in plaque brachytherapy practices was high among OOSC institutions. Clinical margins and planning systems were similar among institutions, while prescription dose, dose rates, and dosimetry varied.

    View details for DOI 10.1159/000504312

    View details for PubMedID 32509767

    View details for PubMedCentralID PMC7250354

  • Dosimetry Modeling of Focused kV X-ray Radiotherapy for Wet Age-related Macular Degeneration. Medical physics Yan, H. n., Sun, W. n., Mruthyunjaya, P. n., Beadle, B. n., Yu, W. n., Kanwal, B. n., MacDonald, C. A., Liu, W. n. 2020


    Wet (neovascular) age-related macular degeneration (AMD) is the leading cause of blindness in the USA. The mainstay treatment requires monthly intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs, associated with multiple visits, high cost, and the risk of procedural injury and infection. Anti-VEGF drugs inhibit the formation of neovasculature but do not directly attack it. Radiotherapy can destroy neovasculature and potentially also inhibit wet-AMD associated inflammation and fibrosis not addressed by VEGF inhibitors. However, the current collimation-based radiotherapy device uses fixed 4 mm beams, which are prone to overtreat or undertreat the choroidal neovascularization (CNV) lesions because of their various sizes and shapes. This simulation study evaluates personalized conformal treatment with focused kV radiation using cutting-edge polycapillary x-ray optics.Simulation of the polycapillary optics was achieved via Monte Carlo (MC)-based 3D geometric ray tracing. Phase-space files modeling the focused photons were generated. The method was previously verified by phantom measurements. The ultrasmall ~0.2 mm beam focal spot perpendicular to the beam direction enables spatially fractionated grid therapy, which has been shown to preferentially damage abnormal neovascular blood vessels vs normal ones. Geant4-based MC simulations of scanning while rotating beam delivery were performed to conformally treat three clinical cases of large, medium, and small CNV lesions with regular and grid deliveries. Dose delivery uncertainties due to positioning errors were analyzed, including ±0.75 mm displacement in the three orthogonal directions and ±5° vertical/horizontal rotation of the eyeball.The simulated CNV treatments by 60 kVp focused x-ray beams show highly-conformal delivery of dose to the lesion plus margin (0.75 mm) with sharp dose fall-offs and controllable spatial modulation patterns. The 90%-10% isodose penumbra is <0.5 mm. With a 16 Gy prescription dose to the lesions, the critical structure doses are well below the tolerance. The average CNV dose varies within 10% (mostly within 4%) due to 0.75-mm linear displacements and 5-degree gaze angle rotation of the eyeball.Focused kV technique allows personalized treatment of CNV lesions and reduces unwanted radiation to adjacent healthy tissue. The simulated dose distribution is superior to currently available techniques.

    View details for DOI 10.1002/mp.14404

    View details for PubMedID 32683708

  • Tumor-targeted pH-low insertion peptide delivery of theranostic gadolinium nanoparticles for image-guided nanoparticle-enhanced radiation therapy. Translational oncology Liu, W. n., Deacon, J. n., Yan, H. n., Sun, B. n., Liu, Y. n., Hegan, D. n., Li, Q. n., Coman, D. n., Parent, M. n., Hyder, F. n., Roberts, K. n., Nath, R. n., Tillement, O. n., Engelman, D. n., Glazer, P. n. 2020; 13 (11): 100839


    Tumor targeting studies using metallic nanoparticles (NPs) have shown that the enhanced permeability and retention effect may not be sufficient to deliver the amount of intratumoral and intracellular NPs needed for effective in vivo radiosensitization. This work describes a pH-Low Insertion Peptide (pHLIP) targeted theranostic agent to enable image-guided NP-enhanced radiotherapy using a clinically feasible amount of injected NPs. Conventional gadolinium (Gd) NPs were conjugated to pHLIPs and evaluated in vitro for radiosensitivity and in vivo for mouse MRI. Cultured A549 human lung cancer cells were incubated with 0.5 mM of pHLIP-GdNP or conventional GdNP. Mass spectrometry showed 78-fold more cellular Gd uptake with pHLIP-GdNPs, and clonogenic survival assays showed 44% more enhanced radiosensitivity by 5 Gy irradiation with pHLIP-GdNPs at pH 6.2. In contrast to conventional GdNPs, MR imaging of tumor-bearing mice showed pHLIP-GdNPs had a long retention time in the tumor (>9 h), suitable for radiotherapy, and penetrated into the poorly-vascularized tumor core. The Gd-enhanced tumor corresponded with low-pH areas also independently measured by an in vivo molecular MRI technique. pHLIPs actively target cell surface acidity from tumor cell metabolism and deliver GdNPs into cells in solid tumors. Intracellular delivery enhances the effect of short-range radiosensitizing photoelectrons and Auger electrons. Because acidity is a general hallmark of tumor cells, the delivery is more general than antibody targeting. Imaging the in vivo NP biodistribution and more acidic (often more aggressive) tumors has the potential for quantitative radiotherapy treatment planning and pre-selecting patients who will likely benefit more from NP radiation enhancement.

    View details for DOI 10.1016/j.tranon.2020.100839

    View details for PubMedID 32763504

  • Adaptive Imaging Versus Periodic Surveillance for Intrafraction Motion Management During Prostate Cancer Radiotherapy TECHNOLOGY IN CANCER RESEARCH & TREATMENT Ma, X., Yan, H., Nath, R., Chen, Z., Li, H., Liu, W. 2019; 18: 1533033819844489


    To evaluate the benefits of adaptive imaging with automatic correction compared to periodic surveillance strategies with either manual or automatic correction.Using Calypso trajectories from 54 patients with prostate cancer at 2 institutions, we simulated 5-field intensity-modulated radiation therapy and dual-arc volumetric-modulated arc therapy with periodic imaging at various frequencies and with continuous adaptive imaging, respectively. With manual/automatic correction, we assumed there was a 30/1 second delay after imaging to determine and apply couch shift. For adaptive imaging, real-time "dose-free" cine-MV images during beam delivery are used in conjunction with online-updated motion pattern information to estimate 3D displacement. Simultaneous MV-kV imaging is only used to confirm the estimated overthreshold motion and calculate couch shift, hence very low additional patient dose from kV imaging.Without intrafraction intervention, the prostates could on average have moved out of a 3-mm margin for ∼20% of the beam-on time after setup imaging in current clinical situation. If the time interval from the setup imaging to beam-on can be reduced to only 30 seconds, the mean over-3 mm percentage can be reduced to ∼7%. For intensity-modulated radiation therapy simulation, with manual correction, 110 and 70 seconds imaging periods both reduced the mean over-3 mm time to ∼4%. Automatic correction could give another 1% to 2% improvement. However, with either manual or automatic correction, the maximum patient-specific over-3 mm time was still relatively high (from 6.4% to 12.6%) and those patients are actually clinically most important. In contrast, adaptive imaging with automatic intervention significantly reduced the mean percentage to 0.6% and the maximum to 2.7% and averagely only ∼1 kV image and ∼1 couch shift were needed per fraction. The results of volumetric-modulated arc therapy simulation show a similar trend to that of intensity-modulated radiation therapy.Adaptive continuous monitoring with automatic motion compensation is more beneficial than periodic imaging surveillance at similar or even less imaging dose.

    View details for DOI 10.1177/1533033819844489

    View details for Web of Science ID 000472040500001

    View details for PubMedID 31177934

    View details for PubMedCentralID PMC6558533

  • Novel Eye Plaque Designs for Brachytherapy of Iris and Ciliary Body Melanoma and the First Clinical Application OCULAR ONCOLOGY AND PATHOLOGY Liu, W., Kim, J., Young, B. K., Nath, R., Chen, Z., Decker, R. H., Astrahan, M. A., Pointdujour-Lim, R. 2019; 5 (3): 220–27


    While traditional eye plaque brachytherapy can be used for the treatment of iris melanoma, it faces challenges of poor patient tolerability due to cornea-plaque touch caused by radius of curvature mismatch and potential dosimetric inaccuracy from incomplete coverage. We present novel plaque designs and the first clinical application of the plaques for iris melanoma.Two dome-shaped plaques (EP2132 and EP1930) were designed to vault above the cornea to treat tumors of the iris and ciliary body. Image-based treatment planning of the first 2 clinical cases using the EP2132 plaque covered the tumor base plus a 2 mm margin and the involved ciliary body with at least 75 Gy to the tumor apex.The tumors decreased in size following treatment. The patients tolerated the treatment well. There was no adverse event associated with the traditional iris plaques, such as decreased vision, pain, corneal edema, glaucoma, or cataract.The novel dome-shaped plaques for the treatment of iris melanoma provide effective dose distribution, improved surgical maneuverability, and increased tolerability for the patient. This plaque model can be used to treat iris melanoma of various sizes, configurations, and locations, including the ciliary body. The need for a customized plaque platform for each patient is minimized.

    View details for DOI 10.1159/000493269

    View details for Web of Science ID 000466137200012

    View details for PubMedID 31049331

    View details for PubMedCentralID PMC6489066

  • Monte Carlo dosimetry modeling of focused kV x-ray radiotherapy of eye diseases with potential nanoparticle dose enhancement MEDICAL PHYSICS Yan, H., Ma, X., Sun, W., Mendez, S., Stryker, S., Starr-Baier, S., Delliturri, G., Zhu, D., Nath, R., Chen, Z., Roberts, K., MacDonald, C. A., Liu, W. 2018; 45 (10): 4720–33


    Eye plaque brachytherapy is the most common approach for intraocular cancer treatment. It is, however, invasive and subject to large setup uncertainty due to the surgical operation. We propose a novel-focused kV x-ray technique with potential nanoparticle (NP) enhancement and evaluate its application in treating choroidal melanoma and iris melanoma by Monte Carlo (MC) dosimetry modeling.A polycapillary x-ray lens was used to focus 45 kVp x rays to achieve pinpoint accuracy of dose delivery to small tumors near critical structures. In addition to allowing for beam focusing, the use of kV x rays takes advantage of the strong photoelectric absorption of metallic NPs in that energy regime and hence strong radiosensitization. We constructed an MC simulation program that takes into account the x-ray optic modeling and used GEANT4 for dosimetric calculation. Extensive phantom measurements using a prototype-focused x-ray system were carried out. The MC simulation of simple geometry phantom irradiation was first compared to measurements to verify the x-ray optic lens modeling in conjunction with the Geant4 dosimetric calculation. To simulate tumor treatment, a geometric eye model and two tumor models were constructed. Dose distributions of the simulated treatments were then calculated. NP radiosensitization was also simulated for two concentrations of 2 nm gold NP (AuNP) uniformly distributed in the tumor.The MC-simulated full width at half maximum (FWHM) and central-axis depth dose of the focused kV x-ray beam match those measured on EBT3 films within ~10% around the depth of focus of the beam. Dose distributions of the simulated ocular tumor treatments show that focused x-ray beams can concentrate the high-dose region in or close to the tumor plus margin. For the simulated posterior choroidal tumor treatment, with sufficient tumor coverage, the doses to the optic disc and fovea are substantially reduced with focused x-ray therapy compared to eye plaque treatment (3.8 vs 39.8 Gy and 11.1 vs 53.8 Gy, respectively). The eye plaque treatment was calculated using an Eye Physics plaque with I-125 seeds under TG43 assumption. For the energy spectrum used in this study, the average simulated dose enhancement ratios (DERs) are roughly 2.1 and 1.1 for 1.0% and 0.1% AuNP mass concentration in the tumor, respectively.Compared to eye plaque brachytherapy, the proposed focused kV x-ray technique is noninvasive and shows great advantage in sparing healthy critical organs without sacrificing the tumor control. The NP radiation dose enhancement is considerable at our proposed kV range even with a low NP concentration in the tumor, providing better critical structure protection and more flexibility for treatment planning.

    View details for DOI 10.1002/mp.13144

    View details for Web of Science ID 000446995000052

    View details for PubMedID 30133705

  • On the use of bolus for pacemaker dose measurement and reduction in radiation therapy JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS Yan, H., Guo, F., Zhu, D., Stryker, S., Trumpore, S., Roberts, K., Higgins, S., Nath, R., Chen, Z., Liu, W. 2018; 19 (1): 125–31


    Special attention is required in planning and administering radiation therapy to patients with cardiac implantable electronic devices (CIEDs), such as pacemaker and defibrillator. The range of dose to CIEDs that can induce malfunction is large among CIEDs. Clinically significant defects have been reported at dose as low as 0.15 Gy. Therefore, accurate estimation of dose to CIED and dose reduction are both important even if the dose is expected to be less than the often-used 2-Gy limit. We investigated the use of bolus in in vivo dosimetry for CIEDs. Solid water phantom measurements of out-of-field dose for a 6-MV beam were performed using parallel plate chamber with and without 1- to 2-cm bolus covering the chamber. In vivo dosimetry at skin surface above the CIED was performed with and without bolus covering the CIED for three patients with the CIED <5 cm from the field edge. Chamber measured dose at depth ~0.5-1.5 cm below the skin surface, where the CIED is normally located, was reduced by ~7-48% with bolus. The dose reduction became smaller at deeper depths and with smaller field size. In vivo dosimetry at skin surface also indicated ~20%-60% lower dose when using bolus for the three patients. The dose measured with bolus more accurately reflects the dose to CIED and is less affected by contaminant electrons and linac head scatter. In general, the treatment planning system (TPS) calculation underestimated the dose to CIED, but it predicts the CIED dose more accurately when bolus is used. We recommend the use of 1- to 2-cm bolus to cover the CIED during in vivo CIED dose measurements for more accurate CIED dose estimation. If the CIED is placed <2 cm in depth and its dose is mainly from anterior beams, we recommend using the bolus during the entire course of radiation delivery to reduce the dose to CIED.

    View details for DOI 10.1002/acm2.12229

    View details for Web of Science ID 000427481300014

    View details for PubMedID 29152840

    View details for PubMedCentralID PMC5768029

  • Incorporating patient-specific CT-based ophthalmic anatomy in modeling iodine-125 eye plaque brachytherapy dose distributions BRACHYTHERAPY Tien, C. J., Astrahan, M. A., Kim, J. M., Materin, M., Chen, Z., Nath, R., Liu, W. 2017; 16 (5): 1057–64


    To quantify the dosimetric impact of incorporating patient-specific CT-based models rather than the conventional stylized-standard model for eye plaque brachytherapy planning.Plaque Simulator was used to plan 16 patients using both CT-based patient-specific eye model and stylized-standard (SS) eye models. Plaque position was initially based on the SS model and compared against their patient-specific model without changing the plaque loading pattern and seed strength. Dosimetric parameters were compared for tumor and healthy ocular structures.Patient-specific ocular parameters ranged from 0.40 to 1.38 of SS model values. If plaques were placed based on SS model eyelet positions, target volume receiving prescription dose (V100%) is overpredicted by 5.9% on average (max: 27%), and D95% is overpredicted by 17.2 Gy on average (max: 58.1 Gy). If the plaques were recentered, 13 of 16 patients had changes in V100% of less than 2%, whereas half of the patients still had optic disc dose difference greater than 5 Gy (max: 36.2 Gy). The largest differences were observed with a target-to-optic disk distance less than 6 mm. No substantial dose differences were observed for the tumor apex, fovea, lens, and opposing retina.Patient-specific modeling is recommended for clinical planning, especially with target-to-optic disk distances less than 6 mm, due to significant differences compared with SS model.

    View details for DOI 10.1016/j.brachy.2017.06.014

    View details for Web of Science ID 000411920100020

    View details for PubMedID 28778599

  • Comparison of 2D and 3D modeled tumor motion estimation/prediction for dynamic tumor tracking during arc radiotherapy PHYSICS IN MEDICINE AND BIOLOGY Liu, W., Ma, X., Yan, H., Chen, Z., Nath, R., Li, H. 2017; 62 (9): N168–N179


    Many real-time imaging techniques have been developed to localize a target in 3D space or in a 2D beam's eye view (BEV) plane for intrafraction motion tracking in radiation therapy. With tracking system latency, the 3D-modeled method is expected to be more accurate even in terms of 2D BEV tracking error. No quantitative analysis, however, has been reported. In this study, we simulated co-planar arc deliveries using respiratory motion data acquired from 42 patients to quantitatively compare the accuracy between 2D BEV and 3D-modeled tracking in arc therapy and to determine whether 3D information is needed for motion tracking. We used our previously developed low kV dose adaptive MV-kV imaging and motion compensation framework as a representative of 3D-modeled methods. It optimizes the balance between additional kV imaging dose and 3D tracking accuracy and solves the MLC blockage issue. With simulated Gaussian marker detection errors (zero mean and 0.39 mm standard deviation) and ~155/310/460 ms tracking system latencies, the mean percentage of time that the target moved  >2 mm from the predicted 2D BEV position are 1.1%/4.0%/7.8% and 1.3%/5.8%/11.6% for the 3D-modeled and 2D-only tracking, respectively. The corresponding average BEV RMS errors are 0.67/0.90/1.13 mm and 0.79/1.10/1.37 mm. Compared to the 2D method, the 3D method reduced the average RMS unresolved motion along the beam direction from ~3 mm to ~1 mm, resulting in on average only  <1% dosimetric advantage in the depth direction. Only for a small fraction of the patients, when tracking latency is long, the 3D-modeled method showed significant improvement of BEV tracking accuracy, indicating potential dosimetric advantage. However, if the tracking latency is short (~150 ms or less), those improvements are limited. Therefore, 2D BEV tracking has sufficient targeting accuracy for most clinical cases. The 3D technique is, however, still important in solving the MLC blockage problem during 2D BEV tracking.

    View details for DOI 10.1088/1361-6560/aa64c8

    View details for Web of Science ID 000399214300001

    View details for PubMedID 28263949

  • Tissue feature-based intra-fractional motion tracking for stereoscopic x-ray image guided radiotherapy. Physics in medicine and biology Xie, Y., Xing, L., Gu, J., Liu, W. 2013; 58 (11): 3615-3630


    Real-time knowledge of tumor position during radiation therapy is essential to overcome the adverse effect of intra-fractional organ motion. The goal of this work is to develop a tumor tracking strategy by effectively utilizing the inherent image features of stereoscopic x-ray images acquired during dose delivery. In stereoscopic x-ray image guided radiation delivery, two orthogonal x-ray images are acquired either simultaneously or sequentially. The essence of markerless tumor tracking is the reliable identification of inherent points with distinct tissue features on each projection image and their association between two images. The identification of the feature points on a planar x-ray image is realized by searching for points with high intensity gradient. The feature points are associated by using the scale invariance features transform descriptor. The performance of the proposed technique is evaluated by using images of a motion phantom and four archived clinical cases acquired using either a CyberKnife equipped with a stereoscopic x-ray imaging system, or a LINAC equipped with an onboard kV imager and an electronic portal imaging device. In the phantom study, the results obtained using the proposed method agree with the measurements to within 2 mm in all three directions. In the clinical study, the mean error is 0.48 ± 0.46 mm for four patient data with 144 sequential images. In this work, a tissue feature-based tracking method for stereoscopic x-ray image guided radiation therapy is developed. The technique avoids the invasive procedure of fiducial implantation and may greatly facilitate the clinical workflow.

    View details for DOI 10.1088/0031-9155/58/11/3615

    View details for PubMedID 23648334

  • Real-time automatic fiducial marker tracking in low contrast cine-MV images MEDICAL PHYSICS Lin, W., Lin, S., Yang, S., Liou, S., Nath, R., Liu, W. 2013; 40 (1): 011715


    To develop a real-time automatic method for tracking implanted radiographic markers in low-contrast cine-MV patient images used in image-guided radiation therapy (IGRT).Intrafraction motion tracking using radiotherapy beam-line MV images have gained some attention recently in IGRT because no additional imaging dose is introduced. However, MV images have much lower contrast than kV images, therefore a robust and automatic algorithm for marker detection in MV images is a prerequisite. Previous marker detection methods are all based on template matching or its derivatives. Template matching needs to match object shape that changes significantly for different implantation and projection angle. While these methods require a large number of templates to cover various situations, they are often forced to use a smaller number of templates to reduce the computation load because their methods all require exhaustive search in the region of interest. The authors solve this problem by synergetic use of modern but well-tested computer vision and artificial intelligence techniques; specifically the authors detect implanted markers utilizing discriminant analysis for initialization and use mean-shift feature space analysis for sequential tracking. This novel approach avoids exhaustive search by exploiting the temporal correlation between consecutive frames and makes it possible to perform more sophisticated detection at the beginning to improve the accuracy, followed by ultrafast sequential tracking after the initialization. The method was evaluated and validated using 1149 cine-MV images from two prostate IGRT patients and compared with manual marker detection results from six researchers. The average of the manual detection results is considered as the ground truth for comparisons.The average root-mean-square errors of our real-time automatic tracking method from the ground truth are 1.9 and 2.1 pixels for the two patients (0.26 mm/pixel). The standard deviations of the results from the 6 researchers are 2.3 and 2.6 pixels. The proposed framework takes about 128 ms to detect four markers in the first MV images and about 23 ms to track these markers in each of the subsequent images.The unified framework for tracking of multiple markers presented here can achieve marker detection accuracy similar to manual detection even in low-contrast cine-MV images. It can cope with shape deformations of fiducial markers at different gantry angles. The fast processing speed reduces the image processing portion of the system latency, therefore can improve the performance of real-time motion compensation.

    View details for DOI 10.1118/1.4771931

    View details for Web of Science ID 000313033200019

    View details for PubMedID 23298085

  • Hybrid MV-kV 3D respiratory motion tracking during radiation therapy with low imaging dose PHYSICS IN MEDICINE AND BIOLOGY Yan, H., Li, H., Liu, Z., Nath, R., Liu, W. 2012; 57 (24): 8455–69


    A novel real-time adaptive MV-kV imaging framework for image-guided radiation therapy is developed to reduce the thoracic and abdominal tumor targeting uncertainty caused by respiration-induced intrafraction motion with ultra-low patient imaging dose. In our method, continuous stereoscopic MV-kV imaging is used at the beginning of a radiation therapy delivery for several seconds to measure the implanted marker positions. After this stereoscopic imaging period, the kV imager is switched off except for the times when no fiducial marker is detected in the cine-MV images. The 3D time-varying marker positions are estimated by combining the MV 2D projection data and the motion correlations between directional components of marker motion established from the stereoscopic imaging period and updated afterwards; in particular, the most likely position is assumed to be the position on the projection line that has the shortest distance to the first principal component line segment constructed from previous trajectory points. An adaptive windowed auto-regressive prediction is utilized to predict the marker position a short time later (310 ms and 460 ms in this study) to allow for tracking system latency. To demonstrate the feasibility and evaluate the accuracy of the proposed method, computer simulations were performed for both arc and fixed-gantry deliveries using 66 h of retrospective tumor motion data from 42 patients treated for thoracic or abdominal cancers. The simulations reveal that using our hybrid approach, a smaller than 1.2 mm or 1.5 mm root-mean-square tracking error can be achieved at a system latency of 310 ms or 460 ms, respectively. Because the kV imaging is only used for a short period of time in our method, extra patient imaging dose can be reduced by an order of magnitude compared to continuous MV-kV imaging, while the clinical tumor targeting accuracy for thoracic or abdominal cancers is maintained. Furthermore, no additional hardware is required with the proposed method.

    View details for DOI 10.1088/0031-9155/57/24/8455

    View details for Web of Science ID 000312106200022

    View details for PubMedID 23202376

  • Dose verification for respiratory-gated volumetric modulated arc therapy PHYSICS IN MEDICINE AND BIOLOGY Qian, J., Xing, L., Liu, W., Luxton, G. 2011; 56 (15): 4827-4838


    A novel commercial medical linac system (TrueBeam™, Varian Medical Systems, Palo Alto, CA) allows respiratory-gated volumetric modulated arc therapy (VMAT), a new modality for treating moving tumors with high precision and improved accuracy by allowing for regular motion associated with a patient's breathing during VMAT delivery. The purpose of this work is to adapt a previously-developed dose reconstruction technique to evaluate the fidelity of VMAT treatment during gated delivery under clinic-relevant periodic motion related to patient breathing. A Varian TrueBeam system was used in this study. VMAT plans were created for three patients with lung or pancreas tumors. Conventional 6 and 15 MV beams with flattening filter and high-dose-rate 10 MV beams with no flattening filter were used in these plans. Each patient plan was delivered to a phantom first without gating and then with gating for three simulated respiratory periods (3, 4.5 and 6 s). Using the adapted log-file-based dose reconstruction procedure supplemented with ion chamber array (Seven29™, PTW, Freiburg, Germany) measurements, the delivered dose was used to evaluate the fidelity of gated VMAT delivery. Comparison of Seven29 measurements with and without gating showed good agreement with gamma-index passing rates above 99% for 1%/1 mm dose accuracy/distance-to-agreement criteria. With original plans as reference, gamma-index passing rates were 100% for the reconstituted plans (1%/1 mm criteria) and 93.5-100% for gated Seven29 measurements (3%/3 mm criteria). In the presence of leaf error deliberately introduced into the gated delivery of a pancreas patient plan, both dose reconstruction and Seven29 measurement consistently indicated substantial dosimetric differences from the original plan. In summary, a dose reconstruction procedure was demonstrated for evaluating the accuracy of respiratory-gated VMAT delivery. This technique showed that under clinical operation, the TrueBeam system faithfully realized treatment plans with gated delivery. This methodology affords a useful tool for machine- and patient-specific quality assurance of the newly available respiratory-gated VMAT.

    View details for DOI 10.1088/0031-9155/56/15/013

    View details for Web of Science ID 000292885000014

    View details for PubMedID 21753232

    View details for PubMedCentralID PMC3360016

  • Clinical development of a failure detection-based online repositioning strategy for prostate IMRT-Experiments, simulation, and dosimetry study MEDICAL PHYSICS Liu, W., Qian, J., Hancock, S. L., Xing, L., Luxton, G. 2010; 37 (10): 5287-5297


    To implement and evaluate clinic-ready adaptive imaging protocols for online patient repositioning (motion tracking) during prostate IMRT using treatment beam imaging supplemented by minimal, as-needed use of on-board kV.The authors examine the two-step decision-making strategy: (1) Use cine-MV imaging and online-updated characterization of prostate motion to detect target motion that is potentially beyond a predefined threshold and (2) use paired MV-kV 3D localization to determine overthreshold displacement and, if needed, reposition the patient. Two levels of clinical implementation were evaluated: (1) Field-by-field based motion correction for present-day linacs and (2) instantaneous repositioning for new-generation linacs with capabilities of simultaneous MV-kV imaging and remote automatic couch control during treatment delivery. Experiments were performed on a Varian Trilogy linac in clinical mode using a 4D motion phantom programed with prostate motion trajectories taken from patient data. Dosimetric impact was examined using a 2D ion chamber array. Simulations were done for 536 trajectories from 17 patients.Despite the loss of marker detection efficiency caused by the MLC leaves sometimes obscuring the field at the marker's projected position on the MV imager, the field-by-field correction halved (from 23% to 10%) the mean percentage of time that target displacement exceeded a 3 mm threshold, as compared to no intervention. This was achieved at minimal cost in additional imaging (average of one MV-kV pair per two to three treatment fractions) and with a very small number of repositionings (once every four to five fractions). Also with low kV usage (approximation 2/fraction), the instantaneous repositioning approach reduced overthreshold time by more than 75% (23% to 5%) even with severe MLC blockage as often encountered in current IMRT and could reduce the overthreshold time tenfold (to < 2%) if the MLC blockage problem were relieved. The information acquired for repositioning using combined MV-kV images was found to have submillimeter accuracy.This work demonstrated with a current clinical setup that substantial reduction of adverse targeting effects of intrafraction prostate motion can be realized. The proposed adaptive imaging strategy incurs minimal imaging dose to the patient as compared to other stereoscopic imaging techniques.

    View details for DOI 10.1118/1.3488887

    View details for Web of Science ID 000283483700016

    View details for PubMedID 21089763

    View details for PubMedCentralID PMC2951998

  • Dose reconstruction for volumetric modulated arc therapy (VMAT) using cone-beam CT and dynamic log files PHYSICS IN MEDICINE AND BIOLOGY Qian, J., Lee, L., Liu, W., Chu, K., Mok, E., Luxton, G., Le, Q., Xing, L. 2010; 55 (13): 3597-3610


    Volumetric modulated arc therapy (VMAT) has recently emerged as a new clinical modality for conformal radiation therapy. The aim of this work is to establish a methodology and procedure for retrospectively reconstructing the actual dose delivered in VMAT based on the pre-treatment cone-beam computed tomography (CBCT) and dynamic log files. CBCT was performed before the dose delivery and the system's log files were retrieved after the delivery. Actual delivery at a control point including MLC leaf positions, gantry angles and cumulative monitor units (MUs) was recorded in the log files and the information was extracted using in-house developed software. The extracted information was then embedded into the original treatment DICOM-radiation therapy (RT) file to replace the original control point parameters. This reconstituted DICOM-RT file was imported into the Eclipse treatment planning system (TPS) and dose was computed on the corresponding CBCT. A series of phantom experiments was performed to show the feasibility of dose reconstruction, validate the procedure and demonstrate the efficacy of this methodology. The resultant dose distributions and dose-volume histograms (DVHs) were compared with those of the original treatment plan. The studies indicated that CBCT-based VMAT dose reconstruction is readily achievable and provides a valuable tool for monitoring the dose actually delivered to the tumor target as well as the sensitive structures. In the absence of setup errors, the reconstructed dose shows no significant difference from the original pCT-based plan. It is also elucidated that the proposed method is capable of revealing the dosimetric changes in the presence of setup errors. The method reported here affords an objective means for dosimetric evaluation of VMAT delivery and is useful for adaptive VMAT in future.

    View details for DOI 10.1088/0031-9155/55/13/002

    View details for Web of Science ID 000279004300002

    View details for PubMedID 20526034

  • Trade-Offs in Data Acquisition and Processing Parameters for Backscatter and Scatterer Size Estimations IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL Liu, W., Zagzebski, J. A. 2010; 57 (2): 340-352


    By analyzing backscattered echo signal power spectra and thereby obtaining backscatter coefficient vs. frequency data, the size of subresolution scatterers contributing to echo signals can be estimated. Here we investigate trade-offs in data acquisition and processing parameters for reference phantom-based backscatter and scatterer size estimations. RF echo data from a tissue-mimicking test phantom were acquired using a clinical scanner equipped with linear array transducers. One array has a nominal frequency bandwidth of 5 to 13 MHz and the other 4 to 9 MHz. Comparison of spectral estimation methods showed that the Welch method provided spectra yielding more accurate and precise backscatter coefficient and scatterer size estimations than spectra computed by applying rectangular, Hanning, or Hamming windows and much reduced computational load than if using the multitaper method. For small echo signal data block sizes, moderate improvements in scatterer size estimations were obtained using a multitaper method, but this significantly increases the computational burden. It is critical to average power spectra from lateral A-lines for the improvement of scatterer size estimation. Averaging approximately 10 independent A-lines laterally with an axial window length 10 times the center frequency wavelength optimized trade-offs between spatial resolution and the variance of scatterer size estimates. Applying the concept of a time-bandwidth product, this suggests using analysis blocks that contain at least 30 independent samples of the echo signal. The estimation accuracy and precision depend on the ka range where k is the wave number and a is the effective scatterer size. This introduces a region-of-interest depth dependency to the accuracy and precision because of preferential attenuation of higher frequency sound waves in tissuelike media. With the 5 to 13 MHz, transducer ka ranged from 0.5 to 1.6 for scatterers in the test phantom, which is a favorable range, and the accuracy and precision of scatterer size estimations were both within approximately 5% using optimal analysis block dimensions. When the 4- to 9-MHz transducer was used, the ka value ranged from 0.3 to 0.8 to 1.1 for the experimental conditions, and the accuracy and precision were found to be approximately 10% and 10% to 25%, respectively. Although the experiments were done with 2 specific models of transducers on the test phantom, the results can be generalized to similar clinical arrays available from a variety of manufacturers and/or for different size of scatterers with similar ka range.

    View details for DOI 10.1109/TUFFC.2010.1414

    View details for Web of Science ID 000274817300008

    View details for PubMedID 20178900

    View details for PubMedCentralID PMC2853955

  • A failure detection strategy for intrafraction prostate motion monitoring with on-board imagers for fixed-gantry IMRT International journal of radiation oncology, biology, physics Liu, W., Luxton, G., Xing, L. 2010; 78 (3): 904-911
  • Optimized hybrid megavoltage-kilovoltage imaging protocol for volumetric prostate arc therapy International journal of radiation oncology, biology, physics Liu, W., Wiersma, R. D., Xing, L. 2010; 78 (2): 595-604
  • Real-time 3D internal marker tracking during arc radiotherapy by the use of combined MV-kV imaging PHYSICS IN MEDICINE AND BIOLOGY Liu, W., Wiersma, R. D., Mao, W., Luxton, G., Xing, L. 2008; 53 (24): 7197-7213


    To minimize the adverse dosimetric effect caused by tumor motion, it is desirable to have real-time knowledge of the tumor position throughout the beam delivery process. A promising technique to realize the real-time image guided scheme in external beam radiation therapy is through the combined use of MV and onboard kV beam imaging. The success of this MV-kV triangulation approach for fixed-gantry radiation therapy has been demonstrated. With the increasing acceptance of modern arc radiotherapy in the clinics, a timely and clinically important question is whether the image guidance strategy can be extended to arc therapy to provide the urgently needed real-time tumor motion information. While conceptually feasible, there are a number of theoretical and practical issues specific to the arc delivery that need to be resolved before clinical implementation. The purpose of this work is to establish a robust procedure of system calibration for combined MV and kV imaging for internal marker tracking during arc delivery and to demonstrate the feasibility and accuracy of the technique. A commercially available LINAC equipped with an onboard kV imager and electronic portal imaging device (EPID) was used for the study. A custom built phantom with multiple ball bearings was used to calibrate the stereoscopic MV-kV imaging system to provide the transformation parameters from imaging pixels to 3D world coordinates. The accuracy of the fiducial tracking system was examined using a 4D motion phantom capable of moving in accordance with a pre-programmed trajectory. Overall, spatial accuracy of MV-kV fiducial tracking during the arc delivery process for normal adult breathing amplitude and period was found to be better than 1 mm. For fast motion, the results depended on the imaging frame rates. The RMS error ranged from approximately 0.5 mm for the normal adult breathing pattern to approximately 1.5 mm for more extreme cases with a low imaging frame rate of 3.4 Hz. In general, highly accurate real-time tracking of implanted markers using hybrid MV-kV imaging is achievable and the technique should be useful to improve the beam targeting accuracy of arc therapy.

    View details for DOI 10.1088/0031-9155/53/24/013

    View details for Web of Science ID 000261310200013

    View details for PubMedID 19043177

  • Acoustic backscatter and effective scatterer size estimates using a 2D CMUT transducer PHYSICS IN MEDICINE AND BIOLOGY Liu, W., Zagzebski, J. A., Hall, T. J., Madsen, E. L., Varghese, T., Kliewer, M. A., Panda, S., Lowery, C., Barnes, S. 2008; 53 (15): 4169-4183


    Compared to conventional piezoelectric transducers, new capacitive microfabricated ultrasonic transducer (CMUT) technology is expected to offer a broader bandwidth, higher resolution and advanced 3D/4D imaging inherent in a 2D array. For ultrasound scatterer size imaging, a broader frequency range provides more information on frequency-dependent backscatter, and therefore, generally more accurate size estimates. Elevational compounding, which can significantly reduce the large statistical fluctuations associated with parametric imaging, becomes readily available with a 2D array. In this work, we show phantom and in vivo breast tumor scatterer size image results using a prototype 2D CMUT transducer (9 MHz center frequency) attached to a clinical scanner. A uniform phantom with two 1 cm diameter spherical inclusions of slightly smaller scatterer size was submerged in oil and scanned by both the 2D CMUT and a conventional piezoelectric linear array transducer. The attenuation and scatterer sizes of the sample were estimated using a reference phantom method. RF correlation analysis was performed using the data acquired by both transducers. The 2D CMUT results indicate that at a 2 cm depth (near the transmit focus for both transducers) the correlation coefficient reduced to less than 1/e for 0.2 mm lateral or 0.25 mm elevational separation between acoustic scanlines. For the conventional array this level of decorrelation requires a 0.3 mm lateral or 0.75 mm elevational translation. Angular and/or elevational compounding is used to reduce the variance of scatterer size estimates. The 2D array transducer acquired RF signals from 140 planes over a 2.8 cm elevational direction. If no elevational compounding is used, the fractional standard deviation of the size estimates is about 12% of the mean size estimate for both the spherical inclusion and the background. Elevational compounding of 11 adjacent planes reduces it to 7% for both media. Using an experimentally estimated attenuation of 0.6 dB cm(-1) MHz(-1), scatterer size estimates for an in vivo breast tumor also demonstrate improvements using elevational compounding with data from the 2D CMUT transducer.

    View details for DOI 10.1088/0031-9155/53/15/011

    View details for Web of Science ID 000257759400011

    View details for PubMedID 18635893

    View details for PubMedCentralID PMC2758163

  • Spectral and scatterer-size correlation during angular compounding: simulations and experimental studies. Ultrasonic imaging Liu, W., Zagzebski, J. A., Varghese, T., Gerig, A. L., Hall, T. J. 2006; 28 (4): 230-44


    In a previous study, theoretical expressions were derived for the correlation between ultrasonic scatterer-size estimates and their associated spectral measures when echo data are acquired from the same location but at different angles. The results were verified using simulations. In the present work, we further analyze simulation data for these conditions; in addition, we measure the correlations using a cylindrical tissue-mimicking phantom. Experimental and theoretical results show that the relationship of scatterer-size correlation to insonification angle depends on gate duration, gate type and beam profile. Some discrepancies are noted between experimental results and theoretical predictions, particularly when using smaller gated windows. The sources of the discrepancies are discussed. Experimental results using a 6-MHz linear array suggest that, to save acquisition and processing time while reducing variance, a 2 degree-3 degree angular increment step provides efficient angular compounding for scatterer-size imaging with this array. Theoretical predictions can provide estimates of expected correlations between angular acquisitions when compounding with other transducers.

    View details for DOI 10.1177/016173460602800403

    View details for PubMedID 17521044

  • Segmentation of elastographic images using a coarse-to-fine active contour model. Ultrasound in medicine & biology Liu, W., Zagzebski, J. A., Varghese, T., Dyer, C. R., Techavipoo, U., Hall, T. J. 2006; 32 (3): 397-408


    Delineation of radiofrequency-ablation-induced coagulation (thermal lesion) boundaries is an important clinical problem that is not well addressed by conventional imaging modalities. Elastography, which produces images of the local strain after small, externally applied compressions, can be used for visualization of thermal coagulations. This paper presents an automated segmentation approach for thermal coagulations on 3-D elastographic data to obtain both area and volume information rapidly. The approach consists of a coarse-to-fine method for active contour initialization and a gradient vector flow, active contour model for deformable contour optimization with the help of prior knowledge of the geometry of general thermal coagulations. The performance of the algorithm has been shown to be comparable to manual delineation of coagulations on elastograms by medical physicists (r = 0.99 for volumes of 36 radiofrequency-induced coagulations). Furthermore, the automatic algorithm applied to elastograms yielded results that agreed with manual delineation of coagulations on pathology images (r = 0.96 for the same 36 lesions). This algorithm has also been successfully applied on in vivo elastograms.

    View details for DOI 10.1016/j.ultrasmedbio.2005.11.011

    View details for PubMedID 16530098

    View details for PubMedCentralID PMC1764611

  • Monitoring stiffness changes in lesions after radiofrequency ablation at different temperatures and durations of ablation. Ultrasound in medicine & biology Bharat, S., Techavipoo, U., Kiss, M. Z., Liu, W., Varghese, T. 2005; 31 (3): 415-22


    The variations in the stiffness or stiffness contrast of lesions resulting from radiofrequency (RF) ablation of canine liver tissue at different temperatures and for different ablation durations at a specified temperature are analyzed. Tissue stiffness, in general, increases with temperature; however, an anomaly exists around 80 degrees C, where the stiffness of the lesion is lower than that of the lesion ablated at 70 degrees C. On the other hand, the stiffness increases monotonically with the duration of ablation. Plots illustrating the ratio of mean strains in normal canine liver tissue to mean strains in ablated thermal lesions demonstrate the variation in the stiffness contrast of the thermal lesions. The contrast-to-noise ratio (CNRe) of the lesions, which serves as an indicator of the detectability of the lesions under the different experimental imaging conditions described above, is also presented. The results presented in this paper show that the elastographic depiction of stiffer thermal lesions is better, in terms of the CNRe parameter. An important criterion in the elastographic depiction of RF-ablated regions of tissue is the trade-off between ablation temperature and duration of ablation. Tissue necrosis can occur either by ablating tissue to high temperatures for short durations or to lower temperatures for longer durations. In this paper, we attempt to characterize the elastographic depiction of thermal lesions under these different experimental conditions. This paper provides results that may be utilized by practitioners of RF ablation to decide the ablation temperature and duration, on the basis of the strain images of normal liver tissue and ablated thermal lesions discussed in this paper.

    View details for DOI 10.1016/j.ultrasmedbio.2004.12.020

    View details for PubMedID 15749565

  • Elastographic versus x-ray CT imaging of radio frequency ablation coagulations: an in vitro study. Medical physics Liu, W., Techavipoo, U., Varghese, T., Zagzebski, J. A., Chen, Q., Lee, F. T. 2004; 31 (6): 1322-32


    Techniques to image elasticity parameters (i.e., elastography) have recently become of great interest to researchers. In this paper we use conventional ultrasound elastography and x-ray CT to image radio frequency (RF) ablation sites of excised canine liver enclosed in gelatin. Thermal coagulations of different sizes were produced by applying the RF procedure for various times and end point temperatures. Dimensions, areas and volumes computed from CT and elastography were compared with those on whole mount pathology specimens. Ultrasound elastography exhibited high contrast for the thermal coagulations and performed better than CT. The correlation between pathology and elastography for this sample set of 40 thermal coagulations (r = 0.94 for volume estimation, r = 0.87 for area estimation) is better than the correlation between pathology and CT (r = 0.89 for volume estimation, r = 0.82 for area estimation).

    View details for DOI 10.1118/1.1738963

    View details for PubMedID 15259635

  • Semiautomated thermal lesion segmentation for three-dimensional elastographic imaging. Ultrasound in medicine & biology Techavipoo, U., Varghese, T., Zagzebski, J. A., Chen, Q., Liu, W. 2004; 30 (5): 655-64


    Several studies have demonstrated that lesion volumes computed from multiple planar slices through the region-of-interest (ROI) are more accurate than volumes estimated assuming simple shapes and incorporating single or orthogonal diameter estimates. However, manual delineation of boundaries on multiple planar 2-D images is tedious and labor-intensive. Automatic extraction of lesion boundaries is, therefore, attractive and imperative to remove subjectivity and reduce assessment time. This paper presents a semiautomated segmentation algorithm for thermal lesions on 3-D elastographic data to obtain both area and volume information. The semiautomated segmentation algorithm is based on thresholding and morphologic opening of both 2-D and 3-D elastographic data. Results obtained on 44 thermal lesions imaged in vitro using elastography were compared to manual delineation of both elastographic and pathology images. Results obtained using semiautomated segmentation demonstrate a close correspondence with manual delineation results. However, area and volume estimates obtained using both manual and semiautomated segmentation of lesions seen on elastograms slightly underestimate areas and volumes measured from pathology.

    View details for DOI 10.1016/j.ultrasmedbio.2004.01.002

    View details for PubMedID 15183232

  • Elastographic measurement of the area and volume of thermal lesions resulting from radiofrequency ablation: pathologic correlation. AJR. American journal of roentgenology Varghese, T., Techavipoo, U., Liu, W., Zagzebski, J. A., Chen, Q., Frank, G., Lee, F. T. 2003; 181 (3): 701-7


    Elastography is a promising tool for visualizing the zone of necrosis in liver tissue resulting from radiofrequency tumor ablation. Because heat-ablated tissues are stiffer than normal untreated tissue, elastography may prove useful for following up patients who undergo radiofrequency ablative therapy. We sought to report the initial evaluations of the reliability of elastography for delineating thermal lesion boundaries in liver tissue by comparing lesion dimensions determined by elastography with the findings at whole-mount pathology.Radiofrequency ablation was performed in vitro on liver tissue specimens encased in gelatin phantoms. The imaging plane for elastography was perpendicular to the axis of the radiofrequency electrode so that the ablated region was around the center of the plane. To obtain three-dimensional visualization of thermal lesions, we reconstructed the lesions from multiple elastograms by linearly translating the elastographic scanning plane. Pathology photographs were obtained in the same image plane used for elastography by slicing through the gelatin and tissue phantom using external markers. We used digitized gross pathology photographs obtained at a specified slice thickness to compute the areas and volumes of the lesions. These measurements were then compared to the measurements obtained from the elastograms.In a sample of 40 thermal lesions, we obtained a correlation between in vitro elastographic and pathologic measurements of r = 0.9371 (p < 0.00001) for area estimates and r = 0.979 (p < 0.00001) for volume estimates.We found excellent correlation between the measurements of the dimensions, areas, and volumes of thermal lesions that were based on elastographic images and the measurements that were based on digitized pathologic images. When compared with digitized pathologic measurements, elastographic measurements showed a tendency to slightly underestimate both the areas and volumes of lesions. Nevertheless, elastography is a reliable technique for delineating thermal lesions resulting from radiofrequency ablation.

    View details for DOI 10.2214/ajr.181.3.1810701

    View details for PubMedID 12933463

  • Spectroscopic confirmation of northern and equatorial cataclysmic variables. III. 32 poorly known objects ASTROPHYSICAL JOURNAL SUPPLEMENT SERIES Liu, W., Hu, J. Y. 2000; 128 (1): 387–401

    View details for DOI 10.1086/313380

    View details for Web of Science ID 000088749300015

  • Spectroscopic identification for 20 cataclysmic variables and related objects CHINESE ASTRONOMY AND ASTROPHYSICS Li, Z., Liu, W., Hu, J. 1999; 23 (3): 324–38
  • Spectroscopic confirmation of 55 northern and equatorial cataclysmic variables. I. 27 confirmed cataclysmic variables ASTROPHYSICAL JOURNAL SUPPLEMENT SERIES Liu, W., Hu, J. Y., Zhu, X. H., Li, Z. Y. 1999; 122 (1): 243–55

    View details for DOI 10.1086/313210

    View details for Web of Science ID 000081297800010

  • Spectroscopic confirmation of 55 northern and equatorial cataclysmic variables. II. 28 disproved and suspected cataclysmic variable candidates ASTROPHYSICAL JOURNAL SUPPLEMENT SERIES Liu, W., Hu, J. Y., Li, Z. Y., Cao, L. 1999; 122 (1): 257–68

    View details for DOI 10.1086/313211

    View details for Web of Science ID 000081297800011

  • EG Cancri: A new WZ Sge type dwarf nova ASTROPHYSICS AND SPACE SCIENCE Liu, W., Li, Z. Y., Hu, J. Y. 1998; 257 (2): 183–99