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Shrestha B, Stern NB, Zhou A, Dunn A, Porter T. Current trends in the characterization and monitoring of vascular response to cancer therapy. Cancer Imaging 2024; 24:143. [PMID: 39438891 PMCID: PMC11515715 DOI: 10.1186/s40644-024-00767-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 08/26/2024] [Indexed: 10/25/2024] Open
Abstract
Tumor vascular physiology is an important determinant of disease progression as well as the therapeutic outcome of cancer treatment. Angiogenesis or the lack of it provides crucial information about the tumor's blood supply and therefore can be used as an index for cancer growth and progression. While standalone anti-angiogenic therapy demonstrated limited therapeutic benefits, its combination with chemotherapeutic agents improved the overall survival of cancer patients. This could be attributed to the effect of vascular normalization, a dynamic process that temporarily reverts abnormal vasculature to the normal phenotype maximizing the delivery and intratumor distribution of chemotherapeutic agents. Longitudinal monitoring of vascular changes following antiangiogenic therapy can indicate an optimal window for drug administration and estimate the potential outcome of treatment. This review primarily focuses on the status of various imaging modalities used for the longitudinal characterization of vascular changes before and after anti-angiogenic therapies and their clinical prospects.
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Affiliation(s)
- Binita Shrestha
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.
| | - Noah B Stern
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Annie Zhou
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Andrew Dunn
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Tyrone Porter
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
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Molecular Profiling of EGFR Status to Identify Skin Toxicity in Colorectal Cancer: A Clinicopathological Review. CURRENT HEALTH SCIENCES JOURNAL 2019; 45:127-133. [PMID: 31624638 PMCID: PMC6778291 DOI: 10.12865/chsj.45.02.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/20/2019] [Indexed: 11/24/2022]
Abstract
Colorectal cancer (CRC) represents an important health problem, being the third most common type of cancer. In Romania, the CRC incidence has doubled over the years. Both environmental factors and genetic susceptibility are very important for the pathogenesis of CRC. The epidermal growth factor receptor (EGFR) plays an extremely important role in CRC tumorigenesis. Overexpression or dysregulation of EGFR pathway molecules are frequently associated with tumor aggressiveness and patient response to treatment. Based on these considerations, EGFR became one of the first targets of molecular therapies used in CRC. At present, cetuximab and panitumumab are considered to be essential in the treatment of patients with metastatic colorectal cancer expressing the KRAS wild-type gene and EGFR. The main adverse effect for both cetuximab and panitumumab is skin toxicity, present in approximately 80% of patients. The risk of secondary infections, in particular of bacterial infections, is also increased. Cases of staphylococcal infection associated with skin peeling, cellulite, erysipelas, and even Staphylococcus sepsis, were reported. For a long time cutaneous toxicity has been a positive predictor in the efficacy of anti-EGFR treatment, but compliance with treatment and the quality of life of patients with metastatic CRC decreases in the presence of these skin reactions. That is why we emphasize the necessity and importance of using a modern method (molecular analysis of gene polymorphisms possibly supplemented by targeted confocal laser endomicroscopy) to identify a molecular diagnosis, in order to foresee and prevent the appearance of skin reactions and to manage skin toxicity.
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Patelunas AJ, Nishiguchi MK. Vascular architecture in the bacteriogenic light organ of Euprymna tasmanica (Cephalopoda: Sepiolidae). INVERTEBRATE BIOLOGY : A QUARTERLY JOURNAL OF THE AMERICAN MICROSCOPICAL SOCIETY AND THE DIVISION OF INVERTEBRATE ZOOLOGY/ASZ 2018; 137:240-249. [PMID: 30853777 PMCID: PMC6405259 DOI: 10.1111/ivb.12223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Symbiosis between southern dumpling squid, Euprymna tasmanica (Cephalopoda: Sepiolidae), and its luminescent symbiont, the bacterium Vibrio fischeri, provides an experimentally tractable system to examine interactions between the eukaryotic host and its bacterial partner. Luminescence emitted by the symbiotic bacteria provides light for the squid in a behavior termed "counter-illumination," which allows the squid to mask its shadow amidst downwelling moonlight. Although this association is beneficial, light generated from the bacteria requires large quantities of oxygen to maintain this energy-consuming reaction. Therefore, we examined the vascular network within the light organ of juveniles of E. tasmanica with and without V. fischeri. Vessel type, diameter, and location of vessels were measured. Although differences between symbiotic and aposymbiotic squid demonstrated that the presence of V. fischeri does not significantly influence the extent of vascular branching at early stages of symbiotic development, these finding do provide an atlas of blood vessel distribution in the organ. Thus, these results provide a framework to understand how beneficial bacteria influence the development of a eukaryotic closed vascular network and provide insight to the evolutionary developmental dynamics that form during mutualistic interactions.
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Cârţână ET, Gheonea DI, Cherciu IF, Streaţă I, Uscatu CD, Nicoli ER, Ioana M, Pirici D, Georgescu CV, Alexandru DO, Şurlin V, Gruionu G, Săftoiu A. Assessing tumor angiogenesis in colorectal cancer by quantitative contrast-enhanced endoscopic ultrasound and molecular and immunohistochemical analysis. Endosc Ultrasound 2018; 7:175-183. [PMID: 28685747 PMCID: PMC6032701 DOI: 10.4103/eus.eus_7_17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Data on contrast-enhanced endoscopic ultrasound (CE-EUS) for colorectal cancer (CRC) evaluation are scarce. Therefore, we aimed to assess the vascular perfusion pattern in CRC by quantitative CE-EUS and compare it to immunohistochemical and genetic markers of angiogenesis. PATIENTS AND METHODS We performed a retrospective analysis of CE-EUS examinations of 42 CRC patients, before any therapy. CE-EUS movies were processed using a dedicated software. Ten parameters were automatically generated from the time-intensity curve (TIC) analysis: peak enhancement (PE), rise time (RT), mean transit time, time to peak (TTP), wash-in area under the curve (WiAUC), wash-in rate (WiR), wash-in perfusion index (WiPI), wash-out AUC (WoAUC), and wash-in and wash-out AUC (WiWoAUC). The expression levels of the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 genes were assessed from biopsy samples harvested during colonoscopy. Microvascular density and vascular area were calculated after CD31 and CD105 immunostaining. RESULTS Forty-two CE-EUS video sequences were analyzed. We found positive correlations between the parameters PE, WiAUC, WiR, WiPI, WoAUC, WiWoAUC, and N staging (Spearman r = 0.437, r = 0.336, r = 0.462, r = 0.437, r = 0.358, and r = 0.378, respectively, P < 0.05), and also between RT and TTP and CD31 vascular area (r = 0.415, and r = 0.421, respectively, P < 0.05). VEGFR1 and VEGFR2 expression did not correlate with any of the TIC parameters. CONCLUSIONS CE-EUS with TIC analysis enables minimally invasive assessment of CRC angiogenesis and may provide information regarding the lymph nodes invasion. However, further studies are needed for defining its role in the evaluation of CRC patients.
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Affiliation(s)
- Elena-Tatiana Cârţână
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Dan Ionuţ Gheonea
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Irina Florina Cherciu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Ioana Streaţă
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | | | - Elena-Raluca Nicoli
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Mihai Ioana
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Daniel Pirici
- Department of Research Methodology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | | | - Dragoş-Ovidiu Alexandru
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Valeriu Şurlin
- Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Gabriel Gruionu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Clinical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Department of Endoscopy, Copenhagen University Hospital Herlev, Denmark
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De Palma GD, Colavita I, Zambrano G, Giglio MC, Maione F, Luglio G, Sarnelli G, Rispo A, Schettino P, D’Armiento FP, De Palma FDE, D’Argenio V, Salvatore F. Detection of colonic dysplasia in patients with ulcerative colitis using a targeted fluorescent peptide and confocal laser endomicroscopy: A pilot study. PLoS One 2017; 12:e0180509. [PMID: 28666016 PMCID: PMC5493408 DOI: 10.1371/journal.pone.0180509] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 06/18/2017] [Indexed: 02/07/2023] Open
Abstract
AIM Targeted molecular probes have been used to detect sporadic colonic dysplasia during confocal laser endomicroscopy (CLE) with promising results. This is a feasibility pilot study aiming to assess the potential role of CLE combined with a fluorescent-labeled peptide to stain and detect dysplasia associated with Ulcerative Colitis. METHOD A phage-derived heptapeptide with predicted high binding affinity for dysplastic tissue, was synthesized and labeled with fluorescein. Eleven lesions with suspected dysplasia at endoscopy were excised from nine patients with long-standing ulcerative colitis. Specimens were sprayed with the peptide and examined by CLE. The CLE images were then compared to the corresponding histological sections. RESULTS At definitive histology, 4 lesions were diagnosed as inflammatory polyps, 6 as dysplastic lesions and one as invasive cancer. In inflammatory polyps, the fluorescence signal came from peri-cryptal spaces and crypt lumen due to passive accumulation of the peptide in these areas. Dysplasia was associated with active binding of the peptide to dysplastic colonocytes. CONCLUSION Ex vivo staining of ulcerative colitis-associated dysplasia using a fluorescent labeled molecular probe and CLE is feasible. In vivo studies on larger populations are required to evaluate the safety and the effective contribution of molecular probes in cancer surveillance of ulcerative colitis.
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Affiliation(s)
| | | | - Gerardo Zambrano
- CEINGE-Biotecnologie Avanzate, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Mariano Cesare Giglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Francesco Maione
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Gaetano Luglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonio Rispo
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Pietro Schettino
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | | | - Fatima Domenica Elisa De Palma
- CEINGE-Biotecnologie Avanzate, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Valeria D’Argenio
- CEINGE-Biotecnologie Avanzate, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Francesco Salvatore
- CEINGE-Biotecnologie Avanzate, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
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Li C, Guan X, Sun B, Ma M, Wang P, Gai X. Vector-mediated Tum-5 expression in neovascular endothelial cells for treating hepatocellular carcinoma. Exp Ther Med 2017; 13:1521-1525. [PMID: 28413503 DOI: 10.3892/etm.2017.4127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 10/18/2016] [Indexed: 12/15/2022] Open
Abstract
Hypervascular hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality. Angiogenesis is an important contributor to HCC progression and metastasis; therefore, inhibiting angiogenesis may be an effective method of treating HCC. Tumstatin is a novel type of efficient endogenous vascular endothelial cell growth inhibiting factor. The anti-angiogenic activity of tumstatin is localized to the 54-132 amino acid region (Tum-5). In a previous study performed by our group, the gene fragment encoding Tum-5 was cloned and inserted into a pLXSN retroviral vector. In the present study, the anti-angiogenic effects of Tum-5 and the antitumor effects exerted by the pLXSN-Tum-5 vector in vivo were investigated. The results demonstrated that pLXSN-Tum-5 significantly inhibited the growth of human umbilical vein endothelial cells compared with pLXSN, but had no obvious effect on HepG2 cell growth. Moreover, the antitumor and anti-angiogenic activity of Tum-5 was examined in vivo using a xenograft of H22 HCC cells. The results indicated that pLXSN-Tum-5 significantly inhibited tumor growth following 5 injections over 10 days. The size and weight of tumors in the pLXSN-Tum-5 group were lower than those in the saline and pLXSN groups. Furthermore, immunohistochemical analysis with CD31 antibodies indicated that the average microvessel density in the pLXSN-Tum-5 group were significantly lower than that in the saline and pLXSN groups. These results suggested that Tum-5 exerts its antitumor activity by suppressing vascular endothelial cells. The gene fragment of Tum-5 may be developed as an effective inhibitor of angiogenesis and used to treat patients with HCC.
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Affiliation(s)
- Chun Li
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Xingang Guan
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Boqian Sun
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Mingyao Ma
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Peng Wang
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Xiaodong Gai
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin City, Jilin 132013, P.R. China
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Marien KM, Croons V, Waumans Y, Sluydts E, De Schepper S, Andries L, Waelput W, Fransen E, Vermeulen PB, Kockx MM, De Meyer GRY. Development and Validation of a Histological Method to Measure Microvessel Density in Whole-Slide Images of Cancer Tissue. PLoS One 2016; 11:e0161496. [PMID: 27583442 PMCID: PMC5008750 DOI: 10.1371/journal.pone.0161496] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/05/2016] [Indexed: 12/17/2022] Open
Abstract
Despite all efforts made to develop predictive biomarkers for antiangiogenic therapies, no unambiguous markers have been identified so far. This is due to among others the lack of standardized tests. This study presents an improved microvessel density quantification method in tumor tissue based on stereological principles and using whole-slide images. Vessels in tissue sections of different cancer types were stained for CD31 by an automated and validated immunohistochemical staining method. The stained slides were digitized with a digital slide scanner. Systematic, uniform, random sampling of the regions of interest on the whole-slide images was performed semi-automatically with the previously published applications AutoTag and AutoSnap. Subsequently, an unbiased counting grid was combined with the images generated with these scripts. Up to six independent observers counted microvessels in up to four cancer types: colorectal carcinoma, glioblastoma multiforme, ovarian carcinoma and renal cell carcinoma. At first, inter-observer variability was found to be unacceptable. However, after a series of consensus training sessions and interim statistical analysis, counting rules were modified and inter-observer concordance improved considerably. Every CD31-positive object was counted, with exclusion of suspected CD31-positive monocytes, macrophages and tumor cells. Furthermore, if interconnected, stained objects were considered a single vessel. Ten regions of interest were sufficient for accurate microvessel density measurements. Intra-observer and inter-observer variability were low (intraclass correlation coefficient > 0.7) if the observers were adequately trained.
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Affiliation(s)
- Koen M. Marien
- Division of Physiopharmacology, University of Antwerp, Antwerp, Belgium
- HistoGeneX NV, Antwerp, Belgium
- * E-mail:
| | | | | | | | | | | | - Wim Waelput
- Department of Pathology, University Hospital Brussels (UZ Brussel), Brussels, Belgium
| | - Erik Fransen
- StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium
| | - Peter B. Vermeulen
- CORE (Translational Cancer Research Unit, GZA Hospitals), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Karstensen JG, Săftoiu A, Brynskov J, Hendel J, Ciocalteu A, Klausen P, Klausen TW, Riis LB, Vilmann P. Confocal laser endomicroscopy in ulcerative colitis: a longitudinal study of endomicroscopic changes and response to medical therapy (with videos). Gastrointest Endosc 2016; 84:279-286.e1. [PMID: 26945556 DOI: 10.1016/j.gie.2016.01.069] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy enables real-time in vivo microscopy during endoscopy and can predict relapse in patients with inflammatory bowel disease in remission. However, little is known about how endomicroscopic features change with time. The aim of this longitudinal study was to correlate colonic confocal laser endomicroscopy (CLE) in ulcerative colitis with histopathology and macroscopic appearance before and after intensification of medical treatment. METHODS Twenty-two patients with ulcerative colitis in clinical relapse and 7 control subjects referred for colonoscopy were enrolled. The colonic mucosa was examined with high-definition colonoscopy, histopathology, and CLE at 4 colonic sites. Subsequently, patients requiring medical treatment escalation were referred for repeat endoscopy with CLE after 6 to 8 weeks. RESULTS The baseline frequency of fluorescein leakage (P < .001), microerosions (P < .001), tortuosity of the crypts (P = .001), distortion of the crypts openings (P = .001), presence of inflammatory infiltrates (P < .001), and decreased crypt density (P < .001) were significantly higher in active ulcerative colitis compared with inactive ulcerative colitis and control subjects. A decrease in histopathologic score after medical treatment escalation was correlated with improvement in crypt tortuosity (rs = .35, P = .016), distortion of crypt openings (rs = .30, P = .045), and decreased crypt density (rs = .33, P = .026) but not in other features. CONCLUSIONS CLE is an emerging endoscopic technique that reproducibly identifies mucosal changes in ulcerative colitis. With the exception of crypt changes, endomicroscopic features appear to improve slowly with time after medical treatment. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01684514.).
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Affiliation(s)
- John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Adrian Săftoiu
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark; Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Craiova, Romania
| | - Jørn Brynskov
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Jakob Hendel
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Adriana Ciocalteu
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark; Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Craiova, Romania
| | - Pia Klausen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | | | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
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Ştefănescu D, Streba C, Cârţână ET, Săftoiu A, Gruionu G, Gruionu LG. Computer Aided Diagnosis for Confocal Laser Endomicroscopy in Advanced Colorectal Adenocarcinoma. PLoS One 2016; 11:e0154863. [PMID: 27144985 PMCID: PMC4856267 DOI: 10.1371/journal.pone.0154863] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 04/20/2016] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Confocal laser endomicroscopy (CLE) is becoming a popular method for optical biopsy of digestive mucosa for both diagnostic and therapeutic procedures. Computer aided diagnosis of CLE images, using image processing and fractal analysis can be used to quantify the histological structures in the CLE generated images. The aim of this study is to develop an automatic diagnosis algorithm of colorectal cancer (CRC), based on fractal analysis and neural network modeling of the CLE-generated colon mucosa images. MATERIALS AND METHODS We retrospectively analyzed a series of 1035 artifact-free endomicroscopy images, obtained during CLE examinations from normal mucosa (356 images) and tumor regions (679 images). The images were processed using a computer aided diagnosis (CAD) medical imaging system in order to obtain an automatic diagnosis. The CAD application includes image reading and processing functions, a module for fractal analysis, grey-level co-occurrence matrix (GLCM) computation module, and a feature identification module based on the Marching Squares and linear interpolation methods. A two-layer neural network was trained to automatically interpret the imaging data and diagnose the pathological samples based on the fractal dimension and the characteristic features of the biological tissues. RESULTS Normal colon mucosa is characterized by regular polyhedral crypt structures whereas malignant colon mucosa is characterized by irregular and interrupted crypts, which can be diagnosed by CAD. For this purpose, seven geometric parameters were defined for each image: fractal dimension, lacunarity, contrast correlation, energy, homogeneity, and feature number. Of the seven parameters only contrast, homogeneity and feature number were significantly different between normal and cancer samples. Next, a two-layer feed forward neural network was used to train and automatically diagnose the malignant samples, based on the seven parameters tested. The neural network operations were cross-entropy with the results: training: 0.53, validation: 1.17, testing: 1.17, and percent error, resulting: training: 16.14, validation: 17.42, testing: 15.48. The diagnosis accuracy error was 15.5%. CONCLUSIONS Computed aided diagnosis via fractal analysis of glandular structures can complement the traditional histological and minimally invasive imaging methods. A larger dataset from colorectal and other pathologies should be used to further validate the diagnostic power of the method.
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Affiliation(s)
- Daniela Ştefănescu
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy, Craiova, Romania
| | - Costin Streba
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy, Craiova, Romania
| | - Elena Tatiana Cârţână
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy, Craiova, Romania
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy, Craiova, Romania
- Endoscopy Department, Copenhagen University Hospital, Herlev, Denmark
| | - Gabriel Gruionu
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
- Department of Engineering and Management of Technological Systems, Faculty of Mechanics, University of Craiova, Craiova, Romania
| | - Lucian Gheorghe Gruionu
- Department of Engineering and Management of Technological Systems, Faculty of Mechanics, University of Craiova, Craiova, Romania
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Fugazza A, Gaiani F, Carra MC, Brunetti F, Lévy M, Sobhani I, Azoulay D, Catena F, de'Angelis GL, de'Angelis N. Confocal Laser Endomicroscopy in Gastrointestinal and Pancreatobiliary Diseases: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4638683. [PMID: 26989684 PMCID: PMC4773527 DOI: 10.1155/2016/4638683] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/31/2015] [Indexed: 12/15/2022]
Abstract
Confocal laser endomicroscopy (CLE) is an endoscopic-assisted technique developed to obtain histopathological diagnoses of gastrointestinal and pancreatobiliary diseases in real time. The objective of this systematic review is to analyze the current literature on CLE and to evaluate the applicability and diagnostic yield of CLE in patients with gastrointestinal and pancreatobiliary diseases. A literature search was performed on MEDLINE, EMBASE, Scopus, and Cochrane Oral Health Group Specialized Register, using pertinent keywords without time limitations. Both prospective and retrospective clinical studies that evaluated the sensitivity, specificity, or accuracy of CLE were eligible for inclusion. Of 662 articles identified, 102 studies were included in the systematic review. The studies were conducted between 2004 and 2015 in 16 different countries. CLE demonstrated high sensitivity and specificity in the detection of dysplasia in Barrett's esophagus, gastric neoplasms and polyps, colorectal cancers in inflammatory bowel disease, malignant pancreatobiliary strictures, and pancreatic cysts. Although CLE has several promising applications, its use has been limited by its low availability, high cost, and need of specific operator training. Further clinical trials with a particular focus on cost-effectiveness and medicoeconomic analyses, as well as standardized institutional training, are advocated to implement CLE in routine clinical practice.
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Affiliation(s)
- Alessandro Fugazza
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | - Federica Gaiani
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | | | - Francesco Brunetti
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Michaël Lévy
- Department of Gastroenterology and Digestive Endoscopy, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Iradj Sobhani
- Department of Gastroenterology and Digestive Endoscopy, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
- Cancer Research Lab. EC2M3, Université Paris-Est, Val de Marne UPEC, 94010 Créteil, France
| | - Daniel Azoulay
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
| | - Fausto Catena
- Emergency Surgery Department, University of Parma, 43100 Parma, Italy
| | - Gian Luigi de'Angelis
- Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy
| | - Nicola de'Angelis
- Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, 94010 Créteil, France
- Cancer Research Lab. EC2M3, Université Paris-Est, Val de Marne UPEC, 94010 Créteil, France
- Department of Advanced Biomedical Sciences, University Federico II of Naples, 80138 Naples, Italy
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De Palma GD, Maione F, Esposito D, Luglio G, Giglio MC, Siciliano S, Gennarelli N, Cassese G, Campione S, D'Armiento FP, Bucci L. In vivo assessment of tumour angiogenesis in colorectal cancer: the role of confocal laser endomicroscopy. Colorectal Dis 2016; 18:O66-O73. [PMID: 26589643 DOI: 10.1111/codi.13222] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 10/08/2015] [Indexed: 12/13/2022]
Abstract
AIM Tumour neoangiogenesis is a key factor in tumour progression and metastatic spread and the possibility to assess tumour angiogenesis might provide prognostic information. The aim of this study was to establish the role of probe-based confocal laser endomicroscopy (p-CLE) in the identification of vascular architecture and specific morphological patterns in normal colorectal mucosa and malignant lesions during routine endoscopy. METHOD Fourteen consecutive patients with colorectal cancer were included. The following features were identified and then compared between normal and neoplastic mucosa on p-CLE images: vessel shape (straight vs irregular) vessel diameter the 'branching patterns' vessel permeability (fluorescein leakage) and blood flow (normal vs defective flux). Immunohistochemistry was used to confirm the presence and to study the morphology of vascular structures (CD-34 staining) and 'neo-vessels' (WT-1 staining) on tumour and normal mucosal sections. RESULTS Tumour vessels appeared as irregular, ectatic and with a highly variable calibre and branching patterns on p-CLE images. The mean diameter of tumour vessels was significantly larger than those in normal mucosa (weighted mean difference 3.38, 95% CI 2.65-4.11, P = 0.01). Similarly, 'vessel branching' (OR 2.74, 95% CI 1.23-6.14, P = 0.01), fluorescent dye 'extravasation' (OR 3.46, 95% CI 1.39-8.57, P = 0.01) were significantly more frequent in colorectal cancer than in normal colorectal mucosa. Immunohistochemistry corroborated the p-CLE findings, showing higher vascularity in tumour sections due to neoformed vessels, presenting irregular patterns. CONCLUSION Probe-based confocal laser endomicroscopy provides a noninvasive characterization of the microvascular architecture of colonic mucosa. Different morphological patterns have been described, discriminating normal and malignant microvascular networks in colorectal mucosa.
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Affiliation(s)
- G D De Palma
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - F Maione
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - D Esposito
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - G Luglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - M C Giglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - S Siciliano
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - N Gennarelli
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - G Cassese
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
| | - S Campione
- Department of Advanced Biomedical Sciences, University of Naples Federico II, School of Medicine, Naples, Italy
| | - F P D'Armiento
- Department of Advanced Biomedical Sciences, University of Naples Federico II, School of Medicine, Naples, Italy
| | - L Bucci
- Department of Clinical Medicine and Surgery, University of Naples Federico II, School of Medicine, Naples, Italy
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Atkinson CD, Singh SK. Luminal Confocal Laser Endomicroscopy. ENDOSCOPIC IMAGING TECHNIQUES AND TOOLS 2016:83-114. [DOI: 10.1007/978-3-319-30053-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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13
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Ciocâlteu A, Săftoiu A, Pirici D, Georgescu CV, Cârţână T, Gheonea DI, Gruionu LG, Cristea CG, Gruionu G. Tumor neoangiogenesis detection by confocal laser endomicroscopy and anti-CD105 antibody: Pilot study. World J Gastrointest Oncol 2015; 7:361-368. [PMID: 26600936 PMCID: PMC4644859 DOI: 10.4251/wjgo.v7.i11.361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/09/2015] [Accepted: 08/25/2015] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate neoangiogenesis in patients with colon cancer by two fluorescently labeled antibodies on fresh biopsy samples imaged with confocal laser endomicroscopy (CLE). METHODS CLE is an imaging technique for gastrointestinal endoscopy providing in vivo microscopy at subcellular resolution. An important question in validating tumor angiogenesis is what proportion of the tumor vascular network is represented by pre-existing parent tissue vessels and newly formed vessels. CD105 (endoglin) represents a proliferation-associated endothelial cell adhesion molecule. In contrast to pan-endothelial markers, such as CD31, CD105 is preferentially expressed in activated endothelial cells that participate in neovascularization. Thus, we evaluated CD105 and CD31 expression from samples of ten patients with primary rectal adenocarcinoma, using a dedicated endomicroscopy system. A imaging software was used to obtain the Z projection of the confocal serial images from each biopsy sample previously combined into stacks. Vascular density and vessel diameters were measured within two 50 μm x 475 μm rectangular regions of interest centered in the middle of each image in the horizontal and vertical direction. The results were averaged over all the patients and were expressed as the mean ± SE. RESULTS The use of an anti-CD105 antibody was found to be suitable for the detection of blood vessels in colon cancer. Whereas anti-CD31 antibodies stained blood vessels in both normal and pathologic colon equally, CD105 expression was observed primarily in malignant lesions, with little or no expression in the vessels of the normal mucosa (244.21 ± 130.7 vessels/mm(3) in only four patients). The average diameter of anti-CD105 stained vessels was 10.97 ± 0.6 μm in tumor tissue, and the vessel density was 2787.40 ± 134.8 vessels/mm(3). When using the anti-CD31 antibody, the average diameter of vessels in the normal colon tissue was 7.67 ± 0.5 μm and the vessel density was 3191.60 ± 387.8 vessels/mm(3), while in the tumors we obtained an average diameter of 10.88 ± 0.8 μm and a vessel density of 4707.30 ± 448.85 vessels/mm(3). Thus, there were more vessels stained with CD31 than CD105 (P < 0.05). The average vessel diameter was similar for both CD31 and CD105 staining. A qualitative comparison between CLE vs immunohistochemistry lead to similar results. CONCLUSION Specific imaging and quantification of tumor microvessels are feasible in human rectal cancer using CLE examination and CD105 immunostaining of fresh tissue samples.
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Ciocâlteu A, Pirici D, Stefanescu A, Georgescu CV, Şurlin V, Săftoiu A. Endomicroscopy with Fluorescent CD105 Antibodies for "In Vivo" Imaging of Colorectal Cancer Angiogenesis. CURRENT HEALTH SCIENCES JOURNAL 2015; 41:288-292. [PMID: 30538832 PMCID: PMC6246985 DOI: 10.12865/chsj.41.03.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/15/2015] [Indexed: 11/25/2022]
Abstract
The aim of this case report was to evaluate the feasibility of in vivo acquisition of microscopic images using fluorescent CD105 antibodies for molecular imaging in human colorectal cancer. After excluding the presence of tissue autofluorescence, the antibody solution was topically administered through a spray-catheter. The targeted area was analyzed by eCLE and images were recorded. The fractal dimension of tumor vessels and the vessel density were determined using ImageJ software. Immunohistochemistry was used as a gold standard. In vivo CLE analysis of CD105 expression enabled the study of tumor vascular network, revealing a chaotic structure.
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Affiliation(s)
- A Ciocâlteu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
| | - D Pirici
- Department of Research Methodology, University of Medicine and Pharmacy of Craiova, Romania
| | - A Stefanescu
- Department of Research Methodology, University of Medicine and Pharmacy of Craiova, Romania
| | - C V Georgescu
- Department of Pathology, Emergency County Hospital, Craiova, Romania
| | - V Şurlin
- Department of Surgery, University of Medicine and Pharmacy of Craiova, Romania
| | - A Săftoiu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania
- Endoscopy Department, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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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.
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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.
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Ciocâlteu A, Săftoiu A, Cârţână T, Gruionu LG, Pirici D, Georgescu CC, Georgescu CV, Gheonea DI, Gruionu G. Evaluation of new morphometric parameters of neoangiogenesis in human colorectal cancer using confocal laser endomicroscopy (CLE) and targeted panendothelial markers. PLoS One 2014; 9:e91084. [PMID: 24614504 PMCID: PMC3948726 DOI: 10.1371/journal.pone.0091084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 02/07/2014] [Indexed: 12/17/2022] Open
Abstract
The tumor microcirculation is characterized by an abnormal vascular network with dilated, tortuous and saccular vessels. Therefore, imaging the tumor vasculature and determining its morphometric characteristics represent a critical goal for optimizing the cancer treatment that targets the blood vessels (i.e. antiangiogenesis therapy). The aim of this study was to evaluate new vascular morphometric parameters in colorectal cancer, difficult to achieve through conventional immunohistochemistry, by using the confocal laser endomicroscopy method. Fresh biopsies from tumor and normal tissue were collected during colonoscopy from five patients with T3 colorectal carcinoma without metastasis and were marked with fluorescently labeled anti-CD31 antibodies. A series of optical slices spanning 250 µm inside the tissue were immediately collected for each sample using a confocal laser endomicroscope. All measurements were expressed as the mean ± standard error. The mean diameter of tumor vessels was significantly larger than the normal vessels (9.46±0.4 µm vs. 7.60±0.3 µm, p = 0.0166). The vessel density was also significantly higher in the cancer vs. normal tissue samples (5541.05±262.81 vs. 3755.79±194.96 vessels/mm3, p = 0.0006). These results were confirmed by immunohistochemistry. In addition, the tortuosity index and vessel lengths were not significantly different (1.05±0.016 and 28.30±3.27 µm in normal tissue, vs. 1.07±0.008 and 26.49±3.18 µm in tumor tissue respectively, p = 0.5357 and p = 0.7033). The daughter/mother ratio (ratio of the sum of the squares of daughter vessel radii over the square of the mother vessel radius) was 1.15±0.09 in normal tissue, and 1.21±0.08 in tumor tissue (p = 0.6531). The confocal laser endomicroscopy is feasible for measuring more vascular parameters from fresh tumor biopsies than conventional immunohistochemistry alone. Provided new contrast agents will be clinically available, future in vivo use of CLE could lead to identification of novel biomarkers based on the morphometric characteristics of tumor vasculature.
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Affiliation(s)
- Adriana Ciocâlteu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Tatiana Cârţână
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Lucian Gheorghe Gruionu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Department of Mechanical Engineering, University of Craiova, Craiova, Romania
| | - Daniel Pirici
- Department of Histology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Corneliu Cristian Georgescu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Department of Anesthesiology and Intensive Care, Emergency County Hospital, Craiova, Romania
| | | | - Dan Ionuţ Gheonea
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Gabriel Gruionu
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Edwin L. Steele Laboratory of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
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Qiu Y, Fu XS, Peng Y. Endoscopic diagnosis of sessile serrated adenoma. Shijie Huaren Xiaohua Zazhi 2014; 22:801-806. [DOI: 10.11569/wcjd.v22.i6.801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sessile serrated adenoma (SSA) is a special type of serrated adenoma, and recent studies have found that SSA has a malignant potential, progresses quickly and is closely related to right-sided colorectal cancer. SSA is usually located in the proximal colon, which is flat and sessile, and for this reason, SSA is difficult to find by conventional endoscopy and has a high rate of missed diagnosis. There is currently an urgent need to develop new endoscopic technologies to raise the diagnosis rate. In this paper, we will review recent progress in the diagnosis of sessile serrated adenoma using new endoscopic technologies.
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Gong L, Cumpian AM, Caetano MS, Ochoa CE, De la Garza MM, Lapid DJ, Mirabolfathinejad SG, Dickey BF, Zhou Q, Moghaddam SJ. Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase. Mol Cancer 2013; 12:154. [PMID: 24321240 PMCID: PMC3923587 DOI: 10.1186/1476-4598-12-154] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 11/29/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. Neutrophils are among the first cells to arrive at sites of inflammation, and the increased number of tumor-associated neutrophils is linked to poorer outcome in patients with lung cancer. RESULTS We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with severe lung neutrophilic influx due to the increased level of neutrophil chemoattractant, KC. To further study the role of neutrophils in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody. This resulted in a significant reduction in lung tumor number. We further selectively inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2. Similarly, this resulted in suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant tumor reduction. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. We crossed the CC-LR mice with NE knock-out mice, and found that lack of NE significantly inhibits lung cancer development. These were associated with significant reduction in tumor cell proliferation and angiogenesis. CONCLUSION We conclude that lung cancer promotion by inflammation is partly mediated by activation of the IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trials using the IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer.
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Affiliation(s)
- Lei Gong
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
- Department of Esophageal Cancer, Key Laboratory of Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Amber M Cumpian
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Mauricio S Caetano
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Cesar E Ochoa
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Maria Miguelina De la Garza
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Daniel J Lapid
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Seyedeh Golsar Mirabolfathinejad
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Burton F Dickey
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
| | - Qinghua Zhou
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Seyed Javad Moghaddam
- Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
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