Cell death is an essential event in normal life and development, as well as in the pathophysiological processes that lead to disease. Although the literature on cell death has grown enormously in size and complexity, a pattern has emerged that each of several distinct organelles (plasma membrane, mitochondrion, nucleus, endoplasmic reticulum, lysosome) gives rise to signals that induce cell death. Most often these signals converge on mitochondria to initiate a common pathway to either caspase-dependent apoptosis or ATP depletion-dependent necrosis. This brief overview emphasizes the multiple and often redundant pathways between different organelles that lead ultimately to a cell's demise.

Collagenous mucosal inflammatory diseases involve the columnar-lined gastric and intestinal mucosa and have become recognized increasingly as a significant cause of symptomatic morbidity, particularly in middle-aged and elderly women, especially with watery diarrhea. Still, mechanisms involved in the pathogenesis of this diarrhea remain poorly understood and require further elucidation. The prognosis and long-term outcome of these disorders has been documented only to a limited extent. Recent clinical and pathologic studies have indicated that collagenous mucosal inflammatory disease is a more extensive pathologic process that concomitantly may involve several sites in the gastric and intestinal mucosa. The dominant pathologic lesion is a distinct subepithelial hyaline-like deposit that has histochemical and ultrastructural features of collagen overlying a microscopically defined inflammatory process. An intimate relationship with other autoimmune connective tissue disorders is evident, particularly celiac disease. This is intriguing because these collagenous disorders have not been shown to be gluten dependent. Collagenous mucosal inflammatory disorders may represent a relatively unique but generalized inflammatory response to a multitude of causes, including celiac disease, along with a diverse group of pharmacologic agents. Some recent reports have documented treatment success but histopathologic reversal has been more difficult to substantiate owing to the focal, sometimes extensive nature, of this pathologic process.

Computed tomography colonography (CTC), particularly using noncathartic techniques, has the clear potential to increase compliance for colorectal cancer screening. Because the geometry for CTC is highly advantageous, it can be performed with lower radiation doses than almost any other CT examination. If CTC were to become a standard screening tool for the population age 50 years and older, the potential market in the United States would soon be over 100 million people. Therefore, it is pertinent to consider the radiation exposure and any potential radiation risk to the population from such a mass CTC screening program.

Helicobacter pylori "test and treat" has been recommended for the management of young dyspeptic patients without alarm symptoms, and trials have suggested that it is as effective as endoscopy. However, none of these trials have had sufficient sample size to confirm that "test and treat" costs less or to detect small differences in effect. A collaborative group has prospectively registered trials comparing prompt endoscopy with a "test and treat" approach, with the aim of performing an individual patient data meta-analysis of both effect and resource utilization data.

Gastrointestinal (GI) carcinoids are ill-understood, enigmatic malignancies, which, although slow growing compared with adenocarcinomas, can behave aggressively. Carcinoids are classified based on organ site and cell of origin and occur most frequently in the GI (67%) where they are most common in small intestine (25%), appendix (12%), and rectum (14%). Local manifestations--mass, bleeding, obstruction, or perforation--reflect invasion or tumor-induced fibrosis and often result in incidental detection at emergency surgery. Symptoms are protean (flushing, sweating, diarrhea, bronchospasm), usually misdiagnosed, and reflect secretion of diverse amines and peptides. Biochemical diagnosis is established by elevation of plasma chromogranin A (CgA), serotonin, or urinary 5-hydroxyindoleacetic acid (5-HIAA), while topographic localization is by Octreoscan, computerized axial tomography (CAT) scan, or endoscopy/ultrasound. Histological identification is confirmed by CgA and synaptophysin immunohistochemistry. Primary therapy is surgical excision to avert local manifestations and decrease hormone secretion. Hepatic metastases may be amenable to cytoreduction, radiofrequency ablation, embolization alone, or with cytotoxics. Hepatic transplantation may rarely be beneficial. Chemotherapy and radiotherapy have minimal efficacy and substantially decrease quality of life. Intravenously administered receptor-targeted radiolabeled somatostatin analogs are of use in disseminated disease. Local endoscopic excision for gastric (type I and II) and rectal carcinoids may be adequate. Somatostatin analogues provide the most effective symptomatic therapy, although interferon has some utility. Overall 5-year survival for carcinoids of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colonic carcinoids is 62%, and gastric type III/IV is 33%.

The genes associated with each of the inherited syndromes of colon cancer have now been identified, and genetic testing is available for diagnosis. These syndromes include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and, possibly, Cowden's syndrome. Clinical genetic testing approaches have been developed for each of these syndromes and are now a part of accepted clinical care. Disease-causing mutations can be found in the majority of families affected with one of the inherited syndromes, and, most importantly, once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near 100% accuracy. Cancer screening and management in syndrome families is then based on the results of genetic testing. For the physician to order and properly interpret genetic tests, a basic understanding of the types of mutations that lead to inherited disease and the methods for detecting them is vital. These issues will be presented. Additional clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing, both of which will also be reviewed. Often the most difficult aspect of genetic testing is deciding which patients and families should undergo the testing. Furthermore, this issue is quite specific for each of the syndromes. Thus, following presentation of general principles of selection for genetic testing, a detailed approach for identifying persons who should undergo testing for each of the individual syndromes will be given, together with relevant descriptions of the syndromes. Finally, the ongoing work to discover new and possibly more common but less penetrant colon cancer susceptibility genes that cause common familial colon cancer will be presented.

Only relatively recently has there been an increased clinical recognition and characterization of the heterogeneous group of rare gastroenteropancreatic neuroendocrine neoplasms. Most have endocrine function and exhibit varying degrees of malignancy. This review summarizes the derivation of these tumors and the advances in their diagnosis and treatment over the past decade and a half. They are varied in their biological behavior and clinical courses and, depending on their cell type, can produce different hormones causing distinct clinical endocrine syndromes (insulinoma [hypoglycemia], gastrinoma [Zollinger-Ellison syndrome (ZES)], vasoactive intestinal peptideoma [VIPoma], watery diarrhea, hypokalemia-achlorhydria [WDHA], glucagonoma [glucagonoma syndrome], and so forth). In addition to surgery for cure or palliation (by excision and a variety of other cytoreductive techniques), they each are treated with anti-hormonal agents or drugs targeted to each tumor's specific product or its effects. The majority have benefited from the gut hormone-inhibiting action of somatostatin analogs. Because of their usual slow rate of growth it is recommended that, even when they are advanced and incurable, unlike in patients with common and more malignant cancers, patients with neuroendocrine tumors often can be palliated and appear to survive longer when managed with an active approach using sequential multimodality treatment. Advances in these various therapies are reviewed and the beneficial emergence of global self-help patient support groups is noted.

In the last decade, continued efforts in pancreas cancer research have led to the development of new, more effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for the development of more effective treatment strategies. Recent clinical trials have provided reason for hope that novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for patients with this disease. This article will summarize the data that has led to the current standards of therapy for patients with resectable and advanced pancreatic cancer and review new treatment strategies for this disease.

Pancreatic duct carcinoma remains a common disease with a poor prognosis. More than 30,000 Americans will die of the disease in 2004, making it the fourth leading cause of cancer death. Despite significant advances in the treatment of many other human tumors, the 5-year survival rate for persons diagnosed with pancreatic cancer has not changed in decades and remains <5%. This is due both to the inherently aggressive biology of the disease and to its late diagnosis in most cases. Surgical resection of localized disease remains the only hope for cure of pancreatic cancer. Over the past 2 decades, significant advances in diagnostic imaging, staging, surgical technique, and perioperative care have led to marked improvement in the surgical management of pancreatic cancer patients. Operative mortality rates for pancreaticoduodenectomy are now <5% at major centers, and the average length of hospital stay has been reduced to <2 weeks. Improvements in patient outcome after pancreatic cancer surgery have made possible, for the first time, the design and conduct of large adjuvant therapy studies in pancreatic cancer. Such clinical trials are critical for improving outcomes for pancreatic cancer patients.

Although gastric cancer has been investigated for centuries, the association with Helicobacter pylori infection has been recognized for only the past few decades. Although the disease has been declining in most industrialized countries, it remains the second most common cause of cancer death worldwide and is, in theory, a largely preventable disease. We have gained many new insights and advances from studies of Helicobacter-infected mouse models. These models corroborate findings in human patients, in whom disease outcome is largely determined by the expression of host proinflammatory cytokines. Studies of the cellular origins of cancer in the Helicobacter-infected mouse model has led to the surprising insight that gastric cancer may originate from circulating bone marrow-derived stem cells (BMDC) and not from resident tissue stem cells as previously believed. It is likely that this new BMDC paradigm of epithelial cancer will prove useful in future investigations of gastrointestinal metaplasia and gastrointestinal cancers associated with chronic inflammation.

Despite advances in diagnosis and therapy, esophageal adenocarcinoma remains an aggressive and usually lethal tumor. This review focuses on the epidemiology of esophageal adenocarcinoma and its presumed precursor lesion, Barrett's esophagus; the pathogenesis of the cancer; advances in treatment of adenocarcinoma and Barrett's esophagus; and strategies for cancer prevention. Emphasis is placed on recent literature. Although the absolute number of cases of adenocarcinoma in the United States is still small, the incidence of this cancer has increased dramatically in the last 40 years, and adenocarcinoma is now the predominant form of esophageal cancer in this country. Recent evidence suggests that Barrett's esophagus is more prevalent in asymptomatic individuals than previously appreciated. The pathogenesis of Barrett's esophagus is poorly understood. Given that some subjects will have repeated bouts of severe erosive esophagitis and never develop Barrett's esophagus, host factors must play an important role. The utility of neoadjuvant radiation and chemotherapy in those with adenocarcinoma, although they are widely practiced, is not of clear benefit, and some authorities recommend against it. Ablative therapies, as well as endoscopic mucosal resection, hold promise for those with superficial cancer or high-grade dysplasia. Most series using these modalities feature relatively short follow-up, and longer-term data will be necessary to better describe the effects of these therapies. The value of chemoprevention in subjects with dysplastic Barrett's esophagus by use of cyclooxygenase 2 inhibitors, nonsteroidal anti-inflammatory drugs, or proton pump inhibitors is unknown. Similarly, although endoscopic screening is widely practiced, its value in patients with chronic gastroesophageal reflux disease symptoms is of unproven value, and recommending bodies are divided as to its practice.