Preservation of gastric acid secretion may be important for the development of gastroesophageal junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status

BACKGROUND: We have previously reported that Helicobacter pylori infection prevents reflux esophagitis (RE) and Barrett's esophagus (BE) by decreasing gastric acid secretion. Gastroesophageal (GE) junction adenocarcinoma, including Barrett's adenocarcinoma, has been thought to be a complication of gastroesophageal reflux disease (GERD). However, the relationship between H. pylori infection, gastric acid secretion, and GE junction adenocarcinoma has not yet been investigated in Japan. The aim of this study was to evaluate this relationship in the Japanese population. METHODS: A total of 168 Japanese patients (RE alone: 80, short-segment BE (SSBE): 16, long-segment BE (LSBE): 20, GE junction adenocarcinoma: 12, distal early gastric cancer (EGC): 40; male/female = 106/62; mean age 61.5 yr) and 80 Japanese control subjects who had no localized lesions in the upper gastrointestinal tract (male/female = 43/37, mean age 58.1 yr) were enrolled for this study. The prevalence of H. pylori infection was determined by biopsy, the rapid urease test, and measurement of the serum H. pylori IgG antibody. Gastric acid secretion was assessed by the endoscopic gastrin test (EGT). RE was diagnosed according to the Los Angeles classification. RESULTS: The prevalence of H. pylori infection in the patients with RE alone (30%) was significantly lower than that in control subjects (71.2%). There was also a tendency for the prevalence of H. pylori infection to be lower in patients with BE (SSBE, 18.7%; LSBE, 0%) when compared to that in patients with RE alone. On the other hand, while the prevalence of H. pylori infection in patients with GE junction adenocarcinoma (58.3%) was significantly lower than that in patients with EGC (87.5%), it tended to be higher than that in patients with RE alone or BE. The mean EGT value in patients with RE alone (3.74 mEq/10 min) was significantly higher than that in control subjects (1.83). The mean EGT value in patients with BE (SSBE, 4.74; LSBE, 4.76) tended to be even higher than that in patients with RE alone. The mean EGT value in patients with GE junction adenocarcinoma (3.94) was significantly higher than that in control subjects and patients with EGC (0.67), but it was comparable to that independent of the H. pylori infection status in patients with RE alone or BE. CONCLUSION: Preservation of gastric acid secretion may be important for the development of GE junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status.     

Risk of Barrett's oesophagus,oesophageal adenocarcinoma and reflux oesophagitis and the use of nitrates and asthma medications

Abstract

Objective. To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Material and methods. Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. Results. Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15–4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09–4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. Conclusions. Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.     

Structural alterations of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence

Background and Aim: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia‐dysplasia‐adenocarcinoma sequence. Methods: A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron‐microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. Results: The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P < 0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P < 0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P = 0.0043). Conclusions: The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia‐dysplasia‐adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.     

Sorafenib inhibits MAPK‐mediated proliferation in a Barrett's esophageal adenocarcinoma cell line

SUMMARY. Esophageal adenocarcinoma continues to rise in incidence. Despite recognition of Barrett's metaplasia as the histological precursor, prognosis remains poor. The mitogen‐activated protein kinases (MAPK) pathway is activated in Barrett's‐associated dysplasia and adenocarcinoma and this activation is, in part, due to acid and bile acid reflux. We investigated the effects of sorafenib, an orally active Raf‐inhibitor, on acid and bile acid‐stimulated growth and signaling in SEG‐1 cells, derived from a Barrett's esophageal cancer. SEG‐1 cells were pretreated with sorafenib or vehicle and subsequently stimulated with acid or bile acid. MAPK signals, including phospho‐ERK and phospho‐p38, as well as cyclin D1 expression were assessed by Western blotting. Cell proliferation was measured by WST‐1 colorimetric assay. Acid (pH 3.0–4.0) and bile acid (taurocholate 50–100 µmol/L) activated ERK and p38. Acid and bile acid exposure also increased levels of cyclin D1, a G1 to S cell cycle regulator. Furthermore, acid and taurocholate exposure increased cell proliferation. Sorafenib abrogated MAPK activation and cyclin D1 up‐regulation and significantly inhibited cell growth. In summary, sorafenib inhibits acid or bile acid‐stimulated Barrett's esophageal cancer cell proliferation by a mechanism involving the MAPK pathway. Our results suggest that sorafenib might be useful in the management of Barrett's‐associated dysplasia and adenocarcinoma. These findings provide a foundation for in vivo studies to assess the efficacy of sorafenib in Barrett's‐related neoplasia.     

A cross sectional study of p504s,CD133, and Twist expression in the esophageal metaplasia dysplasia adenocarcinoma sequence

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk‐stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low‐grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross‐sectional study. Twenty‐five cases each of Barrett's esophagus, low‐grade dysplasia, and esophageal adenocarcinoma were included along‐with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana^® immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.     

Role of gastric acid secretion in the pathogenesis of Barrett’s esophageal cancer in a Japanese population

The acidity of the refluxate into the esophagus is an important factor not only for reflux esophagitis, but also for Barrett’s esophagus and the development of Barrett’s esophageal cancer. On the other hand, H. pylori infection is thought to prevent reflux esophagitis and Barrett’s esophagus by causing atrophic gastritis, which in turn decreases gastric acid secretion. Moreover, the preservation of gastric acid secretion may be important for the development of gastroesophageal junction cancer, including Barrett’s esophageal cancer, irrespective of the H. pylori infection status. An increase in gastric acid secretion in Japanese populations has been predicted based on a decreasing rate of H. pylori infection and the westernization of eating habits in Japan; this, in turn, may lead to an increase in the prevalence of Barrett’s esophageal cancer in Japan in the future.     

Intravenous Bilirubin,Dibromosulfophthalein, and Bromosulfophthalein Infusions Uncouple Biliary Phospholipid and Cholesterol Secretion from Bile Acid Secretion by Inhibiting Hepatic Phosphoglycoprotein-3 Activity in Pigs

Objective. Barrett's esophagus with the intestinal predominant mucin phenotype is considered to have a higher malignant potential than that with the gastric predominant mucin phenotype. The purpose of this prospective study was to investigate the prevalence of and risk factors for Barrett's esophagus with the intestinal predominant mucin phenotype in patients undergoing endoscopy. Material and methods. A total of 1699 consecutive patients undergoing esophagogastroduodenoscopy were enrolled in the study. A targeted biopsy was performed when endoscopically observed columnar-appearing esophagus was stained with crystal violet. The sample, histologically evidenced as Barrett's esophagus, was immunohistochemically evaluated and categorized as of either gastric or intestinal predominant mucin phenotype. All the patients were requested to complete the structured questionnaire indicating their symptoms and food consumption patterns. Prevalence of and risk factors for Barrett's esophagus with and without the intestinal predominant mucin phenotype were investigated. Results. Out of 1668 patients, 629 (37.7%) were found to have endoscopic Barrett's esophagus. In 333 out of 1668 patients (19.9%), histological studies were diagnostic of Barrett's esophagus. One hundred and six of these 333 patients (31.8%) had the intestinal predominant mucin phenotype. Age, male gender and the presence of hiatal hernia were confirmed by multivariate analysis as the independent predictors for the presence of Barrett's esophagus with the intestinal predominant mucin phenotype. Conclusions. Barrett's esophagus with the intestinal predominant mucin phenotype was immunohistochemically found in 6.4% of all study patients. Older age, male gender and the presence of hiatal hernia were the risk factors for the presence of Barrett's esophagus with the intestinal predominant mucin phenotype.     

Expression of the putative stem cell marker Musashi‐1 in Barrett's esophagus and esophageal adenocarcinoma

The cancer stem cell theory states that cancers contain tumor‐forming cells that have the ability to self‐renew as well as give rise to cells that differentiate. Cancer stem cells have been identified in several solid tumors, but stem cells in normal human esophagus or in Barrett's esophagus or adenocarcinoma have not been reported. Musashi‐1 is expressed by the crypt base columnar cells identified as intestinal stem cells. In other diseases of the gastrointestinal tract, local inflammation of the tunica mucosa may be an initiating factor of alteration of focal tissue ‘niches,’ where dormant stem cells locate. The present study investigated whether Musashi‐1 is expressed in the esophagus and its relation to immune inflammation of the mucosa in Barrett's esophagus and esophageal adenocarcinoma. A total of 41 esophageal tissue specimens from 41 patients were studied. Of these, 15 were esophageal adenocarcinoma, 17 were Barrett's esophagus (10 intestinal metaplasia and 7 dysplasia), and 9 were normal squamous esophagus tissue specimens from patients without esophageal pathology. Immunohistochemistry was performed using antibodies to Musashi‐1 and to a set of cell type‐specific markers. A multiplexed tandem polymerase chain reaction method was used to measure the relative mRNA expression levels of Musashi‐1 and the specific dendritic cell marker dendritic cell‐specific intercellular molecule‐3 (ICAM‐3)‐grabbing nonintegrin. Immunohistochemistry demonstrated the presence of small numbers of Musashi‐1+ cells scattered in the connective tissue stroma and within the epithelium in cardiac‐type glands in biopsies from patients without Barrett's esophagus. Musashi‐1 expression was present in Barrett's intestinal metaplasia and in dysplastic Barrett's in which the majority of epithelial cells in individual glands expressed this antigen. Expression of Musashi‐1 was highest in esophageal adenocarcinoma, where it was most intense in glands that displayed features of early stages of adenocarcinoma formation. In contrast, Musashi‐1 staining level was weaker in glands that displayed features of advanced adenocarcinoma. Double immunostaining with proliferating cell nuclear antigen showed low proliferation in the vast majority of Musashi‐1+ cells. Musashi‐1 mRNA expression levels were significantly higher in esophageal adenocarcinoma than in normal esophagus or Barrett's esophagus tissues. Dendritic cell‐specific intercellular molecule‐3 (ICAM‐3)‐grabbing nonintegrin (DC‐SIGN) mRNA expression levels were significantly increased in both Barrett's tissues and adenocarcinoma tissues. Expression of the putative stem cell marker Musashi‐1 is absent in normal squamous epithelium, weak in esophageal cardiac‐type glands and Barrett's esophagus, and markedly increased in adenocarcinoma, especially in glands displaying features of early cancer development. Musashi‐1 expressing cells may be significant in the etiology of Barrett's esophagus and adenocarcinoma, and perhaps even a cell of origin for this disease. We speculate that immune inflammation occurring in Barrett's esophagus alters the mucosal microenvironment in a manner which is favorable to the activation of dormant stem cells.     

In vivo molecular imaging of HER2 expression in a rat model of Barrett's esophagus adenocarcinoma

Human epidermal growth factor receptor 2 (HER2) is involved in the malignant progression of several human cancers, including esophageal adenocarcinoma (EAC). The purpose of this study was to evaluate HER2 overexpression and to explore the feasibility of confocal laser endomicroscopy for in vivo molecular imaging of HER2 status in an animal model of Barrett's‐related EAC. Rats underwent esophagojejunostomy with gastric preservation. At 30 weeks post‐surgery, the esophagus of 46 rats was studied; endoscopic and histological findings were correlated with HER2 immunofluorescence on excised biopsies and gross specimens. At this age, 23/46 rats developed Barrett's esophagus (BE), and 6/46 had cancer (four EAC and two squamous cell carcinomas). A significant overexpression of HER2 was observed in esophageal adenocarcinoma compared with normal squamous esophagus (9.4‐fold) and BE (6.0‐fold). AKT and its phosphorylated form were also overexpressed in cancer areas. Molecular imaging was performed at 80 weeks post‐surgery in four rats after tail injection of fluorescent‐labeled anti‐HER2 antibody. At this age, 3/4 rats developed advance adenocarcinoma and showed in vivo overexpression of HER2 by molecular confocal laser endomicroscopy with heterogeneous distribution within cancer; no HER2 signal was observed in normal or Barrett's tissues. Therefore, HER2 overexpression is a typical feature of the surgical induced model of EAC that can be easily quantified in vivo using an innovative mini‐invasive approach including confocal endomicroscopy; this approach may avoid limits of histological evaluation of HER2 status on ‘blinded’ biopsies.     

ADENOCARCINOMA IN SITU ARISING FROM THE ECTOPIC SUBMUCOSAL CARDIAC GLANDS OF SHORT‐SEGMENT BARRETT's EPITHELIUM

Adenocarcinoma of the esophagocardiac junction is a condition difficult to define. It is often necessary to differentiate between esophagocardiac junctional adenocarcinoma and carcinoma in Barrett's esophagus. We herein report a case of an 83‐year‐old Japanese man with adenocarcinoma in situ arising from ectopic submucosal cardiac glands in short‐segment Barrett's epithelium, associated with squamous cell carcinoma. Despite the visualization of a nodule in short‐segment Barrett's epithelium, we diagnosed the present case as one of esophagocardiac junctional cancer arising from ectopic submucosal cardiac glands, using Alcian‐blue staining.     

Evaluation of sensitivity and inter- and intra-observer variability in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus with enhanced magnification endoscopy

Objective. Magnification endoscopy with acetic acid or dye for diagnosis of Barrett's esophagus is presently undergoing clinical evaluation. Current studies report good accuracy in predicting specialized intestinal metaplasia. To date, however, there is no definitive information on the inter- and intra-observer variability of these methods applied to the diagnosis of normal and dysplastic Barrett's mucosa. Material and methods. Sixty patients with endoscopically suspected Barrett's esophagus were investigated prospectively with the zoom endoscope after contrast enhancement of the mucosa with 1.5% acetic acid. Two hundred and twenty-three enlarged and histologically investigated areas of gastric, cardiac, normal and dysplastic Barrett's mucosa were photodocumented and in randomized sequence presented to 4 endoscopists in a blinded manner (2 with and 2 without experience of zoom endoscopy for evaluation). The reference for the first evaluation (A1) was standard endoscopic photographs of the respective, histologically confirmed mucosal entity. In a second evaluation (A2), the pictures were again interpreted by the same blinded investigators, but this time a modified pit-pattern classification as proposed by Sharma et al. was employed as the evaluation reference. Results. The diagnostic sensitivity for specialized intestinal metaplasia and dysplasia in Barrett's esophagus calculated for the A1 evaluation ranged – investigator dependently – from 54.9% to 80.7% and for A2 from 42.2% to 81.5%. The inter- and intra-observer variability for the evaluation procedure A1 and A2 was high (all kappa values <0.4). In particular, the inexperienced investigators demonstrated high intra-observer variability and low sensitivity in comparison with the experienced investigators. Conclusions. The diagnosis of Barrett's mucosa using enhanced magnification endoscopy after acetic acid instillation is associated with a high level of interobserver variability. One reason is a frequent mismatch between cardiac mucosa and non-dysplastic Barrett's mucosa.     

Physiological and molecular analysis of acid loading mechanisms in squamous and columnar‐lined esophagus

SUMMARY. Barrett's esophagus (BE) may be an adaptive cellular response to repeated acid exposure. The aims of this study were to compare intracellular acid loading in BE cells with normal squamous esophageal cells. Primary squamous and BE cells were obtained endoscopically and cultured for up to 24 h. Barrett's adenocarcinoma cell lines TE7 and OE‐33 were compared with a normal esophageal (NE) cell line OE‐21. Extracellular pH was lowered to 6.0 using HCl; specific ion exchangers were blocked pharmacologically and pH microfluorimetry was performed using 2′7′‐bis(carboxyethyl)‐5(6)‐carboxyfluorescein. The effect of prolonged acid preincubations and repeated acid exposure on acid loading and recovery were examined. Acid loading was greater in primary BE than NE cells (ΔpHi ?0.22 ± 0.08 vs.?0.13 ± 0.01) and maximal in the BE carcinoma cell line TE7 (ΔpHi ?0.30 ± 0.01). Whereas TE7 cells were able to recover fully from repeated acid exposure, OE‐21 cells remained profoundly acidic. BE primary and transformed cells utilize DIDS inhibitable sodium‐independent chloride/bicarbonate exchange as well as sodium/hydrogen ion exchange for acid loading. In contrast, SE only requires sodium‐independent chloride/bicarbonate exchange for acidification. The degree of acid loading is greater in BE than NE cells and it occurs via dual ion exchangers similar to gastric mucosa. Only Barrett's epithelial cells can maintain a physiological pHi following prolonged and repeated reflux exposure, which may confer a teleological advantage.     

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.     

Gastric acid secretion of normal Japanese subjects in relation to Helicobacter pylori infection,aging, and gender

Background: In Japan, where the incidence of gastric cancer is high, Helicobacter pylori infection could affect gastric acid secretion differently from that in Western countries. The aim of this study was to investigate the relationship between H. pylori infection, acid secretion, aging, and gender in normal Japanese subjects. Methods: The study comprised 193 Japanese subjects who had undergone routine endoscopy. Gastrin‐stimulated acid output was performed during the routine endoscopic examination using the endoscopic method of gastric acid secretory testing (EGT: endoscopic gastrin test), which has been reported previously. H. pylori status was determined by histology, rapid urease test, and serology. Results: Mean EGT values were 3.9?±?1.5?mEq/10?min in H. pylori‐negative men, 1.6?±?2.5 in H. pylori‐positive men, 2.2?±?0.9 in H. pylori‐negative women, and 1.5?±?1.2 in H. pylori‐positive women. Although acid secretion was lower in H. pylori‐positive subjects compared with H. pylori‐negative subjects in both men and women, the decrease was more marked in men with H. pylori infection. Multiple linear regression analysis showed that aging is positively associated with gastric acid secretion in the H. pylori‐negative subjects, whereas a negative association was found between them in the H. pylori‐positive subjects. Conclusions: In Japanese subjects, aging affects gastric acid secretion differently depending on the status of H. pylori infection. H. pylori infection showed a stronger inhibitory effect on the acid secretion in men than in women. This gender‐related difference in the susceptibility of acid secretion to H. pylori infection may explain the higher rates of gastric cancer in men in Japan.     

Activity of mitogen‐activated protein kinases in the esophageal epithelium of patients with Barrett's esophagus

Barrett's esophagus (BE), a complication of gastroesophageal reflux disease, is associated with an increased risk of esophageal cancer. Mitogen‐activated protein kinases may play an important role in the pathogenesis of this process. We aimed to evaluate mitogen‐activated protein kinases activity in esophageal mucosa of patients with BE and find possible relationship between reflux type and BE. Twenty‐four patients (mean age: 59 years) with gastroesophageal reflux disease symptoms and endoscopically suspected esophageal metaplasia (ESEM) were prospectively enrolled for testing by a multichannel intraluminal impedance monitoring along with a Bilitec 2000. Endoscopic biopsies were taken from methylene blue‐positive pit patterns (sites suggesting specialized intestinal metaplasia [SIM]), from 2 cm above the Z‐line and from cardial parts of the stomach. The biopsies were analyzed for extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), p38 activity by Western blot. Seventeen ESEMs had histologically proven metaplasia: eight patients had SIM and nine had gastric‐type epithelia (GE). Biliary reflux was more evident in SIM (P = 0.019) but not in GE (P = 0.019); non‐biliary reflux was typical for GE (P = 0.005) but not for SIM (P = 0.04). Strong activations of ERK and p38 were found predominantly in SIM, but not in normal esophageal mucosa (NE) (P = 0.01 and P < 0.001 respectively). Strong signals for active JNK and p38 were detected in GE, but not in NE (P = 0.006 and P = 0.02 respectively). ERK activity was significantly higher than p38 activity in ESEM patients only with GE (P = 0.02). The strong activation of ERK, but not JNK is indicative of SIM. The presence of bile in gastroesophageal refluxate is predisposing to SIM, but not to GE in esophageal mucosa.     

Multiple early esophageal cancers arising from Barrett's esophagus, and a review of cases of early adenocarcinoma in Barrett's esophagus in Japan

A case of early esophageal adenocarcinoma arising in Barrett's esophagus is reported. Many cases of Barrett's esophagus, which is considered a premalignant condition, have been reported in Western countries, but few cases have been reported in Japan. The patient, a 53-year-old man with nausea and vomiting, was a drinker (four glasses wine/day for about 30 years), but did not smoke. He had had a hiatal hernia of the esophagus. Since endoscopic biopsies demonstrated an early adenocarcinoma in Barrett's esophagus, subtotal esophagectomy was performed. In the resected esophageal material, Barrett's esophagus was seen to extend for 12 cm. In addition to the cancer detected preoperatively as a 0-IIc lesion (1.5 cm in diameter), a 0-IIb lesion (1.5 cm in diameter) was also detected in the post-operative survey. Both lesions were well differentiated adenocarcinoma that had invaded only into the lamina propria mucosa. The 23 cases of early adenocarcinoma in Barrett's esophagus that have been reported in Japan were reviewed, and it was learned that the present case is the second of multiple early cancer arising in Barrett's esophagus so far reported in Japan.     

Risk factors and chemoprevention in Barrett's esophagus – an update

Abstract

Objective. Barrett's esophagus (BO) is a precursor of esophageal adenocarcinoma (OAC), a cancer with a poor prognosis and an increasing incidence. Hence there is an interest in mapping causal factors underlying BO and finding strategies to reduce the risk of dysplasia progression in patients with BO. Here we review current knowledge on established as well as less risk factors for the development of BO. Additionally, we summarize today's status on the use of chemoprevention aiming to reduce the risk of cancer progression in BO patients. Methods. We searched Medline and the Cochrane Library using the MeSH terms “Barrett's esophagus” and “Barrett esophagus,” both alone and combined with the terms “risk factor,” “aetiology,” “diet,” or “prevention.” Focus was on original contributions, systematic reviews, and meta-analyses. Results. Established risk factors for the development of BO include gastro-esophageal reflux, obesity, male gender, Caucasian ethnicity, and increasing age. Smoking might increase the risk of BO, while aspirin/NSAIDs, Helicobacter pylori infection, and specific “healthy” dietary factors may lower the risk. The potential value of using chemoprevention with proton pump inhibitors, aspirin/NSAIDs, or statins is still uncertain. Conclusions. There is today a substantial knowledge of risk factors of BO. Certain diet may be protective of BO, albeit yet to be proven. The efficiency of chemoprevention in BO is currently addressed further in randomized clinical trials.     

Heterotopic Gastric Mucosa in the Distal Part of Esophagus in a Teenager: Case Report

Heterotopic gastric mucosa (HGM) of the esophagus is a congenital anomaly consisting of ectopic gastric mucosa. It may be connected with disorders of the upper gastrointestinal tract, exacerbated by Helicobacter pylori. The diagnosis of HGM is confirmed via endoscopy with biopsy. Histopathology provides the definitive diagnosis by demonstrating gastric mucosa adjacent to normal esophageal mucosa. HGM located in the distal esophagus needs differentiation from Barrett''s esophagus. Barrett''s esophagus is a well-known premalignant injury for adenocarcinoma of the esophagus. Malignant progression of HGM occurs in a stepwise pattern, following the metaplasia–dysplasia–adenocarcinoma sequence.We present a rare case of a teenage girl with HGM located in the distal esophagus, associated with chronic gastritis and biliary duodenogastric reflux. Endoscopy combined with biopsies is a mandatory method in clinical evaluation of metaplastic and nonmetaplastic changes within HGM of the esophagus.