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      1. Author :
        Missbach-Guentner, J.; Hunia, J.; Alves, F.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Int J Dev Biol
      6. Products :
      7. Volume :
        55
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Angiogenesis Inhibitors/therapeutic use; Animals; Diagnostic Imaging/*methods; Fluorescence; Humans; Luminescence/diagnostic use; Magnetic Resonance Angiography/methods; Magnetic Resonance Imaging/methods; Microscopy/methods; Neoplasms/*blood supply/therapy; *Neovascularization, Pathologic/pathology/ultrasonography; Positron-Emission Tomography/methods; Tomography/methods; Tomography, Emission-Computed, Single-Photon/methods; Tomography, X-Ray Computed/methods; X-Ray Microtomography/methods
      12. Abstract :
        Significant advances have been made in understanding the role of tumor angiogenesis and its influence on tumor progression in cancer. Based on this knowledge, a series of inhibitors of angiogenesis have been developed and evaluated in preclinical and clinical trials. Since detailed information of tumor progression in response to therapy is important to assess the efficacy of anti-tumor treatment in vivo, noninvasive imaging techniques emerge more and more as important tools to monitor alterations in tumor growth and vessel recruitment, as well as metastatic spread over time. So far, remarkable efforts have been made to improve the technical capability of these imaging modalities based on better resolution, as well as to implement multimodal approaches combining molecular with anatomical information. Advanced imaging techniques not only allow the detection and monitoring of tumor development, but also facilitate a broad understanding of the cellular and molecular events that propagate tumor angiogenesis, as well as those occurring in response to therapy. This review provides an overview of different imaging techniques in preclinical settings of oncological research and discusses their potential impact on clinical translation. Imaging modalities will be presented that have been implemented to address key biological issues by exploring tumor angiogenic processes and evaluating antiangiogenic therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21858774
      14. Call Number :
        PKI @ kd.modi @ 32
      15. Serial :
        10373
      1. Author :
        Meincke, M.; Tiwari, S.; Hattermann, K.; Kalthoff, H.; Mentlein, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Clin Exp Metastasis
      6. Products :
      7. Volume :
        28
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Breast Neoplasms/metabolism/*pathology; Cattle; Chemokine CXCL12/metabolism; Female; Fluorescent Dyes/diagnostic use; Glioma/metabolism/*pathology; Humans; Image Processing, Computer-Assisted; Mice; Mice, Nude; Receptors, CXCR/*metabolism; Receptors, CXCR4/*metabolism; Serum Albumin, Bovine/metabolism; Spectroscopy, Near-Infrared; Tumor Cells, Cultured
      12. Abstract :
        The chemokine CXCL12/SDF-1 and its receptors CXCR4 and CXCR7 play a major role in tumor invasion, proliferation and metastasis. Since both receptors are overexpressed on distinct tumor cells and on the tumor vasculature, we evaluated their potential as targets for detection of cancers by molecular imaging. We synthesized conjugates of CXCL12 and the near-infrared (NIR) fluorescent dye IRDye((R))800CW, tested their selectivity, sensitivity and biological activity in vitro and their feasibility to visualize tumors in vivo. Purified CXCL12-conjugates detected in vitro as low as 500 A764 human glioma cells or MCF-7 breast cancer cells that express CXCR7 alone or together with CXCR4. Binding was time- and concentration-dependent, and the label could be competitively displaced by the native peptide. Control conjugates with bovine serum albumin or lactalbumin failed to label the cells. In mice, the conjugate distributed rapidly. After 1-92 h, subcutaneous tumors of human MCF-7 and A764 cells in immunodeficient mice were detected with high sensitivity. Background was observed in particular in liver within the first 24 h, but also skull and hind limbs yielded some background. Overall, fluorescent CXCL12-conjugates are sensitive and selective probes to detect solid and metastatic tumors by targeting tumor cells and tumor vasculature.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21735100
      14. Call Number :
        PKI @ kd.modi @ 13
      15. Serial :
        10372
      1. Author :
        Mathew, B.; Jacobson, J. R.; Berdyshev, E.; Huang, Y.; Sun, X.; Zhao, Y.; Gerhold, L. M.; Siegler, J.; Evenoski, C.; Wang, T.; Zhou, T.; Zaidi, R.; Moreno-Vinasco, L.; Bittman, R.; Chen, C. T.; LaRiviere, P. J.; Sammani, S.; Lussier, Y. A.; Dudek, S. M.; Natarajan, V.; Weichselbaum, R. R.; Garcia, J. G.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Faseb J
      6. Products :
      7. Volume :
        25
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Bronchoalveolar Lavage Fluid/chemistry; Ceramides/metabolism; Female; Gene Deletion; Gene Expression Regulation/physiology; Lung/*radiation effects; Lysophospholipids/*chemistry/*pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; *Radiation Injuries, Experimental; Receptors, Lysosphingolipid/genetics/metabolism; Sphingolipids/*metabolism; Sphingosine/*analogs & derivatives/chemistry/pharmacology
      12. Abstract :
        Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1(-/-)) or with reduced expression of S1P receptors (S1PR1(+/-), S1PR2(-/-), and S1PR3(-/-)) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2x/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2x/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21712494
      14. Call Number :
        PKI @ kd.modi @ 18
      15. Serial :
        10371
      1. Author :
        Leuschner, F.; Rauch, P. J.; Ueno, T.; Gorbatov, R.; Marinelli, B.; Lee, W. W.; Dutta, P.; Wei, Y.; Robbins, C.; Iwamoto, Y.; Sena, B.; Chudnovskiy, A.; Panizzi, P.; Keliher, E.; Higgins, J. M.; Libby, P.; Moskowitz, M. A.; Pittet, M. J.; Swirski, F. K.; Weissleder, R.; Nahrendorf, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Exp Med
      6. Products :
      7. Volume :
        209
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Adoptive Transfer; Animals; Biological Markers/metabolism; Cell Death/genetics; Disease Models, Animal; Female; *Hematopoiesis, Extramedullary; Inflammation/immunology/metabolism; Interleukin-1beta/genetics/metabolism; Kinetics; Macrophages/cytology/*physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Monocytes/*cytology/*physiology; Myeloid Cells/metabolism; Myocardial Infarction/immunology/pathology/*physiopathology; Signal Transduction; Spleen/physiology; Stroke/immunology/metabolism; Wound Healing/physiology
      12. Abstract :
        Monocytes (Mo) and macrophages (MPhi) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MPhi and their effector functions without compromising innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MPhi in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1beta; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MPhi exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MPhi flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22213805
      14. Call Number :
        PKI @ kd.modi @ 27
      15. Serial :
        10370
      1. Author :
        Keereweer, S.; Sterenborg, H. J.; Kerrebijn, J. D.; Van Driel, P. B.; de Jong, R. J.; Lowik, C. W.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Head Neck
      6. Products :
      7. Volume :
        34
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense
      12. Abstract :
        A key aspect for the postoperative prognosis of patients with head and neck cancer is complete tumor resection. In current practice, the intraoperative assessment of the tumor-free margin is dependent on visual appearance and palpation of the tumor. Optical imaging has the potential of traversing the gap between radiology and surgery by providing real-time visualization of the tumor, thereby allowing for image-guided surgery. The use of the near-infrared light spectrum offers 2 essential advantages: increased tissue penetration of light and an increased signal-to-background ratio of contrast agents. In this review, the current practice and limitations of image-guided surgery by optical imaging using intrinsic fluorescence or contrast agents are described. Furthermore, we provide an overview of the various molecular contrast agents targeting specific hallmarks of cancer that have been used in other fields of oncologic surgery, and we describe perspectives on its future use in head and neck cancer surgery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21284051
      14. Call Number :
        PKI @ kd.modi @ 31
      15. Serial :
        10369
      1. Author :
        Keereweer, S.; Mol, I. M.; Kerrebijn, J. D.; Van Driel, P. B.; Xie, B.; Baatenburg de Jong, R. J.; Vahrmeijer, A. L.; Lowik, C. W.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Surg Oncol
      6. Products :
      7. Volume :
        105
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Carcinoma, Squamous Cell/*pathology/surgery; Fluorescent Dyes/*diagnostic use; Humans; Integrin alphaVbeta3/*metabolism; Mice; Mice, Inbred BALB C; Mouth Neoplasms/*pathology/surgery; Spectroscopy, Near-Infrared; *Surgery, Computer-Assisted
      12. Abstract :
        BACKGROUND AND OBJECTIVES: Near-infrared (NIR) fluorescence optical imaging is a promising technique to assess the tumor margins during cancer surgery. This technique requires targeting by specific fluorescence agents to differentiate tumor from normal surrounding tissue. We assessed the feasibility of cancer detection using NIR fluorescence agents that target either alphavbeta3 integrins or the enhanced permeability and retention (EPR) effect in an orthotopic mouse model of oral cancer. METHODS: Binding of the integrin-targeted agent to tumor cells was assessed in vitro. Oral cancer was induced in 6 BALB/c nu/nu mice by submucosal inoculation of human OSC19-luc cells into the tongue. Tumor growth was followed with bioluminescence imaging. A combination of agents targeting integrins or EPR effect was injected followed by fluorescence imaging in vivo and ex vivo after resection of the tongues. RESULTS: Oral cancer was clearly demarcated in vitro; in vivo; and on histological analysis with sufficient tumor-to-background ratios of the contrast agents. CONCLUSION: This study demonstrates the feasibility of optical imaging of oral squamous cell carcinoma based on targeting of alphavbeta3 integrins and the EPR effect. Once these NIR fluorescence agents become available for clinical testing, optical image-guided surgery could reduce residual disease after oral cancer surgery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21952950
      14. Call Number :
        PKI @ kd.modi @ 28
      15. Serial :
        10368
      1. Author :
        Keereweer, S.; Kerrebijn, J. D.; van Driel, P. B.; Xie, B.; Kaijzel, E. L.; Snoeks, T. J.; Que, I.; Hutteman, M.; van der Vorst, J. R.; Mieog, J. S.; Vahrmeijer, A. L.; van de Velde, C. J.; Baatenburg de Jong, R. J.; Lowik, C. W.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Mol Imaging Biol
      6. Products :
      7. Volume :
        13
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense,Animals; Fluorescent Dyes/metabolism; Humans; Nanoparticles/diagnostic use; Optics and Photonics/*methods; Surgery, Computer-Assisted/*methods
      12. Abstract :
        In cancer surgery, intra-operative assessment of the tumor-free margin, which is critical for the prognosis of the patient, relies on the visual appearance and palpation of the tumor. Optical imaging techniques provide real-time visualization of the tumor, warranting intra-operative image-guided surgery. Within this field, imaging in the near-infrared light spectrum offers two essential advantages: increased tissue penetration of light and an increased signal-to-background-ratio of contrast agents. In this article, we review the various techniques, contrast agents, and camera systems that are currently used for image-guided surgery. Furthermore, we provide an overview of the wide range of molecular contrast agents targeting specific hallmarks of cancer and we describe perspectives on its future use in cancer surgery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20617389
      14. Call Number :
        PKI @ kd.modi @ 4
      15. Serial :
        10367
      1. Author :
        Hutteman, M.; Mieog, J. S.; van der Vorst, J. R.; Dijkstra, J.; Kuppen, P. J.; van der Laan, A. M.; Tanke, H. J.; Kaijzel, E. L.; Que, I.; van de Velde, C. J.; Lowik, C. W.; Vahrmeijer, A. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Eur J Surg Oncol
      6. Products :
      7. Volume :
        37
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Colorectal Neoplasms/*metabolism/*secondary; Disease Models, Animal; Image Processing, Computer-Assisted; Integrin alphaVbeta3/*metabolism; Intraoperative Period; Liver Neoplasms/*pathology; Male; Neoplasm Transplantation; Rats; Spectroscopy, Near-Infrared/*methods; Tumor Cells, Cultured
      12. Abstract :
        AIM: Near-infrared (NIR) fluorescence optical imaging is a promising technique to assess the extent of colorectal metastases during curative-intended surgery. However, NIR fluorescence imaging of liver metastases is highly challenging due to hepatic uptake and clearance of many fluorescent dyes. In the current study, the biodistribution and the ability to demarcate liver and peritoneal metastases were assessed during surgery in a syngeneic rat model of colorectal cancer using an integrin alpha(v)beta(3)-directed NIR fluorescence probe. METHODS: Liver tumors and peritoneal metastases were induced in 7 male WAG/Rij rats by subcapsular inoculation of 0.5 x 10(6) CC531 colorectal cancer rat cells into three distinct liver lobes. Intraoperative and ex vivo fluorescence measurements were performed 24 (N = 3 rats, 7 tumors) and 48 h (N = 4 rats, 9 tumors) after intravenous administration of the integrin alpha(v)beta(3)-directed NIR fluorescence probe. RESULTS: Colorectal metastases had a minimal two-fold higher NIR fluorescence signal than healthy liver tissue and other abdominal organs (p < 0.001). The tumor-to-background ratio was independent of time of imaging (24 h vs. 48 h post-injection; p = 0.31), which facilitates flexible operation planning in future clinical applications. Total fluorescence intensity was significantly correlated with the size of metastases (R(2) = 0.92 for the 24 h group, R(2) = 0.96 for the 48 h group). CONCLUSION: These results demonstrate that colorectal intra-abdominal metastases can be clearly demarcated during surgery using an integrin alpha(v)beta(3) targeting NIR fluorescence probe. Translating these findings to the clinic will have an excellent potential to substantially improve the quality of cancer surgery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21215590
      14. Call Number :
        PKI @ kd.modi @ 23
      15. Serial :
        10366
      1. Author :
        Herzog, E.; Taruttis, A.; Beziere, N.; Lutich, A. A.; Razansky, D.; Ntziachristos, V.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Radiology
      6. Products :
      7. Volume :
        263
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Adenocarcinoma/*diagnosis; Animals; Colonic Neoplasms/*diagnosis; Contrast Media/pharmacokinetics; Disease Models, Animal; Female; Fluorescent Dyes/pharmacokinetics; Gold/pharmacokinetics; Image Processing, Computer-Assisted; Indocyanine Green/pharmacokinetics; Mammary Neoplasms, Experimental/*diagnosis; Mice; Nanoparticles; Spectrum Analysis/methods; Tomography, Optical/*methods
      12. Abstract :
        PURPOSE: To investigate whether multispectral optoacoustic tomography (MSOT) can reveal the heterogeneous distributions of exogenous agents of interest and vascular characteristics through tumors of several millimeters in diameter in vivo. MATERIALS AND METHODS: Procedures involving animals were approved by the government of Upper Bavaria. Imaging of subcutaneous tumors in mice was performed by using an experimental MSOT setup that produces transverse images at 10 frames per second with an in-plane resolution of approximately 150 mum. To study dynamic contrast enhancement, three mice with 4T1 tumors were imaged before and immediately, 20 minutes, 4 hours, and 24 hours after systemic injection of indocyanine green (ICG). Epifluorescence imaging was used for comparison. MSOT of a targeted fluorescent agent (6 hours after injection) and hemoglobin oxygenation was performed simultaneously (4T1 tumors: n = 3). Epifluorescence of cryosections served as validation. The accumulation owing to enhanced permeability and retention in tumors (4T1 tumors: n = 4, HT29 tumors: n = 3, A2780 tumors: n = 2) was evaluated with use of long-circulating gold nanorods (before and immediately, 1 hour, 5 hours, and 24 hours after injection). Dark-field microscopy was used for validation. RESULTS: Dynamic contrast enhancement with ICG was possible. MSOT, in contrast to epifluorescence imaging, showed a heterogeneous intratumoral agent distribution. Simultaneous imaging of a targeted fluorescent agent and oxy- and deoxyhemoglobin gave functional information about tumor vasculature in addition to the related agent uptake. The accumulation of gold nanorods in tumors seen at MSOT over time also showed heterogeneous uptake. CONCLUSION: MSOT enables live high-spatial-resolution observations through tumors, producing images of distributions of fluorochromes and nanoparticles as well as tumor vasculature.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22517960
      14. Call Number :
        PKI @ kd.modi @ 12
      15. Serial :
        10365
      1. Author :
        He, T.; Xue, Z.; Lu, K.; Valdivia y Alvarado, M.; Wong, K. K.; Xie, W.; Wong, S. T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Comput Med Imaging Graph
      6. Products :
      7. Volume :
        36
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        N/A
      12. Abstract :
        BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States, with more than half of the cancers are located peripherally. Computed tomography (CT) has been utilized in the last decade to detect early peripheral lung cancer. However, due to the high false diagnosis rate of CT, further biopsy is often necessary to confirm cancerous cases. This renders intervention for peripheral lung nodules (especially for small peripheral lung cancer) difficult and time-consuming, and it is highly desirable to develop new, on-the-spot earlier lung cancer diagnosis and treatment strategies. PURPOSE: The objective of this study is to develop a minimally invasive multimodality image-guided (MIMIG) intervention system to detect lesions, confirm small peripheral lung cancer, and potentially guide on-the-spot treatment at an early stage. Accurate image guidance and real-time optical imaging of nodules are thus the key techniques to be explored in this work. METHODS: The MIMIG system uses CT images and electromagnetic (EM) tracking to help interventional radiologists target the lesion efficiently. After targeting the lesion, a fiber-optic probe coupled with optical molecular imaging contrast agents is used to confirm the existence of cancerous tissues on-site at microscopic resolution. Using the software developed, pulmonary vessels, airways, and nodules can be segmented and visualized for surgical planning; the segmented results are then transformed onto the intra-procedural CT for interventional guidance using EM tracking. Endomicroscopy through a fiber-optic probe is then performed to visualize tumor tissues. Experiments using IntegriSense 680 fluorescent contrast agent labeling alphavbeta3 integrin were carried out for rabbit lung cancer models. Confirmed cancers could then be treated on-the-spot using radio-frequency ablation (RFA). RESULTS: The prototype system is evaluated using the rabbit VX2 lung cancer model to evaluate the targeting accuracy, guidance efficiency, and performance of molecular imaging. Using this system, we achieved an average targeting accuracy of 3.04 mm, and the IntegriSense signals within the VX2 tumors were found to be at least two-fold higher than those of normal tissues. The results demonstrate great potential for applying the system in human trials in the future if an optical molecular imaging agent is approved by the Food and Drug Administration (FDA). CONCLUSIONS: The MIMIG system was developed for on-the-spot interventional diagnosis of peripheral lung tumors by combining image-guidance and molecular imaging. The system can be potentially applied to human trials on diagnosing and treating earlier stage lung cancer. For current clinical applications, where a biopsy is unavoidable, the MIMIG system without contrast agents could be used for biopsy guidance to improve the accuracy and efficiency.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22483054
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10364
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