Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery (RISE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor:
Information provided by (Responsible Party):
Megan J. Reiniers, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01700660
First received: October 3, 2012
Last updated: September 5, 2014
Last verified: September 2014
  Purpose

Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in order to prevent excessive blood loss. However, this predisposes the liver to a detrimental inflammatory response once the circulation is restored. Altogether, the effects that result from this temporary withdrawal of blood are known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs determines the functional outcome of the liver after surgery.

Recently, it has become clear that (over)activation of the immune system forms the mainstay of I/R injury in the liver. More importantly, it has been shown in animal models that self-antigens, which are normal cellular constituents that become immunogenic mediators following their release from dying cells, are involved in the earliest stages of I/R injury of the liver. Clinical data on the release self-antigens in I/R injury are however scarce to date. Therefore, the aim of this study is to investigate the release of self-antigens in patients that undergo a major liver resection with or without withdrawal of the liver's blood flow. Also, the results will be correlated to genes involved in the inflammatory response as well as clinical parameters for liver damage and function.


Condition
Warm Hepatic Ischemia-reperfusion Injury

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery

Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • DAMPs in systemic circulation [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    Plasma DAMP levels will be determined perioperatively.


Secondary Outcome Measures:
  • Up regulation of acute inflammatory response genes [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
    Up regulation of acute inflammatory response genes will be determined in liver biopsy tissue (acquired intraoperatively) by means of qPCR.

  • Parenchymal damage [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    Measured as plasma ALT and AST.

  • Liver function [ Time Frame: 8 hours ] [ Designated as safety issue: Yes ]
    Assessed by means of total bilirubin levels and prothrombin time.


Biospecimen Retention:   Samples With DNA

2 liver biopsies


Estimated Enrollment: 40
Study Start Date: October 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
VIO
Patients operated under VIO.
Control
Patients operated without VIO.

Detailed Description:

Rationale

Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in order to prevent excessive blood loss. Vascular inflow occlusion (VIO) however predisposes the liver to a detrimental inflammatory response once the circulation is restored. Altogether, the ramifications that result from this temporary withdrawal of oxygen supply are known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs determines the functional outcome of the liver after surgery. Recently, it has become clear that (over)activation of the immune system forms the mainstay of hepatic I/R injury. More importantly, it has been shown in animal models that endogenous self-antigens, known as damage-associated molecular patterns (DAMPs), are released from stressed liver cells in the earliest stages of reperfusion and, as such, form the most proximal triggers of hepatic I/R injury. Clinical data on DAMP release following hepatic I/R are however scarce to date. Therefore, the aim of this study is to investigate DAMP release in patients that undergo a major liver resection with or without VIO and to correlate the results to the expression of acute- phase inflammatory response genes and routine clinical parameters for hepatocellular damage.

Objective

To investigate the release of damage-associated molecular patterns (DAMPs) following major hepatic resection with or without VIO and to correlate the outcomes to the acute inflammatory response and clinical parameters for hepatocellular damage.

Study design

The study is designed as an observational study. Because the decision to apply VIO is often made during surgery, patients will be allocated to a group postoperatively. Therefore, the inclusion of subjects in this study will continue until the calculated sample size of 15 patients has been reached in each group.

Study population

Eligible patients for participation in this study are those diagnosed with a malignant or benign hepatic tumor that are scheduled to undergo major hepatectomy (resection of ≥3 segments).

Main study parameters/endpoints

The primary endpoint of this study is defined as the effect of I/R on the release of DAMPs, measured in the systemic circulation. Secondary parameters constitute the expression of acute inflammatory response genes, AST, ALT, total bilirubin, and INR.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Patients diagnosed with a malignant or benign hepatic tumor that are scheduled for a liver resection.

Criteria

Inclusion Criteria:

  • Patients scheduled to undergo a major liver resection for a benign or malignant hepatic tumor
  • Signed informed consent obtained prior to any study-specific procedure
  • ASA classification I-III

Exclusion Criteria:

  • VIO <20 min
  • ASA classification IV/V
  • Emergency operations
  • Pregnancy or breast feeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01700660

Contacts
Contact: Megan J. Reiniers, MSc 0031205666683 m.j.reiniers@amc.uva.nl
Contact: Rowan F. van Golen, MSc 0031205666653 r.f.vangolen@amc.uva.nl

Locations
Netherlands
Academic Medical Center Recruiting
Amsterdam, Noord Holland, Netherlands, 1105 AZ
Contact: Megan J. Reiniers, MSc    0031205666683    m.j.reiniers@amc.uva.nl   
Contact: Rowan F. van Golen, MSc    0031205666653    r.f.vangolen@amc.uva.nl   
Principal Investigator: Megan J. Reiniers, MSc         
Sub-Investigator: Rowan F. van Golen, MSc         
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
Study Director: Thomas M. van Gulik, MD, PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Megan J. Reiniers, MSc Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  More Information

Publications:
Responsible Party: Megan J. Reiniers, PhD student at the Department of Surgery, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01700660     History of Changes
Other Study ID Numbers: 2012_238, NL41737.018.12
Study First Received: October 3, 2012
Last Updated: September 5, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Additional relevant MeSH terms:
Reperfusion Injury
Cardiovascular Diseases
Pathologic Processes
Postoperative Complications
Vascular Diseases

ClinicalTrials.gov processed this record on October 21, 2014