Assay of molecular markers in stool represents a promising noninvasive approach to screen colorectal cancer. Given that neoplasms exfoliate abundantly into the lumen and that DNA recovered from stool can be assayed with sensitive techniques, there is a strong biologic rationale to pursue this emerging technology. A challenge with DNA-based testing relates to the selection of markers. Because of the molecular heterogeneity of cancer, no single marker has yielded perfect sensitivity. Several combinations of markers in early stool assays have produced high detection rates of both colorectal cancer and advanced adenomas in selected patient groups, but observations from large representative populations are lacking at present. Potential expanded applications of stool DNA testing include detection of supracolonic aerodigestive cancers and of dysplasia in inflammatory bowel disease. Further marker discovery and technologic refinements should translate into improved test performance and fuel a continued evolution with this screening approach.

Despite dramatic fluctuations in calorie intake, animals maintain a very stable body weight. The reason is that energy intake and expenditure are precisely matched. Long-term regulation of energy balance is dependent on the coordination and interpretation of signals such as those given by insulin and leptin indicating sufficient long-term energy stores as well as short-term, meal-related signals such as those given by cholecystokinin (CCK). Within the last 30 years, our knowledge of short-term signals has increased dramatically. Throughout the cephalo-caudal axis of the gastrointestinal system, discrete enteroendocrine cells respond to both mechanical and chemical stimulation. Meal-associated hormone release is dependent on the concentration and composition of the nutrients ingested. Released signals are transmitted neurally through vagal afferents or humorally as circulating ligands for specific receptor populations in the periphery and central nervous system. These signals are interpreted by the CNS and manifested as a behavioral modification of feeding. This review will present past and recent literature in support of gut hormones and their roles as mediators of satiety. Evidence from pharmacologic and physiologic studies involving both humans and rodents will be presented, along with a short section outlining the knowledge gained through the use of murine knockout models. Last, the contribution of satiety hormones as likely mediators of the effectiveness seen following obesity surgery will be reviewed. Although traditionally thought of as short-term, meal-related signals, enhanced, chronic hormone secretion and signaling resulting from gut reconstruction as seen with gastric bypass surgery most likely contributes to the superior efficacy of surgery as a treatment for obesity.

In the search for novel therapeutic approaches to treat patients with colorectal carcinoma, anticancer vaccination holds promise. A large body of preclinical and clinical evidence has demonstrated that the immune system can be polarized against malignant cells by means of several active specific immunotherapy strategies. Although no vaccination regimen can be currently recommended outside clinical trials, tumor response and immunologic findings observed in animal models and humans prompt researchers to explore further the antitumor potential of such biotherapy in an effort to reproduce in a larger set of patients the cascade of molecular events that characterizes the successful tumor immune rejection currently observed in a minority of vaccinated subjects. In this work, we summarize the principles and the main results of cancer vaccine strategies so far implemented for the treatment of patients with colorectal carcinoma. We also discuss the most recent preclinical tumor immunology insights that might change the way to design the next generation of cancer vaccines, hopefully improving the effectiveness of such a biotherapeutic approach.

This literature review and the recommendations herein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on May 16, 2004, and by the AGA Governing Board on September 23, 2004.

This document presents the official recommendations of the American Gastroenterological Association (AGA) on Diagnosis and Treatment of Gastroparesis. It was approved by the Clinical Practice Committee on May 16, 2004, and by the AGA Governing Board on September 23, 2004.

Fifteen years after the first demonstration of epigenetic tumor-suppressor gene inactivation associated with promoter methylation, the field has reached a level of understanding that threatens a re-writing of established biologic concepts. In gastrointestinal malignancies, epigenetic analysis has led to novel hypotheses regarding the etiology of age-associated cancer susceptibility and the interactions between environmental exposures and neoplasia. Methylation profiling has uncovered a distinct pathway to colorectal neoplasia that may arise from a hitherto underestimated precursor lesion, the proximal hyperplastic polyp-serrated adenoma pathway. Epigenetic information has shown promise in clarifying susceptibility to cancer and defining poor prognosis groups in gastrointestinal cancers. Finally, the field has engendered renewed interest in therapeutic targeting of epigenetic regulatory molecules, and several such drugs are currently in clinical trials. It is likely that epigenetic pathways will be integrated in the routine management of gastrointestinal malignancies over the next decade.

The evidence that proton pump inhibitor (PPI) therapy affects symptoms of nonulcer dyspepsia is conflicting. We conducted a systematic review to evaluate whether PPI therapy had any effect in nonulcer dyspepsia and constructed a health economic model to assess the cost-effectiveness of this approach.

Epidemiological studies have shown that obesity is a risk factor for hepatocellular carcinoma. Similar studies further indicate that diabetes is also a major risk factor. Both obesity and diabetes are frequently associated with nonalcoholic fatty liver disease, and case reports have shown progression of nonalcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma. Although no study has clearly tied all of these variables together, it is likely that the association of hepatocellular carcinoma with obesity represents the progression of underlying nonalcoholic fatty liver disease to cirrhosis. The mechanism most likely involves replicative senescence of steatotic mature hepatocytes and compensatory hyperplasia of progenitor (oval) cells as a reaction to chronic injury due to ongoing nonalcoholic steatohepatitis and resultant hepatic fibrosis. Growth factors associated with chronic inflammation, type 2 diabetes, and DNA mutations as a result of lipid peroxidation probably play significant roles in clonal expansion and hepatocellular carcinoma progression. It remains unclear whether cirrhosis is a prerequisite for the development of hepatocellular carcinoma or whether hepatocellular carcinoma can develop in fatty liver in the absence of cirrhosis. However, well-documented case reports suggest that most cases of hepatocellular carcinoma arise in the setting of nonalcoholic steatohepatitis with cirrhosis. Whether therapy aimed at nonalcoholic fatty liver disease reduces the risk of hepatocellular carcinoma remains to be shown. Prophylactic measures and the role of cancer surveillance have not been adequately investigated, but current evidence suggests a risk for hepatocellular carcinoma in nonalcoholic steatohepatitis-related cirrhosis that rivals that of hepatocellular carcinoma in hepatitis C virus-related cirrhosis, particularly in older male patients.

More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world.

Hereditary hemochromatosis (HH) is associated with an increased risk for hepatocellular carcinoma (HCC). The risk previously had been estimated to be as high as 200-fold increased. Recent studies suggest that the risk for HCC in HFE -associated HH may be much lower and occurs predominantly in patients with cirrhosis at the time of diagnosis. The risk for HCC also is increased among patients with African iron overload and possibly in other iron-loading disorders such as homozygous beta thalassemia. The greatly increased iron stores in the liver observed in these disorders can stimulate carcinogenesis via both direct and indirect pathways. The prevalence of HCC also appears to be higher among patients with end-stage liver disease undergoing liver transplantation. It is not clear whether mildly to moderately increased hepatic iron stores or HFE mutations are associated independently with an increased risk for HCC among patients with other types of liver disease. In this article, the incidence and prevalence of HCC in patients with HH and other liver diseases associated with iron overload are discussed as well as the possible mechanisms for the increased risk for hepatic carcinogenesis in these disorders.

Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important risk factors for the development of hepatocellular carcinoma (HCC) in humans. HBV is the primary cause of HCC in high-risk areas including China and Africa, whereas in developed countries such as the United States, HCV plays a more prominent role and is at least partially responsible for the increase in HCC incidence in this country. Humans are exposed to hepatocarcinogenic aflatoxins through ingestion of moldy foods, a consequence of poor storage of susceptible grains. Highly exposed populations are primarily in sub-Sahara Africa and Asia, where dietary aflatoxins significantly enhance the carcinogenic effects of viral hepatitis. Heavy, long-term alcohol use is a risk factor for HCC, whereas moderate use (1-3 drinks/day) is not. Constituents of cigarette smoke are hepatic carcinogens in animals, and there is mounting evidence that the liver is an organ susceptible to tobacco carcinogenicity. Diabetic patients are at risk for HCC probably as a result of the hepatic injury, fibrosis, and eventual cirrhosis resulting from fatty liver disease. Given the current epidemic of obesity and diabetes in the United States, this risk factor will be increasingly important. Increased risk for HCC is evident in young noncirrhotic users of oral contraceptives in the United States and Europe. In summary, risk factors for HCC are identifiable in most patients and primarily are associated with chronic hepatic injury.

Epidemiologic, clinical, and virologic data have shown a close association between chronic infection with hepatitis C virus (HCV) and the development of hepatocellular carcinoma (HCC). In many countries of the developed world, HCV infection accounts for more than half of the cases of HCC. HCC usually arises after 2-4 decades of infection, typically in the context of an underlying cirrhosis. Treatment of hepatitis C with interferon-alfa can lead to sustained clearance of HCV, and small prospective studies as well as larger retrospective analyses suggest that interferon therapy leads to a decrease in the incidence of HCC. Without a reliable tissue culture system or a small animal model of HCV infection, analysis of the mechanisms by which HCV leads to cancer has been difficult. Nevertheless, both in vitro expression systems and in vivo transgenic mice studies suggest that HCV has an inherent carcinogenic potential. Understanding the pathogenesis of HCV-associated HCC is important in developing effective means of prevention and treatment of this highly malignant form of cancer.

Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of hepatocellular carcinoma (HCC). The pathogenesis of cancer in HBV infection has been extensively analyzed, and multiple factors appear to play a role. A major factor is chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation. Also important is the role of integration of HBV DNA into host cellular DNA, which, in some situations, acts to disrupt or promote expression of cellular genes that are important in cell growth and differentiation. In addition, expression of HBV proteins may have a direct effect on cellular functions, and some of these gene products can favor malignant transformation. Several HBV genes have been found in infected tissues more frequently than others, including truncated pre-S2/S, hepatitis B X gene, and a novel spliced transcript of HBV, referred to as the hepatitis B spliced protein. The proteins expressed from these integrated genes have been shown to have intracellular activities that may account for their association with HCC, including effects on cellular growth and apoptosis. Finally, some patients with HCC have no detectable hepatitis B surface antigen in serum but do have low levels of HBV DNA in serum and integrated molecules of HBV DNA in tissue. Occult HBV infection may account for a proportion of cases of HCC that occur in patients without serologic markers for hepatitis B and C and may be a cofactor in HCC in patients with chronic hepatitis C who have coexistent occult HBV infection.

The heterogeneous nature of human hepatocellular carcinoma (HCC) has hampered both treatment and prognostic predictions. Gene expression profiles of human HCC were analyzed to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. By applying global gene expression analyses, including unsupervised and supervised methods, 2 distinctive subclasses of HCC that were highly homogeneous for both the underlying biology and the clinical outcome were discovered. Tumors from the low survival subclass had strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and sumoylation, suggesting an etiologic involvement of these processes in accelerating the progression of HCC. Genes most strongly associated with survival were identified by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provided new molecular insights into the pathogenesis of HCC. Future studies will evaluate potential diagnostic markers and therapeutic targets identified during the global gene expression studies. Furthermore, cross-species similarity of gene expression patterns will also allow prioritization of a long list of genes obtained from human gene expression profiling studies and focus on genes whose expression is altered during tumorigenesis in both species.

Estimates from the year 2000 indicate that liver cancer remains the fifth most common malignancy in men and the eighth in women worldwide. The number of new cases is estimated to be 564,000 per year, including 398,000 in men and 166,000 in women. In high-risk countries, liver cancer can arise before the age of 20 years, whereas, in countries at low risk, liver cancer is rare before the age of 50 years. Rates of liver cancer in men are typically 2 to 4 times higher than in women. The incidence of primary liver cancer is increasing in several developed countries, including the United States, and the increase will likely continue for some decades. The trend is a result of a cohort effect related to infection with hepatitis B and C viruses, the incidence of which peaked in the 1950s to 1980s. In selected areas of some developing countries, the incidence of primary liver cancer has decreased, possibly as a result of the introduction of hepatitis B virus vaccine. The geographic variability in incidence of primary liver cancer is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.

Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising in some developed countries, whereas mortality from non-HCC complications of cirrhosis is decreasing or is stable. Cohort studies indicate that HCC is currently the major cause of liver-related death in patients with compensated cirrhosis. Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively), followed by hereditary hemochromatosis (5-year cumulative incidence, 21%). In hepatitis B virus (HBV)-related cirrhosis, the 5-year cumulative HCC risk is 15% in high endemic areas and 10% in the West. In the absence of HCV and HBV infection, the HCC incidence is lower in alcoholic cirrhotics (5-year cumulative risk, 8%) and subjects with advanced biliary cirrhosis (5-year cumulative risk, 4%). There are limited data on HCC risk in cirrhosis of other causes. Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC, independent of etiology of cirrhosis. In viral-related cirrhosis, HBV/HCV and HBV/HDV coinfections increase the HCC risk (2- to 6-fold relative to each infection alone) as does alcohol abuse (2- to 4-fold relative to alcohol abstinence). Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate other viral factors (eg, HBV genotype/mutant, occult HBV, HIV coinfection) and preventable or treatable comorbidities (eg, obesity, diabetes) in the HCC risk in cirrhosis.