We read with great interest the study by Gigante et al. in Liver International and commend the authors for evaluating bile VEGF, MMPs and PDGF-AA in patients undergoing ERCP, identifying VEGF as the leading diagnostic marker and PDGF-AA as a favourable prognostic signal 1. Because the article frames these markers as having clinical potential for malignant biliary strictures, three issues warrant discussion. First, the central VEGF finding may be weakened by spectrum and comparator bias. The benign group consisted almost entirely of choledocholithiasis, whereas current practice is challenged mainly by truly indeterminate strictures after cross-sectional imaging and ERCP/EUS sampling, for which ESGE recommends integrated tissue acquisition rather than tumour markers alone 2. Moreover, the incremental comparison mainly benchmarked VEGF against bile cytology, a low-sensitivity comparator, whereas bile cfDNA NGS has shown high sensitivity in suspicious or initially indeterminate biliary strictures and may outperform plasma cfDNA in mutation detection 3. In comparison, a prospective methylated-DNA marker panel in biliary brushings achieved an AUC of 0.86 with 73.4% sensitivity and 92.9% specificity, outperforming cytology and FISH in a validation framework closer to a diagnostic algorithm 4. Second, the statistical stability of the VEGF and MMP-2 signals deserves caution. Cutoffs were derived internally by the Youden index, while disease-specific multivariable estimates were based on small strata and borderline confidence limits, including VEGF for PDAC and MMP-2 for CCA 1. Serum bilirubin differed substantially between benign and malignant groups and remained independently associated with malignancy or CCA, so adjustment for a single cholestasis measure may not fully decouple tumour biology from obstruction severity, duration or bile dilution 1. Third, the favourable prognostic interpretation of PDGF-AA is intriguing but biologically under-resolved. PDGF-AA was available in only 42 malignant cases, the survival threshold was selected for maximal discrimination, and the analysis did not clearly separate PDAC from CCA treatments, stage or resection status 1. Conversely, recent CCA data link high PDGF-CC expression to poor prognosis and show that genetic or pharmacologic PDGF-CC inhibition suppresses proliferation, invasion and xenograft growth, highlighting isoform-specific, compartment-specific PDGF biology 5. These concerns do not diminish the value of bile as a proximal liquid biopsy, but they shift the next step from biomarker discovery to prospective validation in indeterminate strictures. A clinically useful test should be benchmarked against contemporary endoscopic tissue acquisition and molecular bile assays, with prespecified thresholds and cancer-specific prognostic models. Declaration of generative AI and AI-assisted technologies: During the preparation of this work, the author used ChatGPT to improve the English language, grammar, and overall readability of the manuscript. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication. The author has nothing to report. The author declares no conflicts of interest. This article is linked to Gigante et al. papers. To view this article, visit https://doi.org/10.1111/liv.70637. The author has nothing to report.
Jiayue Yuan (Tue,) studied this question.