Radiomics signature based on computed tomography images for the preoperative prediction of lymph node metastasis at individual stations in gastric cancer: A multicenter study

  • Author Footnotes
    1 Contributed equally as first authors.
    Zepang Sun
    Footnotes
    1 Contributed equally as first authors.
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    1 Contributed equally as first authors.
    Yuming Jiang
    Footnotes
    1 Contributed equally as first authors.
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    1 Contributed equally as first authors.
    Chuanli Chen
    Footnotes
    1 Contributed equally as first authors.
    Affiliations
    Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Huan Zheng
    Affiliations
    Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Weicai Huang
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Benjamin Xu
    Affiliations
    Lynbrook High School, San Jose, USA
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  • Weijing Tang
    Affiliations
    Department of Pathology, Stanford University School of Medicine, USA
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  • Qingyu Yuan
    Affiliations
    Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Kangneng Zhou
    Affiliations
    School of Computer and Communication Engineering, University of Science and Technology Beijing, China
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  • Xiaokun Liang
    Affiliations
    Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Shenzhen Colleges of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen, China
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  • Hao Chen
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Zhen Han
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Hao Feng
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Shitong Yu
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Yanfeng Hu
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Jiang Yu
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    2 Contributed equally as senior authors.
    Zhiwei Zhou
    Correspondence
    Corresponding authors at: Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China (G. Li). Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China (Y. Xu). Department of Gastric Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, P. R. 510060, China (W. Wang). Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (Z. Zhou).
    Footnotes
    2 Contributed equally as senior authors.
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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  • Author Footnotes
    2 Contributed equally as senior authors.
    Wei Wang
    Correspondence
    Corresponding authors at: Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China (G. Li). Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China (Y. Xu). Department of Gastric Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, P. R. 510060, China (W. Wang). Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (Z. Zhou).
    Footnotes
    2 Contributed equally as senior authors.
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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  • Author Footnotes
    2 Contributed equally as senior authors.
    Yikai Xu
    Correspondence
    Corresponding authors at: Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China (G. Li). Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China (Y. Xu). Department of Gastric Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, P. R. 510060, China (W. Wang). Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (Z. Zhou).
    Footnotes
    2 Contributed equally as senior authors.
    Affiliations
    Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    2 Contributed equally as senior authors.
    Guoxin Li
    Correspondence
    Corresponding authors at: Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China (G. Li). Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China (Y. Xu). Department of Gastric Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, P. R. 510060, China (W. Wang). Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (Z. Zhou).
    Footnotes
    2 Contributed equally as senior authors.
    Affiliations
    Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    1 Contributed equally as first authors.
    2 Contributed equally as senior authors.
Published:November 10, 2021DOI:https://doi.org/10.1016/j.radonc.2021.11.003

      Highlight

      • Preoperative individualized lymph node metastasis prediction can guide surgical treatment for gastric cancer.
      • Radiomics using CT images can effectively predict lymph node metastasis at individual stations.
      • CT images contain substantial information on lymph node metastases.

      Abstract

      Background

      Specific diagnosis and treatment of gastric cancer (GC) require accurate preoperative predictions of lymph node metastasis (LNM) at individual stations, such as estimating the extent of lymph node dissection. This study aimed to develop a radiomics signature based on preoperative computed tomography (CT) images, for predicting the LNM status at each individual station.

      Methods

      We enrolled 1506 GC patients retrospectively from two centers as training (531) and external (975) validation cohorts, and recruited 112 patients prospectively from a single center as prospective validation cohort. Radiomics features were extracted from preoperative CT images and integrated with clinical characteristics to construct nomograms for LNM prediction at individual lymph node stations. Performance of the nomograms was assessed through calibration, discrimination and clinical usefulness.

      Results

      In training, external and prospective validation cohorts, radiomics signature was significantly associated with LNM status. Moreover, radiomics signature was an independent predictor of LNM status in the multivariable logistic regression analysis. The radiomics nomograms revealed good prediction performances, with AUCs of 0.716–0.871 in the training cohort, 0.678–0.768 in the external validation cohort and 0.700–0.841 in the prospective validation cohort for 12 nodal stations. The nomograms demonstrated a significant agreement between the actual probability and predictive probability in calibration curves. Decision curve analysis showed that nomograms had better net benefit than clinicopathologic characteristics.

      Conclusion

      Radiomics nomograms for individual lymph node stations presented good prediction accuracy, which could provide important information for individual diagnosis and treatment of gastric cancer.

      Keywords

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      References

        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
      1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11-20. Epub 2006/07/11. 10.1056/NEJMoa055531. PubMed PMID: 16822992.

        • Pyo J.H.
        • Shin C.M.
        • Lee H.
        • Min B.H.
        • Kim S.
        A Risk-prediction Model Based on Lymph-node Metastasis for Incorporation Into a Treatment Algorithm for Signet Ring Cell-type Intramucosal Gastric Cancer.
        Ann Surg. 2016; 150
        • Datta J.
        • Mcmillan M.T.
        • Ecker B.L.
        • Karakousis G.C.
        • Roses R.E.
        Implications of lymph node staging on selection of adjuvant therapy for gastric cancer in the United States: A propensity score-matched analysis.
        Ann Surgery. 2015; 263: 298
      2. Association JGC. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer. 2020; 1-21.

        • Hosono S.
        • Ohtani H.
        • Arimoto Y.
        • Kanamiya Y.
        Endoscopic stenting versus surgical gastroenterostomy for palliation of malignant gastroduodenal obstruction: a meta-analysis.
        J Gastroenterol. 2007; 42 (Epub 2007/04/28. 10.1007/s00535-006-2003-y. PubMed PMID: 17464457): 283-290
        • Hosono S.
        • Arimoto Y.
        • Ohtani H.
        • Kanamiya Y.
        Meta-analysis of short-term outcomes after laparoscopy-assisted distal gastrectomy.
        World J Gastroenterol. 2006; 12 (Epub 2006/12/16. 10.3748/wjg.v12.i47.7676. PubMed PMID: 17171799; PubMed Central PMCID: PMCPMC4088052): 7676-7683
        • Imaoka W.
        • Ida K.
        • Katoh T.
        • Okuda J.
        • Kawai K.
        Is curative endoscopic treatment of early gastric cancer possible?.
        Endoscopy. 1987; 19: 7-11
        • Schwarz R.E.
        • Smith D.D.
        Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial.
        J Clin Oncol. 2005; 23 (author reply 5. Epub 2005/08/11. PubMed PMID: 16091352): 5404-5405https://doi.org/10.1200/JCO.2005.05.189
        • Degiuli M.
        • Sasako M.
        • Ponti A.
        • Vendrame A.
        • Tomatis M.
        • Mazza C.
        • et al.
        Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer.
        Br J Surg. 2014; 101 (Epub 2014/01/01. 10.1002/bjs.9345. PubMed PMID: 24375296): 23-31
        • Ajani J.A.
        • D 'Amico T.A.
        • Almhanna K.
        • Bentrem D.J.
        • Chao J.
        • Das P.
        • et al.
        Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology.
        J Natl Compreh Cancer Netwk JNCCN. 2016; 14: 1286
        • Yoshikawa T.
        Is D2 lymph node dissection necessary for early gastric cancer?.
        Ann Surg Oncol. 2002; 9: 401-405
        • Wang F.H.
        • Shen L.
        • Li J.
        • Zhou Z.W.
        • Liang H.
        • Zhang X.T.
        • et al.
        The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer.
        Cancer Commun. 2019; 39
        • Valsecchi M.E.
        • Silbermins D.
        • de Rosa N.
        • Wong S.L.
        • Lyman G.H.
        Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma: a meta-analysis.
        J Clin Oncol. 2011; 29 (PubMed PMID: 21383281): 1479-1487https://doi.org/10.1200/JCO.2010.33.1884
        • Straver M.E.
        • Meijnen P.
        • Tienhoven G.V.
        • Velde C.J.H.V.D.
        • Rutgers E.J.T.
        Sentinel node identification rate and nodal involvement in the EORTC 10981–22023 AMAROS trial.
        Ann Surg Oncol. 2010; 17: 1854-1861
      3. Ichikura T, Morita D, Uchida T, Okura E, Majima T, Ogawa T, et al. Sentinel node concept in gastric carcinoma. World J Surg. 2002;26(3):318-22. Epub 2002/02/28. 10.1007/s00268-001-0226-x. PubMed PMID: 11865368.

        • Liu C.G.
        • Lu P.
        • Lu Y.
        • Jin F.
        • Xu H.M.
        • Wang S.B.
        • et al.
        Distribution of solitary lymph nodes in primary gastric cancer: a retrospective study and clinical implications.
        World J Gastroenterol. 2007; 13 (Epub 2007/08/31. 10.3748/wjg.v13.i35.4776. PubMed PMID: 17729400; PubMed Central PMCID: PMCPMC4611200): 4776-4780
        • Jung M.K.
        • Cho M.
        • Roh C.K.
        • Seo W.J.
        • Choi S.
        • Son T.
        • et al.
        Assessment of diagnostic value of fluorescent lymphography-guided lymphadenectomy for gastric cancer.
        Gastric Cancer. 2020; (Epub 2020/09/19. PubMed PMID: 32945996)https://doi.org/10.1007/s10120-020-01121-0
        • Miyashiro I.H.M.
        • Sasako M.
        • et al.
        High false-negative proportion of intraoperative histological examination as a serious problem for clinical application of sentinel node biopsy for early gastric cancer: final results of the Japan Clinical Oncology Group multicenter trial JCOG0302.
        Gastric Cancer. 2013;
      4. National Comprehensive Cancer Network (NCCN) guidelines. Available at http://www.nccn.org/. Accessed January 10.

        • Kim H.J.
        • Kim A.Y.
        • Oh S.T.
        • Kim J.S.
        • Kim K.W.
        • Kim P.N.
        • et al.
        Gastric cancer staging at multi-detector row CT gastrography: comparison of transverse and volumetric CT scanning.
        Radiology. 2005; 236 (Epub 2005/07/16. 10.1148/radiol.2363041101. PubMed PMID: 16020558): 879-885
      5. Saito T, Kurokawa Y, Takiguchi S, Miyazaki Y, Takahashi T, Yamasaki M, et al. Accuracy of multidetector-row CT in diagnosing lymph node metastasis in patients with gastric cancer. Eur Radiol. 2015;25(2):368-74. Epub 2014/08/07. 10.1007/s00330-014-3373-9. PubMed PMID: 25097136.

      6. Kim AY, Kim HJ, Ha HK. Gastric cancer by multidetector row CT: preoperative staging. Abdom Imaging. 2005;30(4):465-72. Epub 2005/03/24. 10.1007/s00261-004-0273-5. PubMed PMID: 15785907.

      7. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. Epub 2008/12/23. 10.1016/j.ejca.2008.10.026. PubMed PMID: 19097774.

        • Li B.
        • Zheng P.
        • Zhu Q.
        • Lin J.
        Accurate preoperative staging of gastric cancer with combined endoscopic ultrasonography and PET-CT.
        Tohoku J Exp Med. 2012; 228 (Epub 2012/08/07. 10.1620/tjem.228.9. PubMed PMID: 22864063.): 9-16
        • Cardoso R.
        • Coburn N.
        • Seevaratnam R.
        • Sutradhar R.
        • Lourenco L.G.
        • Mahar A.
        • et al.
        A systematic review and meta-analysis of the utility of EUS for preoperative staging for gastric cancer.
        Gastric Cancer. 2012; (15 Suppl 1:S19-Epub 2012/01/13. 10.1007/s10120-011-0115-4. PubMed PMID: 22237654)
        • Lee D.H.
        • Kim S.H.
        • Joo I.
        • Hur B.Y.
        • Han J.K.
        Comparison between 18F-FDG PET/MRI and MDCT for the assessment of preoperative staging and resectability of gastric cancer.
        Eur J Radiol. 2016; 1085–91
      8. Yu JW, Wu JG, Tajima Y, Li XQ, Du GY, Zheng LH, et al. Study on lymph node metastasis correlated to lymphangiogenesis, lymphatic vessel invasion, and lymph node micrometastasis in gastric cancer. J Surg Res. 2011;168(2):188-96. Epub 2010/03/02. 10.1016/j.jss.2009.10.030. PubMed PMID: 20189585.

        • Jin E.H.
        • Lee D.H.
        • Jung S.A.
        • Shim K.N.
        • Seo J.Y.
        • Kim N.
        • et al.
        Clinicopathologic factors and molecular markers related to lymph node metastasis in early gastric cancer.
        World J Gastroenterol. 2015; 21 (Epub 2015/01/17. 10.3748/wjg.v21.i2.571. PubMed PMID: 25593477; PubMed Central PMCID: PMCPMC4294168): 571-577
        • Gillies R.J.
        • Kinahan P.E.
        • Hricak H.
        Radiomics: Images Are More than Pictures.
        They Are Data Radiology. 2016; 278: 563-577
      9. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nature Communications. 2014;5(1):4006.

        • Jiang Y.
        • Jin C.
        • Yu H.
        • Wu J.
        • Chen C.
        • Yuan Q.
        • et al.
        Development and validation of a deep learning CT Signature to predict survival and chemotherapy benefit in gastric cancer: A multicenter, retrospective study.
        Ann Surg. 2020; (Epub 2020/01/09. PubMed PMID: 31913871)https://doi.org/10.1097/SLA.0000000000003778
      10. Jiang Y, Wang W, Chen C, Zhang X, Zha X, Lv W, et al. Radiomics Signature on Computed Tomography Imaging: Association With Lymph Node Metastasis in Patients With Gastric Cancer. Front Oncol. 2019;9:340. Epub 2019/05/21. 10.3389/fonc.2019.00340. PubMed PMID: 31106158; PubMed Central PMCID: PMCPMC6498894.

      11. Huang YQ, Liang CH, He L, Tian J, Liang CS, Chen X, et al. Development and Validation of a Radiomics Nomogram for Preoperative Prediction of Lymph Node Metastasis in Colorectal Cancer. J Clin Oncol. 2016;34(18):2157-64. Epub 2016/05/04. 10.1200/JCO.2015.65.9128. PubMed PMID: 27138577.

      12. Zwanenburg A, Vallieres M, Abdalah MA, Aerts H, Andrearczyk V, Apte A, et al. The Image Biomarker Standardization Initiative: Standardized Quantitative Radiomics for High-Throughput Image-based Phenotyping. Radiology. 2020;295(2):328-38. Epub 2020/03/11. 10.1148/radiol.2020191145. PubMed PMID: 32154773; PubMed Central PMCID: PMCPMC7193906.

      13. Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101-12. Epub 2011/05/17. 10.1007/s10120-011-0041-5. PubMed PMID: 21573743.

      14. Daghir-Wojtkowiak E, Wiczling P, Bocian S, Kubik L, Koslinski P, Buszewski B, et al. Least absolute shrinkage and selection operator and dimensionality reduction techniques in quantitative structure retention relationship modeling of retention in hydrophilic interaction liquid chromatography. J Chromatogr A. 2015;1403:54-62. Epub 2015/06/04. 10.1016/j.chroma.2015.05.025. PubMed PMID: 26037317.

      15. Harrell FE, Jr., Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361-87. Epub 1996/02/28. 10.1002/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>3.0.CO;2-4. PubMed PMID: 8668867.

      16. Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Making. 2006;26(6):565-74. Epub 2006/11/14. 10.1177/0272989X06295361. PubMed PMID: 17099194; PubMed Central PMCID: PMCPMC2577036.

        • Wang J.
        • Dang P.
        • Raut C.P.
        • Pandalai P.K.
        • Maduekwe U.N.
        • Rattner D.W.
        • et al.
        Comparison of a lymph node ratio-based staging system with the 7th AJCC system for gastric cancer.
        Ann Surg. 2012; 255: 478-485
        • Dong D.
        • Fang M.J.
        • Tang L.
        • Shan X.H.
        • Gao J.B.
        • Giganti F.
        • et al.
        Deep learning radiomic nomogram can predict the number of lymph node metastasis in locally advanced gastric cancer: an international multicenter study.
        Ann Oncol. 2020; 31: 912-920https://doi.org/10.1016/j.annonc.2020.04.003. PubMed PMID: WOS:000540695500014
      17. Gao XJ, Ma TT, Cui JL, Zhang YW, Wang LW, Li H, et al. A radiomics-based model for prediction of lymph node metastasis in gastric cancer. European Journal Of Radiology. 2020;129. ARTN 109069. 10.1016/j.ejrad.2020.109069. PubMed PMID: WOS:000548599500018.

        • Jin C.
        • Jiang Y.
        • Yu H.
        • Wang W.
        • Li B.
        • Chen C.
        • et al.
        Deep learning analysis of the primary tumour and the prediction of lymph node metastases in gastric cancer.
        Br J Surg. 2020; (Epub 2020/09/30. PubMed PMID: 32990326)https://doi.org/10.1002/bjs.11928
        • Hoshida T.
        • Isaka N.
        • Hagendoorn J.
        • di Tomaso E.
        • Chen Y.L.
        • Pytowski B.
        • et al.
        Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: Therapeutic implications.
        Cancer Res. 2006; 66 (PubMed PMID: WOS:000239828200032): 8065-8075https://doi.org/10.1158/0008-5472.Can-06-1392