Esophageal sphincter device for gastroesophageal reflux disease.

BACKGROUND: Patients with gastroesophageal reflux disease who have a partial response to proton-pump inhibitors often seek alternative therapy. We evaluated the safety and effectiveness of a new magnetic device to augment the lower esophageal sphincter. METHODS: We prospectively assessed 100 patients with gastroesophageal reflux disease before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality of life related to gastroesophageal reflux disease and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. For each outcome, the prespecified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study are reported. RESULTS: The primary outcome was achieved in 64% of patients (95% confidence interval [CI], 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of proton-pump inhibitors occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking proton-pump inhibitors. The most frequent adverse event was dysphagia (in 68% of patients postoperatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in six patients, and in six patients the device was removed. CONCLUSIONS: In this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of proton-pump inhibitors decreased. Follow-up studies are needed to assess long-term safety. (Funded by Torax Medical; ClinicalTrials.gov number, NCT00776997.).

Quality indicators for the management of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma: international consensus recommendations from the American Gastroenterological Association Symposium.

The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barrett's esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barrett's esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barrett's esophagus.

Macrophage subtype predicts lymph node metastasis in oesophageal adenocarcinoma and promotes cancer cell invasion in vitro.

BACKGROUND: Currently, there is a lack of ideal biomarkers for predicting nodal status in preoperative stage of oesophageal adenocarcinoma (EAC) to aid optimising therapeutic options. We studied the potential of applying subtype macrophages to predict lymph node metastasis and prognosis in EAC. MATERIAL AND METHODS: Fifty-three EAC resection specimens were immunostained with CD68, CD40 (M1), and CD163 (M2). Lymphatic vessel density (LVD) was estimated with the staining of D2-40. Subsequently, we tested if M2d macrophage could promote EAC cell migration and invasion. RESULTS: In EAC without neoadjuvant treatment, an increase in M2-like macrophage was associated with poor patient survival, independent of the locations of macrophages in tumour. The M2/M1 ratio that represented the balance between M2- and M1-like macrophages was significantly higher in nodal-positive EACs than that in nodal-negative EACs, and inversely correlated with patient overall survival. The M2/M1 ratio was not related to LVD. EAC cell polarised THP1 cell into M2d-like macrophage, which promoted EAC cell migration and invasion. Neoadjuvant therapy appeared to diminish the correlation between the M2/M1 ratio and survival. CONCLUSIONS: The ratio of M2/M1 macrophage may serve as a sensitive marker to predict lymph node metastasis and poor prognosis in EAC without neoadjuvant therapy. M2d macrophage may have important roles in EAC metastasis.

International Consensus on Standardization of Data Collection for Complications Associated With Esophagectomy: Esophagectomy Complications Consensus Group (ECCG).

INTRODUCTION: Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS: The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS: A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS: The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

24-h multichannel intraluminal impedance-pH monitoring may be an inadequate test for detecting gastroesophageal reflux in patients with mixed typical and atypical symptoms.

BACKGROUND: The detection of gastroesophageal reflux (GERD) via pH testing is the key component of the evaluation of patients considered for antireflux surgery. Two common pH testing systems exist, a multichannel, intraluminal impedance-pH monitoring (MII-pH) catheter, and wireless (Bravo(®)) capsule; however, discrepancies between the two systems exist. In patients with atypical symptoms, MII-pH catheter is often used preferentially. We aimed to elucidate the magnitude of this discrepancy and to assess the diagnostic value of MII-pH and the Bravo wireless capsule in a population of patients with mixed respiratory and typical symptoms. METHODS: The study population consisted of 66 patients tested with MII-pH and Bravo pH testing within 90 days between July 2009 and 2013. All patients presented with laryngo-pharyngo-respiratory (LPR) symptoms. Patient demographics, symptomatology, manometric and endoscopic findings, and pH monitoring parameters were analyzed. Patients were divided into four comparison groups: both pH tests positive, MII-pH negative/Bravo positive, MII-pH positive/Bravo negative, and both pH tests negative. RESULTS: Nearly half of the patients (44%) had discordant pH test results. Of these, 90% (26/29) had a negative MII-pH but positive Bravo study. In this group, the difference in the DeMeester score was large, a median of 29.3. These patients had a higher BMI (28.5 vs. 26.1, p = 0.0357), were more likely to complain of heartburn (50 vs. 23%, p = 0.0110), to have a hiatal hernia, (85 vs. 53%, p = 0.0075) and a structurally defective lower esophageal sphincter (LES, 85 vs. 58%, p = 0.0208). CONCLUSIONS: In patients with LPR symptoms, we found a high prevalence of discordant esophageal pH results, most commonly a negative MII-pH catheter and positive Bravo. As these patients exhibited characteristics consistent with GERD (heartburn, defective LES, hiatal hernia), the Bravo results are likely true. A 24-h MII-pH catheter study may be inadequate to diagnose GERD in this patient population.

Comparison of cancer-associated genetic abnormalities in columnar-lined esophagus tissues with and without goblet cells.

OBJECTIVE: To determine and compare the frequency of cancer-associated genetic abnormalities in esophageal metaplasia biopsies with and without goblet cells. BACKGROUND: Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma (EAC), but the appropriate histologic definition of Barrett's esophagus is debated. Intestinal metaplasia (IM) is defined by the presence of goblet cells whereas nongoblet cell metaplasia (NGM) lacks goblet cells. Both have been implicated in EAC risk but this is controversial. Although IM is known to harbor genetic changes associated with EAC, little is known about NGM. We hypothesized that if NGM and IM infer similar EAC risk, then they would harbor similar genetic aberrations in genes associated with EAC. METHODS: Ninety frozen NGM, IM, and normal tissues from 45 subjects were studied. DNA copy number abnormalities were identified using microarrays and fluorescence in situ hybridization. Targeted sequencing of all exons from 20 EAC-associated genes was performed on metaplasia biopsies using Ion AmpliSeq DNA sequencing. RESULTS: Frequent copy number abnormalities targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In 1 subject, fluorescence in situ hybridization confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing revealed 11 nonsynonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. CONCLUSIONS: This study reports the largest and most comprehensive comparison of DNA aberrations in IM and NGM genomes. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM.

Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies.

BACKGROUND: Cyclin E is a cell cycle regulator which is critical for driving G1/S transition. Abnormal levels of cyclin E have been found in many cancers. However, the level changes of cyclin E in esophageal adenocarcinoma and its precancerous lesion have not been well studied. Here, we focus on the gene amplification and expression of cyclin E in these lesions, and aim to ascertain the relationship with clinicopathological characteristics. METHODS: Genomic DNA was analyzed from 116 esophageal adenocarcinoma and 26 precancerous lesion patients using Affymetrix SNP 6.0 arrays. The protein overexpression of cyclin E was also detected using immunohistochemistry from tissue microarrays containing esophageal adenocarcinoma and precancerous lesions. Patient survival and other clinical data were collected and analyzed. The intensity and percentage of the cyclin E expressing cells in tissue microarrays were scored by two pathologists. Fisher exact tests and Kaplan-Meier methods were used to analyze data. RESULTS: By genomic analysis, cyclin E was amplified in 19.0% of the EAC samples. By immunohistochemistry, high expression of cyclin E was observed in 2.3% of squamous mucosa tissues, 3.7% in columnar cell metaplasia, 5.8% in Barrett's esophagus, 19.0% in low grade dysplasia, 35.7% in high grade dysplasia, and 16.7% in esophageal adenocarcinoma. The differences in cyclin E high expression between neoplastic groups and non-dysplasia groups are statistically significant (p < 0.05). The prognosis for patients with high cyclin E expression appeared slightly better than for those with low cyclin E expression although this was not statistically significant (p = 0.13). CONCLUSIONS: The expression of cyclin E significantly increases from non-dysplasia esophageal lesion to low and high grade dysplasia, suggesting that cyclin E plays an important role in the early stage of carcinogenesis. Importantly, cyclin E is also amplified and highly expressed in a subset of esophageal adenocarcinoma patients, but this increase is not associated with worse prognosis.

Bile exposure inhibits expression of squamous differentiation genes in human esophageal epithelial cells.

OBJECTIVE: This study aimed to identify pathways and cellular processes that are modulated by exposure of normal esophageal cells to bile and acid. BACKGROUND: Barrett's esophagus most likely develops as a response of esophageal stem cells to the abnormal reflux environment. Although insights into the underlying molecular mechanisms are slowly emerging, much of the metaplastic process remains unknown. METHODS: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile or acid exposure. Differentially expressed genes were classified into major biological functions using pathway analysis and interaction network software. Array data were verified by quantitative PCR and western blot both in vitro and in human esophageal biopsies. RESULTS: Bile modulated expression of 202 genes, and acid modulated expression of 103 genes. Genes involved in squamous differentiation formed the largest functional group (n = 45) all of which were downregulated by bile exposure. This included genes such as involucrin (IVL), keratinocyte differentiation-associated protein (KRTDAP), grainyhead-like 1 (GRHL1), and desmoglein1 (DSG1) the downregulation of which was confirmed by quantitative PCR and western blot. Bile also caused expression changes in genes involved in cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling, and lipid metabolism. Analysis of human esophageal biopsies demonstrated greatly reduced expression of IVL, KRTDAP, DSG1, and GRHL1 in metaplastic compared to squamous epithelia. CONCLUSIONS: We report for the first time that bile inhibits the squamous differentiation program of esophageal epithelial cells. This, coordinated with induction of genes driving intestinal differentiation, may be required for the development of Barrett's esophagus.

Clinicopathologic characteristics of high expression of Bmi-1 in esophageal adenocarcinoma and squamous cell carcinoma.

BACKGROUND: High expression of Bmi-1, a key regulatory component of the polycomb repressive complex-1, has been associated with many solid and hematologic malignancies including esophageal squamous cell carcinoma. However, little is known about the role of Bmi-1 in esophageal adenocarcinoma. The aim of this study is to investigate the amplification and high expression of Bmi-1 and the associated clinicopathologic characteristics in esophageal adenocarcinoma and squamous cell carcinoma. METHODS: The protein expression level of Bmi-1 was detected by immunohistochemistry (IHC) from tissue microarrays (TMA) constructed at the University of Rochester from using tissues accrued between 1997 and 2005. Types of tissues included adenocarcinoma, squamous cell carcinoma and precancerous lesions. Patients' survival data, demographics, histologic diagnoses and tumor staging data were collected. The intensity (0-3) and percentage of Bmi-1 expression on TMA slides were scored by two pathologists. Genomic DNA from 116 esophageal adenocarcinoma was analyzed for copy number aberrations using Affymetrix SNP 6.0 arrays. Fisher exact tests and Kaplan-Meier methods were used to analyze data. RESULTS: By IHC, Bmi-1 was focally expressed in the basal layers of almost all esophageal squamous mucosa, which was similar to previous reports in other organs related to stem cells. High Bmi-1 expression significantly increased from squamous epithelium (7%), columnar cell metaplasia (22%), Barrett's esophagus (22%), to low- (45%) and high-grade dysplasia (43%) and adenocarcinoma (37%). The expression level of Bmi-1 was significantly associated with esophageal adenocarcinoma differentiation. In esophageal adenocarcinoma, Bmi-1 amplification was detected by DNA microarray in a low percentage (3%). However, high Bmi-1 expression did not show an association with overall survival in both esophageal adenocarcinoma and squamous cell carcinoma. CONCLUSIONS: This study demonstrates that high expression Bmi-1 is associated with esophageal adenocarcinoma and precancerous lesions, which implies that Bmi-1 plays an important role in early carcinogenesis in esophageal adenocarcinoma.

Update on fundoplication for the treatment of GERD.

Rudolph Nissen firstly implemented the idea of surgical treatment of gastroesophageal reflux more than 55 years ago. Today, laparoscopic fundoplication has become the surgical "golden standard" for the treatment of GERD. However, the initial enthusiasm and increasing number of performed procedures in the early 1990s declined dramatically between 2000 and 2006. Despite its excellent outcome, laparoscopic fundoplication is only offered to a minority of patients who are suffering from GERD. In this article we review the current indications for antireflux surgery, technical and intraoperative aspects of fundoplication, perioperative complications as well as short and long-term outcome. The focus is on the laparoscopic approach as the current surgical procedure of choice.

HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma.

The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of Barrett's esophagus, 18 cases of low-grade dysplasia and 15 cases of high-grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and chromogenic in situ hybridization methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by chromogenic in situ hybridization and high-density microarrays. We further confirm the similar frequency of HER2 amplification by chromogenic in situ hybridization (18%; 21 out of 116) and SNP 6.0 microarrays (16%, 19 out of 116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12% (14 out of 116) of esophageal adenocarcinoma and 7% (1 out of 15) of high-grade dysplasia. No HER2 amplification or overexpression was identified in Barrett's esophagus or low-grade dysplasia. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by chromogenic in situ hybridization than protein overexpression in esophageal adenocarcinoma (18 vs 12%). A modified two-step model for esophageal adenocarcinoma HER2 testing is recommended for clinical esophageal adenocarcinoma HER2 trial.

Esophageal perforation: surgical, endoscopic and medical management strategies.

PURPOSE OF REVIEW: The purpose of this article is to review current therapeutic strategies and outcomes in the management of esophageal perforation. The relative rarity and unpredictability of esophageal perforation has precluded a randomized or multiinstitutional study of this condition. Practice standards are based primarily on retrospective reviews and expert opinions. RECENT FINDINGS: The last decade has observed a shift from an aggressive early operative intervention to a judicious, nonoperative management of esophageal perforation in selected patients. Encouraging outcomes for nonoperative management published in recent literature result from advancements in esophageal stent technology, imaging sciences, and critical care. SUMMARY: Perforation of the esophagus, regardless of the cause, remains a major life-threatening event. Early recognition and aggressive care by a clinical team with experience in a variety of treatment modalities is increasingly important in achieving optimal outcomes in this difficult problem. Recently, encouraging results have been published utilizing esophageal stents and diligent nonoperative care in patients with esophageal perforation. The guiding principles in the treatment of this challenging condition remain early diagnosis, appropriate resuscitation, sepsis control, nutritional support, and re-establishment of esophageal continuity. Herein, we review the recent reports on the surgical, medical, and endoscopic treatment of esophageal perforation.

A population-based analysis of emergent vs. elective hospital admissions for an intrathoracic stomach.

BACKGROUND: Large-scale, population-based analyses of the demographics, management, and healthcare resource utilization of patients with an intrathoracic stomach are largely unknown, an issue which has become more important with the aging of the population. Our objective was to understand the magnitude of the problem and to assess clinical outcomes and hospital costs in elective and emergent admissions of patients with an intrathoracic stomach in a large population-based study. METHODS: The New York Statewide Planning and Research Cooperative System (SPARCS) administrative database was queried for primary ICD-9-CM codes 553.3 and 552.3 in patients 18 years or older; 4858 hospital admissions were identified over a 5-year period (2002-2006). Database variables included age, gender, race, type of admission, operative intervention, in-hospital mortality, length of stay, and cost. RESULTS: Approximately 1000 patients are admitted to the hospital each year with primary diagnosis of intrathoracic stomach, an estimated 52 per 1 million of the population in New York State. Over half of those (53%) were emergent admissions. Interestingly, the majority of emergent admissions (66%) were discharged before any surgical intervention. Patients admitted emergently were older (68.0 vs. 62.1 years, p < 0.0001) and more likely African-American (12% vs. 6%, p < 0.0001). Compared to elective admissions, emergent admissions had higher mortality (2.7% vs. 1.2%, p < 0.001), longer length of stay (LOS) (7.3 vs. 4.9 days, p < 0.0001), and higher cost ($28,484 vs. $24,069, p < 0.001). Among patients who underwent surgery, emergent admissions had higher mortality (5.1% vs. 1.1%, p < 0.0001), greater LOS (13.1 vs. 4.9 days, p < 0.0001), and higher costs ($55,460 vs. $24,760, p < 0.0001). Multivariate regression analysis demonstrated age, emergent presentation, and operative admission as independent predictors for hospital mortality, LOS, and cost (p < 0.0001). CONCLUSIONS: Strikingly, more than half of admissions for intrathoracic stomach were emergent. Emergent admissions had higher mortality, longer LOS, and higher cost than elective admissions. These data support consideration of early elective repair.

Laparoscopic Nissen fundoplication assessment: task analysis as a model for the development of a procedural checklist.

BACKGROUND: Learning an advanced laparoscopic procedure is a complex process that requires clinical exposure, direct teaching, and deliberate practice. Expert surgeons automate their knowledge, making it difficult to teach incremental steps. Our aim was to deconstruct the steps of a laparoscopic Nissen fundoplication (LNF) and develop a procedural checklist assessment instrument. METHODS: A behavioral task analysis was conducted with five experts using the Delphi technique to identify all steps of a LNF. The Delphi survey included video analysis of expert performance, two electronic iterative rounds and final group interview to reach consensus. The created checklist was then used to assess the performance of 14 general surgery residents. Participants viewed a brief instructional video and performed a LNF on a porcine model. Laparoscope video recordings were evaluated by a blinded investigator using the created LNF checklist. RESULTS: The task analysis produced a 65-step procedural checklist with six major components (patient positioning and port placement, dissection of crura and esophagus, closure of crura, mobilization of fundus, orientation of fundoplication, and creation of fundoplication). Thirteen of 14 participants completed the procedure. Median score for all residents was 31 (range 13-38) with senior residents (36, 34-38) having significantly higher scores than junior residents (30, 13-36) (p = 0.0162). Most residents attempted the major components of the procedure; 13 of 14 dissected the crura and created the fundoplication, 12 closed the crura, and 11 mobilized the fundus. However, residents frequently failed to complete key elements such as protection of the vagus nerve or mediastinal mobilization of the esophagus. CONCLUSIONS: The task analysis and Delphi technique was successful in reaching expert consensus on the procedural steps of a LNF and in creating a valid checklist. By capturing automated knowledge in a checklist form, we can scaffold resident learning and improve feedback for an advanced laparoscopic case.

Pathogenesis of Barrett esophagus: deoxycholic acid up-regulates goblet-specific gene MUC2 in concert with CDX2 in human esophageal cells.

HYPOTHESIS: Bile acid exposure can induce caudal-related homeobox 2 (CDX2) messenger RNA (mRNA) expression, a transcription factor that plays a crucial role in the development of Barrett esophagus. We investigated mucin 2 (MUC2) and CDX2 mRNA expression before and after treatment with deoxycholic acid in 4 human esophageal cell lines. DESIGN, SETTING, AND PARTICIPANTS: Four human esophageal cell lines-(1) normal squamous cells immortalized by SV40 (Het-1A), (2) adenocarcinoma (SEG-1), and (3 and 4) squamous cell carcinoma (HKESC-1 and HKESC-2)-were exposed in culture for 1 to 24 hours to 100 microM to 1000 microM deoxycholic acid. Total RNA was extracted before and after bile acid treatment and reverse transcribed to complementary DNA. MAIN OUTCOME MEASURE: MUC2 and CDX2 mRNA expression as determined by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: MUC2 mRNA expression was absent before deoxycholic acid exposure in all 4 cell lines. MUC2 expression increased in a dose- and time-dependent manner with deoxycholic acid in all cell lines. Deoxycholic acid activated MUC2 up-regulation, which correlated directly with CDX2 up-regulation in all 4 cell lines. CONCLUSIONS: Bile acids up-regulate both intestinal differentiation factor CDX2 and goblet cell-specific gene MUC2 in normal esophageal and cancer cell lines. Further, bile acid-stimulated MUC2 up-regulation correlates directly with CDX2 up-regulation. The simultaneous up-regulation of both CDX2 and MUC2 after bile acid exposure provides molecular evidence of the role of bile acid in the pathogenesis of Barrett esophagus.

The pathogenesis of Barrett's esophagus: secondary bile acids upregulate intestinal differentiation factor CDX2 expression in esophageal cells.

INTRODUCTION: Clinical evidence strongly suggests that bile acids are important in the development of Barrett's esophagus, although the mechanism remains unknown. Caudal-related homeobox 2 (CDX2) is a transcription factor recently implicated in early differentiation and maintenance of normal intestinal epithelium and is suggested to play a key role in the pathogenesis of intestinal metaplasia in Barrett's esophagus. OBJECTIVE: The aim of this study was to investigate the effect of primary and secondary bile acids on CDX2 mRNA expression in human esophageal cells. METHODS: Human esophageal cells: (1) squamous, immortalized by SV40 (Het-1A); (2) adenocarcinoma (SEG-1); and (3) squamous cell carcinoma (HKESC-1 & HKESC-2), were exposed in cell culture for 1-24 h to 100-1,000 microM deoxycholic, chenodeoxycholic, and glycocholic acids. Total RNA was extracted before and after bile acid treatment and reverse transcribed to cDNA. CDX2 mRNA expression was determined by both quantitative real-time and reverse transcription PCR (RT-PCR). RESULTS: CDX2 mRNA expression was absent before bile acid exposure in all cell lines. CDX2 expression increased in a dose- and time-dependent fashion with deoxycholic and chenodeoxycholic, but not glycocholic, acid in all four cell lines. The maximal induction of CDX2 expression was seen in SEG-1 adenocarcinoma cells. Expression in Het-1A cells also increased significantly as did expression in HKESC-1,2 cells, although to a lesser extent than in adenocarcinoma. CONCLUSIONS: These findings show that secondary bile acid stimulation upregulates CDX2 gene expression in both normal and cancer cell lines. They further support the role of bile acids in the pathogenesis of Barrett's esophagus and link the clinical evidence of a high prevalence of luminal bile acids in Barrett's to expression of the gene thought to be responsible for the phenotypic expression of intestinal metaplasia.

Esophagectomy for high grade dysplasia is safe, curative, and results in good alimentary outcome.

BACKGROUND: The increasing adoption of endoscopic therapies and expectant surveillance for patients with high grade dysplasia (HGD) in Barrett's esophagus has created considerable controversy regarding the ideal treatment choice. Confusion may be due, in part, to a limited understanding of the outcomes associated with surgical resection for HGD and extrapolation of data derived from patients undergoing an esophagectomy for invasive cancer. The purpose of our study was to document the perioperative and symptomatic outcomes and long-term survival after esophagectomy for HGD of the esophagus. MATERIAL AND METHODS: The study population consisted of 38 patients who underwent esophagectomy for biopsy-proven HGD between 10/1999 and 6/2005. Three patients were excluded from analysis due to obvious tumor on upper endoscopy. Patients were evaluated regarding ten different foregut symptoms and administered a ten-question appraisal of eating and bowel habits. Outcome measures included postoperative morbidity and mortality, the prevalence of invasive cancer in the esophagectomy specimens, symptomatic and functional alimentary results, patient satisfaction, and long-term survival. Median follow-up was 32 months (range, 7-83). RESULTS: Thirty-day postoperative and in-hospital mortality was zero. Complications occurred in 37% (13/35), and median length of stay was 10 days. Occult adenocarcinoma was found in 29% (10/35) of surgical specimens (intramucosal in four; submucosal in five; and intramuscular in one with a single positive lymph node.) Patients consumed a median of three meals per day, most (76%, 26/34) had no dietary restrictions, and two-thirds (23/34) considered their eating pattern to be normal or only mildly impacted. Meal size, however, was reported to be smaller in the majority (79%, 27/34) of patients. Median body mass index (BMI) decreased slightly after surgery (28.6 vs 26.6, p>0.05), but no patient's BMI went below normal. The number of bowel movements/day was unchanged or less in a majority (82%) of patients after surgery. Fifteen of 34 (44%) patients reported loose bowel movements, which occurred less often than once per week in 10 of the 15. One patient had symptoms of dumping. Mean symptom severity scores improved for all symptoms except dysphagia and choking. Four patients developed foregut symptoms that occurred daily. Most patients (82%) required at least one postoperative dilation for dysphagia. Almost all (97%) patients were satisfied. Disease-free survival was 100%, and overall survival was 97% (34/35) at a median of 32 months. CONCLUSION: Esophagectomy is an effective and curative treatment for HGD and can be performed with no mortality, acceptable morbidity, and good alimentary outcome. These data provide a gold standard for comparison to alternative therapies.

Gastrectomy as a remedial operation for failed fundoplication.

The decision for, and choice of, a remedial antireflux procedure after a failed fundoplication is a challenging clinical problem. Success depends upon many factors including the primary symptom responsible for failure, the severity of underlying anatomic and physiologic defects, and the number and type of previous remedial attempts. Satisfactory outcomes after reoperative fundoplication have been reported to be as low as 50%. Consequently, the ideal treatment option is not clear. The purpose of this study was to evaluate the outcome of gastrectomy as a remedial antireflux procedure for patients with a failed fundoplication. The study population consisted of 37 patients who underwent either gastrectomy (n = 12) with Roux-en-Y reconstruction or refundoplication (n = 25) between 1997-2005. Average age, M/F ratio, and preoperative BMI were not significantly different between the two groups. Outcome measures included perioperative morbidity, relief of primary and secondary symptoms, and the patients' overall assessment of outcome. Mean follow up was 3.5 and 3.3 years in the gastrectomy and refundoplication groups, respectively (p = 0.43). Gastrectomy patients had a higher prevalence of endoscopic complications of GERD (58% vs 4%, p = 0.006) and of multiple prior fundoplications than those having refundoplication (75% vs 24%, p = 0.004). Mean symptom severity scores were improved significantly by both gastrectomy and refundoplication, but were not significantly different from each other. Complete relief of the primary symptom was significantly greater after gastrectomy (89% vs 50%, p = 0.044). Overall patient satisfaction was similar in both groups (p = 0.22). In-hospital morbidity was higher after gastrectomy than after refundoplication (67% vs 20%, p = 0.007) and new onset dumping developed in two gastrectomy patients. In select patients with severe gastroesophageal reflux disease (GERD) and multiple previous fundoplications, primary symptom resolution occurs significantly more often after gastrectomy than after repeat fundoplication. Gastrectomy, however, is associated with higher morbidity. Gastrectomy is an acceptable treatment option for recurrent symptoms particularly when another attempt at fundoplication is ill advised, such as in the setting of multiple prior fundoplications or failed Collis gastroplasty.