Background and Aims: Biliary tract cancers (BTCs) are aggressive gastrointestinal malignancies characterized by a dismal 5-year overall survival rate less than 20%. Current diagnostic modalities suffer from limitations regarding sensitivity and specificity. This study aimed to develop a bile metabolite-based platform for precise discrimination between malignant and benign biliary diseases. Approach and Results: Samples were collected from 336 patients with BTC or benign biliary diseases across three independent cohorts. Untargeted metabolic fingerprinting was performed on 300 bile samples using novel nanoparticle-enhanced laser desorption/ionization mass spectrometry (NPELDI MS). Subsequently, a diagnostic assay was developed based on the exploratory cohort using a selected bile metabolic biomarker panel, with performance evaluated in the validation cohort. Further external validation of disease-specific metabolites from bile samples was conducted in a prospective cohort (n=36) using quantitative analysis. As a result, we established a novel bile-based assay, BileMet, for the rapid and precise detection of malignancies in the biliary tract system with an area under the curve of 0.891. We identified 6 metabolite biomarker candidates and discovered the critical role of the chenodeoxycholic acid glycine conjugate as a protective metabolite associated with BTC. Conclusions: Our findings confirmed the improved diagnostic capabilities of BileMet assay in a clinical setting. If applied, the BileMet assay enables intraoperative testing and fast medical decision-making for cases with suspected malignancy where brush cytology detection fails to support malignancy, ultimately reducing the economic burden by over 90%.

中文翻译：

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胆汁代谢指纹区分胆道癌和良性胆道疾病


背景和目的：胆道癌 (BTC) 是一种侵袭性胃肠道恶性肿瘤，其特点是 5 年总生存率低于 20%。目前的诊断方式在敏感性和特异性方面存在局限性。本研究旨在开发一个基于胆汁代谢物的平台，用于精确区分恶性和良性胆道疾病。方法和结果：样本采集自三个独立队列的 336 名 BTC 或良性胆道疾病患者。使用新型纳米粒子增强激光解吸/电离质谱 (NPELDI MS) 对 300 个胆汁样本进行非靶向代谢指纹分析。随后，使用选定的胆汁代谢生物标志物组基于探索性队列开发了诊断测定法，并在验证队列中评估了性能。使用定量分析在前瞻性队列 (n=36) 中对胆汁样本中的疾病特异性代谢物进行了进一步的外部验证。因此，我们建立了一种新型的基于胆汁的检测方法 BileMet，用于快速、精确地检测胆道系统中的恶性肿瘤，曲线下面积为 0.891。我们鉴定了 6 种候选代谢物生物标志物，并发现鹅去氧胆酸甘氨酸缀合物作为与 BTC 相关的保护性代谢物的关键作用。结论：我们的研究结果证实了 BileMet 检测在临床环境中诊断能力的提高。如果应用，BileMet 检测可以对刷细胞学检测无法支持恶性肿瘤的疑似恶性肿瘤病例进行术中检测和快速医疗决策，最终将经济负担减轻 90% 以上。