Hepatocellular carcinoma is one of the most common cancers worldwide. Infection with hepatitis B virus and exposure to aflatoxins in the diet act synergistically to amplify risk. From a public health perspective, hepatitis virus vaccination programs and efforts to both reduce aflatoxin exposures and to attenuate the toxicological consequences of unavoidable exposures should have major impacts on the global incidence of this disease. Experimentally, aflatoxin-induced hepatocarcinogenesis can be inhibited by over a score of different chemopreventive agents with multiple mechanisms of action. One agent, oltipraz, is a potent inducer of phase 2 enzymes involved in the detoxication of carcinogens including aflatoxin. A second agent, chlorophyllin, impedes the bioavailability of carcinogens by forming molecular complexes and enhances their elimination in the fecal stream. This review highlights the findings of recent randomized clinical trials with oltipraz and chlorophyllin conducted in individuals exposed to dietary aflatoxins and at high risk for development of liver cancer. Both chemopreventive agents modulated levels of aflatoxin biomarkers in the study participants in manners consonant with protection. Although pharmacological approaches establish proof of principle and help identify key molecular targets for interventions, food-based approaches that also use these molecular targets may be the most practical for widespread application in high-risk populations.

The most effective means of preventing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is to prevent HBV infection via global vaccination of infants. Universal vaccination of newborns has been shown to significantly reduce the incidence of HCC among Taiwanese children. Among HBV carriers, the incidence of HCC was significantly higher in those who were hepatitis B e antigen positive, suggesting that antiviral therapy that results in viral clearance or sustained suppression of HBV replication should reduce the incidence of HCC. Review of data from >1000 chronic hepatitis B patients who received interferon treatment found that interferon has no or minimal overall effect on preventing HCC, but a beneficial effect may be attained in responders. The negative results are in part related to the small number of patients, short duration of follow-up, and low response rate to interferon therapy. Only 1 prospective randomized controlled trial of antiviral therapy with incidence of HCC as an endpoint has been reported. In this trial, 651 Asian patients with compensated HBV-related cirrhosis were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, HCC was diagnosed in 3.9% lamivudine-treated patients and in 7.4% placebo controls ( P = 0.047). Further studies using antiviral agents with lower risk of drug-resistance are needed to confirm these results. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made.

The incidence of hepatocellular carcinoma (HCC) is increasing in North America, Europe, and Japan, caused largely by the high rates of chronic hepatitis C virus (HCV) infection. In such individuals, the risk factors for developing HCC are advancing age, male gender, worsening hepatic fibrosis (particularly cirrhosis), and greater degrees of hepatic inflammation. Additional, potentially modifiable risk factors include coinfection with hepatitis B, excessive alcohol use, iron overload, and diabetes/obesity. Thus, approaches to preventing HCC should focus on eradicating HCV infection, responsible for the inflammation and fibrosis, and also on treating or reducing the modifiable risks, such as through hepatitis B vaccination, decreasing alcohol use, phlebotomy for iron overload, and weight control and diabetes prevention. These approaches have yet to be proven effective. Meta-analyses of standard interferon monotherapy trials in patients with HCV-related cirrhosis suggest that interferon has a small but significant effect on reducing HCC risk, particularly in those who achieve a sustained response. Other studies indicate that the reduction in HCC is greatest if a response is achieved before cirrhosis develops. Secondary prevention when HCC has been ablated or resected may be partially effected with interferon treatment or oral polyprenoic acid. No long-term studies of the effect of the currently recommended regimen of peginterferon and ribavirin have been reported, and no current trials include untreated control groups. Studies of maintenance peginterferon therapy in virological nonresponders are under way in the hope of proving that this approach is effective in decreasing the risk of HCC.

The Eastern woodchuck ( Marmota monax ) harbors a DNA virus (Woodchuck hepatitis virus [WHV]) that is similar in structure and replicative life cycle to the human hepatitis B virus (HBV). Like HBV, WHV infects the liver and can cause acute and chronic hepatitis. Furthermore, chronic WHV infection in woodchucks usually leads to development of hepatocellular carcinoma (HCC) within the first 2-4 years of life. The woodchuck model has been important in the preclinical evaluation of safety and efficacy of the antiviral drugs now in use for treatment of HBV infection and continues to serve as an important, predictive model for innovative forms of therapy of hepatitis B using antiviral nucleosides and immune response modifiers alone or in combination. Almost all woodchucks that become chronic WHV carriers after experimental neonatal inoculation develop HCC with a median HCC-free survival of 24 months and a median life expectancy of 30-32 months. The woodchuck model of viral-induced HCC has been used effectively for the development of new imaging agents for enhancement of detection of hepatic neoplasms by ultrasound and magnetic resonance imaging. The chemoprevention of HCC using long-term antiviral nucleoside therapy has been shown in the woodchuck, and "proof of principal" has been established for some of the innovative, molecular methods for treatment of HCC. The model is available for fundamental investigations of the viral and molecular mechanisms responsible for hepatocarcinogenesis and should have substantial value for future development of innovative methods for chemoprevention and gene therapy of human HCC.

The incidence of hepatocellular carcinoma (HCC) is increasing at an alarming rate in the United States, such that HCC has become an important indication for liver transplantation. The role of liver transplantation in patients with HCC has evolved over the past 2 decades, and transplantation has become one of the few curative treatment modalities for patients with HCC, especially in selected patients with favorable tumors. The advent of living donor liver transplantation for adult recipients provides another therapeutic venue, in particular for patients with HCC who are disadvantaged by current allocation algorithms for grafts from deceased donors. Living donor transplantation may limit the waiting time and, as a result, may decrease the progression of disease so that intuitively the recurrence rate should be lower than for recipients who wait for an organ from a deceased donor. There are limited data on the efficacy of living donor liver transplantation in the setting of HCC. Based on a limited cohort of patients undergoing transplantation for HCC at Northwestern University Medical Center, a higher recurrence rate, stage for stage, was found in recipients whose transplants were accelerated ("fast-tracked") by performing a living donor transplant, especially in the era in which patients with HCC were disadvantaged by the allocation algorithm. Clearly, the role of living donor liver transplantation in management of patients with HCC requires prospective direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either deceased or living donor liver transplantation.

Hepatocellular carcinoma (HCC) is increasing in frequency in the United States. The age-adjusted incidence rates have doubled over the past 2 decades. Similar increases have affected the mortality and hospitalization rates. Although there has been a small recent improvement in survival, it remains generally dismal (median, 8 months). It is estimated that 8500 to 11,500 new cases of HCC occur annually in the United States. There are striking differences in the incidence of HCC related to age, gender, race, and geographic region. Although it remains an affliction of the elderly (mean age, 65 years) population, there has been a shift toward relatively younger age cases. Men are affected 3 times more frequently than women, Asians are affected 2 times more than blacks, and Hispanics are affected 2 times more often than whites. However, the recent increase has disproportionately affected white (and Hispanic) men between ages 45 and 65 years. The temporal changes of risk factors among HCC cases in the United States remain unclear. However, available studies indicate that hepatitis C virus (HCV) infection acquired 2-4 decades ago explains at least half of the observed increase in HCC; HCV-related HCC is likely to continue to increase for the next decade. A variable but significant proportion of cases (15% to 50%) do not have evidence of the risk factors of viral hepatitis or heavy alcohol consumption. The insulin resistance syndrome, manifesting as obesity and diabetes, is emerging as a risk factor for HCC in the United States; however, its impact on the current trend in HCC remains unclear.

Because hepatocellular carcinoma (HCC) arises in cirrhotic livers and is often multifocal, transplantation seems to be a rational approach. Early results were poor, but current restrictive selection criteria can yield excellent results. Patients with 1 HCC nodule </=5 cm in diameter, or 2-3 nodules </=3cm, receive United Network Organ Sharing priority; nevertheless, dropout from the waiting list is common. Predictors of dropout include multiple tumors and tumors with a diameter >3 cm. Nonsurgical methods are commonly used to prevent tumor progression and thus prevent dropout. Expanding selection criteria results in more patients with HCC being cured at the expense of a higher incidence of recurrence. Molecular/biologic information is beginning to be incorporated into current staging systems in order to better predict HCC recurrence. In considering liver transplantation, the impact of the underlying liver disease is an important consideration; recurrent hepatitis C after transplant lowers patient survival independent of tumor recurrence.

Recent reports suggest that selected patients undergoing liver transplantation for stage 1-2 hepatocellular cancer (HCC) have an excellent long-term survival and a low incidence of recurrence. In the past, over 45% of HCC patients on the United Network for Organ Sharing/Organ Procurement Transplantation Network waiting list did not receive a donor organ for up to 2 years. This resulted in not only a high mortality rate but a high rate of being removed from the waiting list because of progression of HCC to advanced stages. The introduction of the Model for End-Stage Liver Disease (MELD) allocation policy has had a positive effect on HCC liver transplant candidates with the number of patients transplanted for HCC significantly increasing over the past several years. In addition, waiting time for HCC patients to receive a deceased donor has decreased significantly and the number of patients dropping out from the waiting list because of advanced stage disease has also decreased. An early assessment of the MELD allocation policy suggests that posttransplant survival for HCC patients comparing pre-MELD to post-MELD eras is similar. Using the data we have collected on the MELD allocation policy, we have already made modifications to the MELD allocation policy for HCC patients. It is hoped that through continued data collection and assessment, a consensus can be reached to further optimize the use of deceased donors in HCC recipients.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world, responsible for 500,000 deaths globally every year. Although HCC is a slow-growing tumor, it is often rapidly fatal because it is usually not discovered until the disease is advanced. HCC occurs primarily in individuals with cirrhosis, a condition that increases the risk of performing potentially curative surgical therapy. Over the last 2 decades, however, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative care. As such, the operative mortality rate for hepatectomy has decreased from the 10%-20% level seen in the 1980s to less than 5% today. The ultimate goal of treatment of HCC is to prolong the quality of life by eradicating the malignancy while preserving hepatic function. For treatment with a curative intent, the gold standard remains surgical resection, by either partial hepatectomy or total hepatectomy followed by liver transplantation. Resectability and choice of procedure depend on many factors, including baseline liver function, absence of extrahepatic metastases, size of residual liver, availability of resources including liver graft, and expertise of the surgical team. Patients without cirrhosis can tolerate extensive resections, and partial hepatectomy should be considered first. For Child class B and C patients with a small HCC, liver transplantation offers the best results, whereas partial liver resection is indicated in patients with well-compensated cirrhosis. Living donor liver transplantation should be considered using the same criteria as that used for cadaveric transplantation.

A number of minimally invasive methods have been tested for the thermal ablation of liver tumors as an alternative to surgical resection. The use of focused ultrasound transducers to ablate deep tumors offers the first completely noninvasive alternative to these techniques. By increasing the flexibility of this technology with modern phased-array transducer design and by combining it with magnetic resonance imaging for targeting and online guidance, a powerful tool results with the potential to offer treatment to a larger population of patients, to reduce trauma to the patient, and to reduce the cost of treatment. In this article, we review previous work with focused ultrasound in the liver and recent experimental results with magnetic resonance imaging guidance.

There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy for cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumor-associated self-antigens (for example, alpha-fetoprotein [AFP]). Gene array studies have added to the list of HCC-specific gene products that can be targeted. Alternatively, the immune response can be targeted against viral antigens in those patients infected with hepatitis B or C virus. Uncharacterized and mutated antigens can also be targeted with whole tumor cell or tumor lysate-based immunization strategies or with vectors coding for genes that make the tumor immunogenic, allowing the immune system to naturally evolve specificity against immunogenic target antigens. Strategies being investigated in animal models include increasing tumor immunogenicity by targeting cytokines or costimulatory molecules to tumor; immunization with tumor cells fused with antigen-presenting cells; adoptive transfer of viral antigen-specific T cells; and targeting AFP-expressing HCC cells by DNA, adenovirus, peptide, and dendritic cell (DC) strategies. Strategies that have been tested in human clinical trials include adoptive transfer of lymphocytes and autologous tumor-pulsed DC as well as 2 AFP-based strategies: AFP-derived peptides in Montanide and AFP peptides pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunologic responses and have impacted recurrence and survival in HCC subjects.

The goals of our research are to develop high-affinity and high-stability antibodies and fragments thereof for targeting tumor-specific antigens in an attempt to develop new therapeutic agents for human hepatocellular carcinoma (HCC). Tumor-associated antigens are excellent targets for drug and gene delivery, and offer the advantage of high cellular specificity. We have explored the use of a monoclonal antibody (Mab) AF-20 raised against a human hepatoma cell line (FOCUS) as a model system. This antibody binds to a 180-kDa homodimeric cell surface glycoprotein with high affinity. The antigen is uniformly expressed in HCC-derived cell lines and human tumors, including those with distant metastasis. There is minimal expression in nontumor tissues, and none detectable in normal liver. Because the AF-20 antigen antibody interactions on the cell surface is rapidly internalized at 37 degrees C, there is an opportunity to deliver cytotoxic payloads to tumor cells. In addition, high-affinity single-chain monoclonal antibody fragments (scFv) have been created using a novel yeast display system. Drug conjugates with AF-20 monoclonal antibodies have been prepared for gene targeting of HCC both in vitro and in vivo using preclinical animal model systems. These studies show that it is possible to generate high-affinity intact scFv antibody fragments that will allow specific tumor targeting of adenoviruses containing suicide genes, chemotherapeutic agents such as methotrexate, and cytotoxic peptides to produce antitumor effects. Therefore, specific antibody targeting of antitumor agents to HCC cells has the potential for therapeutic application in this devastating disease.

The hallmarks of hepatocellular carcinoma (HCC) are that it is identified clinically at an advanced stage and usually together with cirrhosis. Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients qualify for surgery, and there is a high rate of recurrence. Approaches to prevent recurrence have included chemoembolization before and neoadjuvant therapy after surgery, neither of which has proven to be beneficial. Liver transplantation has been successful in treating limited-stage HCC, affecting cure of both the tumor and underlying cirrhosis. However, only a minority of patients with HCC qualify for transplantation. Recently, chemoembolization has been shown to prolong survival in selected patients who do not qualify for transplantation or resection. Other innovative, relatively noninvasive local ablative therapies have been introduced and have been shown to be effective in reducing tumor size but not in prolonging survival. Standard chemotherapy is poorly tolerated in patients who do not qualify for resection. Both doxorubicin and cisplatin are frequently used, but overall response rates are low, and neither seems to prolong survival. Prospective, randomized controlled trials using current therapies are needed to better define optimal management of this important tumor. Most needed, however, are new therapeutic agents that are effective against HCC, are noncytotoxic, and are tolerated by the typical patient with underlying cirrhosis. Newly emerging agents with promise include 90 Y microspheres, antiangiogenesis agents, inhibitors of growth factors and their receptors, and K vitamins.

External beam radiotherapy has historically played a minor role in the primary treatment of hepatocellular carcinoma. Although there is evidence for tumor response to external beam radiotherapy and despite the fact that a radiation dose-response relationship has been established, the limited radiation tolerance of the adjacent normal liver has prohibited wider use of radiation therapy in this disease. Recent technological and conceptual developments in the field of radiation therapy-such as intensity-modulated radiation therapy, image-guided radiation therapy, and stereotactic body radiation therapy-have the potential to improve radiation treatments by conforming the delivered radiation dose distribution tightly to the tumor or target volume outline while sparing normal liver tissue from high-dose radiation. Image guidance allows for a reduction of added (normal tissue) safety margins designed to account for interfraction patient and target setup variability, and stereotactic targeting will further reduce residual target setup uncertainty. Combining improvements in tumor targeting with normal tissue sparing, radiation dose delivery will enable clinically effective and safe radiation delivery for liver tumors such as hepatocellular carcinoma. This article reviews the role of radiotherapy for hepatocellular carcinoma; presents modern radiation therapy modalities and concepts such as intensity-modulated, image-guided, and stereotactic body radiation therapy; and hypothesizes about their future effect on primary treatment alternatives.

Curative therapies for hepatocellular carcinoma (HCC), such as resection, liver transplantation, and percutaneous ablation, can be applied in selected patients with early tumors; this includes approximately 30%-40% of all cases. More advanced stages require local or systemic therapies. Data on the efficacy of these treatments are derived from small randomized controlled trials (RCT) and meta-analysis. Chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has produced modest survival advantages in 2 RCTs and a meta-analysis, and is currently the mainstay of treatment for these stages. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion, who constitute less than 15% of the HCC population. In these cases, the benefits derived by achieving objective responses (30%-50% of cases) are not offset by the deterioration of the liver function. Treatment-related mortality is less than 4%. No survival advantages have yet been shown with embolization or intra-arterial chemotherapy alone. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal retreatment schedule. The analysis of efficacy in these trials should be adjusted for prognostic factors, such as the presence of symptoms, Child-Pugh class, and segmental vascular invasion.

During the past 20 years, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. The numbers of deaths and death rate from HCC showed a sharp increase beginning in 1975. Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes, HCV-related HCC has accounted for most of the recent increase and now represents 75% of all HCC in Japan. Geographically, HCC is more frequent in western than eastern Japan, and the death rate of HCC in each prefecture correlates with prevalence of anti-HCV. Among patients with HCV-related HCC, a history of blood transfusion was a relatively important source of infection in the 1990s, whereas community-acquired infections increased after 2000. There was a negative correlation between the duration from onset of infection to development of HCC and the age at onset. Interferon therapy for chronic hepatitis C has reduced the risk for HCC, indicating that early detection of HCV carriers and better treatment will contribute to improved outcomes. Nationwide screening for HCV and HBV began in 2002 in Japan, and reduction of HCC is anticipated. Further research should focus on mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and treatment approaches. Better understanding of HCC unrelated to HCV and HBV and possibly because of steatohepatitis and diabetes should also be a major concern in future studies.

Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy, usually develops in patients with cirrhosis, growing sequentially from low-grade dysplastic nodules to frank malignant HCC. Its recognition is critical because curative treatment and prognosis require early diagnosis. Survival in patients with HCC relates directly to the number, size, and extent of lesions at diagnosis. Imaging of HCC is complicated because the tumor has a varied imaging appearance and frequently coexists with other cirrhotic nodules. Magnetic resonance imaging (MRI), the best available diagnostic technique, offers good contrast resolution and diagnostic sensitivity ranging from 33% to 77%. The main difficulty is not in diagnosing large tumors, but rather small tumors (<2 cm), because of considerable overlap on imaging between benign (regenerative), borderline (dysplastic), and malignant nodules. Increasing degrees of histological malignancy are associated with increasing arterialization and loss of portal blood supply; therefore, recognition of HCC requires dynamic imaging with gadolinium-enhanced T1-weighted sequence. Typically, HCC is a focal lesion with high signal intensity on T2-weighted images, variable signal intensity on T1-weighted images, intense arterial phase enhancement after gadolinium injection, and isointensity or hypointensity at the portal venous phase. The sensitivity of MRI for detecting small lesions is low, and improvement is still needed. Newer contrast agents, higher field strength (3 Tesla) imaging, and perfusion and diffusion MRI techniques possibly will provide greater sensitivity and specificity for detecting small HCCs in the future.

The ability of x-ray computed tomography (CT) to detect and characterize liver lesions has been one of the most studied issues in radiology during the past 20 years. Technological advances, combined with increased knowledge about the pathophysiological characteristics of these tumors, have dramatically increased the ability to detect and characterize large hepatocellular carcinomas (HCCs). Nonetheless, detection and characterization of early and small HCC lesions remains a difficult task. We review the imaging appearances of HCC on CT and discuss the sensitivity and specificity of computed tomographic imaging in screening patients with cirrhosis for HCC.

The diagnosis of hepatocellular carcinoma (HCC) includes detection of the index lesion, staging of the lesion within the liver, and assessment for extrahepatic metastasis. HCC is a highly vascular neoplasm usually arising in a cirrhotic liver. Based on this concept, consensus criteria have been developed for the radiographic diagnosis of HCC. These include: (1) identification of a mass >2 cm in diameter in a cirrhotic liver in 2 imaging modalities, and (2) contrast enhancement on computed tomography, magnetic resonance, or angiography. A mass lesion within a cirrhotic liver in the presence of a serum alpha-fetoprotein level >400 ng/mL also is diagnostic. For lesions <2 cm in diameter, histological confirmation is required. Serum markers for the diagnosis of early HCC (<2 cm in diameter) have not been established. Staging HCC for metastases is insensitive and is based on conventional criteria (eg, pulmonary nodules, skeletal metastases, and lymphadenopathy). Additional diagnostic techniques based on cytological advances, genomics, and proteomics are needed for the diagnosis and staging of this highly malignant neoplasm.

Refinements of serological markers and screening of patients at high risk for developing hepatocellular carcinoma (HCC) may lead to better HCC detection, earlier intervention, and successful treatment, improving long-term outcomes. Proteomics promises the discovery of biomarkers for early HCC detection and diagnosis. Proteomic-based profiling uniquely allows delineation of global changes in expression patterns resulting from transcriptional and posttranscriptional control, posttranslational modifications, and shifts in proteins between cellular compartments. Approaches to that effect include direct serum protein profiling and comparative analysis of protein expression in normal, precancerous, and early-stage tumor tissues. Identification of panels of tumor antigens that elicit a humoral response also may contribute to the discovery of new markers for HCC screening and diagnosis. Today, 2-dimensional polyacrylamide gel electrophoresis, multidimensional liquid chromatography, mass spectrometry, and protein microarrays are among the proteomic tools available for biomarker and drug target discovery. We review these technologies and their application to the study of HCC. Our objective is to provide a framework for appreciating the promise, while at the same time understanding the challenges behind translating proteomics discovery into novel diagnostic tests.