The diagnostic value of Near-Infrared Indocyanine Green Imaging for Endometriosis: A systematic review and meta-analysis

The diagnostic value of Near-Infrared Indocyanine Green Imaging for Endometriosis: A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The diagnostic value of Near-Infrared Indocyanine Green Imaging for Endometriosis: A systematic review and meta-analysis Yuan Zhuang, Honghui Ou, Yue Xu, Hua Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3974057/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To evaluate the diagnostic effect of Near-Infrared Indocyanine Green (ICG) imaging for Endometriosis(EMs). Methods: We searched Chinese National Knowledge Infrastructure (CNKI), Clinical Trials, WanFang Database, Web of Science, Cochrane Library, and Medline electronic databases up to January 2024. Reference lists of enrolled studies, Google Scholar, and reports of scientific meetings were also searched manually. Results: Through systematic literature search and screening, six studies compared the diagnostic effect of ICG imaging to White Light imaging(WL) for EMs during laparoscopic surgery were enrolled. Two studies found that ICG imaging improved the diagnostic rate of EMs. The others found the diagnostic value of ICG imaging was minimal. Cumulative results found the sensitivity is 0.88 (95%CI: 0.81-0.93) for WL and 0.64 (95%CI: 0.36-0.84) for ICG respectively. The specificity is 0.85 (95%CI: 0.49-0.97) for WL and 0.88 (95%CI: 0.66-0.97) for ICG respectively. The positive likelihood ratio (LR+) is 5.8 (95%CI: 1.4-24.5) for WL and 5.4 (95%CI: 1.2-24.1) for ICG respectively. The negative likelihood ratio (LR-) is 0.14 (95%CI: 0.09-0.20) for WL and 0.41 (95%CI: 0.18-0.94) for ICG respectively. The diagnostic odds ratio (DOR) is 42 (95%CI: 10-182) for WL and 13(95%CI: 1-124) for ICG respectively. Conclusion: Although ICG may be helpful for the visualization of occult EMs, the diagnostic value of ICG is nonsuperior to WL. However, the results should be minded with caution owing to the limited studies and small sample size. More reliable evidence based on larger simple-size studies and multicentric studies are needed urgently. endometriosis Near-Infrared Indocyanine Green imaging White Light imaging diagnostic value meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Endometriosis(EMs) is typically characterized by adhesion, growth, implantation, infiltration, and erosion of viable ectopic endometrial tissue outside the uterus, which may cause chronic pain, subfertility, nodules, or masses due to repeated bleeding and inflammatory reaction. EMs is a common and frequent disease that affects almost 10% of women of childbearing age. Approximately 196 million women suffer from this disease worldwide [1-3] . The diagnosis is challenging and often delayed due to the absence of non-invasive diagnostic methods. Laparoscopic exploration with histological confirmation is considered to be the gold standard and the only way to define EMs. Nevertheless, the diagnostic ratio is highly dependent on the experience of the surgeon and the types of EMs, the small/hidden or non-pigmented endometriotic lesions (occult EMs) are hard to recognize [4] . Laparoscopic radical excision of lesions is regarded as standard treatment for EMs with no response to pharmacologic treatment or infertility. However, simple laparoscopic excision is known to face a high recurrence rate and high risk of re-operation, which may be partially explained by inadequate visualization of occult EMs [5] . So, the improvement of intra-operative diagnosis may be conducive to recognize occult EMs, may be conducive to radically remove lesions, may improve the treatment effect, and reduce the risk of recurrence. Due to hypervascularization of EMs, visualization of hypervascular lesions may be useful to recognize EMs [6-7] . ICG can bind to plasma proteins and distribute in blood vessels and can serve as vascular imaging. New immature vascular is high permeability, which permits diffusion and retention of ICG during EMs. These characteristics can provide a solution to intraoperatively identify EMs by near-infrared radiation (NIR) imaging after intravenous injection of ICG [8-9] . In 2014, Levey [10] reported the first case of fluorescence imaging technology to identify peritoneal EMs by the da Vinci Si surgical assistant platform. There have been several prospective studies that evaluated the diagnostic value of near-infrared ICG imaging for EMs with inconsistent results. Whether ICG imaging can improve the diagnostic rate of EMs is indeterminate still. We designed the present meta-analysis to quantitatively synthesize the whole existing studies which compared diagnostic values between WL imaging and ICG imaging to solve the clinical confusion. Materials And Methods 2.1 Literature search At first, a normative protocol was drawn up according to the standardized process of systematic review and meta-analysis. Meanwhile, the present study was approved and registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD42023430867) [11] . Our systematic review was performed by Preferred Reporting Items for Systematic Reviews and Meta Examinations (PRISMA) statement [12] step by step. A comprehensive literature search was performed up to January 2024 during multiple mainstream databases with no limitation of region or language, including the WanFang Database, Chinese National Knowledge Infrastructure (CNKI), Medline electronic databases, Web of Science, Cochrane Library, and Clinical Trials. We sought to identify all research compared the diagnostic value of laparoscopic exploration between WL imaging and ICG imaging for EMs. We also searched BIOSIS Previews [13] , NLM Gateway [14] , SIGLE [15] , and GreyNet [16] to avoid omitting unpublished negative results. Google Scholar, reports of scientific meetings, and references of enrolled studies were also searched to avoid omitting newly published and internet resources. Systematic literature retrieval was through MeSH combined with keywords, the searching terms was summarized as: ((((Endometriosis) OR (Endometrioses)) OR (Endometrioma)) OR (Endometriomas)) AND ((((((((((((Indocyanine Green) OR (Green, Indocyanine)) OR (Wofaverdin)) OR (Vophaverdin)) OR (Ujoveridin)) OR (Vofaverdin)) OR (Cardio-Green)) OR (Cardio Green)) OR (Cardiogreen)) OR (ICG)) OR (fluorescence)) OR (Near-Infrared)). Clinical studies compared diagnostic values between WL imaging and ICG imaging were enrolled without time, territory, and language restriction. Pathological diagnosis is regarded as the gold standard of EMs. We tried to enroll prospective RCTs or quasi-RCTs, case-control, cohort, and observational studies. We gathered the key factors for each study from medical records and files including the first author, research duration, sample size, demographic characteristic, intraoperative data, sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and adverse events if possible. Two reviewers (ZY and YH) filtrate all searched citations independently according to predetermined inclusion and exclusion criteria of protocol. Firstly, we exclude obvious unmatched studies including in vivo and/or in vitro studies, reviews, case reports, descriptive studies, comments, and letters by titles and abstracts of citations. Secondly, full-text versions are obtained and further filtrated according to the inclusion criteria: (1) original studies concerned EMs, (2) outcomes included diagnostic value, (3) with comparative outcomes between WL imaging and ICG imaging, (4) with outcome of pathological diagnosis, and (5) full text available. Any differences are resolved through mutual consultation. Two reviewers (XY and OH) independently assess the risk of bias in the included studies via the following nine criteria. (1) prospective design, (2) study size greater than 30, (3) verification of all by the same method, (4) satisfactory description of the index test, (5) satisfactory description of ref test, (6) adequate description of study subjects, (7) satisfactory reporting of results, (8) broad spectrum of disease, (9) bound interpretation of ref and index. Review authors' judgement is categorized as "yes", or "no". Discrepancies are resolved by discussion through mutual consultation. 2.2 Statistical analysis A funnel plot is generated to assess publication bias, which is a scatterplot of the odds ratio (OR) of individual studies on the x-axis against the standard error (SE) of the log OR on the y-axis. An asymmetrical inverter funnel resembles the absence of publication bias; whereas asymmetry resembles potential publication bias. Sensitivity analysis is conducted for all outcomes to determine whether the conclusions are stable, we perform sensitivity analysis by eliminating a single study step by step to survey whether the cumulative results change significantly. True-positive (TP): Lesions are pathological confirmed EMs, and WL/ICG imaging correctly identifies the lesions as EMs. False-positive (FP): Lesions are pathologically confirmed non-EMs, and WL/ICG imaging incorrectly identifies the lesions as EMs. True-negative (TN): Lesions are pathologically confirmed non-EMs, and WL/ICG imaging correctly identifies the lesions as non-EMs. False-negative (FN): Lesions are pathological confirmed EMs, and WL/ICG imaging incorrectly identifies the lesions as non-EMs. Sensitivity is calculated as TP/(TP + FN) Specificity is calculated as TN/(TN + FP). Positive predictive value (PPV) is calculated as TP/(TP + FP). Negative predictive value (NPV) is calculated as TN/(FN + TN). The positive likelihood ratio (LR+) is calculated as Sensitivity/(1 - Specificity). The negative likelihood ratio (LR-) is calculated as (1-Sensitivity)/Specificity. The diagnostic odds ratio (DOR) is calculated as LR+/LR-. Heterogeneity is assessed using Higgins I 2 , which measures the degree of dissimilarity among individual study results. I 2 is evaluated as follows: I2=(Q−df) /Q×100%, Q-value is calculated by summing the squared deviations of the estimate of each study from the overall estimate, and df is degrees of freedom [17] . I 2 50% is considered as substantial heterogeneity. The meta-analysis is performed using the Review Manager 5.3 and Stata/MP 14.0, p < 0.05 is considered statistically significant. Results 3.1. Evidence acquisition Through systematically searching multiple databases, we retrieve 1128 pieces of literature, and six comparative studies are enrolled after filtrating independently according to predetermined inclusion and exclusion criteria. The detailed evidence acquisition course is exhibited in Fig.1. The main features of enrolled studies are exhibited in Table 1. On the whole, 223 patients with suspected EMs are enrolled, 1271 lesions are evaluated by WL imaging, and 1240 lesions are evaluated by ICG imaging, all lesions are removed for pathological diagnosis. 3.2. The diagnostic value of WL imaging for EMs Overall, we enrolled 223 patients and 1271 lesions came from 6 comparative study studies. 821 lesions are pathologically confirmed EMs, and 450 lesions are pathologically confirmed non-EMs.Polled results suggest that the sensitivity is 0.88 (95%CI: 0.81-0.93), and the specificity is 0.85 (95%CI: 0.49-0.97) (Figure 2A). The diagnostic score is 3.74 (95%CI: 2.28-5.21), and the diagnostic odds ratio (DOR) is 42.18 (95%CI: 9.76-182.27) (Figure 2B). The positive likelihood ratio (LR+) is 5.8 (95%CI: 1.4-24.5), and the negative likelihood ratio (LR-) is 0.14(95%CI: 0.09-0.20) (Figure 2C). The receiver operating characteristic (ROC) area was 0.92(95%CI:0.89 - 0.94) (Figure 2D). The asymmetry test finds no publication bias (p = 0.26) (Figure 2E). These results suggest that WL imaging has satisfactory diagnostic value for EMs. There is significant heterogeneity between studies (I2 >50% ). 3.3. The diagnostic value of ICG imaging for EMs Overall, we enrolled 223 patients and 1240 lesions came from 6 comparative study studies. 805 lesions are pathologically confirmed EMs, and 435 lesions are pathologically confirmed non-EMs. Polled results suggest that the sensitivity is 0.64 (95%CI: 0.36-0.84), and the specificity is 0.88 (95%CI: 0.66-0.97) (Figure 3A). The diagnostic score is 2.58 (95%CI: 0.33-4.82), and the DOR is 13.15 (95%CI: 1.39-124.19) (Figure 3B). The LR+ is 5.4 (95%CI: 1.2-24.1), and the LR- is 0.41(95%CI: 0.18-0.94) (Figure 3C). The ROC area is 0.84(95%CI:0.81 - 0.87) (Figure 3D). The asymmetry test finds no publication bias (p = 0.10) (Figure 3E). These results suggest that ICG imaging has satisfactory diagnostic value for EMs. There is significant heterogeneity between studies (I2 >50% ). 3.4. The comparison of diagnostic value between WL and ICG imaging for EMs We adopt Review Manager 5.3 to compare the diagnostic value between WL and ICG imaging, the forest plot of enrolled studies is detailed in Figure 4A. The direct comparison test finds the diagnostic value of ICG imaging is non-superior to WL imaging (Figure 4B). A sensitivity test by culling individual studies one by one, finds insignificant changes in the polled results, which means the result is reliable. The quality assessment of included 6 studies are summarized in Figure 4C. In summary, the enrolled studies have a low bias on prospective design, study size greater than 30, bound interpretation of ref and index, satisfactory description of the index test, satisfactory description of ref test, an adequate description of study subjects, and satisfactory reporting of results; have a moderate bias on a broad spectrum of disease, and verification of all by the same method. Discussion The present meta-analysis quantitatively synthesizes the whole existing studies that evaluated the diagnostic value of ICG imaging for EMs, thus finding noteworthy results. Firstly, we report reliable outcomes based on the largest series (N=223 patients) until now, this is the first meta-analysis to evaluate the diagnostic value of ICG imaging for EMs to our knowledge. Secondly, we find that the diagnostic value of ICG imaging is non-superior to conventional WL imaging. Laparoscopic WL imaging with histological confirmation is still the gold standard to define EMs. EMs is a benign gynecological disorder with malignant biological behaviors, that can cause chronic pelvic pain (CPP) and impaired fertility. It affects about 10% of childbearing period women, 20-50% of women with infertility, and 71-87% of women with CPP [18] . Despite recent advances in medication and long-term management, a significant number of patients require surgery due to not responding well to medication or infertility. Radical removal of all lesions can relieve pain and improve fertility, however, it is challenging due to intra-operative incomplete identification of EMs. Indeed, the intra-operative diagnosis of EMs is highly subjective, the diagnostic accuracy rate is highly dependent on the appearance of EMs, the extent of lesions, and the experience of the surgeon. The missed diagnosis and misdiagnosis are frequent, even by experienced surgeons. Studies [19-21] suggested EMs lesions might be missed up to 25% during laparoscopic WL imaging surgery, and 16% to 53% of suspicious EMs lesions were not pathologically confirmed to be EMs. Thinking about the high risk of recurrence and re-operation, and the potential impact of removing extra healthy tissue, laparoscopic enhanced imaging that can improve intra-operative real-time visualization of EMs lesions is needed urgently. Several enhanced imaging have been explored during EMs surgery to improve the diagnostic accuracy of EMs, such as 3dimensions (3D) white light [22] , 5-Aminolevulinic acid (5-ALA) induced fluorescence [23] , Autofluorescence imaging (AFI) [24] and Narrow-band imaging(NBI) [25] , with a certain improvement but not satisfactory enough diagnostic accuracy compared to conventional WL imaging. Near-infrared ICG imaging is a more recent technique. Intravenous ICG binds to plasma proteins and can serve as an ideal angiographic agent. EMs are characterized by chronic inflammation, neovascularization, and hyperangiogenesis, which may be identifiable by ICG imaging. Indeed, ICG imaging for the detection of peritoneal EMs was first described by Levey in 2014 [10] . Park and Farnam [26] proposed its utilization for the intraoperative visualization of the ureter during the dissection of DIE. Guan et al [27] reported the first case of robot-assisted ICG imaging for the management of deep endometriosis of the rectum. Several comparative studies have compared the diagnostic value of ICG imaging to conventional WL imaging for EMs, the results were inconsistent. Lier. et al [28] compared the diagnostic efficiency of conventional two-dimensional WL imaging to NBI, ICG, and 3D imaging during 20 patients with stage III–IV EMs, and found the single use of NBI or ICG imaging showed no improvement in the detection of EMs. Cosentino. et al [29] compared the diagnostic efficiency of conventional WL imaging to ICG imaging for 27 patients with EMs and found that ICG imaging might be a tool for identifying occult EMs, with a sensitivity of 82% and a specificity of 97.9% respectively. Taher. et al [30] compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 15 patients with EMs and found the additional value of ICG imaging was limited for the intraoperative detection of EMs lesions, with a positive predictive value (PPV) of 64% in WL imaging, 69% in ICG imaging and 61% in both imaging respectively. Vizzielli. et al [31] evaluated the diagnostic efficiency of ICG imaging coupled with robotic technical advances during 47 patients with EMs, the results supported its role in this clinical setting as a confirmatory diagnostic test for EMs. Siegenthaler. et al [32] compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 63 patients with EMs and found the diagnostic value of ICG imaging was minimal, with a PPV of 89.8%, 68.8%, and 86.7% for WL imaging, ICG imaging and the combination of WL and ICG respectively. Turco. et al [33] compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 51 patients with EMs and found that ICG imaging alone and combined with WL imaging showed good results in the intraoperative detection rate of EMs. These inconsistent results make the diagnostic value of ICG imaging uncertain, through the quantitative synthesis of existing homogeneous results can provide more reliable conclusions, this is the main purpose of the present meta-analysis. By polling the results, we find the the diagnostic value of ICG imaging is non-superior to WL imaging, with an ROC area of 0.92(95%CI:0.89 - 0.94) and 0.84(95%CI:0.81 - 0.87) for WL and ICG imaging respectively. The important aim of meta-analysis is to solve the key clinical confusion. The key confusion we focus on is whether the administration of ICG imaging can improve the intra-operative diagnostic rate of EMs. However, the intra-operative diagnosis is highly dependent on the appearance of EMs, the extent of lesions, the experience of the surgeon, the performance of laparoscopic equipment, and so on. As the present meta-analysis shows, there is significant heterogeneity between enrolled studies. By systematically evaluating enrolled studies, we find there are significant differences in the selected patients, stages and types of EMs, surgical procedures, control methods, whether to biopsy the normal peritoneum as control, dosages of ICG, and the interval from intravenous injection of ICG to exploration. These may be the sources of heterogeneity and may affect the reliability of the conclusion. This is the main limitation of the present meta-analysis. Another important limitation is the limited cases, may significantly affect the final results. The main strength of our meta-analysis is the first quantitative synthesis of existing studies on the diagnostic value of ICG imaging for EMs until now. Even though we get a negative result, a main point has to be addressed. All the original studies found that certain EMs lesions can only be identified by ICG imaging, which was omitted by WL imaging, suggesting ICG imaging may be helpful for the visualization of occult EMs. This is vital for radical removal of EMs lesions, relief of chronic pelvic pain, improvement of fertility, decrease of recurrence, and re-operation. As a novel intra-operative real-time diagnostic technology, ICG imaging needs more exploration to fulfill its potential. In the future, we should evaluate the long-term clinical outcomes of EMs after ICG-guiding surgery, such as re-intervention rates, pain-free interval, and quality of life. Meanwhile, we should adopt homogeneous large sample multi-center randomized controlled studies to evaluate its diagnostic value. Conclusions Although ICG imaging may be helpful for the visualization of occult EMs, the diagnostic value of ICG imaging is non-superior to WL imaging. However, the results should be minded with caution owing to the limited studies and small sample size. More reliable evidence based on larger simple-size studies and multicentric studies are needed urgently. Declarations Author contributions YH and ZY are major contributors in writing the manuscript, and OH and XY are major contributors in retrieving the literature. All authors read and approve the final manuscript. Ethics approval An ethics statement is not applicable because this study is based exclusively on published literature. Acknowledgment Not applicable. Availability of data and material All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author. Funding This work is supported by the Medical Science and Technology Research Foundation of Guangdong Province (A2022317) Conflict of interest The authors declare no conflict of interest. Consent for Publication Not applicable. References Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N; ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis. Hum Reprod Open. 2022 Feb 26;2022(2):hoac009. Kalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis EP, Eberhard M, Dinas K, Daniilidis A. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Womens Health. 2021 Nov 29;21(1):397. Findeklee S, Radosa JC, Hamza A, Haj Hamoud B, Iordache I, Sklavounos P, Takacs ZF, Solomayer EF, Radosa M. Treatment algorithm for women with endometriosis in a certified Endometriosis Unit. Minerva Ginecol. 2020 Feb;72(1):43-49. 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Real three-dimensional approach vs two-dimensional camera with and without real-time near-infrared imaging with indocyanine green for detection of endometriosis: A case-control study. Acta Obstet Gynecol Scand. 2020 Oct;99(10):1330-1338. Siegenthaler F, Knabben L, Mohr S, Nirgianakis K, Imboden S, Mueller MD. Visualization of endometriosis with laparoscopy and near-infrared optics with indocyanine green. Acta Obstet Gynecol Scand. 2020 May;99(5):591-597. Turco LC, Vizzielli G, Vargiu V, Gueli Alletti S, De Ninno M, Ferrandina G, Pedone Anchora L, Scambia G, Cosentino F. Near-Infrared Imaging With Indocyanine Green for the Treatment of Endometriosis: Results From the Gre-Endo Trial. Front Oncol. 2021 Nov 15;11:737938. Table 1 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3974057","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":278262255,"identity":"f216d5f4-bb81-47fe-9de5-eb715f126229","order_by":0,"name":"Yuan Zhuang","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Zhuang","suffix":""},{"id":278262256,"identity":"7be030e7-ce05-4496-8b03-ed5650132864","order_by":1,"name":"Honghui Ou","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Honghui","middleName":"","lastName":"Ou","suffix":""},{"id":278262257,"identity":"99693436-80f7-452b-9855-44104b90daf4","order_by":2,"name":"Yue Xu","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Xu","suffix":""},{"id":278262258,"identity":"41b05cfd-95b8-4d69-9dde-ea7fb1e05792","order_by":3,"name":"Hua Yang","email":"data:image/png;base64,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","orcid":"","institution":"The Fifth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Hua","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-02-20 23:44:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3974057/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3974057/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52602508,"identity":"ebef717e-c046-4a5a-9f0c-5a34d1a871ef","added_by":"auto","created_at":"2024-03-13 13:08:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":478041,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram for evidence acquisition in the systematic review and meta-analysis\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3974057/v1/5ee5eebc06e7c4b8707e8163.png"},{"id":52602512,"identity":"efb0b39b-f948-45cc-a5be-81d52e8bf859","added_by":"auto","created_at":"2024-03-13 13:08:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":560706,"visible":true,"origin":"","legend":"\u003cp\u003eThe diagnostic value of WL imaging for EMs. A). The sensitivity and specificity. B). The diagnostic score and diagnostic odds ratio (DOR). C). The positive likelihood ratio (LR+) and negative likelihood ratio (LR-). D)The receiver operating characteristic (ROC) area. E).The asymmetry test for publication bias.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3974057/v1/7110a532b68d0696e63dcdf7.png"},{"id":52603327,"identity":"4d601932-8457-41cf-8c0c-5343e61e1d5d","added_by":"auto","created_at":"2024-03-13 13:16:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":608651,"visible":true,"origin":"","legend":"\u003cp\u003eThe diagnostic value of ICG imaging for EMs. A). The sensitivity and specificity. B). The diagnostic score and diagnostic odds ratio (DOR). C). The positive likelihood ratio (LR+) and negative likelihood ratio (LR-). D)The receiver operating characteristic (ROC) area. E).The asymmetry test for publication bias.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3974057/v1/76268b0518293c1587d3d922.png"},{"id":52602509,"identity":"61333e3f-7c8a-4125-98f3-59bd86003355","added_by":"auto","created_at":"2024-03-13 13:08:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1431444,"visible":true,"origin":"","legend":"\u003cp\u003eThe comparison of diagnostic value between WL and ICG imaging for EMs. A). The forest plot of enrolled studies. B). The direct comparison of ROC between WL and ICG imaging. C). The quality assessment of enrolled studies.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3974057/v1/dbd2af0ca37a385292bfd707.png"},{"id":57314551,"identity":"cd270a40-f9e5-406b-bcad-dbc18c740ebd","added_by":"auto","created_at":"2024-05-29 04:02:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3793515,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3974057/v1/c4fb1f67-af56-4346-ae57-1fd8de73a50e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The diagnostic value of Near-Infrared Indocyanine Green Imaging for Endometriosis: A systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis(EMs) is typically characterized by adhesion, growth, implantation, infiltration, and erosion of viable ectopic endometrial tissue outside the uterus, which may cause chronic pain, subfertility, nodules, or masses due to repeated bleeding and inflammatory reaction. EMs is a common and frequent disease that affects almost 10% of women of childbearing age. Approximately 196 million women suffer from this disease worldwide\u003csup\u003e\u0026nbsp;[1-3]\u003c/sup\u003e. The diagnosis is challenging and often delayed due to the absence of non-invasive diagnostic methods. Laparoscopic exploration with histological confirmation is considered to be the gold standard and the only way to define EMs. Nevertheless, the diagnostic ratio is highly dependent on the experience of the surgeon and the types of EMs, the small/hidden or non-pigmented endometriotic lesions (occult EMs) are hard to recognize\u003csup\u003e[4]\u003c/sup\u003e. Laparoscopic radical excision of lesions is regarded as standard treatment for EMs with no response to pharmacologic treatment or infertility. However, simple laparoscopic excision is known to face a high recurrence rate and high risk of re-operation, which may be partially explained by inadequate visualization of occult EMs\u003csup\u003e[5]\u003c/sup\u003e. So, the improvement of intra-operative diagnosis may be conducive to recognize occult EMs, may be conducive to radically remove lesions, may improve the treatment effect, and reduce the risk of recurrence. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDue to hypervascularization of EMs, visualization of hypervascular lesions may be useful to recognize EMs\u003csup\u003e[6-7]\u003c/sup\u003e. ICG can bind to plasma proteins and distribute in blood vessels and can serve as vascular imaging. New immature vascular is high permeability, which permits diffusion and retention of ICG during EMs. These characteristics can provide a solution to intraoperatively identify EMs by near-infrared radiation (NIR) imaging after intravenous injection of ICG\u003csup\u003e[8-9]\u003c/sup\u003e. In 2014, Levey\u003csup\u003e[10]\u003c/sup\u003e reported the first case of fluorescence imaging technology to identify peritoneal EMs by the da Vinci Si surgical assistant platform. There have been several prospective studies that evaluated the diagnostic value of near-infrared ICG imaging for EMs with inconsistent results. Whether ICG imaging can improve the diagnostic rate of EMs is indeterminate still. We designed the present meta-analysis to quantitatively synthesize the whole existing studies which compared diagnostic values between WL imaging and ICG imaging to solve the clinical confusion.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Literature search\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt first, a normative protocol was drawn up according to the standardized process of systematic review and meta-analysis. Meanwhile, the present study was approved and registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD42023430867)\u003csup\u003e[11]\u003c/sup\u003e. Our systematic review was performed by Preferred Reporting Items for Systematic Reviews and Meta Examinations (PRISMA) statement\u003csup\u003e[12]\u003c/sup\u003e step by step. A comprehensive literature search was performed up to January 2024 during multiple mainstream databases with no limitation of region or language, including the WanFang Database, Chinese National Knowledge Infrastructure (CNKI), Medline electronic databases, Web of Science, Cochrane Library, and Clinical Trials. We sought to identify all research compared the diagnostic value of laparoscopic exploration between WL imaging and ICG imaging for EMs. We also searched BIOSIS Previews\u003csup\u003e[13]\u003c/sup\u003e, NLM Gateway\u003csup\u003e[14]\u003c/sup\u003e, SIGLE\u003csup\u003e[15]\u003c/sup\u003e, and GreyNet\u003csup\u003e[16]\u003c/sup\u003e to avoid omitting unpublished negative results. Google Scholar, reports of scientific meetings, and references of enrolled studies were also searched to avoid omitting newly published and internet resources.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSystematic literature retrieval was through MeSH combined with keywords, the searching terms was summarized as: ((((Endometriosis) OR (Endometrioses)) OR (Endometrioma)) OR (Endometriomas)) AND ((((((((((((Indocyanine Green) OR (Green, Indocyanine)) OR (Wofaverdin)) OR (Vophaverdin)) OR (Ujoveridin)) OR (Vofaverdin)) OR (Cardio-Green)) OR (Cardio Green)) OR (Cardiogreen)) OR (ICG)) OR (fluorescence)) OR (Near-Infrared)). Clinical studies compared diagnostic values between WL imaging and ICG imaging were enrolled without time, territory, and language restriction. Pathological diagnosis is regarded as the gold standard of EMs. We tried to enroll prospective RCTs or quasi-RCTs, case-control, cohort, and observational studies. We gathered the key factors for each study from medical records and files including the first author, research duration, sample size, demographic characteristic, intraoperative data, sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and adverse events if possible.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo reviewers (ZY and YH) filtrate all searched citations independently according to predetermined inclusion and exclusion criteria of protocol. Firstly, we exclude obvious unmatched studies including in vivo and/or in vitro studies, reviews, case reports, descriptive studies, comments, and letters by titles and abstracts of citations. Secondly, full-text versions are obtained and further filtrated according to the inclusion criteria: (1) original studies concerned EMs, (2) outcomes included diagnostic value, (3) with comparative outcomes between WL imaging and ICG imaging, (4) with outcome of pathological diagnosis, and (5) full text available. Any differences are resolved through mutual consultation.\u003c/p\u003e\n\u003cp\u003eTwo reviewers (XY and OH) independently assess the risk of bias in the included studies via the following nine criteria. (1) prospective design, (2) study size greater than 30, (3) verification of all by the same method, (4) satisfactory description of the index test, (5) satisfactory description of ref test, (6) adequate description of study subjects, (7) satisfactory reporting of results, (8) broad spectrum of disease, (9) bound interpretation of ref and index. Review authors\u0026apos; judgement is categorized as \u0026quot;yes\u0026quot;, \u0026nbsp;or \u0026quot;no\u0026quot;. Discrepancies are resolved by discussion through mutual consultation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA funnel plot is generated to assess publication bias, which is a scatterplot of the odds ratio (OR) of individual studies on the x-axis against the standard error (SE) of the log OR on the y-axis. An asymmetrical inverter funnel resembles the absence of publication bias; whereas asymmetry resembles potential publication bias. Sensitivity analysis is conducted for all outcomes to determine whether the conclusions are stable, we perform sensitivity analysis by eliminating a single study step by step to survey whether the cumulative results change significantly.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrue-positive (TP): Lesions are pathological confirmed EMs, and WL/ICG imaging correctly identifies the lesions as EMs.\u003c/p\u003e\n\u003cp\u003eFalse-positive (FP): Lesions are pathologically confirmed non-EMs, and WL/ICG imaging incorrectly identifies the lesions as EMs.\u003c/p\u003e\n\u003cp\u003eTrue-negative (TN): Lesions are pathologically confirmed non-EMs, and WL/ICG imaging correctly identifies the lesions as non-EMs.\u003c/p\u003e\n\u003cp\u003eFalse-negative (FN): Lesions are pathological confirmed EMs, and WL/ICG imaging incorrectly identifies the lesions as non-EMs.\u003c/p\u003e\n\u003cp\u003eSensitivity is calculated as TP/(TP + FN)\u003c/p\u003e\n\u003cp\u003eSpecificity is calculated as TN/(TN + FP).\u003c/p\u003e\n\u003cp\u003ePositive predictive value (PPV) is calculated as TP/(TP + FP).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNegative predictive value (NPV) is calculated as TN/(FN + TN).\u003c/p\u003e\n\u003cp\u003eThe positive likelihood ratio (LR+) is calculated as Sensitivity/(1 - Specificity).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe negative likelihood ratio (LR-) is calculated as (1-Sensitivity)/Specificity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe diagnostic odds ratio (DOR) is calculated as LR+/LR-.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHeterogeneity is assessed using Higgins I\u003csup\u003e2\u003c/sup\u003e, which measures the degree of dissimilarity among individual study results. I\u003csup\u003e2\u003c/sup\u003e is evaluated as follows: I2=(Q\u0026minus;df) /Q\u0026times;100%, Q-value is calculated by summing the squared deviations of the estimate of each study from the overall estimate, and df is degrees of freedom\u003csup\u003e[17]\u003c/sup\u003e. I\u003csup\u003e2\u003c/sup\u003e \u0026lt;50% is considered as insignificant heterogeneity; I\u003csup\u003e2\u003c/sup\u003e \u0026gt;50% is considered as substantial heterogeneity.\u003c/p\u003e\n\u003cp\u003eThe meta-analysis is performed using the Review Manager 5.3 and Stata/MP 14.0, p \u0026lt; 0.05 is considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1. Evidence acquisition\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThrough systematically searching multiple databases, we retrieve 1128 pieces of literature, and six comparative studies are enrolled after filtrating independently according to predetermined inclusion and exclusion criteria. The detailed evidence acquisition course is exhibited in Fig.1. The main features of enrolled studies are exhibited in Table 1. On the whole, 223 patients with suspected EMs are enrolled, 1271 lesions are evaluated by WL imaging, and 1240 lesions are evaluated by ICG imaging, all lesions are removed for pathological diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. The diagnostic value of WL imaging for EMs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, we enrolled 223 patients and 1271 lesions came from 6 comparative study studies. 821 lesions are pathologically confirmed EMs, and 450 lesions are pathologically confirmed non-EMs.Polled results suggest that the sensitivity is 0.88 (95%CI: 0.81-0.93), and the specificity is 0.85 (95%CI: 0.49-0.97) (Figure 2A). The diagnostic score is 3.74 (95%CI: 2.28-5.21), and the diagnostic odds ratio (DOR) is 42.18 (95%CI: 9.76-182.27) (Figure 2B). The positive likelihood ratio (LR+) is 5.8 (95%CI: 1.4-24.5), and the negative likelihood ratio (LR-) is 0.14(95%CI: 0.09-0.20) (Figure 2C). The receiver operating characteristic (ROC) area was 0.92(95%CI:0.89 - 0.94) (Figure 2D). The asymmetry test finds no publication bias (p = 0.26) (Figure 2E). These results suggest that WL imaging has satisfactory diagnostic value for EMs. There is significant heterogeneity between studies (I2 \u0026gt;50% ).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. The diagnostic value of ICG imaging for EMs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, we enrolled 223 patients and 1240 lesions came from 6 comparative study studies. 805 lesions are pathologically confirmed EMs, and 435 lesions are pathologically confirmed non-EMs. Polled results suggest that the sensitivity is 0.64 (95%CI: 0.36-0.84), and the specificity is 0.88 (95%CI: 0.66-0.97) (Figure 3A). The diagnostic score is 2.58 (95%CI: 0.33-4.82), and the DOR is 13.15 (95%CI: 1.39-124.19) (Figure 3B). The LR+ is 5.4 (95%CI: 1.2-24.1), and the LR- is 0.41(95%CI: 0.18-0.94) (Figure 3C). The ROC area is 0.84(95%CI:0.81 - 0.87) (Figure 3D). The asymmetry test finds no publication bias (p = 0.10) (Figure 3E). These results suggest that ICG imaging has satisfactory diagnostic value for EMs. There is significant heterogeneity between studies (I2 \u0026gt;50% ).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4. The comparison of diagnostic value between WL and ICG imaging for EMs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe adopt Review Manager 5.3 to compare the diagnostic value between WL and ICG imaging, the forest plot of enrolled studies is detailed in Figure 4A. The direct comparison test finds the diagnostic value of ICG imaging is non-superior to WL imaging (Figure 4B). A sensitivity test by culling individual studies one by one, finds insignificant changes in the polled results, which means the result is reliable. The quality assessment of included 6 studies are summarized in Figure 4C. In summary, the enrolled studies have a low bias on prospective design, study size greater than 30, bound interpretation of ref and index, satisfactory description of the index test, satisfactory description of ref test, an adequate description of study subjects, and satisfactory reporting of results; have a moderate bias on a broad spectrum of disease, and verification of all by the same method.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u0026nbsp; The present meta-analysis quantitatively synthesizes the whole existing studies that evaluated the diagnostic value of ICG imaging for EMs, thus finding noteworthy results. Firstly, we report reliable outcomes based on the largest series (N=223 patients) until now, this is the first meta-analysis to evaluate the diagnostic value of ICG imaging for EMs to our knowledge. Secondly, we find that the diagnostic value of ICG imaging is non-superior to conventional WL imaging. Laparoscopic WL imaging with histological confirmation is still the gold standard to define EMs.\u003c/p\u003e\n\u003cp\u003eEMs is a benign gynecological disorder with malignant biological behaviors, that can cause chronic pelvic pain (CPP) and impaired fertility. It affects about 10% of childbearing period women, 20-50% of women with infertility, and 71-87% of women with CPP\u003csup\u003e[18]\u003c/sup\u003e. Despite recent advances in medication and long-term management, a significant number of patients require surgery due to not responding well to medication or infertility. Radical removal of all lesions can relieve pain and improve fertility, however, it is challenging due to intra-operative incomplete identification of EMs. Indeed, the intra-operative diagnosis of EMs is highly subjective, the diagnostic accuracy rate is highly dependent on the appearance of EMs, the extent of lesions, and the experience of the surgeon. The missed diagnosis and misdiagnosis are frequent, even by experienced surgeons. Studies\u003csup\u003e[19-21]\u003c/sup\u003e suggested EMs lesions might be missed up to 25% during laparoscopic WL imaging surgery, and 16% to 53% of suspicious EMs lesions were not pathologically confirmed to be EMs. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThinking about the high risk of recurrence and re-operation, and the potential impact of removing extra healthy tissue, laparoscopic enhanced imaging that can improve intra-operative real-time visualization of EMs lesions is needed urgently. Several enhanced imaging have been explored during EMs surgery to improve the diagnostic accuracy of EMs, such as 3dimensions (3D) white light\u003csup\u003e[22]\u003c/sup\u003e, 5-Aminolevulinic acid (5-ALA) induced fluorescence\u003csup\u003e[23]\u003c/sup\u003e, Autofluorescence imaging (AFI)\u003csup\u003e[24]\u003c/sup\u003e and Narrow-band imaging(NBI)\u003csup\u003e[25]\u003c/sup\u003e, with a certain improvement but not satisfactory enough diagnostic accuracy compared to conventional WL imaging. Near-infrared ICG imaging is a more recent technique. Intravenous ICG binds to plasma proteins and can serve as an ideal angiographic agent. EMs are characterized by chronic inflammation, neovascularization, and hyperangiogenesis, which may be identifiable by ICG imaging. Indeed, ICG imaging for the detection of peritoneal EMs was first described by Levey in 2014\u003csup\u003e[10]\u003c/sup\u003e. Park and Farnam\u003csup\u003e[26]\u0026nbsp;\u003c/sup\u003eproposed its utilization for the intraoperative visualization of the ureter during the dissection of DIE. Guan et al\u003csup\u003e[27]\u003c/sup\u003e reported the first case of robot-assisted ICG imaging for the management of deep endometriosis of the rectum.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral comparative studies have compared the diagnostic value of ICG imaging to conventional WL imaging for EMs, the results were inconsistent. Lier. et al\u003csup\u003e[28]\u003c/sup\u003e compared the diagnostic efficiency of conventional two-dimensional WL imaging to NBI, ICG, and 3D imaging during 20 patients with stage III\u0026ndash;IV EMs, and found the single use of NBI or ICG imaging showed no improvement in the detection of EMs. Cosentino. et al\u003csup\u003e[29]\u003c/sup\u003e compared the diagnostic efficiency of conventional WL imaging to ICG imaging for 27 patients with EMs and found that ICG imaging might be a tool for identifying occult EMs, with a sensitivity of 82% and a specificity of 97.9% respectively. Taher. et al\u003csup\u003e[30]\u003c/sup\u003e compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 15 patients with EMs and found the additional value of ICG imaging was limited for the intraoperative detection of EMs lesions, with a positive predictive value (PPV) of 64% in WL imaging, 69% in ICG imaging and 61% in both imaging respectively. Vizzielli. et al\u003csup\u003e[31]\u003c/sup\u003e evaluated the diagnostic efficiency of ICG imaging coupled with robotic technical advances during 47 patients with EMs, the results supported its role in this clinical setting as a confirmatory diagnostic test for EMs. Siegenthaler. et al\u003csup\u003e[32]\u003c/sup\u003e compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 63 patients with EMs and found the diagnostic value of ICG imaging was minimal, with a PPV of 89.8%, 68.8%, and 86.7% for WL imaging, ICG imaging and the combination of WL and ICG respectively. Turco. et al\u003csup\u003e[33]\u003c/sup\u003e compared the diagnostic efficiency of conventional WL imaging to ICG imaging during 51 patients with EMs and found that ICG imaging alone and combined with WL imaging showed good results in the intraoperative detection rate of EMs. These inconsistent results make the diagnostic value of ICG imaging uncertain, through the quantitative synthesis of existing homogeneous results can provide more reliable conclusions, this is the main purpose of the present meta-analysis. By polling the results, we find the the diagnostic value of ICG imaging is non-superior to WL imaging, with an ROC area of 0.92(95%CI:0.89 - 0.94) and 0.84(95%CI:0.81 - 0.87) for WL and ICG imaging respectively.\u003c/p\u003e\n\u003cp\u003eThe important aim of meta-analysis is to solve the key clinical confusion. The key confusion we focus on is whether the administration of ICG imaging can improve the intra-operative diagnostic rate of EMs. However, the intra-operative diagnosis is highly dependent on the appearance of EMs, the extent of lesions, the experience of the surgeon, the performance of laparoscopic equipment, and so on. As the present meta-analysis shows, there is significant heterogeneity between enrolled studies. By systematically evaluating enrolled studies, we find there are significant differences in the selected patients, stages and types of EMs, surgical procedures, control methods, whether to biopsy the normal peritoneum as control, dosages of ICG, and the interval from intravenous injection of ICG to exploration. These may be the sources of heterogeneity and may affect the reliability of the conclusion. This is the main limitation of the present meta-analysis. Another important limitation is the limited cases, may significantly affect the final results.\u003c/p\u003e\n\u003cp\u003eThe main strength of our meta-analysis is the first quantitative synthesis of existing studies on the diagnostic value of ICG imaging for EMs until now. Even though we get a negative result, a main point has to be addressed. All the original studies found that certain EMs lesions can only be identified by ICG imaging, which was omitted by WL imaging, suggesting ICG imaging may be helpful for the visualization of occult EMs. This is vital for radical removal of EMs lesions, relief of chronic pelvic pain, improvement of fertility, decrease of recurrence, and re-operation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;As a novel intra-operative real-time diagnostic technology, ICG imaging needs more exploration to fulfill its potential. In the future, we should evaluate the long-term clinical outcomes of EMs after ICG-guiding surgery, such as re-intervention rates, pain-free interval, and quality of life. Meanwhile, we should adopt homogeneous large sample multi-center randomized controlled studies to evaluate its diagnostic value. \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAlthough ICG imaging may be helpful for the visualization of occult EMs, the diagnostic value of ICG imaging is non-superior to WL imaging. However, the results should be minded with caution owing to the limited studies and small sample size. More reliable evidence based on larger simple-size studies and multicentric studies are needed urgently.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYH and ZY are major contributors in writing the manuscript, and OH and XY are major contributors in retrieving the literature. All authors read and approve the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn ethics statement is not applicable because this study is based exclusively on published literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work is supported by the Medical Science and Technology Research Foundation of Guangdong Province (A2022317)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBecker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N; ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis. 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Surg Endosc. 2020 Jan;34(1):96-104.\u003c/li\u003e\n\u003cli\u003eCosentino F, Vizzielli G, Turco LC, Fagotti A, Cianci S, Vargiu V, Zannoni GF, Ferrandina G, Scambia G. Near-Infrared Imaging with Indocyanine Green for Detection of Endometriosis Lesions (Gre-Endo Trial): A Pilot Study. J Minim Invasive Gynecol. 2018 Nov-Dec;25(7):1249-1254. \u003c/li\u003e\n\u003cli\u003eAl-Taher M, van den Bos J, Terink I, van Kuijk S, van Hanegem N, Bouvy N, Bongers M, Stassen L, Lim A. Near-Infrared Fluorescence Imaging for the Intraoperative Detection of Endometriosis: A Pilot Study. Life (Basel). 2021 Dec 23;12(1):15. \u003c/li\u003e\n\u003cli\u003eVizzielli G, Cosentino F, Raimondo D, Turco LC, Vargiu V, Iodice R, Mastronardi M, Mabrouk M, Scambia G, Seracchioli R. Real three-dimensional approach vs two-dimensional camera with and without real-time near-infrared imaging with indocyanine green for detection of endometriosis: A case-control study. Acta Obstet Gynecol Scand. 2020 Oct;99(10):1330-1338. \u003c/li\u003e\n\u003cli\u003eSiegenthaler F, Knabben L, Mohr S, Nirgianakis K, Imboden S, Mueller MD. Visualization of endometriosis with laparoscopy and near-infrared optics with indocyanine green. Acta Obstet Gynecol Scand. 2020 May;99(5):591-597. \u003c/li\u003e\n\u003cli\u003eTurco LC, Vizzielli G, Vargiu V, Gueli Alletti S, De Ninno M, Ferrandina G, Pedone Anchora L, Scambia G, Cosentino F. Near-Infrared Imaging With Indocyanine Green for the Treatment of Endometriosis: Results From the Gre-Endo Trial. Front Oncol. 2021 Nov 15;11:737938.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1710245095.png\"\u003e\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"endometriosis, Near-Infrared, Indocyanine Green imaging, White Light imaging, diagnostic value, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3974057/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3974057/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo evaluate the diagnostic effect of Near-Infrared Indocyanine Green (ICG) imaging for Endometriosis(EMs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We searched Chinese National Knowledge Infrastructure (CNKI), Clinical Trials, WanFang Database, Web of Science, Cochrane Library, and Medline electronic databases up to January 2024. Reference lists of enrolled studies, Google Scholar, and reports of scientific meetings were also searched manually.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThrough systematic literature search and screening, six studies compared the diagnostic effect of ICG imaging to White Light imaging(WL) for EMs during laparoscopic surgery were enrolled. Two studies found that ICG imaging improved the diagnostic rate of EMs. The others found the diagnostic value of ICG imaging was minimal. Cumulative results found the sensitivity is 0.88 (95%CI: 0.81-0.93) for WL and 0.64 (95%CI: 0.36-0.84) for ICG respectively. The specificity is 0.85 (95%CI: 0.49-0.97) for WL and 0.88 (95%CI: 0.66-0.97) for ICG respectively. The positive likelihood ratio (LR+) is 5.8 (95%CI: 1.4-24.5) for WL and 5.4 (95%CI: 1.2-24.1) for ICG respectively. The negative likelihood ratio (LR-) is 0.14 (95%CI: 0.09-0.20) for WL and 0.41 (95%CI: 0.18-0.94) for ICG respectively. The diagnostic odds ratio (DOR) is 42 (95%CI: 10-182) for WL and 13(95%CI: 1-124) for ICG respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eAlthough ICG may be helpful for the visualization of occult EMs, the diagnostic value of ICG is nonsuperior to WL. However, the results should be minded with caution owing to the limited studies and small sample size. More reliable evidence based on larger simple-size studies and multicentric studies are needed urgently.\u003c/p\u003e","manuscriptTitle":"The diagnostic value of Near-Infrared Indocyanine Green Imaging for Endometriosis: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-13 13:07:59","doi":"10.21203/rs.3.rs-3974057/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d9d9a4d8-430f-470d-8559-6aba6510c707","owner":[],"postedDate":"March 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-29T03:54:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-13 13:07:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3974057","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3974057","identity":"rs-3974057","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}