Impact of Surveillance on Barrett's-Associated MortalityBarrett’s esophagus is considered to be the major risk factor for the development of esophageal/gastroesophageal junction adenocarcinoma (EA). The incidence of this cancer has increased significantly over the last 3 decades. Although endoscopic surveillance of patients with Barrett’s esophagus is recommended by specialty society guidelines, surveillance of all patients with Barrett’s esophagus has not been shown to be cost effective and there are no randomized, controlled trials to support these recommendations. Given current clinical practices, such trials are unlikely to be performed. In this issue of Gastroenterology (accompanied by an editorial), Corley et al have instead conducted a case-control study involving members of a large, integrated health care delivery system, Kaiser Permanente, Northern California, to evaluate whether endoscopic surveillance of Barrett’s esophagus is associated with a lower risk of death from EA. They identified 8272 patients with a diagnosis of Barrett’s esophagus over a 15-year period, 351 of whom were simultaneously or subsequently diagnosed with EA. Of these 351 patients, 70 had their EA diagnosed ≥6 months after the diagnosis of Barrett’s esophagus and, therefore, were eligible for surveillance. Death from EA occurred in 38 of these patients and surveillance history in these patients was contrasted with 101 control patients with Barrett’s esophagus, matched for age, gender, and duration of follow-up. Death from EA was more likely to occur in patients with low- or high-grade dysplasia on either their first examination or any examination prior to the three-year surveillance period (47.4% of cases vs. 13.9% of controls) and prior dysplasia was associated with cancer mortality (OR=4.68, 95% CI 1.75-12.51). However, surveillance within 3 years was not associated with a decreased risk of death from EA, even controlling for factors such as dysplasia status and Barrett’s esophagus length >3 cm or excluding patients with high-grade dysplasia before the 3-year surveillance period (Table 1). Excluding deaths related to treatment and patients who did not undergo potentially curative resection did not significantly affect the effectiveness of surveillance. These results show that despite the detection of early stage disease in the majority of patients with Barrett’s esophagus undergoing endoscopic surveillance, an overall reduced risk of death from EA was not associated with the use of endoscopic surveillance.Table 1Associations Between Surveillance Endoscopy and Fatal AdenocarcinomasCasesControlsOR (95% CI)aORs and 95% CIs from conditional logistic regression. Controls were matched to cases by age at Barrett’s esophagus diagnosis, year of Barrett’s esophagus diagnosis, sex, race, and medical center of Barrett’s esophagus diagnosis.In surveillance n (%)In surveillance n (%)Unadjusted1 Surveillance examination within 3 years21 (55.3)61 (60.4)0.82 (0.35–2.00)Controlling factors Dysplasia status (main model)bCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination).21 (55.3)61 (60.4)0.99 (0.36–2.75) Barrett's esophagus lengthcMore than 3 cm vs less than 3 cm vs not defined.21 (55.3)61 (60.4)0.97 (0.38–2.50) Dysplasia status and Barrett's esophagus lengthbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., cMore than 3 cm vs less than 3 cm vs not defined.21 (55.3)61 (60.4)1.14 (0.39–3.32) Excluding cases with 7–12 months between Barrett's esophagus and cancer diagnoses, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.19 (52.8)57 (60.0)0.95 (0.32–2.70) Excluding cases with high-grade dysplasia before 3-year surveillance interval, adjusted for other dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.16 (55.2)38 (52.8)1.00 (0.34–2.94) Excluding cases with gastroesophageal junction adenocarcinomas, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.19 (61.3)57 (67.1)0.88 (0.29–2.67) Excluding cases unable to be treated, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.18 (56.3)54 (64.3)0.80 (0.27–2.34) Excluding cases with treatment-related mortality or unable to be treated, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.14 (51.9)47 (65.3)0.46 (0.13–1.64)Total38 (100)101 (100)a ORs and 95% CIs from conditional logistic regression. Controls were matched to cases by age at Barrett’s esophagus diagnosis, year of Barrett’s esophagus diagnosis, sex, race, and medical center of Barrett’s esophagus diagnosis.b Categories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination).c More than 3 cm vs less than 3 cm vs not defined.d Excluded cases and their matched controls. Open table in a new tab See page 312; editorial on page 273.Liver-Related Mortality in the United StatesAccurate data on the burden of certain diseases are necessary to inform health care policy and develop guidelines, prioritize research and clinical interventions, and appropriately allocate resources. Although chronic liver disease and cirrhosis are recognized as important causes of morbidity and mortality in the United States, particularly among persons aged 45–64 years, there are concerns that the burden of chronic liver disease may be underestimated using current mortality reports. In this issue of Gastroenterology, Asrani et al using 2 population-based databases, one from Olmsted County, Minnesota and the other national mortality data from the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC), to better estimate the burden of chronic liver disease in the United States. Using the CDC definition, 71 liver-related deaths occurred among Olmsted County residents between 1999 and 2008. Using an updated definition of liver-related deaths that included diagnoses specific to liver disease, such as hepatorenal syndrome, as well as viral hepatitis and malignant neoplasms of the liver and intrahepatic bile ducts, 190 additional liver-related deaths were identified. Similarly, using the CDC definition, there were 29,951 liver-related deaths in the United States in 2008, but 66,007 deaths if the updated definition was used. The magnitude of liver-related deaths underestimated by the CDC definition varied by race; for example, only 34.3% of deaths in African Americans and only 48% of deaths in persons of Hispanic ethnicity were captured by the CDC definition. In contrast with the 38% decline in liver-related deaths over three eras from 1979 to 2008 observed when the CDC definition is used, liver-related mortality was found to increase from 23.9 to 24.4 per 100,000 persons using the updated definition and death from viral hepatitis and hepatobiliary malignancies demonstrated a progressive rise (Figure 1). The greatest increase during this time period in age-specific, liver-related mortality was observed in persons aged 45–54 and 55–64, driven by an increase in hepatobiliary malignancies in this latter age group. These results demonstrate that liver-related mortality as currently reported is underestimated, in particular among non-whites and persons of Hispanic ethnicity. The implications of these findings on health care and public policy and priorities are likely to be significant.See page 375.Isolation and Characterization of Intestinal Stem CellsRapid progress in the last decade has been made in the identification and characterization of intestinal cell lineages, including the tissue specific stem cell. Fluorescence-activated cell sorting (FACS) represents the most common and precise approach used to date for the isolation of intestinal stem cells. Successful isolation of intestinal stem cells has been achieved using genetically modified mice in which green fluorescence protein (GFP) is expressed in place of a stem cell–specific protein such as LGR5 or Bmi1. This approach, however, does not enable the isolation of stem cells from the human intestine.FACS has also played an essential role in the isolation and characterization of cells in the hematopoietic system by using fluorescence-emitting antibodies that bind cell surface proteins that identify specific cell lineages. In this issue of Gastroenterology, Wang et al report on their success in establishing a protocol for the isolation of intestinal stem cells using antibodies against cell surface markers. A major advantage the intestine provides in studying stem cells is the specific spatial distribution of cell types. It has been long known that the intestinal crypt is the source for stem cells and other proliferating cells. Wang et al in this study utilized previously characterized cell surface markers whose distribution of expression was consistent with that of stem cells.CD44 expression is one such protein whose expression is restricted to the intestinal crypt, which seemed to be higher in putative stem cells. CD24 and CD166 represented additional surface markers that designated cells deeper in the intestinal crypts. The c-Kit receptor was recently reported to be associated with Paneth cells, which reside next to the LGR5+ stem cells at the crypt base. Last, GRP78 is expressed in highly differentiated cells in the villus and lowest in the regions where stem cells reside. The authors used different combinations of these cell surface markers to successively purify intestinal subpopulations. Whether the final product was enriched for stem cells was determined by quantifying RNA transcripts with real-time polymerase chain reaction for known stem cells markers, and finally by the cells, ability to establish organoids that expressed all the intestinal cell lineages in culture. The authors determined that a cell profile of CD44hiCD24loCD166+ and either GRP78-/lo or c-Kit– most closely approximated the efficiency of LGR5-GFPhi intestinal stem cells to form organoids (Figure 2).Figure 2Progressive enrichment of cells capable of forming intestinal organoids in culture.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition, the authors also report on enhancements in the propagation of organoids that incorporates a GSK-3b inhibitor, CHIR99021. These reported advances should greatly facilitate future studies on intestinal stem cells.See page 383.Effect of Fibrosis on Chronic Pancreatitis ExacerbationsRecent reports have indicated that obesity increases the risk for severe acute pancreatitis. One explanation is that the fat that is adjacent to pancreatic acinar cells may also cause damage. Pancreatic infiltration with fat, however, is also observed in chronic pancreatitis, but is rarely associated with severe acute pancreatitis. In this issue of Gastroenterology, Acharya et al report on a retrospective review of patient autopsies with acute or chronic pancreatitis that assessed the impact of intrapancreatic fat and fibrosis on the clinical course of pancreatitis. The authors reviewed autopsy cases of acute pancreatitis (n = 23), chronic pancreatitis (n = 35), and acute on chronic pancreatitis (n = 15).The amount of intrapancreatic fat as determined by computed tomography correlated with body mass index (BMI) in controls, and patients with acute pancreatitis or acute on chronic pancreatitis, but not in the chronic pancreatitis group. In contrast, chronic pancreatitis patients contained significantly more intrapancreatic fat with a BMI of <30 kg/m2. Histologic examination revealed that patients with acute pancreatitis exhibited greater amounts of perifat–acinar cell necrosis than chronic pancreatitis, which was usually greatest adjacent to fat necrosis (Figure 3). The authors proposed that the lower rates of perifat–acinar cell necrosis observed in patients with chronic pancreatitis was due to the presence of fibrosis surrounding the intrapancreatic fat. Fibrosis that intervened between the intrapancreatic fat and acinar cells was found to be much more common in chronic pancreatitis patients.Figure 3Area of intrapancreatic fat (brown) surrounded by fibrosis (blue).View Large Image Figure ViewerDownload Hi-res image Download (PPT)The authors then studied in vitro potential mechanisms that may contribute to the lower parenchymal injury observed in chronic pancreatitis patients. The authors used transwell filter cell culture supports in which pancreatic acini were grown on one side and adipocytes on the other side. Non-esterified fatty acids and resistin, which are produced by adipocytes and are toxic to pancreatic acinar cells, were found to be freely diffusible across the membrane filter to the acinar cells. When collagen I, a major component of fibrosis, was coated on the transwell filters between the 2 cell types, a significant reduction in diffusible fatty acids and resistin was observed. Thus, fibrosis may serve as a protective barrier to fat-induced acinar cell necrosis in chronic pancreatitis.See page 466. Impact of Surveillance on Barrett's-Associated MortalityBarrett’s esophagus is considered to be the major risk factor for the development of esophageal/gastroesophageal junction adenocarcinoma (EA). The incidence of this cancer has increased significantly over the last 3 decades. Although endoscopic surveillance of patients with Barrett’s esophagus is recommended by specialty society guidelines, surveillance of all patients with Barrett’s esophagus has not been shown to be cost effective and there are no randomized, controlled trials to support these recommendations. Given current clinical practices, such trials are unlikely to be performed. In this issue of Gastroenterology (accompanied by an editorial), Corley et al have instead conducted a case-control study involving members of a large, integrated health care delivery system, Kaiser Permanente, Northern California, to evaluate whether endoscopic surveillance of Barrett’s esophagus is associated with a lower risk of death from EA. They identified 8272 patients with a diagnosis of Barrett’s esophagus over a 15-year period, 351 of whom were simultaneously or subsequently diagnosed with EA. Of these 351 patients, 70 had their EA diagnosed ≥6 months after the diagnosis of Barrett’s esophagus and, therefore, were eligible for surveillance. Death from EA occurred in 38 of these patients and surveillance history in these patients was contrasted with 101 control patients with Barrett’s esophagus, matched for age, gender, and duration of follow-up. Death from EA was more likely to occur in patients with low- or high-grade dysplasia on either their first examination or any examination prior to the three-year surveillance period (47.4% of cases vs. 13.9% of controls) and prior dysplasia was associated with cancer mortality (OR=4.68, 95% CI 1.75-12.51). However, surveillance within 3 years was not associated with a decreased risk of death from EA, even controlling for factors such as dysplasia status and Barrett’s esophagus length >3 cm or excluding patients with high-grade dysplasia before the 3-year surveillance period (Table 1). Excluding deaths related to treatment and patients who did not undergo potentially curative resection did not significantly affect the effectiveness of surveillance. These results show that despite the detection of early stage disease in the majority of patients with Barrett’s esophagus undergoing endoscopic surveillance, an overall reduced risk of death from EA was not associated with the use of endoscopic surveillance.Table 1Associations Between Surveillance Endoscopy and Fatal AdenocarcinomasCasesControlsOR (95% CI)aORs and 95% CIs from conditional logistic regression. Controls were matched to cases by age at Barrett’s esophagus diagnosis, year of Barrett’s esophagus diagnosis, sex, race, and medical center of Barrett’s esophagus diagnosis.In surveillance n (%)In surveillance n (%)Unadjusted1 Surveillance examination within 3 years21 (55.3)61 (60.4)0.82 (0.35–2.00)Controlling factors Dysplasia status (main model)bCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination).21 (55.3)61 (60.4)0.99 (0.36–2.75) Barrett's esophagus lengthcMore than 3 cm vs less than 3 cm vs not defined.21 (55.3)61 (60.4)0.97 (0.38–2.50) Dysplasia status and Barrett's esophagus lengthbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., cMore than 3 cm vs less than 3 cm vs not defined.21 (55.3)61 (60.4)1.14 (0.39–3.32) Excluding cases with 7–12 months between Barrett's esophagus and cancer diagnoses, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.19 (52.8)57 (60.0)0.95 (0.32–2.70) Excluding cases with high-grade dysplasia before 3-year surveillance interval, adjusted for other dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.16 (55.2)38 (52.8)1.00 (0.34–2.94) Excluding cases with gastroesophageal junction adenocarcinomas, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.19 (61.3)57 (67.1)0.88 (0.29–2.67) Excluding cases unable to be treated, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.18 (56.3)54 (64.3)0.80 (0.27–2.34) Excluding cases with treatment-related mortality or unable to be treated, adjusted for dysplasia statusbCategories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination)., dExcluded cases and their matched controls.14 (51.9)47 (65.3)0.46 (0.13–1.64)Total38 (100)101 (100)a ORs and 95% CIs from conditional logistic regression. Controls were matched to cases by age at Barrett’s esophagus diagnosis, year of Barrett’s esophagus diagnosis, sex, race, and medical center of Barrett’s esophagus diagnosis.b Categories of dysplasia in models include the following: none, indeterminate, low grade, and high grade. The main model adjusted for dysplasia status before the 3-year surveillance window because this could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient’s cancer risk. Thus, dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination, which diagnosed Barrett’s esophagus, by definition was not itself considered a surveillance examination).c More than 3 cm vs less than 3 cm vs not defined.d Excluded cases and their matched controls. Open table in a new tab See page 312; editorial on page 273. Barrett’s esophagus is considered to be the major risk factor for the development of esophageal/gastroesophageal junction adenocarcinoma (EA). The incidence of this cancer has increased significantly over the last 3 decades. Although endoscopic surveillance of patients with Barrett’s esophagus is recommended by specialty society guidelines, surveillance of all patients with Barrett’s esophagus has not been shown to be cost effective and there are no randomized, controlled trials to support these recommendations. Given current clinical practices, such trials are unlikely to be performed. In this issue of Gastroenterology (accompanied by an editorial), Corley et al have instead conducted a case-control study involving members of a large, integrated health care delivery system, Kaiser Permanente, Northern California, to evaluate whether endoscopic surveillance of Barrett’s esophagus is associated with a lower risk of death from EA. They identified 8272 patients with a diagnosis of Barrett’s esophagus over a 15-year period, 351 of whom were simultaneously or subsequently diagnosed with EA. Of these 351 patients, 70 had their EA diagnosed ≥6 months after the diagnosis of Barrett’s esophagus and, therefore, were eligible for surveillance. Death from EA occurred in 38 of these patients and surveillance history in these patients was contrasted with 101 control patients with Barrett’s esophagus, matched for age, gender, and duration of follow-up. Death from EA was more likely to occur in patients with low- or high-grade dysplasia on either their first examination or any examination prior to the three-year surveillance period (47.4% of cases vs. 13.9% of controls) and prior dysplasia was associated with cancer mortality (OR=4.68, 95% CI 1.75-12.51). However, surveillance within 3 years was not associated with a decreased risk of death from EA, even controlling for factors such as dysplasia status and Barrett’s esophagus length >3 cm or excluding patients with high-grade dysplasia before the 3-year surveillance period (Table 1). Excluding deaths related to treatment and patients who did not undergo potentially curative resection did not significantly affect the effectiveness of surveillance. These results show that despite the detection of early stage disease in the majority of patients with Barrett’s esophagus undergoing endoscopic surveillance, an overall reduced risk of death from EA was not associated with the use of endoscopic surveillance. See page 312; editorial on page 273. Liver-Related Mortality in the United StatesAccurate data on the burden of certain diseases are necessary to inform health care policy and develop guidelines, prioritize research and clinical interventions, and appropriately allocate resources. Although chronic liver disease and cirrhosis are recognized as important causes of morbidity and mortality in the United States, particularly among persons aged 45–64 years, there are concerns that the burden of chronic liver disease may be underestimated using current mortality reports. In this issue of Gastroenterology, Asrani et al using 2 population-based databases, one from Olmsted County, Minnesota and the other national mortality data from the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC), to better estimate the burden of chronic liver disease in the United States. Using the CDC definition, 71 liver-related deaths occurred among Olmsted County residents between 1999 and 2008. Using an updated definition of liver-related deaths that included diagnoses specific to liver disease, such as hepatorenal syndrome, as well as viral hepatitis and malignant neoplasms of the liver and intrahepatic bile ducts, 190 additional liver-related deaths were identified. Similarly, using the CDC definition, there were 29,951 liver-related deaths in the United States in 2008, but 66,007 deaths if the updated definition was used. The magnitude of liver-related deaths underestimated by the CDC definition varied by race; for example, only 34.3% of deaths in African Americans and only 48% of deaths in persons of Hispanic ethnicity were captured by the CDC definition. In contrast with the 38% decline in liver-related deaths over three eras from 1979 to 2008 observed when the CDC definition is used, liver-related mortality was found to increase from 23.9 to 24.4 per 100,000 persons using the updated definition and death from viral hepatitis and hepatobiliary malignancies demonstrated a progressive rise (Figure 1). The greatest increase during this time period in age-specific, liver-related mortality was observed in persons aged 45–54 and 55–64, driven by an increase in hepatobiliary malignancies in this latter age group. These results demonstrate that liver-related mortality as currently reported is underestimated, in particular among non-whites and persons of Hispanic ethnicity. The implications of these findings on health care and public policy and priorities are likely to be significant.See page 375. Accurate data on the burden of certain diseases are necessary to inform health care policy and develop guidelines, prioritize research and clinical interventions, and appropriately allocate resources. Although chronic liver disease and cirrhosis are recognized as important causes of morbidity and mortality in the United States, particularly among persons aged 45–64 years, there are concerns that the burden of chronic liver disease may be underestimated using current mortality reports. In this issue of Gastroenterology, Asrani et al using 2 population-based databases, one from Olmsted County, Minnesota and the other national mortality data from the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC), to better estimate the burden of chronic liver disease in the United States. Using the CDC definition, 71 liver-related deaths occurred among Olmsted County residents between 1999 and 2008. Using an updated definition of liver-related deaths that included diagnoses specific to liver disease, such as hepatorenal syndrome, as well as viral hepatitis and malignant neoplasms of the liver and intrahepatic bile ducts, 190 additional liver-related deaths were identified. Similarly, using the CDC definition, there were 29,951 liver-related deaths in the United States in 2008, but 66,007 deaths if the updated definition was used. The magnitude of liver-related deaths underestimated by the CDC definition varied by race; for example, only 34.3% of deaths in African Americans and only 48% of deaths in persons of Hispanic ethnicity were captured by the CDC definition. In contrast with the 38% decline in liver-related deaths over three eras from 1979 to 2008 observed when the CDC definition is used, liver-related mortality was found to increase from 23.9 to 24.4 per 100,000 persons using the updated definition and death from viral hepatitis and hepatobiliary malignancies demonstrated a progressive rise (Figure 1). The greatest increase during this time period in age-specific, liver-related mortality was observed in persons aged 45–54 and 55–64, driven by an increase in hepatobiliary malignancies in this latter age group. These results demonstrate that liver-related mortality as currently reported is underestimated, in particular among non-whites and persons of Hispanic ethnicity. The implications of these findings on health care and public policy and priorities are likely to be significant. See page 375. Isolation and Characterization of Intestinal Stem CellsRapid progress in the last decade has been made in the identification and characterization of intestinal cell lineages, including the tissue specific stem cell. Fluorescence-activated cell sorting (FACS) represents the most common and precise approach used to date for the isolation of intestinal stem cells. Successful isolation of intestinal stem cells has been achieved using genetically modified mice in which green fluorescence protein (GFP) is expressed in place of a stem cell–specific protein such as LGR5 or Bmi1. This approach, however, does not enable the isolation of stem cells from the human intestine.FACS has also played an essential role in the isolation and characterization of cells in the hematopoietic system by using fluorescence-emitting antibodies that bind cell surface proteins that identify specific cell lineages. In this issue of Gastroenterology, Wang et al report on their success in establishing a protocol for the isolation of intestinal stem cells using antibodies against cell surface markers. A major advantage the intestine provides in studying stem cells is the specific spatial distribution of cell types. It has been long known that the intestinal crypt is the source for stem cells and other proliferating cells. Wang et al in this study utilized previously characterized cell surface markers whose distribution of expression was consistent with that of stem cells.CD44 expression is one such protein whose expression is restricted to the intestinal crypt, which seemed to be higher in putative stem cells. CD24 and CD166 represented additional surface markers that designated cells deeper in the intestinal crypts. The c-Kit receptor was recently reported to be associated with Paneth cells, which reside next to the LGR5+ stem cells at the crypt base. Last, GRP78 is expressed in highly differentiated cells in the villus and lowest in the regions where stem cells reside. The authors used different combinations of these cell surface markers to successively purify intestinal subpopulations. Whether the final product was enriched for stem cells was determined by quantifying RNA transcripts with real-time polymerase chain reaction for known stem cells markers, and finally by the cells, ability to establish organoids that expressed all the intestinal cell lineages in culture. The authors determined that a cell profile of CD44hiCD24loCD166+ and either GRP78-/lo or c-Kit– most closely approximated the efficiency of LGR5-GFPhi intestinal stem cells to form organoids (Figure 2).In addition, the authors also report on enhancements in the propagation of organoids that incorporates a GSK-3b inhibitor, CHIR99021. These reported advances should greatly facilitate future studies on intestinal stem cells.See page 383. Rapid progress in the last decade has been made in the identification and characterization of intestinal cell lineages, including the tissue specific stem cell. Fluorescence-activated cell sorting (FACS) represents the most common and precise approach used to date for the isolation of intestinal stem cells. Successful isolation of intestinal stem cells has been achieved using genetically modified mice in which green fluorescence protein (GFP) is expressed in place of a stem cell–specific protein such as LGR5 or Bmi1. This approach, however, does not enable the isolation of stem cells from the human intestine. FACS has also played an essential role in the isolation and characterization of cells in the hematopoietic system by using fluorescence-emitting antibodies that bind cell surface proteins that identify specific cell lineages. In this issue of Gastroenterology, Wang et al report on their success in establishing a protocol for the isolation of intestinal stem cells using antibodies against cell surface markers. A major advantage the intestine provides in studying stem cells is the specific spatial distribution of cell types. It has been long known that the intestinal crypt is the source for stem cells and other proliferating cells. Wang et al in this study utilized previously characterized cell surface markers whose distribution of expression was consistent with that of stem cells. CD44 expression is one such protein whose expression is restricted to the intestinal crypt, which seemed to be higher in putative stem cells. CD24 and CD166 represented additional surface markers that designated cells deeper in the intestinal crypts. The c-Kit receptor was recently reported to be associated with Paneth cells, which reside next to the LGR5+ stem cells at the crypt base. Last, GRP78 is expressed in highly differentiated cells in the villus and lowest in the regions where stem cells reside. The authors used different combinations of these cell surface markers to successively purify intestinal subpopulations. Whether the final product was enriched for stem cells was determined by quantifying RNA transcripts with real-time polymerase chain reaction for known stem cells markers, and finally by the cells, ability to establish organoids that expressed all the intestinal cell lineages in culture. The authors determined that a cell profile of CD44hiCD24loCD166+ and either GRP78-/lo or c-Kit– most closely approximated the efficiency of LGR5-GFPhi intestinal stem cells to form organoids (Figure 2). In addition, the authors also report on enhancements in the propagation of organoids that incorporates a GSK-3b inhibitor, CHIR99021. These reported advances should greatly facilitate future studies on intestinal stem cells. See page 383. Effect of Fibrosis on Chronic Pancreatitis ExacerbationsRecent reports have indicated that obesity increases the risk for severe acute pancreatitis. One explanation is that the fat that is adjacent to pancreatic acinar cells may also cause damage. Pancreatic infiltration with fat, however, is also observed in chronic pancreatitis, but is rarely associated with severe acute pancreatitis. In this issue of Gastroenterology, Acharya et al report on a retrospective review of patient autopsies with acute or chronic pancreatitis that assessed the impact of intrapancreatic fat and fibrosis on the clinical course of pancreatitis. The authors reviewed autopsy cases of acute pancreatitis (n = 23), chronic pancreatitis (n = 35), and acute on chronic pancreatitis (n = 15).The amount of intrapancreatic fat as determined by computed tomography correlated with body mass index (BMI) in controls, and patients with acute pancreatitis or acute on chronic pancreatitis, but not in the chronic pancreatitis group. In contrast, chronic pancreatitis patients contained significantly more intrapancreatic fat with a BMI of <30 kg/m2. Histologic examination revealed that patients with acute pancreatitis exhibited greater amounts of perifat–acinar cell necrosis than chronic pancreatitis, which was usually greatest adjacent to fat necrosis (Figure 3). The authors proposed that the lower rates of perifat–acinar cell necrosis observed in patients with chronic pancreatitis was due to the presence of fibrosis surrounding the intrapancreatic fat. Fibrosis that intervened between the intrapancreatic fat and acinar cells was found to be much more common in chronic pancreatitis patients.The authors then studied in vitro potential mechanisms that may contribute to the lower parenchymal injury observed in chronic pancreatitis patients. The authors used transwell filter cell culture supports in which pancreatic acini were grown on one side and adipocytes on the other side. Non-esterified fatty acids and resistin, which are produced by adipocytes and are toxic to pancreatic acinar cells, were found to be freely diffusible across the membrane filter to the acinar cells. When collagen I, a major component of fibrosis, was coated on the transwell filters between the 2 cell types, a significant reduction in diffusible fatty acids and resistin was observed. Thus, fibrosis may serve as a protective barrier to fat-induced acinar cell necrosis in chronic pancreatitis.See page 466. Recent reports have indicated that obesity increases the risk for severe acute pancreatitis. One explanation is that the fat that is adjacent to pancreatic acinar cells may also cause damage. Pancreatic infiltration with fat, however, is also observed in chronic pancreatitis, but is rarely associated with severe acute pancreatitis. In this issue of Gastroenterology, Acharya et al report on a retrospective review of patient autopsies with acute or chronic pancreatitis that assessed the impact of intrapancreatic fat and fibrosis on the clinical course of pancreatitis. The authors reviewed autopsy cases of acute pancreatitis (n = 23), chronic pancreatitis (n = 35), and acute on chronic pancreatitis (n = 15). The amount of intrapancreatic fat as determined by computed tomography correlated with body mass index (BMI) in controls, and patients with acute pancreatitis or acute on chronic pancreatitis, but not in the chronic pancreatitis group. In contrast, chronic pancreatitis patients contained significantly more intrapancreatic fat with a BMI of <30 kg/m2. Histologic examination revealed that patients with acute pancreatitis exhibited greater amounts of perifat–acinar cell necrosis than chronic pancreatitis, which was usually greatest adjacent to fat necrosis (Figure 3). The authors proposed that the lower rates of perifat–acinar cell necrosis observed in patients with chronic pancreatitis was due to the presence of fibrosis surrounding the intrapancreatic fat. Fibrosis that intervened between the intrapancreatic fat and acinar cells was found to be much more common in chronic pancreatitis patients. The authors then studied in vitro potential mechanisms that may contribute to the lower parenchymal injury observed in chronic pancreatitis patients. The authors used transwell filter cell culture supports in which pancreatic acini were grown on one side and adipocytes on the other side. Non-esterified fatty acids and resistin, which are produced by adipocytes and are toxic to pancreatic acinar cells, were found to be freely diffusible across the membrane filter to the acinar cells. When collagen I, a major component of fibrosis, was coated on the transwell filters between the 2 cell types, a significant reduction in diffusible fatty acids and resistin was observed. Thus, fibrosis may serve as a protective barrier to fat-induced acinar cell necrosis in chronic pancreatitis. See page 466. Fibrosis Reduces Severity of Acute-on-Chronic Pancreatitis in HumansGastroenterologyVol. 145Issue 2PreviewAcute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. Full-Text PDF Garlic, Silver Bullets, and Surveillance Upper Endoscopy for Barrett's EsophagusGastroenterologyVol. 145Issue 2PreviewSurveillance upper endoscopy for cancer prevention has, over the years, been ascribed almost magical powers in mortality prevention. The concept is grounded in unassailable logic—Barrett’s esophagus (BE) is the precancerous condition for esophageal adenocarcinoma (EAC). EAC seems to have a long, precancerous latency period. Therefore, periodic endoscopy and biopsy in subjects with BE should detect early and potentially more curable neoplasia, avoiding the poor outcomes associated with cancers presenting symptomatically. Full-Text PDF Impact of Endoscopic Surveillance on Mortality From Barrett's Esophagus–Associated Esophageal AdenocarcinomasGastroenterologyVol. 145Issue 2PreviewAlthough patients with Barrett’s esophagus commonly undergo endoscopic surveillance, its effectiveness in reducing mortality from esophageal/gastroesophageal junction adenocarcinomas has not been evaluated rigorously. Full-Text PDF Isolation and Characterization of Intestinal Stem Cells Based on Surface Marker Combinations and Colony-Formation AssayGastroenterologyVol. 145Issue 2PreviewIdentification of intestinal stem cells (ISCs) has relied heavily on the use of transgenic reporters in mice, but this approach is limited by mosaic expression patterns and difficult to directly apply to human tissues. We sought to identify reliable surface markers of ISCs and establish a robust functional assay to characterize ISCs from mouse and human tissues. Full-Text PDF Underestimation of Liver-Related Mortality in the United StatesGastroenterologyVol. 145Issue 2PreviewAccording to the National Center for Health Statistics (NCHS), chronic liver disease and cirrhosis is the 12th leading cause of death in the United States. However, this single descriptor might not adequately enumerate all deaths from liver disease. The aim of our study was to update data on liver mortality in the United States. Full-Text PDF