Introduction

Biliary strictures are usually caused by malignancies such as Cholangiocarcinoma (CCA) or Pancreatic Ductal Adenocarcinoma (PDAC). 70% of these neoplasms are diagnosed at advanced stages due to late-onset symptoms, lack of biomarkers, and challenges in obtaining histological samples. Curative surgical resection with adjuvant therapy is the first-line treatment, but 20% of cases are resectable at diagnosis and 80% relapse within 3 years^1,2. The impact of systemic therapies on overall survival remains limited, however new targeted therapies have shown remarkable efficacy in patients with actionable mutations based on tumor genetic profiling. Clinical guidelines advocate multigene panel analysis of tumor tissue prior to or during first-line treatment^3,4, considering that 40% of CCA patients and around 25% of PDAC patients harbor actionable genetic mutations^5,6. When tumor tissue is insufficient, liquid biopsies using cfDNA can be considered³. Liquid biopsy of bile, collected during an Endoscopic Retrograde Cholangiopancreatography (ERCP) in malignant biliary stricture cases, could potentially detect therapeutic targets.

Aims & Methods

This prospective proof-of-concept pilot study aims to assess NGS-based cfDNA analysis in bile as a novel liquid biopsy for detecting genetic mutations, and specifically actionable mutations, compared to tissue NGS.
19 CCA and 9 PDAC patients with malignant biliary stenosis undergoing ERCP in a tertiary hospital (2017-2020) were included. Bile samples were collected during the first ERCP and the Pathological Anatomy department selected tissue samples with ≥40% tumor content. Massive sequencing of DNA libraries was performed using the Pan-Cancer Panel^TM (52-genes) for bile samples, and the Oncomine^TM Comprehensive Assay Panel v3 (161 genes) for tissue.

Results

Concerning CCA patients, bile NGS identified all patients with mutations (19/19) opposite to 84.3% (16/19) of patients in tissue. Bile NGS identified 7 patients (37%) with actionable mutations, none was detected in tissue. We detected 47/49 mutations in bile NGS vs. 22/49 in tissue. High concordance was observed: 91% (20/22) of tissue mutations were also in bile. Regarding actionable mutations considered in ESMO guidelines³; 7 were detected in bile NGS, none detected in tissue. The actionable mutations identified were ERBB2 (5), IDH2 (1), and KRAS^G12C(1).
In the PDAC group, bile NGS identified 89% (8/9) of patients with mutations, compared to 66.6% (6/9) of patients in tissue. Bile NGS identified 5 patients (55%) with actionable mutations vs. 4 (44%) in tissue. Bile NGS detected 16/18 mutations in bile in contrast to 12/18 in tissue. High concordance was observed: 83.3% (10/12) of tissue mutations were also in bile. NGS in bile detected 6 actionable mutations considered in ESMO guidelines^4,; KRAS^G12D (5) and ERBB3, compared to 4 in tissue; KRAS^G12D.

Conclusion

These results highlight the potential of bile liquid biopsy in detecting actionable mutations; bile NGS increased the diagnosis sensibility and the number of mutations detected, compared with tissue NGS, which could allow more patients to be considered for targeted therapies. This approach does not require histological material consumption and collecting bile during an ERCP is simple and secure. In addition, NGS technology is available in all molecular laboratories. We consider that the application of liquid biopsy in bile can be accessible and an effective tool, with direct and immediate clinical implementation, improving precision medicine strategies and the therapeutic management of CCA and PDAC patients with biliary stenosis.

References

1. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. Epub 2020 Jun 30.
2.Park W, Chawla A, O’Reilly EM. Pancreatic Cancer: A Review. JAMA. 2021 Sep 7;326(9):851–62.3.
3.Vogel A, Ducreux M; ESMO Guidelines Committee. ESMO Clinical Practice Guideline interim update on the management of biliary tract cancer. ESMO Open. 2025 Jan;10(1):104003. Epub 2024 Dec 17.
4.Conroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O’Reilly EM, et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Nov;34(11):987–1002.
5. Gilbert TM, Randle L, Quinn M, McGreevy O, O'leary L, Young R, et al. Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management. Eur J Surg Oncol. 2025 Feb;51(2):108352. Epub 2024 Apr 17
6. Boileve A, Smolenschi C, Lambert A, Boige V, Tarabay A, Valery M, et al. Role of molecular biology in the management of pancreatic cancer. World J Gastrointest Oncol. 2024 Jul 15;16(7):2902-2914.

Introduction

Cholestatic pruritus is common, debilitating and undertreated in patients with primary biliary cholangitis (PBC). Here, we describe the results of GLISTEN (NCT04950127), a Phase 3 study investigating the efficacy and safety of the ileal bile acid transporter inhibitor linerixibat for pruritus in PBC.

Aims & Methods

In this double-blind, randomised, placebo-controlled study, patients with PBC and moderate-to-severe pruritus received oral linerixibat 40 mg or placebo twice daily. Pruritus severity and pruritus-related sleep interference were assessed using a 0–10 numerical rating scale. The primary endpoint was change from baseline in worst itch over 24 weeks. Secondary endpoints included: at Week 2, change in worst itch; over 24 weeks, change in sleep interference; at Week 24, proportion of responders (≥ 2-, ≥ 3-, ≥ 4-point reduction in worst itch) and analysis of responses to 2 patient global impression items (itch severity and change). Safety endpoints included adverse event (AE) reporting.

Results

238 patients were randomised; 95% were female, itch severity was mean (standard deviation [SD]) 7.34 (1.54), 52% had alkaline phosphatase < 1.67 times upper limit of normal, and 47% were receiving stable therapy for pruritus. Pruritus improvement over 24 weeks was significantly greater with linerixibat than placebo: least-squares (LS) mean change -2.86 versus -2.15, adjusted mean difference -0.72; p = 0.001. At Week 24, the observed mean (SD) difference from baseline in pruritus was -3.66 (2.50) with linerixibat and -2.82 (2.32) with placebo. The effect of linerixibat was rapid and superior to placebo at Week 2: LS mean change -1.78 versus -1.07, adjusted mean difference -0.71; p < 0.001. Linerixibat also significantly improved pruritus-related sleep interference over 24 weeks versus placebo: LS mean change ‑2.77 versus -2.24, adjusted mean difference -0.53; p = 0.024. At Week 24, more patients on linerixibat than placebo achieved a ≥ 2-point (68% vs 64%), ≥ 3-point (56% vs 43%) or ≥ 4-point (41% vs 29%) reduction in pruritus and a higher proportion of linerixibat than placebo-treated patients reported their pruritus was very much improved (55% vs 37%) or absent (21% vs 9%). AEs reported more frequently with linerixibat than placebo were predominantly gastrointestinal (GI), including diarrhoea (61% vs 18% of patients) and abdominal pain (18% vs 3% of patients); 4% of patients in the linerixibat group discontinued treatment due to diarrhoea.

Conclusion

In patients with PBC and moderate-to-severe pruritus, linerixibat rapidly and significantly improved pruritus and pruritus-related sleep interference versus placebo. While GI AEs were more common with linerixibat than placebo, they rarely led to treatment discontinuation.

Disclosure

Funded by GSK. Various authors declare conflicts of interest as consultants, employee, recipients of grants and stockholders. These will be reported in full during the presentation.

Introduction

Histopathology remains the gold standard for the assessment of diminutive (≤5 mm) colorectal polyps, but it requires considerable cost and resources allocation. Optical diagnosis supported by artificial intelligence (AI) has shown promise, though its integration into clinical decision-making is limited. Our prior work showed the feasibility of replacing histopathology with AI-assisted human optical diagnosis in real-time practice.¹

Aims & Methods

This study aimed to assess patient acceptance, and diagnostic performance of autonomous computer-aided optical diagnosis (CADx) when used as the sole determinant in resect-and-discard (RD) and diagnose-and-leave (DL) strategies.
This prospective study was conducted at the University of Montreal Hospital Center between August and November 2024 (ID: CER23.095, NCT06059378). Consecutive patients aged 45–80 years undergoing elective colonoscopy were approached and provided detailed information about the use of CADx, and the principles of the RD and DL strategies. For consented patients, procedures were performed using CADEYE system, which autonomously provided an optical diagnosis for detected diminutive polyps. Lesions predicted to be neoplastic were removed and discarded without histopathologic analysis (RD), while rectosigmoid lesions predicted to be hyperplastic were left in place (DL). All colonoscopies were video-recorded. To establish the reference standard, the videos of all polyps undergoing optical diagnosis were independently reviewed by two expert endoscopists. In cases of disagreement, a third reviewer arbitrated the final decision. The primary outcome was the proportion of patients consenting to undergo autonomous CADx. Secondary outcomes included the accuracy of the RD strategy, the negative predictive value (NPV) of the DL approach, and the agreement between CADx- and expert-driven surveillance interval recommendations.

Results

95/102 patients approached (93.1%) consented to undergo CADx-based optical diagnosis (mean age 65.7 years). Among 149 diminutive polyps detected (51 (34.2%) in the rectosigmoid and 98 (65.8%) in the proximal colon), CADx provided optical diagnosis in 98.7% (n=147) of cases. The RD and DL strategies were applied to 113 (76.9%) and 30 (20.4%) of polyps, respectively. After excluding indeterminate cases (n=5) and sessile serrated lesions (SSLs) (n=14), the RD strategy achieved an accuracy of 83.5% and the DL strategy demonstrated a NPV of 92.3%. Surveillance interval agreement between CADx and expert recommendations was 100% (95%CI 96.2-100.0). Sensitivity analyses showed reduced performance when SSLs were classified as neoplastic, but Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) benchmarks were met when SSLs were considered hyperplastic.

Table 1. Diagnostic performance of computer- assisted optical diagnosis (CADx), using expert optical diagnosis as the reference.

Conclusion

Autonomous CADx achieved high patient acceptance and met key performance benchmarks for managing diminutive polyps using RD and DL strategies. These findings support its potential for safe, real-world implementation, though further development is needed to address current limitations in SSL detection and to enable quality optical diagnosis practice.

References

1. Taghiakbari M, Rex DK, Pohl H, et al. Pragmatic Resect and Discard Implementation Using Computer-Assisted Optical Polyp Diagnosis. Gastroenterology 2025;168:154-156.e2.

Disclosure

Daniel von Renteln has received research funding from ERBE Elektromedizin GmbH, Ventage, Pendopharm, Fujifilm and Pentax, and has received consultant or speaker fees from Boston Scientific Inc., ERBE Elektromedizin GmbH, and Pendopharm. Roupen Djinbachian has received speaker fees from Fujifilm. The remaining authors declare that they have no conflict of interest.