MicroRNAs As Bile-based Biomarkers In Pancreaticobiliary Cancers

Study Overview

MicroRNAs as Bile-based Biomarkers in Pancreaticobiliary Cancers

pancreatic or biliary-tract cancer can be a serious diagnosis, as many patients present too late for surgery. Cancer cells have been found to release small messenger molecules called that regulate cancer genes called microRNAs (miRNAs). The goal of this observational study is to learn about the role of miRNAs from bile and blood samples in patients with pancreatic cancer and bile duct cancer. The main question[s] it aims to answer are: * Can this detect patients presenting with jaundice (yellow-skin) undergoing endoscopy? * Can this distinguish between the types of cancer? Participants will have blood and bile samples collected prior to diagnosis and their clinical pathway will be followed up for 6 months.

Biliary strictures may be benign or malignant. The major aetiology of a malignant biliary stricture includes a primary tumour or local extension, such as cholangiocarcinoma (CCA) or pancreatic ductal adenocarcinoma (PDAC). There is still ongoing debate about adequate diagnostics in bile duct strictures of unknown aetiology. The application of endoscopic retrograde cholangio-pancreatography (ERCP) is considered to be an essential tool in bile duct strictures. The advantage of ERCP is the ability to achieve biliary decompression and take transpapillary specimens for histological or cytological analysis at the same time. Unfortunately, biliary brush cytology and/or biopsies are often insensitive at detecting malignancy, especially PDAC. MicroRNAs (miRNAs) are newly recognised, small pieces of genetic code that are crucial for regulating cancer genes. It has been previously shown that miRNA "signatures" in tissue and biofluids can be used to detect and prognosticate PDAC. Bile is potentially a rich source of novel biomarkers for PDAC and BTC due to its intimate proximity to the malignant lesion. This prospective, non-randomised, observational, single-blinded study will investigate, as its primary endpoint, whether candidate biliary miRNAs can differentiate between benign and malignant pancreaticobiliary disease/strictures in patients undergoing ERCP. In order to also generate hypotheses, this study also has several exploratory endpoints for translational research. This will focus on patients with presenting with PDAC, correlating miRNA levels with clinicopathologic factors and survival outcomes, in order to establish bile miRNAs as predictive and prognostic biomarkers. Moreover, the study will aim to elucidate the molecular mechanisms and source of the dysregulated biliary miRNAs in PDAC. In summary, there is currently no effective method to differentiate malignant from benign biliary strictures, or the ability to stratify these tumours pre-operatively based on their biological subtype and aggressiveness. The proposed study aims to improve the speed and accuracy of diagnosing these tumours by using measuring bile-based miRNA signatures. Importantly, it has been shown that biliary miRNAs can be easily extracted and analysed, and these molecules are stable in clinical settings. The development of clinically useful biliary miRNA biomarkers will result in considerable patient benefits.

Pancreatic Cancer
Cholangiocarcinoma
Ampullary Cancer
Biliary Stricture
Gallstone Disease

DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs

MIRABILE

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2024-02-06	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-02-06
First Submitted that Met QC Criteria 2024-02-06	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-02-14
First Posted (ACTUAL) 2024-02-14	Results First Posted N/A	Last Verified 2024-02

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
N/A

Allocation:
N/A

Interventional Model:
N/A

Masking:
N/A

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
: Pancreatic Cancer (PDAC) A clinical diagnosis of PDAC was defined by results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiolo	DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba
: Cholangiocarcinoma (CCA) A clinical diagnosis of CCA was defined by radiological criteria according to results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histo	DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba
: Benign A clinical diagnosis of benign disease was defined by assessment at ERCP as well as results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant	DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba

Participant Group/Arm

Intervention/Treatment

: Pancreatic Cancer (PDAC)

A clinical diagnosis of PDAC was defined by results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiolo

DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs

Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba

: Cholangiocarcinoma (CCA)

A clinical diagnosis of CCA was defined by radiological criteria according to results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histo

DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs

Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba

: Benign

A clinical diagnosis of benign disease was defined by assessment at ERCP as well as results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant

DIAGNOSTIC_TEST: Small RNA Sequencing and Validation of candidate miRNAs

Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 ba

Primary Outcome Measures	Measure Description	Time Frame
Diagnostic Value as measured by Area under the Curve (AUC) for candidate miRNAs	Expression values for each miRNA is calculated and used to undertake Multiple logistic regression was undertaken for candidates individually and in combination using GraphPad Prism. Data was prepared as a binary outcome and all main effects are included in the model. Optimum cut-offs were determined using thresholds obtained from the ROC curve at the maximum Youden index. Youden's J statistic (also called Youden's index) is a single statistic that ranges from 0 to 1 and is determined by the formula (Specificity + Sensitivity -1). Where multiple hypotheses were tested, an appropriate Benjamini-Hochberg (False Discovery Rate) correction was applied to give an adjusted p-value. A p (adjusted) value of <0.05 was considered to be statistically significant.	On the day of ERCP

Secondary Outcome Measures	Measure Description	Time Frame

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:
1

Age ≥ 18 years.
Scheduled for clinical reason to undergo an ERCP (endoscopic retrograde cholangiopancreatography).
WHO performance status 0, 1 or 2.
Willing and mentally able to provide written informed consent.
Suspected of having benign pancreaticobiliary disease (e.g. chronic pancreatitis, primary sclerosing cholangitis, common bile duct gallstones (choledocholithiasis), sphincter of Oddi dysfunction); or suspected of having PDAC or BTC.
Presenting with obstructive jaundice and/or an indeterminate biliary stricture.

Age <18years old.
Patients undergoing ERCP post-bariatric surgery, hepatico-jejunostomy or Bilroth II .
Pregnancy.
WHO performance status 3 or 4.
Not willing or able to sign informed consent.
Not scheduled for endoscopic procedures for clinical reasons.
No clinical or image data suggestive of pancreaticobiliary disease and need for endoscopic intervention or investigation.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Royal Surrey County Hospital NHS Foundation Trust
Royal Free Hospital NHS Foundation Trust

Investigators

PRINCIPAL_INVESTIGATOR: Adam E Frampton, MB BS FRCS PhD, Imperial College London

Publications

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