The Impact of Total Intravenous Anesthesia Following Cancer Surgery (TIVACS) Study
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: Ohio State University Comprehensive Cancer Center

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The Impact of Total Intravenous Anesthesia Following Cancer Surgery 
(TIVACS) Study 
 
Principal Investigator  
Aslam Ejaz, MD, MPH 
Assistant Professor of Surgery 
Department of Surgery / Division of Surgical Oncology 
The Ohio State University Wexner Medical Center  
614-293-7171 
Aslam.Ejaz@osumc.edu 
 
 
Sponsor : 2020 Fall IRP Clinical Trial Award 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
I. Hypothesis / Objectives ............................................................................................................................. 3 
Objectives ................................................................................................................................................. 3 
Primary Objective.................................................................................................................................. 3 
Secondary Objective ............................................................................................................................. 3 
II. Background and Rationale ........................................................................................................................ 3 
III. Procedures ............................................................................................................................................... 5 
A. Research Design .................................................................................................................................... 5 
B. Sample .................................................................................................................................................. 6 
Inclusions: ............................................................................................................................................. 6 
Exclusions: ............................................................................................................................................. 7 
C. Measurement / Instrumentation .......................................................................................................... 7 
D. Detailed study procedures ................................................................................................................... 8 
E. Data Analysis ........................................................................................................................................... 10 
IV. Data and Safety Monitoring ................................................................................................................... 11 
V. Regulatory ............................................................................................................................................... 11 
VI. Bibliography ........................................................................................................................................... 12 
Appendix A .................................................................................................................................................. 14 
 
 
 
 

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I. Hypothesis / Objectives 
We hypothesize that total intravenous anesthesia (TIVA) used during cancer-directed 
abdominal surgery will decrease the immunosuppressive state in the peri-surgical period as 
measured by NET activation in the circulation.  
 
 
Objectives 
Primary Objective  - To evaluate the impact of anesthetic agent on inflammation and 
immunosuppression among patients undergoing abdominal cancer surgery 
Secondary Objective – To determine the impact of anesthetic choice on short-term anesthetic 
and surgical outcomes 
 
Primary Endpoint –  
1. Circulating levels of myeloperoxidase (MPO)-DNA complexes, which represent NET 
formation 
Secondary Endpoints –  
1. Circulating inflammatory cytokines (TGF-β, IL-17, IFN-g, TNF-a, IL-6) 
2. Circulating immune cell levels (CD3+ CD4+ and CD8+ T-cells and B cells) 
3. Circulating levels of markers of systemic inflammation (ESR, CRP) 
4. Postoperative nausea scores 
5. Frequency of antiemetic administration 
6. Total hospital opioid use (total morphine equivalents) 
7. Post-operative cognitive impairment, as measured by the Saint Louis University Mental 
Status (SLUMS) Examination 
8. Surgical morbidity as measured by the comprehensive complication index 
9. Overall survival 
10. Disease-free survival, defined as time from surgery to recurrence, or death 
II. Background and Rationale  
Surgical resection is the central treatment for many abdominal solid organ cancers, yet 
upwards of 1 in 3 patients will experience a local or distant recurrence of disease following 
resection.1 For patients undergoing surgery for pancreatic cancer, one major contributor to the 
development and progression of cancer following curative-intent surgery is immune 
suppression. Surgery and the anesthesia delivered causes physiologic stress and trauma 
resulting in immune suppression.2-4 This immunosuppressive state contributes to the 
development of a post-operative pre-metastatic niche that promotes tumor recurrence.2-4  As 
opposed to the commonly used volatile inhalation agents, the use of total intravenous 

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anesthesia (TIVA) is thought to blunt this immunosuppressive state, and is associated with 
improved cancer outcomes.5-8 
General anesthesia administered with volatile inhalational agents are 
immunsuppressive,9 tumorgenic10, and prometastatic.11,12 Through the use of the intravenous 
anesthetic Propofol, TIVA is an alternative method of general anesthesia that has several 
benefits over volatile inhalation agents. TIVA reduces nausea, vomiting, and opioid 
consumption, promotes earlier return of bowel function following surgery, and decreases post-
operative delirium in patients with pre-existing mild cognitive impariment.11,13 In addition, TIVA 
is less immunosuppressive than inhalational agents and has been shown to decrease cancer cell 
proliferation, migration, and metastasis 
formation.5-7 Previous retrospective studies 
have associated TIVA with improved disease 
specific and overall survival among cancer 
patients undergoing surgery.8,14-20 Despite 
these and other clinical and oncologic 
benefits (Figure 1), the adoption and use of 
TIVA in general practice is limited.11,21  
One method in detecting early cancer 
progression following surgery for pancreatic 
cancer is through the detection of reliable 
blood biomarkers. Recent studies have 
shown that exaggerated neutrophil 
activation and formation of circulating 
neutrophil extracellular trap (NETs) are 
linked to tumor progression and metastasis. 
22-25 Furthermore, NETs found in resected 
tumor tissue are associated with worse 
recurrence-free and overall survival following cancer surgery.26 Within the tumor micro-
environment, NETs are known to mediate resistance to immune checkpoint inhibitors. 27 
Through immunomodulatory effects, preliminary studies have suggested propofol decreases 
NET formation in animal models.28,29 These findings provide evidence for the central hypothesis 
that TIVA use during cancer-directed surgery will decrease the immunosuppressive state in the 
peri-surgical period as measured by NET activation in the circulation. 
There are recent discoveries suggesting that NETs formation is involved in the tumor 
microenvironment (TME). NET formation in the TME could be the initiator of disease or a side 
effect of the general overwhelming response of the immune system. There is potential for NET-
related molecules to be used as biomarkers and as targets for therapeutic intervention in 
cancer-related diseases. Important progress has been made to show that NETs may induce 
tumor proliferation, distant metastasis, and tumor-associated thrombosis. The 
immunosuppressive role of NETs has been recently studied in pancreatic ductal 
adenocarcinoma (PDAC) where remains a lethal malignancy with an immunosuppressive 

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microenvironment that is resistant to most therapies. It has recently been shown that NETs are 
the mechanism that maintaining immunosuppression and resistance to immunotherapy in 
pancreatic ductal adenocarcinoma (PDAC). NETs were found to be triggered in PDAC by IL17 
and exclude cytotoxic CD8 T cells form tumors. Inhibition of Padi4-dependent NET formation 
increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Higher expression of PADI4 
(promote NET formation) in human PDAC corresponds with a poorer prognosis, and the serum 
of patients with PDAC has a higher potential for NETosis. Therefore, inhibition of NETs to 
suppress immunosuppression may have a beneficial function in cancer development. A better 
understanding of the function and impact of NETs on cancer patients will enable the 
suppression of their detrimental attributes and ultimately, allow us to exploit therapeutic 
strategies for NETs to treat cancer.  
III. Procedures  
A. Research Design  
This is a randomized controlled pilot study. All patients with pancreatic adenocarcinoma that 
present at the Martha Morehouse Outpatient clinics between 1 May, 2023 and March 31, 2025 
and scheduled to undergo surgical resection will be eligible for the study. 
 
Enrolled subjects will be randomized 1:1 among those to receive either TIVA (n=40) or volatile 
inhalation agents (n=40). Randomization will be stratified based on the receipt of neoadjuvant 
chemotherapy and surgical procedure (whipple vs distal pancreatectomy) and accomplished by 
the random permuted block methodology through a computer-generated mechanism. 
Randomization will be performed the day prior to the surgical procedure. The anesthesia and 
operating room staff will be notified of the randomization results via email. 

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Patients will be randomized prior to the day of surgery by the research staff. The research staff 
will then inform the attending anesthesiologist and operating room staff assigned to the 
operation of the randomization details the day before surgery.  Blood samples will be drawn 
pre-operatively, immediately postoperatively, on post-operative days (POD) 1  during morning 
laboratory evaluations and at post-operative visits at 4 weeks, 3 months, and 1 year.  Patients 
will be followed for recurrence and survival for two years post-operatively, which is also the 
end of study (EOS).  All blood specimen analysis will be performed by Dr. Mark Rubinstein’s 
laboratory in BRT 550A/B, and subsequently stored until study completion. (See Schedule of 
Events – pg 6) 
 
Following pancreatic resection, all patients will be treated according to standard post-operative 
clinical protocols, which include basic laboratory analysis every morning and at post-operative 
visits. Research labs will be drawn at the time of standard clinical labs. 
 
B. Sample  
We plan to enroll 80 patients in total, with 40 in each group, over two years between 1 May 
2023,  and  March 31, 2025. 
 
Inclusions: 
• 
Adults: ≥18 years old on the day of consent 
• 
Non-metastatic pancreatic adenocarcinoma 
• 
Able to provide consent 

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• 
ECOG performance status of 0 or 1 
• 
Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy 
test for the patient at the time of surgery. 
• 
Ability to understand and the willingness to sign a written informed consent document. 
 
Exclusions: 
• 
Previous identified allergy or hypersensitivity to any component of the study treatment  
• 
Allergies to eggs, egg products, soybeans, or soy products 
• 
Personal or first degree relative with a history of malignant hyperthermia  
• 
Has a known additional malignancy that is expected to require active treatment within two 
years, or is likely to be life-limiting in the opinion of the treating investigator. Superficial 
bladder cancer, non-melanoma skin cancers, or low-grade prostate cancer not requiring 
therapy would not exclude participation in this trial.  
• 
Uncontrolled intercurrent illness including, but not limited to: Symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that would limit compliance with study requirements.  
• 
Pregnant or lactating females 
• 
Major surgery within 2 months before enrollment. Complete healing from major surgery 
must have occurred 1 month before enrollment. Complete healing from minor surgery (eg, 
simple excision, tooth extraction) must have occurred at least 7 days before enrollment. 
Subjects with clinically relevant complications from prior surgery are not eligible.  
o Patients who undergo reoperation during their initial hospitalization will be 
censored at the time of reoperation.   
• 
Prisoner status 
 
C. Measurement / Instrumentation  
Study subjects age, gender, tumor characteristics, medical history, medications will be 
recorded. Markers of inflammation and immunosuppression will be measured through 
circulating levels of myeloperoxidase (MPO)-DNA complexes, which represent NET 
formation24, at multiple pre- and postoperative time points. Other measures of circulating 
immune cells (CD3+ CD4+ and CD8+ T-cells and B cells), levels of immune cytokines (IL-2, IL-4, 
IL-5, IL-6, IL-10, IL-12, IL-17, TGF-β, IFN-g, TNF-a) and inflammatory markers (ESR, CRP) 
implicated in anesthesia-mediated immune suppression, tumorigenesis, and metastasis 
development will also be measured.  Patients will also receive daily post-operative labs as part 
of standard clinical care. 
 
We will evaluate clinical anesthetic (post-operative nausea and vomiting, opioid consumption, 
post-operative cognitive impairment) and surgical (return of bowel function, surgical morbidity 
within 90 days, mortality within 90 days) outcomes based on type of anesthesia received. 
Furthermore, we will attempt to correlate adverse anesthetic and surgical outcomes with 

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circulating NET levels. Enrolled subject’s medical records will be reviewed approximately every 
3 months for outcomes for a total of two years. 
 
D. Detailed study procedures  
Following consent for pancreatectomy at their preoperative surgical appointment, the study 
team will explain the clinical trial and provide a copy of the Informed Consent Form to the 
patient.  All patients undergoing pancreatectomy are referred to the OSU Preoperative 
Assessment Clinic (OPAC), which is always staffed by an anesthesia attending.  Patients 
interested in this clinical trial will have that noted in their OPAC referral.  At the OPAC 
appointment, the anesthesia attending will confirm they are medically stable for either 
anesthesia approach and consent them for general anesthesia.  Permuted block randomization 
will be used to allocate the patients to treatment or control group. Following, randomization 
will be performed by a computer-generated method by the research staff.  Patients will be 
randomized based on the receipt of neoadjuvant chemotherapy, clinical stage at diagnosis 
(primary resectable vs borderline resectable or locally advanced), and surgical procedure 
(whipple vs distal pancreatectomy). OPAC documentation will include that the patient has 
consented for the trial and has been randomized, but will not contain the arm they are 
randomized. The randomization arm will be entered into the OnCore system. Anesthesia 
assignments are finalized the day before surgery, and at that time, the anesthesia team 
(attending anesthesiologist, CRNA, anesthesia resident) will receive an email from the team 
with the patient’s randomization assignment.  On the morning of surgery, the surgery and 
anesthesia teams will meet the patient and answer any final questions about the trial.  Intra-
operatively, patients will receive general anesthesia within the standard guidelines of the OSU 
Department of Anesthesiology. Patients will be treated according to standard of care clinical 
pathways. Propofol is a widely used induction agent and is used even if patients receive volatile 
anesthesia.  The use of propofol for induction in patients randomized to receive volatile 
anesthesia is permitted.  Currently, anesthetic choice is largely based on provider preferences.11 
Both Propofol-based TIVA and inhaled volatile anesthetics are FDA-approved methods of 
anesthesia during cancer surgery, are safe, and are familiar to members of the anesthesia staff 
at OSU and The James. As post-operative care for a patient who has undergone pancreas 
resection is standardized within the division of surgical oncology and independent of type of 
anesthesia delivered, blinding will not be performed. The anesthesia and operating room staff 
and faculty will be aware of the randomization. 
 
Enrolled subjects will be registered in OSU’s OnCore system as well as stored in the PIs REDCap 
database. Electronic data will be located on password protect university network computers or 
REDCap. REDCap instance is located on an internal OSUWMC network. Remote access to this 
network can be obtained over an encrypted VPN tunnel (AnyConnect). This VPN uses Protocol: 
DTLS and Cipher: RSA_AES_128_SHA1. Background checks are performed on all staff that are 
on the network or obtaining VPN access. 
 
 

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Schedule of Events 
 
V0 
V1 
POD-0 
(DOS) 
V2 
POD-1* 
V3 
4 weeks 
(±2 weeks) 
V4 
3 m 
(±4 weeks) 
V5 
1 yr 
(± 4 week) 
LTFU/EOS 
Consent 
x 
 
 
 
 
 
 
Eligibility  
x 
 
 
 
 
 
 
Med History / 
Physical Exam 
x 
 
 
 
 
 
 
Medications 
x 
 
 
 
 
 
 
Randomization
1 
x 
 
 
 
 
 
 
Blood draw* 
x 
x 
x 
x 
x 
 
X 
 
Med Record  
Review 
x 
 
 
x 
x 
 
X 
x 
AE / SAE 
 
x 
x 
 
 
 
 
 
AE – adverse event 
SAE – serious adverse event 
EOS – End of Study 
LTFU – Long term follow-up (up to 2 years) 
DOS – day of surgery 
1will occur prior to day of surgery, but may not occur on V0 
*within the day at time of other clinical labs  
 
Patients who withdraw their research consent prior to surgery will be withdrawn from the 
study.  Patients whose surgery is cancelled and not rescheduled will be withdrawn from the 
study.  Patients who require a change in anesthetic approach intra-operatively will be followed 
with blood draws as originally planned, and the reason for change in anesthesia plan will be 
documented by the attending anesthesiologist and reported to the IRB. Patients who are 
unexpectedly unable to undergo a curative-intent pancreas resection (ie. aborted procedure) 
will be removed from the study, as will subjects who undergo reoperation during their index 
hospitalization. Subjects will be informed however, they may choose to leave the study at any 
time. 
 
Both anesthetic approaches use FDA approved medications and equipment and are NOT 
experimental anesthetic techniques, but rather are standard of care techniques that 
anesthesiologists are expected to have mastered over the course of training. Neither approach 
poses a significant risk to the patient.  
 

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All subjects will have their blood drawn per the established procedure for biospecimen 
collection in the Martha Morehouse Outpatient Center or the James Cancer Hospital. About 30 
cc of peripheral blood in heparinized solid green top tubes, and/or red top serum separator 
tubes, will be drawn from patients once consent has been signed at each time point. Samples 
will be processed and stored in the laboratory of Dr. Mark Rubinstein, in the Biomedical 
Research Tower at The Ohio State University, identified with their study ID number.  Research 
blood will be drawn at the time of standard clinical blood draws and then held for Dr. 
Rubinstein’s lab.  After processing of blood samples within 24 hours of the blood draw, will be 
stored in a –70° C freezer or in liquid nitrogen in the Rubinstein lab until subsequent analysis. 
The cytokine panel is based on previous studies which have investigated the role of anesthesia 
delivery on post-operative immunosuppression and cancer outcomes.  
 
 
E. Data Analysis  
Clinical data on the impact of anesthetic agents on NET formation are lacking.  In vitro 
experiments have shown that Propofol decreases NET formation approximately 20% when 
compared to baseline levels.22,23 In this pilot trial, we are assuming there is a 10% difference in 
NET levels between inhaled anesthetics and Propofol-based TIVA. A repeated measures design 
has two treatment groups, and a total of 80 patients (32 patients per group and we anticipate a 
follow-up loss rate of 20%, so we will enroll 40 patients per group) are needed. NETs will be 
measured at 8 different post-anesthesia time points as described. This trial design achieves 80% 
power to test the 10% group difference with a standard deviation of 0.08 using a Geisser-
Greenhouse Corrected F Test for a two-sided 5% significance level, and the medium effect size 
of 0.3.  Previous translational studies536-42 have identified differences in circulating cytokine 
levels and immune cell phenotypes with sample sizes of 40 patients / arm or fewer. For the 
repeated measurements of continuous variables (NET, Circulating inflammatory cytokines, 
immune cell levels and markers of systemic inflammation), linear mixed model accounting for 
within-subject correlations of different time points and individual differences will be used for 
the comparisons of effects of TIVA and inhaled Volatile anesthetics. In addition, time under 
general anesthesia, amount of medication administered, and the presence or absence of major 
vein or artery resection during surgery will be adjusted in the mixed effect model. Furthermore, 
type of operative approach (open vs. minimally-invasive) as well as pathologic stage (TNM) will 
be adjusted in the mixed effect model. T-test will be applied to compare the baseline 
continuous variables (age, tumor characteristics), nausea scores, frequency of antiemetic 
administration, and Chi2 test will be used to assess the baseline categorical variables (gender, 
medications) of the TIVA and inhaled Volatile anesthetics groups. Surgical morbidity (measured 
by the comprehensive complication index) will be compared using two sample T test. Kaplan–
Meier estimator and Logrank test will be employed to compare overall survival and disease-free 
survival analysis. Cox’s proportional hazards model will be used for multivariable survival 
regression analysis. We will carefully check model assumptions, and in the event that violations 

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are detected, appropriate transformations or non-parametric analysis method will be used. For 
multiple comparisons, the adjusted p-values will be reported. A two-sided p-value < 0.05 will be 
considered statistically significant.    
We will monitor short-term peri-operative and anesthetic outcomes based on the anesthetic 
agent of choice.  The incidence of these outcomes will also be associated with NET levels. We 
expect increased NETs among patients with worse short-term surgical and anesthetic 
outcomes. Return of bowel function will be measured by concordance with our institutional 
post-pancreatectomy clinical pathway. Post-operative nausea and vomiting will be measured by 
nursing evaluated nausea scores and frequency of antiemetic medication administration. To 
quantitatively assess the degree of post-operative pain, we will measure total oral morphine 
equivalents during the patient’s hospital stay. Post-operative cognitive impairment will be 
assessed using the Saint Louis University Mental Status (SLUMS) Examination in the pre-
operative clinic, the morning of the first post-operative day, the day of discharge, and at post-
operative clinical visits.  Surgical morbidity will be assessed using standardized case report 
forms, and complication burden will then be calculated using the Comprehensive Complication 
Index (CCI) 30. This method is more powerful than standard binary measures of morbidity 
(presence/absence of individual events) as it presents a quantitative score based on an 
aggregate weighted total ranging from 0 (no complications) to 100 (death). 
IV. Data and Safety Monitoring 
The data and safety monitoring plan will involve the continuous evaluation of safety, data 
quality and data timeliness. Investigators will conduct continuous review of data and patient 
safety at their regular Disease Group meetings (at least monthly). The PI of the trial will review 
toxicities and responses of the trial where applicable at these disease center meetings and 
determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse 
events will be reviewed by the PI and compared to what is known about the agent/device from 
other sources; including published literature, scientific meetings and discussions with the 
sponsors, to determine if the trial should be terminated before completion. Serious adverse 
events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring 
Committee (DSMC). All Serious Adverse Events are to be submitted to the DSMC for their 
review. 
V. Regulatory  
Before protocol-specified procedures are carried out, consenting professionals approved on the 
study, will explain full details of the protocol and study procedures as well as the risks involved, 
aspects of patient privacy concerning research specific information, Research Authorization to 
participants prior to their inclusion in the study. Participants will also be informed that 
participation is voluntary and that they are free to withdraw from the study at any time. All 

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patients must sign an IRB approved consent form indicating their consent to participate. The 
participant must receive a copy of the signed informed consent form.  
Patient information will be stored in a secured, computerized database that is behind the Ohio 
State University Wexner Medical Center firewall. Only study personnel will have access to these 
records. Any hard copies of study-related materials will be kept in locked cabinets within the 
CTO offices, only accessible to approved research personnel.  
VI. Bibliography  
1. 
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outcomes: a meta-analysis of total intravenous versus volatile anesthesia. Can J Anaesth. 
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2. 
Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer 
recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205-218. 
3. 
Chen Z, Zhang P, Xu Y, et al. Surgical stress and cancer progression: the twisted tango. Mol 
Cancer. 2019;18(1):132. 
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2017;77(7):1548-1552. 
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Inada T, Yamanouchi Y, Jomura S, et al. Effect of propofol and isoflurane anaesthesia on the 
immune response to surgery. Anaesthesia. 2004;59(10):954-959. 
6. 
Mammoto T MM, Mammoto A, Yamanaka Y, Hayashi Y, Mashimo T, Kishi Y Nakamura H. 
Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Letters. 2002;184:165-
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Yang C, Gao J, Yan N, et al. Propofol inhibits the growth and survival of gastric cancer cells in 
vitro through the upregulation of ING3. Oncol Rep. 2017;37(1):587-593. 
8. 
Chang CY, Wu MY, Chien YJ, Su IM, Wang SC, Kao MC. Anesthesia and Long-term Oncological 
Outcomes: A Systematic Review and Meta-analysis. Anesthesia and analgesia. 2021;132(3):623-
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9. 
Stollings LM, Jia LJ, Tang P, Dou H, Lu B, Xu Y. Immune Modulation by Volatile Anesthetics. 
Anesthesiology. 2016;125(2):399-411. 
10. 
Luo X, Zhao H, Hennah L, et al. Impact of isoflurane on malignant capability of ovarian cancer in 
vitro. Br J Anaesth. 2015;114(5):831-839. 
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Lim A, Braat S, Hiller J, Riedel B. Inhalational versus propofol-based total intravenous 
anaesthesia: practice patterns and perspectives among Australasian anaesthetists. Anaesth 
Intensive Care. 2018;46(5):480-487. 
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Zhu M, Li M, Zhou Y, et al. Isoflurane enhances the malignant potential of glioblastoma stem 
cells by promoting their viability, mobility in vitro and migratory capacity in vivo. Br J Anaesth. 
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Tang N, Ou C, Liu Y, Zuo Y, Bai Y. Effect of inhalational anaesthetic on postoperative cognitive 
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Wigmore TJ, Mohammed K, Jhanji S. Long-term Survival for Patients Undergoing Volatile versus 
IV Anesthesia for Cancer Surgery: A Retrospective Analysis. Anesthesiology. 2016;124(1):69-79. 

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15. 
Lee JH, Kang SH, Kim Y, Kim HA, Kim BS. Effects of propofol-based total intravenous anesthesia 
on recurrence and overall survival in patients after modified radical mastectomy: a retrospective 
study. Korean journal of anesthesiology. 2016;69(2):126-132. 
16. 
Wu ZF, Lee MS, Wong CS, et al. Propofol-based Total Intravenous Anesthesia Is Associated with 
Better Survival Than Desflurane Anesthesia in Colon Cancer Surgery. Anesthesiology. 
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17. 
Zheng X, Wang Y, Dong L, et al. Effects of propofol-based total intravenous anesthesia on gastric 
cancer: a retrospective study. Onco Targets Ther. 2018;11:1141-1148. 
18. 
Lai HC, Lee MS, Lin C, et al. Propofol-based total intravenous anaesthesia is associated with 
better survival than desflurane anaesthesia in hepatectomy for hepatocellular carcinoma: a 
retrospective cohort study. Br J Anaesth. 2019;123(2):151-160. 
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Lai HC, Lee MS, Lin KT, et al. Propofol-based total intravenous anesthesia is associated with 
better survival than desflurane anesthesia in intrahepatic cholangiocarcinoma surgery. 
Medicine. 2019;98(51):e18472. 
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Lai HC, Lee MS, Lin KT, et al. Propofol-based total intravenous anesthesia is associated with 
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Kos K, de Visser KE. Neutrophils create a fertile soil for metastasis. Cancer Cell. 2021. 
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Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil Extracellular Traps Promote the 
Development and Progression of Liver Metastases after Surgical Stress. Cancer research. 
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Albrengues J, Shields MA, Ng D, et al. Neutrophil extracellular traps produced during 
inflammation awaken dormant cancer cells in mice. Science. 2018;361(6409). 
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Yang L, Liu Q, Zhang X, et al. DNA of neutrophil extracellular traps promotes cancer metastasis 
via CCDC25. Nature. 2020;583(7814):133-138. 
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Jin W, Xu HX, Zhang SR, et al. Tumor-Infiltrating NETs Predict Postsurgical Survival in Patients 
with Pancreatic Ductal Adenocarcinoma. Annals of surgical oncology. 2019;26(2):635-643. 
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Zhang Y, Chandra V, Riquelme Sanchez E, et al. Interleukin-17-induced neutrophil extracellular 
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Chen MS, Lin WC, Yeh HT, Hu CL, Sheu SM. Propofol specifically reduces PMA-induced 
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2019;221:178-186. 
29. 
Meier A, Chien J, Hobohm L, Patras KA, Nizet V, Corriden R. Inhibition of Human Neutrophil 
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Appendix A 
Package Insert 
 

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OSU-20306 
IRB #: 2022C0114 
IRB Approval Date: 7/17/2023 
Version: 1.6 
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OSU-20306 
IRB #: 2022C0114 
IRB Approval Date: 7/17/2023 
Version: 1.6 
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OSU-20306 
IRB #: 2022C0114 
IRB Approval Date: 7/17/2023 
Version: 1.6 
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OSU-20306 
IRB #: 2022C0114 
IRB Approval Date: 7/17/2023 
Version: 1.6 
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OSU-20306 
IRB #: 2022C0114 
IRB Approval Date: 7/17/2023 
Version: 1.6 
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