Introduction

Factors influencing the exposure to targeted therapies (biologics/JAKi), intestinal resections and hospitalisations in newly diagnosed IBD patients have been scarcely studied.

Aims & Methods

Aim: To identify predictive factors of exposure to biologics/JAKi, surgeries, and hospitalisations within the first five years in IBD patients.
Methods: Prospective, population-based, nationwide registry. Adult patients diagnosed with IBD [Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)] during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years after diagnosis. Multivariate analyses were performed to identify the predictive factors for biologics/JAKi use, surgeries, and hospitalisations. To this end, only abdominal surgeries were analysed, and early treatment with immunomodulators or biologics/JAKi drugs were considered if these had been prescribed within the first six months of diagnosis.

Results

A total of 1,526 patients diagnosed with CD and 1,633 with UC were included. Regarding the predictors of exposure to biologics/JAKi treatments, we observed that younger age, more aggressive phenotype of CD and greater extent of UC were associated with a higher risk of exposure (table 1). Furthermore, smoking was associated with a higher likelihood of exposure to biologics/JAKi drugs in patients with CD (HR=1.33, 95%CI=1.11-1.60) while in UC patients it was associated with a lower risk (HR=0.56, 95%CI=0.35-0.89). Concerning surgeries (table 1), early treatment with immunomodulators was associated with a lower risk in patients with CD (HR=0.33, 95%CI=0.22-0.49), whereas early use of biologics/JAKi drugs was associated with a higher likelihood of surgery in patients with UC (HR=11.86, 95%CI=4.62-30.42). Finally, the exposure to biologics/JAKi drugs was associated with a lower risk of hospital admissions both in patients with CD (HR=0.37, 95%CI=0.24-0.56) and UC (HR=0.45, 95%CI=0.22-0.91) (table 1).

Table 1: Predictors of biologics/JAKi use (A), surgeries (B) and hospitalisations (C) in patients with Corhn´s disease (CD) and ulcerative colitis (UC)

Conclusion

The exposure to biologics/JAKi drugs is mediated by the more aggressive phenotype of CD, greater extent of UC, and younger patient age. The use of biologics/JAKi drugs, as currently practiced, is associated with a lower risk of hospitalisations but does not reduce the need for surgery, even when administered early. There is an unmet need for more accurate identification of patients who require these treatments to modify the natural course of the disease.

Disclosure

SR has received support for conference attendance, speaker fees, research support, and consulting fees from AbbVie, Adacyte, Faes Pharma, Ferring, Tillots, Galapagos, Janssen, Pfizer, and Lilly.
RF has received support for conference attendance, and research support from AbbVie, Faes Pharma, Ferring, Janssen, Pfizer, Takeda, and Galapagos.
RC: has received support from Janssen, Johnson&Johnson, Ferring, Abbvie, Falk, Pfizer y Galápagos.
AN: has received financial support for travelling and educational activities from Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma and Ferring.
JPG has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma.
MC has served as a speaker, or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma.

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

The first and further decompensation mark the natural history and the risk of mortality in patients with cirrhosis. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD).

Aims & Methods

International multicenter retrospective study (17 centers) on 6,061 consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD. First and further decompensation were defined according to Baveno VII criteria. Competing risk analysis by cumulative incidence functions and Cause-specific Cox models with baseline and time-dependent variables were performed. A multistate model was built to better assess the clinical course of cACLD due to MASLD.

Results

The cumulative incidence of the first decompensation was 3.5% (95% C.I 3.0-4.1) at 5 years, increasing 19-fold the risk of LR-D using Cox analysis; the cumulative incidence of further decompensation was 43.9% (95% C.I 37.2-50.2) at 5 years among patients with first decompensation, additionally increasing 1.5-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D by 3- and 1.4-fold in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation, respectively.

Conclusion

The first and further decompensations represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 19-times and additionally 1.5-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation.