Barrett's Metaplasia Research Articles

MicroRNAs in Barrett's esophagus: future prospects.

MicroRNAs in Barrett's esophagus: future prospects.

Long-term maintenance effect of radiofrequency energy delivery for refractory GERD: a decade later

Patients with gastroesophageal reflux disease (GERD) often seek alternative therapy for inadequate symptom control, with over 40% not responding to medical treatment. We evaluated the long-term safety, efficacy, and durability of response to radiofrequency treatment of the lower esophageal sphincter (Stretta). Using an intent-to-treat analysis, we prospectively assessed 217 patients with medically refractory GERD before and after Stretta. There was no concurrent control group in the study. Primary outcome measure was normalization of GERD-health-related quality of life (GERD-HRQL) in 70% or greater of patients at 10 years. Secondary outcomes were 50% reduction or elimination of proton pump inhibitors (PPIs) and 60% or greater improvement in satisfaction at 10 years. Successful treatment was defined as achievement of secondary outcomes in a minimum of 50% of patients. Complications and effect on existing comorbidities were evaluated. The results of a 10-year study are reported. The primary outcome was achieved in 72% of patients (95% confidence interval 65-79). For secondary outcomes, a 50% or greater reduction in PPI use occurred in 64% of patients, (41% eliminating PPIs entirely), and a 60% or greater increase in satisfaction occurred in 54% of patients. Both secondary endpoints were achieved. The most common side effect was short-term chest pain (50%). Pre-existing Barrett's metaplasia regressed in 85% of biopsied patients. No cases of esophageal cancer occurred. In this single-group evaluation of 217 patients before and after Stretta, GERD-HRQL scores, satisfaction, and PPI use significantly improved and results were immediate and durable at 10 years.

Impact of Inflammation–Metaplasia–Adenocarcinoma Sequence and Inflammatory Microenvironment in Esophageal Carcinogenesis Using Surgical Rat Models

Chronic inflammation has been demonstrated to correlate with tumor onset and progression. Tumor-associated macrophages (TAMs) play an important role in inflammatory tumor microenvironment. We hypothesized that an inflammatory microenvironment around TAMs may promote the development of esophageal carcinomas when induced by duodenal content reflux without carcinogens. A total gastrectomy followed by esophagojejunostomy was performed on rats in order to induce chronic duodenal content reflux esophagitis. The animals were sacrificed sequentially, at the 20th, 30th, 40th and 50th week after surgery, and their esophagi were examined. The primary antibodies against CD68, CD163, pStat3 and Foxp3 were used. Expression and localization of infiltrated cells was assessed by immunohistochemical analysis. At 20-weeks' post-surgery, squamous proliferative hyperplasia (PHP) and Barrett's metaplasia (BM) were observed. Adenocarcinoma (ADC) associated with BM, and squamous cell carcinoma (SCC) were observed 30-50weeks' post-surgery. Numerous CD68 and pStat3-positive cells were identified surrounding PHP and BM after 20weeks, and around ADC and SCC after 30weeks. Moderate infiltration of CD163-positive macrophages was seen with BM, ADC, and SCC after 30weeks. However, very few Foxp3-positive cells were observed around ADC and SCC. Macrophages infiltrate the esophagus and activate the pStat3 pathway in stromal cells and epithelium. M2 phenotype macrophages infiltrate following infiltration of M1 macrophage and contribute to tumor development through regulatory T cells (Tregs). The involvement of immune cells such as TAMs and Tregs in the inflammatory microenvironment promotes esophageal carcinogenesis.

Immunohistochemical assessment of NY-ESO-1 expression in esophageal adenocarcinoma resection specimens.

To assess NY-ESO-1 expression in a cohort of esophageal adenocarcinomas. A retrospective search of our tissue archive for esophageal resection specimens containing esophageal adenocarcinoma was performed, for cases which had previously been reported for diagnostic purposes, using the systematised nomenclature of human and veterinary medicine coding system. Original haematoxylin and eosin stained sections were reviewed, using light microscopy, to confirm classification and tumour differentiation. A total of 27 adenocarcinoma resection specimens were then assessed using immunohistochemistry for NY-ESO-1 expression: 4 well differentiated, 14 moderately differentiated, 4 moderate-poorly differentiated, and 5 poorly differentiated. Four out of a total of 27 cases of esophageal adenocarcinoma examined (15%) displayed diffuse cytoplasmic and nuclear expression for NY-ESO-1. They displayed a heterogeneous and mosaic-type pattern of diffuse staining. Diffuse cytoplasmic staining was not identified in any of these structures: stroma, normal squamous epithelium, normal submucosal gland and duct, Barrett's esophagus (goblet cell), Barrett's esophagus (non-goblet cell) and high grade glandular dysplasia. All adenocarcinomas showed an unexpected dot-type pattern of staining at nuclear, paranuclear and cytoplasmic locations. Similar dot-type staining, with varying frequency and size of dots, was observed on examination of Barrett's metaplasia, esophageal submucosal gland acini and the large bowel negative control, predominantly at the crypt base. Furthermore, a prominent pattern of apical (luminal) cytoplasmic dot-type staining was observed in some cases of Barrett's metaplasia and also adenocarcinoma. A further morphological finding of interest was noted on examination of haematoxylin and eosin stained sections, as aggregates of lymphocytes were consistently noted to surround submucosal glands. We have demonstrated for the first time NY-ESO-1 expression by esophageal adenocarcinomas, Barrett's metaplasia and normal tissues other than germ cells.

Immunohitochemical study of p53 protein expression in gastroesophageal reflux disease

ObjectiveThis study aimed to determine p53 protein expression by immunohistochemistry in the esophageal mucosa of patients with gastroesophageal reflux disease (GERD).BackgroundGERD is a common clinical disorder that can significantly impact the patient's quality of life and pose a significant burden on healthcare systems worldwide. The incidence of esophageal adenocarcinoma has been increasing rapidly over the past few decades. The major risk factors predisposing to the development of adenocarcinoma are long-standing GERD and Barrett's esophagus. P53 protein expression in esophageal carcinogenesis is still being studied. The identification of tumor markers in patients with GERD may enable recognition of subgroups of patients who are more at risk of developing dysplasia and/or cancer.Patients and methodsThis study was carried out on 200 patients with symptoms of GERD. They were recruited from the endoscopy unit of Menoufia University Hospital between August 2010 and March 2013, and were included in group 1. According to the results of upper endoscopy and histopathology, they were subdivided as follows: group 1a included patients with GERD with erosive esophagitis ( n = 180), group 1b included patients with GERD and Barrett's esophagus ( n = 20), and group 2 included 20 patients with other GIT symptoms with no reflux and normal esophageal squamous epithelium; this was the control group. Written valid consent was obtained from every patient for examination and upper endoscopy; the clinical sheet for every case was completed, including assessment of history, examination, and the investigations required.ResultsWe found negative reactivity for p53 in 20 histologically normal patients (0%), and positive p53 protein expression in 76 patients (40%) in the esophagitis group and in 14 patients (70%) with Barrett's metaplasia ( n = 20). According to the Los Angeles classification grade, p53 was overexpressed in 33.3% ( n = 24) of esophagitis grade A (mild esophagitis) patients, 46.3% ( n = 32) of esophagitis grade B (moderate esophagitis) patients, 56.4% ( n = 22) of esophagitis grade C patients, and 60% ( n = 12) of esophagitis grade D (severe esophagitis) patients.ConclusionGERD grades C and D were more prevalent in Barrett's esophagus. P53 expression was higher in Barrett's esophagus than in erosive esophagitis compared with the normal group. P53 protein expression increases gradually with the severity of esophagitis caused by GERD.

Columnar metaplasia in the esophageal remnant after esophagectomy: a systematic review

Barrett's metaplasia is a well-recognized risk factor for esophageal adenocarcinoma. It is believed to develop in response to the injurious effects of gastroesophageal reflux. Following subtotal esophagectomy and reconstruction with a gastric conduit, many patients experience profound reflux into the remnant esophagus. Barrett's-like epithelium has been described in these patients, and they have been identified as a potential human model in which to study the early events in the development of metaplasia. This phenomenon also raises clinical concerns about the long-term fate of the esophageal remnant following surgery and the potential for further malignant change. This systematic review summarizes the literature on the prevalence and timing of Barrett's metaplasia occurring after esophagectomy, reviews the evidence regarding risk factors and malignant progression in such patients, and considers the implications for clinical practice.

Development and Characterization of a Surgical Mouse Model of Reflux Esophagitis and Barrett's Esophagus

Ideally, an animal model of Barrett's esophagus should recapitulate the human disease histologically and immunohistochemically, and be readily susceptible to genetic manipulation. We have developed such a model using a strain of mice commonly used for transgenic and knockout manipulations. We induced reflux by esophagojejunostomy (EJ) in 20 C57Bl/6 mice. At defined time points, sections of the esophagus were stained with H&E and Alcian blue, and immunohistochemical staining was performed for Sox9 (a transcription factor in Barrett's metaplasia), cytokeratin (CK) 8/18 (a columnar marker) and CK14 (a squamous marker). Procedural mortality was 40% for the first ten animals, 20% for the next 10. Reflux esophagitis developed by 13 weeks, and intestinal metaplasia with goblet cells developed by 34 weeks. The metaplasia expressed CK8/18, but not CK14, and exhibited nuclear immunostaining for Sox9. Nuclear Sox9 was also seen in scattered basal cells of squamous epithelium close to the EJ anastomosis. EJ can be performed successfully in C57Bl/6 mice, resulting in reflux esophagitis and intestinal metaplasia that exhibits phenotypic and molecular features of human Barrett's metaplasia. This surgical model in a mouse strain that is easy to manipulate genetically should be a valuable tool for studying the pathogenesis of Barrett's esophagus.

Viral Load and Integration Status of High-Risk Human Papillomaviruses in the Barrett's Metaplasia–dysplasia–adenocarcinoma Sequence

Viral Load and Integration Status of High-Risk Human Papillomaviruses in the Barrett's Metaplasia–dysplasia–adenocarcinoma Sequence

MUC2 expression is an adverse prognostic factor in superficial gastroesophageal adenocarcinomas

Mucin core proteins (MUCs) are expressed in tissue-specific patterns in the gastrointestinal tract and expression is deregulated in Barrett's metaplasia. Based on differential expression, MUCs have been used to classify adenocarcinomas into distinct phenotypes (eg, intestinal, gastric, pancreaticobiliary, etc). Because MUC expression patterns carry prognostic significance in other tumors, we evaluated MUC expression in superficial adenocarcinomas of the gastroesophageal junction and esophagus (EAC) to determine whether there are differences in outcome associated with MUC subtype in this potentially curable subset of EAC. We classified 142 resected, superficial (T1) EAC based on their pattern of expression of MUC2, MUC5AC, MUC6 and MUC1. The association between survival and MUC expression pattern was determined in univariate and multivariate analyses. The MUC2 positive "intestinal" phenotype was associated with significantly worse prognosis in submucosal EAC (hazard ratio 2.2, 95% confidence interval 1.2-4.2), independent of node stage and other prognostic factors. MUC2 expression in submucosal EAC also showed significantly accelerated time to recurrence (hazard ratio 2.8, 95% confidence interval 1.2-6.8) after adjusting for node stage. The classification of superficial EAC by MUC protein expression has prognostic significance. MUC2 expression is an adverse prognostic indicator in submucosal EAC, independent of node stage and other prognostic factors.

Autocrine Extra-Pancreatic Trypsin 3 Secretion Promotes Cell Proliferation and Survival in Esophageal Adenocarcinoma

Trypsin or Tumor associated trypsin (TAT) activation of Protease-activated receptor 2 (PAR-2) promotes tumor cell proliferation in gastrointestinal cancers. The role of the trypsin/PAR-2 network in esophageal adenocarcinoma (EA) development has not yet been investigated. The aim of this study is to investigate the role of trypsin/PAR-2 activation in EA tumorogenesis and therapy. We found that esophageal adenocarcinoma cells (EACs) and Barrett’s Metaplasia (BART) expressed high levels of type 3 extra-pancreatic trypsinogen (PRSS3), a novel type of TAT. Activity of secreted trypsin was detected in cultured media from EA OE19 and OE33 cultures but not from BART culture. Surface PAR-2 expression in BART and EACs was confirmed by both flow cytometry and immunofluorescence. Trypsin induced cell proliferation (∼ 2 fold; P<0.01) in all tested cell lines at a concentration of 10 nM. Inhibition of PAR-2 activity in EACs via the PAR-2 antagonist ENMD (500 µM), anti-PAR2 antibody SAM-11 (2 µg/ml), or siRNA PAR-2 knockdown, reduced cell proliferation and increased apoptosis by up to 4 fold (P<0.01). Trypsin stimulation led to phosphorylation of ERK1/2, suggesting involvement of MAPK pathway in PAR-2 signal transduction. Inhibition of PAR-2 activation or siRNA PAR-2 knockdown in EACs prior to treatment with 5 FU reduced cell viability of EACs by an additional 30% (P<0.01) compared to chemotherapy alone. Our data suggest that extra-pancreatic trypsinogen 3 is produced by EACs and activates PAR-2 in an autocrine manner. PAR-2 activation increases cancer cell proliferation, and promotes cancer cell survival. Targeting the trypsin activated PAR-2 pathway in conjunction with current chemotherapeutic agents may be a viable therapeutic strategy in EA.

Predictors of Response to Endoscopic Therapy of Barrettʼs High-Grade Dysplasia (HGD) and Intramucosal Cancer (IMC)

Purpose: Modalities of endoscopic therapy of Barrett's HGD and IMC include endoscopic mucosal resection (EMR), radiofrequency ablation (RFA), cryotherapy and argon plasma coagulation (APC). Although these are highly effective in most patients for eradication of dysplasia, some patients continue to have small areas of residual Barrett's or continue to progress to HGD or cancer. Our aims were to assess eradication rates of Barrett's metaplasia and dysplasia as well as factors which predict complete eradication. Methods: Review of prospectively collected database of patients who underwent endoscopic therapy for Barrett's dysplasia or IMC from 2006 to 2011. Patients who underwent EMR only excluded. Variables such as age, race, sex, BMI, alcohol use, smoking, diabetes, hypertension, hyperlipidemia, medication use were analyzed. Endoscopic data included length of Barrett's segment, hiatal hernia size, number of endoscopies and biopsy results. Results: Among 118 patients included, there were 60 patients in RFA and 58 patients in cryotherapy group. Compared to RFA patients, cryotherapy patients were found to be older and were more likely to have never used alcohol. In addition, they had longer treatment period and higher number of treatment sessions (table 1). Patients with RFA were more likely to have complete eradication of dysplasia (100% vs. 90%; p=0.012). There were no other significant differences between two groups. PREDICTORS: There was complete eradication of Barrett's in 72 patients (61%). There was Barrett's without dysplasia in 40 patients (33.8 %). Six patients had persistent HGD or progression to cancer (5%). On univariable analysis, subjects who had eradication of metaplasia had a longer treatment period (months 32.8± 20 vs 23.3±18.8, p=0.011) and follow-up time (months 36.8±21.5 vs. 25.9±18.7; p=0.006). There were no other significant differences. After adjusting for all variables in the model, subjects who had RFA had 3-fold higher odds of having eradication of metaplasia than those who had cryotherapy (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.1-7.7; p = 0.031). In addition, for every 1 month increase in the EGD followup time, the odds of having complete metaplasia eradication increased by 4% (OR 1.04; 95% CI 1.01-1.07; p= 0.002). Younger age was associated with eradication of metaplasia/dysplasia (66.7± 10.6 vs. 75.8±9.3 years p=0.042). In addition, EMR and RFA were associated with eradication of metaplasia/dysplasia while patients without eradication were more likely to have had cryotherapy or APC/band ligation.Table 1: Endoscopic therapyConclusion: Endoscopic therapy is highly effective in eradication of Barrett's HGD and IMC. RFA with or without EMR and younger age are predictors for complete eradication of BE.

Prevention of Barrett's metaplasia in a human model of duodenogastro-oesophageal reflux

The development of Barrett’s esophagus above the anastomosis following esophagogastrectomy has been reported in several studies. In this prospective study we set out to examine the prevalence of this phenomenon in a group of patients who have been strictly adherent to post operative proton pump inhibitor (PPI) therapy. Forty-six postoesophagectomy patients were prospectively assessed by upper gastrointestinal endoscopy. Four quadrant biopsies were taken 1 cm proximal to the esophago-gastric anastomosis in all patients and details of endoscopic appearance, biopsy pathology, operative pathology and PPI dose were recorded. All 46 patients had been commenced on a PPI in the immediate postoperative period. Two patients were not taking a PPI regularly. The average time from operation to endoscopy was 3 years (range 0.5 to 9). Mild (Grade 1) erosive oesophagitis was observed in 5 patients. Barrett’s epithelium was not identified in any patient. One patient who was taking a PPI intermittently had macroscopic columnar epithelium for 2 cm above the anastomosis without intestinal metaplasia. One other patient who had no macroscopic abnormality had columnar epithelium without intestinal metaplasia, seen in one of four biopsy specimens. This is the first study to assess for endoscopic evidence of neo-Barrett’s following oesophagogastrectomy, where PPI therapy has been commenced in the immediate postoperative period. Columnar epithelium was present in 2 patients and intestinal metaplasia was not detected in any of the cohort. These outcomes may be due to early commencement of PPI therapy and a high level of compliance.

Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects - a retro-pro study

BackgroundInformation about gastro-oesophageal reflux disease (GERD) in patients with Diabetes mellitus type 2 (T2D) is scarce, although the incidence of both disorders is increasing.We aimed to determine GERD symptoms and their underlying pathophysiologic characteristics in T2D patients.MethodsThis “retro-pro” study compared 65 T2D patients to a control group of 130 age- and sex-matched non-diabetics. GERD was confirmed by gastroscopy, manometry, pH-metry and barium swallow.ResultsIn patients with T2D compared to controls, dysphagia (32.3% vs. 13.1%; p = 0.001) and globus sensation (27.7% vs. 13.8%; p = 0.021) were found more frequently, whereas heartburn (76.9% vs. 88.5%; p = 0.046) and regurgitation (47.7% vs. 72.3%; p = 0.001) were predominant in non-diabetics. Despite higher body mass indices (31.1 ± 5.2 vs. 27.7 ± 3.7 kg/m2; p < 0.001), hiatal hernia was less frequent in T2D patients compared to controls (60.0% vs. 90.8%, p < 0.001). Lower oesophageal sphincter (LES) pressure was higher in patients with T2D (median 10.0 vs. 7.2 mmHg, p = 0.016). DeMeester scores did not differ between the groups. Helicobacter pylori infections were more common in T2D patients (26.2% vs. 7.7%, p = 0.001). Barrett metaplasia (21.5% vs. 17.7%), as well as low- (10.8% vs. 3.8%) and high-grade dysplasia (1.5% vs. 0%) were predominant in T2D patients.ConclusionsT2D patients exhibit different GERD symptoms, higher LES pressures and a decreased prevalence of hiatal hernia than non-diabetics, which may be related to worse oesophageal motility and, thus, a more functional rather than anatomical cause of GERD. Low-grade dysplasia was more than twice as high in T2D than in non-diabetics patients.Trial registrationEthics committee of the Medical University of Vienna, IRB number 720/2011.

Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer

Endoglin (ENG) is a 180-kilodalton transmembrane glycoprotein that functions as a component of the transforming growth factor-β receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers. The authors examined ENG promoter hypermethylation using real-time, quantitative, methylation-specific polymerase chain reaction in 260 human esophageal tissues. ENG hypermethylation demonstrated highly discriminative receiver operating characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P<.01). It is interesting to note that ENG normalized methylation values were significantly higher in ESCC compared with normal tissue (P<.01) or EAC (P<.01). The ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in normal esophageal tissue, but increased early and sequentially during EAC-associated neoplastic progression to 13.3% in Barrett metaplasia (BE), 25% in dysplastic BE, and 26.9% in frank EAC. ENG hypermethylation was significantly higher in normal esophageal tissue from patients with ESCC (mean, 0.0186) than in normal tissue from patients with EAC (mean, 0.0117; P<.05). Treatment of KYSE220 ESCC cells with the demethylating agent 5-aza-2'-deoxycytidine was found to reverse ENG methylation and reactivate ENG mRNA expression. Promoter hypermethylation of ENG appears to be a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.

Amplification of Her-2/neu oncogene in GERD - Barrett's metaplasia – dysplasia - adenocarcinoma sequence.

Esophageal adenocarcinoma (ADC) incidence has been increasing dramatically in the past 3 decades despite the surveillance programs in patients with Barrett’s esophagus (BE). Therefore, markers of early neoplastic progression are required to predict of cancer risk in BE patients. The aim of this study was to investigate the frequency of Her2/neu amplification in different stages during Barrett’s-related carcinogenesis. Her2/neu amplification analysis in 39 patients with gastroesophageal reflux disease (GERD), in 34 with BE, in 11 with dysplasia and 13 with ADC were performed with PCR. Her2/neu amplification was detected in 8% (3/39) GERD patients, 15% (5/34) with BE, 41% (7/17) with dysplasia and in 54% (7/13) with ADC. We observed an increasing trend in the frequency of Her2/neu alteration between BE-carcinogenesis stages (p=0.001). This finding was confirmed in the logistic regression analysis showing gradient in odds ratios between BE (2.07; 95% CI: 0.46-9.39), dysplasia (8.4; 95% CI: 1-83-38.53) and ADC (14.0; 95% CI: 2.81-69.69) compared to GERD; it was even higher after adjustment for age and gender. Her2/neu alterations may occur early and increasingly during Barrett’s malignant progression. We suggest that it may be useful to stratify the risk of adenocarcinoma in patients with Barrett’s esophagus.

Dpp Signaling Determines Regional Stem Cell Identity in the Regenerating Adult Drosophila Gastrointestinal Tract

The gastrointestinal tract is lined by a series of epithelia that share functional requirements but also have distinct, highly specialized roles. Distinct populations of somatic stem cells (SCs) regenerate these epithelia, yet the mechanisms that maintain regional identities of these SCs are not well understood. Here, we identify a role for the BMP-like Dppsignaling pathway in diversifying regenerative processes in the adult gastrointestinal tract of Drosophila. Dpp secreted from enterocytes at the boundary between the posterior midgut and the middle midgut (MM) sets up a morphogen gradient that selectively directs copper cell (CC) regeneration from gastric SCs in the MM and thus determines the size of the CC region. In vertebrates, deregulation of BMP signaling has been associated with Barrett's metaplasia, wherein the squamous esophageal epithelium is replaced by a columnar epithelium, suggesting that the maintenance of regional SC identities by BMP is conserved.

Erfolgreicher Fibrinkleber-basierter Verschluss einer postoperativen ösophagobronchialen Fistel nach Ösophagusresektion

HISTORY AND INTERVENTION: A 52-year-old female patient underwent open abdominothoracic cardia and esophageal resection with gastric transposition because of histologically diagnosed Barrett metaplasia with "high-grade" intraepithelial neoplasia (HGIEN) and parts of an invasive adenocarcinoma. The anastomotic insufficiency on the 10th postoperative day including an esophagobronchial fistula prompted to a subsequent surgical re-intervention with suture of the fistula, lavage and additional drainage, an endoscopic stenting of the fistula from esophageal site, as well as repeated (n = 22) bronchoscopic applications of fibrin glue (1-3 ml each) into the lumen of the fistula after each bronchoscopic lavage of the fistula until the complete closure was achieved. The changeful clinical course of 77 days on the surgical ICU was characterized by secondary complications such as pneumonia, mediastinitis and respiratory insufficiency with long-term artificial respiration and creation of a percutaneous dilatation tracheotomy. The application of fibrin glue can be considered a promising, minimally invasive therapeutic option in the management of postoperative fistula after esophageal resection, which requires expertise in decision-making and the finding-specific approach, in particular, if indicated inital steps of the sequential complication management such as surgical re-intervention and conventional endoscopic measures (stenting, Endo-VAC[-sponge]) do not provide great therapeutic potential any more due to the prolonged postoperative time course and the unfavorable local findings. In the presented case, modes of an assisted artificial respiration with low pressure and short phases of apnoe after fibrin glue application were the crucial predictions for an initial and favorable adhesion of this glue and finally for a successful sealing resulting in a sufficient closure of the fistula.

Proinflammatory Cytokines and Bile Acids Upregulate ΔNp73 Protein, an Inhibitor of p53 and p73 Tumor Suppressors

Gastroesophageal reflux disease (GERD) is the main etiological factor behind the recent rapid increase in the incidence of esophageal adenocarcinoma. During reflux, esophageal cells are exposed to bile at low pH resulting in cellular damage and inflammation, which are known to facilitate cancer development. In this study, we investigated the regulation of p73 isoform, ΔNp73α, in the reflux condition. Previous studies have reported that ΔNp73 exhibits anti-apoptotic and oncogenic properties through inhibition of p53 and p73 proteins. We found that direct exposure of esophageal cells to bile acids in an acidic environment alters the phosphorylation of ΔNp73, its subcellular localization and increases ΔNp73 protein levels. Upregulation of ΔNp73 was also observed in esophageal tissues collected from patients with GERD and Barrett’s metaplasia, a precancerous lesion in the esophagus associated with gastric reflux. c-Abl, p38 MAPK, and IKK protein kinases were identified to interact in the regulation of ΔNp73. Their inhibition with chemotherapeutic agents and siRNA suppresses ΔNp73. We also found that pro-inflammatory cytokines, IL-1β and TNFα, are potent inducers of ΔNp73α, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic ΔNp73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.

Anti-reflux surgery for patients with esophageal atresia

Gastroesophageal reflux (GER) is almost constant in esophageal atresia and tracheoesophageal fistula (EA/TEF). These patients resist medical treatment and require antireflux surgery quite often. The present review examines why this happens, the long-term consequences of GER and the main indications and results of fundoplication in this particular group of patients. The esophagus of EA/TEF patients is malformed and has abnormal extrinsic and intrinsic innervation and, consequently, deficient sphincter function and dysmotility. These anomalies are permanent. Fifty percent of patients overall have GER, and one-fifth have Barrett's metaplasia. Close to 100%, GER of pure and long-gap cases require fundoplication. In the long run, these patients have 50-fold higher risk of carcinoma than the control population. GER in EA/TEF does not respond well to dietary, antacid, or prokinetic medication. Surgery is necessary in protracted anastomotic stenoses, in pure and long-gap cases, and when there is an associated duodenal atresia. It should be indicated as well in other symptomatic cases when conservative treatment fails. However, confection of a suitable wrap is anatomically difficult in this condition as shown by a failure rate of 30% that is also explained by the persistence for life of the conditions facilitating GER.

Esophageal atresia: metaplasia, Barrett

Barrett's esophagus is characterized by the replacement of squamous epithelium by columnar epithelium that is intestinal metaplasia-positive or -negative in the distal esophagus. Gastroesophageal reflux disease, which is frequent and prolonged in esophageal atresia, probably plays a major role in the development of Barrett's esophagus through repeated mucosal damage. Long-term acid exposure contributes to carcinogenesis in Barrett's esophagus of intestinal type, but its effect on gastric metaplasia is less well defined. Recent studies have suggest that metaplasia arises in about 15% of patients with esophageal atresia, with a lag time to developing metaplasia from initial surgical correction of about 10 years. Preliminary data from an ongoing multicenter study including 88 patients with esophageal atresia aged 15-19 years showed gastric metaplasia in 42% of patients (29 fundic and 7 cardial metaplasia), while one patient presented intestinal metaplasia. Esophageal mucosal abnormalities can be observed in esophageal atresia patients at endoscopy despite the absence of symptoms. Whether prolonged, aggressive, acid suppression is beneficial in these situations remains to be determined. Barrett's metaplasia can be removed by endoscopic mucosal resection or destroyed with endoscopic ablative techniques, such as photodynamic therapy, radiofrequency ablation, and cryotherapy. The risk of developing esophageal carcinoma is still a controversial issue as only a few clinical cases have been reported in young adults with esophageal atresia. As late complications of esophageal atresia, particularly esophagitis and Barrett's esophagus, are increasingly being recognized, long-time systematic follow up of the esophageal mucosa including multistage biopsies is therefore required even in asymptomatic patients.