- Email: [email protected]
Technetium and rhenium in nuclear medicine
ABSTRACTS OF NIH GRANTS
vasive image-guided therapy methods can reduce the morality and morbidity of cancer and most likely will result in an improvement of the quality of life. The goal of the program is to train postdoctoral candidates (radiologists, radiation oncologists, surgeons, bioengineers and computer scientists) in cancer related clinical and translational research settings in this emerging field which is highly inter- disciplinary and collaborative. The Image-Guided Therapy Program at the Brigham and Women’s Hospital/Harvard Medical School is a rich multidisciplinary environment that brings researchers and clinical teams with diverse backgrounds together. In this program various, mostly MRI-guided procedures, are practiced using several therapy methods (percutaneous thermal ablations, focused ultrasound surgery, brachytherapy and open surgeries) in multiple organs (brain, spine, liver, breast, prostate and musculoskeletal system). We propose the training of postdoctoral students (M.D.s and Ph.D.s) by an outstanding qualified and experienced group of preceptors with adequate funding and research support and specialized research skills. We plan to develop a specialized curriculum to augment the research and education and to attract highly qualified candidates for this exciting area of translational research. Thesaurus Terms: education evaluation/planning, imaging/ visualization/scanning, neoplasm/cancer, neoplasm/cancer education, neoplasm/cancer therapy career, curriculum, oncology, postdoctoral investigator, training program/project clinical research, human subject, magnetic resonance imaging
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham And Women’s Hospital 75 Francis Street Boston, MA 02115 2002 24-Sep-2001 30-Jun-2006 National Cancer Institute NCI
MR GUIDED THERAPY Grant Number: PI Name:
5P01CA067165-06 Jolesz, Ferenc A.
Abstract: MRI-guided therapy procedures have the potential to reduce the invasiveness of surgical approaches. The use of intraoperative MRI can also result in the discovery of novel interventional surgical applications. The long-term objective of this Program Project has been to provide the scientific medical and technical infrastructure for the development of intraoperative MRI. The work proposed involves an integrated, coordinated, multi-disciplinary translational research effort in developing MRI-guided procedures that can be
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Academic Radiology, Vol 10, No 9, September 2003
tested in future clinical trials. The proposal addresses critical areas of intraoperative MRI that may have significant impact on the future of this emerging field. These specific areas are: MRI-guided neurosurgery; MRI-guided, ultrasound surgery; image processing technologies and display tools for surgical for surgical guidance; and dynamic, adaptive volumetric image acquisition techniques. Project 1 aims to develop an integrated system of pre- and intra-operative image acquisition, online image processing, and intraoperative display, which allows the utilization of all the accessible intraoperative and preoperative information for image-guided neurosurgery. The objective of Project 2 is to implement MRI guided and monitored focused ultrasound surgery used in combination with radiation therapy for the effective treatment of small malignant breast tumors. In Project 3 we continue to develop and implement high performance computer integration of preoperative MR data with intraoperative images in order to guide surgery intraoperatively. The proposed research in Project 4 is to develop, implement and improve fast 3D dynamic adaptive MRI techniques to meet the specific needs of several interventional MR applications. This Program Project emphasizes the interaction of closely related individual research projects. The individual components are not only well integrated but there is also significant cross-fertilization and active interchange between them. We present a plant for the integrated development of therapeutic techniques that are optimized through MRI-guidance, monitoring and control. We have been providing a rapid transfer of new developments from the laboratory to clinical applications. With this translational research we refine and validate the experimental methods and techniques development and implemented previously. Thesaurus Terms: magnetic resonance imaging, method development, neoplasm/cancer thermotherapy, bioimaging/ biomedical imaging, human subject
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham And Women’s Hospital 75 Francis Street Boston, MA 02115 2002 30-Sep-1995 30-Apr-2005 National Cancer Institute ZCA1
TECHNETIUM AND RHENIUM IN NUCLEAR MEDICINE Grant Number: PI Name:
5R01CA034970-24 Jones, Alun G.
Abstract: Description (Adapted from Applicant’s Abstract): The radionuclide technetium-99m continues to be the main-
ABSTRACTS OF NIH GRANTS
Academic Radiology, Vol 10, No 9, September 2003
stay of routine clinical nuclear medicine. This research program was originally conceived on the premise that the usefulness of this radionuclide in diagnosis can only be maintained by conducting a rigorous study of the basic chemistry of the element and incorporating this knowledge into the design of new radiopharmaceuticals. This is equally true of therapeutic applications based on the use of radionuclides of its congener rhenium. In this next period the applicants proposed to concentrate primarily on two broad areas of chemistry: low valent chemistry in oxidation states (⫹1) and (⫹2), including the study of complexes continuing weak-field ligands that may provide routes into the production of new classes of complexes in aqueous media from routine precursors such as pertechnetate ion: and organohydrazine chemistry, a highly complex area that has begun to be used in certain radiopharmaceutical applications, for example, the chelate 6-hydrazinonicotinamide (HYNIC). In applications of the chemistry, the work will include an investigation of monoamide-monoamine bisthiol (MAMA or AAST) conjugated ligands targeted to 5HT-1A receptors in the brain. Factors affecting localization such as structure, choice of chelate lipophilicity, the pKa of the complex under physiological conditions, and selectivity against other receptor types will be studied. In parallel, a solid-state synthesis for producing high-specific-activity samples of technetium complexes designed for receptor targeting will be explored. This is vital in circumstances where unlabeled precursor ligand could compete with the final complex for sites of occupation. The last section among the applications will focus on tumor detection. First, the 5HT-1A ligands developed for studying the brain will be evaluated for their ability to detect neuroendocrine mediated cancer of the prostate. Second, a program is being established to study smallmolecule detection of cancer, in the first instance using conjugated analogs of iodinated compounds that have already bee shown by others to be avidly taken up by melanoma cells. Thesaurus Terms: heavy metal, nuclear medicine, radiopharmacology, technetium carbonyl compound, chemical structure function, drug design/synthesis/production, hydrazine, ligand, neoplasm/cancer radionuclide diagnosis, serotonin receptor, solid state, Animalia, radiotracer
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Harvard University (Medical School) Medical School Campus Boston, MA 02115 2002 Radiology 01-Feb-1977 31-Mar-2005 National Cancer Institute ZRG1
HIGH SPECTRAL & SPATIAL RESOLUTION MRI OF RODENT TUMORS Grant Number: PI Name:
1R21CA089408-01A1 Karczmar, Groegory S.
Abstract: Description (provided by applicant): Because of its excellent soft tissue contrast, Magnetic Resonance Imaging (MRI) may aid early detection and staging of breast and prostate cancer. MRI has high sensitivity but its specificity has been disappointing. New methods that improve identification of metastatic lesions by MRI would have a significant impact on early detection and treatment of cancer. Previous work in this laboratory showed that high spectral and spatial resolution (HiSS) MRI improves image quality and detection of the effects of contrast agents. HiSS images can be acquired with clinically acceptable run times by using frequency resolved echo planar methods to obtain detailed spectra of the water and fat resonances associated with each image voxel. The proposed research tests the hypothesis that contrast enhanced HiSS MRI can distinguish metastatic tumors from non-metastatic tumors based on measures of image texture and edge delineation. We will develop methods for acquiring and processing HiSS datasets to maximize contrast, edge delineation and signal-to-noise ratio. Contrast media will be used to enhance contrast, improve depiction of tumor boundaries, and detect tumor vascular structure. We will test these experimental MRI methods using the wellcharacterized Dunning system of prostatic cancers. We propose to use four cell lines that vary in metastatic ability. HiSS MRI data will be correlated with tumor growth rate and size, microvessel density, degree and spatial distribution of necrosis, and number of overt metastases. This will improve our understanding of the biological processes that determine contrast in HiSS images and optimize HiSS MRI to detect features that differentiate metastatic and non-metastatic cancers. We will determine whether properties of the primary tumor measured by MRI can predict the behavior of metastases. The specific areas of innovation are: 1) Use of HiSS for anatomic and functional imaging 2) Application of HiSS to differentiate between metastatic and non-metastatic cancers 3) Application of CAD (computer aided diagnosis) methods developed by Dr. Giger and coworkers to analyze HiSS data 4) Use of molecular biologic methods to produce model tumors that guide the development of new imaging methods. The proposed research brings together a strong interdisciplinary team including Dr. Giger (image analysis, CAD), Dr. Rinker-Schaeffer (molecular biology, cancer biology), and Dr. Karczmar (MRI, tumor physiology). This work would have a significant and rapid impact on clinical practice. Thesaurus Terms: diagnosis design/evaluation, magnetic resonance imaging, neoplasm/cancer diagnosis, prostate neoplasm, computer-assisted diagnosis, computer system design/ evaluation, metastasis bioimaging/biomedical imaging, laboratory mouse
1077
vasive image-guided therapy methods can reduce the morality and morbidity of cancer and most likely will result in an improvement of the quality of life. The goal of the program is to train postdoctoral candidates (radiologists, radiation oncologists, surgeons, bioengineers and computer scientists) in cancer related clinical and translational research settings in this emerging field which is highly inter- disciplinary and collaborative. The Image-Guided Therapy Program at the Brigham and Women’s Hospital/Harvard Medical School is a rich multidisciplinary environment that brings researchers and clinical teams with diverse backgrounds together. In this program various, mostly MRI-guided procedures, are practiced using several therapy methods (percutaneous thermal ablations, focused ultrasound surgery, brachytherapy and open surgeries) in multiple organs (brain, spine, liver, breast, prostate and musculoskeletal system). We propose the training of postdoctoral students (M.D.s and Ph.D.s) by an outstanding qualified and experienced group of preceptors with adequate funding and research support and specialized research skills. We plan to develop a specialized curriculum to augment the research and education and to attract highly qualified candidates for this exciting area of translational research. Thesaurus Terms: education evaluation/planning, imaging/ visualization/scanning, neoplasm/cancer, neoplasm/cancer education, neoplasm/cancer therapy career, curriculum, oncology, postdoctoral investigator, training program/project clinical research, human subject, magnetic resonance imaging
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham And Women’s Hospital 75 Francis Street Boston, MA 02115 2002 24-Sep-2001 30-Jun-2006 National Cancer Institute NCI
MR GUIDED THERAPY Grant Number: PI Name:
5P01CA067165-06 Jolesz, Ferenc A.
Abstract: MRI-guided therapy procedures have the potential to reduce the invasiveness of surgical approaches. The use of intraoperative MRI can also result in the discovery of novel interventional surgical applications. The long-term objective of this Program Project has been to provide the scientific medical and technical infrastructure for the development of intraoperative MRI. The work proposed involves an integrated, coordinated, multi-disciplinary translational research effort in developing MRI-guided procedures that can be
1076
Academic Radiology, Vol 10, No 9, September 2003
tested in future clinical trials. The proposal addresses critical areas of intraoperative MRI that may have significant impact on the future of this emerging field. These specific areas are: MRI-guided neurosurgery; MRI-guided, ultrasound surgery; image processing technologies and display tools for surgical for surgical guidance; and dynamic, adaptive volumetric image acquisition techniques. Project 1 aims to develop an integrated system of pre- and intra-operative image acquisition, online image processing, and intraoperative display, which allows the utilization of all the accessible intraoperative and preoperative information for image-guided neurosurgery. The objective of Project 2 is to implement MRI guided and monitored focused ultrasound surgery used in combination with radiation therapy for the effective treatment of small malignant breast tumors. In Project 3 we continue to develop and implement high performance computer integration of preoperative MR data with intraoperative images in order to guide surgery intraoperatively. The proposed research in Project 4 is to develop, implement and improve fast 3D dynamic adaptive MRI techniques to meet the specific needs of several interventional MR applications. This Program Project emphasizes the interaction of closely related individual research projects. The individual components are not only well integrated but there is also significant cross-fertilization and active interchange between them. We present a plant for the integrated development of therapeutic techniques that are optimized through MRI-guidance, monitoring and control. We have been providing a rapid transfer of new developments from the laboratory to clinical applications. With this translational research we refine and validate the experimental methods and techniques development and implemented previously. Thesaurus Terms: magnetic resonance imaging, method development, neoplasm/cancer thermotherapy, bioimaging/ biomedical imaging, human subject
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham And Women’s Hospital 75 Francis Street Boston, MA 02115 2002 30-Sep-1995 30-Apr-2005 National Cancer Institute ZCA1
TECHNETIUM AND RHENIUM IN NUCLEAR MEDICINE Grant Number: PI Name:
5R01CA034970-24 Jones, Alun G.
Abstract: Description (Adapted from Applicant’s Abstract): The radionuclide technetium-99m continues to be the main-
ABSTRACTS OF NIH GRANTS
Academic Radiology, Vol 10, No 9, September 2003
stay of routine clinical nuclear medicine. This research program was originally conceived on the premise that the usefulness of this radionuclide in diagnosis can only be maintained by conducting a rigorous study of the basic chemistry of the element and incorporating this knowledge into the design of new radiopharmaceuticals. This is equally true of therapeutic applications based on the use of radionuclides of its congener rhenium. In this next period the applicants proposed to concentrate primarily on two broad areas of chemistry: low valent chemistry in oxidation states (⫹1) and (⫹2), including the study of complexes continuing weak-field ligands that may provide routes into the production of new classes of complexes in aqueous media from routine precursors such as pertechnetate ion: and organohydrazine chemistry, a highly complex area that has begun to be used in certain radiopharmaceutical applications, for example, the chelate 6-hydrazinonicotinamide (HYNIC). In applications of the chemistry, the work will include an investigation of monoamide-monoamine bisthiol (MAMA or AAST) conjugated ligands targeted to 5HT-1A receptors in the brain. Factors affecting localization such as structure, choice of chelate lipophilicity, the pKa of the complex under physiological conditions, and selectivity against other receptor types will be studied. In parallel, a solid-state synthesis for producing high-specific-activity samples of technetium complexes designed for receptor targeting will be explored. This is vital in circumstances where unlabeled precursor ligand could compete with the final complex for sites of occupation. The last section among the applications will focus on tumor detection. First, the 5HT-1A ligands developed for studying the brain will be evaluated for their ability to detect neuroendocrine mediated cancer of the prostate. Second, a program is being established to study smallmolecule detection of cancer, in the first instance using conjugated analogs of iodinated compounds that have already bee shown by others to be avidly taken up by melanoma cells. Thesaurus Terms: heavy metal, nuclear medicine, radiopharmacology, technetium carbonyl compound, chemical structure function, drug design/synthesis/production, hydrazine, ligand, neoplasm/cancer radionuclide diagnosis, serotonin receptor, solid state, Animalia, radiotracer
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Harvard University (Medical School) Medical School Campus Boston, MA 02115 2002 Radiology 01-Feb-1977 31-Mar-2005 National Cancer Institute ZRG1
HIGH SPECTRAL & SPATIAL RESOLUTION MRI OF RODENT TUMORS Grant Number: PI Name:
1R21CA089408-01A1 Karczmar, Groegory S.
Abstract: Description (provided by applicant): Because of its excellent soft tissue contrast, Magnetic Resonance Imaging (MRI) may aid early detection and staging of breast and prostate cancer. MRI has high sensitivity but its specificity has been disappointing. New methods that improve identification of metastatic lesions by MRI would have a significant impact on early detection and treatment of cancer. Previous work in this laboratory showed that high spectral and spatial resolution (HiSS) MRI improves image quality and detection of the effects of contrast agents. HiSS images can be acquired with clinically acceptable run times by using frequency resolved echo planar methods to obtain detailed spectra of the water and fat resonances associated with each image voxel. The proposed research tests the hypothesis that contrast enhanced HiSS MRI can distinguish metastatic tumors from non-metastatic tumors based on measures of image texture and edge delineation. We will develop methods for acquiring and processing HiSS datasets to maximize contrast, edge delineation and signal-to-noise ratio. Contrast media will be used to enhance contrast, improve depiction of tumor boundaries, and detect tumor vascular structure. We will test these experimental MRI methods using the wellcharacterized Dunning system of prostatic cancers. We propose to use four cell lines that vary in metastatic ability. HiSS MRI data will be correlated with tumor growth rate and size, microvessel density, degree and spatial distribution of necrosis, and number of overt metastases. This will improve our understanding of the biological processes that determine contrast in HiSS images and optimize HiSS MRI to detect features that differentiate metastatic and non-metastatic cancers. We will determine whether properties of the primary tumor measured by MRI can predict the behavior of metastases. The specific areas of innovation are: 1) Use of HiSS for anatomic and functional imaging 2) Application of HiSS to differentiate between metastatic and non-metastatic cancers 3) Application of CAD (computer aided diagnosis) methods developed by Dr. Giger and coworkers to analyze HiSS data 4) Use of molecular biologic methods to produce model tumors that guide the development of new imaging methods. The proposed research brings together a strong interdisciplinary team including Dr. Giger (image analysis, CAD), Dr. Rinker-Schaeffer (molecular biology, cancer biology), and Dr. Karczmar (MRI, tumor physiology). This work would have a significant and rapid impact on clinical practice. Thesaurus Terms: diagnosis design/evaluation, magnetic resonance imaging, neoplasm/cancer diagnosis, prostate neoplasm, computer-assisted diagnosis, computer system design/ evaluation, metastasis bioimaging/biomedical imaging, laboratory mouse
1077