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Before randomization, the endosonographer chooses the needle gauge to perform biopsy preferring the 25 gauge caliber for "difficult" lesions. The needle advances inside the lesion and the operator will perform some needle movements back and forth into the lesion while slowly withdrawn the stylet (slow-pull technique). If possible the direction of the needle inside the lesion will be changed during the movements (fanning technique) to sample different areas of the lesion. Three needle passes will be performed and the material acquired at each pass will be placed directly in formalin in a single vial.

Diagnostic Test: Histologic evaluation

Intervention: like above.

Diagnostic Test: Histologic evaluation.

Samples collected by EUS-FNB without ROSE will be processed as histologic samples

Histologic evaluation

Stefano Francesco Crinò

Rationale: Until now there are no prospective studies comparing the 22 gauge and 25 gauge side-fenestrated and fork-tip needles.

In the present study we will compare the two types of needles in terms of histological yield for the evaluation of solid pancreatic lesions in the absence of rapid on-site evaluation (ROSE). Moreover diagnostic accuracy and the number of passes necessary to achieve the maximum diagnostic and histological yield, and safety will be investigated.

Objectives: To evaluate and compare the histologic retrieval rate of two different EUS-FNB needles of the same caliber (22 or 25 gauge). The passes will be 3 for each patient.

Study design: Randomized monocentric trial. Study population: Patients ≥18 years old, referred for EUS-guided tissue sampling of a solid pancreatic mass.

Intervention: EUS-guided tissue acquisition by mean EUS-FNB, using one of the following FNB needles: side-fenestrated 22 gauge, side-fenestrated 25 gauge, fork-tip 22 gauge or fork-tip 25 gauge.

Main study parameters/endpoints: The main endpoint is the histologic yield (defined as the percentage of a tissue core of at least 550 micron at the greatest axis), obtained at each of the 3 needle passes. Secondary endpoints include: i) safety; ii) concordance between macroscopic on-site evaluation (MOSE) and histopathological evaluation ; iii) Accuracy using 1, 2 or 3 passes.

Endoscopic ultrasound (EUS) has become an essential procedure in the last decade for evaluation of focal pancreatic lesions and for tissue acquisition for diagnostic purposes. In these patients the endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and, more recently, the introduction of EUS fine needle biopsy (EUS-FNB), is a safe instrument, with high sensitivity (75-98 %) and specificity (71-100%).

The obtaining of bioptic tissue samples reduces the need for rapid on site-evaluation (ROSE) and allows an easier interpretation of the diagnosis even by non-expert pathologist. It also makes possible to perform ancillary investigations such as immunohistochemical, often useful for the differential diagnosis.

Two different EUS-FNB needles are available: the side-fenestrated reverse bevel and the fork-tip forward-acquiring". Both are available in 25, 22 and 19 gauge. The 22 gauge is the most commonly used since it combines the ease of use of small-sized caliber with the advantages of larger sized needles. The 25 gauge is universally recognized as the most manageable and flexible needle and is preferred when the lesion is small (\<20mm) or is in "difficult" conditions (lesion localized to the uncinate process or to distal tail, lesion distant from the transducer \> 15mm, need to cross \> 1cm of healthy pancreas, angled position of the instrument).

There are no prospective studies comparing the 22 and 25 gauge side-fenestrated and fork-tip needles. We therefore propose a prospective randomized study, to compare the two types of needles in terms of histologic and diagnostic yield, number of passes necessary to reach it in solid pancreatic lesions, in the absence of ROSE.

This is a randomized single center trial with two parallel arms in a (1:1) ratio. Consecutive patients with solid pancreatic masses and an indication to perform EUS-guided tissue acquisition will be evaluated and, if eligible, will be enrolled into the study. Randomization will take place after the lesion will have been visualized with EUS and the patient will be found suitable for inclusion.

The choice of needle gauge (22 or 25 gauge) will be at the discretion of the endosonographer in relation to the difficulty/risk of the procedure; therefore, two randomization lists will be drawn up, (one for the 22 gauge and one for the 25 gauge).

The choice of the needle gauge will be done before randomization so that the choice of the needle does not create bias in the results. The pathologist will be blinded to the needle caliber and type.

The sample size has been calculated for the primary outcome (histologic retrieval rate) using a group sequential design to define a proper interim analysis after at least 50% enrolment. The histologic yield of the two needle types can be summarized as follows:

22 gauge: 77% and 92% for the side-fenestrated and the fork-tip, respectively. 25 gauge: 60.5% and 85% for the side-fenestrated and the fork-tip, respectively.

With a type I error α of 5% and a power 1 - β of 80%, the total required sample size amounts to 330 patients (210 patients for 22G group and 120 patients for 25G group). Considering that 18% of patients must be added to counteract the estimated and lost drop-out rate at follow-up, overall 362 patients will be needed (196 patients for the 22G group and 112 patients for the 25G group).

Based on sample size calculation the two lists will consist in 24 blocks of 8 patients and 1 block of 4 patients for the 22G group and 14 blocks of 8 patients for the 25G group.

EUS-FNB for Solid Pancreatic Lesions: Side-fenestrated Vs Fork-tip Needle

Single Center Randomized Clinical Trial to Evaluate the Histological and Diagnostic Accuracy of Two EUS Fine Needles Biopsy for the Diagnosis of Solid Pancreatic Lesions

Procurement percentage of a "core" (defined as a piece of tissue at least 550 micron in the greatest axis) in the two arms.

Diagnostic accuracy (defined as the ratio between the sum of true positive and true negative values divided by the number of lesions) will be calculated for each study arm.

Diagnostic accuracy (defined as the ratio between the sum of true positive and true negative values divided by the number of lesions) will be calculated after 1, 2 or 3 needle passes in the two study arms.

Percentage of tissue core (defined as an intact piece of tissue of at least 550 micron in the greatest axis) will be calculated after 1, 2 or 3 needle passes in the two study arms.

Percentage of intra-procedural and post-procedural adverse events in the 2 arms (e.g haemorrhage, perforation, pancreatitis) will be compared.

Percentage of serous adverse events in the 2 arms (e.g long hospitalization, disability, death) will be compared.

Tissue integrity will be evaluated by attributing a score from zero to 6 (6 represents the better outcome), according to the following score system:

0=Insufficient material for interpretation. 1=Sufficient material for limited cytological interpretation; probably not representative. 2=Sufficient material for adequate cytological interpretation. 3=Sufficient material for low quality histological interpretation (tissue fragments \< 550 micron in greatest axis). 4=Sufficient material for good quality histological interpretation (1 to 5 cores \> 550 micron in greatest axis). 5=Sufficient material for high quality histological interpretation (6 to 10 cores \> 550 micron in greatest axis). 6=Sufficient material for excellent quality histological interpretation (more than 10 cores \> 550 micron in greatest axis or total tissue length \> 5.500 micron);

Blood contamination will be evaluated by attributing a score from 0 to 3 (3 represents the better outcome), according to the following score system:

0=Only blood; 1=Much blood contamination, surface area \> 50 % of the slide; 2=Medium blood contamination, surface area 25-50 % of the slide; 3=Little blood contamination, surface area \< 25 % of slide.

Concordance between presence of a core at Macroscopic on-site evaluation (MOSE) and presence of core at histopathological evaluation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
EUS-FNB for Solid Pancreatic Lesions: Side-fenestrated Vs Fork-tip Needle	NCT03622229	Biopsy, Fine-ne... Pancreatic Neop...	Histologic eval...	18 Years - 80 Years	Azienda Ospedaliera Universitaria Integrata Verona
EUS-FNB for Solid Pancreatic Lesions: Side-fenestrated Vs Fork-tip Needle	NCT03622229	Biopsy, Fine-ne... Pancreatic Neop...	Histologic eval...	18 Years - 80 Years	Azienda Ospedaliera Universitaria Integrata Verona
EUS-FNB for Solid Pancreatic Lesions: Side-fenestrated Vs Fork-tip Needle	NCT03622229	Biopsy, Fine-ne... Pancreatic Neop...	Histologic eval...	18 Years - 80 Years	Azienda Ospedaliera Universitaria Integrata Verona

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