1
|
Zhang H, Zheng M, Cai Y, Kamara S, Chen J, Zhu S, Zhang L. Novel affibody molecules targeting the AXL extracellular structural domain for molecular imaging and targeted therapy of gastric cancer. Gastric Cancer 2025; 28:174-186. [PMID: 39644434 PMCID: PMC11842530 DOI: 10.1007/s10120-024-01568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 11/10/2024] [Indexed: 12/09/2024]
Abstract
Gastric cancer (GC) has a poor prognosis and high mortality because it is often diagnosed at an advanced stage. Targeted therapeutics are considered an important class for advanced GC treatment. However, the fewer effective therapeutic targets and the poor coverage of the GC population limit the use of GC targeted therapies. Recent research suggests that the AXL receptor tyrosine kinase (AXL) plays an vital role in the survival and proliferation of GC cells, and blocking AXL pathway may be an effective strategy for targeted therapies. On the other hand, the affibody molecule, with its small size and faster penetration of tissue, has great potential in tumor imaging and targeted therapy. In this study, we report the novel AXL-binding affibody molecules (ZAXL:239) screened by a phage-displayed peptide library. The ZAXL:239 could specifically bind and interact with AXL proteins in vitro and in vivo, as demonstrated by surface plasmon resonance, co-immunoprecipitation, immuno-fluorescence co-localization, and near infrared fluorescent imaging. In addition, ZAXL:239 affibody molecules could significantly inhibit the proliferative activity and induce apoptosis of AXL-positive GC cells by decreasing the phosphorylation levels of the PI3K/AKT1 and MEK/ERK pathway, leading to the suppression of the downstream nuclear protein c-myc. Moreover, ZAXL:239 was found to have significant anti-tumor effects in AXL-positive GC transplantation tumor nude mouse models. In brief, we provide strong evidence that the novel ZAXL:239 affibody molecules have great potential as a potent tumor-specific molecular imaging and targeted therapeutic agents for GC.
Collapse
Affiliation(s)
- HuiHui Zhang
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Maolin Zheng
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - YiQi Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Saidu Kamara
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Jun Chen
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Shanli Zhu
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Lifang Zhang
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
| |
Collapse
|
2
|
Atreya R, Rath T, Neurath MF. Molecular Imaging: The New Frontier for Endoscopic Diagnosis and Personalization in Inflammatory Bowel Disease. Gastrointest Endosc Clin N Am 2025; 35:255-263. [PMID: 39510691 DOI: 10.1016/j.giec.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Molecular endoscopy in inflammatory bowel disease (IBD) has made the translation from preclinical studies to clinical trials. The so far performed in vivo studies, using fluorescent antibodies, have addressed areas of heightened clinical interest with unmet needs. These include the distribution of targeted therapies within the mucosa, which could elucidate the most fitting dosing for the individual patient, the mode of action of currently used treatments, and subsequently also the prediction of therapeutic response. Altogether, molecular endoscopy might enable us to base individualized therapeutic decisions on preceded in vivo molecular analysis to optimize treatment in IBD.
Collapse
Affiliation(s)
- Raja Atreya
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen 91054, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
| | - Timo Rath
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen 91054, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Markus Friedrich Neurath
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen 91054, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| |
Collapse
|
3
|
Atreya R. Glowing insights: tracking vedolizumab in the mucosa of patients with IBD via molecular endoscopy. Gut 2024; 73:1406-1408. [PMID: 38821860 DOI: 10.1136/gutjnl-2024-332503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 05/22/2024] [Indexed: 06/02/2024]
Affiliation(s)
- Raja Atreya
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| |
Collapse
|
4
|
Xiao R, Zheng F, Kang K, Xiao L, Bi A, Chen Y, Zhou Q, Feng X, Chen Z, Yin H, Wang W, Chen Z, Cheng X, Zeng W. Precise visualization and ROS-dependent photodynamic therapy of colorectal cancer with a novel mitochondrial viscosity photosensitive fluorescent probe. Biomater Res 2023; 27:112. [PMID: 37941059 PMCID: PMC10634017 DOI: 10.1186/s40824-023-00450-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/17/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a prominent global cancer with high mortality rates among human beings. Efficient diagnosis and treatment have always been a challenge for CRC management. Fluorescence guided cancer therapy, which combines diagnosis with therapy into one platform, has brought a new chance for achieving precise cancer theranostics. Among this, photosensitizers, applied in photodynamic therapy (PDT), given the integration of real-time imaging capacity and efficacious treatment feasibility, show great potential to serve as remarkable tools. Although much effort has been put into constructing photosensitizers for locating and destroying CRC cells, it is still in high need to develop novel photosensitizers to attain specific detection and fulfil effective therapy. METHODS Probe HTI was rational synthesized for the diagnosis and treatment of CRC. Spectrometric determination was carried out first, followed by the 1O2 generation ability test. Then, HTI was displayed in distinguishing CRC cells from normal cells Further, the PDT effect of the photosensitizer was studied in vitro. Additionally, HTI was used in CRC BALB/c nude mice model to validate its viscosity labelling and tumor suppression characteristics. RESULTS We successfully fabricated a mitochondrial targeting probe, HTI, together with remarkable viscosity sensitivity, ultralow background interference, and excellent 1O2 generation capacity. HTI was favorably applied to the viscosity detection, displaying a 11-fold fluorescent intensity enhancement in solvents from 1.57 cp to 2043 cp. Then, it was demonstrated that HTI could distinguish CRC cells from normal cells upon the difference in mitochondrial viscosity. Moreover, HTI was qualified for producing 1O2 with high efficiency in cells, supported by the sparkling signals of DCFH after incubation with HTI under light irradiation. More importantly, the viscosity labelling and tumor suppression performance in CRC CDX model was determined, enriching the multifunctional validation of HTI in vivo. CONCLUSIONS In this study, HTI was demonstrated to show a sensitive response to mitochondrial viscosity and possess a high 1O2 generation capacity. Both in vitro cell imaging and in vivo tumor treatment trials proved that HTI was effectively served as a robust scaffold for tumor labeling and CRC cells clearance. This breakthrough discovery held immense potential for advancing the early diagnosis and management of CRC through PDT. By leveraging HTI's properties, medical professionals could benefit from improved diagnostic accuracy and targeted treatment in CRC management, ultimately leading to enhanced patient outcomes.
Collapse
Affiliation(s)
- Runsha Xiao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410013, Changsha, People's Republic of China
| | - Fan Zheng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People's Republic of China
- Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, People's Republic of China
| | - Kuo Kang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410013, Changsha, People's Republic of China
| | - Lei Xiao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Department of Colorectal Surgery, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People's Republic of China
| | - Anyao Bi
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People's Republic of China
- Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, People's Republic of China
| | - Yiting Chen
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
| | - Qi Zhou
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
| | - Xueping Feng
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
| | - Zhikang Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410013, Changsha, People's Republic of China
| | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai, 200003, People's Republic of China
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, 410013, People's Republic of China
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, 410013, People's Republic of China
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China.
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410013, Changsha, People's Republic of China.
| | - Xiaomiao Cheng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China.
- Department of Nephrology, Xiangya Changde Hospital, Changde, 415000, People's Republic of China.
| | - Wenbin Zeng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People's Republic of China.
- Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, People's Republic of China.
| |
Collapse
|
5
|
Pietschner R, Rath T, Neurath MF, Atreya R. Current and Emerging Targeted Therapies for Ulcerative Colitis. Visc Med 2023; 39:46-53. [PMID: 37405327 PMCID: PMC10315689 DOI: 10.1159/000530983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 05/03/2023] [Indexed: 07/06/2023] Open
Abstract
Background Ulcerative colitis is one of the main entities of inflammatory bowel diseases. The clinical course of this immune-mediated disorder is marked by unpredictable exacerbations and asymptomatic remission, causing lifelong morbidity. Optimized anti-inflammatory treatment is a prerequisite to not only restore the quality of life of the affected patients but also halt progressive bowel damage and reduce the risk for colitis-associated neoplasia. Advances in understanding the underlying immunopathogenesis of ulcerative colitis have led to the advent of targeted therapies that selectively inhibit crucial molecular structures or signaling pathways that perpetuate the inflammatory reaction. Summary We will delineate the mode of action and summarize efficacy and safety data of current and emerging targeted therapies in ulcerative colitis, which encompasses representatives of the drug classes of antibodies, small molecules, and oligonucleotides. These substances have already been approved for induction and maintenance treatment or are being tested in late-stage clinical trials in moderately-to-severely active ulcerative colitis patients. These advanced therapies have enabled us to define and achieve novel therapeutic outcomes, such as clinical and endoscopic remission, histological remission, mucosal healing, and recently, also barrier healing as an emerging outcome measure. Key Messages Established and emerging targeted therapies and monitoring modalities broaden our therapeutic armamentarium and have enabled us to define novel therapeutic outcomes that have the potential to modify the individual disease course of patients with ulcerative colitis.
Collapse
Affiliation(s)
- Robert Pietschner
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
6
|
Kim J, Kim H, Yoon YS, Kim CW, Hong SM, Kim S, Choi D, Chun J, Hong SW, Hwang SW, Park SH, Yang DH, Ye BD, Byeon JS, Yang SK, Kim SY, Myung SJ. Investigation of artificial intelligence integrated fluorescence endoscopy image analysis with indocyanine green for interpretation of precancerous lesions in colon cancer. PLoS One 2023; 18:e0286189. [PMID: 37228164 DOI: 10.1371/journal.pone.0286189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
Indocyanine green (ICG) has been used in clinical practice for more than 40 years and its safety and preferential accumulation in tumors has been reported for various tumor types, including colon cancer. However, reports on clinical assessments of ICG-based molecular endoscopy imaging for precancerous lesions are scarce. We determined visualization ability of ICG fluorescence endoscopy in colitis-associated colon cancer using 30 lesions from an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and 16 colon cancer patient tissue-samples. With a total of 60 images (optical, fluorescence) obtained during endoscopy observation of mouse colon cancer, we used deep learning network to predict four classes (Normal, Dysplasia, Adenoma, and Carcinoma) of colorectal cancer development. ICG could detect 100% of carcinoma, 90% of adenoma, and 57% of dysplasia, with little background signal at 30 min after injection via real-time fluorescence endoscopy. Correlation analysis with immunohistochemistry revealed a positive correlation of ICG with inducible nitric oxide synthase (iNOS; r > 0.5). Increased expression of iNOS resulted in increased levels of cellular nitric oxide in cancer cells compared to that in normal cells, which was related to the inhibition of drug efflux via the ABCB1 transporter down-regulation resulting in delayed retention of intracellular ICG. With artificial intelligence training, the accuracy of image classification into four classes using data sets, such as fluorescence, optical, and fluorescence/optical images was assessed. Fluorescence images obtained the highest accuracy (AUC of 0.8125) than optical and fluorescence/optical images (AUC of 0.75 and 0.6667, respectively). These findings highlight the clinical feasibility of ICG as a detector of precancerous lesions in real-time fluorescence endoscopy with artificial intelligence training and suggest that the mechanism of ICG retention in cancer cells is related to intracellular nitric oxide concentration.
Collapse
Affiliation(s)
- Jinhyeon Kim
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hajung Kim
- Convergence Medicine Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Yong Sik Yoon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chan Wook Kim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Mo Hong
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sungjee Kim
- Department of Chemistry and School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science & Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Doowon Choi
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science & Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jihyun Chun
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung Wook Hong
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byong Duk Ye
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sun Young Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Jae Myung
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Edis Biotech, Songpa-gu, Seoul, Republic of Korea
| |
Collapse
|
7
|
Uno K, Koike T, Hatta W, Saito M, Tanabe M, Masamune A. Development of Advanced Imaging and Molecular Imaging for Barrett's Neoplasia. Diagnostics (Basel) 2022; 12:2437. [PMID: 36292126 PMCID: PMC9600913 DOI: 10.3390/diagnostics12102437] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Barrett esophagus (BE) is a precursor to a life-threatening esophageal adenocarcinoma (EAC). Surveillance endoscopy with random biopsies is recommended for early intervention against EAC, but its adherence in the clinical setting is poor. Dysplastic lesions with flat architecture and patchy distribution in BE are hardly detected by high-resolution endoscopy, and the surveillance protocol entails issues of time and labor and suboptimal interobserver agreement for diagnosing dysplasia. Therefore, the development of advanced imaging technologies is necessary for Barrett's surveillance. Recently, non-endoscopic or endoscopic technologies, such as cytosponge, endocytoscopy, confocal laser endomicroscopy, autofluorescence imaging, and optical coherence tomography/volumetric laser endomicroscopy, were developed, but most of them are not clinically available due to the limited view field, expense of the equipment, and significant time for the learning curve. Another strategy is focused on the development of molecular biomarkers, which are also not ready to use. However, a combination of advanced imaging techniques together with specific biomarkers is expected to identify morphological abnormalities and biological disorders at an early stage in the surveillance. Here, we review recent developments in advanced imaging and molecular imaging for Barrett's neoplasia. Further developments in multiple biomarker panels specific for Barrett's HGD/EAC include wide-field imaging systems for targeting 'red flags', a high-resolution imaging system for optical biopsy, and a computer-aided diagnosis system with artificial intelligence, all of which enable a real-time and accurate diagnosis of dysplastic BE in Barrett's surveillance and provide information for precision medicine.
Collapse
Affiliation(s)
- Kaname Uno
- Division of Gastroenterology, Tohoku University Hospital, Sendai 981-8574, Japan
| | | | | | | | | | | |
Collapse
|
8
|
The development and clinical application of microscopic endoscopy for in vivo optical biopsies: Endocytoscopy and confocal laser endomicroscopy. Photodiagnosis Photodyn Ther 2022; 38:102826. [PMID: 35337998 DOI: 10.1016/j.pdpdt.2022.102826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/21/2022] [Indexed: 12/20/2022]
Abstract
Endoscopies are crucial for detecting and diagnosing diseases in gastroenterology, pulmonology, urology, and other fields. To accurately diagnose diseases, sample biopsies are indispensable and are currently considered the gold standard. However, random 4-quadrant biopsies have sampling errors and time delays. To provide intraoperative real-time microscopic images of suspicious lesions, microscopic endoscopy for in vivo optical biopsy has been developed, including endocytoscopy and confocal laser endomicroscopy. This article reviews recent advances in technology and clinical applications, as well as their shortcomings and future directions.
Collapse
|
9
|
Waldner MJ, Neurath MF. Molecular Endoscopy for the Diagnosis and Therapeutic Monitoring of Colorectal Cancer. Front Oncol 2022; 12:835256. [PMID: 35280747 PMCID: PMC8913894 DOI: 10.3389/fonc.2022.835256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/26/2022] [Indexed: 11/23/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer related death in the western world. Its successful treatment requires early detection and removal of precursor lesions as well as individualized treatment of advanced disease. During recent years, molecular imaging techniques have shown promising results to improve current clinical practice. For instance, molecular endoscopy resulted in higher detection rates of precursors in comparison to conventional endoscopy in preclinical and clinical studies. Molecular confocal endomicroscopy allowed a further classification of suspect lesions as well as the prediction and monitoring of the therapeutic response. In this review, we summarize recent achievements for molecular imaging of CRC in preclinical studies, initial clinical trials and the remaining challenges for future translation into clinical practice.
Collapse
Affiliation(s)
- Maximilian J Waldner
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
10
|
Parigi TL, Mastrorocco E, Da Rio L, Allocca M, D’Amico F, Zilli A, Fiorino G, Danese S, Furfaro F. Evolution and New Horizons of Endoscopy in Inflammatory Bowel Diseases. J Clin Med 2022; 11:jcm11030872. [PMID: 35160322 PMCID: PMC8837111 DOI: 10.3390/jcm11030872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/30/2022] [Accepted: 02/01/2022] [Indexed: 12/15/2022] Open
Abstract
Endoscopy is the mainstay of inflammatory bowel disease (IBD) evaluation and the pillar of colorectal cancer surveillance. Endoscopic equipment, both hardware and software, are advancing at an incredible pace. Virtual chromoendoscopy is now widely available, allowing the detection of subtle inflammatory changes, thus reducing the gap between endoscopic and histologic assessment. The progress in the field of artificial intelligence (AI) has been remarkable, and numerous applications are now in an advanced stage of development. Computer-aided diagnosis (CAD) systems are likely to reshape most of the evaluations that are now prerogative of human endoscopists. Furthermore, sophisticated tools such as endocytoscopy and probe-based confocal laser endomicroscopy (pCLE) are enhancing our assessment of inflammation and dysplasia. Finally, pCLE combined with molecular labeling could pave the way to a new paradigm of personalized medicine. This review aims to summarize the main changes that occurred in the field of IBD endoscopy and to explore the most promising novelties.
Collapse
Affiliation(s)
- Tommaso Lorenzo Parigi
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (T.L.P.); (E.M.); (L.D.R.)
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Elisabetta Mastrorocco
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (T.L.P.); (E.M.); (L.D.R.)
| | - Leonardo Da Rio
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (T.L.P.); (E.M.); (L.D.R.)
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy; (M.A.); (F.D.); (A.Z.); (G.F.); (S.D.)
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy; (M.A.); (F.D.); (A.Z.); (G.F.); (S.D.)
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy; (M.A.); (F.D.); (A.Z.); (G.F.); (S.D.)
| | - Gionata Fiorino
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy; (M.A.); (F.D.); (A.Z.); (G.F.); (S.D.)
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy; (M.A.); (F.D.); (A.Z.); (G.F.); (S.D.)
| | - Federica Furfaro
- IBD Center, Humanitas Research Hospital, 20089 Milan, Italy
- Correspondence: ; Tel.: +39-0282245555
| |
Collapse
|
11
|
Bojarski C, Waldner M, Rath T, Schürmann S, Neurath MF, Atreya R, Siegmund B. Innovative Diagnostic Endoscopy in Inflammatory Bowel Diseases: From High-Definition to Molecular Endoscopy. Front Med (Lausanne) 2021; 8:655404. [PMID: 34368180 PMCID: PMC8333704 DOI: 10.3389/fmed.2021.655404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/22/2021] [Indexed: 12/30/2022] Open
Abstract
High-definition endoscopy is one essential step in the initial diagnosis of inflammatory bowel disease (IBD) characterizing the extent and severity of inflammation, as well as discriminating ulcerative colitis (UC) from Crohn's disease (CD). Following general recommendations and national guidelines, individual risk stratification should define the appropriate surveillance strategy, biopsy protocol and frequency of endoscopies. Beside high-definition videoendoscopy the application of dyes applied via a spraying catheter is of additional diagnostic value with a higher detection rate of intraepithelial neoplasia (IEN). Virtual chromoendoscopy techniques (NBI, FICE, I-scan, BLI) should not be recommended as a single surveillance strategy in IBD, although newer data suggest a higher comparability to dye-based chromoendoscopy than previously assumed. First results of oral methylene blue formulation are promising for improving the acceptance rate of classical chromoendoscopy. Confocal laser endomicroscopy (CLE) is still an experimental but highly innovative endoscopic procedure with the potential to contribute to the detection of dysplastic lesions. Molecular endoscopy in IBD has taken application of CLE to a higher level and allows topical application of labeled probes, mainly antibodies, against specific target structures expressed in the tissue to predict response or failure to biological therapies. First pre-clinical and in vivo data from label-free multiphoton microscopy (MPM) are now available to characterize mucosal and submucosal inflammation on endoscopy in more detail. These new techniques now have opened the door to individualized and highly specific molecular imaging in IBD in the future and pave the path to personalized medicine approaches. The quality of evidence was stated according to the Oxford Center of evidence-based medicine (March 2009). For this review a Medline search up to January 2021 was performed using the words “inflammatory bowel disease,” “ulcerative colitis,” “crohn's disease,” “chromoendoscopy,” “high-definition endoscopy,” “confocal laser endomicroscopy,” “confocal laser microscopy,” “molecular imaging,” “multiphoton microscopy.”
Collapse
Affiliation(s)
- Christian Bojarski
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Maximilian Waldner
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Schürmann
- Department of Chemical and Biological Engineering, Institute of Medical Biotechnology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| |
Collapse
|
12
|
Li Y, Li C, Tu Y, Tao J, Liu P, Xu H, Tang Y, Gu Y. In vivo assessing colitis severity by topical administration of fluorescent probe against neutrophils. Talanta 2021; 233:122519. [PMID: 34215134 DOI: 10.1016/j.talanta.2021.122519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease has become a global burden given its high incidence and refractory to medical treatment. Improved diagnostic strategies to monitor disease activity more accurately are necessary to conduct and evaluate medical treatment. High level of neutrophil infiltration in colon is associated with poor prognosis and enhanced risk of developing colitis-associated cancer. Herein, to accurately monitor neutrophil levels in colitis condition, we designed and constructed a specific probe (CPM), consisting of a neutrophil formyl peptide receptor targeting group (cFLFLFK), a short PEG linker and a near-infrared fluorescent dye. CPM selectively identified neutrophils in vitro and preferentially recognized neutrophils in vivo with enhanced targeting ability and biodistribution property. After verified the ability to target activated neutrophils, CPM was used to detect neutrophils in experimental colitis by systemic and topical administration. Compared to systemic administration, topical administration of CPM allows lower dosage, higher target-to-background ratio and longer duration of effective monitoring. More importantly, we used CPM to assess neutrophil levels in the course of colitis development. The fluorescence intensity of CPM increased along with colitis progression. Additionally, CPM was used to detected neutrophil levels in colitis-associated cancer and enhanced neutrophil infiltration in the tumor sites was detected. In conclusion, the probe CPM is a promising tool for in vivo improved diagnosis of colitis severity by monitoring the extent of neutrophil infiltration.
Collapse
Affiliation(s)
- Yi Li
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Chang Li
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yuanbiao Tu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China; Jiangzhong Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, No.1688 Meiling Road, Wanli District, Nanchang, 330004, China
| | - Ji Tao
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Peifei Liu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Haoran Xu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yongjia Tang
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yueqing Gu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China.
| |
Collapse
|
13
|
Rath T, Neurath MF, Atreya R. Molecular Imaging and its Applications in Selected GI Diseases. TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY 2021; 23:87-98. [DOI: 10.1016/j.tige.2020.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
|
14
|
Zhang D, Huang J, Li W, Zhang Z, Zhu M, Feng Y, Zhao Y, Li Y, Lu S, He S. Screening and identification of a CD44v6 specific peptide using improved phage display for gastric cancer targeting. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1442. [PMID: 33313187 PMCID: PMC7723568 DOI: 10.21037/atm-19-4781] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Peptide probes can be applied for biomarker targeting to improve the diagnostic accuracy. Cluster of differentiation 44 (CD44) is up-regulated in gastric cancer (GC). Among all the variants of CD44, CD44v6 is reported the most promising biomarker for GC. The purpose of this study was generating and identification a peptide ligand specific to CD44v6. Methods A 12-mer phage peptide library was screened on CD44v overexpressed HEK-293 cells with an improved subtractive method. Five candidate sequences emerged. Candidate phages were selected using enzyme-linked immunosorbent assay and competitive inhibition assays. Then the sequence (designated ELT) was chosen for further study. Its binding affinity and specificity were verified on recombinant protein, GC cells, GC tissues and xenograft models based on BALB/c-nu/nu mice using dissociation constant calculation, immunofluorescence, immunohistochemistry and in vivo imaging separately. Results The dissociation constant of ELT with recombinant protein was 611.2 nM. ELT stained CD44v overexpressed HEK-293 but not the cell expressing wild-type CD44s. On GC cell lines, ELT co-stained with anti-CD44v6 antibody. ELT binding on tumor tissues significantly increased compared with that of paracancer tissues, also showed a linear positive correlation with CD44v6 expression. ELT specifically accumulated in tumor and eliminated in short time in vivo. Conclusions ELT can target GC in vitro and in vivo via CD44v6, indicating its potential to serve as a probe for GC targeting diagnosis and therapy.
Collapse
Affiliation(s)
- Dan Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin Huang
- School of Electronic Information and Artificial Intelligence, Shannxi University of Science &Technology, Xi'an, China.,School of Materials Science and Engineering, Shannxi Normal University, Xi'an, China
| | - Weiming Li
- Department of Vascular Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhiyong Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Meng Zhu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yun Feng
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Zhao
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yarui Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shaoying Lu
- Department of Vascular Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
15
|
Cell-penetrating peptides in oncologic pharmacotherapy: A review. Pharmacol Res 2020; 162:105231. [PMID: 33027717 DOI: 10.1016/j.phrs.2020.105231] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/23/2020] [Accepted: 09/30/2020] [Indexed: 01/10/2023]
Abstract
Cancer is the second leading cause of death in the world and its treatment is extremely challenging, mainly due to its complexity. Cell-Penetrating Peptides (CPPs) are peptides that can transport into the cell a wide variety of biologically active conjugates (or cargoes), and are, therefore, promising in the treatment and in the diagnosis of several types of cancer. Some notable examples are TAT and Penetratin, capable of penetrating the central nervous system (CNS) and, therefore, acting in cancers of this system, such as Glioblastoma Multiforme (GBM). These above-mentioned peptides, conjugated with traditional chemotherapeutic such as Doxorubicin (DOX) and Paclitaxel (PTX), have also been shown to induce apoptosis of breast and liver cancer cells, as well as in lung cancer cells, respectively. In other cancers, such as esophageal cancer, the attachment of Magainin 2 (MG2) to Bombesin (MG2B), another CPP, led to pronounced anticancer effects. Other examples are CopA3, that selectively decreased the viability of gastric cancer cells, and the CPP p28. Furthermore, in preclinical tests, the anti-tumor efficacy of this peptide was evaluated on human breast cancer, prostate cancer, ovarian cancer, and melanoma cells in vitro, leading to high expression of p53 and promoting cell cycle arrest. Despite the numerous in vitro and in vivo studies with promising results, and the increasing number of clinical trials using CPPs, few treatments reach the expected clinical efficacy. Usually, their clinical application is limited by its poor aqueous solubility, immunogenicity issues and dose-limiting toxicity. This review describes the most recent advances and innovations in the use of CPPs in several types of cancer, highlighting their crucial importance for various purposes, from therapeutic to diagnosis. Further clinical trials with these peptides are warranted to examine its effects on various types of cancer.
Collapse
|
16
|
Atreya R, Neurath MF, Siegmund B. Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? Front Med (Lausanne) 2020; 7:517. [PMID: 32984386 PMCID: PMC7492550 DOI: 10.3389/fmed.2020.00517] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
Collapse
Affiliation(s)
- Raja Atreya
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.,The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- The Transregio 241 IBDome Consortium, Berlin, Germany.,Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
17
|
Schmitt H, Neufert C, Neurath MF, Atreya R. Resolution of Crohn's disease. Semin Immunopathol 2019; 41:737-746. [PMID: 31552470 DOI: 10.1007/s00281-019-00756-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 09/05/2019] [Indexed: 12/19/2022]
Abstract
Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract and represents one of the main inflammatory bowel disease (IBD) forms. The infiltration of immune cells into the mucosa and uncontrolled production of pro-inflammatory cytokines and other mediators trigger the chronic inflammatory reaction in the intestine [1]. The inflammatory setting consists of subsequent events that comprise an induction phase, the peak of inflammation which is subsequently followed by the resolution phase. The induction phase, which represents the first phase of inflammation, is important for the rapid and efficient activation of the immune system for sufficient host defense. The permanent sensing of exogenous or endogenous danger signals enables the fast initiation of the inflammatory reaction. The immune cell infiltrate initiates an inflammatory cascade where released lipid and protein mediators play an indispensable role [2, 3]. The last decades of research strongly suggest that resolution of inflammation is similarly a tightly coordinated and active process. The basic concept that resolution of inflammation has to be regarded as an active process has been thoroughly described by others [4-6]. The following review focuses on mechanisms, pathways, and specific mediators that are actively involved in the resolution of inflammation in CD.
Collapse
Affiliation(s)
- Heike Schmitt
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Clemens Neufert
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Markus F Neurath
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Raja Atreya
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
| |
Collapse
|
18
|
Nagengast WB, Hartmans E, Garcia-Allende PB, Peters FTM, Linssen MD, Koch M, Koller M, Tjalma JJJ, Karrenbeld A, Jorritsma-Smit A, Kleibeuker JH, van Dam GM, Ntziachristos V. Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A. Gut 2019; 68:7-10. [PMID: 29247063 PMCID: PMC6839834 DOI: 10.1136/gutjnl-2017-314953] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/25/2017] [Accepted: 11/16/2017] [Indexed: 01/07/2023]
Affiliation(s)
- Wouter B Nagengast
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Elmire Hartmans
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Pilar B Garcia-Allende
- Chair for Biological Imaging and Institute for Biological and Medical Imaging, Technical University of Munich and Helmholtz Centre Munich, Munich, Germany
| | - Frans T M Peters
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Matthijs D Linssen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands,Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Maximilian Koch
- Chair for Biological Imaging and Institute for Biological and Medical Imaging, Technical University of Munich and Helmholtz Centre Munich, Munich, Germany
| | - Marjory Koller
- Department of Surgery, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Jolien J J Tjalma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Arend Karrenbeld
- Department of Pathology, University of Groningen, University MedicalCenter, Groningen, The Netherlands
| | - Annelies Jorritsma-Smit
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Jan H Kleibeuker
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Gooitzen M van Dam
- Department of Surgery, University of Groningen, University Medical Center, Groningen, The Netherlands,Department of Nuclear Medicine & Molecular Imaging and Intensive Care, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Vasilis Ntziachristos
- Chair for Biological Imaging and Institute for Biological and Medical Imaging, Technical University of Munich and Helmholtz Centre Munich, Munich, Germany
| |
Collapse
|
19
|
Rath T, Kiesslich R, Neurath MF, Atreya R. Molecular imaging within the lower gastrointestinal tract: From feasibility to future. Dig Endosc 2018; 30:730-738. [PMID: 30075487 DOI: 10.1111/den.13251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 07/30/2018] [Indexed: 12/13/2022]
Abstract
Molecular imaging is based on the labelling of defined molecular targets through the utilization of fluorescently linked probes and their subsequent detection with high-resolution endoscopic devices, thereby enabling visualization of single molecules including receptors. Whereas early studies have used molecular imaging for improved visualization and detection of early dysplasia and cancer as well as for assessing intestinal inflammation and inflammation-associated cancer within the gastrointestinal (GI) tract, more recent studies have impressively demonstrated that molecular imaging can also be used to characterize and visualize the molecular fingerprint of cancer and inflammation in vivo and in real time. With this, molecular imaging can be used to guide expression-tailored individualized therapy. With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel disease and cancer, this approach is gaining increasing attention. Within this review, we first summarize the technical components commonly used for molecular imaging and then review preclinical and clinical studies and evolving clinical applications on molecular imaging within the lower GI tract. Molecular imaging has the potential to significantly change endoscopic diagnosis and subsequent targeted therapy of gastrointestinal cancer and chronic gastrointestinal diseases.
Collapse
Affiliation(s)
- Timo Rath
- Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Erlangen, Germany
| | - Ralf Kiesslich
- Department of Medicine, Division of Gastroenterology, Helios-Dr.-Horst-Schmidt-Kliniken, Wiesbaden, Germany
| | - Markus F Neurath
- Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Erlangen, Germany
| | - Raja Atreya
- Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Erlangen, Germany
| |
Collapse
|
20
|
Klenske E, Neurath MF, Atreya R, Rath T. Molecular imaging in gastroenterology: A route for personalized endoscopy. Dig Liver Dis 2018; 50:878-885. [PMID: 30005960 DOI: 10.1016/j.dld.2018.06.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/08/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023]
Abstract
With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel diseases and cancer and the increase in oncological patients in gastroenterology, visualization of single receptor or molecular target expression and the subsequent initiation of expression tailored therapy are gaining increasing attention. Through the combination of utilizing fluorescently labeled probes with high specificity towards defined molecular targets and their subsequent detection and visualization with endoscopic devices, molecular imaging is a new emerging field focusing on the receptor expression within the mucosa on a cellular level rather than on macroscopic changes. In the past years various new technological and molecular probes have been successfully utilized for molecular imaging. Within this review, we summarize different technologies as well as molecular probes applied in molecular imaging and review current and past approaches for functional imaging with molecular endoscopy within the GI Tract and resulting clinical applications. It can be expected that molecular imaging allows for individualized diagnostic approaches and patient tailored medicine in the future.
Collapse
Affiliation(s)
- Entcho Klenske
- Department of Medicine I, Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine I, Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Germany
| | - Raja Atreya
- Department of Medicine I, Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Germany
| | - Timo Rath
- Department of Medicine I, Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, University Hospital of Erlangen, Germany.
| |
Collapse
|
21
|
Nagahara R, Onda N, Yamashita S, Kojima M, Inohana M, Eguchi A, Nakamura M, Matsumoto S, Yoshida T, Shibutani M. Fluorescence tumor imaging by i.v. administered indocyanine green in a mouse model of colitis-associated colon cancer. Cancer Sci 2018. [PMID: 29520973 PMCID: PMC5980401 DOI: 10.1111/cas.13564] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Fluorescence tumor imaging using exogenous fluorescent tumor‐targeting agents has potential to improve early tumor detection. The fluorescent contrast agent indocyanine green (ICG) is used in medical diagnostics. The aim of the present study is to investigate the tumor imaging capability and the imaging mechanism of i.v. administered ICG in a mouse model of colitis‐associated colon cancer. To do this, an azoxymethane/dextran sodium sulfate‐induced colon cancer mouse model was used. Ex vivo imaging experiments were carried out 1 hour after i.v. injection of ICG. The ICG fluorescence was observed in the colon tumor tissues, with sufficient tumor to normal tissue ratio, correlating with tumor malignancy. In the tumor tissues, ICG fluorescence was localized in the vascular interstitial tissue. Immunofluorescence microscopy revealed that tumor cells formed tight junctions normally, suggesting an inability of tumor cellular uptake of ICG. In contrast, tumor tissues increased the CD31‐immunoreactive endothelial cell area, and accumulated stromal cells immunoreactive for COX‐2 and tumor cell population immunoreactive for inducible nitric oxide synthase. In vivo vascular permeability assay revealed that prostaglandin E2 promoted the endothelial cell permeability of ICG. In conclusion, our data indicated that fluorescence contrast‐enhanced imaging following i.v. administered ICG can be applied to the detection of colon tumors in a mouse colitis‐associated colon cancer model. The tumor tissue preference of ICG in the present model can be attributed to the enhanced vascular leakage of ICG involving inflammatory mediators, such as COX‐2 and inducible nitric oxide synthase, in conjunction with increased tumor vascularity.
Collapse
Affiliation(s)
- Rei Nagahara
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Nobuhiko Onda
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.,Evaluation Technology Department 1, R&D Group, Olympus Corporation, Tokyo, Japan
| | - Susumu Yamashita
- Evaluation Technology Department 1, R&D Group, Olympus Corporation, Tokyo, Japan
| | - Miho Kojima
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.,Evaluation Technology Department 1, R&D Group, Olympus Corporation, Tokyo, Japan
| | - Mari Inohana
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Ayumi Eguchi
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Misato Nakamura
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Shinya Matsumoto
- Evaluation Technology Department 1, R&D Group, Olympus Corporation, Tokyo, Japan
| | - Toshinori Yoshida
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Makoto Shibutani
- Division of Animal Life Science, Laboratory of Veterinary Pathology, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.,Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Tokyo, Japan
| |
Collapse
|
22
|
Waldner MJ, Rath T, Schürmann S, Bojarski C, Atreya R. Imaging of Mucosal Inflammation: Current Technological Developments, Clinical Implications, and Future Perspectives. Front Immunol 2017; 8:1256. [PMID: 29075256 PMCID: PMC5641553 DOI: 10.3389/fimmu.2017.01256] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022] Open
Abstract
In recent years, various technological developments markedly improved imaging of mucosal inflammation in patients with inflammatory bowel diseases. Although technological developments such as high-definition-, chromo-, and autofluorescence-endoscopy led to a more precise and detailed assessment of mucosal inflammation during wide-field endoscopy, probe-based and stationary confocal laser microscopy enabled in vivo real-time microscopic imaging of mucosal surfaces within the gastrointestinal tract. Through the use of fluorochromes with specificity against a defined molecular target combined with endoscopic techniques that allow ultrastructural resolution, molecular imaging enables in vivo visualization of single molecules or receptors during endoscopy. Molecular imaging has therefore greatly expanded the clinical utility and applications of modern innovative endoscopy, which include the diagnosis, surveillance, and treatment of disease as well as the prediction of the therapeutic response of individual patients. Furthermore, non-invasive imaging techniques such as computed tomography, magnetic resonance imaging, scintigraphy, and ultrasound provide helpful information as supplement to invasive endoscopic procedures. In this review, we provide an overview on the current status of advanced imaging technologies for the clinical non-invasive and endoscopic evaluation of mucosal inflammation. Furthermore, the value of novel methods such as multiphoton microscopy, optoacoustics, and optical coherence tomography and their possible future implementation into clinical diagnosis and evaluation of mucosal inflammation will be discussed.
Collapse
Affiliation(s)
- Maximilian J Waldner
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Schürmann
- Institute of Medical Biotechnology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Bojarski
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
23
|
Onda N, Mizutani-Morita R, Yamashita S, Nagahara R, Matsumoto S, Yoshida T, Shibutani M. Fluorescence contrast-enhanced proliferative lesion imaging by enema administration of indocyanine green in a rat model of colon carcinogenesis. Oncotarget 2017; 8:90278-90290. [PMID: 29163827 PMCID: PMC5685748 DOI: 10.18632/oncotarget.21744] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/08/2017] [Indexed: 12/19/2022] Open
Abstract
The fluorescent contrast agent indocyanine green (ICG) is approved by the Food and Drug Administration for clinical applications. We previously reported that cultured human colon tumor cells preferentially take up ICG by endocytic activity in association with disruption of their tight junctions. The present study explored ICG availability in fluorescence imaging of the colon to identify proliferative lesions during colonoscopy. The cellular uptake of ICG in cultured rat colon tumor cells was examined using live-cell imaging. Colon lesions in rats administered an ICG-containing enema were further assessed in rats with azoxymethane-induced colon carcinogenesis, using in vivo endoscopy, ex vivo microscopy, and immunofluorescence microscopy. The uptake of ICG by the cultured cells was temperature-dependent. The intracellular retention of the dye in the membrane trafficking system suggested endocytosis as the uptake mechanism. ICG administered via enema accumulated in colon proliferative lesions ranging from tiny aberrant crypt foci to adenomas and localized in proliferating cells. Fluorescence endoscopy detected these ICG-positive colonic proliferative lesions in vivo. The immunoreactivity of the tight-junction molecule occludin was altered in the proliferative lesions, suggesting the disruption of the integrity of tight junctions. These results suggest that fluorescence contrast-enhanced imaging following the administration of an ICG-containing enema can enhance the detection of mucosal proliferative lesions of the colon during colonoscopy. The tissue preference of ICG in the rat model evaluated in this study can be attributed to the disruption of tight junctions, which in turn promotes endocytosis by proliferative cells and the cellular uptake of ICG.
Collapse
Affiliation(s)
- Nobuhiko Onda
- Evaluation Technology Department 1, R&D Group, Olympus Corporation, Hachioji, Tokyo 192-8512, Japan.,Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
| | - Reiko Mizutani-Morita
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
| | - Susumu Yamashita
- Evaluation Technology Department 1, R&D Group, Olympus Corporation, Hachioji, Tokyo 192-8512, Japan
| | - Rei Nagahara
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
| | - Shinya Matsumoto
- Evaluation Technology Department 1, R&D Group, Olympus Corporation, Hachioji, Tokyo 192-8512, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.,Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
| |
Collapse
|
24
|
Kim J, Do EJ, Moinova H, Bae SM, Kang JY, Hong SM, Fink SP, Joo J, Suh YA, Jang SJ, Hwang SW, Park SH, Yang DH, Ye BD, Byeon JS, Choe J, Yang SK, Markowitz SD, Kim SY, Myung SJ. Molecular Imaging of Colorectal Tumors by Targeting Colon Cancer Secreted Protein-2 (CCSP-2). Neoplasia 2017; 19:805-816. [PMID: 28886423 PMCID: PMC5587890 DOI: 10.1016/j.neo.2017.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 07/17/2017] [Accepted: 07/24/2017] [Indexed: 12/31/2022] Open
Abstract
A versatile biomarker for detecting colonic adenoma and colon cancer has yet to be developed. Colon cancer secreted protein-2 (CCSP-2) is a protein specifically expressed and secreted in colon adenomas and cancers. We developed a fluorescent imaging method based on CCSP-2 targeting for a more sensitive and specific detection of colorectal tumors. CCSP-2 expression was evaluated in human colon adenoma and colorectal specimens. Anti–CCSP-2 antibody was labeled with a near-infrared fluorescent dye, FPR-675, and molecular imaging of surgical human colorectal tumors was performed. Immunohistochemistry identified CCSP-2 expression in 87.0% of colorectal cancer specimens and 89.5% of colon adenoma specimens. Fluorescence imaging of surgical human colon specimens after spraying treatment with the probe permitted a clear distinction of cancer from paired normal colon tissue (target-to-background ratio, 4.09 ± 0.42; P < .001). CCSP-2 targeting imaging was also evaluated in patient-derived colon cancer xenograft mouse and liver metastasis murine models. CCSP-2–positive colon cancer xenografts and liver metastases were visualized by near-infrared fluorescence imaging after intravenous injection of the probe, which showed significantly higher fluorescence. Our results show that CCSP-2 is a promising marker for colorectal tumor detection in clinical settings and that a CCSP-2–targeting molecular imaging strategy might improve the diagnosis of colorectal tumors in metastatic or recurrent cancers and aid in early colonoscopic detection of premalignant lesions.
Collapse
Affiliation(s)
- Jaeil Kim
- Health Screening & Promotion Center, Asan Medical Center, Seoul, Republic of Korea
| | - Eun-Ju Do
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Helen Moinova
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Sang Mun Bae
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Ja Young Kang
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Stephen P Fink
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Jinmyoung Joo
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Ah Suh
- Institute for Innovative Cancer Research, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Se Jin Jang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewon Choe
- Health Screening & Promotion Center, Asan Medical Center, Seoul, Republic of Korea; Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sanford D Markowitz
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Sang-Yeob Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Seung-Jae Myung
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
25
|
Beintaris I, Rutter M. Advanced imaging in colonoscopy: contemporary approach to dysplasia surveillance in inflammatory bowel disease. Frontline Gastroenterol 2016; 7:308-315. [PMID: 28839872 PMCID: PMC5369495 DOI: 10.1136/flgastro-2016-100735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 07/19/2016] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn's disease (CD)) is a chronic relapsing/remitting condition characterised by intestinal inflammation. One of the main concerns in patients with longstanding ulcerative and Crohn's colitis is development of colonic dysplasia and colorectal cancer (CRC), a risk higher than that of the general population. Colonoscopy surveillance programmes have been developed by major societies worldwide to improve early dysplasia detection and treatment, thus preventing progression to colorectal cancer. Colonoscopy is an imperfect tool as lesions can be missed, an issue even more relevant to colitic patients, where mucosal inspection and lesion recognition may prove challenging. Extensive research has been undertaken on performance improvement in this area while technical advances in optical imaging, such as high-definition, have made their way into modern endoscopy units. Techniques and technologies available to enhance optical diagnosis of dysplasia in inflammatory bowel disease are reviewed in this paper, focusing on those that are realistic, widely available and feasible for everyday practice.
Collapse
Affiliation(s)
| | - Matt Rutter
- University Hospital of North Tees, Cleveland, UK
| |
Collapse
|
26
|
Abstract
PURPOSE OF REVIEW Standard structural imaging procedures such as endoscopy, ultrasonography, or MRI are an integral part of the rational management of patients with inflammatory bowel diseases (IBDs). There is nevertheless the need for further refined imaging approaches that are able to overcome the limitations of currently used formats. The advent of molecular imaging modalities that allow real-time visualization of cellular processes not only in the preclinical setting but also in clinical trials has demonstrated its ability to improve current therapeutic strategies. The purpose of this review is to present and discuss advancements in the field of molecular imaging approaches in the IBD field. RECENT FINDINGS Recent preclinical and clinical studies have addressed the applicability of molecular imaging for improving the differentiation between benign and malignant mucosal alterations, increasing the detection of dysplastic intestinal lesions, and predicting individual responses to biological therapies. SUMMARY Molecular imaging in IBD represents an exciting and evolving field that has the potential to impact on current diagnostic and therapeutic algorithms in the treatment of IBD patients by analyzing and visualizing the molecular mechanisms that drive mucosal inflammation. It might enable us to base individualized therapeutic decisions on preceded molecular level analysis by suitable imaging modalities.
Collapse
|
27
|
Atreya R, Neurath MF. Predicting Therapeutic Response by in vivo Molecular Imaging in Inflammatory Bowel Diseases. Dig Dis 2016; 34:552-7. [PMID: 27333283 DOI: 10.1159/000445262] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Different invasive and non-invasive imaging modalities are indispensable tools in the management of inflammatory bowel disease (IBD) patients. Standard imaging procedures like white light endoscopy or MRI are used to define gut inflammation based on structural changes and altered morphology of the mucosa. Nevertheless, it has thus far not been possible to analyse biological processes at the cellular level, which drive intestinal inflammation in IBD patients. The recent advent of molecular imaging in the field of IBD has opened new promising avenues to allow personalized medicine approaches based on in vivo-detected molecular findings. KEY MESSAGES Recent clinical studies have attempted to address the issue of predicting therapeutic response to anti-tumor necrosis factor (TNF) treatment in IBD patients based on the molecular mechanism of action of these agents and corresponding in vivo assessment of mucosal immune responses. Several experimental studies have indicated that one of the main functions of efficacious anti-TNF therapy in IBD is the induction of intestinal cell apoptosis. Fittingly, a corresponding molecular-imaging study using single-photon emission CT for the localization and quantification of cell apoptosis, demonstrated that induction of mucosal T-cell apoptosis correlated with the therapeutic response to anti-TNF therapy in Crohn's disease patients. There was moreover a predictive capacity regarding therapeutic efficacy. As the main biological properties of anti-TNF antibodies in IBD are mediated through binding to membrane-bound TNF (mTNF) expressing intestinal cells, another study used molecular imaging for in vivo visualization of these cells via fluorescent anti-TNF antibodies to predict therapeutic efficacy of these agents. It could be shown that patients with high amounts of mTNF positive cells showed significantly better response rates compared to patients with low amounts of mTNF positive cells. CONCLUSION In vivo molecular imaging in IBD has the potential to have an impact on our current treatment approaches and may allow us to individualize specific therapies based on molecular level analysis.
Collapse
Affiliation(s)
- Raja Atreya
- Medical Clinic I, Friedrich-Alexander Universitx00E4;t Erlangen-Nx00FC;rnberg, Erlangen, Germany
| | | |
Collapse
|
28
|
Onda N, Kimura M, Yoshida T, Shibutani M. Preferential tumor cellular uptake and retention of indocyanine green for in vivo tumor imaging. Int J Cancer 2016; 139:673-82. [PMID: 27006261 DOI: 10.1002/ijc.30102] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 02/25/2016] [Accepted: 03/11/2016] [Indexed: 12/29/2022]
Abstract
Indocyanine green (ICG) is a fluorescent agent approved for clinical applications by the Food and Drug Administration and European Medicines Agency. This study examined the mechanism of tumor imaging using intravenously administered ICG. The in vivo kinetics of intravenously administered ICG were determined in tumor xenografts using microscopic approaches that enabled both spatio-temporal and high-magnification analyses. The mechanism of ICG-based tumor imaging was examined at the cellular level in six phenotypically different human colon cancer cell lines exhibiting different grades of epithelioid organization. ICG fluorescence imaging detected xenograft tumors, even those < 1 mm in size, based on their preferential cellular uptake and retention of the dye following its rapid tissue-non-specific delivery, in contrast to its rapid clearance by normal tissue. Live-cell imaging revealed that cellular ICG uptake is temperature-dependent and occurs after ICG binding to the cellular membrane, a pattern suggesting endocytic uptake as the mechanism. Cellular ICG uptake correlated inversely with the formation of tight junctions. Intracellular ICG was entrapped in the membrane traffic system, resulting in its slow turnover and prolonged retention by tumor cells. Our results suggest that tumor-specific imaging by ICG involves non-specific delivery of the dye to tissues followed by preferential tumor cellular uptake and retention. The tumor cell-preference of ICG is driven by passive tumor cell-targeting, the inherent ability of ICG to bind to cell membranes, and the high endocytic activity of tumor cells in association with the disruption of their tight junctions.
Collapse
Affiliation(s)
- Nobuhiko Onda
- R&D Group, Olympus Corporation, 2-3 Kuboyama-Cho, Hachioji, Tokyo, 192-8512, Japan.,Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-Cho, Fuchu, Tokyo, 183-8509, Japan
| | - Masayuki Kimura
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-Cho, Fuchu, Tokyo, 183-8509, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-Cho, Fuchu, Tokyo, 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-Cho, Fuchu, Tokyo, 183-8509, Japan
| |
Collapse
|
29
|
Tontini GE, Rath T, Neumann H. Advanced gastrointestinal endoscopic imaging for inflammatory bowel diseases. World J Gastroenterol 2016; 22:1246-1259. [PMID: 26811662 PMCID: PMC4716035 DOI: 10.3748/wjg.v22.i3.1246] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/15/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn’s disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection.
Collapse
|
30
|
Neumann H, Neurath MF, Atreya R. Endoscopic Therapy in Inflammatory Bowel Diseases. VISZERALMEDIZIN 2015; 31:280-6. [PMID: 26557837 PMCID: PMC4608609 DOI: 10.1159/000435851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background Endoscopy is an essential diagnostic and therapeutic modality in the clinical care of inflammatory bowel disease (IBD) patients. Endoscopic therapy can be used for treatment of disease-related strictures, surveillance and resection of intraepithelial neoplasia, and treatment of fistulas or disease-related complications, and is currently being evaluated regarding its capacity in in vivo molecular imaging procedures. Methods A literature search using Medline and Science Citation Index was performed in March 2015. All studies on endoscopic therapy in IBD published from 1980 to 2015 (March) were reviewed. Potential studies were initially screened by title and abstract. The terms ‘endoscopy IBD’, ‘endoscopy therapy IBD’, ‘dilatation IBD’, ‘strictureplasty Crohn's disease’, ‘endoscopy therapy fistula’, ‘endoscopy toxic megacolon’, ‘endoscopy dysplasia IBD’, ‘endoscopy complications IBD’, and ‘molecular imaging IBD’ were used in the search. A total of 115 articles were studied to construct this review. Results Dilatation is most useful in short anastomotic strictures, but can be also undertaken in colonic strictures. Strictures in ulcerative colitis are always suspicious for neoplasia and should be evaluated carefully. Lesions with intraepithelial neoplasia can be resected when complete removal can be assured. The finding of carcinoma or high-grade dysplasia in a random biopsy is an indication for colectomy. If intraepithelial neoplasia is present in random biopsy specimens, colectomy should similarly be recommended. Endoscopic therapy of Crohn's fistulas is a possible emerging technology. In vivo molecular imaging is currently being studied in IBD patients and offers promising therapeutic opportunities. Conclusion Therapeutic endoscopy is indispensable in the management of IBD. It has to be carefully evaluated against alternative surgical options but often offers an effective therapeutic approach. © 2015 S. Karger GmbH, Freiburg
Collapse
Affiliation(s)
- Helmut Neumann
- Medical Clinic I, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Medical Clinic I, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Raja Atreya
- Medical Clinic I, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
31
|
Rath T, Tontini GE, Neurath MF, Neumann H. From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease. World J Gastroenterol 2015; 21:11260-11272. [PMID: 26523101 PMCID: PMC4616203 DOI: 10.3748/wjg.v21.i40.11260] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/31/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) comprise the two major entities Crohn’s disease and ulcerative colitis and endoscopic imaging of the gastrointestinal tract has always been an integral and central part in the management of IBD patients. Within the recent years, mucosal healing emerged as a key treatment goal in IBD that substantially decides about the clinical outcome of IBD patients, thereby demanding for a precise, timely and detailed endoscopic assessment of the mucosal inflammation associated with IBD. Further, molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapy response. Within this review we describe novel endoscopic approaches and advanced endoscopic imaging methods for the diagnosis, treatment and surveillance of IBD patients. We begin by providing an overview over novel and advanced imaging techniques such as magnification endoscopy and dye-based and dye-less chromoendoscopy, endomicroscopy and endocytoscopy. We then describe how these techniques can be utilized for the precise and ultrastructural assessment of mucosal inflammation and dysplasia development associated with IBD and outline how they have enabled the endoscopist to gain insight onto the cellular level in real-time. Finally, we provide an outlook on how molecular imaging has rapidly evolved in the recent past and can be used to make individual predictions about the therapeutic response towards biological treatment.
Collapse
|
32
|
Zhang D, Jia H, Li W, Hou Y, Lu S, He S. Screening and Identification of a Phage Display Derived Peptide That Specifically Binds to the CD44 Protein Region Encoded by Variable Exons. ACTA ACUST UNITED AC 2015; 21:44-53. [PMID: 26423339 DOI: 10.1177/1087057115608604] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 08/23/2015] [Indexed: 12/12/2022]
Abstract
CD44, especially the isoforms with variable exons (CD44v), is a promising biomarker for the detection of cancer. To develop a CD44v-specific probe, we screened a 7-mer phage peptide library against the CD44v3-v10 protein using an improved subtractive method. The consensus sequences with the highest frequency (designated CV-1) emerged after four rounds of panning. The binding affinity and specificity of the CV-1 phage and the synthesized peptide for the region of CD44 encoded by the variable exons were confirmed using enzyme-linked immunosorbent assay and competitive inhibition assays. Furthermore, the binding of the CV-1 probe to gastric cancer cells and tissues was validated using immunofluorescence and immunohistochemistry assays. CV-1 sensitively and specifically bound to CD44v on cancer cells and tissues. Thus, CV-1 has the potential to serve as a promising probe for cancer molecular imaging and target therapy.
Collapse
Affiliation(s)
- Dan Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, China
| | - Huan Jia
- Department of General Surgery, the First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Weiming Li
- Department of General Surgery, the First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, China
| | - Yingchun Hou
- College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Shaoying Lu
- Department of General Surgery, the First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, China
| |
Collapse
|
33
|
Goetz M. Characterization of lesions in the stomach: will confocal laser endomicroscopy replace the pathologist? Best Pract Res Clin Gastroenterol 2015; 29:589-99. [PMID: 26381304 DOI: 10.1016/j.bpg.2015.05.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 04/27/2015] [Accepted: 05/21/2015] [Indexed: 01/31/2023]
Abstract
Confocal laser endomicroscopy (CLE) permits microscopic visualization of the mucosa during endoscopy at an approximately 1000fold magnification, permitting endoscopists to obtain microscopic analysis during gastroscopy. This can result in optimized diagnosis of diffuse alterations such as gastric atrophy and intestinal metaplasia and may limit the sampling error of untargeted biopsies. It also allows risk stratification prior to endoscopic therapy of neoplastic lesions of the stomach. In these areas, CLE represents a valuable adjunct for targeted histopathology. In addition, CLE allows on-site in vivo imaging, and by this insight into physiologic and pathophysiologic as well as molecular events of the stomach without major artifacts.
Collapse
Affiliation(s)
- Martin Goetz
- Innere Medizin I, Universitätsklinikum Tübingen, 72076 Tübingen, Germany.
| |
Collapse
|
34
|
Zhang D, Jia H, Wang Y, Li WM, Hou YC, Yin SW, Wang TD, He SX, Lu SY. A CD44 specific peptide developed by phage display for targeting gastric cancer. Biotechnol Lett 2015; 37:2311-20. [PMID: 26140900 DOI: 10.1007/s10529-015-1896-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/23/2015] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To develop a peptide probe that could be used for gastric cancer detection via binding to CD44 protein with specificity and affinity. RESULTS A 12-mer phage peptide library was screened against immobilized CD44 protein. Bound phage counts using ELISA were performed to identify phage clones carrying the most highly selective peptide, which termed RP-1. Immunofluorescence and flow cytometry analysis indicated that the consensus peptide RP-1 could bind to CD44-positive gastric cancer cells with mean fluorescence intensities significantly higher than that of CD44-negative cells. CD44 knockdown led to decreased binding activity of RP-1 to the same cell line. Tissue array technique was used to identify the relationship (r = 0.556) between peptide binding and CD44 detection on gastric cancer tissues. Further, the hyaluronan-binding domain of CD44 was docked with RP-1 using computer modeling/docking approaches, revealing a RP-1/CD44 interaction with geometrical and energy match (-8.6 kcal/mol). CONCLUSIONS The RP-1 peptide we screened exhibits affinity and specificity to CD44 on cells and has the potential to be used as a candidate probe for gastric cancer cell targeting.
Collapse
Affiliation(s)
- Dan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, 710061, China.
| | - Huan Jia
- Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China.
| | - Yan Wang
- Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China.
| | - Wei-Ming Li
- Department of General Surgery, The First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Ying-Chun Hou
- College of Life Science, Shaanxi Normal University, Xi'an, 710119, Shaanxi, China.
| | - Shi-Wei Yin
- College of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, 710119, Shaanxi, China.
| | - Thomas D Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Michigan Ann Arbor, Ann Arbor, MI, 48109, USA.
| | - Shui-Xiang He
- Department of Gastroenterology, The First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, 710061, China.
| | - Shao-Ying Lu
- Department of General Surgery, The First Affiliated Hospital of Medical School, Xian Jiaotong University, Xi'an, 710061, Shaanxi, China.
| |
Collapse
|
35
|
Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: State of the art and future perspectives. World J Gastroenterol 2015; 21:21-46. [PMID: 25574078 PMCID: PMC4284336 DOI: 10.3748/wjg.v21.i1.21] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/31/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Distinction between Crohn’s disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
Collapse
|
36
|
Abstract
PURPOSE OF REVIEW The introduction of novel molecular imaging modalities that can not only define disease states on the basis of structural changes and morphology, but also allow in-vivo visualization and characterization of molecular and biochemical alterations on a cellular level add a new dimension to our current diagnostic possibilities. The advents of innovative endoscopic devices coupled with the introduction of novel targeting ligands contribute to the recent advances made in the field of molecular imaging. The purpose of this review is to present and discuss the concepts and the potential of novel endoscopic imaging modalities for immune cell monitoring in the intestine. RECENT FINDINGS Recent progress concerning molecular imaging studies in animals and human patients implicates that this approach can be used to improve detection of mucosal lesions in wide-field imaging and for in-vivo characterization of the mucosa with the ultimate goal of assessing the likelihood of response to targeted therapy with biological agents. In particular, molecular endomicroscopy for assessment of mucosal immune responses ('immunoendoscopy') emerges as a novel approach for optimized endoscopic diagnosis and individualized therapy. SUMMARY Molecular imaging modalities in the intestine have the immediate potential to have an impact on current clinical practice and could therefore open new frontiers for clinical endoscopy and give hope for improved diagnosis and targeted therapies.
Collapse
|
37
|
Teubner D, Kiesslich R, Matsumoto T, Rey JW, Hoffman A. Beyond standard image-enhanced endoscopy confocal endomicroscopy. Gastrointest Endosc Clin N Am 2014; 24:427-34. [PMID: 24975533 DOI: 10.1016/j.giec.2014.03.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Endomicroscopy is a new imaging tool for gastrointestinal endoscopy. In vivo histology becomes possible at subcellular resolution during ongoing colonoscopy. Panchromoendoscopy with targeted biopsies has become the method of choice for surveillance of patients with inflammatory bowel disease. Endomicroscopy can be added after chromoendoscopy to clarify whether standard biopsies are needed. This smart biopsy concept can increase the diagnostic yield of intraepithelial neoplasia and substantially reduce the need for biopsies. Clinical acceptance is increasing because of a multitude of positive studies about the diagnostic value of endomicroscopy. Smart biopsies, functional imaging, and molecular imaging may represent the future for endomicroscopy.
Collapse
Affiliation(s)
- Daniel Teubner
- Department for Internal Medicine, Gastroenterology and Oncology, St Marienkrankenhaus, Richard-Wagner-Street, 14, Frankfurt 60318, Germany
| | - Ralf Kiesslich
- Department for Internal Medicine, Gastroenterology and Oncology, St Marienkrankenhaus, Richard-Wagner-Street, 14, Frankfurt 60318, Germany.
| | - Takayuki Matsumoto
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Johannes W Rey
- Department for Internal Medicine, Gastroenterology and Oncology, St Marienkrankenhaus, Richard-Wagner-Street, 14, Frankfurt 60318, Germany
| | - Arthur Hoffman
- Department for Internal Medicine, Gastroenterology and Oncology, St Marienkrankenhaus, Richard-Wagner-Street, 14, Frankfurt 60318, Germany
| |
Collapse
|
38
|
Karstensen JG, Klausen PH, Saftoiu A, Vilmann P. Molecular confocal laser endomicroscopy: A novel technique for in vivo cellular characterization of gastrointestinal lesions. World J Gastroenterol 2014; 20:7794-7800. [PMID: 24976717 PMCID: PMC4069308 DOI: 10.3748/wjg.v20.i24.7794] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/15/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
While flexible endoscopy is essential for macroscopic evaluation, confocal laser endomicroscopy (CLE) has recently emerged as an endoscopic method enabling visualization at a cellular level. Two systems are currently available, one based on miniprobes that can be inserted via a conventional endoscope or via a needle guided by endoscopic ultrasound. The second system has a confocal microscope integrated into the distal part of an endoscope. By adding molecular probes like fluorescein conjugated antibodies or fluorescent peptides to this procedure (either topically or systemically administered during on-going endoscopy), a novel world of molecular evaluation opens up. The method of molecular CLE could potentially be used for estimating the expression of important receptors in carcinomas, subsequently resulting in immediate individualization of treatment regimens, but also for improving the diagnostic accuracy of endoscopic procedures by identifying otherwise invisible mucosal lesions. Furthermore, studies have shown that fluorescein labelled drugs can be used to estimate the affinity of the drug to a target organ, which probably can be correlated to the efficacy of the drug. However, several of the studies in this research field have been conducted in animal facilities or in vitro, while only a limited number of trials have actually been carried out in vivo. Therefore, safety issues still needs further evaluations. This review will present an overview of the implications and pitfalls, as well as future challenges of molecular CLE in gastrointestinal diseases.
Collapse
|
39
|
Oh G, Yoo SW, Jung Y, Ryu YM, Park Y, Kim SY, Kim KH, Kim S, Myung SJ, Chung E. Intravital imaging of mouse colonic adenoma using MMP-based molecular probes with multi-channel fluorescence endoscopy. BIOMEDICAL OPTICS EXPRESS 2014; 5:1677-89. [PMID: 24877024 PMCID: PMC4026906 DOI: 10.1364/boe.5.001677] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 04/19/2014] [Accepted: 04/21/2014] [Indexed: 05/18/2023]
Abstract
Intravital imaging has provided molecular, cellular and anatomical insight into the study of tumor. Early detection and treatment of gastrointestinal (GI) diseases can be enhanced with specific molecular markers and endoscopic imaging modalities. We present a wide-field multi-channel fluorescence endoscope to screen GI tract for colon cancer using multiple molecular probes targeting matrix metalloproteinases (MMP) conjugated with quantum dots (QD) in AOM/DSS mouse model. MMP9 and MMP14 antibody (Ab)-QD conjugates demonstrate specific binding to colonic adenoma. The average target-to-background (T/B) ratios are 2.10 ± 0.28 and 1.78 ± 0.18 for MMP14 Ab-QD and MMP9 Ab-QD, respectively. The overlap between the two molecular probes is 67.7 ± 8.4%. The presence of false negative indicates that even more number of targeting could increase the sensitivity of overall detection given heterogeneous molecular expression in tumors. Our approach indicates potential for the screening of small or flat lesions that are precancerous.
Collapse
Affiliation(s)
- Gyungseok Oh
- School of Mechatronics, Gwangju Institute of Science and Technology, Gwangju, South Korea
| | - Su Woong Yoo
- Department of Medical System Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea
| | - Yebin Jung
- Department of Chemistry, Pohang University of Science and Technology, Pohang, South Korea
| | - Yeon-Mi Ryu
- Asan Institute for Life sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Youngrong Park
- Department of Chemistry, Pohang University of Science and Technology, Pohang, South Korea
| | - Sang-Yeob Kim
- Asan Institute for Life sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Deparment of Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ki Hean Kim
- Division of Integrative Biosciences and Biotechnology and Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, South Korea
| | - Sungjee Kim
- Department of Chemistry, Pohang University of Science and Technology, Pohang, South Korea
| | - Seung-Jae Myung
- Asan Institute for Life sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Gastroenterology, Asan Medical Center,University of Ulsan College of Medicine, Seoul, South Korea
| | - Euiheon Chung
- School of Mechatronics, Gwangju Institute of Science and Technology, Gwangju, South Korea
- Department of Medical System Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea
| |
Collapse
|
40
|
Chen ZY, Wang YX, Lin Y, Zhang JS, Yang F, Zhou QL, Liao YY. Advance of molecular imaging technology and targeted imaging agent in imaging and therapy. BIOMED RESEARCH INTERNATIONAL 2014; 2014:819324. [PMID: 24689058 PMCID: PMC3943245 DOI: 10.1155/2014/819324] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/29/2013] [Accepted: 12/30/2013] [Indexed: 02/06/2023]
Abstract
Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy.
Collapse
Affiliation(s)
- Zhi-Yi Chen
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yi-Xiang Wang
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Yan Lin
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Jin-Shan Zhang
- Department of Nuclear Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Feng Yang
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Qiu-Lan Zhou
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yang-Ying Liao
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| |
Collapse
|
41
|
Yang C, Hou VW, Girard EJ, Nelson LY, Seibel EJ. Target-to-background enhancement in multispectral endoscopy with background autofluorescence mitigation for quantitative molecular imaging. JOURNAL OF BIOMEDICAL OPTICS 2014; 19:76014. [PMID: 25027002 PMCID: PMC4098034 DOI: 10.1117/1.jbo.19.7.076014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 06/25/2014] [Indexed: 05/05/2023]
Abstract
Fluorescence molecular imaging with exogenous probes improves specificity for the detection of diseased tissues by targeting unambiguous molecular signatures. Additionally, increased diagnostic sensitivity is expected with the application of multiple molecular probes. We developed a real-time multispectral fluorescence-reflectance scanning fiber endoscope (SFE) for wide-field molecular imaging of fluorescent dye-labeled molecular probes at nanomolar detection levels. Concurrent multichannel imaging with the wide-field SFE also allows for real-time mitigation of the background autofluorescence (AF) signal, especially when fluorescein, a U.S. Food and Drug Administration approved dye, is used as the target fluorophore. Quantitative tissue AF was measured for the ex vivo porcine esophagus and murine brain tissues across the visible and nearinfrared spectra. AF signals were then transferred to the unit of targeted fluorophore concentration to evaluate the SFE detection sensitivity for sodium fluorescein and cyanine. Next, we demonstrated a real-time AF mitigation algorithm on a tissue phantom, which featured molecular probe targeted cells of high-grade dysplasia on a substrate containing AF species. The target-to-background ratio was enhanced by more than one order of magnitude when applying the real-time AF mitigation algorithm. Furthermore, a quantitative estimate of the fluorescein photodegradation (photobleaching) rate was evaluated and shown to be insignificant under the illumination conditions of SFE. In summary, the multichannel laser-based flexible SFE has demonstrated the capability to provide sufficient detection sensitivity, image contrast, and quantitative target intensity information for detecting small precancerous lesions in vivo.
Collapse
Affiliation(s)
- Chenying Yang
- University of Washington, Department of Bioengineering, Seattle, Washington 98195, United States
| | - Vivian W. Hou
- University of Washington, Department of Biology, Seattle, Washington 98195, United States
| | - Emily J. Girard
- Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington 98109, United States
| | - Leonard Y. Nelson
- University of Washington, Department of Mechanical Engineering, Seattle, Washington 98195, United States
| | - Eric J. Seibel
- University of Washington, Department of Mechanical Engineering, Seattle, Washington 98195, United States
- Address all correspondence to: Eric J. Seibel,
| |
Collapse
|
42
|
Kim SY, Myung SJ. Optical molecular imaging for diagnosing intestinal diseases. Clin Endosc 2013; 46:620-6. [PMID: 24340254 PMCID: PMC3856262 DOI: 10.5946/ce.2013.46.6.620] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 10/12/2013] [Accepted: 10/17/2013] [Indexed: 12/20/2022] Open
Abstract
Real-time visualization of the molecular signature of cells can be achieved with advanced targeted imaging techniques using molecular probes and fluorescence endoscopy. This molecular optical imaging in gastrointestinal endoscopy is promising for improving the detection of neoplastic lesions, their characterization for patient stratification, and the assessment of their response to molecular targeted therapy and radiotherapy. In inflammatory bowel disease, this method can be used to detect dysplasia in the presence of background inflammation and to visualize inflammatory molecular targets for assessing disease severity and prognosis. Several preclinical and clinical trials have applied this method in endoscopy; however, this field has just started to evolve. Hence, many problems have yet to be solved to enable the clinical application of this novel method.
Collapse
Affiliation(s)
- Sang-Yeob Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | |
Collapse
|