John V Frangioni
Beth Israel Deaconess Medical Center
Project start date: 2009-02-01
Project end date: 2013-12-31
Sponsored Links Excellgen http://Excellgen.com
A PLATFORM FOR CANCER BIOMARKER VALIDATION: IMAGE FUSION USING NIR FLUORESCENCE
John V Frangioni, Principal Investigator
Beth Israel Deaconess Medical Center, Boston, Ma 02215
Grant 5R01CA134493-02 from National Cancer Institute
Abstract: Clinical imaging using magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and/or single-photon emission computed tomography (SPECT) is the standard of care for the detection and staging of human cancer. However, clinical imaging is a macroscopic process, with up to 106 malignant cells filling every 1 mm3 voxel. At present, it is extremely difficult to correlate clinical imaging findings with the cellular genotype and/or phenotype leading to the finding. Hence, "biomarkers," such as dynamic contrast enhancement (DCE) on MRI, or a "hot" voxel on PET seen after injection of a targeted radiotracer, are difficult to validate since the fusion of macroscopic clinical imaging findings with microscopic histological findings is fraught with technical challenges. To solve this problem, our laboratory has developed new near-infrared (NIR) fluorescence technology that permits simultaneous (same slide) immunostaining and hematoxylin/eosin (H&E) staining of any pathological specimen. Hence, the chronic problem of co-registering tissue slices at the cellular level is eliminated, while the "gold-standard" of H&E histology is preserved. This technology lays the foundation for an integrated platform that permits high accuracy co-registration of macroscopic and microscopic data sets from an individual patient´s cancer. We have also developed an automated microscope that acquires H&E and NIR fluorescence simultaneously, and which permits up to 28 2"x3" whole-mount slides (or 56 1"x3" slides) to be scanned without human intervention. Using this technology, and several other innovations described in the application, 3-D data sets of clinical pathological specimens, at microscopic resolution, can now be generated. However, to bridge the gap between the microscopic and macroscopic domains, we have formed an academic-industrial partnership with the Imaging Department of Siemens Corporate Research (SCR) in Princeton, NJ. SCR is expert in the co-registration of 3-D volumes that have undergone non-linear deformations, in image segmentation, and in pattern recognition. Using algorithms developed by SCR for this study, we present an automated and integrated platform for cancer biomarker validation. Our study also leverages a unique clinical resource at the Beth Israel Deaconess Medical Center, the Hershey Prostate Cancer Tissue Bank. Through the Hershey Tissue Bank, men undergoing radical prostatectomy for prostate cancer receive a preoperative endorectal coil 3T MRI (pre- and post-Gd DCE), and at prostatectomy, the entire gland is available for whole-mount preparation. The paired data sets of clinical imaging (DCE-MRI) and whole mount histology will provide proof of principle for our biomarker validation platform, and will also be used to determine the mechanism of DCE-MRI at the cellular level. Completion of the specific aims by academic and industrial teams with complementary skill sets will permit virtually any proposed biomarker, for any type of cancer, to be validated rapidly and efficiently. Biomarkers for cancer imaging are extremely difficult to validate, since clinical imaging is performed on a macroscopic scale and histological evaluation of resected tissue is performed on a microscopic scale. We have formed an academic-industrial partnership between the Frangioni Laboratory at the Beth Israel Deaconess Medical Center in Boston, MA and Siemens Corporate Research in Princeton, NJ aimed at developing an integrated platform for biomarker validation using new near-infrared fluorescence and image fusion technology. This study also leverages a unique prostate cancer tissue bank that provides paired DCE-MRI and histological whole mounts from individual prostate cancer patients
Keywords: 3-D; 3-D analysis; 3-Dimensional; 3-dimensional analysis; 3D analysis; Abscission; Algorithms; Antibodies; Artifacts; Au element; Blood Vessels; Body Tissues; Boston; CAT Scan, X-Ray; CAT scan; CT X Ray; CT scan; Cancer Patient; Cancer of Prostate; Cancers; Cell Communication and Signaling; Cell Signaling; Chronic; City of Boston; Clinical; Clinical Research; Clinical Study; Complex; Computed Tomography; Computerized Axial Tomography (Computerized Tomography); Computerized Tomography, X-Ray; Data Set; Data Storage and Retrieval; Dataset; Detection; EMI scan; Epithelial; Evaluation; Excision; Extirpation; Fixation; Fluorescence; Foundations; Frequencies (time pattern); Frequency; Gadolinium; Gd element; Genetic Markers; Genital System, Male, Prostate; Genitourinary; Genitourinary system; Genotype; Gland; Gleason Grade; Gleason Grade for Prostate Cancer; Gleason Score; Gleason Score for Prostate Cancer; Gleason Sum; Gleason-SC; Goals; Gold; H and E; Hematoxylin and Eosin; Hematoxylin and Eosin Staining Method; Histology; Human; Human Prostate; Human Prostate Gland; Human, General; Image; Image Enhancement; Individual; Injection of therapeutic agent; Injections; Inter-Observer Variability; Inter-Observer Variation; Interobserver Variability; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Israel; Laboratories; Lymphatic; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Malignant Cell; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Man (Taxonomy); Man, Modern; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Imaging, Positron Emission Tomography; Medical Imaging, Single Photon Emission Computed Tomography; Medical center; Microscope; Microscopic; Morphologic artifacts; NDUL; NMR Imaging; NMR Tomography; Nodule; Nuclear Magnetic Resonance Imaging; PET; PET Scan; PET imaging; PETSCAN; PETT; Pathologist; Pattern Recognition; Pattern Recognition/Display/Analysis; Phenotype; Positron Emission Tomography Scan; Positron-Emission Tomography; Post-Operative; Postoperative; Postoperative Period; Preparation; Problem Solving; Process; Prostate; Prostate CA; Prostate Cancer; Prostate Gland; Prostatectomy; Prostatic Cancer; Prostatic Gland; Prostatovesiculectomy; Proton Magnetic Resonance Spectroscopic Imaging; Rad.-PET; Radical Prostatectomy; Radionuclide Tomography, Single-Photon Emission-Computed; Removal; Research; Research Resources; Research Specimen; Resected; Resolution; Resources; SPECT; SPECT imaging; Sampling; Scanning; Signal Transduction; Signal Transduction Systems; Signaling; Slice; Slide; Specimen; Staging; Staining method; Stainings; Stains; Surgical Removal; Technology; Three-dimensional analysis; Time; Tissue Banking; Tissue Banks; Tissue Collection; Tissue Expansion; Tissue/Specimen Collection; Tissues; Tomodensitometry; Tomography, Emission-Computed, Single-Photon; Tomography, Xray Computed; Training; Urogenital; Urogenital System; Validation; Variations, Interobserver; Work; X-Ray Computed Tomography; Zeugmatography; base; biological signal transduction; biomarker; cancer cell; cancer imaging; cancer type; catscan; computed axial tomography; computerized axial tomography; computerized tomography; data retrieval; data storage; develop software; developing computer software; ergonomics; experiment; experimental research; experimental study; fluorescence imaging; fluorophore; imaging; imaging Segmentation; innovate; innovation; innovative; interest; interventional strategy; malignancy; men; men`s; neoplasm/cancer; public health relevance; radiolabel; radiotracer; research study; resection; sample fixation; skills; software development; standard of care; tissue processing; urogenital system (urinary part); vascular
Relevance: 7. : Biomarkers for cancer imaging are extremely difficult to validate, since clinical imaging is performed on a macroscopic scale and histological evaluation of resected tissue is performed on a microscopic scale. We have formed an academic-industrial partnership between the Frangioni Laboratory at the Beth Israel Deaconess Medical Center in Boston, MA and Siemens Corporate Research in Princeton, NJ aimed at developing an integrated platform for biomarker validation using new near-infrared fluorescence and image fusion technology. This study also leverages a unique prostate cancer tissue bank that provides paired DCE-MRI and histological whole mounts from individual prostate cancer patients
Project start date: 2009-02-01
Project end date: 2013-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PAR-07-214
5R01CA134493-02 (2010): $661011
Grants awarded to John V Frangioni
MOLECULAR IMAGING OF ADVANCED BLADDER CANCER
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Br 264
boston, Ma 02215
Grant 1R21CA088870-01 from National Cancer Institute IRG: RNM
Abstract: Verbatim from ´s ) The major hypothesis guiding this research is that modular low-molecular weight ligands, specific for the surface of bladder cancer cells, will be clinically useful reagents. Using peptide phage display screening of live bladder cancer cells, we have discovered two families of peptides, each ten amino acids in iength which bind with high afffinity and specificity to bladder cancer cells, and which exhibit no binding to normai bladder urothelial cells. These ligands offer several potential advantages including rapid biodistribution excellent tissue/tumor penetration, and ease of conjugation to imaging reagents. The long-range goal of this research is to improve bladder cancer staging and treatment by developing novel in vivo molecular imaging reagents and novel therapeutics. The specific aims of this study are designed to expedite future clinical studies of molecular imaging in , advanced bladder cancer. One specific aim is to create, and to optimize, novel magnetic resonance imaging contrast agents by conjugating the bladder cancer-specific peptides to ferromagnetic monocrystalline iron oxide nanocompounds (MlONs). The second specific aim is to create, and to optimize, novel radioscintigraphic imaging reagents by conjugaffng the bladder cancer-specific peptides to radiometal chelators. For each imaging modality, a systematic development scheme including in vitro optimization, in vivo biodistribution and pharrnacokinetics, and in vivo three-dimensional imaging is described. We believe that bladder cancer-specific, low-molecular weight ligands will someday be clinically useful reagents for improved detection and guided therapy of transitional cell carcinoma of the bladder
Keywords: bladder neoplasm, diagnosis design /evaluation, neoplasm /cancer diagnosis, urinary tract imaging/visualization chemical conjugate, iron oxide, ligand, pharmacokinetics, radiotracer, technetium athymic mouse, laboratory rat, magnetic resonance imaging
Project start date: 2001-09-01
Project end date: 2003-08-31
1R21CA088870-01 (2001): $170000
SPATIALLY-MODULATED NEAR-INFRARED LIGHT FOR IMAGE-GUIDED ONCOLOGIC SURGERY
John V Frangioni, Principal Investigator
University Of California Irvine, Irvine, Ca 92697-7600
Grant 5P41RR001192-30_5049 from National Center For Research Resources
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this application, we propose the use of spatially-modulated NIR light (SMNL) to produce quantitative imaging of ¿¿A, ¿¿S´, and QY in essentially real-time. The Modulated Imaging group at the Beckman Laser Institute of the University of California, Irvine, has pioneered the use of this technology for quantitative, depth-resolved spectroscopic imaging as part of the NIH Biomedical Technology Center, the Laser Microbeam and Medical Program (LAMMP) at the Beckman Laser Institute (www.bli.uci.edu/lammp). Recent results shown in Preliminary Studies suggest that SMNL can now be optimized for use over a large surgical field without the need for a laser excitation source. When combined with a novel LED-based light source proposed in this study, and recent advances in cardiac and respiratory gating technology from the PI´s laboratory, SMNL should be able to provide surgeons with direct measurement of ¿¿A, ¿¿S´, and QY, and thus improve virtually all image-guided surgical interventions
Keywords: Biomedical Technology; Biotechnology; CRISP; California; Cardiac; Computer Retrieval of Information on Scientific Projects Database; Electromagnetic, Laser; Funding; Grant; Image; Institutes; Institution; Investigators; Laboratories; Lasers; Light; Measurement; Medical; NIH; National Institutes of Health; National Institutes of Health (U.S.); Operation; Operative Procedures; Operative Surgical Procedures; Photoradiation; Programs (PT); Programs [Publication Type]; Radiation, Laser; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Surgeon; Surgical; Surgical Interventions; Surgical Oncology; Surgical Procedure; Technology; Time; United States National Institutes of Health; Universities; base; imaging; improved; novel; oncologic surgery; programs; respiratory; spectroscopic imaging; surgery
Project start date: 2009-04-01
Project end date: 2010-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2010
5P41RR001192-30_5049 (2009): $17363
Intraoperative Near-Infrared Fluorescence Imaging
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 5R01CA115296-03 from National Cancer Institute IRG: ZRG1
Abstract: The major hypothesis guiding this study is that near-infrared (NIR) fluorescence imaging has the potential to improve human cancer surgery by providing sensitive, specific, and real-time intraoperative visualization of normal and disease processes. The Pi s laboratory has developed a low-cost, safe, and easy to use NIR fluorescence imaging system that permits the surgeon to see surgical anatomy and invisible NIR fluorescence simultaneously, in real-time, and with high spatial resolution. To translate this technology to the clinic, we have established a Bioengineering Research Partnership (BRP) comprised of members of the Pi s laboratory, academic veterinary surgeons at the Purdue University School of Veterinary Medicine, and our industrial partner GE Healthcare. GE is committed to translating the imaging system to the clinic, and will provide their extensive expertise in biomedical system design and implementation. GE and the BIDMC have also signed a model agreement concerning intellectual property and shared development, which ensures that academic and industrial resources are fully leveraged during technology translation. The end-point of our study will be the development of an intraoperative NIR fluorescence imaging system ready for human clinical trials. To achieve this goal, we describe a systematic series of small and large animal studies, and a closed-loop feedback development process designed to optimize each system component. The timeline for our study is as follows Project Year (PY) 1 - initial design of the prototype imaging system for open surgeries. PY 2 - addition of endoscopy/laparoscopy capabilities for minimally invasive surgery. PY 3 - addition of optical diffusion technology to the open surgery system. PY 4 - final prototype development for the open and minimally-invasive imaging systems, and PY Ji - final optimization of system components and software, final validation studies, and preparation for translation to the clinic. Immediate cancer surgery applications of the imaging system include image-guided sentinel lymph node mapping, image-guided cancer resection with real-time assessment of surgical margins, and intraoperative detection of occult metastases in the surgical field. The imaging system will also ensure that critical structures such as nerves and blood vessels are visualized and avoided. Taken together, this BRP application describes an academic/industrial partnership engineered for successful translation of a general-purpose optical imaging technology to the clinic.
Keywords: fluorimetry, fluoroscopy, image guided surgery /therapy, neoplasm /cancer surgery, technology /technique development, infrared radiation, bioimaging /biomedical imaging, laboratory rat, swine
Project start date: 2005-09-29
Project end date: 2010-07-31
5R01CA115296-03 (2007): $1241997
5R01CA115296-02 (2006): $1258102
1R01CA115296-01A1 (2005): $1326280
5R01CA115296-05 (2009): $1235683
5R01CA115296-04 (2008): $1217958
Improved Optical Sub-Systems For In Vivo Cancer Imaging
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 5R21CA110185-02 from National Cancer Institute IRG: ZCA1
Abstract: The major hypothesis guiding this study is that intraoperative near-infrared (NIR) fluorescence imaging has the potential to improve human cancer surgery. At the present time, cancer surgery is performed "blindly", without the ability to identify un-resected tumor cells, or to avoid critical nerves and vessels via optical guidance. By introducing exogenous NIR fluorophores targeted to either tumor cells or normal cells, sensitive and specific optical contrast is generated. Cancer-specific applications of intraoperative NIR fluorescence imaging include image-guided resection with real-time assessment of surgical margins, image-guided sentinel lymph node mapping, and intraoperative detection of occult metastases in the surgical field. The Pl s laboratory at the Beth Israel Deaconess Medical Center has developed the concept of a low-cost, safe, and easy to use NIR fluorescence imaging system that permits the surgeon to "see" surgical anatomy and NIR fluorescence simultaneously, non-invasively, with high spatial resolution, in real-time, and without moving parts. The specific aims of this study are to improve the performance of this cancer imaging system by optimizing three critical optical sub-systems. In response to PAR 03-157, and in anticipation of future clinical trials with the imaging system, we have formed an academic-industrial partnership with our laboratory and General Electric Corporation (GE). GE is a world leader in biomedical engineering and medical imaging systems, and brings a wealth of experience in sub-system optimization. Together, we will systematically redesign the optical sub-systems for ambient light rejection, respiratory/cardiac gating, and automated zoom and focus. Each modification will be accompanied by small and large animal validation using targeted NIR fluorescence contrast agents and model systems already developed by our laboratory. Taken together, our study leverages the significant resources of academic and industrial partners to bring intraoperative NIR fluorescence cancer imaging one step closer to the clinic.
Keywords: image guided surgery /therapy, imaging /visualization /scanning, neoplasm /cancer surgery, technology /technique development, cardiovascular imaging /visualization, fluorescent dye /probe, image processing, ionophore, optics, respiratory imaging /visualization, bioimaging /biomedical imaging, charge coupled device camera, laboratory rat, swine
Project start date: 2004-07-01
Project end date: 2007-06-30
5R21CA110185-02 (2005): $256573
1R21CA110185-01 (2004): $215661
LOW-MOLECULAR WEIGHT LIGANDS FOR PROSTATE CANCER
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 5R33CA088245-04 from National Cancer Institute IRG: ZCA1
Abstract: The major hypothesis guiding this research is that modular low- molecular weight ligands, specific for the surface of prostate epithelial cells, will be clinically useful reagents for prostate cancer. As prostate-targeting agents, low-molecular weight (less than or equal to 1,100 M.W.) ligands offer several advantages including rapid biodistribution, excellent tissue/tumor penetration, and ease of conjugation to imaging reagents. The long range goal of this research is to improve prostate cancer detection, and guided therapy, by developing novel radiocintigraphic and magnetic resonance imaging (MRI) reagents. The R21 phase of the proposal describes a phage display screening approach for finding prostate-and prostate cancer-specific ligands. Some ligands will be directed against two previously described prostate-specific cell surface proteins, prostate- specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA). The R21 proposal also describes a phage display screening approach to find ligands with differential binding to metastatic prostate cancer cells over normal prostate epithelial cells. The final phase of the R21 focuses on using peptide libraries incorporating D- and unnatural amino acids to optimize ligands for biochemical properties such as solubility, protease- resistance and modularity. Modularity should permit conjugation of prostate-specific ligands to contrast agents for nuclear medicine and MRI scanning, without loss of prostate-specific binding. The R33 phase of the proposal aims to create, and to optimize, novel imaging reagents by conjugation of radiopharmaceuticals (for radioscintigrpahy) and ferromagnetic particles (for MRI) to the prostate-specific, low-molecular weight ligands developed during the R21. A systematic development scheme including in vitro optimization, in vivo biodistribution and pharmacokinetics, and in vivo three-dimensional imaging is described. Prostate cancer models in rats, and normal prostate models in dogs, will be imaged in vivo by nuclear medicine and Mri approaches. In collaboration with industry, we describe two new 3T-compatible endorectal coils, one of which permits image-guided biopsy of the prostate. In conjunction with the novel imaging reagents, these coils should permit improved contrast of the prostate gland, and should permit analysis of aging-related effects on the performance of our technology. We believe that prostate- specific, low-molecular weight ligands will someday be clinically useful reagents for improved prostate cancer detection and guided therapy.
Keywords: biomarker, biotechnology, chemical binding, differential display technique, prostate neoplasm, prostate specific antigen, reagent /indicator, tumor antigen, chemical conjugate, contrast media, gene expression, image guided surgery /therapy, neoplasm /cancer diagnosis, peptide library, radiopharmacology, athymic mouse, clinical research, dog, human tissue, laboratory rat, tissue /cell culture
Project start date: 2000-09-06
Project end date: 2005-08-31
5R33CA088245-04 (2003): $734696
Sponsored Links Excellgen http://Excellgen.com
5R21CA088245-02 (2001): $174000
1R21CA088245-01 (2000): $154394
Near-Infrared Quantum Dots For In Vivo Imaging
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Br 264
boston, Ma 02215
Grant 5R33EB000673-05 from National Institute Of Biomedical Imaging And Bioengineering IRG: ZRG1
Abstract: The major hypothesis guiding this research is that fluorescent semiconductor nanocrystals (quantum dots) will be clinically useful reagents for in vivo imaging. As contrast agents, quantum dots offer several advantages over traditional fluorophores including broad absorption bands, extremely high extinction coefficients, quantum yields approaching 50%, photostability at high fluence rate, and high capacity for ligand conjugation. To date, however, quantum dots with optimal properties for in vivo imaging have not been developed. The long-range goal of this research is to improve cancer cell detection and vascular imaging by developing quantum dots with optimal in vivo properties. The R21 phase of the proposal focuses on the design, synthesis, and initial characterization of nearinfrared (NIR) quantum dots. Although invisible to the human eye, the NIR (700 nm to 900 nm) portion of the spectrum is characterized by low autofluorescence, deep tissue penetration, and low tissue scatter of light. Using a model that incorporates both tissue and quantum dot photonic properties, we have predicted the absorption and emission characteristics of "optimal" NIR quantum dots. We describe strategies to synthesize such contrast agents, and present preliminary data of how NIR quantum dots might be expected to perform in vivo by using an intraoperative imaging technique recently developed by our laboratory. The R33 phase of the proposal focuses on the in vivo characterization of NIR quantum dots. Two distinct clinical applications are explored cancer cell detection/imaging and vascular imaging. Our laboratory has developed prostate and bladder cancer-specific low-molecular weight ligands that can be used to target contrast agents to tumor cells (see Preliminary Studies). We propose to conjugate these ligands to NIR quantum dots and to characterize their biodistribution, pharmacokinetics, and tumor localization. It is hypothesized that such contrast agents will provide unparalleled improvements in cancer cell detection in vivo. We also propose to optimize NIR quantum clots for intraoperative vascular imaging and image-guided delivery of cardiac gene therapy using animal models of cardiac ischemia and necrosis. If completed, the specific aims of this proposal will generate a clinically useful set of contrast agents, and a more complete understanding of the in vivo behavior of fluorescent semiconductor nanocrystals
Keywords: contrast media, imaging /visualization /scanning, nanotechnology, technology /technique development biological model, biomarker, blood flow measurement, chemical conjugate, diagnosis design /evaluation, fluorescent dye /probe, image guided surgery /therapy, optics, peptide chemical synthesis, phosphine, semiconduction angiography, bioimaging /biomedical imaging, infrared spectrometry, laboratory rat, transmission electron microscopy
Project start date: 2003-09-01
Project end date: 2008-08-31
5R33EB000673-05 (2006): $586022
5R33EB000673-04 (2005): $559383
5R33EB000673-03 (2004): $497992
4R33EB000673-02 (2003): $583184
FLEX TM MicroPET/SPECT/CT To Support Cancer Research At Harvard Medical School
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Br 264
boston, Ma 02215
Grant 1S10RR023010-01 from National Center For Research Resources IRG: ZRG1
Abstract: The Longwood Medical Area (LMA) of Harvard Medical School (HMS) houses the Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer Institute (DFCI), Brigham and Women´s Hospital (BWH), and Children´s Hospital Boston (CHB), all within walking distance. Within these institutions are hundreds of Pis dedicated to modern cancer research. At the present time, however, there isn´t a single small animal positron emission tomography (PET) scanner in the LMA, and the only small animal single photon emission computed tomography (SPECT) scanner has limited availability and no computed tomography (CT) capabilities. Without microPET/CT and microSPECT/CT, it is now impossible to screen transgenic animals for tumor formation and growth, to develop mouse models that replicate human cancer, or to follow therapeutic efficacy in vivo and longitudinally in the same animal. In this High-End Instrumentation Grant, we demonstrate how the purchase of a single trimodality microPET/SPECT/CT (FLEX?) scanner from Gamma Medica Ideas, Inc., in conjunction with a $1.1 M+ commitment from the BIDMC, will be able to service the needs of cancer researchers of the LMA. Siting this instrument in a central and easily accessible location at the BIDMC enables the NIH to make a significant investment that will benefit numerous NIH-funded research projects across multiple institutions. We see this as an opportunity not only to bring the best resources to our research area, but also as an opportunity to foster greater interaction among the investigators themselves. In particular, this instrument will service the Program Project Grant of Dr. Lewis C. Cantley (BIDMC), who in collaboration with Dr. Ronald A. De Pinho (DFCI), has developed novel transgenic models of cancer based on phospholipid signal transduction. Currently, these animals can only be screened at necropsy for tumor formation, which has greatly slowed progress. With the installation of the FLEX scanner, Drs. Cantley and De Pinho will be able to pinpoint the location of tumors in living animals, and follow their responses to treatment. Dr. William R. Sellers (DFCI) has developed several animal models of prostate cancer that could potentially replicate the osteoblastosis seen in humans, and with the FLEX scanner, would be able to perform high-throughput screening for this phenotype. Dr. Bruce R. Zetter (CHB), an expert on angiogenesis and tumor cell homing, would finally have a methodology to monitor neovascularization and to quantify metastatic spread in his animal models. Dr. Yolonda L. Colson (BWH), in her studies on host cell tolerance during transplantation, would be able to follow white blood cells over days to weeks in vivo. Thus, this single investment in the densely-populated LMA would fulfill the goal of PAR-05-124 by having a "significant impact on biomedical/behavioral research and contribute to the advancement of human health."
Keywords: neoplasm /cancer, school human, model
Project start date: 2006-08-01
Project end date: 2008-07-31
1S10RR023010-01 (2006): $938175
A MINI-CYCLOTRON FACILITY TO SUPPORT CANCER RESEARCH AT THE BIDMC/HMS
John V Frangioni, Principal Investigator
Beth Israel Deaconess Medical Center, Boston, Ma 02215
Grant 1C06RR028581-01 from National Center For Research Resources
Abstract: The Beth Israel Deaconess Medical Center (BIDMC) is a 566-bed teaching hospital of Harvard Medical School (HMS) with over 114 principal investigators (PIs) engaged in NIH-funded pre-clinical and clinical cancer research. In 2006, the BIDMC was awarded a high-end instrumentation grant (S10-RR-023010; PI Frangioni, JV) to purchase microPET/CT instrumentation. The BIDMC then invested $1.6M to build a new state-of-the-art infrastructure named the Longwood Small Animal Imaging Facility (www.longwoodsaif.org). The Longwood SAIF is now thriving, and provides animal imaging to PIs at the BIDMC and throughout HMS. Although positron emission tomography (PET) has superior sensitivity and resolution compared to other nuclear medicine tests used for cancer detection, the fundamental limitation of microPET imaging, and more importantly, of clinical PET imaging, is the lack of availability of various F-18 and C-11 labeled radiotracers. Even in Boston, the only PET radiotracers available on a daily basis are 18FDG and Na18F, used for metabolic imaging and bone imaging, respectively. Due to a complex web of economic, intellectual property, and logistical issues, commercial availability of other useful radiotracers is severely limited and is not expected to improve significantly over the next 5 to 10 years. Our investigators are now desperate for various PET radiotracers needed for their pre-clinical and clinical cancer research. Fortunately, a new trend in the production of PET radioisotopes is to utilize a turnkey "mini-cyclotron," in conjunction with an integrated microfluidics chemistry system, to produce "on-demand" radiotracers. Such a "biomarker generator" can be installed in a small room and has minimal operational cost. Although not powerful enough to produce radiotracers on a commercial scale, such 8 MeV mini-cyclotrons can produce enough radiotracer to serve the needs of the entire BIDMC pre-clinical and clinical cancer research communities. Continuing its extraordinary institutional commitment to molecular imaging, the BIDMC has agreed to a major move of existing departments, and will pay for swing space renovation costs, in order to provide 1,400 sq ft of empty space for construction of a mini-cyclotron facility that includes full compliance with USP-797 and radiation regulatory guidelines. Housed next to the Longwood SAIF, and just one level below the division of Nuclear Medicine, this mini-cyclotron facility will be capable of producing PET radiotracers for pre-clinical and clinical cancer research, while requiring minimal operational costs. A LEED-certified architect who has designed much larger, conventional cyclotron facilities for other academic groups has designed our facility. The BIDMC Facilities person most experienced with imaging center construction, and who has previously managed the construction of Dr. Frangioni´s present laboratory and the Longwood SAIF, is managing the project. Taken together, the facility we propose leverages prior NCRR funding, creates both temporary and permanent new jobs, and will have a sustained and powerful influence on cancer research at the BIDMC
Keywords: Animals; Arts; Atomic Medicine; Award; Beds; Boston; Cancer Detection; Chemistry; City of Boston; Clinical; Communities; Complex; Cyclotrons; Discipline of Nuclear Medicine; Economics; Funding; Guidelines; Housing; Image; Infrastructure; Instrumentation, Other; Intellectual Property; Internet; Investigators; Israel; Jobs; Label; Laboratories; Medical Imaging, Positron Emission Tomography; Medical center; Metabolic; Microfluidic; Microfluidics; NCRR; Names; National Center for Research Resources; Nuclear Medicine; Occupations; PET; PET Scan; PET imaging; PETSCAN; PETT; Persons; Positron Emission Tomography Scan; Positron-Emission Tomography; Principal Investigator; Production; Professional Postions; Proton Magnetic Resonance Spectroscopic Imaging; Rad.-PET; Radiation; Radioactive Isotopes; Radioisotopes; Radiology / Radiation Biology / Nuclear Medicine; Radiology-Nuclear Medicine; Radionuclides; Research Infrastructure; Research Personnel; Researchers; Resolution; S10 grant; Science of Chemistry; System; System, LOINC Axis 4; Teaching Hospitals; Testing; WWW; anticancer research; base; biomarker; bone imaging; bone scanning; cancer research; cost; design; designing; experience; imaging; improved; instrumentation; medical schools; molecular imaging; pre-clinical; preclinical; radiolabel; radiotracer; ray (radiation); skeletal imaging; square foot; trend; web; world wide web
Project start date: 2010-03-04
Project end date: 2011-03-03
Budget start date: 4-MAR-2010
Budget end date: 3-MAR-2011
PFA/PA: RFA-RR-09-008
1C06RR028581-01 (2010): $1793470
Objective Flap Assessment During Reconstructive Surgery
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center
boston, Ma 02215
Grant 5R01EB005805-03 from National Institute Of Biomedical Imaging And Bioengineering IRG: BTSS
Abstract: Reconstructive surgery is presently performed without real-time, objective intraoperative assessment. As such, reconstructive surgeons face three major problems in decision-making flap design, assessment of flap thrombosis, and treatment of flap salvage. Important decisions regarding each of these are now based solely on subjective criteria rather than patient-specific objective data. Because intraoperative decisions ultimately lead to the success or failure of a flap, our study focuses on the application of recent advances in optical imaging technology to provide the reconstructive surgeon with objective assessment of flap design, flap viability, and candidacy for flap salvage. Our laboratory has previously developed a near-infrared (NIR) fluorescence imaging system for intraoperative use and has validated its utility in sentinel lymph node mapping and other surgeries. This system uses harmless, invisible NIR light, makes no contact with the patient, and has no moving parts. Surgical anatomy is displayed in color simultaneously with an overlay of NIR fluorescence to assess, objectively, specific areas of interest. Our laboratory also has considerable experience with the chemistry of NIR fluorophores and has developed several targeted NIR fluorescence contrast agents. In this application, we describe pre-clinical and clinical studies whose long-range goal is to provide the plastic and reconstructive surgeon with real-time, objective image guidance during complex surgeries. In Specific Aim 1, we develop sensitive, real-time, intraoperative techniques for patient-specific flap planning using an NIR fluorophore that is already FDA-approved. In Specific Aim 2, we assess tissue and flap thrombosis before, during, and after reconstructive procedures using long-circulating autologous NIR fluorescent platelets developed by our laboratory. In Specific Aim 3, we guide decision-making regarding salvage therapy with fibrinolytics using an NIR fibrinogen derivative also developed by our laboratory. Finally, in Specific Aim 4, we translate the results from our pre-clinical studies to human reconstructive surgery during a Phase I clinical trial utilizing an FDA-approved NIR fluorophore. With the completion of these studies, we foresee being able to solve major clinical problems in reconstructive surgery using real-time, intraoperative objective assessment
Project start date: 2006-09-30
Project end date: 2010-08-31
5R01EB005805-03 (2008): $404854
5R01EB005805-02 (2007): $347757
Sponsored Links Excellgen http://Excellgen.com
1R01EB005805-01A1 (2006): $347710
ULTRA-LOW BACKGROUND NIR FLUOROPHORES FOR IN VIVO IMAGING AND IMAGE-GUIDED SURGER
John V Frangioni, Principal Investigator
Beth Israel Deaconess Medical Center, Boston, Ma 02215
Grant 1R01EB010022-01A1 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: Near-infrared (NIR) fluorescence has the potential to revolutionize image-guided surgery. However, ideal fluorophores for in vivo, and eventually clinical, use have not yet been described. Under an NIH Bioengineering Research Partnership (BRP) grant, the PI´s laboratory has developed a surgical imaging system that simultaneously, and in real-time, acquires two independent wavelengths of NIR fluorescence emission images along with color video images. The imaging system has already been translated to the clinic, and is being formally evaluated in three NIH-funded clinical trials. Nevertheless, the fundamental limitation to the future success of this technology is the development of NIR fluorophores that perform optimally in the body, and which can be made widely available to other academic researchers. To be clinically viable, the ideal NIR fluorophore requires certain optical properties, including excitation and emission H800 nm, and both a high extinction coefficient (5) and quantum yield (QY) in serum. However, the reason why existing NIR fluorophores perform so poorly in vivo has more to do with biodistribution and clearance. After IV injection, the ideal NIR fluorophore would rapidly equilibrate between the intravascular and extra vascular spaces and would be cleared efficiently via renal filtration. To date, every NIR fluorophore described in the literature suffers from two fundamental flaws 1) hepatic clearance, which results in NIR fluorescence signal throughout the GI tract that persists for hours, and/or 2) non-specific background uptake in normal tissues, which typically persists for hours and results in a low signal-to-background ratio (SBR). This grant builds upon an observation we made two years ago using NIR fluorescent quantum dots (Choi et al., Nature Biotechnol. 2007; 25 1165-70). Unexpectedly, and for reasons only partially understood, zwitterionic organic coatings resulted in extremely low non-specific tissue uptake, rapid renal clearance, and no serum protein binding. However, purely anionic or cationic coatings gave the opposite results. Based on these data, we began collaborating with Drs. Patonay and Strekowski at Georgia State University, leaders in the field of NIR fluorophore chemistry, to synthesize zwitterionic heptamethine indocyanine NIR fluorophores. The preliminary results, described herein, demonstrate that both non-targeted and tumor-targeted zwitterionic NIR fluorophores have remarkable optical and in vivo properties, including 800 nm fluorescence, high 5 and QY, rapid renal clearance, absence of protein binding, and ultra-low non-specific tissue uptake (i.e., background). The specific aims of this grant are focused on the synthesis of optimized zwitterionic NIR fluorophores for in vivo and surgical imaging, on validating their use as targeted diagnostic agents for prostate cancer, and for scale-up from analytical to preparative production. Completion of these aims will lay the foundation for future clinical testing during image-guided surgery. Importantly, we also present an intellectual property strategy that will permit free sharing of optimized NIR fluorophores within the academic community. Near-infrared light is invisible to the human eye, but penetrates relatively deeply into living tissue. It is therefore ideal for image-guided surgery, because it provides surgeons with high- sensitivity, high-resolution detection of diseases, such as cancer, without changing the look of the surgical field. Although hardware systems that use near-infrared fluorescent light for image-guided surgery are already available, optimized fluorophores, or "light bulbs" are not. The goal of this grant is to develop a new class of ideal near-infrared fluorophores that can be injected into the bloodstream. These fluorophores would "stick" to tumors and other diseased tissue, but not to normal tissue
Keywords: Abscission; Affinity; Alimentary Canal; Amines; Antigen Targeting; Biodistribution; Biomedical Engineering; Blood Circulation; Blood Serum; Blood Vessels; Bloodstream; Body Tissues; Cancer of Prostate; Cancers; Carboxylic Acids; Cell Communication and Signaling; Cell Signaling; Charge; Chemistry; Circulation; Clinic; Clinical; Clinical Evaluation; Clinical Testing; Clinical Trials; Clinical Trials, Unspecified; Color; Communities; Country; Data; Detection; Development; Diagnostic; Digestive Tract; Disease; Disorder; Ensure; Equilibrium; Esters; Excision; Exercise; Exercise, Physical; Extinction; Extinction (Psychology); Extirpation; Eye; Eyeball; FOLH1 Protein; Family; Family suidae; Filtration; Fluorescence; Fluorescence Agents; Fluorescent Agents; Fluorescent Dyes; Folate Hydrolase 1; Folate Hydrolase I; Foundations; Fractionation, Filtration; Funding; Future; GI Tract; Gastrointestinal Tract; Gastrointestinal tract structure; Glutamate Carboxypeptidase II; Goals; Grant; Hepatic; Hour; Human; Human, General; Image; Image-Guided Surgery; Injection of therapeutic agent; Injections; Intellectual Property; Intracellular Communication and Signaling; Investigators; Kidney; Laboratories; Life; Ligands; Light; Literature; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Man (Taxonomy); Man, Modern; Metric; N-Acetylaspartylglutamate Peptidase; N-Acetylated-alpha-Linked Acidic Dipeptidase; NAAG Peptidase; NAALADase; NAALADase II; NAALADase L; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nature; Normal Tissue; Normal tissue morphology; Operation; Operative Procedures; Operative Surgical Procedures; Optics; Organ; Organic Synthesis; PSMA; Performance; Photoradiation; Pigs; Procedures; Production; Property; Property, LOINC Axis 2; Prostate CA; Prostate Cancer; Prostate-Specific Membrane Antigen; Prostatic Cancer; Protein Binding; Q-Dot; Quantum Dots; Removal; Renal clearance function; Reporting; Research; Research Personnel; Researchers; Resolution; Science of Chemistry; Serum; Serum Proteins; Signal Transduction; Signal Transduction Systems; Signaling; Suidae; Surgeon; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Swine; System; System, LOINC Axis 4; Technology; Time; Tissues; Translating; Translatings; United States National Institutes of Health; Universities; Urinary System, Kidney; alimentary tract; balance; balance function; base; behavioral extinction; bioengineering; bioengineering/biomedical engineering; biological signal transduction; cancer surgery; clinical investigation; clinical test; design; designing; digestive canal; disease/disorder; experience; fluorescence imaging; fluorescent dye/probe; fluorophore; imaging; in vivo; intravenous injection; language translation; malignancy; neoplasm/cancer; porcine; public health relevance; quantum; renal; renal clearance; research clinical testing; resection; scale up; small molecule; success; suid; surgery; tumor; uptake; vascular
Relevance: 7. : Near-infrared light is invisible to the human eye, but penetrates relatively deeply into living tissue. It is therefore ideal for image-guided surgery, because it provides surgeons with high- sensitivity, high-resolution detection of diseases, such as cancer, without changing the look of the surgical field. Although hardware systems that use near-infrared fluorescent light for image-guided surgery are already available, optimized fluorophores, or "light bulbs" are not. The goal of this grant is to develop a new class of ideal near-infrared fluorophores that can be injected into the bloodstream. These fluorophores would "stick" to tumors and other diseased tissue, but not to normal tissue
Project start date: 2010-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PAR-09-016
1R01EB010022-01A1 (2010): $724966
Spatially Modulated Near-Infrared Light For Image-Guided Cancer Surgery
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center
boston, Ma 02215
Grant 5R21CA129758-02 from National Cancer Institute IRG: ZEB1
Abstract: Human surgery, and especially oncologic surgery, is in need of improved image-guidance. Presently, surgery is performed "blindly," without visual cues for tissue that needs to be removed (e.g., cancer), tissue that needs to be avoided (e.g., nerves), or otherwise healthy tissue that is becoming inadvertently ischemic during the procedure (e.g., from clamping). As part of a Bioengineering Research Partnership, the PI´s laboratory has developed a near-infrared (NIR) fluorescence imaging system that utilizes exogenous fluorophores and invisible NIR light to help guide surgery. The imaging system uses continuous wave (CW) excitation and simple reflectance optics, and is now entering clinical trials. Although likely to find utility in many types of surgery, the present imaging system produces only qualitative information, and is unable to reconstruct, quantitatively, the absorbing (i.e., fA) and scattering (i.e., fS´) properties of living tissue, and fluorophore quantum yield (QY). Such information will have immediate clinical impact since it will, for the first time, permit non-invasive, image-based assessment of tissue oxygenation, and will greatly improve NIR fluorophore sensitivity by reducing autofluorescence. In this application, we propose the use of spatially-modulated NIR light (SMNL) to produce quantitative imaging of fA, fS´, and QY in essentially real-time. Our collaborator, the Tromberg group at the Beckman Laser Institute of the University of California, Irvine, has pioneered the use of this technology for quantitative, depth-resolved spectroscopic imaging as part of the Laser Microbeam and Medical Program (LAMMP) at the Beckman Laser Institute (www.bli.uci.edu/lammp). Recent results shown in Preliminary Studies suggest that SMNL can now be optimized for use over a large surgical field without the need for a laser excitation source. When combined with a novel LED-based light source proposed in this study, and recent advances in cardiac and respiratory gating technology from the PI´s laboratory, SMNL should be able to provide surgeons with direct measurement of fA, fS´, and QY, and thus improve virtually all image-guided surgical interventions. Phase I of this project leverages the complementary expertise of two imaging groups, and uses "collaborative feedback," to rapidly optimize the performance of a novel clinical imaging system. The Specific Aims are focused on the mathematical modeling of those SMNL acquisition parameters and performance metrics required for human surgery; the engineering of a novel, LED-based light source capable of projecting multi-wavelength, high fluence rate patterned light over a 15 cm diameter FoV; and the optimization of the technology for real-time imaging using large animal surgical models. Successful completion of the Specific Aims and Milestones will ensure that this new technology for image-guided interventions is translated efficiently to the clinic during project Phase II. 7. PROJECT NARRATIVE Human surgery, and especially oncologic surgery, is in need of improved image-guidance. Presently, surgery is performed "blindly," without visual cues for tissue that needs to be removed, tissue that needs to be avoided, or otherwise healthy tissue that is becoming inadvertently injured during the procedure. Successful completion of the specific aims in this application will ensure that a novel optical imaging technology for image-guided surgical interventions is translated efficiently to the clinic
Project start date: 2007-09-17
Project end date: 2010-08-31
5R21CA129758-02 (2008): $331361
1R21CA129758-01 (2007): $371307
A Platform For Cancer Biomarker Validation: Image Fusion Using NIR Fluorescence
John V Frangioni
Beth Israel Deaconess Medical Center
Grant 1R01CA134493-01A1 from National Cancer Institute IRG: ZRG1
Abstract: Clinical imaging using magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and/or single-photon emission computed tomography (SPECT) is the standard of care for the detection and staging of human cancer. However, clinical imaging is a macroscopic process, with up to 106 malignant cells filling every 1 mm3 voxel. At present, it is extremely difficult to correlate clinical imaging findings with the cellular genotype and/or phenotype leading to the finding. Hence, "biomarkers," such as dynamic contrast enhancement (DCE) on MRI, or a "hot" voxel on PET seen after injection of a targeted radiotracer, are difficult to validate since the fusion of macroscopic clinical imaging findings with microscopic histological findings is fraught with technical challenges. To solve this problem, our laboratory has developed new near-infrared (NIR) fluorescence technology that permits simultaneous (same slide) immunostaining and hematoxylin/eosin (H&E) staining of any pathological specimen. Hence, the chronic problem of co-registering tissue slices at the cellular level is eliminated, while the "gold-standard" of H&E histology is preserved. This technology lays the foundation for an integrated platform that permits high accuracy co-registration of macroscopic and microscopic data sets from an individual patient´s cancer. We have also developed an automated microscope that acquires H&E and NIR fluorescence simultaneously, and which permits up to 28 2"x3" whole-mount slides (or 56 1"x3" slides) to be scanned without human intervention. Using this technology, and several other innovations described in the application, 3-D data sets of clinical pathological specimens, at microscopic resolution, can now be generated. However, to bridge the gap between the microscopic and macroscopic domains, we have formed an academic-industrial partnership with the Imaging Department of Siemens Corporate Research (SCR) in Princeton, NJ. SCR is expert in the co-registration of 3-D volumes that have undergone non-linear deformations, in image segmentation, and in pattern recognition. Using algorithms developed by SCR for this study, we present an automated and integrated platform for cancer biomarker validation. Our study also leverages a unique clinical resource at the Beth Israel Deaconess Medical Center, the Hershey Prostate Cancer Tissue Bank. Through the Hershey Tissue Bank, men undergoing radical prostatectomy for prostate cancer receive a preoperative endorectal coil 3T MRI (pre- and post-Gd DCE), and at prostatectomy, the entire gland is available for whole-mount preparation. The paired data sets of clinical imaging (DCE-MRI) and whole mount histology will provide proof of principle for our biomarker validation platform, and will also be used to determine the mechanism of DCE-MRI at the cellular level. Completion of the specific aims by academic and industrial teams with complementary skill sets will permit virtually any proposed biomarker, for any type of cancer, to be validated rapidly and efficiently. Biomarkers for cancer imaging are extremely difficult to validate, since clinical imaging is performed on a macroscopic scale and histological evaluation of resected tissue is performed on a microscopic scale. We have formed an academic-industrial partnership between the Frangioni Laboratory at the Beth Israel Deaconess Medical Center in Boston, MA and Siemens Corporate Research in Princeton, NJ aimed at developing an integrated platform for biomarker validation using new near-infrared fluorescence and image fusion technology. This study also leverages a unique prostate cancer tissue bank that provides paired DCE-MRI and histological whole mounts from individual prostate cancer patients
Project start date: 2009-02-01
Project end date: 2013-12-31
Improved Optical Sub-Systems For In Vivo Cancer Imaging
John V Frangioni, Associate Professor Of Medicine And Assi
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 3R21CA110185-01S1 from National Cancer Institute IRG: ZCA1
Project start date: 2004-07-01
Project end date: 2006-06-30
3R21CA110185-01S1 (2005): $61674