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400 patients with primary HCC (Hepatocellular carcinoma)

800 patients with chronic liver disease (high risk non-cancer cases)

800 population-based controls, identified through a OMV database that will match cases by age, gender, race, and county of residency

Xin Wang, M.D.

Background:

* Liver cancer is the third most deadly and fifth most common cancer worldwide. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and it has grown more prevalent in the United States.
* More information is needed about the causes and effects of liver cancer, and further research into individuals who are at high risk for developing liver cancer is needed for early diagnosis and prevention.

Objectives:

* To identify genetic factors that may help to explain the aggressiveness of liver cancer.
* To determine if HCC biomarkers exist in blood, urine, and tissue samples.

Eligibility:

* Patients between the ages of 18 and 90 who have been diagnosed with HCC or have a high risk for developing HCC because of fatty liver disease (alcohol-related or non-alcohol-related) or chronic hepatitis B or C.
* Participants will reside in Baltimore City and the surrounding areas.

Design:

* Participants will complete a questionnaire and provide blood and urine samples for testing:
* The questionnaire will include questions about individual and family medical history, tobacco use, and exposure to known factors for liver cancer.
* Blood and urine samples will be collected from all participants after the questionnaire.
* Tumor tissue and healthy tissue will be collected from selected participants if they undergo surgery for their cancer or disease.
* No specific treatment will be offered as part of this protocol, but participants have the option to be treated under different protocols.

BACKGROUND:

Liver cancer is the third most deadly and fifth most common cancer worldwide. Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver with rising incidence in the United States. HCC patients have a dismal outcome and are an underserved cancer population. We are proposing a liver cancer case-control and case-case study to be conducted in Baltimore, Maryland.

OBJECTIVES:

Our research is aimed to identify genetic and genomic changes that might explain the aggressive nature of liver cancer. We will test the primary hypothesis that HCC biomarkers exist in blood products (or mouth wash), urine and/or tissues that can be used for early diagnosis and prevention. A unique study factor is the use of urine samples for biomarker identification. A secondary goal will be to examine whether certain genetic and genomic factors modify liver cancer susceptibility using candidate and genome wide association study approaches. Although other studies have investigated genetic susceptibility, large scale studies have not been conducted for liver cancer. Our study will also be valuable due to access to frozen tumor specimens from pre-therapy resection, whose collection is required for gene expression analysis. If certain genes are related to HCC risk and progression, this tissue resource will be used to further validate our findings with laboratory investigations. The proposed study is designed to be exploratory and hypothesis generating.

ELIGIBILITY:

The participants will reside in Baltimore City and surrounding areas. Cases will have pathologically confirmed liver cancer or risk factors for HCC development. Risk factors include chronic liver disease due to hepatitis B and/or C viral infection, nonalcoholic steatohepatitis or alcoholic cirrhosis. The study will be supported by an epidemiological infrastructure developed by our University of Maryland School of Medicine resource contractor for ongoing lung and prostate cancer case-control studies. The enrollment of controls will begin concurrently with case accrual, and will continue for 5 years. Population-based controls will be recruited using a triple eligibility criterion, such that controls eligible for the lung/prostate study will be asked to complete a supplemental questionnaire for the liver study.

DESIGN:

The study will include 400 primary HCC cases, 800 patients with chronic liver disease (high risk non-cancer cases) and a sample of 800 population-based controls. The HCC and high risk non-cancer cases will be recruited at two Baltimore hospitals, the Veterans Affairs Medical Center, and the University of Maryland School of Medicine over a period of 13-15 years. Controls will be identified through a Department of Motor Vehicle database and match cases by age, gender, race and county of residency. The study will involve administration of a questionnaire and collection of blood (or mouth wash) from all study subjects. Fresh-frozen tumor and tumor surrounding non-cancerous specimens will be obtained from approximately 20 percent of the cancer patients. The cases will receive one questionnaire.

Blood and tissue samples, mouth wash and urine.

A Study of Molecular and Genetic Factors for Liver Cancer in the Greater Baltimore Area

Identification of HCC biomarkers for early diagnosis and prevention.

National Cancer Institute (NCI)

Antineoplastic Agents

Ethiodized Oil

intra-arterial hepatic administration, one 2200 MBQ dose, duration of treatment 1 week

intra-arterial hepatic administration of Lipiocis will occur, 11 to 12 weeks after the initial curative treatment

131 I-lipiodol

Olivier Rosmorduc, MD

Fabrice Carrat, MD

The recurrence of hepatocellular carcinoma (HCC), two years after curative treatment is high, about 40% - 50%. Recently, it has been shown that intra-arterial radioactive lipiodol (Lipiocis®) could reduce the recurrence of cancer and increase the survival after resection of HCC developed on cirrhosis B. The aim of the present trial is to investigate the effect of Lipiocis® in preventing recurrence after curative treatment of HCC in patients with viral or alcoholic hepatitis related cirrhosis by surgical or percutaneous ablation.

The usual therapeutic approaches of early hepatocellular carcinoma (HCC) are partial hepatectomy or percutaneous ethanol injection. However, these therapeutic procedures do not suppress the cirrhotic liver tissue which represents a major risk factor for recurrence and/or occurrence of a second tumor in the liver. Recently, it has been shown that intra-arterial radioactive lipiodol (Lipiocis®) could reduce the recurrence of cancer and increase the survival after resection of HCC developed on cirrhosis B. The aim of the present randomized and multicenter trial is to investigate the effect of iodine-131-labelled lipiodol (131I-lipiodol = Lipiocis®) in preventing recurrence after curative treatment of HCC (hepatocellular carcinoma) in patients with viral or alcoholic hepatitis related cirrhosis by surgical or percutaneous ablation. The period of this study will be 3 years including 1 year for the enrollment and 2 years for the follow-up. Fifty patients will receive one 2200 MBq dose of Lipiocis and 50 patients will not be treated by Lipiocis (control group). The intra-arterial hepatic administration of Lipiocis will occur 11 to 12 weeks after the initial curative treatment.

The inclusion criteria are as follows : 1) men or women, aged between 18 and 75 years old, with cirrhosis or chronic hepatitis associated with C, B, delta infection or alcool intake or both and confirmed by liver biopsy and 2) one or two HCC nodules treated by surgical or percutaneous ablation (ethanol, acetic acid 50% or radiofrequency).

The efficacy of the initial curative treatment will be assessed by the following criteria: alpha-fetoprotein concentration below 25ng/ml, no progression in size of the tumour demonstrated by ultrasonography and no arterial hypervascularization on CT scan imaging.

The patients with the following criteria will be excluded: co-infection with HIV (Human Immunodeficiency Virus)associated with a CD count \<200/mm3 and a viral charge \>5000 HIV RNA copies/ml, documented iodine intolerance, respiratory disease, decompensated cirrhosis (Child-Pugh score over or equal 8), bilirubin concentration over 51µmol/l, portal or hepatic vein thrombosis, extra-hepatic metastasis, excessive alcohol intake (over 50g per day), blood platelet count below 50,000/mm3, neutrophil count below 1500/mm3, creatininemia over 120µmol/l, other severe concurrent disease, previous treatment for hepatocellular carcinoma and women who can be pregnant or breastfeeding.

The main endpoint will be to determine whether the Lipiocis® treatment reduces the percentage of recurrence from 50% to 20% at 24 months. The secondary end-points will be the overall survival, the survival without recurrence of the primary tumor, the survival without new tumor, the deterioration of hepatocellular function and the side effects of the Lipiocis® treatment.

Trial for Hepatocellular Carcinoma Adjuvant Treatment by Lipiocis

A Randomized and Multicenter Trial for Hepatocellular Carcinoma Adjuvant Treatment by Lipiocis

ANRS, Emerging Infectious Diseases

Hepatitis B

Disease Susceptibility

Blood-Borne Infections

Hepadnaviridae Infections

DNA Virus Infections

Herpes Simiae (B Virus)

Daniel W McVicar, Ph.D.

This study, conducted by the Beijing University First Hospital of China and the National Cancer (NCI), will try to identify genes associated with either susceptibility or resistance to chronic infection by the hepatitis B virus (HBV). Some people recover from HBV infection; others become chronically infected and may go on to develop severe liver disease such as cirrhosis or liver cancer. About 350 million people worldwide have chronic HBV infection. Of 120 million infected Chinese, 90 percent of children infected at less than 5 years of age and 10 percent of infected adults develop persistent infection.

HBV-infected and non-infected healthy persons of Han ethnicity born before 1963 may be eligible for this study. Offspring of infected candidates (born in any year) may also be enrolled. Infected adults must have at least one infected parent or sibling. Persons who resided in Fusui County of Guangxi Zhuang Autonomous Region or in the Qidong district of Jiangsu Province for at least 6 months before 1986 may not participate.

All participants (except offspring of the study subjects) will fill out a health questionnaire (providing information about eating, drinking, and smoking habits and a personal and family health history) and will donate no more than 20 milliliters of blood. The blood will be tested for antibodies, antigens, and other substances that may indicate infection with hepatitis viruses. Some of the blood will be sent to the NCI for DNA analysis to identify genetic factors that may influence clearance of the hepatitis virus after infection or progression to liver diseases associated with HBV infection. Infected patients who have had a liver biopsy in the past will be asked permission to examine tissue from the biopsy and to review laboratory results of any tests done for diagnostic and treatment purposes.

When the study is completed, specimens sent to the NCI will have identifiers linking the material to the donor removed. The anonymous samples may then be used for other genetic studies. Specimens remaining in China will continue to have identifiers linked to them and may be used for future studies designed to identify who is at greatest risk of developing serious liver diseases. Participants who do not want their blood used for future studies may request that the samples be destroyed.

Because children inherit one-half of their DNA from each parent, DNA samples from HBV infected study participants may provide additional information about the parent s DNA structure. Offspring who participate in this study will provide a DNA sample. The sample is obtained by swishing a mouthwash in the mouth for 30 seconds and then spitting the mouth wash into a cup. The DNA is then isolated from the mouth cells.

Persistent hepatitis B viral (HBV) infection is a significant public health problem because of the occurence of chronic liver disease, cirrhosis, and hepatocarcinoma (HCC) \[1-3\]. Roughly one-third of the world population has been infected with HBV and there are about 350 million (5-6%) persistent carriers. HBV causes 80% of all liver cancer and is the second most important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a persistent carrier following perinatal infection in infants born to e antigen positive carrier mothers and 30% risk in pre-school children. Only 5-10% of adults become persistent carriers following infection. Like HIV, HBV is transmitted by contaminated blood through transfusion or intravenous drug use and by high-risk sexual behavior.

The purpose of this investigation is to study how different outcomes of hepatitis B exposure and infection are affected by host genetic factors in the Chinese population, where more than 120 million individuals are infected with HBV. Of people persistently infected with HBV, 10-30% will develop liver cirrhosis (LC) and hepatocellular carcinoma (HCC). These highly variable outcomes in both clearance rates and disease outcomes in persistently infected individuals cannot be fully explained by differences in viral or environmental factors. Thus, differences in host genetic factors may affect hepatitis B natural history.

Blood will be collected from volunteers in China. Healthy donors unexposed to HBV or HCV, individuals who have cleared HBV, and asymptomatic carriers of HBV will be identified by the Peking University hospitals and blood bank. HBV infected individuals with chronic hepatitis, cirrhosis or HCC will be identified by the Peking University hospital hepatitis clinics. Targeted individuals will be asked to participate by letter or a telephone interview by trained hospital staff. A database of clinical and family information will be created from a questionnaire completed by hospital staff. A database of clinical and family information will be created from a questionnaire completed by hospital staff interviewers. Blood will be separated into plasma and peripheral blood mononuclear cells (PBMCs) and cryopreserved in China. Serum will be tested in China for hepatitis viral markers, HBV genotypes, and HBV viral load. Two vials of PBMC will be transferred to the LGD, NCI-USA, for mRNA expression assays and host genetic analysis. Lymphoblastoid cell lines will be established by the LGD-NCI as a source of renewable DNA. RNA will be extracted from PBMCs for determination of mRNA expression by the microarray method. Results of mRNA expression assays and literature searches will be used to identify candidate genes. DNA extracted from cell lines will be genotyped for single nucleotide polymorphisms (SNPs) in candidate genes and DNA markers, including HLA, cytokines, chomokines, and their receptors, and putative HBV cell entry targets by DNA genotyping methods. SNPs in candidate genes will be identified using public and private SNP databases and SNP discovery methods. SNPs will be genotyped study participants and analyzed to detect associations between polymorphisms and phenotypes obtained from clinical and laboratory testing. If a genetic marker associated with the development of a disease phenotype is found, there are potential applications in diagnostics and therapy. The identification of allelic polymorphisms in genes involved in the pathway from chronic viral infection to LC and ultimately HCC would provide insight into the carcinogenic process.

Genes Involved in Resistance or Susceptibility to Hepatitis B Virus

Human Genes Involved in Susceptibility or Resistance to Hepatitis B Virus

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Molecular and Genetic Factors for Liver Cancer in the Greater Baltimore Area	NCT00913757	Carcinoma, Hepa... Liver Cirrhosis... Hepatitis, Alco... Hepatitis, Chro... Hepatitis, Vira...		18 Years - 90 Years	National Institutes of Health Clinical Center (CC)
Trial for Hepatocellular Carcinoma Adjuvant Treatment by Lipiocis	NCT00116454	Carcinoma, Hepa... Hepatitis, Vira...	131 I-lipiodol	18 Years - 75 Years	ANRS, Emerging Infectious Diseases
Genes Involved in Resistance or Susceptibility to Hepatitis B Virus	NCT00342186	Hepatitis, Vira...		8 Years - 90 Years	National Institutes of Health Clinical Center (CC)
Trial for Hepatocellular Carcinoma Adjuvant Treatment by Lipiocis	NCT00116454	Carcinoma, Hepa... Hepatitis, Vira...	131 I-lipiodol	18 Years - 75 Years	ANRS, Emerging Infectious Diseases
Genes Involved in Resistance or Susceptibility to Hepatitis B Virus	NCT00342186	Hepatitis, Vira...		8 Years - 90 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for hepatitis, viral, human