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Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Chronic Gastroesophageal Reflux Disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Accordingly, EAC cells are subjected to high levels of oxidative stress and subsequent DNA damage. In this study, we investigated the expression and role of Apurinic/apyrimidinic endonuclease 1 (APE1) protein in promoting cancer cell survival by counteracting the lethal effects of acidic bile salts (ABS)-induced DNA damage. Immunohistochemistry analysis of human tissue samples demonstrated overexpression of APE1 in more than half of EACs (70 of 130), as compared to normal esophagus and non-dysplastic BE samples (P < 0.01). To mimic in vivo conditions, we treated in vitro cell models with a cocktail of ABS. The knockdown of endogenous APE1 in EAC FLO-1 cells significantly increased oxidative DNA damage (P < 0.01) and DNA single- and double-strand breaks (P < 0.01), whereas overexpression of APE1 in EAC OE33 cells reversed these effects. Annexin V/PI staining indicated that the APE1 expression in OE33 cells protects against ABS-induced apoptosis. In contrast, knockdown of endogenous APE1 in FLO-1 cells increased apoptosis under the same conditions. Mechanistic investigations indicated that the pro-survival function of APE1 was associated with the regulation of stress response c-Jun N-terminal protein kinase (JNK) and p38 kinases. Pharmacological inhibition of APE1 base excision repair (BER) function decreased cell survival and enhanced activation of JNK and p38 kinases by ABS. Our findings suggest that constitutive overexpression of APE1 in EAC may be an adaptive pro-survival mechanism that protects against the genotoxic lethal effects of bile reflux episodes.
Idiopathic achalasia is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter relaxation in response to deglutition. Patients with achalasia commonly complain of dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor, and chest pain. Weight loss is present in many, but not all patients. Although the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. The diagnosis is based on history of the disease, barium esophagogram, and esophageal motility testing. Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achalasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III. Although achalasia cannot be permanently cured, excellent outcomes are achieved in over 90 % of patients. Current medical and surgical therapeutic options (pneumatic dilation, endoscopic and surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. The prognosis in achalasia patients is excellent. Most patients who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.
Achalasia is an esophageal motility disorder that is commonly misdiagnosed initially as gastroesophageal reflux disease. Patients with achalasia often complain of dysphagia with solids and liquids but may focus on regurgitation as the primary symptom, leading to initial misdiagnosis. Diagnostic tests for achalasia include esophageal motility testing, esophagogastroduodenoscopy and barium swallow. These tests play a complimentary role in establishing the diagnosis of suspected achalasia. High-resolution manometry has now identified three subtypes of achalasia, with therapeutic implications. Pneumatic dilation and surgical myotomy are the only definitive treatment options for patients with achalasia who can undergo surgery. Botulinum toxin injection into the lower esophageal sphincter should be reserved for those who cannot undergo definitive therapy. Close follow-up is paramount because many patients will have a recurrence of symptoms and require repeat treatment.
Gastroesophageal reflux disease (GERD) is a condition that develops when there is reflux of stomach contents, which typically manifests as heartburn and regurgitation. These esophageal symptoms are well recognized; however, there are extra-esophageal manifestations of GERD, which include asthma, chronic cough, laryngitis and sinusitis. With the rising incidence of asthma, there is increasing interest in identifying how GERD impacts asthma development and therapy. Due to the poor sensitivity of endoscopy and pH monitoring, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. If unresponsive, diagnostic testing with pH monitoring off therapy and/or impedance/pH monitoring on therapy, may be reasonable in order to assess for baseline presence of reflux with the former and exclude continued acid or weakly acid reflux with the latter tests. PPI-unresponsive asthmatics, without overt regurgitation, usually have either no reflux or causes other than GERD. In this group, PPI therapy should be discontinued. In those with GERD as a contributing factor acid suppressive therapy should be continued as well as optimally treating other etiologies requiring concomitant treatment. Surgical fundoplication is rarely needed but in those with a large hiatal hernia, moderate-to-severe reflux by pH monitoring surgery might be helpful in eliminating the need for high-dose acid suppressive therapy.
OBJECTIVES - Symptom eradication in patients with Barrett's esophagus (BE) does not guarantee control of acid or duodenogastroesophageal reflux (DGER). Continued reflux of acid and/or DGER may increase risk of neoplastic progression and may decrease the likelihood of columnar mucosa eradication after ablative therapy. To date, no study has addressed whether both complete acid and DGER control is possible in patients with BE. This prospective study was designed to assess the effect of escalating-dose proton pump inhibitor (PPI) therapy on esophageal acid and DGER.
METHODS - Patients with BE (≥3 cm in length) underwent simultaneous ambulatory prolonged pH and DGER monitoring after at least 1 week off PPI therapy followed by testing on therapy after 1 month of twice-daily rabeprazole (20 mg). In those with continued acid and/or DGER, the tests were repeated after 1 month of double-dose (40 mg twice daily) rabeprazole. The primary study outcome was normalization of both acid and DGER. Symptom severity was assessed on and off PPI therapy employing a four-point ordinal scale.
RESULTS - A total of 29 patients with BE consented for pH monitoring, of whom 23 also consented for both pH and DGER monitoring off and on therapy (83% male; mean age 58 years; mean body mass index 29; mean Barrett's length 6.0 cm). Median (interquartile range) total % time pH <4 and bilirubin absorbance >0.14 off PPI therapy were 18.4 (11.7-20.0) and 9.7 (5.0-22.2), respectively. In addition, 26/29 (90%) had normalized acid and 18/23 (78%) had normalized DGER on rabeprazole 20 mg. Among those not achieving normalization on 20 mg twice daily, 3/3 (100%) had normalized acid and 4/5 (80%) had normalized DGER on rabeprazole 40 mg twice daily. All subjects had symptoms controlled on rabeprazole 20 mg twice daily. Univariate analysis found no predictor for normalization of physiologic parameters based on demographics.
CONCLUSIONS - Symptom control does not guarantee normalization of acid and DGER at standard dose of twice-daily PPI therapy. Normalization of acid and DGER can be achieved in 79% of BE patients on rabeprazole 20 mg p.o. twice daily, and in the majority of the remainder at high-dose twice-daily PPI. In patients undergoing ablative therapy, pH or DGER monitoring may not be needed to ensure normalization of reflux if patients are treated with high-dose PPI therapy.
BACKGROUND & AIMS - Current diagnostic tests for gastroesophageal reflux disease (GERD) are suboptimal and do not accurately and reliably measure chronicity of reflux. A minimally invasive device has been developed to assess esophageal mucosal impedance (MI) as a marker of chronic reflux. We performed a prospective longitudinal study to investigate MI patterns in patients with GERD and common nonreflux conditions, to assess MI patterns before and after treatment with proton pump inhibitors and to compare the performance of MI and wireless pH tests.
METHODS - We evaluated MI in 61 patients with erosive esophagitis, 81 with nonerosive but pH-abnormal GERD, 93 without GERD, 18 with achalasia, and 15 with eosinophilic esophagitis. MI was measured at the site of esophagitis and at 2, 5, and 10 cm above the squamocolumnar junction in all participants. MI was measured before and after acid suppressive therapy, and findings were compared with those from wireless pH monitoring.
RESULTS - MI values were signiﬁcantly lower in patients with GERD (erosive esophagitis or nonerosive but pH-abnormal GERD) or eosinophilic esophagitis than in patients without GERD or patients with achalasia (P < .001). The pattern of MI in patients with GERD differed from that in patients without GERD or patients with eosinophilic esophagitis; patients with GERD had low MI closer to the squamocolumnar junction, and values increased axially along the esophagus. These patterns normalized with acid suppressive therapy. MI patterns identified patients with esophagitis with higher levels of specificity (95%) and positive predictive values (96%) than wireless pH monitoring (64% and 40%, respectively).
CONCLUSIONS - Based on a prospective study using a prototype device, measurements of MI detect GERD with higher levels of specificity and positive predictive values than wireless pH monitoring. Clinical Trials.gov, Number: NCT01556919.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
PURPOSE - Although risk factors for squamous cell carcinoma of the esophagus and adenocarcinomas of the esophagus (EA), gastric cardia (GC), and other (noncardia) gastric (OG) sites have been identified, little is known about interactions among risk factors. We sought to examine interactions of diet, other lifestyle, and medical factors with risks of subtypes of esophageal and gastric cancers.
METHODS - We used classification tree analysis to analyze data from a population-based case-control study (1095 cases, 687 controls) conducted in Connecticut, New Jersey, and western Washington State.
RESULTS - Frequency of reported gastroesophageal reflux disease symptoms was the most important risk stratification factor for EA, GC, and OG, with dietary factors (EA, OG), smoking (EA, GC), wine intake (GC, OG), age (OG), and income (OG) appearing to modify the risk of these cancer sites. For esophageal squamous cell carcinoma, smoking was the most important risk stratification factor, with gastroesophageal reflux disease, income, race, noncitrus fruit, and energy intakes further modifying risk.
CONCLUSION - Various combinations of risk factors appear to interact to affect risk of each cancer subtype. Replication of these data mining analyses are required before suggesting causal pathways; however, the classification tree results are useful in partitioning risk and mapping multilevel interactions among risk variables.
Copyright © 2014 Elsevier Inc. All rights reserved.