Digestive System Diseases

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Liver Cirrhosis

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Carcinoma, Hepatocellular

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Patients notified on the national waiting list for hepatic transplant

Morphological, chronological, anatomy-pathological and molecular search

search of factors predicting tumor recurrence

Thomas Decaens, MD, PhD

Results of liver transplantation, the best theoretical treatment for HCC, are limited by tumor recurrence. In order to limit this risk Milan criteria was proposed in 1996. However, these criteria are to restrictive and approximately 40% of patients denied by Milan criteria may be cured by liver transplantation.

The purpose of this study was thus to prospectively evaluate factors predicting tumor recurrence after liver transplantation for HCC and then to reassess criteria for liver transplantation.

In this study, the investigators studied the predictive value of imaging techniques such as CT, MRI, PET scan, of serological markers and molecular markers assessed before liver transplantation at listing.

The investigators also evaluated the predictive value of tumor growing during the waiting time (imaging and serological).

Finally, the investigators compared pre-LT data and explanted liver analysis to evaluate accuracy of liver biopsy and of imaging.

Blood and serum sample (28 ml at M0, M3, M6) Tissues (one pretransplant, hepatic explant, potential resection)

Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma (HCC)

Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma

Assistance Publique - Hôpitaux de Paris

Immunomodulating Agents

Immunologic Factors

In this group, the patients will receive liver cryosurgery first to destroy big tumors, then receive multiple NK immunotherapy (intensive treatment: 6 times in first 3 months; then interval treatment: once every 3 months). The check indexes are CT scan and blood tests (including tumor markers, lymphocyte subsets and circulating tumor cell).

In this group, the patients will receive liver cryosurgery to destroy big tumors. The check indexes are CT scan and blood tests (including tumor markers, lymphocyte subsets and circulating tumor cell).

Argon-helium cryosurgical system (percutaneous ablation under CT or ultrasound guidance)

Cryosurgery

Natural killer cell(each treatment: about 10 billion cells transfusion in 3 times, i.v.)

NK immunotherapy

Jibing Chen, MD, PhD

The aim of this study is the safety and efficacy of cryosurgery plus natural killer(NK) immunotherapy to tumors in transplanted liver.

By enrolling patients with tumors in transplanted liver adapted to enrolled criteria, this study will document for the first time the safety and the short and long term efficacy of the combined therapy using cryosurgery and NK cells.

The safety will be evaluated by statistics of adverse reactions. The efficacy will be evaluated according to local relief degree, progress free survival (PFS) and overall survival (OS).

Combination of Cryosurgery and NK Immunotherapy for Tumors in Transplanted Liver

Shenzhen Hank Bioengineering Institute

Fuda Cancer Hospital, Guangzhou

From the donor liver perfusate, mononuclear cell will be extracted and cultured. Then, the cells will be stimulated with IL-2. The number of inoculation cells( mainly NK cells) is between 10 and 100 million cells. The cells will be given to the liver transplant recipient who had the same donor for liver and liver perfusate. Patient of this arm receive small dose of liver NK cell inoculation as described.

From the donor liver perfusate, mononuclear cell will be extracted and cultured. Then, the cells will be stimulated with IL-2. The number of inoculation cells(mainly NK cells) is between 100 and 1000 million cells. The cells will be given to the liver transplant recipient who had the same donor for liver and liver perfusate.Patient of this arm receive large dose of liver NK cell inoculation as described.

Liver transplant recipients will receive once liver NK cell inoculation several days after liver transplantation.

Liver NK cell inoculation

Seigo Nishida, MD PhD

The objective of this study is to evaluate feasibility and safety of the adoptive transfer of activated natural killer (NK) cells extracted from cadaveric donor liver graft perfusate for liver transplant recipients with hepatocellular carcinoma (HCC)

To investigate whether adoptive transfer of IL-2 stimulated NKcells extracted from cadaveric donor liver graft exudates into recipient with HCC will lead to prevent recurrence of HCC after liver transplantation.

The method we plan to use is to collect NK cells from the cadaveric donor liver perfusate at the time of organ recovery. The perfusate will be condensed by centrifuging and liver mononuclear cells (LMNC) were isolated by gradient centrifugation. LMNC will be cultured with anti-CD3 antibody. LMNC will be separted into a CD3-/CD56+ NK cell fraction and a non-NK cell fraction. The purity of isolated fractions will be assessed by Flow cytometric analyses. NK cells will be cultured with human recombinant IL-2 in 10% RPMI at 37 ºC in a 5% CO2 incubator. NK cells will be infused intravenously to the recipient with HCC who have liver transplant from the same cadaveric donor at post operative day 4 in attempt to prevent the metastasis and recurrence of HCC.

Safety Study of Liver Natural Killer Cell Therapy for Hepatoma Liver Transplantation

A Novel Immunotherapy for Liver Transplant Patients With Hepatocellular Carcinoma: Anti-tumor Effect of IL2-activated Donor Liver Natural Killer Cell

Side effect of cadaveric donor liver NK cell infusion We will measure the occurence of the side effect of the liver NK cell infusion. We will monitor the patient condition clinically. If any side effect are noticed, we will record them and report to the data safety monitoring comittee.

To assess NK cell infusion -related toxicity at the bedside. We will monitor the patient and check the vital sign. If any side effect are noticed, we will record and report to the data safety monitoring comittee.

Florida Department of Health

Seigo Nishida

Professor of clinical surgery

Adverse events will be graded according to the Common terminology criteria for Adverse Events Guide.

A Data Safety Monitoring Committee will be constituted to analyze safety and preliminary evidence of efficacy of the trial.

Adverse events will be reported to the IRB and DSMB. Serious adverse events will be reported to the DSMB within 24 hours.

The number of inoculation cells is between 10 and 100 million cells.

Liver NK cell inoculation: Liver transplant recipients will receive once liver NK cell inoculation several days after liver transplantation.

Small Dose

The number of inoculation cells is between 100 and 1000 million cells

Liver NK cell inoculation: Liver transplant recipients will receive once liver NK cell inoculation several days after liver transplantation.

Large Dose

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr. Seigo Nishida

Side Effect of Cadaveric Donor Liver NK Cell Infusion

From the donor liver perfusate, mononuclear cell will be extracted and cultured. Then, the cells will be stimulated with IL-2. The number of inoculation cells( mainly NK cells) is between 10 and 100 million cells. The cells will be given to the liver transplant recipient who had the same donor for liver and liver perfusate. Patient of this arm receive small dose of liver NK cell inoculation as described.

Liver NK cell inoculation: Liver transplant recipients will receive once liver NK cell inoculation several days after liver transplantation.

From the donor liver perfusate, mononuclear cell will be extracted and cultured. Then, the cells will be stimulated with IL-2. The number of inoculation cells(mainly NK cells) is between 100 and 1000 million cells. The cells will be given to the liver transplant recipient who had the same donor for liver and liver perfusate.Patient of this arm receive large dose of liver NK cell inoculation as described.

Liver NK cell inoculation: Liver transplant recipients will receive once liver NK cell inoculation several days after liver transplantation.

Participants were devided two group( small and large dose) as described based on the dose of infused cell numbers.

NK Cell Infusion-related Toxicity

Anti-HCC Effect of This Treatment

Anti-HCV Effect of This Treatment (If Applicable)

The number of inoculation cells is between 10 and 100 million cells.

Liver NK cell inoculation: Liver transplant recipients will receive liver NK cell inoculation several days after liver transplantation.

The number of inoculation cells is between 100 and 1000 million cells

Liver NK cell inoculation: Liver transplant recipients will receive liver NK cell inoculation several days after liver transplantation.

Overall Study

Norman Kneteman, MD

Norman Kneteman, MD, PhD

The investigators propose a prospective, web-based database (developed within the framework of Quickbase, Intuit) which will allow an evaluation of the data for patients with a liver tumour who receive a liver transplant. Each site will continue to transplant according to their own criteria for inclusion on the waiting list. Each center will be responsible to enter a short list of data points at time of listing, transplant, and at 1 and 2 years post transplant. Data will be gathered prospectively through a web-based anaonymized database, and outcomes analyzed yearly X5 for tumour recurrence and patient survival.

A previous retrospective study evaluated the UNOS database of liver transplant recipients for use of total tumor volume (TTV) and alphafetoprotein (AFP) as criteria for selection of candidates for liver transplantation. The results confirmed a prior publication demonstrating that tumors modestly beyond Milan size limitation and irrespective of tumor numbers can achieve excellent outcomes, while providing important insight into which tumors within Milan criteria remain with a high likelihood of recurrence (high AFP). The work has now been published in Hepatology.

The investigators propose a prospective evaluation of these composite criteria, using data from patients receiving a liver transplant in order to have a larger population. Centers will continue to transplant according to their own criteria for inclusion on the waiting list. Data will be gathered prospectively through a web-based database (Quickbase, Intuit) and outcomes analyzed yearly for 5 years follow-up for tumour recurrence and patient survival.

Each center will be responsible to enter a short list of data points for their patients at time of listing, time of transplant, and yearly post transplant. Data points have been kept to a minimum in the hope that this will encourage participation in this database.

The database will be set up with 3 levels of access:

1. data entry only (one at each site)
2. review site data and composite data from other sites(one at each site)
3. review all sites and aggregate (for analysis and publication) Sites will only be able to edit and review their own patient data. They will be able to view aggregate data from other sites from which all identifiers have been removed.

Data will not be used to manage patient care in any way. The data will be used only to evaluate outcomes of patients who had a liver tumour at the time of their liver transplant.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma (HCC)	NCT01198704	Hepatocellular ... Liver Cirrhosis Evidence of Liv...	search of facto...	18 Years - 70 Years	Assistance Publique - Hôpitaux de Paris
Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma (HCC)	NCT01198704	Hepatocellular ... Liver Cirrhosis Evidence of Liv...	search of facto...	18 Years - 70 Years	Assistance Publique - Hôpitaux de Paris
Combination of Cryosurgery and NK Immunotherapy for Tumors in Transplanted Liver	NCT02849015	Liver Tumor Evidence of Liv...	Cryosurgery NK immunotherap...	30 Years - 60 Years	Fuda Cancer Hospital, Guangzhou
Safety Study of Liver Natural Killer Cell Therapy for Hepatoma Liver Transplantation	NCT01147380	Liver Cirrhosis Hepatocellular ... Evidence of Liv...	Liver NK cell i...	18 Years -	University of Miami
Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma (HCC)	NCT01198704	Hepatocellular ... Liver Cirrhosis Evidence of Liv...	search of facto...	18 Years - 70 Years	Assistance Publique - Hôpitaux de Paris
Safety Study of Liver Natural Killer Cell Therapy for Hepatoma Liver Transplantation	NCT01147380	Liver Cirrhosis Hepatocellular ... Evidence of Liv...	Liver NK cell i...	18 Years -	University of Miami
Study of Factors Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma (HCC)	NCT01198704	Hepatocellular ... Liver Cirrhosis Evidence of Liv...	search of facto...	18 Years - 70 Years	Assistance Publique - Hôpitaux de Paris
Prospective Liver Tumor (ProLiT) Database	NCT01607788	Hepatocellular ... Evidence of Liv...		18 Years -	University of Geneva, Switzerland

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