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      Diagnostic performance of various liquid biopsy methods in detecting colorectal cancer: A meta‐analysis

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          Abstract

          Liquid biopsy is a promising method in detecting colorectal cancer (CRC). However, previous meta‐analyses only focused on the diagnostic performance of cell‐free DNA (cfDNA). Therefore, we firstly evaluated the overall performance of all liquid biopsy methods. The pooled sensitivities, specificities, diagnostic odds ratios, and area under curve (AUC) of summary receiver operating characteristic curve for all liquid biopsy methods, exosomes, circulating tumor cells (CTCs), and cfDNA were calculated, respectively. A total of 62 articles involving 18 739 individuals were included. Fifty‐one articles were about cfDNA, five articles were about CTCs, and six articles were about exosomes. The overall performance of all liquid biopsy methods had a pooled sensitivity, specificity, and AUC of 0.77 (95% confidence interval [CI] 0.76‐0.78), 0.89 (95% CI 0.88‐0.90), and 0.9004, respectively. The sensitivities were 0.82 (95% CI 0.79‐0.85), 0.76 (95% CI 0.72‐0.80), and 0.76 (95% CI 0.75‐0.77) for CTCs, exosomes, and cfDNA, respectively. The specificities were 0.97 (95% CI95% CI 0.95‐0.99), 0.92 (95% CI 0.89‐0.94), and 0.88 (95% CI 0.87‐0.89) for CTCs, exosomes, and cfDNA, respectively. The AUC were 0.9772, 0.9037, and 0.8963 for CTCs, exosomes, and cfDNA, respectively. The overall performance of all liquid biopsy methods had great diagnostic value in detecting CRC, regardless of subtypes. Among all liquid biopsy methods, CTCs showed the best diagnostic performance.

          Abstract

          The area under curve was 0.9772, 0.9037, 0.8963, and 0.9004 for circulating tumor cells (CTCs), exosomes, cell‐free DNA, and overall performance of all liquid biopsy methods in detecting colorectal cancer, respectively. The liquid biopsy had great diagnostic value in detecting CRC, regardless of subtypes. Among all liquid biopsy methods, CTCs showed the best diagnostic performance.

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          Meta-DiSc: a software for meta-analysis of test accuracy data

          Background Systematic reviews and meta-analyses of test accuracy studies are increasingly being recognised as central in guiding clinical practice. However, there is currently no dedicated and comprehensive software for meta-analysis of diagnostic data. In this article, we present Meta-DiSc, a Windows-based, user-friendly, freely available (for academic use) software that we have developed, piloted, and validated to perform diagnostic meta-analysis. Results Meta-DiSc a) allows exploration of heterogeneity, with a variety of statistics including chi-square, I-squared and Spearman correlation tests, b) implements meta-regression techniques to explore the relationships between study characteristics and accuracy estimates, c) performs statistical pooling of sensitivities, specificities, likelihood ratios and diagnostic odds ratios using fixed and random effects models, both overall and in subgroups and d) produces high quality figures, including forest plots and summary receiver operating characteristic curves that can be exported for use in manuscripts for publication. All computational algorithms have been validated through comparison with different statistical tools and published meta-analyses. Meta-DiSc has a Graphical User Interface with roll-down menus, dialog boxes, and online help facilities. Conclusion Meta-DiSc is a comprehensive and dedicated test accuracy meta-analysis software. It has already been used and cited in several meta-analyses published in high-ranking journals. The software is publicly available at .
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            Exosome mediated communication within the tumor microenvironment.

            It is clear that exosomes (endosome derived vesicles) serve important roles in cellular communication both locally and distally and that the exosomal process is abnormal in cancer. Cancer cells are not malicious cells; they are cells that represent 'survival of the fittest' at its finest. All of the mutations, abnormalities, and phenomenal adaptations to a hostile microenvironment, such as hypoxia and nutrient depletion, represent the astute ability of cancer cells to adapt to their environment and to intracellular changes to achieve a single goal - survival. The aberrant exosomal process in cancer represents yet another adaptation that promotes survival of cancer. Cancer cells can secrete more exosomes than healthy cells, but more importantly, the content of cancer cells is distinct. An illustrative distinction is that exosomes derived from cancer cells contain more microRNA than healthy cells and unlike exosomes released from healthy cells, this microRNA can be associated with the RNA-induced silencing complex (RISC) which is required for processing mature and biologically active microRNA. Cancer derived exosomes have the ability to transfer metastatic potential to a recipient cell and cancer exosomes function in the physical process of invasion. In this review we conceptualize the aberrant exosomal process (formation, content selection, loading, trafficking, and release) in cancer as being partially attributed to cancer specific differences in the endocytotic process of receptor recycling/degradation and plasma membrane remodeling and the function of the endosome as a signaling entity. We discuss this concept and, to advance comprehension of exosomal function in cancer as mediators of communication, we detail and discuss exosome biology, formation, and communication in health and cancer; exosomal content in cancer; exosomal biomarkers in cancer; exosome mediated communication in cancer metastasis, drug resistance, and interfacing with the immune system; and discuss the therapeutic manipulation of exosomal content for cancer treatment including current clinical trials of exosomal therapeutics. Often referred to as cellular nanoparticles, understanding exosomes, and how cancer cells use these cellular nanoparticles in communication is at the cutting edge frontier of advancing cancer biology.
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              Circulating Exosomal microRNAs as Biomarkers of Colon Cancer

              Purpose Exosomal microRNAs (miRNAs) have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC). To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined. Experimental Design Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA) using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients. Results The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis. Conclusion Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and several miRNAs are promising biomarkers for non-invasive diagnosis of the disease.
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                Author and article information

                Contributors
                wangziqiang@scu.edu.cn
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                06 July 2020
                August 2020
                : 9
                : 16 ( doiID: 10.1002/cam4.v9.16 )
                : 5699-5707
                Affiliations
                [ 1 ] Department of Gastrointestinal Surgery West China Hospital Sichuan University Chengdu Sichuan Province China
                [ 2 ] West China Hospital Sichuan University Chengdu Sichuan Province China
                Author notes
                [*] [* ] Correspondence

                Ziqiang Wang, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Alley, Chengdu 610041, Sichuan Province, China.

                Email: wangziqiang@ 123456scu.edu.cn

                Author information
                https://orcid.org/0000-0002-0415-2699
                Article
                CAM43276
                10.1002/cam4.3276
                7433831
                32628360
                82900bef-e995-4d2f-b365-75d7137157c9
                © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 November 2019
                : 06 May 2020
                : 08 June 2020
                Page count
                Figures: 1, Tables: 1, Pages: 10, Words: 7111
                Funding
                Funded by: Department of Science and Technology of Sichuan Province , open-funder-registry 10.13039/501100004829;
                Award ID: 2018RZ0091
                Categories
                Review Article
                Clinical Cancer Research
                Review
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.6 mode:remove_FC converted:18.08.2020

                Oncology & Radiotherapy
                cell‐free dna,colorectal cancer,ctcs,exosomes,liquid biopsy
                Oncology & Radiotherapy
                cell‐free dna, colorectal cancer, ctcs, exosomes, liquid biopsy

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