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Accurately diagnosing and staging chronic and idiopathic pancreatitis

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Accurately diagnosing and staging chronic and idiopathic pancreatitis

Julia Mayerle 1

1 Klinikum der LMU München-Grosshadern, München, Germany

Event

UEG Week Copenhagen 2023

Topics

Pancreas Standards & Guidelines Surgery

Session

Update on chronic pancreatitis: How to diagnose and how to treat?

Published

2023

UEG Poster

Standard Poster

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Introduction

MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed MASH and fibrosis. 966 patients with biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo once daily. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage improvement in fibrosis with no worsening of NAS (FI). Both Week 52 liver biopsy endpoints, NR and FI, were achieved. Resmetirom was recently approved for the treatment of adult patients with noncirrhotic NASH and liver fibrosis consistent with F2 to F3 stages. Expert guidance recommends treatment with resmetirom based on staging fibrosis using Vibration-Controlled Transient Elastography (VCTE). EASL recommends stratifying patients using Fibrosis-4 Index (FIB-4). Most guidelines recommend using VCTE cutoffs lower than 10 to <15 kPa for treatment.

Aims & Methods

We assessed results from baseline noninvasive tests (FIB-4, VCTE) against biopsy results in MAESTRO-NASH to measure how well they diagnosed noncirrhotic patients with NASH (consistent
with F2-F3 stages at baseline). We assessed the utility of a lower VCTE cutoff (8.5 to <10 kPa) in capture of F2 and F3 patients who otherwise would be missed. Also evaluated was the addition of
MRE/MRI-PDFF or ELF to VCTE to assess diagnostic utility.

Results

FIB-4 poorly predicted patients in the non-cirrhotic fibrosis stages: F2 (60% patients fell into low-risk) and F3 (40% fell into low-risk). Including a lower cutoff of VCTE (8.5 to <10 kPa) captured
F1B (34% 8.5 to <10 kPa) and many F2 (25% 8.5 to <10 kPa) and F3 patients (19% 8.5 to <10 kPa). The addition of MRE/MRI-PDFF to VCTE increased diagnostic accuracy for F2/F3 to 68% and
F4 to 81%. The addition of the ELF to the VCTE suggested that a low ELF result paired with high VCTE may warrant a VCTE repeat.

Conclusion

Identification of patients with NASH F2 to F3 was achieved with VCTE. F1B are F2 equivalent (F1B is moderate fibrosis on biopsy). Patients with fibrosis stage F4 were effectively ruled out. In addition to VCTE, practitioners may consider expanded noninvasive criteria (ELF, MRE) to help refine fibrosis staging.

Disclosure

This study was supported by Madrigal Pharmaceuticals, Inc.

USE OF NONINVASIVE TESTS (NITS) TO DIAGNOSE AND FOLLOW METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH) WITH LIVER FIBROSIS PATIENTS TREATED WITH RESMETIROM

Jörn Schattenberg 1

1 Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany

Conference

UEG Week Berlin 2025

Topics

Hepatobiliary

Submission format

Abstract

Session

MASH: Screening, monitoring and treatment (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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AN IMMUNE RESPONSIVE TUMOR MICROENVIRONMENT IMPRINTS INTO PBMCS AND ALLOWS TO PREDICT PATIENT OUTCOME USING MACHINE LEARNING IN ADVANCED PANCREATIC CANCER: LESSONS FROM THE PREDICT TRIAL

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Introduction

Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor. Few patients benefit from second-line chemotherapy, while most experience side effects, highlighting the need for biomarkers. The PREDICT trial examined in aPDAC patients whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) but found no association. In our translational study we hypothesized that the responsiveness of the tumor immune microenvironment (TiME) might determine second-line therapy outcome and examined whether treatment-naive tissue immune features are also reflected in the peripheral blood after one line of chemotherapy.

Aims & Methods

In the PREDICT trial, patients received 5-FU/LV plus nanoliposomal irinotecan second-line after gemcitabine/nab-paclitaxel (Gem-nabPac) first-line therapy. We stratified PREDICT patients by shortest vs. longest TTF2. Treatment-naive primary tumor tissues from 20 patients were analyzed by NanoString transcriptomic profiling and multiplexed immunohistochemistry to characterize differences in the TiME. Peripheral blood mononuclear cells (PBMCs) were obtained immediately before second-line therapy from 82 patients and analyzed using multiparameter flow cytometry with an automated gating procedure and gene expression profiling via RT-qPCR. A feature selection and machine learning pipeline integrated PBMC and clinical data to derive a minimal predictor for TTF2 outcome and prognosis that was validated across different treatment regimens on an independent external cohort of 30 patients with aPDAC.

Results

Treatment-naive tumors of patients in the long-TTF2 group exhibited an immune-active (“hot”) TiME with CXCR3⁺CD8⁺ cytotoxic T cell infiltration into the cancer cell compartment via CXCR3-dependant inflammatory chemokine signaling. Analysis of PBMCs obtained directly before second-line therapy showed that these immune features were sustained over one line of treatment and reflected in PBMCs. A PBMC-based machine learning model (“TTF2Pred”) identified a 7-feature immune signature that accurately distinguished long vs. short TTF2 patient groups outperforming multivariate clinical data or CA19-9 benchmark models. TTF2Pred robustness was confirmed by external validation and showed the best overall performance post-Gem-nabPac first-line treatment. Among the seven TTF2Pred features, long-TTF2 patients exhibited more circulating CXCR3⁺ activated T cells and plasmacytoid dendritic cells, while short-TTF2 patients had more circulating platelet–leukocyte (platelet-monocyte, platelet-neutrophil) aggregates and exhausted T cells.

Conclusion

PDAC patients with an immune-active, treatment-naïve TiME have a better outcome on second-line therapy, and these tissue characteristics are reflected in circulating PBMCs after one line of chemotherapy. A parsimonious circulating PBMC-based signature offers a minimally invasive predictor of second-line outcome that could inform personalized therapy.