HOPE to Reduce Tumour Recurrence After LT In Patients With HCC

Study Overview
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Brief Summary
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Hypothermic oxygenated ex-situ machine perfusion (HOPE) is a dynamic preservation method that has been developed to reduce the incidence and severity of ischaemia-reperfusion injury and to improve outcomes after liver transplantation. Whit this study Pi and collaborators hypothesize that the application of ex-situ liver perfusion before LT in HCC recipients leads to an optimization of graft function, with a decrease in ischaemia-reperfusion injury and a possible decrease in tumor cell growth. This is multicentre, prospective, two-arm, randomized, controlled, clinical trial, that will will involve patients with HCC candidate to LT. The liver grafts will be randomized in two groups to compare HOPE and static cold storage (SCS) preservation before transplantation. For each group evaluation of clinical outcomes, graft function tests, histologic findings, perfusate, tumor characteristics, and recurrence will be done.

Detailed Description
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Tumor recurrence after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is a major complication leading to decreased long-term survival of patients. However, the mechanisms leading to tumor emergence and growth remain incompletely understood. Several factors, can promote cancer growth or recurrence. Ischemia-reperfusion injury (IRI) has been recognized as an important early driver of microvascular dysfunction resulting in tissue hypoxia and inflammation, which promotes tumor cell growth. A recent therapeutic strategy used to reduce the incidence and severity of IRI and to improve outcomes after transplantation is ex vivo HOPE. Which allows to redirect anaerobic metabolism to aerobic metabolism under hypothermic conditions, protect grafts from oxidative species-related damage, improve graft function and may potentially reduce cancer recurrence after liver transplantation. A multicentre, prospective, two-arm, randomized, controlled, clinical trial will be performed; four Italian centres (Bologna, Palermo, Pisa e Torino) will be involved. A total of 192 patients with a history of HCC or active HCC, already present or about to be placed in the liver transplantation waiting list of the four transplantation center will be enroll. The liver grafts will be randomized in two groups to compare HOPE and SCS preservation before transplantation. For each group evaluation of clinical outcomes, graft function tests, histologic findings, perfusate, tumor characteristics, and recurrence will be done during follow up visit; 1-3-6 and 12 months after transplantation. Livers assigned to HOPE group will be perfused by machine perfusion with cold Belzer solution (4°-10°C) and with continuous oxygenation (partial pressure of oxygen = 500-600 mmHg). Organs will be perfused from the start of the back-table procedure until implantation, without increasing cold ischemia time (CIT). In the control group livers undergoing SCS will be steeped in cold Celsior or Belzer solutions and stored in ice. Presence of bacterial and/or fungal contamination will be tested by setting up microbiological cultures from the preservation fluid, before and after treatment in both groups.

Official Title
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Hypothermic Oxygenated Perfusion To Reduce Tumour Recurrence After Liver Transplantation In Patients With Hepatocarcinoma

Conditions
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Liver Cancer, Tumor Recurrence, Hepatocellular Carcinoma, Liver Transplantation, Ex-vivo Hypothermic Perfusion

Intervention / Treatment
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* Device: Hypothermic oxygenated Perfusion - HOPE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all patients with HCC medical history or active HCC Donation after circulatory death (DBD) donor with standard or extended criteria Exclusion Criteria: Living transplantation Split Transplantation Combined Transplantation Donation after cardiac death (DCD)Transplantation Re-transplantation Patient whose liver graft will undergo ex-vivo machine perfusion for medical decision, regardless the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypothermic oxygenated Perfusion - HOPE<br>Belzer machine perfusion solution at 4°C-10°C in sterile conditions and continuous oxygenation (partial pressure of oxygen=500-600 mmHg) will be used for perfusion, 3000 ml for livers, 1-3 hours. Liver perfusion will be performed through the portal vein at a 5 mmHg pressure. Flow, pressure and temperature will be monitored and registered on REDCap software during organ perfusion. Gas analysis of the effluent perfusate (partial pressure O2 and CO2, pH, lactate and glutamate production) will be accomplished every 15 minutes. | Device: Hypothermic oxygenated Perfusion - HOPE<br>* HOPE will start by flushing the organ at low flow values (30 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 1 hour for livers.<br>|
| No Intervention: Static Cold Storage - SCS<br>Livers undergoing SCS will be stored in sterile organ bags with Belzer or Celsior solution and cooled in ice until transplant. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of liver recurrence | Present/Non present; Diagnosis with abdominal ultrasound and serum tumor markers analysis Date of recurrence and location | 1 year after LT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of early allograft disfunction (EAD) | Present/Non present; Diagnosis with analysis of serum values of : Aspartate transaminase (AST), Alanine transaminase (ALT), Bilirubin and International Normalised Ratio (INR) | starting 24 hours after LT until 7 days after LT |