Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery.

BACKGROUND & AIMS: Gastroesophageal reflux has been proposed as an important risk factor for esophageal and gastric cardia adenocarcinoma, but prospective data are lacking. Furthermore, the effect of antireflux surgery has not yet been studied. We conducted a population-based retrospective cohort study to fill these gaps. METHODS: A cohort of 35,274 male and 31,691 female patients with a discharge diagnosis of gastroesophageal reflux diseases, and another cohort of 6406 male and 4671 female patients who underwent antireflux surgery, were identified in the Swedish Inpatient Register. Follow-up was attained through record linkage with several nationwide registers. Standardized incidence ratio (SIR) was used to estimate relative risk of upper gastrointestinal cancers, using the general Swedish population as reference. RESULTS: After exclusion of the first year follow-up, 37 esophageal and 36 gastric cardia adenocarcinomas were observed among male patients who did not have surgery (SIR, 6.3, 95% confidence interval [CI], 4.5-8.7; SIR, 2.4, 95% CI, 1.7-3.3, respectively). SIR for esophageal adenocarcinoma increased with follow-up time (P = 0.03 for trend). Among male patients who had undergone antireflux surgeries, risks were also elevated (16 esophageal adenocarcinoma, SIR, 14.1, 95% CI, 8.0-22.8; 15 gastric cardia adenocarcinomas, SIR, 5.3, 95% CI, 3.0-8.7) and remained elevated with time after surgery. The cancer risk pattern in women was similar to that for men, but the number of cases were much smaller. CONCLUSIONS: Gastroesophageal reflux is strongly associated with the risk of esophageal adenocarcinoma, and to a lesser extent, with gastric cardia adenocarcinoma. The risk of developing adenocarcinomas of the esophagus and gastric cardia remains increased after antireflux surgery.     

Intestinal cancer after cholecystectomy: is bile involved in carcinogenesis?

BACKGROUND & AIMS: Results concerning an association between cholecystectomy and right-sided colon cancer are inconsistent. Little is known about the relation between cholecystectomy and small bowel cancer. Therefore, we evaluated cholecystectomy and risk of bowel cancer. METHODS: Cholecystectomized patients, identified through the Swedish Inpatient Register, from 1965 through 1997, were followed up for subsequent cancer. The standardized incidence ratio (SIR) estimated relative risk. RESULTS: In total, 278,460 cholecystectomized patients, contributing 3,519,682 person-years, were followed up for a maximum of 33 years after surgery. Cholecystectomized patients had an increased risk of proximal intestinal adenocarcinoma, which gradually declined with increasing distance from the common bile duct. The risk was significantly increased for adenocarcinoma (SIR, 1.77; 95% confidence interval [CI], 1.37-2.24) and carcinoids of the small bowel (SIR, 1.71; 95% CI, 1.39-2.08), and right-sided colon cancer (SIR, 1.16; 95% CI, 1.08-1.24). No association was found with more distal bowel cancer. The gradient was further pronounced when surgery of the common bile duct was included. The associations remained increased up to 33 years after cholecystectomy. No differences between sexes were found. CONCLUSIONS: Cholecystectomy increases the risk of intestinal cancer, a risk that declines with increasing distance from the common bile duct. Changes in the intestinal exposure to bile might be the underlying biological mechanism.     

Effect of Cholecystectomy on Gastric and Esophageal Bile Reflux in Patients with Upper Gastrointestinal Symptoms

Epidemiologic data have shown that cholecystectomy is associated with a moderately increased risk of esophageal adenocarcinoma. The study objective was to evaluate the role of refluxed bile. A total of 696 patients with upper gastrointestinal symptoms were included in the study, of whom 55 had a history of cholecystectomy (CHE). Bilirubin exposure was measured in percent time above absorbance 0.25 in the stomach and above 0.14 in the esophagus. Total gastric and esophageal bilirubin exposure was similar in both groups. Supine gastric bile reflux was slightly increased after cholecystectomy (30.6 ± 30.2 vs. CHE: 37.1 ± 29.5, P < 0.05). In patients with erosive esophagitis or Barrett’s esophagus, there were differences in total gastric exposure (24.3 ± 22.6 vs. CHE: 36.7 ± 26.8, P < 0.05) but not in esophageal exposure. Cholecystectomy slightly augments bile reflux into the stomach without detectable differences in the esophagus. Therefore, increased esophageal bile reflux following cholecystectomy as a potential cause for the associated cancer risk could not be substantiated.     

Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma

BACKGROUND: The incidence of esophageal adenocarcinoma is increasing rapidly. Gastroesophageal reflux is a strong risk factor for this disease. The increase in incidence of esophageal adenocarcinoma coincided with the introduction of medications that promote reflux by relaxing the lower esophageal sphincter (LES), such as nitroglycerin, anticholinergics, beta-adrenergic agonists, aminophyllines, and benzodiazepines. OBJECTIVE: To test the possible association between use of LES-relaxing medications and risk for adenocarcinoma of the esophagus and gastric cardia. DESIGN: A nationwide population-based case-control study with in-person interviews. SETTING: Sweden, 1995 through 1997. PATIENTS: 189 patients with newly diagnosed esophageal adenocarcinoma, 262 with adenocarcinoma of the gastric cardia, and 167 with esophageal squamous-cell carcinoma were compared with 820 population-based controls. MEASUREMENTS: Estimated incidence rate ratios, calculated by using multivariate logistic regression from case-control data with adjustment for potential confounding. RESULTS: Past use of LES-relaxing drugs was positively associated with risk for esophageal adenocarcinoma. Among daily, long-term users (>5 years) of LES-relaxing drugs, the estimated incidence rate ratio was 3.8 (95% CI, 2.2 to 6.4) compared with persons who had never used these drugs. Drugs of all classes contributed to the increased risk, but the association was particularly strong for anticholinergics. Short-term use of other types of LES-relaxing drugs did not seem to be strongly associated with risk. The association almost disappeared after adjustment for reflux symptoms, indicating that promotion of reflux is the link between use of LES-relaxing drugs and esophageal adenocarcinoma. If 15,490 men in any age group take LES-relaxing drugs daily for 5 years, 1 additional case of adenocarcinoma would be expected (number needed to treat for harm); in men older than 60 years of age, the number needed to treat for harm is 5,570. Assuming a causal relation, about 10% of the esophageal adenocarcinomas occurring in the population may be attributable to intake of LES-relaxing drugs. Cardia adenocarcinoma and esophageal squamous-cell carcinoma were not associated with use of LES-relaxing drugs. CONCLUSIONS: The widespread use of LES-relaxing drugs may have contributed to the increasing incidence of esophageal adenocarcinoma.     

Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma

The aim of this study was to examine the association of obesity with esophageal adenocarcinoma, and with the precursor lesions Barrett esophagus and gastroesophageal reflux disease (GERD). This case-control study included cases with GERD (n = 142), Barrett esophagus (n = 130), and esophageal adenocarcinoma (n = 57). Controls comprised 102 asymptomatic individuals. Using logistic regression methods, we compared obesity rates between cases and controls adjusting for differences in age, gender, and lifestyle risk factors. Relative to normal weight, obese individuals were at increased risk for esophageal adenocarcinoma (Odds Ratio [OR] 4.67, 95% Confidence Interval [CI] 1.27-17.9). Diets high in vitamin C were associated with a lower risk for GERD (OR 0.40, 95% CI 0.19-0.87), Barrett esophagus (OR 0.44, 95% CI 0.20-0.98), and esophageal adenocarcinoma (OR 0.21, 95% CI 0.06-0.77). For the more established risk factors, we confirmed that smoking was a significant risk factor for esophageal adenocarcinoma, and that increased liquor consumption was associated with GERD and Barrett esophagus. In light of the current obesity epidemic, esophageal adenocarcinoma incidence rates are expected to continue to increase. Successful promotion of healthy body weight and diets high in vitamin C may substantially reduce the incidence of this disease.     

Have patients with esophagitis got an increased risk of adenocarcinoma？ Results from a population-based study

AIM: To examine an increased risk of esophageal adenocarcinoma is restricted to patients who develop Barrett's esophagus or whether esophagitis per is a risk factor for adenocarcinoma. METHODS: A population-based cohort of patients with histological evidence of esophagitis without Barrett's esophagus was constructed using electronic pathology reports relating to all esophageal biopsies in Northern Ireland between 1993 and 1996. Person-years of follow-up and incident cases of esophageal cancer were calculated by linking the cohort to death files and the Northern Ireland Cancer Registry records. Standardized incidence ratios (SIR) were calculated for esophageal cancers (adenocarcinoma, squamous cell carcinoma (SCC), and historically unspecified cancers). RESULTS: A total of 2 013 patients in the cohort provided 13 559 patient-years of follow-up (mean follow-up 6.7 years). None of the patients developed adenocarcinoma. Three patients developed SCC, and six developed histologically unspecified cancers. The SIR for all esophageal cancers and for SCC were 2.73 (95%CI 1.25-5.19) and 2.93 (95%CI 0.61-8.59), respectively. In a sensitivity analysis in which all unspecified esophageal cancers were treated as adenocarcinomas, the SIR for adenocarcinoma was 2.64 (0.97-5.75). CONCLUSION: The risk of adenocarcinoma is not elevated in patients with histological evidence of esophagitis without Barrett's esophagus; however, these patients may have a moderately increased risk of SCC. Further studies are required to confirm these findings, which suggest that Barrett's esophagus, not esophagitis, is the key precursor lesion in the development of adenocarcinoma.     

Barrett's esophagus and medications that relax the lower esophageal sphincter

OBJECTIVES: Medications that may increase gastroesophageal reflux could be risk factors for esophageal adenocarcinoma; however, epidemiologic studies present conflicting results. We evaluated patients with a high-risk condition, Barrett's esophagus, to identify risk factors that may act early in the carcinogenic process. METHODS: We conducted a nested case-control study within a large integrated health-services organization. Electronic databases were used to identify incident diagnoses of Barrett's esophagus (cases); two controls were matched to each case. Electronic databases provided information on the use of medications that may induce reflux (nitrates, calcium channel blockers, xanthines, benzodiazepines, and beta agonists) and potential confounders. A supplemental mailed questionnaire evaluated additional potential confounders. RESULTS: We identified 421 cases and selected 842 controls. The association between any medication use and a Barrett's esophagus diagnosis was modified by age; an increased risk was observed only among subjects <70 yr of age (adjusted odds ratio [OR] = 2.6; 95% confidence interval [CI] 1.5-4.6). A Barrett's esophagus diagnosis was associated with asthma medication use (OR 5.8; 95% CI 2.2, 14.9), but not with the other medications studied. Subgroup analyses suggested that medication use was not independently associated with reflux symptoms and that adjustment for asthma symptoms substantially reduced the association between medication use and a Barrett's esophagus diagnosis. CONCLUSION: The use of medications that may induce reflux was associated with a Barrett's esophagus diagnosis among younger persons. This association was only observed with asthma medications; the analyses suggested the possibility of confounding by indication, whereby reflux may cause both asthma and Barrett's esophagus.     

Nonsteroidal anti‐inflammatory drugs and esophageal inflammation – Barrett's esophagus – adenocarcinoma sequence: a meta‐analysis

The incidence of esophageal adenocarcinoma has markedly increased in the last few decades and Barrett's esophagus is regarded as the precursor lesion of this cancer. The aim of the study was to quantify the adenocarcinoma risk associated with nonsteroidal anti‐inflammatory drug use and to determine at which stage chemoprevention with this drug is the most effective in esophageal inflammation – Barrett's esophagus – adenocarcinoma sequence. A literature search was performed to identify studies published between 1998 and 2009 for relevant risk estimates. Fixed and random effect meta‐analytical techniques were conducted for aspirin, nonaspirin nonsteroidal anti‐inflammatory drugs, and all nonsteroidal anti‐inflammatory drugs. Four cohort and 10 case‐control studies were included. Use of aspirin and nonaspirin nonsteroidal anti‐inflammatory drugs in normal population was associated with a reduced risk of adenocarcinoma (odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.65–0.83; OR: 0.84, 95% CI: 0.72–0.98, respectively). The use of all nonsteroidal anti‐inflammatory drugs was associated with a reduced risk of adenocarcinoma (relative risk [RR]: 0.64, 95% CI: 0.42–0.96) in Barrett's esophagus patients. However, no obvious dose‐effect relationships were found. In addition, we discovered a reverse association between drugs use and adenocarcinoma risk in people without a history of upper gastrointestinal tract disorders (OR: 0.57, 95% CI: 0.43–0.77, P= 0.12). Our meta‐analyses suggest a protective effect of nonsteroidal anti‐inflammatory drugs on the risk of adenocarcinoma. Our results also suggest that the drugs might act after the formation of Barrett's epithelium in the esophageal inflammation – Barrett's esophagus – adenocarcinoma sequence.     

Risk of cancers of the oesophagus and stomach by histology or subsite in patients hospitalised for pernicious anaemia

BACKGROUND: Although pernicious anaemia is an established risk factor for stomach cancer, data by anatomical subsite are not available. Moreover, a previous suggestion of a link to increased risk of oesophageal cancer needs further exploration. METHODS: We followed 21 265 patients hospitalised for pernicious anaemia in Sweden from 1965 to 1999 for an average of 7.1 years. Standardised incidence ratio (SIR) adjusted for sex, age, and calendar year was used to estimate relative risk, using the Swedish nationwide cancer incidence rates as reference. RESULTS: Significant excess risks for squamous cell carcinoma of the oesophagus, and stomach cancer distal to the cardia, were observed in pernicious anaemia patients (SIR 3.3 (95% confidence interval (CI) 2.4-4.4); SIR 2.4 (95% CI 2.1-2.7), respectively). The excess risks increased with increasing follow up duration. Among distal stomach cancers, the most conspicuous excess risk was for carcinoid tumours (SIR 26.4 (95% CI 14.8-43.5)). Compared with the general population, no significant increased risk was observed for adenocarcinoma of the oesophagus (SIR 1.7 (95% CI 0.7-3.4)) or gastric cardia (SIR 1.2 (95%CI 0.6-2.0)). CONCLUSIONS: Achlorhydria following type A atrophic gastritis is associated with an elevated risk of adenocarcinoma of the non-cardia stomach, and surprisingly, with a risk of oesophageal squamous cell carcinoma. In contrast, no significant association, either positive or negative, was found with oesophageal or cardia adenocarcinoma. The mechanism for the observed increased risk of oesophageal squamous cell carcinoma warrants further study.     

Association between body mass and adenocarcinoma of the esophagus and gastric cardia.

BACKGROUND: The incidence of esophageal and gastric cardia adenocarcinoma is, for unknown reasons, increasing dramatically. A weak and inconsistent association between body mass index (BMI) and adenocarcinoma of the esophagus and gastric cardia has been reported. OBJECTIVE: To reexamine the association between BMI and development of adenocarcinoma of the esophagus and gastric cardia. DESIGN: Nationwide, population-based case-control study. SETTING: Sweden, 1995 through 1997. PATIENTS: Patients younger than 80 years of age who had recently received a diagnosis were eligible. Comprehensive organization ensured rapid case ascertainment. Controls were randomly selected from the continuously updated population register. Interviews were conducted with 189 patients with adenocarcinoma of the esophagus and 262 patients with adenocarcinoma of the gastric cardia; for comparison, 167 patients with incident esophageal squamous-cell carcinoma and 820 controls were also interviewed. MEASUREMENTS: Odds ratios were determined from BMI and cancer case-control status. Odds ratios estimated the relative risk for the two adenocarcinomas studied and were calculated by multivariate logistic regression with adjustment for potential confounding factors. RESULTS: A strong dose-dependent relation existed between BMI and esophageal adenocarcinoma. The adjusted odds ratio was 7.6 (95% CI, 3.8 to 15.2) among persons in the highest BMI quartile compared with persons in the lowest. Obese persons (persons with a BMI > 30 kg/m2) had an odds ratio of 16.2 (CI, 6.3 to 41.4) compared with the leanest persons (persons with a BMI < 22 kg/m2). The odds ratio for patients with cardia adenocarcinoma was 2.3 (CI, 1.5 to 3.6) in those in the highest BMI quartile compared with those in the lowest BMI quartile and 4.3 (CI, 2.1 to 8.7) among obese persons. Esophageal squamous-cell carcinoma was not associated with BMI. CONCLUSIONS: The association between BMI and esophageal adenocarcinoma is strong and is not explained by bias or confounding. The carcinogenic mechanism, however, remains to be clarified. The increasing prevalence of obesity in western countries could be important in understanding the increasing occurrence of this tumor.     

Subsite-specific risk factors for esophageal and gastric adenocarcinoma

BACKGROUND: The incidence rates of adenocarcinoma involving specific gastric and esophageal subsites are changing significantly, but the risk factors associated with those subsite changes remain controversial. We aimed to describe the site-specific risk factors associated with adenocarcinoma of the stomach and esophagus. METHODS: Using the Rochester Epidemiology Project, all cases of gastric and esophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified. Complete inpatient and outpatient records were reviewed and specific subsites defined. Risk factors were assessed in cases, and age- and sex-matched controls. RESULTS: A total of 186 incident cases of gastric or esophageal adenocarcinoma were identified between 1971 and 2000, in Olmsted County. Gastroesophageal reflux disease (GERD) was a significant risk factor for both esophageal (OR 5.5, 95% CI 1.2-25) and esophagogastric junction adenocarcinoma (OR 13.0, 95% CI 1.7-99), but not for either proximal or distal gastric cancer. Smoking (OR 2.8, 95% CI 1.0-7.8) was associated with distal gastric cancer. Proton pump inhibitor (PPI) exposure was limited and was not a significant risk factor at any subsite. CONCLUSIONS: This identification of distinct risk factors by subsite supports the concept that esophageal and gastric adenocarcinomas are two different diseases. Adenocarcinoma of the junction is probably a form of esophageal cancer and should not be coded with gastric neoplasms.     

A case-control study of endoscopy and mortality from adenocarcinoma of the esophagus or gastric cardia in persons with GERD

BACKGROUND: This study assessed whether EGD reduces mortality from adenocarcinoma of the esophagus or gastric cardia for patients with gastroesophageal reflux. METHODS: A case-control study was performed. A total of 245 incident cases of death caused by adenocarcinoma of the esophagus or gastric cardia (1995-1999) in which reflux was present were identified using Veterans Health Administration databases. A total of 980 controls with reflux but no death from adenocarcinoma were frequency matched for age, gender, and race. The occurrences of EGD from 1990 onward were compared for cases and controls. Logistic regression analysis with adjustment for potential confounding factors was performed. RESULTS: All the subjects were men. Cases were significantly less likely to have had an EGD in the time period of interest as compared with controls (adjusted odds ratio 0.66: 95% CI [0.45, 0.96], p = 0.03). This negative association was as strong for any EGD performed within 1 to 8 years before diagnosis as for a more recent EGD. However, there were no controls that included esophagectomy and no controls with a nonfatal diagnosis of adenocarcinoma, raising the question of whether EGD and reduced mortality are causally linked. The risk of dying from adenocarcinoma was significantly lower for men with a diagnosis of GERD as an inpatient relative to men in whom the diagnosis was made as an outpatient (adjusted odds ratio 0.21: 95% CI [0.15, 0.31], p < 0.01). CONCLUSIONS: For patients with GERD, performing an EGD is associated with reduced mortality from adenocarcinoma of the esophagus or gastric cardia, but whether this is a causative association remains unclear.     

The value of medical imaging in uncomplicated and complicated Barrett's esophagus

Barrett's esophagus is an acquired condition characterized by a progressive columnar metaplasia of the distal esophagus caused by longstanding gastroesophageal reflux and reflux esophagitis. Barrett's esophagus is a premalignant condition associated with a significantly increased risk of developing esophageal adenocarcinoma. The purpose of this article is to provide an overview of the radiologic aspects of Barrett's esophagus and esophageal adenocarcinoma. Review of the literature shows that some findings on esophagography that are relatively specific for Barrett's esophagus are not sensitive, while others that are sensitive have a low specificity. Specific radiologic features allowing a confident diagnosis of Barrett's esophagus are a high esophageal stricture or ulcer associated with a hiatal hernia and/or gastroesophageal reflux. A reticular mucosal pattern is a relatively specific sign particularly if located adjacent to a stricture and is highly suggestive of Barrett's esophagus. Unfortunately, these findings are only present in a minority of cases. More common but nonspecific findings include gastroesophageal reflux, hiatal hernia, reflux esophagitis and/or peptic stricture in distal esophagus. These findings may also be present in patients with uncomplicated reflux disease. Barrett's esophagus carries a risk of malignant change. Early adenocarcinoma may appear as a plaque-like lesion or with focal irregularity, nodularity, and ulceration of the esophageal wall. Invasive adenocarcinoma may be seen as an infiltrating ulcerated mass. The radiologic diagnosis of Barrett's esophagus is limited by lack of criteria that are both sensitive and specific. The major value of double-contrast esophagography is its ability to classify patients into high risk (high stricture, ulcer or reticular pattern), moderate risk (esophagitis and/or distal peptic strictures), and low-risk (absence of esophagitis or stricture) for Barrett's esophagus determining the relative need for endoscopy and biopsy. Endoscopy and biopsy are generally advocated to make a definitive diagnosis. Endoscopic ultrasound plays a role in the early detection of invasive carcinoma and the staging of proven carcinoma but has no role in the surveillance of Barrett's esophagus.     

Specialized columnar epithelium of the esophagogastric junction: prevalence and associations. The Central Finland Endoscopy Study Group

OBJECTIVES: In Barrett's esophagus (BE) normal squamous esophageal epithelium is replaced by specialized columnar epithelium (SCE). BE is related to gastroesophageal reflux disease (GERD) and is a risk factor for esophageal adenocarcinoma. SCE is detected also at normal-appearing esophagogastric junction without BE (junctional SCE). The relationships between junctional SCE, GERD, and cardia adenocarcinoma are obscure and controversial. The aims of the present study were to investigate the prevalence and demographics of junctional SCE and to compare these figures with those reported for BE, and esophageal and cardia adenocarcinoma. A further aim was to examine the association between junctional SCE and GERD, Helicobacter pylori infection, and gastritis. METHODS: One thousand one hundred-nineteen consecutive dyspeptic patients underwent gastroscopy and were enrolled into the study. RESULTS: Junctional SCE was detected in 110 patients (10%). The age-specific prevalence of junctional SCE increased with age. The male:female ratio was 1:1.1. In multivariate analysis, junctional SCE was independently and positively related to endoscopic erosive esophagitis (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-3.1), cardia inflammation (carditis) (OR, 3.1; 95% CI, 1.4-6.8), and age (OR, 1.4 per decade; 95% CI, 1.2-1.6), but not to corpus H. pylori infection (OR, 1.4; 95% CI, 0.7-2.8), antral (OR, 1.0; 95% CI, 0.5-2.1) or corpus (OR, 0.8; 95% CI, 0.4-1.8) gastritis, or intestinal metaplasia of the antral mucosa in stomach (OR, 1.2; 95% CI, 0.7-2.1). In univariate analysis, junctional SCE was, however, significantly more common in patients with antral-predominant atrophic gastritis (20%), compared with those with normal gastric histology (8%, p < 0.001). CONCLUSIONS: Junctional SCE is age related and may therefore be an acquired lesion. It is associated with cardia inflammation and endoscopic erosive esophagitis, but not with H. pylori infection or gastric intestinal metaplasia. Unlike BE and cardia cancer, junctional SCE occurs with similar frequency in men and women.     

Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis

BACKGROUND & AIMS: Increasing evidence suggests that a low folate intake and impaired folate metabolism may be implicated in the development of gastrointestinal cancers. We conducted a systematic review with meta-analysis of epidemiologic studies evaluating the association of folate intake or genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, with risk of esophageal, gastric, or pancreatic cancer. METHODS: A literature search was performed using MEDLINE for studies published through March 2006. Study-specific relative risks were weighted by the inverse of their variance to obtain random-effects summary estimates. RESULTS: The summary relative risks for the highest versus the lowest category of dietary folate intake were 0.66 (95% confidence interval [CI], 0.53-0.83) for esophageal squamous cell carcinoma (4 case-control), 0.50 (95% CI, 0.39-0.65) for esophageal adenocarcinoma (3 case-control), and 0.49 (95% CI, 0.35-0.67) for pancreatic cancer (1 case-control, 4 cohort); there was no heterogeneity among studies. Results on dietary folate intake and risk of gastric cancer (9 case-control, 2 cohort) were inconsistent. In most studies, the MTHFR 677TT (variant) genotype, which is associated with reduced enzyme activity, was associated with an increased risk of esophageal squamous cell carcinoma, gastric cardia adenocarcinoma, noncardia gastric cancer, gastric cancer (all subsites), and pancreatic cancer; all but one of 22 odds ratios were >1, of which 13 estimates were statistically significant. Studies of the MTHFR A1298C polymorphism were limited and inconsistent. CONCLUSIONS: These findings support the hypothesis that folate may play a role in carcinogenesis of the esophagus, stomach, and pancreas.     

The changing face of esophageal malignancy

Concern has been expressed about the rapid increase in the incidence of esophageal carcinoma in the United States. This rise is due to an increase in the number of cases of adenocarcinoma of the esophagus. Because of the relatively small number of cases of esophageal carcinoma, the absolute risk of developing this cancer in the United States remains small. Potential origins for this increase in esophageal adenocarcinoma are examined in this review, including the risk induced by obesity, low dietary antioxidants, high dietary fat, family history of breast cancer, smoking, gastroesophageal reflux, and Barrett’s esophagus. The risk of esophageal adenocarcinoma is inversely associated with infection by Helicobacter pylori organisms. A better understanding of risk factors involved in the increased incidence of esophageal adenocarcinoma is important for development of new preventive strategies for this serious disorder.     

Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus

BACKGROUND: The increased risk for esophageal adenocarcinoma associated with long-segment (> or =3 cm) Barrett esophagus is well recognized. Recent studies suggest that short-segment (<3 cm) Barrett esophagus is substantially more common; however, the risk for neoplastic progression in patients with this disorder is largely unknown. OBJECTIVE: To examine the relation between segment length and risk for aneuploidy and esophageal adenocarcinoma in patients with Barrett esophagus. DESIGN: Prospective cohort study. SETTING: University medical center in Seattle, Washington. PATIENTS: 309 patients with Barrett esophagus. MEASUREMENTS: Patients were monitored for progression to aneuploidy and adenocarcinoma by repeated endoscopy with biopsy for an average of 3.8 years. Cox proportional hazards analysis was used to calculate adjusted relative risks and 95% Cls. RESULTS: After adjustment for histologic diagnosis at study entry, segment length was not related to risk for cancer in the full cohort (P > 0.2 for trend). When patients with high-grade dysplasia at baseline were excluded, however, a nonsignificant trend was observed; based on a linear model, a 5-cm difference in segment length was associated with a 1.7-fold (95% CI, 0.8-fold to 3.8-fold) increase in cancer risk. Among all eligible patients, a 5-cm difference in segment length was associated with a small increase in the risk for aneuploidy (relative risk, 1.4 [CI, 1.0 to 2.1]; P = 0.06 for trend). A similar trend was observed among patients without high-grade dysplasia at baseline. CONCLUSIONS: The risk for esophageal adenocarcinoma in patients with short-segment Barrett esophagus was not substantially lower than that in patients with longer segments. Although our results suggest a small increase in risk for neoplastic progression with increasing segment length, additional follow-up is needed to determine whether the patterns of risk occurred by chance or represent true differences. Until more data are available, the frequency of endoscopic surveillance should be selected without regard to segment length.     

Dietary antioxidants, fruits, and vegetables and the risk of Barrett's esophagus

OBJECTIVE: The present study evaluated the associations among antioxidants, fruit and vegetable intake, and the risk of Barrett's esophagus (BE), a potential precursor to esophageal adenocarcinoma.
METHODS: We conducted a case–control study within the Kaiser Permanente Northern California population. Incident BE cases (N = 296) were matched to persons with gastroesophageal reflux disease (GERD) (GERD controls N = 308) and to population controls (N = 309). Nutrient intake was measured using a validated 110-item food frequency questionnaire. The antioxidant results were stratified by dietary versus total intake of antioxidants.
RESULTS: Comparing cases to population controls, dietary intake of vitamin C and beta-carotene were inversely associated with the risk of BE (4th vs 1st quartile, adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.26–0.90; OR 0.56, 95% CI 0.32–0.99, respectively), and the inverse association was strongest for vitamin E (OR 0.25, 95% CI 0.11–0.59). The inverse trends for antioxidant index (total and dietary) and fruit and vegetable intake were statistically significant, while most total intakes were not associated with reduced risk. The use of antioxidant supplements did not influence the risk of BE, and antioxidants and fruits and vegetables were inversely associated with a GERD diagnosis.
CONCLUSION: Dietary antioxidants, fruits, and vegetables are inversely associated with the risk of BE, while no association was observed for supplement intake. Our results suggest that fruits and vegetables themselves or associated undetected confounders may influence early events in the carcinogenesis of esophageal adenocarcinoma.     

High incidence of potentially virus‐induced malignancies in systemic lupus erythematosus: A long‐term followup study in a Danish cohort

Objective

Patients with systemic lupus erythematosus (SLE) seem to experience an increased prevalence of oncogenic virus infections. The aim of the present study was to investigate whether SLE patients have an increased risk of virus‐associated malignancies, defined as malignancies potentially caused by virus infection.

Methods

A hospital‐based cohort of 576 SLE patients was linked to the Danish Cancer Registry. The cohort was followed up for malignancies from the date of SLE diagnosis, and standardized incidence ratios (SIRs) were calculated for various forms of cancer.

Results

The median duration of followup was 13.2 years. Compared to the general population, the patients experienced an increased overall risk of cancer (SIR 1.6 [95% confidence interval (95% CI)] 1.2–2.0). We observed an increased risk of virus‐associated cancers combined (SIR 2.9 [95% CI 2.0–4.1]). Among human papillomavirus (HPV)–associated malignant and premalignant conditions, high risk was found for anal cancer (SIR 26.9 [95% CI 8.7–83.4]), vaginal/vulvar cancer (SIR 9.1 [95% CI 2.3–36.5]), epithelial dysplasia/carcinoma in situ of the uterine cervix (SIR 1.8 [95% CI 1.2–2.7]), and nonmelanoma skin cancer (SIR 2.0 [95% CI 1.2–3.6]). Increased SIRs were also found for other potentially virus‐induced cancer types (liver cancer SIR 9.9 [95% CI 2.5–39.8], bladder cancer SIR 3.6 [95% CI 1.4–9.7], and non‐Hodgkin's lymphoma SIR 5.0 [95% CI 1.9–13.3]).

Conclusion

The patients in this SLE cohort experienced an increased risk of HPV‐associated tumors and other potentially virus‐induced cancers during long‐term followup. Our findings call for clinical alertness to oncogenic virus infections in SLE patients.

     

Hemochromatosis Gene Status as a Risk Factor for Barrett’s Esophagus

Conditions causing high iron levels, such as hemochromatosis, are proposed risk factors for esophageal adenocarcinoma. Although this hypothesis is supported by animal models, no human data currently exist. We conducted a case-control study of persons with a new Barrett’s esophagus diagnosis (cases), persons with gastroesophageal reflux disease (GERD) (without Barrett’s esophagus), and population controls. Subjects completed detailed examinations and assays for hemochromatosis mutations and serum iron stores. We evaluated 317 cases, 306 GERD patients, and 308 population controls. There was no significant association between Barrett’s esophagus and any hemochromatosis gene defect (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 0.95–1.84), a moderate or severe mutation (OR = 1.54, 95% CI: 0.94–2.52), or a severe mutation (C282Y homozygote or C282Y/H63D heterozygote; OR = 0.77, 95% CI: 0.24–2.48) compared with the population controls. As expected, gene defects were associated with increased iron stores. We can conclude from our findings that Barrett’s esophagus was not associated with hemochromatosis gene defects, although we cannot exclude small effects.