Academic Appointments

Honors & Awards

  • Cancer Center Clinical Innovation Fund, Stanford University (2020)
  • SQIMM Award, Stanford University (2020)
  • Teaching Award, Stanford University (2018)
  • SQIMM Award, Stanford University (2017)
  • Stanford Medicine Faculty Innovation Program (Co-PI), Stanford University (2015)
  • Radiation Physics Impact Award, Stanford University (2014)
  • Scholarship for nanostorage research from Ministry of economic affairs, NTU (2004)
  • The AP-NFO student Award, 4th Asia-Pacific International Conference on near-field Optics (2003)

Boards, Advisory Committees, Professional Organizations

  • Executive Committee Member, Northern California Chapter of AAPM (2020 - Present)
  • Associate Editor, Journal of Applied Clinical Medical Physics (JACMP) (2018 - Present)
  • Chair, Unit No. 52 of AAPM - Video Abstracts (2018 - Present)
  • Chair, Unit No. 47 of AAPM - AAPM Journals App and MP and JACMP Websites (2018 - Present)
  • Director, Northern California Chapter of AAPM - Therapy Physics Mock Exam (2018 - Present)
  • Member, Working Group 2 of AAPM (2018 - Present)
  • Member, AAPM - Work Group on Periodic Review of Medical Physics Residency Training (2018 - Present)
  • Member, Unit No. 51 of AAPM - Journal Marketing (2018 - Present)
  • Member, Unit No. 53 of AAPM - California Rulemaking Project (2018 - 2020)
  • President, Northern California Chapter of AAPM (2018 - 2020)
  • President-Elect, Northern California Chapter of AAPM (2017 - 2018)

Professional Education

  • DABR, The American Board of Radiology, Therapeutic Medical Physics (2015)
  • Residency, Stanford University, Therapeutic Medical Physics (CAMPEP Accredited) (2014)
  • Ph.D., University of California, Los Angeles, Biomedical Physics (CAMPEP Accredited) (2011)


  • "United States, A novel integrated multi-modal phantom for combined dosimetry and positioning verification"
  • "United States, Method for analyzing the spatial accuracy for single-isocenter multitarget stereotactic radiosurgery"
  • "United States, Field shaping device for radiation therapy"

All Publications

  • Multi-Institutional Audit of FLASH and Conventional Dosimetry with a 3D-Printed Anatomically Realistic Mouse Phantom. International journal of radiation oncology, biology, physics Ashraf, M. R., Melemenidis, S., Liu, K., Grilj, V., Jansen, J., Velasquez, B., Connell, L., Schulz, J. B., Bailat, C., Libed, A., Manjappa, R., Dutt, S., Soto, L., Lau, B., Garza, A., Larsen, W., Skinner, L., Yu, A. S., Surucu, M., Graves, E. E., Maxim, P. G., Kry, S. F., Vozenin, M. C., Schüler, E., Loo, B. W. 2024


    We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3D-printed mouse phantom.A CT scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom, and each institution performed two replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film.Compared to the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal impact on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3% to 1.2%), while differences from the prescribed dose decreased for both CONV (3.6% to 2.5%) and FLASH (6.4% to 2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, though these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance.This study marks the first dosimetric audit for FLASH using a non-homogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biological findings.

    View details for DOI 10.1016/j.ijrobp.2024.03.017

    View details for PubMedID 38493902

  • A clinical solution for non-toxic 3D-printed photon blocks in external beam radiation therapy. Journal of applied clinical medical physics Schulz, J. B., Dubrowski, P., Gibson, C., Yu, A. S., Skinner, L. B. 2024: e14225


    A well-known limitation of multi-leaf collimators is that they cannot easily form island blocks. This can be important in mantle region therapy. Cerrobend photon blocks, currently used for supplementary shielding, are labor-intensive and error-prone. To address this, an innovative, non-toxic, automatically manufactured photon block using 3D-printing technology is proposed, offering a patient-specific and accurate alternative.The study investigates the development of patient-specific photon shielding blocks using 3D-printing for three different patient cases. A 3D-printed photon block shell filled with tungsten ball bearings (BBs) was designed to have similar dosimetric properties to Cerrobend standards. The generation of the blocks was automated using the Eclipse Scripting API and Python. Quality assurance was performed by comparing the expected and actual weight of the tungsten BBs used for shielding. Dosimetric and field geometry comparisons were conducted between 3D-printed and Cerrobend blocks, utilizing ionization chambers, imaging, and field geometry analysis.The quality assurance assessment revealed a -1.3% average difference in the mass of tungsten ball bearings for different patients. Relative dose output measurements for three patient-specific blocks in the blocked region agreed within 2% of each other. Against the Treatment Planning System (TPS), both 3D-printed and Cerrobend blocks agreed within 2%. For each patient, 6 MV image profiles taken through the 3D-printed and Cerrobend blocks agreed within 1% outside high gradient regions. Jaccard distance analysis of the MV images against the TPS planned images, found Cerrobend blocks to have 15.7% dissimilarity to the TPS, while that of the 3D-printed blocks was 6.7%.This study validates a novel, efficient 3D-printing method for photon block creation in clinical settings. Despite potential limitations, the benefits include reduced manual labor, automated processes, and greater precision. It holds potential for widespread adoption in radiation therapy, furthering non-toxic radiation shielding.

    View details for DOI 10.1002/acm2.14225

    View details for PubMedID 38213084

  • Exploring deep learning for estimating the isoeffective dose of FLASH irradiation from mouse intestinal histology images. International journal of radiation oncology, biology, physics Fu, J., Yang, Z., Melemenidis, S., Viswanathan, V., Dutt, S., Manjappa, R., Lau, B., Soto, L. A., Ashraf, R., Skinner, L., Yu, S. J., Surucu, M., Casey, K. M., Rankin, E. B., Graves, E., Lu, W., Loo, B. W., Gu, X. 2024


    Ultra-high dose rate (FLASH) irradiation has been reported to reduce normal tissue damage compared with conventional dose rate (CONV) irradiation without compromising tumor control. This proof-of-concept study aims to develop a deep learning (DL) approach to quantify the FLASH isoeffective dose (dose of CONV that would be required to produce the same effect as the given physical FLASH dose) with post-irradiation mouse intestinal histological images.84 healthy C57BL/6J female mice underwent 16 MeV electron CONV (0.12Gy/s; n=41) or FLASH (200Gy/s; n=43) single fraction whole abdominal irradiation. Physical dose ranged from 12 to 16Gy for FLASH and 11 to 15Gy for CONV in 1Gy increments. 4 days after irradiation, 9 jejunum cross-sections from each mouse were H&E stained and digitized for histological analysis. CONV dataset was randomly split into training (n=33) and testing (n=8) datasets. ResNet101-based DL models were retrained using the CONV training dataset to estimate the dose based on histological features. The classical manual crypt counting (CC) approach was implemented for model comparison. Cross-section-wise mean squared error (CS-MSE) was computed to evaluate the dose estimation accuracy of both approaches. The validated DL model was applied to the FLASH dataset to map the physical FLASH dose into the isoeffective dose.The DL model achieved a CS-MSE of 0.20Gy2 on the CONV testing dataset compared with 0.40Gy2 of the CC approach. Isoeffective doses estimated by the DL model for FLASH doses of 12, 13, 14, 15, and 16 Gy were 12.19±0.46, 12.54±0.37, 12.69±0.26, 12.84±0.26, and 13.03±0.28 Gy, respectively.Our proposed DL model achieved accurate CONV dose estimation. The DL model results indicate that in the physical dose range of 13 to 16 Gy, the biological dose response of small intestinal tissue to FLASH irradiation is represented by a lower isoeffective dose compared to the physical dose. Our DL approach can be a tool for studying isoeffective doses of other radiation dose modifying interventions.

    View details for DOI 10.1016/j.ijrobp.2023.12.032

    View details for PubMedID 38171387

  • A Couch Mounted Smartphone-based Motion Monitoring System for Radiation Therapy. Practical radiation oncology Capaldi, D. P., Axente, M., Yu, A. S., Prionas, N. D., Hirata, E., Nano, T. F. 2023


    PURPOSE: Surface-guided radiation-therapy (SGRT) systems are being adopted into clinical practice for patient setup and motion monitoring. However, commercial systems remain cost prohibitive to resource-limited clinics around the world. Our aim is to develop and validate a smartphone-based application using LiDAR cameras (such as on recent Apple iOS devices) for facilitating SGRT in low-resource centers. The proposed SGRT application was tested at multiple institutions, and validated using phantoms and volunteers against various commercial systems to demonstrate feasibility.METHODS AND MATERIALS: An iOS application was developed in Xcode and written in Swift using the Augmented-Reality (AR) Kit and implemented on an Apple iPhone 13 Pro with a built-in LiDAR camera. The application contains multiple features: 1) visualization of both the camera and depth video feeds (at a 60Hz sample-frequency), 2) region-of-interest (ROI) selection over the patient's anatomy where motion is measured, 3) chart displaying the average motion over time in the ROI, and 4) saving/exporting the motion traces and surface map over the ROI for further analysis. The iOS application was tested to evaluate depth measurement accuracy for: 1) different angled surfaces, 2) different field-of-views over different distances, and 3) similarity to a commercially available SGRT systems (Vision RT AlignRT and Varian IDENTIFY) with motion phantoms and healthy volunteers across three institutions. Measurements were analyzed using linear-regressions and Bland-Altman analysis.RESULTS: Compared to the clinical system measurements (reference), the iOS application showed excellent agreement for depth (r=1.000,p<0.0001; bias=-0.07±0.24cm) and angle (r=1.000,p<0.0001; bias=0.02±0.69°) measurements. For free-breathing traces, the iOS application was significantly correlated to phantom motion (institute 1: r=0.99,p<0.0001; bias=-0.003±0.03cm; institute 2: r=0.98,p<0.0001; bias=-0.001±0.10cm; institute 3: r=0.97,p<0.0001; bias=0.04±0.06cm) and healthy volunteer motion (institute 1: r=0.98,p<0.0001; bias=-0.008±0.06cm; institute 2: r=0.99,p<0.0001; bias=-0.007±0.12cm; institute 3: r=0.99,p<0.0001; bias=-0.001±0.04cm).CONCLUSION: The proposed approach using a smartphone-based application provides a low-cost platform that could improve access to surface-guided radiation therapy accounting for motion.

    View details for DOI 10.1016/j.prro.2023.11.013

    View details for PubMedID 38052299

  • Tungsten filled 3D printed lung blocks for total body irradiation. Practical radiation oncology Capaldi, D. P., Gibson, C., Villa, A., Schulz, J. B., Ziemer, B. P., Fu, J., Dubrowski, P., Yu, A. S., Fogh, S., Chew, J., Boreta, L., Braunstein, S. E., Witztum, A., Hirata, E., Morin, O., Skinner, L. B., Nano, T. F. 2023


    Lung blocks for total-body-irradiation (TBI) are commonly used to reduce lung dose and prevent radiation pneumonitis. Currently, molten Cerrobend containing toxic materials, specifically lead and cadmium, is poured into molds to construct blocks. Here, we propose a streamlined method to create 3D-printed lung block shells and fill them with tungsten ball-bearings (BBs) to remove lead and improve overall accuracy in the block manufacturing workflow.3D-printed lung block shells were automatically generated using an inhouse software, printed, and filled with 2-3mm diameter tungsten BBs. Clinical Cerrobend blocks were compared to the physician drawn blocks as well as our proposed tungsten filled 3D-printed blocks. Physical and dosimetric comparisons were performed on a linac. Dose transmission through the Cerrobend and 3D-printed blocks were measured using point dosimetry (ion-chamber) and the on-board Electronic-Portal-Imaging-Device (EPID). Dose profiles from the EPID images were used to compute the full-width-half-maximum (FWHM) and to compare with the treatment-planning-system (TPS). Additionally, the coefficient-of-variation (CoV) in the central 80% of FWHM was computed and compared between Cerrobend and 3D-printed blocks.The geometric difference between TPS and 3D-printed blocks was significantly lower than Cerrobend blocks (3D: -0.88±2.21mm, Cerrobend: -2.28±2.40mm, p=0.0002). Dosimetrically, transmission measurements through the 3D-printed and Cerrobend blocks for both ion-chamber and EPID dosimetry were between 42-48%, as compared to the open field. Additionally, CoV was significantly higher in 3D-printed blocks versus Cerrobend blocks (3D: 4.2±0.6%, Cerrobend: 2.6±0.7%, p<0.0001).We designed and implemented a tungsten filled 3D-printed workflow for constructing TBI lung blocks, which serves as an alternative to the traditional Cerrobend based workflow currently used in clinics. This workflow has the capacity of producing clinically useful lung blocks with minimal effort in an attempt to facilitate the removal of toxic materials from the clinic.

    View details for DOI 10.1016/j.prro.2023.11.003

    View details for PubMedID 37981253

  • FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Barghouth, P. G., Melemenidis, S., Montay-Gruel, P., Ollivier, J., Viswanathan, V., Jorge, P. G., Soto, L. A., Lau, B. C., Sadeghi, C., Edlabadkar, A., Zhang, R., Ru, N., Baulch, J. E., Manjappa, R., Wang, J., Le Bouteiller, M., Surucu, M., Yu, A., Bush, K., Skinner, L., Maxim, P. G., Loo, B. W., Limoli, C. L., Vozenin, M. C., Frock, R. L. 2023: 109906


    The impact of radiotherapy (RT) at ultra high vs conventional dose rate (FLASH vs CONV) on the generation and repair of DNA double strand breaks (DSBs) is an important question that remains to be investigated. Here, we tested the hypothesis as to whether FLASH-RT generates decreased chromosomal translocations compared to CONV-RT.We used two FLASH validated electron beams and high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), employing S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs) in HEK239T cells, to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated after various irradiation doses, dose rates and oxygen tensions (normoxic, 21% O2; physiological, 4% O2; hypoxic, 2% and 0.5% O2). Electron irradiation was delivered using a FLASH capable Varian Trilogy and the eRT6/Oriatron at CONV (0.08-0.13Gy/s) and FLASH (1x102-5x106 Gy/s) dose rates. Related experiments using clonogenic survival and γH2AX foci in the 293T and the U87 glioblastoma lines were also performed to discern FLASH-RT vs CONV-RT DSB effects.Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Furthermore, RT dose rate modality on U87 cells did not change γH2AX foci numbers at 1- and 24-hours post-irradiation nor did this affect 293T clonogenic survival.Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

    View details for DOI 10.1016/j.radonc.2023.109906

    View details for PubMedID 37690668

  • Introduction to concept inventories for medical physics education. Journal of applied clinical medical physics Cetnar, A. J., Besemer, A., Bry, V., Buckey, C. R., Burmeister, J., Rodrigues, A., Schubert, L., Speidel, M., Sutlief, S., Yu, A. S. 2023: e14130


    Concept inventories are multiple choice exams designed with the intention to test core concepts on specific subjects and evaluate common misconceptions. These tests serve as a useful tool in the classroom to assess value added by the instructor's educational methods and to better understand how students learn. They can provide educators with a method to evaluate their current teaching strategies and to make modifications that enhance student learning and ultimately elevate the quality of medical physics education. The use of concept inventories in introductory college physics courses revealed important gaps in conceptual understanding of physics by undergraduate students and motivated a shift of physics teaching towards more effective methods, such as active learning techniques. The goal of this review is to introduce medical physicists to concept inventories as educational evaluation tools and discuss potential applications to medical physics education by development through multi-institutional collaboration.

    View details for DOI 10.1002/acm2.14130

    View details for PubMedID 37646429

  • Shaping success: clinical implementation of a 3D-printed electron cutout program in external beam radiation therapy. Frontiers in oncology Schulz, J. B., Gibson, C., Dubrowski, P., Marquez, C. M., Million, L., Qian, Y., Skinner, L., Yu, A. S. 2023; 13: 1237037


    The integration of 3D-printing technology into radiation therapy (RT) has allowed for a novel method to develop personalized electron field-shaping blocks with improved accuracy. By obviating the need for handling highly toxic Cerrobend molds, the clinical workflow is significantly streamlined. This study aims to expound upon the clinical workflow of 3D-printed electron cutouts in RT and furnish one year of in-vivo dosimetry data.3D-printed electron cutouts for 6x6 cm, 10x10 cm, and 15x15 cm electron applicators were designed and implemented into the clinical workflow after dosimetric commissioning to ensure congruence with the Cerrobend cutouts. The clinical workflow consisted of four parts: i) the cutout aperture was extracted from the treatment planning system (TPS). A 3D printable cutout was then generated automatically through custom scripts; ii) the cutout was 3D-printed with PLA filament, filled with tungsten ball bearings, and underwent quality assurance (QA) to verify density and dosimetry; iii) in-vivo dosimetry was performed with optically stimulated luminescence dosimeters (OSLDs) for a patient's first treatment and compared to the calculated dose in the TPS; iv) after treatment completion, the 3D-printed cutout was recycled.QA and in-vivo OSLD measurements were conducted (n=40). The electron cutouts produced were 6x6 cm (n=3), 10x10 cm (n=30), and 15x15 cm (n=7). The expected weight of the cutouts differed from the measured weight by 0.4 + 1.1%. The skin dose measured with the OSLDs was compared to the skin dose in the TPS on the central axis. The difference between the measured and TPS doses was 4.0 + 5.2%.The successful clinical implementation of 3D-printed cutouts reduced labor, costs, and removed the use of toxic materials in the workplace while meeting clinical dosimetric standards.

    View details for DOI 10.3389/fonc.2023.1237037

    View details for PubMedID 37621682

    View details for PubMedCentralID PMC10445153

  • An affordable platform for virtual reality-based patient education in radiation therapy. Practical radiation oncology Schulz, J. B., Dubrowski, P., Blomain, E., Million, L., Qian, Y., Marquez, C., Yu, A. S. 2023


    The goal of this study is to develop and assess the effectiveness of an affordable smartphone-based Virtual Reality (VR) patient education platform with 360-degree videos produced depicting a first-person patient perspective during the radiation therapy (RT) care path to reduce patient anxiety.and Materials Three disease site-specific (breast, pelvis, head and neck) VR-videos were filmed using a 360-degree camera to portray the first-person perspective of a patient's standard RT appointments: including a Computed Tomography (CT) simulation and the first RT treatment session. Instruction is given for possible clinical implementation. Patient participation was divided into two groups: 1) Group-A (n=28) included patients participating before simulation and later after the first treatment, and 2) Group-B (n=33) included patients participating only while undergoing treatment. Patients viewed their disease site-specific video using an inexpensive cardboard VR-viewer and their smartphone, emulating an expensive VR-headset. Surveys were administered assessing patient anxiety, comfort, satisfaction, and knowledge of RT on a 5-point Likert-type scale.Patients in Group-A and Group-B while undergoing treatment both selected their anxiety "decreased a little" in the survey, after watching the VR-video (Group-A, median on a 5-point Likert-type scale, 4 [interquartile range {IQR}, 4-5]; Group-B, 4 [IQR 4-4]). The VR aspect of the videos was especially liked by patients while undergoing treatment, with 96.4% in Group-A and 90.9% in Group-B reporting that the VR aspect of the videos was helpful. All Group-A participants believed that the VR-videos would be beneficial to new patients.Our affordable VR patient education platform effectively immerses a patient in their care path from simulation through initial treatment delivery, reducing anxiety and increasing familiarity with the treatment process.

    View details for DOI 10.1016/j.prro.2023.06.008

    View details for PubMedID 37482182

  • Framework for Quality Assurance of Ultra-High Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps. International journal of radiation oncology, biology, physics Zou, W., Zhang, R., Schueler, E., Taylor, P. A., Mascia, A. E., Diffenderfer, E. S., Zhao, T., Ayan, A. S., Sharma, M., Yu, S. J., Lu, W., Bosch, W. R., Tsien, C., Surucu, M., Pollard-Larkin, J. M., Schuemann, J., Moros, E. G., Bazalova-Carter, M., Gladstone, D. J., Li, H., Simone, C. B., Petersson, K., Kry, S. F., Maity, A., Loo, B. W., Dong, L., Maxim, P. G., Xiao, Y., Buchsbaum, J. C. 2023


    FLASH radiotherapy, delivered with ultra-high dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared to currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology (CIRO) FLASH working group on quality assurance of potential UHDR clinical trials, and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to answer clinical and scientific questions about FLASH most effectively.

    View details for DOI 10.1016/j.ijrobp.2023.04.018

    View details for PubMedID 37121362

  • Clinical LINAC-based electron FLASH: Pathway for practical translation to FLASH clinical trials: LINAC electron FLASH. International journal of radiation oncology, biology, physics No, H. J., Wu, Y. F., Dworkin, M. L., Manjappa, R., Skinner, L., Ashraf, M. R., Lau, B., Melemenidis, S., Viswanathan, V., Yu, A. S., Surucu, M., Schüler, E., Graves, E. E., Maxim, P. G., Loo, B. W. 2023


    Ultra-high dose rate (UHDR) radiotherapy (RT) has produced the FLASH effect in preclinical models: reduced toxicity with comparable tumor control compared to conventional dose rate RT. Early clinical trials focused on UHDR RT feasibility using specialized devices. We explore the technical feasibility of practical electron UHDR RT on a standard clinical linear accelerator (LINAC).We tuned the program board of a decommissioned electron energy for UHDR electron delivery on a clinical LINAC, without hardware modification. Pulse delivery was controlled using the respiratory gating interface. A short SSD electron set-up with a standard scattering foil was configured and tested on an anthropomorphic phantom using circular blocks with 3-20 cm field sizes. Dosimetry was evaluated using radiochromic film and an ion chamber profiler.UHDR open field mean dose rates at 100, 80, 70, and 59 cm SSD were 36.82, 59.52, 82.01, and 112.83 Gy/s, respectively. At 80 cm SSD, mean dose rate was ∼60 Gy/s for all collimated field sizes, with an R80 depth of 6.1 cm corresponding to an energy of 17.5 MeV. Heterogeneity was <5.0% with asymmetry of 2.2 to 6.2%. The short SSD set-up was feasible under realistic treatment conditions simulating broad clinical indications on an anthropomorphic phantom.Short SSD and tuning for high electron beam current on a standard clinical LINAC can deliver flat, homogenous UHDR electrons over a broad, clinically relevant range of field sizes and depths with practical working distances, in a configuration easily reversible to standard clinical use.

    View details for DOI 10.1016/j.ijrobp.2023.04.011

    View details for PubMedID 37105403

  • 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

  • FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates. bioRxiv : the preprint server for biology Barghouth, P. G., Melemenidis, S., Montay-Gruel, P., Ollivier, J., Viswanathan, V., Jorge, P. G., Soto, L. A., Lau, B. C., Sadeghi, C., Edlabadkar, A., Manjappa, R., Wang, J., Bouteiller, M. L., Surucu, M., Yu, A., Bush, K., Skinner, L., Maxim, P. G., Loo, B. W., Limoli, C. L., Vozenin, M., Frock, R. L. 2023


    The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O 2 ) and hypoxic conditions (≤2% O 2 ) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O 2 ) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing ( HTGTS-JoinT-seq ), using S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1*10 2 -5*10 6 Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

    View details for DOI 10.1101/2023.03.27.534408

    View details for PubMedID 37034651

  • Radiation therapy practice changes in the COVID-19 pandemic era: A pilot study in California. Journal of applied clinical medical physics Liu, X., Zhang, J., Ruan, D., Yu, A. S., Sehgal, V., Qi, X. S., Barker, M. C., Shen, Z. L., Goetsch, S. 2022: e13770


    PURPOSE: This study aims to investigate practice changes among Southern and Northern California's radiation oncology centers during the COVID-19 pandemic.METHODS: On the online survey platform SurveyMonkey, we designed 10 survey questions to measure changes in various aspects of medical physics practice. The questions covered patient load and travel rules; scopes to work from home; new protocols to reduce corona virus disease-2019 (COVID-19) infection risk; availability of telemedicine; and changes in fractionation schedules and/or type of treatment plans. We emailed the survey to radiation oncology centers throughout Northern and Southern California, requesting one completed survey per center. All responses were anonymized, and data were analyzed using both qualitative and quantitative research methods.RESULTS: At the end of a 4-month collection period (July 2, 2021 to October 11, 2021), we received a total of 61 responses throughout Southern and Northern California. On average, 4111 patients were treated per day across the 61 centers. New COVID-19-related department and hospital policies, along with hybrid workflow changes, infectious control policies, and changes in patient load have been reported. Results also showed changes in treatment methods during the pandemic, such as increased use of telemedicine, hypofractionation for palliative, breast cancer, and prostate cancer cases; and simultaneous boosts, compared to sequential boosts.CONCLUSION: Our California radiation oncology center population study shows changes in various aspects of radiation oncology practices during the COVID-19 pandemic. This study serves as a pilot study to identify possible correlations and new strategies that allow radiation oncology centers to continue providing quality patient care while ensuring the safety of both staff and patients.

    View details for DOI 10.1002/acm2.13770

    View details for PubMedID 36018624

  • Design and validation of a dosimetric comparison scheme tailored for ultra-high dose-rate electron beams to support multicenter FLASH preclinical studies. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Gonçalves Jorge, P., Melemenidis, S., Grilj, V., Buchillier, T., Manjappa, R., Viswanathan, V., Gondré, M., Vozenin, M. C., Germond, J. F., Bochud, F., Moeckli, R., Limoli, C., Skinner, L., Joshua No, H., Fred Wu, Y., Surucu, M., Yu, A. S., Lau, B., Wang, J., Schüler, E., Bush, K., Graves, E. E., Maxim, P. G., Loo, B. W., Bailat, C. 2022


    We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100-1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups.Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA.Data obtained between replicate experiments for all dosimeters were in excellent agreement (+/- 3 %). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose.In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect.

    View details for DOI 10.1016/j.radonc.2022.08.023

    View details for PubMedID 36030934

  • CT-less electron radiotherapy simulation and planning with a consumer 3D camera. Journal of applied clinical medical physics Skinner, L., Knopp, R., Wang, Y., Dubrowski, P., Bush, K. K., Limmer, A., Trakul, N., Million, L., Marquez, C. M., Yu, A. S. 2021


    PURPOSE: Electron radiation therapy dose distributions are affected by irregular body surface contours. This study investigates the feasibility of three-dimensional (3D) cameras to substitute for the treatment planning computerized tomography (CT) scan by capturing the body surfaces to be treated for accurate electron beam dosimetry.METHODS: Dosimetry was compared for six electron beam treatments to the nose, toe, eye, and scalp using full CT scan, CT scan with Hounsfield Unit (HU) overridden to water (mimic 3D camera cases), and flat-phantom techniques. Radiation dose was prescribed to a depth on the central axis per physician's order, and the monitor units (MUs) were calculated. The 3D camera spatial accuracy was evaluated by comparing the 3D surface of a head phantom captured by a 3D camera and that generated with the CT scan in the treatment planning system. A clinical case is presented, and MUs were calculated using the 3D camera body contour with HU overridden to water.RESULTS: Across six cases the average change in MUs between the full CT and the 3Dwater (CT scan with HU overridden to water) calculations was 1.3% with a standard deviation of 1.0%. The corresponding hotspots had a mean difference of 0.4% and a standard deviation of 1.9%. The 3D camera captured surface of a head phantom was found to have a 0.59mm standard deviation from the surface derived from the CT scan. In-vivo dose measurements (213±8cGy) agreed with the 3D-camera planned dose of 209±6cGy, compared to 192±6cGy for the flat-phantom calculation (same MUs).CONCLUSIONS: Electron beam dosimetry is affected by irregular body surfaces. 3D cameras can capture irregular body contours which allow accurate dosimetry of electron beam treatment as an alternative to costly CT scans with no extra exposure to radiation. Tools and workflow for clinical implementation are provided.

    View details for DOI 10.1002/acm2.13283

    View details for PubMedID 34042253

  • A robotically assisted 3D printed quality assurance lung phantom for Calypso. Physics in medicine and biology Capaldi, D. P., Skinner, L. B., Dubrowski, P. n., Zhang, H. n., Xing, L. n., Chuang, C. F., Loo, B. W., Bush, K. K., Fahimian, B. P., Yu, A. S. 2021


    Purpose:Radiation dose delivered to targets located near the upper-abdomen or in the thorax are significantly affected by respiratory-motion. Relatively large-margins are commonly added to compensate for this motion, limiting radiation-dose-escalation. Internal-surrogates of target motion, such as a radiofrequency (RF) tracking system, i.e. Calypso® System, are used to overcome this challenge and improve normal-tissue sparing. RF tracking systems consist of implanting transponders in the vicinity of the tumor to be tracked using radiofrequency-waves. Unfortunately, although the manufacture provides a universal quality-assurance (QA) phantom, QA-phantoms specifically for lung-applications are limited, warranting the development of alternative solutions to fulfil the tests mandated by AAPM's TG142. Accordingly, our objective was to design and develop a motion-phantom to evaluate Calypso for lung-applications that allows the Calypso® Beacons to move in different directions to better simulate true lung-motion.Methods and Materials:A Calypso lung QA-phantom was designed, and 3D-printed. The design consists of three independent arms where the transponders were attached. A pinpoint-chamber with a buildup-cap was also incorporated. A 4-axis robotic arm was programmed to drive the motion-phantom to mimic breathing. After acquiring a four-dimensional-computed-tomography (4DCT) scan of the motion-phantom, treatment-plans were generated and delivered on a Varian TrueBeam® with Calypso capabilities. Stationary and gated-treatment plans were generated and delivered to determine the dosimetric difference between gated and non-gated treatments. Portal cine-images were acquired to determine the temporal-accuracy of delivery by calculating the difference between the observed versus expected transponders locations with the known speed of the transponders' motion.Results:Dosimetric accuracy is better than TG142 tolerance of 2%. Temporal accuracy is greater than, TG142 tolerance of 100ms for beam-on, but less than 100ms for beam-hold.Conclusions:The robotic QA-phantom designed and developed in this study provides an independent phantom for performing Calypso lung-QA for commissioning and acceptance testing of Calypso for lung treatments.

    View details for DOI 10.1088/1361-6560/abebaa

    View details for PubMedID 33657537

  • Nontoxic electron collimators. Journal of applied clinical medical physics Breitkreutz, D. Y., Skinner, L., Lo, S., Yu, A. 2021


    The goal of this work was to develop and test nontoxic electron collimation technologies for clinical use.Two novel technologies were investigated: tungsten-silicone composite and 3D printed electron cutouts. Transmission, dose uniformity, and profiles were measured for the tungsten-silicone. Surface dose, relative dose output, and field size were measured for the 3D printed cutouts and compared with the standard cerrobend cutouts in current clinical use. Quality assurance tests including mass measurements, Megavoltage (MV) imaging, and drop testing were developed for the 3D printed cutouts as a guide to safe clinical implementation.Dose profiles of the flexible tungsten-silicone skin shields had an 80-20 penumbra values of 2-3 mm compared to 7-8 mm for cerrobend. In MV transmission image measurements of the tungsten-silicone, 80% of the pixels had a transmission value within 2% of the mean. An ∼90% reduction in electron intensity was measured for 6 MeV and a 6.4 mm thickness of tungsten-silicone and 12.7 mm thickness for 16 MeV. The maximum difference in 3D printed cutout versus cerrobend output, surface dose, and full width at half-maximum (FWHM) was 1.7%, 1.2%, and 1.5%, respectively, for the 10 cm × 10 cm cutouts.Both flexible tungsten-silicone and 3D printed cutouts were found to be feasible for clinical use. The flexible tungsten-silicone was of adequate density, flexibility, and uniformity to serve as skin shields for electron therapy. The 3D printed cutouts were dosimetrically equivalent to standard cerrobend cutouts and were robust enough for handling in the clinical environment.

    View details for DOI 10.1002/acm2.13398

    View details for PubMedID 34480841

  • The benefit of using the AAPM Journal app. Journal of applied clinical medical physics Yu, A. S. 2020

    View details for DOI 10.1002/acm2.13019

    View details for PubMedID 32862497

  • FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice Natarajan, S., Levy, K., Wang, J., Chow, S., Eggold, J., Loo, P., Manjappa, R., Lartey, F. M., Schuler, E., Skinner, L., Rafat, M., Ko, R., Kim, A., Al Rawi, D., von Eyben, R., Dorigo, O., Casey, K. M., Graves, E. E., Bush, K., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020
  • Total abdominal ultra-rapid FLASH irradiation enhances the efficacy of PD-1 inhibition in preclinical models of ovarian cancer Chow, S., Eggold, J. T., Levy, K., Wang, J., Manjappa, R., Breitkreutz, D. Y., Yu, A. S., Bush, K., Dorigo, O., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020
  • Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Scientific reports Levy, K. n., Natarajan, S. n., Wang, J. n., Chow, S. n., Eggold, J. T., Loo, P. E., Manjappa, R. n., Melemenidis, S. n., Lartey, F. M., Schüler, E. n., Skinner, L. n., Rafat, M. n., Ko, R. n., Kim, A. n., H Al-Rawi, D. n., von Eyben, R. n., Dorigo, O. n., Casey, K. M., Graves, E. E., Bush, K. n., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. 2020; 10 (1): 21600


    Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

    View details for DOI 10.1038/s41598-020-78017-7

    View details for PubMedID 33303827

  • An integrated quality assurance phantom for frameless single-isocenter multitarget stereotactic radiosurgery. Physics in medicine and biology Capaldi, D. P., Skinner, L. B., Dubrowski, P. n., Yu, A. S. 2020


    Purpose:Brain stereotactic-radiosurgery (SRS) treatments require multiple quality-assurance (QA) procedures to ensure accurate and precise treatment delivery. As single-isocenter multitarget SRS treatments become more popular, the quantification of off-axis accuracy of the linear-accelerator is crucial. In this study, a novel brain SRS integrated phantom was developed and validated to enable SRS QA with a single phantom to facilitate implementation of a frameless single-isocenter, multitarget SRS program. This phantom combines the independent verification of each positioning system, the Winston-Lutz, off-axis accuracy evaluation (i.e. off-axis Winston-Lutz), and the dosimetric accuracy utilizing both point-dose-measurements as well as film-measurement, without moving the phantom.Methods and Materials:A novel 3D-printed phantom, coinedOneIso, was designed with a movable insert which can switch between the Winston-Lutz test target and dose measurement without moving the phantom itself. For dose verification, eight brain SRS clinical-treatment-plans with 10MV Flattening-Filter-Free (FFF) beams were delivered on a Varian TrueBeam with a high-definition-multi-leaf-collimator (HD-MLC). Radiochromic film and pinpoint ion chamber comparison measurements were made between the OneIso and solid water (SW) phantom setups. For the off-axis Winston-Lutz measurements, a row of off-axis ball-bearings (BBs) was integrated into the OneIso. To quantify the spatial accuracy versus distance from isocenter, two-dimensional displacements were calculated between the planned and delivered BB locations relative to their respective MLC defined field border.Results:OneIso and the SW phantoms agree within 1%, for both film and point-dose measurements. OneIso identified a reduction in spatial accuracy further away from isocenter. Differences increased as distance from isocenter increased exceeding recommended SRS accuracy tolerances at 3-4cm away from isocenter.Conclusions:OneIso provides a streamlined, single-setup workflow for single-isocenter multitarget frameless linac-based SRS QA. Additionally, with the ability to quantify off-axis spatial-discrepancies, we can determine limitations on the maximum distance between targets to ensure a single-isocenter multitarget SRS program meets recommended guidelines.

    View details for DOI 10.1088/1361-6560/ab8534

    View details for PubMedID 32235050

  • FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation. Radiation research Soto, L. A., Casey, K. M., Wang, J. n., Blaney, A. n., Manjappa, R. n., Breitkreutz, D. n., Skinner, L. n., Dutt, S. n., Ko, R. B., Bush, K. n., Yu, A. S., Melemenidis, S. n., Strober, S. n., Englemann, E. n., Maxim, P. G., Graves, E. E., Loo, B. W. 2020


    Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.

    View details for DOI 10.1667/RADE-20-00090

    View details for PubMedID 32853385

  • Patient motion tracking for non-isocentric and non-coplanar treatments via fixed frame-of-reference 3D camera. Journal of applied clinical medical physics Gasparyan, S. n., Ko, K. n., Skinner, L. B., Ko, R. B., Loo, B. W., Fahimian, B. P., Yu, A. S. 2020


    As C-arm linac radiation therapy evolves toward faster, more efficient delivery, and more conformal dosimetry, treatments with increasingly complex couch motions are emerging. Monitoring the patient motion independently of the couch motion during non-coplanar, non-isocentric, or dynamic couch treatments is a key bottleneck to their clinical implementation. The goal of this study is to develop a prototype real-time monitoring system for unconventional beam trajectories to ensure a safe and accurate treatment delivery.An in-house algorithm was developed for tracking using a couch-mounted three-dimensional (3D) depth camera. The accuracy of patient motion detection on the couch was tested on a 3D printed phantom created from the body surface contour exported from the treatment planning system. The technique was evaluated against a commercial optical surface monitoring system with known phantom displacements of 3, 5, and 7 mm in lateral, longitudinal, and vertical directions by placing a head phantom on a dynamic platform on the treatment couch. The stability of the monitoring system was evaluated during dynamic couch trajectories, at speeds between 10.6 and 65 cm/min.The proposed monitoring system agreed with the ceiling mounted optical surface monitoring system in longitudinal, lateral, and vertical directions within 0.5 mm. The uncertainty caused by couch vibration increased with couch speed but remained sub-millimeter for speeds up to 32 cm/min. For couch speeds of 10.6, 32.2, and 65 cm/min, the uncertainty ranges were 0.27- 0.73 mm, 0.15-0.87 mm, and 0.28-1.29 mm, respectively.By mounting a 3D camera in the same frame-of-reference as the patient and eliminating dead spots, this proof of concept demonstrates real-time patient monitoring during couch motion. For treatments with non-coplanar beams, multiple isocenters, or dynamic couch motion, this provides additional safety without additional radiation dose and avoids some of the complexity and limitations of room mounted systems.

    View details for DOI 10.1002/acm2.12842

    View details for PubMedID 32107845

  • Probing Estrogen Sulfotransferase-Mediated Inflammation with [11C]-PiB in the Living Human Brain. Journal of Alzheimer's disease : JAD Surmak, A. J., Wong, K., Cole, G. B., Hirata, K., Aabedi, A. A., Mirfendereski, O., Mirfendereski, P., Yu, A. S., Huang, S., Ringman, J. M., Liebeskind, D. S., Barrio, J. R. 2019


    BACKGROUND: 2-(4'- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-beta plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis.OBJECTIVE: In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients.METHODS: Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue.RESULTS: Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p < 0.005). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry.CONCLUSION: Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-beta plaques.

    View details for DOI 10.3233/JAD-190559

    View details for PubMedID 31884462

  • Does 2-FDG-PET Accurately Reflect Quantitative In vivo Glucose Utilization? Journal of nuclear medicine : official publication, Society of Nuclear Medicine Barrio, J. R., Satyamurthy, N., Huang, S. C., Scafoglio, C., Yu, A., Alavi, A., Krohn, K. A. 2019


    2-Deoxy-2-[18F]fluoro-D-glucose (2-FDG) with positron emission tomography (2-FDG-PET) is undeniably useful in the clinic, among other uses, to monitor change over time using the 2-FDG standardized uptake values (SUV) metric. This report suggests some potentially serious caveats for this and related roles for 2-FDG PET. Most critical is the assumption that there is an exact proportionality between glucose metabolism and 2-FDG metabolism, called the lumped constant, LC. This report describes that LC is not constant for a specific tissue and may be variable before and after disease treatment. The purpose of this work is not to deny the clinical value of 2-FDG PET; it is a reminder that when one extends the use of an appropriately qualified imaging method, new observations may arise and further validation would be necessary. Current understanding of glucose-based energetics in vivo is based on the quantification of glucose metabolic rates with 2-FDG PET, a method that permits the non-invasive assessment in various human disorders. However, 2-FDG is only a good substrate for facilitated-glucose transporters (GLUTs) but not for sodium-dependent glucose co-transporters (SGLTs), which have recently been shown to be distributed in multiple human tissues. Thus, the GLUT-mediated in vivo glucose utilization measured by 2-FDG PET would be blinded to the potentially substantial role of functional SGLTs in glucose transport and utilization. Therefore, in these circumstances the 2-FDG LC used to quantify in vivo glucose utilization should not be expected to remain constant. 2-FDG LC variations have been especially significant in tumors, particularly at different stages of cancer development, affecting the accuracy of quantitative glucose measures and potentially limiting the prognostic value of 2-FDG, as well as its accuracy in monitoring treatments. SGLT-mediated glucose transport can be estimated using α-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside (Me-4FDG). Utilizing both 2-FDG and Me-4FDG should provide a more complete picture of glucose utilization via both GLUT and SGLT transporters in health and disease stages. Given the widespread use of 2-FDG PET to infer glucose metabolism, appreciating the potential limitations of 2-FDG as a surrogate for glucose metabolic rate and the potential reasons for variability in LC is relevant. Even when the readout for the 2-FDG PET study is only an SUV parameter, variability in LC is important, particularly if it changes over the course of disease progression (e.g., an evolving tumor).

    View details for DOI 10.2967/jnumed.119.237446

    View details for PubMedID 31676728

  • Tungsten filled 3D printed field shaping devices for electron beam radiation therapy. PloS one Skinner, L., Fahimian, B. P., Yu, A. S. 2019; 14 (6): e0217757


    PURPOSE: Electron radiotherapy is a labor-intensive treatment option that is complicated by the need for field shaping blocks. These blocks are typically made from casting Cerrobend alloys containing lead and cadmium. This is a highly toxic process with limited precision. This work aims to provide streamlined and more precise electron radiotherapy by 3D using printing techniques.METHODS: The 3D printed electron cutout consists of plastic shells filled with 2 mm diameter tungsten ball bearings. Five clinical Cerrobend defined field were compared to the planned fields by measuring the light field edge when mounted in the electron applicator on a linear accelerator. The dose transmitted through the 3D printed and Cerrobend cutouts was measured using an IC profiler ion chamber array with 6 MeV and 16 MeV beams. Dose profiles from the treatment planning system were also compared to the measured dose profiles. Centering and full width half maximum (FWHM) metrics were taken directly from the profiler software.RESULTS: The transmission of a 16MeV beam through a 12 mm thick layer of tungsten ball bearings agreed within 1% of a 15 mm thick Cerrobend block (measured with an ion chamber array). The radiation fields shaped by ball bearing filled 3D printed cutout were centered within 0.4 mm of the planned outline, whereas the Cerrobend cutout fields had shift errors of 1-3 mm, and shape errors of 0.5-2 mm. The average shift of Cerrobend cutouts was 2.3 mm compared to the planned fields (n = 5). Beam penumbra of the 3D printed cutouts was found to be equivalent to the 15 mm thick Cerrobend cutout. The beam profiles agreed within 1.2% across the whole 30 cm profile widths.CONCLUSIONS: This study demonstrates that with a proper quality assurance procedure, 3D-printed cutouts can provide more accurate electron radiotherapy with reduced toxicity compared to traditional Cerrobend methods.

    View details for DOI 10.1371/journal.pone.0217757

    View details for PubMedID 31216296

  • Factor 10 Expedience of Monthly Linac Quality Assurance via an Ion Chamber Array and Automation Scripts. Technology in cancer research & treatment Skinner, L. B., Yang, Y., Hsu, A., Xing, L., Yu, A. S., Niedermayr, T. 2019; 18: 1533033819876897


    PURPOSE: While critical for safe and accurate radiotherapy, monthly quality assurance of medical linear accelerators is time-consuming and takes physics resources away from other valuable tasks. The previous methods at our institution required 5 hours to perform the mechanical and dosimetric monthly linear accelerator quality assurance tests. An improved workflow was developed to perform these tests with higher accuracy, with fewer error pathways, in significantly less time.METHODS: A commercial ion chamber array (IC profiler, Sun Nuclear, Melbourne, Florida) is combined with automation scripts to consolidate monthly linear accelerator QA. The array was used to measure output, flatness, symmetry, jaw positions, gated dose constancy, energy constancy, collimator walkout, crosshair centering, and dosimetric leaf gap constancy. Treatment plans were combined with automation scripts that interface with Sun Nuclear's graphical user interface. This workflow was implemented on a standard Varian clinac, with no special adaptations, and can be easily applied to other C-arm linear accelerators.RESULTS: These methods enable, in 30 minutes, measurement and analysis of 20 of the 26 dosimetric and mechanical monthly tests recommended by TG-142. This method also reduces uncertainties in the measured beam profile constancy, beam energy constancy, field size, and jaw position tests, compared to our previous methods. One drawback is the increased uncertainty associated with output constancy. Output differences between IC profiler and farmer chamber in plastic water measurements over a 6-month period, across 4 machines, were found to have a 0.3% standard deviation for photons and a 0.5% standard deviation for electrons, which is sufficient for verifying output accuracy according to TG-142 guidelines. To minimize error pathways, automation scripts which apply the required settings, as well as check the exported data file integrity were employed.CONCLUSIONS: The equipment, procedure, and scripts used here reduce the time burden of routine quality assurance tests and in most instances improve precision over our previous methods.

    View details for DOI 10.1177/1533033819876897

    View details for PubMedID 31707931

  • A novel-integrated quality assurance phantom for radiographic and nonradiographic radiotherapy localization and positioning systems. Medical physics Yu, A. S., Fowler, T. L., Dubrowski, P. 2018


    PURPOSE: Various localization and positioning systems utilizing radiographic or nonradiographic methods have been developed to improve the accuracy of radiation treatment. Each quality assurance (QA) procedure requires its own phantom and is independent from each other, so the deviation between each system is unavailable. The purpose of this work is to develop and evaluate a single-integrated QA phantom for different localization and positioning systems.METHODS: The integrated phantom was designed in three-dimensional (3D) CAD software and 3D printed. The phantom was designed with laser alignment marks, a raised letter "S" on the anterior surface for optical surface monitoring system registration, a core for radiofrequency (RF) tracking system alignment, eight internal fiducials for image alignment, and an isocentric bearing for Winston-Lutz test. Tilt legs and rotational stage were designed for rotational verification of optical surface mapping system and RF tracking system, respectively. The phantom was scanned using a CT scanner and a QA plan was created. This prototype phantom was evaluated against established QA techniques.RESULTS: The QA result between the proposed procedure and established QA technique are 1.12 ± 0.31 and 1.14 ± 0.31 mm, respectively, for RF tracking system and 0.18 ± 0.06 and 0.18 ± 0.05 mm for Winston-Lutz test. There is no significant difference for the QA results between the established QA and proposed procedure (P > 0.05, t test). The accuracy of rotational verification for surface mapping system and RF tracking system are less than 0.5 and 1° compared the predefined value. The isocenter deviation of each location system is around l mm.CONCLUSION: We have designed and evaluated a novel-integrated phantom for radiographic and nonradiographic localization and positioning systems for radiotherapy. With this phantom, we will reduce the variation in measurements and simplify the QA procedures.

    View details for PubMedID 29730884

  • 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 PubMedID 29332454

    View details for PubMedCentralID PMC5762073

  • Using a handheld stereo depth camera to overcome limited field-of-view in simulation imaging for radiation therapy treatment planning MEDICAL PHYSICS Jenkins, C., Xing, L., Yu, A. 2017; 44 (5): 1857-1864


    A correct body contour is essential for reliable treatment planning in radiation therapy. While modern medical imaging technologies provide highly accurate patient modeling, there are times when a patient's anatomy cannot be fully captured or there is a lack of easy access to computed tomography (CT) simulation. Here, we provide a practical solution to the surface contour truncation problem by using a handheld stereo depth camera (HSDC) to obtain the missing surface anatomy and a surface-surface image registration to stich the surface data into the CT dataset for treatment planning.For a subject with truncated simulation CT images, a HSDC is used to capture the surface information of the truncated anatomy. A mesh surface model is created using a software tool provided by the camera manufacturer. A surface-to-surface registration technique is used to merge the mesh model with the CT and fill in the missing surface information thereby obtaining a complete surface model of the subject. To evaluate the accuracy of the proposed approach, experiments were performed with the following steps. First, we selected three previously treated patients and fabricated a phantom mimicking each patient using the corresponding CT images and a 3D printer. Second, we removed part of the CT images of each patient to create hypothetical cases with image truncations. Next, a HSDC was used to image the 3D-printed phantoms and the HSDC-derived surface models were registered with the hypothetically truncated CT images. The contours obtained using the approach were then compared with the ground truth contours derived from the original simulation CT without image truncation. The distance between the two contours was calculated in order to evaluate the accuracy of the method. Finally, the dosimetric impact of the approach is assessed by comparing the volume within the 95% isodose line and global maximum dose (Dmax ) computed based on the two surface contours for the breast case that exhibited the largest contour variation in the treated breast.A systematic strategy of using a 3D HSDC to compensate for missing surface information caused by the truncation of CT images was established. Our study showed that the proposed technique was able to reliably provide the full contours for treatment planning in the case of severe CT image truncation(s). The root-mean-square error for the registration between the aligned HDSC surface model and the ground truth data was found to be 2.1 mm. The average distance between the two models was 0.4 ± 1.7 mm (mean ± SD). Maximum deviations occurred in areas of high concavity or when the skin was close to the couch. The breast tissue covered by 95% isodose line decreased by 3% and Dmax increased by 0.2% with the use of the HSDC model.The use of HSDC for obtaining missing surface data during simulation has a number of advantages, such as, ease of use, low cost, and no additional ionizing radiation. It may provide a clinically practical solution to deal with the longstanding problem of CT image truncations in radiation therapy treatment planning.

    View details for DOI 10.1002/mp.12207

    View details for Web of Science ID 000401154000024

    View details for PubMedID 28295413

  • Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Ghezzi, C., Yu, A. S., Hirayama, B. A., Kepe, V., Liu, J., Scafoglio, C., Powell, D. R., Huang, S., Satyamurthy, N., Barrio, J. R., Wright, E. M. 2017; 28 (3): 802-810


    Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[(18)F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

    View details for DOI 10.1681/ASN.2016050510

    View details for Web of Science ID 000395049000012

    View details for PubMedID 27620988

  • A Robust and Affordable Table Indexing Approach for Multi-isocenter Dosimetrically Matched Fields. Cureus Yu, A. n., Fahimian, B. n., Million, L. n., Hsu, A. n. 2017; 9 (5): e1270


    Purpose  Radiotherapy treatment planning of extended volume typically necessitates the utilization of multiple field isocenters and abutting dosimetrically matched fields in order to enable coverage beyond the field size limits. A common example includes total lymphoid irradiation (TLI) treatments, which are conventionally planned using dosimetric matching of the mantle, para-aortic/spleen, and pelvic fields. Due to the large irradiated volume and system limitations, such as field size and couch extension, a combination of couch shifts and sliding of patients are necessary to be correctly executed for accurate delivery of the plan. However, shifting of patients presents a substantial safety issue and has been shown to be prone to errors ranging from minor deviations to geometrical misses warranting a medical event. To address this complex setup and mitigate the safety issues relating to delivery, a practical technique for couch indexing of TLI treatments has been developed and evaluated through a retrospective analysis of couch position. Methods The indexing technique is based on the modification of the commonly available slide board to enable indexing of the patient position. Modifications include notching to enable coupling with indexing bars, and the addition of a headrest used to fixate the head of the patient relative to the slide board. For the clinical setup, a Varian Exact Couch(TM) (Varian Medical Systems, Inc, Palo Alto, CA) was utilized. Two groups of patients were treated: 20 patients with table indexing and 10 patients without. The standard deviations (SDs) of the couch positions in longitudinal, lateral, and vertical directions through the entire treatment cycle for each patient were calculated and differences in both groups were analyzed with Student's t-test. Results The longitudinal direction showed the largest improvement. In the non-indexed group, the positioning SD ranged from 2.0 to 7.9 cm. With the indexing device, the positioning SD was reduced to a range of 0.4 to 1.3 cm (p < 0.05 with 95% confidence level). The lateral positioning was slightly improved (p < 0.05 with 95% confidence level), while no improvement was observed in the vertical direction. Conclusions The conventional matched field TLI treatment is error-prone to geometrical setup error. The feasibility of full indexing TLI treatments was validated and shown to result in a significant reduction of positioning and shifting errors.

    View details for PubMedID 28652953

  • Chest wall dose reduction using noncoplanar volumetric modulated arc radiation therapy for lung stereotactic ablative radiation therapy. Practical radiation oncology Yu, A. S., Maxim, P. G., Loo, B. W., Gensheimer, M. F. 2017


    Stereotactic ablative radiation therapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using noncoplanar volumetric modulated arc radiation therapy (VMAT) to reduce chest wall dose from lung SABR.Twenty lung SABR VMAT plans in which the chest wall volume receiving 30 Gy or higher (V30) exceeded 30 mL were replanned by noncoplanar VMAT with opposite 15° couch kicks. Dosimetric parameters including chest wall V30 and V40; lung V5, V10, V20, and mean dose; Paddick high-dose conformity index; intermediate-dose conformity index; and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t test was used to evaluate the difference of the dosimetric parameters between coplanar 1 arc (cVMAT1), coplanar 2 arcs (cVMAT2), and noncoplanar two arcs (nVMAT2) plans; differences with P < .05 were considered statistically significant.V30 and V40 for chest wall were reduced on average by 20% ± 9% and 15% ± 11% (mean ± standard deviation) from cVMAT2 plans to nVMAT2 plans (P < .01 for both comparisons) and by 8% ± 7% and 16% ± 13% from cVMAT1 plans to cVMAT2 plans (P < .003 for both comparisons). The differences in lung mean dose were <0.2 Gy among cVMAT1, cVMAT2, and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared with cVMAT2. The Paddick high-dose conformity indexes were 0.88 ± 0.03, 0.89 ± 0.04, and 0.91 ± 0.03, and intermediate-dose conformity indexes were 3.88 ± 0.49, 3.80 ± 0.44 and 3.51 ± 0.38 for cVMAT1, cVMAT2, and nVMAT2, respectively.We found that noncoplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.

    View details for PubMedID 29452868

  • Automating quality assurance of digital linear accelerators using a radioluminescent phosphor coated phantom and optical imaging. Physics in medicine and biology Jenkins, C. H., Naczynski, D. J., Yu, S. S., Yang, Y., Xing, L. 2016; 61 (17): L29-37


    Performing mechanical and geometric quality assurance (QA) tests for medical linear accelerators (LINAC) is a predominantly manual process that consumes significant time and resources. In order to alleviate this burden this study proposes a novel strategy to automate the process of performing these tests. The autonomous QA system consists of three parts: (1) a customized phantom coated with radioluminescent material; (2) an optical imaging system capable of visualizing the incidence of the radiation beam, light field or lasers on the phantom; and (3) software to process the captured signals. The radioluminescent phantom, which enables visualization of the radiation beam on the same surface as the light field and lasers, is placed on the couch and imaged while a predefined treatment plan is delivered from the LINAC. The captured images are then processed to self-calibrate the system and perform measurements for evaluating light field/radiation coincidence, jaw position indicators, cross-hair centering, treatment couch position indicators and localizing laser alignment. System accuracy is probed by intentionally introducing errors and by comparing with current clinical methods. The accuracy of self-calibration is evaluated by examining measurement repeatability under fixed and variable phantom setups. The integrated system was able to automatically collect, analyze and report the results for the mechanical alignment tests specified by TG-142. The average difference between introduced and measured errors was 0.13 mm. The system was shown to be consistent with current techniques. Measurement variability increased slightly from 0.1 mm to 0.2 mm when the phantom setup was varied, but no significant difference in the mean measurement value was detected. Total measurement time was less than 10 minutes for all tests as a result of automation. The system's unique features of a phosphor-coated phantom and fully automated, operator independent self-calibration offer the potential to streamline the QA process for modern LINACs.

    View details for DOI 10.1088/0031-9155/61/17/L29

    View details for PubMedID 27514654

  • Anatomic optimization of lung tumor stereotactic ablative radiation therapy. Practical radiation oncology Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Shultz, D. B., Loo, B. W., Maxim, P. G. 2015; 5 (6): e607-13


    The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans.Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent.Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent.For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed.

    View details for DOI 10.1016/j.prro.2015.05.008

    View details for PubMedID 26231596

  • Noninvasive pulmonary nodule elastometry by CT and deformable image registration. Radiotherapy and oncology Negahdar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40


    To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring.We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring.For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung.We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.

    View details for DOI 10.1016/j.radonc.2015.03.015

    View details for PubMedID 25824979

  • Monitoring external beam radiotherapy using real-time beam visualization. Medical physics Jenkins, C. H., Naczynski, D. J., Yu, S. S., Xing, L. 2015; 42 (1): 5-?


    To characterize the performance of a novel radiation therapy monitoring technique that utilizes a flexible scintillating film, common optical detectors, and image processing algorithms for real-time beam visualization (RT-BV).Scintillating films were formed by mixing Gd2O2S:Tb (GOS) with silicone and casting the mixture at room temperature. The films were placed in the path of therapeutic beams generated by medical linear accelerators (LINAC). The emitted light was subsequently captured using a CMOS digital camera. Image processing algorithms were used to extract the intensity, shape, and location of the radiation field at various beam energies, dose rates, and collimator locations. The measurement results were compared with known collimator settings to validate the performance of the imaging system.The RT-BV system achieved a sufficient contrast-to-noise ratio to enable real-time monitoring of the LINAC beam at 20 fps with normal ambient lighting in the LINAC room. The RT-BV system successfully identified collimator movements with sub-millimeter resolution.The RT-BV system is capable of localizing radiation therapy beams with sub-millimeter precision and tracking beam movement at video-rate exposure.

    View details for DOI 10.1118/1.4901255

    View details for PubMedID 25563243

    View details for PubMedCentralID PMC4265127

  • Regional distribution of SGLT activity in rat brain in vivo AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Yu, A. S., Hirayama, B. A., Timbol, G., Liu, J., Diez-Sampedro, A., Kepe, V., Satyamurthy, N., Huang, S., Wright, E. M., Barrio, J. R. 2013; 304 (3): C240-C247


    Na(+)-glucose cotransporter (SGLT) mRNAs have been detected in many organs of the body, but, apart from kidney and intestine, transporter expression, localization, and functional activity, as well as physiological significance, remain elusive. Using a SGLT-specific molecular imaging probe, α-methyl-4-deoxy-4-[(18)F]fluoro-D-glucopyranoside (Me-4-FDG) with ex vivo autoradiography and immunohistochemistry, we mapped in vivo the regional distribution of functional SGLTs in rat brain. Since Me-4-FDG is not a substrate for GLUT1 at the blood-brain barrier (BBB), in vivo delivery of the probe into the brain was achieved after opening of the BBB by an established procedure, osmotic shock. Ex vivo autoradiography showed that Me-4-FDG accumulated in regions of the cerebellum, hippocampus, frontal cortex, caudate nucleus, putamen, amygdala, parietal cortex, and paraventricular nucleus of the hypothalamus. Little or no Me-4-FDG accumulated in the brain stem. The regional accumulation of Me-4-FDG overlapped the distribution of SGLT1 protein detected by immunohistochemistry. In summary, after the BBB is opened, the specific substrate for SGLTs, Me-4-FDG, enters the brain and accumulates in selected regions shown to express SGLT1 protein. This localization and the sensitivity of these neurons to anoxia prompt the speculation that SGLTs may play an essential role in glucose utilization under stress such as ischemia. The expression of SGLTs in the brain raises questions about the potential effects of SGLT inhibitors under development for the treatment of diabetes.

    View details for DOI 10.1152/ajpcell.00317.2012

    View details for Web of Science ID 000314632400005

    View details for PubMedID 23151803

  • Functional expression of SGLTs in rat brain AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Yu, A. S., Hirayama, B. A., Timbol, G., Liu, J., Basarah, E., Kepe, V., Satyamurthy, N., Huang, S., Wright, E. M., Barrio, J. R. 2010; 299 (6): C1277-C1284


    This work provides evidence of previously unrecognized uptake of glucose via sodium-coupled glucose transporters (SGLTs) in specific regions of the brain. The current understanding of functional glucose utilization in brain is largely based on studies using positron emission tomography (PET) with the glucose tracer 2-deoxy-2-[F-18]fluoro-D-glucose (2-FDG). However, 2-FDG is only a good substrate for facilitated-glucose transporters (GLUTs), not for SGLTs. Thus, glucose accumulation measured by 2-FDG omits the role of SGLTs. We designed and synthesized two high-affinity tracers: one, α-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyranoside (Me-4FDG), is a highly specific SGLT substrate and not transported by GLUTs; the other one, 4-[F-18]fluoro-4-deoxy-D-glucose (4-FDG), is transported by both SGLTs and GLUTs and will pass through the blood brain barrier (BBB). In vitro Me-4FDG autoradiography was used to map the distribution of uptake by functional SGLTs in brain slices with a comparable result from in vitro 4-FDG autoradiography. Immunohistochemical assays showed that uptake was consistent with the distribution of SGLT protein. Ex vivo 4-FDG autoradiography showed that SGLTs in these areas are functionally active in the normal in vivo brain. The results establish that SGLTs are a normal part of the physiology of specific areas of the brain, including hippocampus, amygdala, hypothalamus, and cerebral cortices. 4-FDG PET imaging also established that this BBB-permeable SGLT tracer now offers a functional imaging approach in humans to assess regulation of SGLT activity in health and disease.

    View details for DOI 10.1152/ajpcell.00296.2010

    View details for Web of Science ID 000284822100008

    View details for PubMedID 20826762

  • Quantification of Cerebral Glucose Metabolic Rate in Mice Using F-18-FDG and Small-Animal PET JOURNAL OF NUCLEAR MEDICINE Yu, A. S., Lin, H., Huang, S., Phelps, M. E., Wu, H. 2009; 50 (6): 966-973


    The aim of this study was to evaluate various methods for estimating the metabolic rate of glucose utilization in the mouse brain (cMR(glc)) using small-animal PET and reliable blood curves derived by a microfluidic blood sampler. Typical values of (18)F-FDG rate constants of normal mouse cerebral cortex were estimated and used for cMR(glc) calculations. The feasibility of using the image-derived liver time-activity curve as a surrogate input function in various quantification methods was also evaluated.Thirteen normoglycemic C57BL/6 mice were studied. Eighteen blood samples were taken from the femoral artery by the microfluidic blood sampler. Tissue time-activity curves were derived from PET images. cMR(glc) values were calculated using 2 different input functions (one derived from the blood samples [IF(blood)] and the other from the liver time-activity curve [IF(liver)]) in various quantification methods, which included the 3-compartment (18)F-FDG model (from which the (18)F-FDG rate constants were derived), the Patlak analysis, and operational equations. The estimated cMR(glc) value based on IF(blood) and the 3-compartment model served as a standard for comparisons with the cMR(glc) values calculated by the other methods.The values of K(1), k(2), k(3), k(4), and K(FDG) estimated by IF(blood) and the 3-compartment model were 0.22 +/- 0.05 mL/min/g, 0.48 +/- 0.09 min(-1), 0.06 +/- 0.02 min(-1), 0.025 +/- 0.010 min(-1), and 0.024 +/- 0.007 mL/min/g, respectively. The standard cMR(glc) value was, therefore, 40.6 +/- 13.3 micromol/100 g/min (lumped constant = 0.6). No significant difference between the standard cMR(glc) and the cMR(glc) estimated by the operational equation that includes k(4) was observed. The standard cMR(glc) was also found to have strong correlations (r > 0.8) with the cMR(glc) value estimated by the use of IF(liver) in the 3-compartment model and with those estimated by the Patlak analysis (using either IF(blood) or IF(liver)).The (18)F-FDG rate constants of normal mouse cerebral cortex were determined. These values can be used in the k(4)-included operational equation to calculate cMR(glc). IF(liver) can be used to estimate cMR(glc) in most methods included in this study, with proper linear corrections applied. The validity of using the Patlak analysis for estimating cMR(glc) in mouse PET studies was also confirmed.

    View details for DOI 10.2967/jnumed.108.060533

    View details for Web of Science ID 000272488000026

    View details for PubMedID 19443595

  • In vivo quantitation of glucose metabolism in mice using small-animal PET and a microfluidic device JOURNAL OF NUCLEAR MEDICINE Wu, H., Sui, G., Lee, C., Prins, M. L., Ladno, W., Lin, H., Yu, A. S., Phelps, M. E., Huang, S. 2007; 48 (5): 837-845


    The challenge of sampling blood from small animals has hampered the realization of quantitative small-animal PET. Difficulties associated with the conventional blood-sampling procedure need to be overcome to facilitate the full use of this technique in mice.We developed an automated blood-sampling device on an integrated microfluidic platform to withdraw small blood samples from mice. We demonstrate the feasibility of performing quantitative small-animal PET studies using (18)F-FDG and input functions derived from the blood samples taken by the new device. (18)F-FDG kinetics in the mouse brain and myocardial tissues were analyzed.The studies showed that small ( approximately 220 nL) blood samples can be taken accurately in volume and precisely in time from the mouse without direct user intervention. The total blood loss in the animal was <0.5% of the body weight, and radiation exposure to the investigators was minimized. Good model fittings to the brain and the myocardial tissue time-activity curves were obtained when the input functions were derived from the 18 serial blood samples. The R(2) values of the curve fittings are >0.90 using a (18)F-FDG 3-compartment model and >0.99 for Patlak analysis. The (18)F-FDG rate constants K(1)(*), k(2)(*), k(3)(*), and k(4)(*), obtained for the 4 mouse brains, were comparable. The cerebral glucose metabolic rates obtained from 4 normoglycemic mice were 21.5 +/- 4.3 mumol/min/100 g (mean +/- SD) under the influence of 1.5% isoflurane. By generating the whole-body parametric images of K(FDG)(*) (mL/min/g), the uptake constant of (18)F-FDG, we obtained similar pixel values as those obtained from the conventional regional analysis using tissue time-activity curves.With an automated microfluidic blood-sampling device, our studies showed that quantitative small-animal PET can be performed in mice routinely, reliably, and safely in a small-animal PET facility.

    View details for DOI 10.2967/jnumed.106.038182

    View details for Web of Science ID 000246326100031

    View details for PubMedID 17475972

  • Bright fluorescent nanodiamonds: No photobleaching and low cytotoxicity JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yu, S. J., Kang, M. W., Chang, H. C., Chen, K. M., Yu, Y. C. 2005; 127 (50): 17604-17605


    Diamond nanocrystals emit bright fluorescence at 600-800 nm after irradiation by a 3 MeV proton beam (5 x 1015 ions/cm2) and annealing at 800 degrees C (2 h) in vacuum. The irradiation/annealing process yields high concentrations of nitrogen-vacancy defect centers ( approximately 107 centers/mum3), making possible visualization of the individual 100 nm diamond crystallites using a fluorescence microscope. The fluorescent nanodiamonds (FND) show no sign of photobleaching and can be taken up by mammalian cells with minimal cytotoxicity. The nanomaterial can have far-reaching biological applications.

    View details for DOI 10.1021/ja0567081

    View details for Web of Science ID 000234008900018

    View details for PubMedID 16351080