Clinical trial NCT04764396
Conditions: Pancreas Mass Lesion
Keywords: biopsy pancreas lesion endoscopic fine needle biopsy
Sponsor: University of Michigan
Start date: 2021-03-12; Completion date: 2021-07-06
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized study that will enroll patients scheduled for an endoscopic ultrasound biopsy of a pancreas lesion to be in the heparin or saline group during the procedure.

The purpose of this study is to examine the effect of blood contamination, heparin priming of the fine needle biopsies, and pass number on tumor tissue quality in fine needle biopsies.

The hypothesis for this study is that fine needle biopsy tissue quality of pancreatic masses decreases with increasing pass number due to blood contamination; this blood contamination can be ameliorated with priming of the needle with an anticoagulant such as heparin.

Detailed description:
A total of 3 fine-needle biopsy passes will be performed on every procedure. The tissue specimens from each of the 3 passes will be collected in 3 separate jars of 10% formalin for tissue analysis. The use of heparin flushing vs. not heparin flushing will be based on their randomized group assignments.

In the heparin arm, between passes, after tissue is extracted from the needle, the needle will be flushed with 1 mL of heparin (100 USP/mL) and flushed with air before the next pass will be made. This means the needle will have no heparin during the first pass. In the standard of care arm, between passes, after tissue is extracted from the needle, the needle will be flushed with saline and/or air as per current standards of care.

This study was amended at the Institutional Review Board (IRB) after having enrolled only two participants. Following the amendment, the responsible party changed and with that change some adjustments were made to the interventions, analysis and some outcomes.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Heparin will be used for needle priming (BD PosiFlush™ Pre-Filled Heparin Lock Flush Syringe) intervention 2: Saline
Intervention descriptions: intervention 1: The fine needle biopsy (FNB) needle will be flushed with 1 mL of heparin (100 USP/mL) and then flushed with air. Pass 1, 2, and 3 will be collected in separate jars and sent to pathology, as per standard clinical procedures. Between passes, after tissue is extracted from the needle, the needle will be flushed with 1 mL of heparin (100 USP/mL) and flushed with air before next pass is made. intervention 2: FNB will be performed as current standard methods in the medical procedure unit without the use of heparin priming. Pass 1, 2, and 3 will be collected in separate jars and sent to pathology, as per standard clinical procedures. Between passes, after tissue is extracted from the needle, the needle will be flushed saline and or air as per current standards of care.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 ____________________________________________________________________________________________ 
1 
Assessing Effects of Heparin Priming and Pass 
Number on Tissue Quality of Fine Needle Biopsies 
 
NCT04764396 
 
IRB Approval Date: February 15, 2023 
 
 


Assessing Effects of Heparin Priming and Pass Number on 
Tissue Quality of Fine Needle Biopsies 
 
Principal Investigator: Jorge D. Machicado, MD, MPH 
 
Funding Mechanism: PI Discretionary Funds 
 
Institution(s): University of Michigan 
 
Other Identifying Numbers: HUM00172203 
 
Protocol Amendments: 
(Any modifications to the protocol should be annotated on the coversheet or in an 
appendix.  The annotation should note the exact words that are changed, the location in 
the protocol the date the modification was approved, and the date it became effective.) 
 
Draft or Version Number: 0.3 
Day Month Year: 6 February 2023 
 


 TABLE OF CONTENTS 
 
1 
Background/Scientific Rationale .............................................................................. 6 
2 
Objectives ............................................................................................................... 7 
3 
Expected Risks/Benefits.......................................................................................... 8 
4 
Eligibility .................................................................................................................. 9 
5 
Subject Enrollment .................................................................................................. 9 
6 
Study Design and Procedures ............................................................................... 10 
7 
Data Collection and Management Procedures ...................................................... 12 
8 
Data Analysis ........................................................................................................ 13 
9 
Quality Control and Quality Assurance.................................................................. 15 
10 
Statistical Considerations ...................................................................................... 15 
11 
Regulatory Requirements ...................................................................................... 15 
11.1 
Informed Consent ....................................................................................... 15 
11.2 
Subject Confidentiality ................................................................................ 16 
11.3 
Unanticipated Problems ............................................................................. 16 
12 
References ............................................................................................................ 17 
 
 
 
 
 
 


 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations. 
Site Investigator:* 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
* The protocol should be signed by the clinical site investigator who is responsible for 
the day to day study implementation at his/her specific clinical site.


 
LIST OF ABBREVIATIONS  
 
 
EUS 
Endoscopic Ultrasound 
 
 
FNB 
Fine Needle Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1 
BACKGROUND/SCIENTIFIC RATIONALE 
Previous studies evaluating the effect of needle priming with heparin for liver biopsies 
have shown that heparinized needles improved histologic yield and tissue adequacy.1,2 
With regards to pancreatic lesions, two retrospective studies showed that needle 
priming with heparin during EUS fine needle aspiration (FNA) of pancreatic solid lesions 
was not superior to conventional methods on tissue yield, sample adequacy, 
bloodiness, and number of passes.3,4 In contrast, a recent crossover RCT from Taiwan, 
found that among 50 patients with solid pancreatic masses, EUS-guided biopsy with a 
heparinized needle obtained longer white tissues with less blood contamination than 
with conventional EUS-FNB.5 However, the study measured tissue length with 
macroscopic on-site evaluation (MOSE), which is prompt to investigator and 
measurement bias. In addition, the investigators used the same needle for each patient 
at the time of the crossover to the 2nd intervention, which introduces the possibility of 
needle contamination in those who were randomized to undergo sampling with the 
heparinized needle first. Finally, EUS sampling was performed using an old needle 
design not commercially available in the United States (20-gauge EchoTip ProCore 
needle) and by a single endoscopist, which limits the external validity of the results. 
Although these results are important, they cannot be generalizable and need to be 
confirmed in high-quality RCTs.  
 
When sampling pancreatic masses with EUS-FNN, multiple passes are often performed 
to improve diagnostic accuracy and reduce false negative results. However, the impact 
of successive EUS-FNB passes on tissue quality is unknown. This may have a direct 
impact on specimens collected for purposes other than diagnostic histopathology, since 
the endoscopist typically reserves the first FNB passes for clinical histopathology and 
may collect the last passes for personalized medicine applications (e.g. next generation 
DNA or RNA sequencing).6 However, it is unclear whether successive passes will have 
the same tissue quality, as needles may progressively become contaminated with 
blood.   
 
In this proposal, we aim to provide guidance on how tissue quality is affected by 
successive EUS-FNB passes, and whether this may be mitigated by heparinizing the 
FNB needle. The results of this study will provide guidance to endoscopists regarding 
whether heparin can improve tissue quality when sampling solid pancreatic masses, the 
number of passes that is needed to obtain adequate tissue, and how to divide up the 
number of FNB passes for multiple applications.  For pancreatic cancer patients, this is 
highly relevant, as precision platforms that may impact their care such as Know Your 
Tumor7, and clinical trials such as Precision Promise8, require adequate tumor tissue 
quality for eligibility.This will be a pilot study, as there have been no studies specifically 
looking at the effects of heparin priming and fine needle biopsy on tissue yield and 
blood contamination of pancreatic masses.   
 
 


 
2 
OBJECTIVES 
Primary objective: 
• Determine whether heparin priming of FNB needle improves tissue quality as 
compared to standard FNB for EUS-tissue acquisition of pancreatic masses. 
Secondary objectives: 
• Determine whether heparin priming of FNB needle improves cellularity. 
• Determine whether heparin priming of FNB needle reduces blood contamination. 
• Determine whether heparin priming of FNB needle improves histologic yield. 
• Determine whether increasing number of FNB passes affects tissue quality, block 
contamination, and histologic yield. 
• Determine the incremental diagnostic yield with a second or third FNB pass as 
compared to a single FNB pass. 
 
Hypothesis: 
 
We hypothesize that the tissue quality of EUS-FNB specimens of pancreatic masses 
decreases with increasing pass number due to blood contamination. This blood 
contamination can be ameliorated with priming of the needle with an anticoagulant such 
as heparin, resulting in improved tissue quality of EUS-FNB of pancreatic masses. 
 
Anticipated Results 
• 
We anticipate that histologic yield will decrease and blood contamination will 
increase with increasing number of FNB passes 
• We anticipate that the intervention of heparin priming of the biopsy needle will 
decrease blood contamination and increase histologic yield. 
Trial design  
• Single center, double-blind, superiority, parallel-group, 1:1 ratio, randomized 
controlled trial 


 
3 
EXPECTED RISKS/BENEFITS 
There are no immediate benefits to participating in this study. Of note, IF a diagnosis of 
malignancy is made on the tissue obtained for research by a blinded clinical pathologist 
AND the diagnosis was not made on the passes obtained for clinical purposes, the 
patient will be notified.  In this event, either the PI or one of the co-investigators (all of 
which are practicing physicians) will reach out to the patient personally to inform them of 
the discrepancy and make arrangements for the research block to be submitted to 
pathology for further evaluation.  Furthermore, the patient’s physician will be notified, 
and the patient will be referred to the appropriate medical specialist to treat the 
incidentally found condition. 
The known or expected risks are: 
1) Bleeding - EUS fine needle aspiration and EUS FNB rarely (<0.01%) cause bleeding 
but this is not expected to be increased measurably by the one additional pass made for 
research purposes. The risk of bleeding will be minimized by the use of experienced 
gastroenterologists who will perform the EUS FNBs with Doppler assistance to identify 
and avoid intervening vasculature during needle puncture. 
2) Pancreatitis - A risk of EUS-FNB is pancreatitis, which is inflammation of the 
pancreas that is uncommonly severe. The reported risk ranges from 0-2% in the 
literature. It is unknown whether increased numbers of FNB passes increases the risk of 
pancreatitis. The risk of pancreatitis as a complication will be minimized by the use of 
experienced gastroenterologists who will perform the EUS procedures. 
3) Infection - EUS fine needle aspiration and EUS FNB rarely (<0.01%) cause infection 
cases but this is not expected to be increased by the one additional pass made for 
research purposes. 
4) Prolongation of procedure time - Acquisition of additional specimens during EUS will 
extend procedure duration by no more than 5 to 10 minutes. The only risk associated 
with this would be additional discomfort. This risk will be minimized through the 
continued use of sedative and pain medications given during the procedure. As per the 
standard of care, vital signs including oxygen saturation, heart rate, blood pressure, and 
cardiac rhythm will be continuously monitored. 
5) Confidentiality breach - Data produced and collected might be revealed to persons 
outside the study. This risk will be minimized through the use of a code number for the 
patient’s name. The samples will be shared with other institutions and companies to 
conduct the research tests, but no information that identifies the patient will be shared.  
 


 
Of note, we do not anticipate any extra risks from heparin priming of the needle, as the 
amount of heparin present in the needle would be a trace amount.   
To further minimize research-related risk, only patient undergoing endoscopic FNB for 
clinical purposes will be consented for the research study. 
4 ELIGIBILITY 
Inclusion criteria: 
• Patient must be at least 18 years old. 
• Patient identified as having a possible solid pancreatic lesion on computed 
tomography or magnetic resonance 
• Patient scheduled for EUS for sampling of pancreatic mass. 
Exclusion criteria: 
1. Patients with known history of coagulopathy  
2. Patients with history of heparin allergy  
3. Patients with evidence of vascular tumors on imaging  
4. Patients with history of chronic pancreatitis 
5. Pregnant patients 
6. Medically unstable patients 
7. Unwillingness or inability to consent for the study 
 
Patient must be willing and able to provide written informed consent. 
We anticipate that 98 patients will be seen within the University of Michigan Health 
System and the surrounding community for this study.  
 
5 
SUBJECT ENROLLMENT 
Patients or their medical records from the Michigan Medicine health system will be used 
to screen for recruitment. 
Patients who present for care and/or consultation to Michigan Medicine, as an inpatient 
or an outpatient, with known or suspected solid mass lesion will be approached for 
recruitment. Patients will be approached by a study team member after their initial 
consultation with the medical staff in a private consultation room. Patient privacy will be 
protected by discussing the study in the private consultation rooms available adjacent to 
the medical procedure unit waiting area before they are brought back to the pre-
operative area. 


 
If individuals that can be consented for this study are identified ahead of procedure 
date, we may attempt to call them by telephone once up to 7 days in advance to discuss 
the research study in an effort to save time and avoid delays on the day of procedure. 
6 
STUDY DESIGN AND PROCEDURES 
Study setting:  University of Michigan- Medical Procedure Unit 
Study type:  Clinical Trial 
Assignment of Interventions:   
Enrollment: 98 patients 
Randomization:  Subjects will be randomized in a 1:1 allocation ratio to the heparin 
group or the non-heparin control group at the time of intra-procedural decision to 
sample the mass. We will use restrictive block randomization to ensure balanced 
number of participants per group.  The randomization sequence will be generated 
centrally from a computerized binary number generator at the University of Michigan. 
The treatment assignments will be in opaque sealed envelopes for allocation 
concealment. The study coordinator will enroll participants and will assign participants to 
the intervention. The randomization key will be kept under lock by the study coordinator 
until completion of the study period. 
Blinding: The participants and the pathologist will be blinded to the group allocation. The 
proceduralist will not be blinded to allocation given the design of the study and for 
patient safety.  
Interventions: all subjects will undergo EUS-FNB using linear echoendoscopes (GF-
UCT180 Olympus America, Center Valley, Pa, USA). All EUS-FNB procedures will be 
performed by 1 of 5 experienced endosonographers (EW, AS, RW, GP, JM). Once the 
site is identified, the lesion will be punctured using a 22-gauge Fork-tip needle 
(Sharkcore needle). The sampling technique will be at the discretion of the endoscopist 
(e.g. stylet vs. not stylet, suction vs. not suction, fanning technique vs. to-and-fro 
technique, number of strokes). A total of 3 FNB passes will be performed on every 
procedure. The use of rapid on-site cytopathology (ROSE) will be used at the discretion 
of the endoscopist and will not be mandatory for this study. The tissue specimens from 
each the 3 passes will be collected in 3 separate jars of 10% formalin for tissue 
analysis. The use of heparin flushing vs. not heparin flushing, will be based on their 
randomized group assignments: 


 
• Intervention group: The FNB needle will be flushed with 1 mL of heparin (100 
USP/mL) and then flushed with air. Pass 1, 2, and 3 will be collected in separate jars 
and sent to pathology, as per standard clinical procedures. The study will pay for the 
cost of utilizing and submitting extra jars to pathology so that no extra cost is 
incurred to the patient for participating in the study.   Between passes, after tissue is 
extracted from the needle, the needle will be flushed with 1 mL of heparin (100 
USP/mL) and flushed with air before next pass is made. 
• Control group: FNB will per performed as current standard methods in the medical 
procedure unit without the use of heparin priming. Pass 1, 2, and 3 will be collected 
in separate jars and sent to pathology, as per standard clinical procedures. The 
study will pay for the cost of utilizing and submitting extra jars to pathology so that no 
extra cost is incurred to the patient for participating in the study.  Between passes, 
after tissue is extracted from the needle, the needle will be flushed saline and or air 
as per current standards of care.  
If proceduralist feels that it is unsafe to continue with the research protocol during the 
procedure (examples would include inadequate tissue acquisition in the clinical jar, or 
clinical instability of patient during procedure), he or she reserves the right to withdraw 
the patient from the protocol.  For patient safety, the proceduralist will not be blinded to 
whether the patient was randomized to the heparin or non-heparin arm.  If the 
proceduralist deems more than 3 passes are needed to for clinical purpuses, the extra 
passes will go into a fourth jar.   
Tissue Analysis: 
H&E slides from the passes 1, 2, and 3 (which will be requested from pathology) will be 
compared in the following manner: 
• A blinded clinical pathologist will examine each slide and determine 
o Is a tissue diagnosis able to be made? 
o Is the tissue adequate quality? The pathologist will create a reference 
scoring system and rate specimens accordingly. 
• In parallel, using the HALO® image analysis platform (Indica Labs), each slide 
will be digitally scanned.  The number of cells present on each H&E slide (cell-
based analysis), the amount of blood present on each H&E slide (area-based 
analysis), and the size of each biopsy will be quantified (area-based analysis).    
 
Tracking and labelling system 
Each research specimen will be given a specimen ID. A spreadsheet key matching the 
specimen ID to the patient name and medical record number will be kept in a password 
and network protected database. Only study team members will have access to the 
spreadsheet. 
 
Heparin priming 


 
This study will use heparin for needle priming. The heparin product used will be BD 
PosiFlush™ Pre-Filled Heparin Lock Flush Syringe, 5 mL (100 USP/mL) in a 10 mL 
syringe. The product will be stored in a secure location within the endoscopy unit at 
room temperature, as per manufacturer instructions. The product has a shelf life of 18 
months and will be discarded after the expiration date. We anticipate actual exposure of 
patient to heparin to be minimal, as after heparin flushing, needles will be air-flushed 
before proceeding with the next pass. We do not anticipate any adverse events from 
heparin priming of the needle. 
 
Saline Flush 
While there is a saline-only PosiFlush, the hospital changes its supplier of saline flushes 
depending on cost.  Therefore, because use of saline for flushing is the routine standard 
of care, we will not be using specialized research PosiFlush saline syringes and instead 
will be using the available supply our unit keeps on stock 
 
7 
DATA COLLECTION AND MANAGEMENT PROCEDURES 
Collection of medical record data for this study will include the following: 
Initial collection: 
• 
Patient demographic data: 
o Age 
o Sex 
o BMI 
o Pack Years 
o Presence of Diabetes, Type 1 or 2 
o Alcohol use  
o History of Pancreatitis 
o History of IPMN (intraductal papillary mucinous neoplasms)  
o Prior Cancer History 
Follow up collection (approximately 4 weeks post-procedure): 
• 
Was patient reached for follow-up? 
• 
Did patient develop post-procedural complications 
• 
Did patient need interventions for post-procedural complications? 
• 
Was hospital admission required for post-procedure complication? 
• 
Did patient require repeated EUS for sampling? 
• 
Age Patient demographic data: 
Chart review at end of study (after 98 patients collected) 
• 
Development of new pancreatic disease other than cancer 
• 
Overall survival (date of death) 
• 
Cancer Stage 
o If resectable, did patient receive surgery? 
 
If yes 
• 
What surgery (distal pancreatectomy vs Whipple?) 


 
• 
Final surgical staging 
• 
Tumor grade 
• 
Chemotherapy treatment 
o Palliative, neoadjuvant, or adjuvant chemo 
o Regimen (FOLFIRINOX, Gemcitabine/abraxane, Gemcitabine/cisplatin) 
• 
ECOG score 
• 
Final Diagnosis 
 
.  Data will be pulled from patient’s medical charts via both DataDirect and chart review. 
Regarding data management we will seek assistance with the MICHR database 
development service.  The study team may collect data from each research participant 
for up to 5 years from when they were consented.  This data will be stripped of patient 
name and stored using REDCap; only the study team members have access to this 
database. On the database, patient identity will not be discernable to the casual 
observer. As indicated in section 6, separate from this, a spreadsheet key matching the 
specimen ID to the patient name and medical record number will be kept in a password 
and network protected database. Only study team members will have access to this 
spreadsheet.   
SCHEDULE OF EVENTS8 
DATA ANALYSIS 
Primary Outcomes 
• Heparin priming increases cellularity captured in fine needle biopsies  
• Heparin priming decrease blood contamination in fine needle biopsies  
Secondary Outcomes 
• Successive fine needle biopsy passes result in more blood contamination 
• Successive fine needle biopsy passes have lower cellular yield 
• Successive fine needle biopsy passes have more blood contamination 
• Need for repeated procedure (at U of M) 
Exploratory Outcomes 
• Identify correlations in patient metadata (i.e. tumor grade, cancer stage) and 
tissue quality, cellular yield, and blood contamination 
Tissue analysis: 


 
H&E slides from the pass 1, 2, and 3 (which will be requested from pathology) will be 
compared in the following manner: 
• A blinded clinical pathologist will examine each slide and determine 
o Is a tissue diagnosis able to be made? 
o Is the tissue adequate quality (pathologist will make a reference scoring 
system and rank specimens accordingly) 
In parallel, using image processing software, the number of cells present on each 
H&E slide will be quantified, the amount of blood present on each H&E slide will 
be quantified by area quantification, and the tissue yield on each H&E slide will 
be quantified by area quantification.   
 
Statistical Comparisons using image analysis: 
The student t test will be utilized to assess if there is a significant difference in the 
following: 
• 
Blood contamination area between passes 1, 2, and 3in the heparin group 
• 
Blood contamination area between passes 1, 2, and 3 in the non-heparin group 
• 
Blood contamination area in pass 1 between the heparin group and non-heparin 
group 
• 
Blood contamination area in pass 2 between the heparin group and non-heparin 
group 
• 
Blood contamination area in pass 3 between the heparin group and non-heparin 
group 
• 
Tissue area between passes 1, 2, and 3 in the heparin group 
• 
Tissue area between passes 1, 2, and 3 in the non-heparin group 
• 
Tissue area in pass 1 between the heparin group and non-heparin group 
• 
Tissue area in pass 2 between the heparin group and non-heparin group 
• 
Tissue area in pass 3 between the heparin group and non-heparin group 
• 
Cell number between passes 1, 2, and 3 in the heparin group 
• 
Cell number between passes 1, 2, and 3 in the non-heparin group 
• 
Cell number in pass 1 between the heparin group and non-heparin group 
• 
Cell number in pass 2 between the heparin group and non-heparin group 
 
• 
Cell number in pass 3 between the heparin group and non-heparin group 
Statistical Comparisons using pathologist scoring: 
The Pearson’s Chi-squared test will be utilized to determine if there is a significant 
difference in the following: 
• 
Tissue score between passes  1, 2, and 3 in the heparin group 
• 
Tissue score between passes  1, 2, and 3 in the non-heparin group 
• 
Tissue score in pass 1 between the heparin and non-heparin group 
• 
Tissue score in pass 2 between the heparin and non-heparin group 
 
• 
Tissue score in pass 3 between the heparin and non-heparin group 
In a previous study the standard deviation for tissue area with fine needle biopsy of 
pancreatic masses was 5 mm2.9 Based on our preliminary results and on results of 


 
recent crossover RCT, we will assume a difference between randomized groups of 3 
mm2.5 Therefore, if the true mean difference in total tissue area between the heparin 
and non-heparin groups is 3 mm2, we will need to study 44 subjects in the heparin 
group and 44 subjects in the non-heparin group, to reject the null hypothesis with 80% 
power and with a type I error of 0.05. To account for 10% dropouts, we will need to 
recruit 98 subjects. 
 
9 
QUALITY CONTROL AND QUALITY ASSURANCE 
Sample collection and processing will be conducted by highly trained proceduralists and 
staff. 
Tissue scoring will be performed by blinded clinical pathologist Jiaqi Shi, MD, PhD. 
10 
STATISTICAL CONSIDERATIONS 
Statistical tests for significance are outlined in section 8.  To be able to achieve 
statistical power of 0.80 with identified differences between groups (with variables of 
pass number and heparin priming) with α = 0.05, we anticipate a sample size of 50 
patients in each arm will be required (98 patients total). 
11 
REGULATORY REQUIREMENTS 
11.1 Informed Consent  
The study team will be responsible for reviewing medical charts in MiChart or 
approved registries of patients that have agreed to be contacted for research for 
potential patients being seen at Michigan Medicine. Potential candidates will be seen in 
their designated patient rooms after consultation with healthcare staff.  
 
In person, the research coordinator or study team member will be responsible for 
explaining the study in full, gauging patient interest, answering questions, and 
consenting patients, when applicable. Estimated time for the first patient visit is 5-15 
minutes. Future interactions between the patient and the research coordinator or study 
team member will be minimal. 


 
11.2 Subject Confidentiality  
Research records will be maintained that will document patient name and 
medical record number. This data will be stripped of patient name and stored 
using REDCap; only the study team members have access to this database. On 
the database, patient identity will not be discernable to the casual observer. The 
Principal Investigator and study team will retain the ability to determine the 
identity of patients in the database by use of a master list. The master list will be 
kept in a password protected and network protected file that will only be 
accessible to the study team. 
11.3 Unanticipated Problems1 
Upon becoming aware of any other incident, experience, or outcome that may 
represent an unanticipated problem, the study team will immediately alert the PI. 
The PI will assess whether the incident, experience, or outcome represents an 
unanticipated problem.  If the PI determines that the incident, experience, or 
outcome represents an unanticipated problem, he will report it promptly to the 
IRB. 
 
 
 
 
 
 
 
 
 
 
 
1 The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to subjects or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-
related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
• 
related or possibly related to participation in the research (in the guidance document, possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
 
An incident, experience, or outcome that meets the three criteria above generally will warrant consideration of substantive 
changes in order to protect the safety, welfare, or rights of subjects or others.   


 
 
 
 
 
 
 
 
 
 
 
12 
REFERENCES 
 
1 
Kasugai, H. et al. Value of heparinized fine-needle aspiration biopsy in liver malignancy. AJR Am J 
Roentgenol 144, 243-244, doi:10.2214/ajr.144.2.243 (1985). 
2 
Mok, S. R. S. et al. A prospective pilot comparison of wet and dry heparinized suction for EUS-
guided liver biopsy (with videos). Gastrointest Endosc 88, 919-925, 
doi:10.1016/j.gie.2018.07.036 (2018). 
3 
Hasan, M. K., Bang, J. Y. & Varadarajulu, S. Diagnostic value of priming the endoscopic 
ultrasound-guided fine-needle aspiration needle with heparin to improve specimen quality. Dig 
Endosc 26, 491, doi:10.1111/den.12233 (2014). 
4 
Diehl, D. L. et al. Heparin priming of EUS-FNA needles does not adversely affect tissue cytology 
or immunohistochemical staining. Endosc Int Open 6, E356-E362, doi:10.1055/s-0043-121880 
(2018). 
5 
Lin, M. Y. et al. Tissue Quality Comparison Between Heparinized Wet Suction and Dry Suction in 
Endoscopic Ultrasound-Fine Needle Biopsy of Solid Pancreatic Masses: A Randomized Crossover 
Study. Gut Liver, doi:10.5009/gnl220030 (2022). 
6 
Imaoka, H. et al. Impact of Endoscopic Ultrasound-Guided Tissue Acquisition on Decision-Making 
in Precision Medicine for Pancreatic Cancer: Beyond Diagnosis. Diagnostics (Basel) 11, 
doi:10.3390/diagnostics11071195 (2021). 
7 
Pishvaian, M. J. et al. Overall survival in patients with pancreatic cancer receiving matched 
therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry 
trial. Lancet Oncol 21, 508-518, doi:10.1016/S1470-2045(20)30074-7 (2020). 
8 
Picozzi, V. J. et al. Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic 
pancreatic ductal adenocarcinoma (PDAC). Journal of Clinical Oncology 40, TPS4188-TPS4188, 
doi:10.1200/JCO.2022.40.16_suppl.TPS4188 (2022). 
9 
Bang, J. Y. et al. Randomized trial comparing the Franseen and Fork-tip needles for EUS-guided 
fine-needle biopsy sampling of solid pancreatic mass lesions. Gastrointest Endosc 87, 1432-1438, 
doi:10.1016/j.gie.2017.11.036 (2018).