Endoscopic Ultrasound-guided Fine-needle Biopsy for Tissue Sampling of Biliary Strictures: a Multicenter Prospective Study

September 25, 2024 updated by: Antonio Facciorusso, Ospedali Riuniti di Foggia

After the disappointing results of first-generation reverse bevel fine-needle biopsy (FNB) needles, newer 'third generation' endoscopic ultrasound (EUS) needles were developed, known as the "end-cutting" needles. These needle types have shown excellent diagnostic accuracy (>90%) in pancreatic masses and several other lesions, even without rapid on site evaluation (ROSE) and are not associated with increased adverse event incidence . The main design of end-cutting FNB needles are the Franseen type, which has three symmetrically distributed needle points and cutting edges, and the Fork-tip type which has 2 protruding asymmetrical sharp points and six distal cutting edges; however, other end-cutting needles are currently available such as the three-prong asymmetric tip needle and the Menghini tip needle.

Given the significant increase in diagnostic accuracy and sensitivity observed in other abdominal lesions, these needles are expected to improve the diagnostic outcomes of EUS-FNB of "pure" biliary strictures although clinical data are still lacking.

The aim of this study is to ascertain the impact of end-cutting FNB needles in the diagnostic algorithm of biliary strictures in absence of a clear pancreatic or abdominal mass.

This is a multicenter international observational prospective study. Consecutive patients diagnosed with biliary strictures in absence of a pancreatic or abdominal mass will be assessed for eligibility.

Patients with jaundice requiring decompression, will undergo endoscopic retrograde cholangiopancreatography (ERCP) with tissue sampling (brushing and/or biopsy) and biliary drainage, preferably in the same session immediately after EUS-FNB.

Endoscopic ultrasound will be performed using a curvilinear array echoendoscope. FNB with 22G or 25G end-cutting needles will be performed. The size of the needles will be based on the personal choice of the endoscopist. Likewise, the sampling technique, whether using the "slow-pull", the "dry suction", or the "wet suction", will be based on the physician's choice. Three passes will be performed as per current guidelines. Specimens will be collected in 3 vials to allow for analysis according to needle pass; one for the first pass, one for the second pass, and one for the third and any eventual subsequent passes.

The ROSE will not be available in this study. Primary outcome will be diagnostic sensitivity of EUS-FNB and 45 patients will be prospectically enrolled.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

INTRODUCTION Tissue sampling to establish the nature of a stricturing lesion represents a key step in the diagnostic work-up of biliary strictures. As already known, a significant proportion (70%-80%) of biliary strictures are malignant, higher in patients with a definitive mass lesion than in those without a mass on cross-sectional imaging (PMID: 23340062). Early diagnosis is thus important for directing patients to the proper therapeutic strategy. While transpapillary brush cytology or forceps biopsy after sphincterotomy during endoscopic retrograde cholangiopancreatography (ERCP) have been the standard sampling modality, endoscopic ultrasound (EUS)-tissue acquisition (TA) is a useful later addition to the diagnostic armamentarium. The pooled sensitivity of brush cytology and intraductal biopsies has been found to be 45% and 48.1% respectively, while the combination of the two only modestly increased the sensitivity to 59.4% (PMID: 25440678). On the contrary, EUS-TA has been reported to have a pooled diagnostic sensitivity of 83% for distal biliary strictures (PMID: 26422979). Moreover, the choice of the modality adopted would depend not only on the availability of expertise, but also on the location of the lesion and presence of jaundice. Indeed, EUS-TA has shown better sensitivity for distal lesions compared to proximal lesions (PMID: 26422979).

The performance of EUS-TA in peri-hilar strictures showed less favourable results. A 2020 prospective evaluation of EUS-fine-needle aspiration (FNA) in the diagnosis of biliary strictures (n=97, 46% hilar) showed an overall sensitivity of 75% (CI 64%-84%). Subgroup sensitivity and negative predictive value (NPV) reached 95% and 93% for distal lesions without stenting, whereas for the group of stented peri-hilar lesions this was much lower at 56% and 33% respectively (PMID: 33140008).

However, data on EUS-TA of biliary strictures are based only to EUS-FNA studies whereas data on EUS-fine-needle biopsy (FNB) are lacking in this setting.

In the last three decades, the evolution of needles has undergone a remarkable change and is constantly under development, by designing innovative tip designs to allow for larger histological specimens with preserved tissue architecture, along with use of tissue for genomic profiling and organoids development that are very important in the era of oncological personalized medicine. As a result, the current era has seen a decisive shift from FNA to FNB needles.

EUS-FNA needles have limitations that are well known: their diagnostic performance is dependent on a cytopathologist to render a rapid on-site evaluation (ROSE), no provision of a histological core tissue is possible, and insufficient tissue for risk stratification to tailor anti-cancer therapy.

After the disappointing results of first-generation reverse bevel FNB needles, newer 'third generation' EUS needles were developed, known as the "end-cutting" needles. These needle types have shown excellent diagnostic accuracy (>90%) in pancreatic masses and several other lesions, even without ROSE and are not associated with increased adverse event incidence (PMID: 37591258; PMID: 36990125; PMID: 35124072). The main design of end-cutting FNB needles are the Franseen type, which has three symmetrically distributed needle points and cutting edges, and the Fork-tip type which has 2 protruding asymmetrical sharp points and six distal cutting edges; however, other end-cutting needles are currently available such as the three-prong asymmetric tip needle and the Menghini tip needle.

Given the significant increase in diagnostic accuracy and sensitivity observed in other abdominal lesions, these needles are expected to improve the diagnostic outcomes of EUS-FNB of "pure" biliary strictures although clinical data are still lacking.

The aim of this study is to ascertain the impact of end-cutting FNB needles in the diagnostic algorithm of biliary strictures in absence of a clear pancreatic or abdominal mass.

STUDY DESIGN Multicenter international observational prospective study. This study will be conducted according to the principles and the recommendations of the 2013 Declaration of Helsinki.

STUDY PATIENTS Consecutive patients diagnosed with biliary strictures in absence of a pancreatic or abdominal mass will be assessed for eligibility. Diagnosis of biliary strictures will be performed according to current guidelines (PMID: 37307900).

Patients with jaundice requiring decompression, will undergo ERCP with tissue sampling (brushing and/or biopsy) and biliary drainage, preferably in the same session immediately after EUS-FNB.

Inclusion criteria

  • Age ≥18 years
  • Suspicious biliary stricture in absence of an abdominal mass at cross-sectional imaging
  • Distal and peri-hilar biliary strictures
  • Informed consent provided by the patient or the closest relative

Exclusion criteria

  • Presence of a pancreatic or abdominal mass structuring the common bile duct
  • EUS not feasible
  • Known bleeding disorder that cannot be sufficiently corrected with fresh frozen plasma (FFP)
  • Use of anticoagulants that cannot be discontinued
  • INR >1.5 or platelet count <50.000
  • Pregnancy

PROCEDURAL TECHNIQUE Endoscopic ultrasound will be performed using a curvilinear array echoendoscope. FNB with 22G or 25G end-cutting needles will be performed. The size of the needles will be based on the personal choice of the endoscopist. Likewise, the sampling technique, whether using the "slow-pull", the "dry suction", or the "wet suction", will be based on the physician's choice. Three passes will be performed as per current guidelines. Specimens will be collected in 3 vials to allow for analysis according to needle pass; one for the first pass, one for the second pass, and one for the third and any eventual subsequent passes.

The rapid-on site cytological evaluation (ROSE) will not be available in this study.

ENDPOINTS Primary Endpoint Primary outcome will be diagnostic sensitivity of EUS-FNB, defined as true positives/true positives + false negatives.

Secondary Endpoints

  • Sample adequacy, defined as the ability to procure histological samples adequate for diagnostic interpretation. A histologic specimen will be defined as an architecturally intact piece of tissue from the target lesion (PMID: 29074447).
  • Diagnostic accuracy (defined as true positive + true negative/ total number of patients). The gold standard for the final diagnosis will be the pathological report in the subset of patients undergoing surgery and the clinical follow-up for 6 months in non-surgical patients.
  • Diagnostic specificity, defined as true negatives/true negatives+false positives
  • Histological quality of the sample quantified using a score for tissue integrity and blood contamination of specimens validated elsewhere (PMID: 32433914)
  • Yield of each needle pass
  • Number of needle passes
  • Adverse events, classified according to ASGE lexicon (PMID: 20189503). Postprocedural AEs will be investigated during follow-up with phone calls at 2 weeks after the procedure.

ENROLLMENT AND DROP-OUT Enrollment will be competitive between centers and will extend for a maximum period of 1 year after local Ethic Committee/IRB approval. Patients will be considered dropped-out in case of consent withdrawn or if lost before the end of follow-up.

SAMPLE SIZE CALCULATION AND STATISTICAL CONSIDERATIONS On the basis of a previous study (PMID: 33140008) reporting 75% sensitivity with EUS-FNA of biliary strictures, the study is designed to detect an increase in diagnostic yield with end-cutting FNB needles to 94.8%, as reported in a previous meta-analysis (PMID: 31579703).

Therefore, 45 patients will be required to have a 90% power to detect the target difference at a 0.025 significance level (adjusted for multiplicity considering the planned subgroup analysis between peri-hilar and distal biliary strictures) and expecting a drop-out rate of 10%. A 2:1 stratification according to the location of the biliary strictures will be considered; therefore, we expect to enroll 30 patients with distal biliary strictures and 15 patients with peri-hilar biliary strictures.

DATA COLLECTED General information

  • Age (years)
  • Sex (M/F)
  • Charlson comorbidity index
  • BMI Lesion information
  • Location
  • Imaging studies performed
  • Lesion size (mm)
  • Main pancreatic duct (MPD) dilation
  • CBD caliber (mm) Procedural information
  • Sampling route (stomach, duodenum)
  • Number of passes
  • Sampling technique (dry suction, wet suction, slow pull) Outcomes
  • Adequacy at each pass
  • Sensitivity
  • Specificity
  • Accuracy
  • Quality of sample
  • Surgery
  • AEs
  • Final diagnosis

Study Type

Interventional

Enrollment (Estimated)

45

Phase

  • Not Applicable

Contacts and Locations

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

Study Contact

Study Locations

  • Italy
    • FG
      • Foggia, FG, Italy, 71122
    • VR
      • Verona, VR, Italy, 37134
        • Recruiting
        • Universita di Verona
        • Contact:

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.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥18 years

    • Suspicious biliary stricture in absence of an abdominal mass at cross-sectional imaging
    • Distal and peri-hilar biliary strictures
    • Informed consent provided by the patient or the closest relative

Exclusion Criteria:

  • Presence of a pancreatic or abdominal mass structuring the common bile duct

    • EUS not feasible
    • Known bleeding disorder that cannot be sufficiently corrected with fresh frozen plasma (FFP)
    • Use of anticoagulants that cannot be discontinued
    • INR >1.5 or platelet count <50.000
    • Pregnancy

Study Plan

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

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: EUS-FNB

Consecutive patients diagnosed with biliary strictures in absence of a pancreatic or abdominal mass will be assessed for eligibility.

Patients with jaundice requiring decompression, will undergo ERCP with tissue sampling (brushing and/or biopsy) and biliary drainage, preferably in the same session immediately after EUS-FNB.
Device: EUS-FNB

Endoscopic ultrasound will be performed using a curvilinear array echoendoscope. FNB with 22G or 25G end-cutting needles will be performed. The size of the needles will be based on the personal choice of the endoscopist. Likewise, the sampling technique, whether using the "slow-pull", the "dry suction", or the "wet suction", will be based on the physician's choice. Three passes will be performed as per current guidelines. Specimens will be collected in 3 vials to allow for analysis according to needle pass; one for the first pass, one for the second pass, and one for the third and any eventual subsequent passes.

The rapid-on site cytological evaluation (ROSE) will not be available in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diagnostic sensitivity
Time Frame: From enrollment to surgery for patients who will undergo surgery or to 6 months of follow-up for patients who will not undergo surgery
It will be defined as true positives/true positives + false negatives.
From enrollment to surgery for patients who will undergo surgery or to 6 months of follow-up for patients who will not undergo surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sample adequacy
Time Frame: 1 week (from patient enrollment to the pathologic examination of the specimen)
Defined as the ability to procure histological samples adequate for diagnostic interpretation. A histologic specimen will be defined as an architecturally intact piece of tissue from the target lesion
1 week (from patient enrollment to the pathologic examination of the specimen)
Diagnostic accuracy
Time Frame: From enrollment to surgery for patients who will undergo surgery or to 6 months of follow-up for patients who will not undergo surgery
defined as true positive + true negative/ total number of patients
From enrollment to surgery for patients who will undergo surgery or to 6 months of follow-up for patients who will not undergo surgery
Adverse event rate
Time Frame: From patient enrollment to 2 weeks
Rates of complications after EUS-FNB
From patient enrollment to 2 weeks

Collaborators and Investigators

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

Sponsor

Ospedali Riuniti di Foggia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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 Major Dates

Study Start (Actual)

September 10, 2024

Primary Completion (Estimated)

September 20, 2025

Study Completion (Estimated)

October 20, 2025

Study Registration Dates

First Submitted

September 23, 2024

First Submitted That Met QC Criteria

September 25, 2024

First Posted (Actual)

September 26, 2024

Study Record Updates

Last Update Posted (Actual)

September 26, 2024

Last Update Submitted That Met QC Criteria

September 25, 2024

Last Verified

September 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EUS-FNB biliary strictures

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

It will be shared upon request

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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