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• W1987524324 abstract "Imaging of gastrointestinal processes may be divided into 2 broad categories. Direct visualization by optical means has typically been performed by gastroenterologists using minimally invasive endoscopic approaches. Whole body cross-sectional imaging, such as magnetic resonance imaging (MRI) and computed tomography (CT), usually fall into traditional radiologic interpretation. Modalities such as ultrasound are split between the 2 areas, depending on the scope of observation and degree of intervention involved. Historically, both categories of imaging have detected pathology based on anatomic changes. Optical imaging intrinsically provides very high spatial resolution, and visualized anatomic changes can range from subtle alterations in mucosal patterns to gross luminal narrowings. Likewise, pathology detected by MRI or CT scanning often relies on anatomic distortion of normal structures augmented in visualization by perfusion differences highlighted using nonspecific small molecules such as iodinated contrast agents and gadolinium.Over the last few years, a major paradigm shift has been taking place in imaging, both in optical and cross-sectional modalities. Molecular imaging, the detection, spatial localization, and quantitation of specific molecular targets and events that form the basis of various pathologies, has expanded from preclinical imaging to clinical trials and in some cases to routine clinical use. Numerous targets, ranging from cell-surface receptors, tyrosine kinases, apoptosis markers, proliferation markers, proteolytic enzymes, extracellular matrix targets, and glucose metabolism levels, among many others, have been evaluated for noninvasive imaging.1Kelloff G.J. Krohn K.A. Larson S.M. Weissleder R. Mankoff D.A. Hoffman J.M. Link J.M. Guyton K.Z. Eckelman W.C. Scher H.I. O’Shaughnessy J. Cheson B.D. Sigman C.C. Tatum J.L. Mills G.Q. Sullivan D.C. Woodcock J. The progress and promise of molecular imaging probes in oncologic drug development.Clin Cancer Res. 2005; 11: 7967-7985Crossref PubMed Scopus (207) Google Scholar A well-known major early success in oncology has been improved detection of cancers including many gastrointestinal cancers through the imaging of glucose metabolism using 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Use of molecularly targeted therapy has increased in cancer treatments; given the specificity of treatment and nonuniversal expression of targets, early evaluation of efficacy has been a driving focus to differentiate responders from nonresponders. Different possibilities exist for such assessment: imaging of drug binding using competitive inhibition of fluorescently tagged, MRI labeled, or radiolabeled agents, has worked in preclinical cases, particularly when the targets are cell-surface receptors. Although this approach holds great promise for a number of important targets, it requires a new imaging drug for each different therapeutic drug target. There is an assumption that drug efficacy (eg, effect cell death rate or proliferation) is correlated in the individual case with drug-to-target binding saturation. An alternative approach is the imaging of changes that are common downstream pathways for multiple therapeutic targets. As an example, long-term response to the tyrosine kinase inhibitor Gleevec for gastrointestinal stromal tumors could be visualized using FDG PET imaging in some cases as soon as 24 hours after the initiation of therapy.2Demetri G.D. von Mehren M. Blanke C.D. Van den Abbeele A.D. Eisenberg B. Roberts P.J. Heinrich M.C. Tuveson D.A. Singer S. Janicek M. Fletcher J.A. Silverman S.G. Silberman S.L. Capdeville R. Kiese B. Peng B. Dimitrijevic S. Druker B.J. Corless C. Fletcher C.D. Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.N Engl J Med. 2002; 347: 472-480Crossref PubMed Scopus (3693) Google ScholarAnother method that has proven useful has been the targeting of normal tissues by imaging agents to highlight pathology by providing a “negative” contrast (the pathology does not take up the agent but the normal surrounding tissue does). This strategy can overcome problem of tumoral genetic diversity that limits imaging targets in individual cases. The approach may be most useful in highlighting metastases to solid organs and lymph nodes where detection is based on loss of normal function of resident macrophages due to their replacement by tumor cells. One example is IV injection of iron oxide nanoparticles, which slowly extravasate into the extracellular space and are cleared by lymphatic drainage. This method has markedly improved the detection of lymph node metastases in a number of genitourinary cancers,3Harisinghani M.G. Barentsz J. Hahn P.F. Deserno W.M. Tabatabaei S. van de Kaa C.H. de la Rosette J. Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer.N Engl J Med. 2003; 348: 2491-2499Crossref PubMed Scopus (1725) Google Scholar and preliminary data suggest improvement in detection of lymph node metastases of other diverse primary cancers. Applications to staging of esophageal, pancreatic, and colorectal cancer are expected.Another common molecular imaging target is based on the detection of angiogenesis typical of neoplastic disease. As in other basic processes of disease, imaging of angiogenesis may be performed by targeting overexpression of specific molecules, such as vascular endothelial growth factor receptor or specific integrin expression. Alternatively imaging can target the angiogenesis phenotypes such as vascular volume fraction (VVF) and vessel permeability.4McDonald D.M. Choyke P.L. Imaging of angiogenesis: from microscope to clinic.Nat Med. 2003; 9: 713-725Crossref PubMed Scopus (839) Google Scholar Dynamic imaging of clinically approved nonspecific small molecule contrast agents allows the determination of related parameters by MRI. Alternatively, agents with a long blood half life, such as the iron oxide nanoparticles or gadolinium-based macromolecules allow the determination of VVF across multiple sites using MRI. Such techniques for evaluation of anti-angiogenic therapy for metastatic sites may increase in importance for clinical trials assessing intermediate effects of such therapy in colorectal cancer.5Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. Ferrara N. Fyfe G. Rogers B. Ross R. Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9094) Google Scholar Current, mortality endpoints and anatomic size criteria may be augmented by quantitative noninvasive analysis of VVF, resulting in an earlier assessment of response. Similarly, fluorescent blood pool agents may allow determination of VVF of primary colorectal cancers by endoscopic imaging methods.Many of the approaches described reflect molecular imaging methods designed to determine whole body extent of disease or markers to assess therapeutic efficacy. An unmet clinical need is the development of techniques to improve on the early detection of primary lesions. Back-to-back colonoscopies have demonstrated a colonic polyp miss rate of approximately 22%.6van Rijn J.C. Reitsma J.B. Stoker J. Bossuyt P.M. van Deventer S.J. Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review.Am J Gastroenterol. 2006; 101: 343-350Crossref PubMed Scopus (1022) Google Scholar A number of diverse approaches are undergoing evaluation to improve on this, both for general screening populations and for screening patients at higher risk. Current clinical practice does not typically employ the use of optical contrast agents. However, exogenously administered agents can markedly extend the range and types of image contrast that can be obtained from tissues. A particularly promising approach has been the development of a new class of optical imaging agents that change their fluorescent properties after target interaction, a so-called molecular beacon.7Weissleder R. Tung C.H. Mahmood U. Bogdanov Jr, A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.Nat Biotechnol. 1999; 17: 375-378Crossref PubMed Scopus (1465) Google Scholar As shown in Figure 1, these “smart probes” are initially optically silent, secondary to fluorochrome-fluorochrome quenching (ie, when the 2 fluorochromes are in close proximity on a backbone molecule, they each absorb the others light), but become brightly fluorescent in areas of disease. The specific target is increased protease expression present in neoplastic colon polyps, which mediate enzymatic cleavage of fluorochromes from a delivery backbone, resulting in signal amplification of up to several hundred-fold. This results in very high signal:noise imaging of protease overexpression and allows rapid screening of a large surface area. This approach has shown particular promise in preclinical studies due to the protease overexpression seen in experimental intestinal adenomas and adenocarcinomas.8Marten K. Bremer C. Khazaie K. Sameni M. Sloane B. Tung C.H. Weissleder R. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice.Gastroenterology. 2002; 122: 406-414Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Moreover, cathepsin B, a major contributor to cleavage of the prototypical imaging probe in this class, has been demonstrated to be up-regulated in early human colorectal adenomas as well as carcinomas.9Emmert-Buck M.R. Roth M.J. Zhuang Z. Campo E. Rozhin J. Sloane B.F. Liotta L.A. Stetler-Stevenson W.G. Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples.Am J Pathol. 1994; 145: 1285-1290PubMed Google Scholar, 10Herszenyi L. Plebani M. Carraro P. De Paoli M. Roveroni G. Cardin R. Tulassay Z. Naccarato R. Farinati F. The role of cysteine and serine proteases in colorectal carcinoma.Cancer. 1999; 86: 1135-1142Crossref PubMed Scopus (95) Google ScholarThe protease-selective probes fluoresce in the near infrared (NIR) region of the spectrum, at slightly longer wavelengths than visible light. This has several advantages: tissue autofluorescence is decreased in this region, helping to ensure imaged signal reflects disease specific enzymatic activity and not intrinsic tissue fluorescence,11Funovics M.A. Weissleder R. Mahmood U. Catheter-based in vivo imaging of enzyme activity and gene expression: feasibility study in mice.Radiology. 2004; 231: 659-666Crossref PubMed Scopus (64) Google Scholar the entire visible spectrum (ie, the white light endoscopic image) and the protease-reporting NIR spectrum can be acquired simultaneously, thereby eliminating the need for complex optical splitting approaches and allowing direct anatomic correlation with fluorescence reporting. The entire color spectrum is preserved, so that the endoscopist retains the use of color cues when evaluating tissue and the fluorescence reporting acts as an adjunct to essentially standard colonoscopy. Newer techniques under development potentially allow realtime quantitation of fluorescence intensity. As seen in Figure 2, two anatomically inapparent lesions are equally fluorescent when the endoscope tip is closer or farther from the targets. The improved target to background ratio in the fluorescence channel compared to the white light channel helps to guide directed sampling. Preclinical endoscopic systems have further evaluated the ability to assess multiple targets simultaneously using different NIR wavelength fluorochromes to report on distinct activities.12Funovics M.A. Alencar H. Montet X. Weissleder R. Mahmood U. Simultaneous fluorescence imaging of protease expression and vascularity during murine colonoscopy for colonic lesion characterization.Gastrointest Endosc. 2006; 64: 589-597Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The imaging agents and endoscopic systems are clinically translatable, and clinical trials are expected to begin for colonoscopy within the next year or two.Figure 2Frames from a murine colonoscopy demonstrates 2 colonic adenocarcinomas that result in minimal anatomic distortion of the lumen (left), but which are readily apparent on simultaneously acquired false-colored NIR images (right).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Molecular imaging is adding information to traditional imaging techniques both for gastroenterologists and radiologists, and will help to provide clinicians with the tools to better detect lesions at an earlier stage, find additional lesions that may be anatomically inapparent, and assess therapeutic efficacy sooner than traditional anatomic imaging. Imaging of gastrointestinal processes may be divided into 2 broad categories. Direct visualization by optical means has typically been performed by gastroenterologists using minimally invasive endoscopic approaches. Whole body cross-sectional imaging, such as magnetic resonance imaging (MRI) and computed tomography (CT), usually fall into traditional radiologic interpretation. Modalities such as ultrasound are split between the 2 areas, depending on the scope of observation and degree of intervention involved. Historically, both categories of imaging have detected pathology based on anatomic changes. Optical imaging intrinsically provides very high spatial resolution, and visualized anatomic changes can range from subtle alterations in mucosal patterns to gross luminal narrowings. Likewise, pathology detected by MRI or CT scanning often relies on anatomic distortion of normal structures augmented in visualization by perfusion differences highlighted using nonspecific small molecules such as iodinated contrast agents and gadolinium. Over the last few years, a major paradigm shift has been taking place in imaging, both in optical and cross-sectional modalities. Molecular imaging, the detection, spatial localization, and quantitation of specific molecular targets and events that form the basis of various pathologies, has expanded from preclinical imaging to clinical trials and in some cases to routine clinical use. Numerous targets, ranging from cell-surface receptors, tyrosine kinases, apoptosis markers, proliferation markers, proteolytic enzymes, extracellular matrix targets, and glucose metabolism levels, among many others, have been evaluated for noninvasive imaging.1Kelloff G.J. Krohn K.A. Larson S.M. Weissleder R. Mankoff D.A. Hoffman J.M. Link J.M. Guyton K.Z. Eckelman W.C. Scher H.I. O’Shaughnessy J. Cheson B.D. Sigman C.C. Tatum J.L. Mills G.Q. Sullivan D.C. Woodcock J. The progress and promise of molecular imaging probes in oncologic drug development.Clin Cancer Res. 2005; 11: 7967-7985Crossref PubMed Scopus (207) Google Scholar A well-known major early success in oncology has been improved detection of cancers including many gastrointestinal cancers through the imaging of glucose metabolism using 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Use of molecularly targeted therapy has increased in cancer treatments; given the specificity of treatment and nonuniversal expression of targets, early evaluation of efficacy has been a driving focus to differentiate responders from nonresponders. Different possibilities exist for such assessment: imaging of drug binding using competitive inhibition of fluorescently tagged, MRI labeled, or radiolabeled agents, has worked in preclinical cases, particularly when the targets are cell-surface receptors. Although this approach holds great promise for a number of important targets, it requires a new imaging drug for each different therapeutic drug target. There is an assumption that drug efficacy (eg, effect cell death rate or proliferation) is correlated in the individual case with drug-to-target binding saturation. An alternative approach is the imaging of changes that are common downstream pathways for multiple therapeutic targets. As an example, long-term response to the tyrosine kinase inhibitor Gleevec for gastrointestinal stromal tumors could be visualized using FDG PET imaging in some cases as soon as 24 hours after the initiation of therapy.2Demetri G.D. von Mehren M. Blanke C.D. Van den Abbeele A.D. Eisenberg B. Roberts P.J. Heinrich M.C. Tuveson D.A. Singer S. Janicek M. Fletcher J.A. Silverman S.G. Silberman S.L. Capdeville R. Kiese B. Peng B. Dimitrijevic S. Druker B.J. Corless C. Fletcher C.D. Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.N Engl J Med. 2002; 347: 472-480Crossref PubMed Scopus (3693) Google Scholar Another method that has proven useful has been the targeting of normal tissues by imaging agents to highlight pathology by providing a “negative” contrast (the pathology does not take up the agent but the normal surrounding tissue does). This strategy can overcome problem of tumoral genetic diversity that limits imaging targets in individual cases. The approach may be most useful in highlighting metastases to solid organs and lymph nodes where detection is based on loss of normal function of resident macrophages due to their replacement by tumor cells. One example is IV injection of iron oxide nanoparticles, which slowly extravasate into the extracellular space and are cleared by lymphatic drainage. This method has markedly improved the detection of lymph node metastases in a number of genitourinary cancers,3Harisinghani M.G. Barentsz J. Hahn P.F. Deserno W.M. Tabatabaei S. van de Kaa C.H. de la Rosette J. Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer.N Engl J Med. 2003; 348: 2491-2499Crossref PubMed Scopus (1725) Google Scholar and preliminary data suggest improvement in detection of lymph node metastases of other diverse primary cancers. Applications to staging of esophageal, pancreatic, and colorectal cancer are expected. Another common molecular imaging target is based on the detection of angiogenesis typical of neoplastic disease. As in other basic processes of disease, imaging of angiogenesis may be performed by targeting overexpression of specific molecules, such as vascular endothelial growth factor receptor or specific integrin expression. Alternatively imaging can target the angiogenesis phenotypes such as vascular volume fraction (VVF) and vessel permeability.4McDonald D.M. Choyke P.L. Imaging of angiogenesis: from microscope to clinic.Nat Med. 2003; 9: 713-725Crossref PubMed Scopus (839) Google Scholar Dynamic imaging of clinically approved nonspecific small molecule contrast agents allows the determination of related parameters by MRI. Alternatively, agents with a long blood half life, such as the iron oxide nanoparticles or gadolinium-based macromolecules allow the determination of VVF across multiple sites using MRI. Such techniques for evaluation of anti-angiogenic therapy for metastatic sites may increase in importance for clinical trials assessing intermediate effects of such therapy in colorectal cancer.5Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. Ferrara N. Fyfe G. Rogers B. Ross R. Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9094) Google Scholar Current, mortality endpoints and anatomic size criteria may be augmented by quantitative noninvasive analysis of VVF, resulting in an earlier assessment of response. Similarly, fluorescent blood pool agents may allow determination of VVF of primary colorectal cancers by endoscopic imaging methods. Many of the approaches described reflect molecular imaging methods designed to determine whole body extent of disease or markers to assess therapeutic efficacy. An unmet clinical need is the development of techniques to improve on the early detection of primary lesions. Back-to-back colonoscopies have demonstrated a colonic polyp miss rate of approximately 22%.6van Rijn J.C. Reitsma J.B. Stoker J. Bossuyt P.M. van Deventer S.J. Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review.Am J Gastroenterol. 2006; 101: 343-350Crossref PubMed Scopus (1022) Google Scholar A number of diverse approaches are undergoing evaluation to improve on this, both for general screening populations and for screening patients at higher risk. Current clinical practice does not typically employ the use of optical contrast agents. However, exogenously administered agents can markedly extend the range and types of image contrast that can be obtained from tissues. A particularly promising approach has been the development of a new class of optical imaging agents that change their fluorescent properties after target interaction, a so-called molecular beacon.7Weissleder R. Tung C.H. Mahmood U. Bogdanov Jr, A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.Nat Biotechnol. 1999; 17: 375-378Crossref PubMed Scopus (1465) Google Scholar As shown in Figure 1, these “smart probes” are initially optically silent, secondary to fluorochrome-fluorochrome quenching (ie, when the 2 fluorochromes are in close proximity on a backbone molecule, they each absorb the others light), but become brightly fluorescent in areas of disease. The specific target is increased protease expression present in neoplastic colon polyps, which mediate enzymatic cleavage of fluorochromes from a delivery backbone, resulting in signal amplification of up to several hundred-fold. This results in very high signal:noise imaging of protease overexpression and allows rapid screening of a large surface area. This approach has shown particular promise in preclinical studies due to the protease overexpression seen in experimental intestinal adenomas and adenocarcinomas.8Marten K. Bremer C. Khazaie K. Sameni M. Sloane B. Tung C.H. Weissleder R. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice.Gastroenterology. 2002; 122: 406-414Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Moreover, cathepsin B, a major contributor to cleavage of the prototypical imaging probe in this class, has been demonstrated to be up-regulated in early human colorectal adenomas as well as carcinomas.9Emmert-Buck M.R. Roth M.J. Zhuang Z. Campo E. Rozhin J. Sloane B.F. Liotta L.A. Stetler-Stevenson W.G. Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples.Am J Pathol. 1994; 145: 1285-1290PubMed Google Scholar, 10Herszenyi L. Plebani M. Carraro P. De Paoli M. Roveroni G. Cardin R. Tulassay Z. Naccarato R. Farinati F. The role of cysteine and serine proteases in colorectal carcinoma.Cancer. 1999; 86: 1135-1142Crossref PubMed Scopus (95) Google Scholar The protease-selective probes fluoresce in the near infrared (NIR) region of the spectrum, at slightly longer wavelengths than visible light. This has several advantages: tissue autofluorescence is decreased in this region, helping to ensure imaged signal reflects disease specific enzymatic activity and not intrinsic tissue fluorescence,11Funovics M.A. Weissleder R. Mahmood U. Catheter-based in vivo imaging of enzyme activity and gene expression: feasibility study in mice.Radiology. 2004; 231: 659-666Crossref PubMed Scopus (64) Google Scholar the entire visible spectrum (ie, the white light endoscopic image) and the protease-reporting NIR spectrum can be acquired simultaneously, thereby eliminating the need for complex optical splitting approaches and allowing direct anatomic correlation with fluorescence reporting. The entire color spectrum is preserved, so that the endoscopist retains the use of color cues when evaluating tissue and the fluorescence reporting acts as an adjunct to essentially standard colonoscopy. Newer techniques under development potentially allow realtime quantitation of fluorescence intensity. As seen in Figure 2, two anatomically inapparent lesions are equally fluorescent when the endoscope tip is closer or farther from the targets. The improved target to background ratio in the fluorescence channel compared to the white light channel helps to guide directed sampling. Preclinical endoscopic systems have further evaluated the ability to assess multiple targets simultaneously using different NIR wavelength fluorochromes to report on distinct activities.12Funovics M.A. Alencar H. Montet X. Weissleder R. Mahmood U. Simultaneous fluorescence imaging of protease expression and vascularity during murine colonoscopy for colonic lesion characterization.Gastrointest Endosc. 2006; 64: 589-597Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The imaging agents and endoscopic systems are clinically translatable, and clinical trials are expected to begin for colonoscopy within the next year or two. Molecular imaging is adding information to traditional imaging techniques both for gastroenterologists and radiologists, and will help to provide clinicians with the tools to better detect lesions at an earlier stage, find additional lesions that may be anatomically inapparent, and assess therapeutic efficacy sooner than traditional anatomic imaging." @default.
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• W1987524324 title "Molecular Imaging in Gastrointestinal Disease" @default.
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