Impact of Graft Reconditioning With Hypothermic Machine Perfusion on HCC Recurrence After Liver Transplantation

The use of devices for liver grafts perfusion before transplantation, either hypothermic (HOPE) or normothermic (NMP), is rapidly spreading thanks to the promising results obtained so far in terms of graft survival and post-operative morbidity. Besides the well-established ability to increase the rate of transplantability of extended criteria donors (ECD) and donors after cardiac death (DCD), the use of machine perfusion (MP) may also improve the oncological outcomes of patients affected by hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). The underlying mechanism is represented by the modulation of the ischemia-reperfusion injury (IRI)-related cellular damage obtained by the liver graft perfusion with HOPE before LT. The identification of biomarkers able to predict graft outcomes and highlight the mechanism of graft injury before transplantation rapidly and in non-invasive manner is therefore needed. Mass spectrometry-based metabolomics has already shown its potential by using perfusion liquids or pre-implantation biopsies.

The aim of the investigators is to run an open-label, randomised, controlled trial to study the impact of treating standard liver grafts from brain dead donors (DBD) with HOPE before liver transplant in patients affected by HCC. Patients aged 18-75 years presenting with HCC Milan-in at listing will be considered for inclusion. Presence of extra-hepatic disease and general contraindications to liver transplantation as defined by the local tumor board are considered as exclusion criteria. Eligible patients will be randomly assigned (1:1) with the use of a dedicated software to MP (intervention group) or no-MP (control group) before liver transplantation. Untargeted mass spectrometry metabolomics (UHPLC-HRMS) will be performed on liver graft perfusate, liver graft biopsy and recipient blood samples, to identify by classification methods, novel predictive markers of IRI. Furthermore, rapid targeted MS approaches will be performed on VIP metabolites and known key compounds (such as TCA, aminoacids, energy metabolism) to rapidly assess graft function as well as post-operative outcome.

Blood samples of the recipient will be collected at two checkpoints (listing, and 3 months after liver transplant) to evaluate exosomes and miRNA expression fluctuations (liquid biopsy).

Primary outcomes of the study will be overall survival, graft survival and recurrence-free survival at 1- and 2-years. Survival results will be compared to those expected based on the Metroticket 2.0 score to assess the impact of MP in reducing the risk of HCC recurrence. Patients will remain in follow-up as for clinical practice to assess 3- and 5-years survival. Secondary end-point will be to define liquid biopsy efficacy to predict HCC recurrence and to define the correlation between metabolomic observations and HCC recurrence pattern.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Liver Transplant; Complications
• Intervention / Treatment: Device: D-HOPE machine perfusion; Procedure: Liver transplantation

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paolo Magistri, MD FACS; Phone Number: +390594225265; Email: paolo.magistri@unimore.it

Study Locations

• Italy
  • MO
    • Modena, MO, Italy, 41124
      • Recruiting
      • AOU di Modena
      • Contact: Paolo Magistri, MD FACS; Phone Number: +390594225178; Email: paolo.magistri@unimore.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with HCC within Milan criteria at listing candidate for liver transplantation
• ECOG 0-2
• DBD donors
• capability to sign an informed consent

Exclusion Criteria:

• pediatric patients
• DCD donors
• DBD extended criteria requiring machine perfusion (no ethical randomization)
• living donor liver transplantation
• split liver

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Machine perfusion; The liver graft to be transplanted is treated with 90 minutes of D-HOPE machine perfusion	Device: D-HOPE machine perfusion; use of the device; Procedure: Liver transplantation; Liver transplantation for HCC within Milan criteria
Active Comparator: No machine perfusion; Standard liver transplantation	Procedure: Liver transplantation; Liver transplantation for HCC within Milan criteria

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Recurrence free survival and overall survival after LT for HCC according to the use of MP This aim will be realized at the Hepato-pancreato-biliary Surgery and Liver Transplantation Unit of Policlinico University Hospital of Modena - University of Modena and Reggio Emilia, supervised by Dr Paolo Magistri. Patients included in the trial according to the following criteria will be treated and followed-up according to the standard of care (SOC). All eligible patients have an indication to LT beyond the aims of this study, and will undergo LT according to National indications. LT is the gold standard treatment for patients affected by HCC inside Milan criteria, however biological features of the tumor may modify the expected recurrence pattern. This aim will be focused on the potential role for MP in the modulation of tumor recurrence pattern. SA1 Deliverables: Modulation of HCC recurrence pattern after MP	5 years after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic markers - MiRNA	Identification of microRNAs from liquid biopsy derived extracellular vesicles, as source of prognostic information on IRI favoring HCC recurrence. This aim will be realized by Research Laboratory at Policlinico University Hospital of Modena - University of Modena and Reggio Emilia, supervised by Dr Valentina Masciale. SA2 Deliverables: 1) miRNAs transcriptomic profile of pre transplanted-patients.	5 years after surgery
Prognostic markers - metabolipiodomics	Identification of at least 1 prognostic markers from the promising miRNA selected on the bases of the transcriptomic analysis. SA3: Identification of prognostic markers of IRI and HCC by MS-based metabolipidomics: This aim will be realized by UNIT2, Unisa-Difarma, Dr. Eduardo Maria Sommella	5 years after surgery
Graft survival	Reduction of early allograft disfunction	1 month after surgery

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero-Universitaria di Modena
• Investigators: Study Chair: Fabrizio Di Benedetto, University of Modena and Reggio Emilia; Study Chair: Massimo Dominici, University of Modena and Reggio Emilia; Study Chair: Pietro Campiglia, University of Salerno; Principal Investigator: Eduardo M Sommella, University of Salerno; Principal Investigator: Valentina Masciale, University of Modena and Reggio Emilia; Principal Investigator: Ilenia Mastrolia, University of Modena and Reggio Emilia

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: January 24, 2024
• First Submitted That Met QC Criteria: January 24, 2024
• First Posted (Actual): February 1, 2024

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Metabolomics; Liquid biopsy; Hepatocellular carcinoma; Liver Transplantation; Ischemia reperfusion injury; Machine perfusion
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma, Hepatocellular; Recurrence
• Other Study ID Numbers: 561/2023/SPER/AOUMO.

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No