- Email: [email protected]
Confocal microendoscope for in vivo molecular imaging
ABSTRACTS OF NIH GRANTS
MID-ATLANTIC IN VIVO CELLULAR & MOLECULAR IMAGING CENTER Grant Number: PI Name:
5P20CA086255-03 Glickson, Jerry D.
Abstract: An In vivo Cellular and Molecular Imaging Center (ICMIC) at the University of Pennsylvania will provide imaging resources and expertise to molecular biologists and clinicians engaged in research on molecular markers of cancer in small animal models and human subjects, respectively. The imaging center, which will be called the Mid-Atlantic Molecular Imaging Center (MAMIC), will serve the greater Philadelphia area as well as a number of outstanding institutions throughout the world. Three imaging modalities will be employed, Nuclear Medicine (including PET and SPECT), NMR (including MRI and MRS), and Optical Imaging (focusing primarily on near infrared imaging, but also including redox scanning of ex vivo specimens). The proposed MAMIC will support a number of interdisciplinary highly interactive projects in three major research areas: 1) Tumor Biology, 2) Gene and Antiangiogenic Therapy, and 3) Radiation Oncology. Core facilities for Molecular Biology, Chemistry, Biostatistics, and the three Imaging modalities are included. The proposal includes six potential developmental projects entitled: 1) Mechanism of apoptosis induction, 2) Peptidomimetic ligands of HER2/Neu receptors in breast cancer, 3) Targeting of LDL receptors on tumor cells, 4) Mechanism of estrogen/tamoxifen effects on Gd enhancement of breast tumor MR images, 5) Treatment of colon tumor liver metastases by interferon transfection using creatine kinase as a marker gene, and 6) Bacteriochlorophyll molecular beacons triggered by specific mRNAs. In addition to support for three developmental projects, the MAMIC will provide core facilities, seminars and assistance in obtaining external funding to all the participants. Each of the Imaging Core Facilities will conduct research directed at development of imaging techniques that will enhance the research programs of the participating scientific community. This imaging research will be supported by a Small Animal Imaging Grant that is in the process of being funded and a Research Resource grant that has supported research in magnetic resonance and optical imaging for the past 15 years. The MAMIC will therefore serve as a catalyst and focal point for ongoing cancer research employing state of the art imaging techniques. Thesaurus Terms: biomedical resource, cellular oncology, magnetic resonance imaging, molecular oncology, positron emission tomography, single photon emission computed tomography, angiogenesis inhibitor, apoptosis, breast neoplasm, chlorophyll, colon neoplasm, creatine kinase, estrogen, gadolinium, gene therapy, genetic marker, interferon, liver neoplasm, low-density lipoprotein receptor, metastasis, protooncogene, tamoxifen bioimaging/biomedical imaging, human subject, laboratory mouse, transfection
1064
Academic Radiology, Vol 10, No 9, September 2003
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 2002 Radiology 12-Sep-2000 31-Aug-2003 National Cancer Institute ZCA1
CONFOCAL MICROENDOSCOPE FOR IN VIVO MOLECULAR IMAGING Grant Number: PI Name:
1R33CA094287-01 Gmitro, Arthur F.
Abstract: Description (provided by applicant): The objective of this research is to develop a practical effective instrument for in-vivo microscopic imaging. The confocal microendoscope is a catheter-based instrument that utilizes a fiber-optic imaging bundle to view tissue at the cellular level in situ. Encouraging preliminary results have been obtained with fluorescence imaging of tissues using a prototype confocal microendoscope system. The primary aims of this research are to complete the technical development of the instrument, to identify and evaluate suitable fluorescent molecular labels, and then to evaluate clinical applications that can exploit this technology. The technical development includes improvements in the catheter and the confocal imaging system. The catheter of the confocal microendoscope consists of a miniature microscope objective and focusing mechanism attached to the distal end of a fiber-optic imaging bundle. A specific aim of the research is to build a small and optimized catheter that can be routed through the instrument channel of clinical endoscopes or through small openings of the body. The development of the catheter represents a significant technical challenge given the desired size and performance characteristics. Improvements in the confocal system and modifications to incorporate multispectral imaging capability are also proposed. The confocal microendoscope can image endogenous tissue autofluorescence or fluorescence from suitable exogenous dyes or fluorescent probes. A major aspect of the work is to investigate the imaging properties and the clinical/scientific utility of the fluorescent signals. Investigations of tissue autofluorescence, disease-specific fluorescent probes, and cell-permeant vital stains are described. The confocal microendoscope is a fundamental tool that could be used to improve the accuracy of diagnosis or the efficacy of therapeutic intervention. An aim of this grant is to investigate and evaluate the potential of the instrument for imaging cancers or pre-cancerous conditions of the colon, pancreas, esophagus, and prostate, which are applications where the instrument could have a significant clinical impact. These studies will be performed using ex vivo human tissues obtained
ABSTRACTS OF NIH GRANTS
Academic Radiology, Vol 10, No 9, September 2003
from surgery and biopsy. Successful development and demonstration of the confocal microendoscope will lead to subsequent in vivo clinical trials. Thesaurus Terms: biomedical equipment development, confocal scanning microscopy, diagnosis quality/standard, endoscopy, fiberoptic microscopy, miniature biomedical equipment, neoplasm/cancer diagnosis, colon neoplasm, esophagus neoplasm, pancreas neoplasm, preneoplastic state, prostate neoplasm, SCID mouse bioimaging/biomedical imaging, clinical research, fluorescent dye/probe, human tissue, laboratory mouse, laboratory rat
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Arizona P O Box 3308 Tucson, AZ 857223308 2002 Radiology 06-May-2002 30-Apr-2005 National Cancer Institute ZCA1
QUANTIFYING RADIATION-THERAPY BRAIN INJURY WITH 1H-MRS Grant Number: PI Name:
we will evaluate the amount of NAA in the entire brain, its signal-to-noise-ratio (SNR) will be excellent, facilitating short, ⬍ 15 min. examinations. It will also not be susceptible to misregistration errors that currently beset serial studies, nor will it be sensitive to the local transient edema common in WBRT. The WBNAA measurements will be augmented by the current tool used to evaluate CNS injury - the minimental status examination (MMSE) for correlation and comparison. We will use these observations to test the following three hypotheses, H1- H3: H1: That WBRT induces neuronal injury quantifiable with WBNAA in these patients. H2: That WBNAA is more sensitive than MMSE to detect neuronal injury consequences of WBRT. H3: That this neuronal injury may be transient, in part, and could resolve within several months after WBRT. Thesaurus Terms: brain disorder diagnosis, brain injury, neoplasm/cancer radiation therapy, noninvasive diagnosis, therapy adverse effect, aspartate, brain disease/disorder prevention/control, longitudinal human study, metastasis, nervous system regeneration, neuron, neurotoxicology, small cell lung cancer adult human (21⫹), clinical research, human subject, hydrogen ion, nuclear magnetic resonance spectroscopy, patient-oriented research, psychological test
Institution:
1R21CA092547-01A1 Gonen, Oded
Abstract: Description (provided by applicant): Brain metastases present in 50-80 percent of small-cell-lung-cancer (SCLC) survivors within two years. To reduce this risk and improve their outcome, prophylactic-cranial-irradiation (PCI) is now offered to certain SCLC patients even in the absence of distinct visible brain pathology. Although neurotoxicity is always a concern in brain radiation-therapy (RT), there is currently no direct method to quantify its damage to the central nervous system (CNS). Such knowledge is critical for (a) risk/benefit assessment; and (b) dose determination. Presently, such damage can only be assessed indirectly, using neurocognitive tests. Unfortunately, the results of such tests are often confounded by other factors such as language barriers, patients’ state of mind and/or their level of fatigue, fear and depression. Clearly, an objective, i.e., preferably instrumental, non-invasive and, most importantly, sensitive method to quantify RT neurotoxicity is necessary. We propose to quantify the extent of neurona1 cell loss imparted to the brain by RT through the decline of the amino acid derivative N-acetylaspartate (NAA) using state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Since NAA is believed to be present in neuronal cells only, its amount is proportional to their number and/or integrity. Consequently, we will obtain the amount of whole-brain-NAA (WBNAA) in 40 patients pre, immediately post- (2-3 weeks later) and six months after whole-brain radiation-therapy (WBRT). Since
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
New York University School Of Medicine 550 1st Ave New York, NY 10016 2002 Radiology 03-Jul-2002 30-Jun-2004 National Cancer Institute ZRG1
INVESTIGATIONS OF MULTI-VIEW CAD FOR MAMMOGRAPHY Grant Number: PI Name:
5R01CA080836-04 Good, Walter F.
Abstract: Over the past 15 years, considerable progress has been made in the development of computer-aided detection (CAD) of abnormalities in mammograms. Nevertheless, because of performance limitations of current CAD algorithms, the question of whether CAD provides a net benefit remains unresolved. In recent years, despite considerable effort by many groups, the rate of improvement in CAD performance has declined to the point that performance statistics seem to be approaching an asymptote, which is well below the performance of mammographers. The most likely reason for this is that essentially all current CAD implementations are founded on traditional methods of signal processing and pattern recognition and derive their performance by detecting
1065
MID-ATLANTIC IN VIVO CELLULAR & MOLECULAR IMAGING CENTER Grant Number: PI Name:
5P20CA086255-03 Glickson, Jerry D.
Abstract: An In vivo Cellular and Molecular Imaging Center (ICMIC) at the University of Pennsylvania will provide imaging resources and expertise to molecular biologists and clinicians engaged in research on molecular markers of cancer in small animal models and human subjects, respectively. The imaging center, which will be called the Mid-Atlantic Molecular Imaging Center (MAMIC), will serve the greater Philadelphia area as well as a number of outstanding institutions throughout the world. Three imaging modalities will be employed, Nuclear Medicine (including PET and SPECT), NMR (including MRI and MRS), and Optical Imaging (focusing primarily on near infrared imaging, but also including redox scanning of ex vivo specimens). The proposed MAMIC will support a number of interdisciplinary highly interactive projects in three major research areas: 1) Tumor Biology, 2) Gene and Antiangiogenic Therapy, and 3) Radiation Oncology. Core facilities for Molecular Biology, Chemistry, Biostatistics, and the three Imaging modalities are included. The proposal includes six potential developmental projects entitled: 1) Mechanism of apoptosis induction, 2) Peptidomimetic ligands of HER2/Neu receptors in breast cancer, 3) Targeting of LDL receptors on tumor cells, 4) Mechanism of estrogen/tamoxifen effects on Gd enhancement of breast tumor MR images, 5) Treatment of colon tumor liver metastases by interferon transfection using creatine kinase as a marker gene, and 6) Bacteriochlorophyll molecular beacons triggered by specific mRNAs. In addition to support for three developmental projects, the MAMIC will provide core facilities, seminars and assistance in obtaining external funding to all the participants. Each of the Imaging Core Facilities will conduct research directed at development of imaging techniques that will enhance the research programs of the participating scientific community. This imaging research will be supported by a Small Animal Imaging Grant that is in the process of being funded and a Research Resource grant that has supported research in magnetic resonance and optical imaging for the past 15 years. The MAMIC will therefore serve as a catalyst and focal point for ongoing cancer research employing state of the art imaging techniques. Thesaurus Terms: biomedical resource, cellular oncology, magnetic resonance imaging, molecular oncology, positron emission tomography, single photon emission computed tomography, angiogenesis inhibitor, apoptosis, breast neoplasm, chlorophyll, colon neoplasm, creatine kinase, estrogen, gadolinium, gene therapy, genetic marker, interferon, liver neoplasm, low-density lipoprotein receptor, metastasis, protooncogene, tamoxifen bioimaging/biomedical imaging, human subject, laboratory mouse, transfection
1064
Academic Radiology, Vol 10, No 9, September 2003
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 2002 Radiology 12-Sep-2000 31-Aug-2003 National Cancer Institute ZCA1
CONFOCAL MICROENDOSCOPE FOR IN VIVO MOLECULAR IMAGING Grant Number: PI Name:
1R33CA094287-01 Gmitro, Arthur F.
Abstract: Description (provided by applicant): The objective of this research is to develop a practical effective instrument for in-vivo microscopic imaging. The confocal microendoscope is a catheter-based instrument that utilizes a fiber-optic imaging bundle to view tissue at the cellular level in situ. Encouraging preliminary results have been obtained with fluorescence imaging of tissues using a prototype confocal microendoscope system. The primary aims of this research are to complete the technical development of the instrument, to identify and evaluate suitable fluorescent molecular labels, and then to evaluate clinical applications that can exploit this technology. The technical development includes improvements in the catheter and the confocal imaging system. The catheter of the confocal microendoscope consists of a miniature microscope objective and focusing mechanism attached to the distal end of a fiber-optic imaging bundle. A specific aim of the research is to build a small and optimized catheter that can be routed through the instrument channel of clinical endoscopes or through small openings of the body. The development of the catheter represents a significant technical challenge given the desired size and performance characteristics. Improvements in the confocal system and modifications to incorporate multispectral imaging capability are also proposed. The confocal microendoscope can image endogenous tissue autofluorescence or fluorescence from suitable exogenous dyes or fluorescent probes. A major aspect of the work is to investigate the imaging properties and the clinical/scientific utility of the fluorescent signals. Investigations of tissue autofluorescence, disease-specific fluorescent probes, and cell-permeant vital stains are described. The confocal microendoscope is a fundamental tool that could be used to improve the accuracy of diagnosis or the efficacy of therapeutic intervention. An aim of this grant is to investigate and evaluate the potential of the instrument for imaging cancers or pre-cancerous conditions of the colon, pancreas, esophagus, and prostate, which are applications where the instrument could have a significant clinical impact. These studies will be performed using ex vivo human tissues obtained
ABSTRACTS OF NIH GRANTS
Academic Radiology, Vol 10, No 9, September 2003
from surgery and biopsy. Successful development and demonstration of the confocal microendoscope will lead to subsequent in vivo clinical trials. Thesaurus Terms: biomedical equipment development, confocal scanning microscopy, diagnosis quality/standard, endoscopy, fiberoptic microscopy, miniature biomedical equipment, neoplasm/cancer diagnosis, colon neoplasm, esophagus neoplasm, pancreas neoplasm, preneoplastic state, prostate neoplasm, SCID mouse bioimaging/biomedical imaging, clinical research, fluorescent dye/probe, human tissue, laboratory mouse, laboratory rat
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Arizona P O Box 3308 Tucson, AZ 857223308 2002 Radiology 06-May-2002 30-Apr-2005 National Cancer Institute ZCA1
QUANTIFYING RADIATION-THERAPY BRAIN INJURY WITH 1H-MRS Grant Number: PI Name:
we will evaluate the amount of NAA in the entire brain, its signal-to-noise-ratio (SNR) will be excellent, facilitating short, ⬍ 15 min. examinations. It will also not be susceptible to misregistration errors that currently beset serial studies, nor will it be sensitive to the local transient edema common in WBRT. The WBNAA measurements will be augmented by the current tool used to evaluate CNS injury - the minimental status examination (MMSE) for correlation and comparison. We will use these observations to test the following three hypotheses, H1- H3: H1: That WBRT induces neuronal injury quantifiable with WBNAA in these patients. H2: That WBNAA is more sensitive than MMSE to detect neuronal injury consequences of WBRT. H3: That this neuronal injury may be transient, in part, and could resolve within several months after WBRT. Thesaurus Terms: brain disorder diagnosis, brain injury, neoplasm/cancer radiation therapy, noninvasive diagnosis, therapy adverse effect, aspartate, brain disease/disorder prevention/control, longitudinal human study, metastasis, nervous system regeneration, neuron, neurotoxicology, small cell lung cancer adult human (21⫹), clinical research, human subject, hydrogen ion, nuclear magnetic resonance spectroscopy, patient-oriented research, psychological test
Institution:
1R21CA092547-01A1 Gonen, Oded
Abstract: Description (provided by applicant): Brain metastases present in 50-80 percent of small-cell-lung-cancer (SCLC) survivors within two years. To reduce this risk and improve their outcome, prophylactic-cranial-irradiation (PCI) is now offered to certain SCLC patients even in the absence of distinct visible brain pathology. Although neurotoxicity is always a concern in brain radiation-therapy (RT), there is currently no direct method to quantify its damage to the central nervous system (CNS). Such knowledge is critical for (a) risk/benefit assessment; and (b) dose determination. Presently, such damage can only be assessed indirectly, using neurocognitive tests. Unfortunately, the results of such tests are often confounded by other factors such as language barriers, patients’ state of mind and/or their level of fatigue, fear and depression. Clearly, an objective, i.e., preferably instrumental, non-invasive and, most importantly, sensitive method to quantify RT neurotoxicity is necessary. We propose to quantify the extent of neurona1 cell loss imparted to the brain by RT through the decline of the amino acid derivative N-acetylaspartate (NAA) using state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Since NAA is believed to be present in neuronal cells only, its amount is proportional to their number and/or integrity. Consequently, we will obtain the amount of whole-brain-NAA (WBNAA) in 40 patients pre, immediately post- (2-3 weeks later) and six months after whole-brain radiation-therapy (WBRT). Since
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
New York University School Of Medicine 550 1st Ave New York, NY 10016 2002 Radiology 03-Jul-2002 30-Jun-2004 National Cancer Institute ZRG1
INVESTIGATIONS OF MULTI-VIEW CAD FOR MAMMOGRAPHY Grant Number: PI Name:
5R01CA080836-04 Good, Walter F.
Abstract: Over the past 15 years, considerable progress has been made in the development of computer-aided detection (CAD) of abnormalities in mammograms. Nevertheless, because of performance limitations of current CAD algorithms, the question of whether CAD provides a net benefit remains unresolved. In recent years, despite considerable effort by many groups, the rate of improvement in CAD performance has declined to the point that performance statistics seem to be approaching an asymptote, which is well below the performance of mammographers. The most likely reason for this is that essentially all current CAD implementations are founded on traditional methods of signal processing and pattern recognition and derive their performance by detecting
1065