19 Versus 22-Gauge Needle for EUS-LB

3 BACKGROUND AND SIGNIFICANCE Chronic liver disease has a number of causes, and leads to significant mortality and morbidity in the United States. It has been estimated that roughly 36,000 individuals die annually from the burden of chronic liver disease, thus early diagnosis and intervention are paramount to preventing such complications. Though serologic markers and non-invasive diagnostic imaging modalities are used as a method for determining the underlying disease process, these methods lack the specificity of determining etiology of a patient's chronic liver disease. Therefore, liver biopsy remains the "gold standard" for obtaining valuable diagnostic and prognostic information.

At present there exist several methods for liver tissue acquisition. The most widely accepted method remains percutaneous route (PLB), which utilizes percussion or imaging to localization the biopsy site. The issue with this approach is its potential complication of post-procedural pain in up to 84%, bleeding in 1/2500-10,000 procedures, with under 1/10,000 of these cases being fatal. Another means for obtaining tissue samples is the transjugular route (TLB), which also allows for portal pressure measurement, and is usually reserved for patients with coagulopathy.

More recently, endoscopic ultrasound guided liver biopsy (EUS-LB) has been developed as a newer LB technique. The feasibility of EUS-LB for liver lesions has been validated yielding excellent diagnostic results in several studies. This technique has also been evaluated for hepatic parenchymal disease with up to 90% diagnostic yield. Subsequently, EUS-LB using a 19-gauge needle was compared to percutaneous/transjugular routes showing at least comparative, and in some instances improved sample acquisition, versus other methods. Different 19-gauge needles have been utilized in this setting yielding variable diagnostic specimens. However, there has yet to be comparison of 19 versus a 22-gauge core biopsy needle for EUS-LB. The safety profile with the 19g needle is remarkably good; it seems logical that a smaller needle would be at least as good, if not better.

Primary End Points

1. Proportion of cases for which a histologic diagnosis could be made based upon the amount of tissue obtained with the needle (using total portal structures > 5 or length of the longest piece (LLP) > 15 mm).
2. Number of portal tracts (PT) in the specimen
3. Aggregate specimen length (ASL), length of the longest piece (LLP), and degree of fragmentation Secondary End Points
4. Presence of a visible core specimen 2. Presence of visible clots in specimen 3. Adverse events (AE) and serious adverse events (SAE) 4 HYPOTHESIS AND SPECIFIC aims

4.1 Hypothesis The investigators predict that the 19-gauge needle and 22-gauge core needle will have similar ability to obtain adequate EUS-LB specimens 4.2 Specific Aim 1 To determine the adequacy of EUS-LB using a 22-gauge core needle as compared with 19-gauge needle 4.3 Specific Aim 2 To determine if the 22-gauge core needle will demonstrate less blood artifact during the time of EUS-LB as compared with 19-gauge needle.

6 STUDY DESIGN 6.1 Description This is a prospective trial comparing the biopsy specimen adequacy of 19 versus 22-gauge core needle for EUS-LB.

6 6.3 Recruitment Patients shall be recruited in the pre-procedural endoscopy area. After identifying subjects, a study investigator shall discuss the study in detail either in person (at which point the patient will read the consent form). A second individual will witness the consent.

6.4 Study Duration 6.4.1 Approximate Duration of Subject Participation Participation in this study is until 1 week post-procedure. 6.4.2 Approximate Duration of Study The duration of the study shall last until 6 months from enrollment of the last study participant. This shall allow for analysis of final data points and construction of a manuscript.

6.5 Procedures Epic electronic health records database will allow for availability of demographic data and office-based follow-up records. Provation MD software information will provide details regarding endoscopic parameters and intervention performed.

Electronic records gathered for study purposes will only be available to study investigators and will be stored on an encrypted hard drive on a computer. Data will initially be entered with protected health information (PHI) attached so that all information can be obtained. Once all data collection is complete identifiers will be removed and random number assigned to the patients.

Paper copies of study questionnaires will be filled out in the endoscopy center and stored in a locked cabinet in the endoscopy center workroom. The door to the workroom with the cabinet is locked after hours and the endoscopy center is locked after hours as well.

Upon initial encounter, the study shall be described to the patient in detail by one of the study investigators and informed consent obtained.

Once the patients has agreed to participate, demographic data will be obtained including; age, gender, height [inches (in)], weight [pounds (lb)], body mass index (BMI)(lb/in2), past medical history [in particular diagnosis of liver disease, biliary or pancreatic disease, ascites, encephalopathy, portal hypertension, portal hypertension-related bleeding (ie. varices), liver cancer or masses]. Past surgical history shall be obtained regarding prior cholecystectomy, hepatobiliary or pancreatic surgery (i.e. pancreaticojejunostomy) or bariatric surgery (ie. Roux-en-Y gastric bypass). Medication and social history shall be performed regarding alcohol intake per week and hepatotoxic medications (i.e. acetaminophen). A baseline INR and platelet count shall be performed on all individuals prior to EUS-LB, as is the standard of care.

EUS-LB Protocol

Patients undergoing EUS-LB receive sedation prior to the procedure, as per normal practice. This is provided by a certified registered nurse anesthetist (CRNA). The endosonographic study will be conducted with a linear array echoendoscope (GF-UC140-AL5; Olympus America, Center Valley, PA). Before needle puncture of the desired lobe, color Doppler imaging will be used to ensure the lack of vascular structures in the trajectory of the needle. The EUS-LB will be performed in widely separated regions of the liver using a 19-gauge EUS-FNA (fine needle aspiration) needle (Expect Flexible 19g, Boston Scientific, Marlborough, MA) and a 22-gauge FNB needle (SharkCore, Beacon Endoscopic, Sunnyvale, CA, or Acquire 22g, Boston Scientific, Marlborough, MA). A computer-generated randomized schema shall determine initial needle gauge selection.

The left lobe is described as liver parenchyma identified a few centimeters below the gastroesophageal junction with the echoendoscope torqued clockwise. The right lobe is consider the large area of liver tissue can be seen through the duodenal bulb, near the gallbladder. The stylet is removed, heparin flushed through the needle lumen, and the suction device set and attached to the needle hub. The prepared needle is then inserted into the echoendoscope, A transgastric approach will be used to obtain samples from the left lobe of the liver; a transduodenal approach, with the linear echoendoscope positioned in the duodenal bulb, will be used to obtain samples from the large amount of liver parenchyma seen in that location. Once adequate liver parenchymal penetration will be achieved with the needle (∼2-6 cm), full suction will be applied with a 20-mL vacuum syringe. One pass consists of a total of 7 to 10 to-and-fro needle motions with the fanning technique applied under direct and continuous endosonographic visualization of the tip of the needle.

The needle will then be removed from the echoendoscope. The specimen will be pushed from the needle with the stylet directly into a microsieve, and blood washed from the specimen with a gentle saline rinse. The endosonographer looks for multiple pieces of light brown tissue approximately 5 to 15 mm in length. The tissue cores are then "floated" off the microsieve into formalin solution. Then, a second pass will be made from the same region of the liver using the alternate needle used from the first pass. Heparin is flushed through the needle lumen prior to the next pass. The biopsy process is then repeated on the opposite liver lobe. Two passes per liver lobe are made; one with the standard 19g EUS-FNA needle, and one with the 22g EUS core needle. All patients are closely observed in the recovery area for 1 hour after the procedure, as per our standard policy. Patients will be followed-up with by a phone call the next day and at 1 week after the procedure.

Sample Processing The surgical pathology department, per a specific protocol for clinical practice, will process the EUS-LB samples. Tissue samples are left in formalin for at least 1 hour before processing. The contents of the formalin jar will be poured into a petri dish, and visible cores of liver tissue picked out with small forceps by the surgical pathology technician. These pieces are arranged in a linear fashion on lens paper, then the specimen photographed alongside a ruler to estimates pre-processing tissue lengths. Samples from both lobes and the different needles will be submitted for evaluation separately. The tissue will be processed in standard fashion, and slide blanks made (5-μm tissue thickness). These blanks are stained with hematoxylin and eosin, trichrome, and reticulin, with other special stains done as needed. The slides is digitized using a whole slide scanner (ScanScope CS; Aperio Technologies, Inc, Vista, CA), and the digitized images used for quantitative analysis (eSlide Manager; Aperio Technologies, Inc). Quantification of sample length (mm) and portal triads is performed by 2 of the investigators, annotating the digital images with the software. Fellowship-trained GI pathologists then perform histologic interpretation for clinical use.

Post-Procedural Follow-up After undergoing the procedure, patients will receive a 1week follow-up phone call to monitor for adverse events (i.e. bleeding).