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Background Gastrointestinal diseases account for considerable health care use and expenditures. We estimated the annual burden, costs, and research funding associated with gastrointestinal, liver, and pancreatic diseases in the United States. Methods We generated estimates using data from National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, Nationwide Emergency Department Sample, National Inpatient Sample, Kids’ Inpatient Database, Nationwide Readmissions Database, Surveillance, Epidemiology, and End Results program, National Vital Statistics System, Centers for Disease Control Wide-ranging Online Data for Epidemiologic Research, MarketScan Commercial Claims and Encounters data, MarketScan Medicare Supplemental data, United Network for Organ Sharing registry, Medical Expenditure Panel Survey, and National Institutes of Health. Results Gastrointestinal health care expenditures totaled $119.6 billion dollars in 2018. Annually, there were more than 36.8 million ambulatory visits for gastrointestinal symptoms and 43.4 million ambulatory visits with a primary gastrointestinal diagnosis. Hospitalizations for a principal gastrointestinal diagnosis accounted for more than 3.8 million admissions with 403,699 readmissions. A total of 22.2 million gastrointestinal endoscopies were performed and 284,844 new gastrointestinal cancers diagnosed. Gastrointestinal diseases and cancers caused 255,407 deaths. The National Institutes of Health supported $3.1 billion dollars (7.5% of the NIH budget) for gastrointestinal research in 2020. Conclusion Gastrointestinal diseases are responsible for millions of health care encounters and hundreds of thousands of deaths which annually costs billions of dollars in the US. To reduce the high burden of gastrointestinal diseases, focused clinical and public health efforts, supported by additional research funding, are warranted.

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

Cancer from the gastrointestinal tract and its associated excretory organs will occur in more than 300,000 Americans in 2017, with colorectal cancer responsible for >40% of that burden; there will be more than 150,000 deaths from this group of cancers in the same time period. Disparities among subgroups related to the incidence and mortality of these cancers exist. The epidemiology and risk factors associated with each cancer bear out differences for racial groups in the United States. Esophageal adenocarcinoma is more frequent in non-Hispanic whites, whereas esophageal squamous cell carcinoma with risk factors of tobacco and alcohol is more frequent among blacks. Liver cancer has been most frequent among Asian/Pacific Islanders, chiefly due to hepatitis B vertical transmission, but other racial groups show increasing rates due to hepatitis C and emergence of cirrhosis from non-alcoholic fatty liver disease. Gastric cancer incidence remains highest among Asian/Pacific Islanders likely due to gene−environment interaction. In addition to esophageal squamous cell carcinoma, cancers of the small bowel, pancreas, and colorectum show the highest rates among blacks, where the explanations for the disparity are not as obvious and are likely multifactorial, including socioeconomic and health care access, treatment, and prevention (vaccination and screening) differences, dietary and composition of the gut microbiome, as well as biologic and genetic influences. Cognizance of these disparities in gastrointestinal cancer risk, as well as approaches that apply precision medicine methods to populations with the increased risk, may reduce the observed disparities for digestive cancers.

Background & Aims: Little is known about the prognosis of patients with malignant digestive endocrine tumors (MDETs), primarily because of their rarity. Methods: Survival from these tumors has been evaluated in a large, well-defined, national population. All patients diagnosed and registered in England and Wales during the 14-year period from 1986 to 1999 were followed up for vital status to the end of 2001. Relative survival was estimated and the impact of age, sex, period, histology, and anatomic site modeled. Results: Among 4104 cases of MDETs, 21.2% were small cell tumors. Relative survival for all MDETs combined was 45.9% at 5 years and 38.4% at 10 years. Five-year survival was 56.8% for well-differentiated tumors but only 5.2% for small cell tumors (P < .0001). Survival was highest for large bowel tumors and lowest for esophageal tumors. Among well-differentiated pancreatic tumors, 5-year relative survival was 49.2% for insulinomas, 39.9% for gastrinomas, 17.1% for glucagonomas, 26.3% for carcinoid tumors, and 29.3% for nonfunctioning tumors. There was no difference in survival between socioeconomic groups. Five-year survival did not improve between 1986 and 2001. Survival was higher for women and for younger patients. Gender, age at diagnosis, and anatomic site were independent prognostic factors. Conclusions: The prognosis of patients with MDETs in the general population is considerably worse than is often reported from small hospital case series. Prognosis varies with tumor differentiation, anatomic site, and histologic type. Early diagnosis is difficult; new therapeutic options appear to represent the best approach to improved prognosis.

Background & Aims: The Peutz–Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary. Methods: We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications. Results: For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old. Conclusions: Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers. GASTROENTEROLOGY 2000;119:1447-1453

Chronic inflammation, regardless of infectious agents, plays important roles in the development of various cancers, particularly in digestive organs, including Helicobacter pylori –associated gastric cancer, hepatitis C virus–positive hepatocellular carcinoma, and colitis-associated colon cancers. Cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations of various proto-oncogenes and tumor-suppressor genes. During chronic inflammation, infectious agents such as H pylori and hepatitis C virus as well as intrinsic mediators of inflammatory responses, including proinflammatory cytokines and reactive oxygen and nitrogen species, can induce genetic and epigenetic changes, including point mutations, deletions, duplications, recombinations, and methylation of various tumor-related genes through various mechanisms. Furthermore, inflammation also modulates the expressions of microRNAs that influence the production of several tumor-related messenger RNAs or proteins. These molecular events induced by chronic inflammation work in concert to alter important pathways involved in normal cellular function, and hence accelerate inflammation-associated cancer development. Among these, recent studies highlighted an important role of activation-induced cytidine deaminase, a nucleotide-editing enzyme essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, as a genomic modulator in inflammation-associated cancer development.

Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.

The development of endoscopic ultrasound (EUS) since its introduction in the early 1980s has added greatly to the quality of imaging of the gastrointestinal tract. EUS is probably the investigation of choice for local staging of several gastrointestinal tumors and evaluation of submucosal masses. In addition to well-established indications, newer applications of EUS are emerging. For example, EUS is proving useful in evaluation of other pathologies such as chronic pancreatitis and choledocholithiasis. However, the applications of EUS are no longer limited to the gastrointestinal system, and recent studies have suggested that it has a significant role to play in the staging of nongastrointestinal tumors, such as non–small cell lung cancer. EUS has progressed from being a purely imaging modality to one that can provide a tissue diagnosis by fine needle aspiration (FNA) and deliver therapy (interventional EUS). Indeed, EUS-guided FNA should now be regarded as a routine extension of EUS. The ability to obtain tissue under EUS has made its acceptance more widespread. The field of interventional EUS is one that is in its relative infancy, but many potential applications are under investigation, and there is real promise with several of these applications. It is likely, as with the development of interventional endoscopic techniques, that many of these procedures will be accepted as standard in the future. There continue to be technological advances in the instrumentation used, such as miniprobes and thinner video echoendoscopes. Because the impact of EUS on patient care is increasingly documented in terms of both improved diagnostic accuracy and reduction in costs, the clinical applications of this tool will be difficult to ignore. After years of being limited mainly to academic centers, EUS is finally being performed more widely, but there are training issues that remain to be addressed. This review describes the established and more tentative indications for EUS (Table 1) and covers the applications of EUS in FNA and as an interventional tool. Potential future applications are also discussed. Instrumentation

The optimal management of primary gastrointestinal lymphoma including the use of surgery remains unsettled. This prospective study aimed to determine the prognostic factors of primary gastrointestinal lymphoma and to evaluate a therapeutic strategy based on surgical tumor reduction, followed by chemotherapy adapted to the histological type of tumor and tumor removal or nonremoval.Ninety-one patients were included (mean age, 50.4 years) with mainly gastric (61%) or several digestive tract organ (18%) involved sites in clinical stages IE (43%), IIE (27%), and IV (30%). Three therapeutic groups were defined: group I, patients with low-grade lymphoma (n = 28); group II, patients with high-grade lymphoma who had complete tumor removal (n = 24); and group III, patients with high-grade lymphoma who had only partial or no tumor removal (n = 39). Each group underwent adapted chemotherapy.The respective overall 5-year survival rates for groups I, II, and III were 81% +/- 6%, 100%, and 56% +/- 8%, respectively (P0.0001). By Cox multivariate analysis, the prognostic factors of survival were age under 65 (P0.05), gastric localization (P0.05), stage IE (P0.001), and radical or incomplete surgery (P0.01).Combined radical surgery and chemotherapy according to histological grading is associated with prolonged remission in patients with primary digestive tract lymphoma. Moreover, compared with chemotherapy alone, incomplete resection of tumor is associated with increased survival of high-grade lymphomas.