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The aim of this study was to determine the accuracy of clinical staging, to assess survival with surgical resection alone, and to determine factors associated with understaging in patients with esophageal adenocarcinoma thought to have limited local-regional disease.Primary surgical resection is the preferred treatment in patients with esophageal adenocarcinoma clinically staged to have limited nodal disease. This approach requires reliable clinical staging.A retrospective chart review was performed of all patients who had primary esophagectomy for clinical stage T1-3 N0-1 adenocarcinoma (seventh edition AJCC) from January 2002 to May 2013. Clinical and pathologic stages were compared and overall survival was analyzed.There were 88 patients who met inclusion criteria. Final pathology confirmed appropriate clinical staging (≤T3N1) in 76% of patients (67/88). There were 21 patients who were understaged (T3N1), and in all cases, understaging was based on the presence of advanced nodal (N2 or N3) disease. Factors independently associated with understaging were the presence of dysphagia, tumor length3 cm, and poor differentiation. At a median follow-up of 35 months, 63% of all patients (55/88) remain alive. The 5-year survival in correctly staged patients was 67%, compared with 33% for those who were understaged (P0.0001).Modern clinical staging will accurately identify the majority of patients with esophageal adenocarcinoma and limited local-regional disease (≤pT3N1). Survival with surgery alone in correctly staged patients was excellent and unlikely to be improved with neoadjuvant therapy. A combination of dysphagia, poor differentiation, and tumor length3 cm was associated with understaging in 92% of patients. Patients with these factors are likely to have more advanced disease than clinically suspected and may benefit from neoadjuvant therapy before resection.

Summary Typical reflux symptoms that respond well to proton pump inhibitor (PPI) therapy are key factors predictive of an excellent outcome with antireflux surgery for gastroesophageal reflux disease (GERD). Our aim was to evaluate whether poor preoperative heartburn (HB) relief with PPIs was associated with a worse outcome after Nissen fundoplication. Patients with a main symptom of HB and a positive pH-test who had a laparoscopic Nissen fundoplication between January 2008 and December 2014 were included. Prior to surgery, patients graded how effectively their HB symptoms were relieved by PPIs. Three groups were defined: good response (76–100% relief), partial response (26–75% relief) and poor response (0–25% relief). Outcomes and satisfaction were assessed at a minimum of 1 year after fundoplication. There were 129 patients who met inclusion criteria and 75 agreed to participate. The median follow-up was 48 months. Prior to Nissen fundoplication 13 patients had a good HB response to PPI-therapy, 36 had a partial response and 26 had a poor response. All patients were satisfied with their HB relief after fundoplication (mean satisfaction score: 9.5/10) and there was no difference in satisfaction score or heartburn relief between groups. Heartburn symptoms that respond poorly to PPI therapy are reliably relieved with a Nissen fundoplication in patients with objectively confirmed GERD. Patient satisfaction after Nissen fundoplication was excellent and was similar in patients with poor versus excellent HB relief with preoperative PPI therapy. Therefore, antireflux surgery is an option for patients with HB and confirmed GERD regardless of the degree of relief of HB symptoms provided by PPI medications.

Attention has been focused on the amplitude of esophageal body contraction to avoid persistent dysphagia after a Nissen fundoplication. The current recommended level is a contraction amplitude in the distal third of esophagus above the fifth percentile. We hypothesized that a more physiologic approach is to measure outflow resistance imposed by a fundoplication, which needs to be overcome by the esophageal contraction amplitude.The esophageal outflow resistance, as reflected by the intra-bolus pressure (iBP) measured 5 cm above the lower esophageal sphincter (LES), was measured in 53 normal subjects and 37 reflux patients with normal esophageal contraction amplitude, before and after a standardized Nissen fundoplication. All were free of postoperative dysphagia. A test population of 100 patients who had a Nissen fundoplication was used to validate the threshold of outflow resistance to avoid persistent postoperative dysphagia.The mean (SD) amplitude of the iBP in normal subjects was 6.8 (3.7) mmHg and in patients before fundoplication was 3.6 (7.0) mmHg (p = 0.003). After Nissen fundoplication, the mean (SD) amplitude of the iBP increased to 12.0 (3.2) mmHg (p0.0001 vs normal subjects or preoperative values). The 95th percentile value for iBP after a Nissen fundoplication was 20.0 mmHg and was exceeded by esophageal contraction in all patients in the validation population, and 97% of these patients were free of persistent postoperative dysphagia at a median 50-month follow-up.Nissen fundoplication increases the outflow resistance of the esophagus and should be constructed to avoid an iBP20 mmHg. Patients whose distal third esophageal contraction amplitude is20 mmHg have a minimal risk of dysphagia after a tension-free Nissen fundoplication.

Protracted dysphagia and bloating are potential troublesome side effects following Nissen fundoplication. The aim of this study was to evaluate the effects of conversion from Nissen to Toupet on dysphagia and bloating. The study used a retrospective chart review of all patients who had undergone conversion from Nissen to Toupet between 2001 and 2014. Endpoints were to determine the effect of conversion on dysphagia, bloating, and reflux control. Twenty-five patients underwent conversion at a median of 3.7 years (1.4–10.5) after initial fundoplication. Indications were dysphagia in 19 (76%) and bloating syndrome in 6 (24%) patients. The median operative time was 104 min (86–146). There were no serious complications or mortality. Median follow-up was 27 months (0.8–130). Dysphagia was relieved in 16 (84%) and bloating in all 6 patients. Two patients developed reflux requiring a redo-Nissen. Two patients had persistent dysphagia and required endoscopic dilation. The GERD-HRQL post-conversion showed a median score of 5 (3–13). Conversion relieved dysphagia in 84% and bloating in 100%. Significant recurrence of GERD was rare. Given the absence of serious complications, conversion should be considered in patients with severe bloating or dysphagia.

SUMMARY Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291

Anastomotic complications are a major source of morbidity after esophagectomy with gastric pull-up and are often related to poor graft perfusion. The aim of this study was to evaluate the use of laser-assisted fluorescent-dye angiography to assess perfusion in gastric grafts and determine the relationship between perfusion and anastomotic leaks., Objective: The aim of the study was to evaluate laser-assisted fluorescent-dye angiography (LAA) to assess perfusion in the gastric graft and to correlate perfusion with subsequent anastomotic leak. Background: Anastomotic leaks are a major source of morbidity after esophagectomy with gastric pull-up (GPU). In large part, they occur as a consequence of poor perfusion in the gastric graft. Methods: Real-time intraoperative perfusion was assessed using LAA before bringing the graft up through the mediastinum. When there was a transition from rapid and bright to slow and less robust perfusion, this site was marked with a suture. The location of the anastomosis relative to the suture was noted and the outcome of the anastomosis ascertained by retrospective record review. Results: Intraoperative LAA was used to assess graft perfusion in 150 consecutive patients undergoing esophagectomy with planned GPU reconstruction. An esophagogastric anastomosis was performed in 144 patients. A leak was found in 24 patients (16.7%) and were significantly less likely when the anastomosis was placed in an area of good perfusion compared with when the anastomosis was placed in an area of less robust perfusion by LAA (2% vs 45%, P < 0.0001). By multivariate analysis perfusion at the site of the anastomosis was the only significant factor associated with a leak. Conclusions: Intraoperative real-time assessment of perfusion with LAA correlated with the likelihood of an anastomotic leak and confirmed the critical relationship between good perfusion and anastomotic healing. The use of LAA may contribute to reduced anastomotic morbidity.

Intramucosal esophageal adenocarcinoma can be reliably treated endoscopically. Controversy exists about the use of endotherapy versus esophagectomy for submucosal tumors. Increasingly endotherapy is considered for submucosal tumors in part because of the presumed high mortality with esophagectomy and the perceived poor prognosis in patients with nodal disease. This study was designed to assess survival following primary en bloc esophagectomy (EBE) in patients with submucosal esophageal adenocarcinoma (EAC). This is a retrospective review of all patients who underwent EBE for submucosal EAC between 1998 and 2015. No patient had neoadjuvant therapy. There were 32 patients (28M/4F; median age 64 years). The median tumor size was 1.5 cm (0.4–8.0), and the median number of resected nodes was 48 (23–85). There was one perioperative death. Lymph node metastases were present in 7 patients (22%). There was one involved node in four patients and 2, 3, and 31 nodes in one patient each. The one N3 patient received adjuvant therapy. The median follow-up was 87 months. Overall survival at 5 and 10 years was 84 and 70% respectively. Disease-specific survival at 10 years was 90%. Eight patients died, but only three deaths (9%) were related to EAC. Disease-specific survival at 10 years in node-positive patients was 71%. Survival after primary en bloc esophagectomy for submucosal adenocarcinoma was excellent even in node-positive patients. Mortality with esophagectomy was low and far less than the 22% risk of node metastases in patients with submucosal tumor invasion. Esophagectomy should remain the preferred treatment for T1b esophageal adenocarcinoma.

Background The long-term outcome after colon interposition for esophageal reconstruction is not well documented. Our objective was to assess quality of life and alimentary satisfaction 10 or more years after colon interposition. Methods Patients who had an esophagectomy that was reconstructed using a colon interposition before April 2003 were identified. Symptoms, alimentary satisfaction, and quality of life were assessed by telephone interview and questionnaires. Results We identified 79 surviving patients, and follow-up was obtained in 63 (80%). The indication for esophagectomy was cancer in 45 patients and benign disease in 18. Vagal-sparing esophagectomy was performed in 48% of patients, en bloc in 44%, and transhiatal in 8%. Median follow-up was 13 years (range, 10 to 38 years). The median Gastrointestinal Quality of Life Index score was 3 of 4 and results from the RAND 36-Item Short Form Health Survey (RAND Corp, Santa Monica, CA) were at or above the published normal means in all categories. Most patients were free of dysphagia (89%), regurgitation (84%), and heartburn (84%). The most common postprandial symptom was early satiety (40%). The body mass index was within normal reference ranges in 90% of patients. Follow-up esophagogastroduodenoscopy in 30 patients at a median of 6 years showed no Barrett's metaplasia in the residual esophagus. Seven patients had a reoperation for colon redundancy. Conclusions Long-term alimentary satisfaction and quality of life were excellent after colon interposition. Most patients were free of dysphagia and few needed revision for redundancy. These results should encourage the use of a colon interposition in patients expected to survive long-term after esophagectomy.

Laparoscopic paraesophageal hernia (PEH) repair is associated with an objective recurrence rate exceeding 50 % at 5 years. Minimizing tension is a critical factor in preventing hernia recurrence. This study aimed to evaluate the outcomes of crural relaxing incisions in patients undergoing PEH repair. Records were reviewed to identify patients who received a relaxing incision during laparoscopic PEH repair. The patients were followed by chest X-ray and videoesophagram at 3 months and then annually. From November 2010 to March 2013, 58 patients underwent PEH repair, and 15 patients received a relaxing incision to accomplish crural closure. The median age of the patients was 72 years (range 58–84 years). The relaxing incision was right-sided in 13 patients, left-sided in one patient, and bilateral in one patient. All the procedures were completed laparoscopically and included a fundoplication. Collis gastroplasty for a short esophagus was performed for 40 % of the patients. No major complications occurred. During a median follow-up period of 4 months, one patient had an asymptomatic mildly elevated left hemidiaphragm, and one patient had a trivial recurrent hernia, as shown on esophagogastroduodenoscopy (EGD). Crural tension likely contributes to the high recurrence rate noted with laparoscopic PEH repair. Relaxing incisions are safe and allow crural approximation. Advanced laparoscopic surgeons should be aware of this option when faced with a large hiatus in a patient with PEH.

ObjectivesSurveillance endoscopy has been recommended for patients with Barrett's esophagus; however, recent studies have questioned the importance owing to the new, lower, estimates of the rate of progression of Barrett's esophagus to cancer. The aim of the present study was to compare the tumor stage, survival, and frequency of esophageal preservation in patients who presented with progression of Barrett's esophagus within a surveillance program versus those who presented with prevalent disease.MethodsA retrospective chart review was performed of all patients treated for high-grade dysplasia or esophageal adenocarcinoma from 2005 to 2010. The surveillance group included patients who had had at least 1 endoscopy and biopsy confirming intestinal metaplasia (with or without low-grade dysplasia) 6 months or more before the endoscopy showing progression.ResultsA total of 224 patients were included in the present study, 36 in the surveillance group and 188 in the prevalence group. The surveillance patients had significantly earlier stage tumors (P

Practitioners have noted a striking increase in the number of young patients under the age of 40 years old who develop esophageal adenocarcinoma. The aim of this study was to characterize the presentation, pathology and therapeutic outcome of these young patients. The records of patients who presented to the Foregut Surgical Service at the University of Southern California with esophageal adenocarcinoma between 2000 and 2007 were retrospectively reviewed. The presentation, tumor stage and histology, therapy and outcome of the patients under the age of 40 were compared to those ≥40. Of the 374 patients reviewed, 20 (5 %) were under the age of 40. There were two patients in their second and 18 in their third decade of life. The youngest patient was 25 years old. A history of gastroesophageal reflux disease or Barrett’s esophagus was less common in patients

UNLABELLED Knowledge of the risk of lymph node metastases is critical to planning therapy for T1 esophageal adenocarcinoma. This study retrospectively reviews 75 T1a and 51 T1b tumors and correlates lymph node metastases with depth of tumor invasion, tumor size, presence of lymphovascular invasion, and tumor grade. OBJECTIVES Increasingly, patients with superficial esophageal adenocarcinoma are being treated endoscopically or with limited surgical resection techniques. Since no lymph nodes are removed with these therapies, it is critical to have a clear understanding of the risk of lymph node metastases in these patients. The aim of this study was to define the risk of lymph node metastases for intramucosal and submucosal (T1) esophageal adenocarcinoma and to analyze factors potentially associated with an increased risk of lymph node involvement. METHODS We reanalyzed the pathology specimens of all patients that had primary esophagectomy for T1 adenocarcinoma of the distal esophagus or gastroesophageal junction from January 1985 to December 2008. The prevalence of lymph node metastases was correlated with tumor size, depth of invasion, presence of lymphovascular invasion, and degree of tumor differentiation. RESULTS There were 126 patients, 102 men (81%) and 24 women (19%), with a mean age of 64 (± 10) years. Tumor invasion was limited to the mucosa (T1a) in 75 patients (60%), whereas submucosal invasion (T1b) was present in 51 patients (40%). Tumors that had poor differentiation, lymphovascular invasion, and size ≥2 cm were significantly more likely to be invasive into the submucosa. Lymph node metastases were rare (1.3%) with intramucosal tumors but increased significantly with submucosal tumor invasion (22%)[P = 0.0003]. Lymph node metastases were also significantly associated with poor differentiation (P = 0.0015), lymphovascular invasion (P < 0.0001), and tumor size ≥2 cm (P = 0.01). Division of the submucosa into thirds did not show a layer with a significantly decreased prevalence of node metastases. CONCLUSIONS Adenocarcinoma invasive deeper than the muscularis mucosa is associated with a significant increase in the prevalence of lymph node metastases,and there is no "safe" level of invasion into the submucosa. Lymphovascular invasion, tumor size ≥2 cm, and poor differentiation are associated with an increased risk of submucosal invasion and lymph node metastases and should be factored into the decision for endoscopic therapy or esophagectomy

Background The Bravo capsule allows monitoring of esophageal acid exposure over a two-day period. Experience has shown that 24–32% of patients will have abnormal esophageal acid exposure detected on only one of the 2 days monitored. This variation has been explained by the effect of endoscopy and sedation. The aim of this study was to assess the day-to-day discrepancy following transnasal placement of the Bravo capsule without endoscopy or sedation and to determine factors related to this variability. Methods Bravo pH monitoring was performed by transnasal placement of the capsule in 310 patients. Patients were divided into groups based on the composite pH score: both days normal, both days abnormal and only one of the 2 days abnormal. Lower esophageal sphincter (LES) characteristics were compared between groups. Results Of the 310 patients evaluated, 60 (19%) showed a discrepancy between the 2 days. A total of 127 patients had a normal pH score on both days and 123 had an abnormal pH score on both days. Of the 60 patients with a discrepancy, 27 were abnormal the first day and 33 (55%) were abnormal the second day. Patients with abnormal esophageal acid exposure on both days had higher degrees of esophageal acid exposure and were more likely to have a defective LES compared to those with an abnormal score on only one day (35 vs. 83%, p = 0.027). Conclusion Patients with a discrepancy between days of Bravo pH monitoring have lower esophageal acid exposure. Variability between the 2 days represents early deterioration of the gastroesophageal barrier and indicates less advanced reflux disease.

BackgroundEsophagectomy has been the traditional therapy for high-grade dysplasia and intramucosal adenocarcinoma. New endoscopic approaches allow treatment of these lesions with esophageal preservation. The aim of this study was to compare the outcome of endoscopic therapy with esophagectomy for high-grade dysplasia and intramucosal cancer.MethodsA retrospective review was performed of all patients treated for high-grade dysplasia or intramucosal adenocarcinoma from 2001 to April 2010.ResultsEndoscopic therapy was performed in 40 patients (high-grade dysplasia = 22, intramucosal cancer = 18) and esophagectomy in 61 patients (high-grade dysplasia = 13, intramucosal cancer = 48). Endotherapy consisted of 102 endoscopic resections and 79 mucosal ablations (median 3 interventions per patient). In the endotherapy group, intramucosal cancer was completely resected in all patients. At last assessment, 10 patients have been converted to intestinal metaplasia without dysplasia and 21 to no residual intestinal metaplasia. Five patients have follow-up biopsy procedures pending after recent ablation, and esophagectomy was performed in 3 patients for failed endotherapy. A laparoscopic Nissen fundoplication has been performed in 8 patients after eradication of intestinal metaplasia. Esophagectomy resected the mucosal disease with negative margins in all patients. Compared with esophagectomy, endotherapy was associated with significantly lower morbidity (39% vs 0; P

Cervical esophageal pH monitoring using a pH threshold of4 in the diagnosis of laryngopharyngeal reflux (LPR) is disappointing. We hypothesized that failure to maintain adequate alkalization instead of acidification of the cervical esophagus may be a better indicator of cervical esophageal exposure to gastric juice. The aim of this study was to define normal values for the percent time the cervical esophagus is exposed to a pH ≥7 and to use the inability to maintain this as an indicator for diagnosis of LPR.Fifty-nine asymptomatic volunteers had a complete foregut evaluation including pH monitoring of the cervical esophagus. Cervical esophageal exposure to a pH4 was calculated, and the records were reanalyzed using the threshold pH ≥7. The sensitivity of these two pH thresholds was compared in a group of 51 patients with LPR symptoms that were completely relieved after an antireflux operation.Compared to normal subjects, patients with LPR were less able to maintain an alkaline pH in the cervical esophagus, as expressed by a lower median percent time pH ≥ 7 (10.4 vs. 38.2, p0.0001). In normal subjects, the fifth percentile value for percent time pH ≥ 7 in the cervical esophagus was 19.6%. In 84% of the LPR patients (43/51), the percent time pH ≥ 7 were below the threshold of 19.6%. In contrast, 69% (35/51) had an abnormal test when the pH records were analyzed using the percent time pH4. Of the 16 patients with a false negative test using pH 4, 11 (69%) were identified as having an abnormal study when the threshold of pH ≥ 7 was used.Normal subjects should have a pH ≥7 in cervical esophagus for at least 19.6% of the monitored period. Failure to maintain this alkaline environment is a more sensitive indicator in the diagnosis of the LPR and identifies two thirds of the patients with a false negative test using pH4.

Factors associated with the risk of progression of Barrett’s esophagus remain unclear, and the impact of therapy on this risk remains uncertain. The aim of this study was to assess patients followed long-term after anti-reflux surgery for Barrett’s esophagus. A retrospective review was performed of all patients with Barrett’s who underwent anti-reflux surgery from 1989 to 2009 and had ≥5 years of follow-up. There were 303 patients and 75 had follow-up ≥5 years. Median follow-up time for the 75 patients was 8.9 years (range 5–18). Regression was seen in 31%. Progression occurred in 8%, and these patients were significantly more likely to have a failed fundoplication (67% vs. 16%, p = 0.0129). The rate of progression from non-dysplastic Barrett’s to high-grade dysplasia or cancer was 0.8% per patient year, and was seven times higher in patients with a failed fundoplication. Compared to the accepted rate of progression of non-dysplastic Barrett’s to high-grade dysplasia or cancer of 1.0% per patient year, anti-reflux surgery reduces this rate during long-term follow-up. The rate of progression was significantly lower in patients with an intact compared to a disrupted fundoplication, further suggesting that anti-reflux surgery can alter the natural history of Barrett’s esophagus.

The lower esophageal sphincter (LES) in patients with gastroesophageal reflux disease often has a low resting pressure and a short abdominal length. The mechanism by which this occurs is unknown. We hypothesize that gastric distension causes progressive effacement of the abdominal portion of the LES, exposing it to acid injury resulting in mucosal and sphincter damage. Our aim was to assess in normal subjects the effect of gastric distension on the LES length and pressure and its exposure to acid gastric juice.Eleven asymptomatic volunteers had their LES length and pressure measured before and during gastric distension. The location of the pH step-up point (shift from gastric pH to a pH4) was also measured before and after distension.Progressive gastric distension with air resulted in progressive shortening of LES (R = 0.89, P0.0001). After infusion of 750 cc of air there was a significant reduction in the median LES length from 4 to 2.6 cm (P = 0.001). This change occurred in the abdominal length of the LES (2.6-1.4 cm [P = 0.001]) and not in the thoracic length. At rest the pH step-up point was 0.5 cm above the lower border of the LES and with distension moved a median of 1 cm cephalad within the LES. Simultaneously with the loss of length there was a reduction in LES pressure (27.4-23.4 mm Hg, P = 0.02).Gastric distension causes progressive shortening of the abdominal length of the LES and a reduction in its pressure. The process exposes the effaced mucosa and sphincter to acid gastric juice.

Objective: The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms. Summary Background Data: Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal growth factor (EGF) have been shown to mediate the regulation of local and early-onset angiogenesis, and in turn may impact the process of tumor growth and disease progression. Methods: We investigated tissue samples from 239 patients with localized EA treated with surgery alone. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism and 5'-end [γ- 33 P] ATP-labeled polymerase chain reaction methods. Results: PAR-1 -506 ins/del (adjusted P value = 0.011) and EGF +61 A>G (adjusted P value = 0.035) showed to be adverse prognostic markers, in both univariate and multivariable analyses. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted P value

Patients with respiratory and laryngeal symptoms are commonly referred for evaluation of reflux disease as a potential cause. Dual-probe pH monitoring is often performed, although data on normal acid exposure in the proximal esophagus are limited because of the small number of normal subjects and inconsistent placement of the proximal pH sensor in relation to the upper esophageal sphincter. We measured proximal esophageal acid exposure using dual-probe pH and calculated a composite pH score in a large number of asymptomatic volunteers to better define normal values.Eighty-one normal subjects free of reflux, laryngeal, or respiratory symptoms were recruited. All had video esophagraphy to exclude hiatal hernia. Esophageal pH monitoring was performed using 1 of 3 different dual-probe catheters with sensors spaced 10, 15, or 18 cm apart. The standard components of esophageal acid exposure were measured, excluding meal periods. A composite pH score for the proximal esophagus was calculated using these components.The final study population consisted of 59 (49% male) subjects, with a median age of 27 years. All had normal distal esophageal acid exposure and no hiatal hernia. The 95(th) percentile values for the percent time the pH was4 for the total, upright, and supine periods were 0.9%, 1.2%, and 0.4%, respectively. The 95(th) percentile for the number of reflux episodes was 24 and for the calculated proximal esophageal composite pH score was 16.4.In a large population of normal subjects, we have defined the normal values and calculated a composite pH score for proximal esophageal acid exposure. The total percent time pH4 was similar to previously published normal values, but the number of reflux episodes was greater.

Patients with gastroesophageal reflux disease (GERD) often complain of dysphagia and are frequently found to have intraepithelial eosinophils on esophageal biopsy. The aim of this study was to investigate the relationship between dysphagia and the number of intraepithelial eosinophils in patients with GERD. Review of all patients studied in our esophageal function laboratory from 1999 to 2007 identified 1,533 patients with increased esophageal acid exposure. Patients who complained of dysphagia without mechanical or motor causes were identified and divided into three groups based on whether dysphagia was their primary, secondary or tertiary symptom. A control group consisted of randomly selected GERD patients with no dysphagia. The highest number of intraepithelial eosinophils per high-power field (HPF) in biopsies from the squamocolumnar junction (SCJ) and esophageal body was compared across groups. There were 71 patients with unexplained dysphagia. Dysphagia was the primary symptom in 13 (18%), secondary symptom in 34 (48%), and tertiary symptom in 24 (34%) patients. The number of eosinophils differed between the four groups, with the highest number in those with dysphagia as the primary symptom (P = 0.0007). This relationship persisted whether biopsies were from the SCJ (P = 0.0057) or esophageal body (P = 0.0096). An association exists between the number of intraepithelial eosinophils and dysphagia in GERD patients, with the highest number of eosinophils in those with the primary symptom of dysphagia.

SUMMARY. It is proposed that epithelial changes induced by gastroesophageal reflux disease are related to the pH environment of the esophageal lumen. We hypothesized that the various types of esophageal epithelium are associated with specific pH environments that induce their formation. The aim of this study was to compare the luminal pH environment to the histology of the distal esophageal epithelium in patients with gastroesophageal reflux disease. A total of 197 symptomatic patients with increased esophageal acid exposure on 24-hour pH monitoring were grouped according to the histology based on biopsies from the distal esophagus: 17 with squamous epithelium, 126 with cardiac epithelium (CE), and 54 with Barrett’s epithelium (BE). All were free of Helicobacter pylori infection and monitored off acid suppression therapy. Acid exposure was expressed as the percent of time the luminal pH was at intervals of 0‐1, 1‐2, 2‐3, 3‐4, 4‐5, 5‐6, and 6‐7 over a 24-hour period. Patients with BE spent significantly more time at pH intervals 2‐3, 3‐4, and 4‐5 than those with CE. This pattern switched at pH interval 5‐6, where patients with cardiac mucosa spent more time than those with BE. Patients with squamous and CE had similar pH exposure at all intervals. Patients with BE have significantly longer exposure time at the pH interval of 2 to 5 compared to those with cardiac and squamous epithelium. This suggests that the exposure of stem cells to a luminal pH between 2 and 5 may trigger the differentiation of CE into intestinalized CE.

High-resolution manometry (HRM) is faster and easier to perform than conventional water perfused manometry. There is general acceptance of its usefulness in evaluating upper esophageal sphincter and esophageal body. There has been less emphasis on the use of HRM to evaluate the lower esophageal sphincter (LES) resting pressure and length, both factors important in LES barrier function. The aim of this study was to compare the resting characteristics of the LES determined by HRM and conventional manometry in the same patients. We performed both HRM and conventional manometry including a slow motorized pull-through technique in 55 patients with foregut symptoms. The characteristics of the LES analyzed were: resting pressure, total length, and abdominal length. Four available modes of HRM analysis were used to assess resting characteristics of the LES: spatiotemporal mode using both abrupt color change and isobaric contour, line tracing, and pressure profile. The values obtained from these four HRM modes were then compared to the conventional manometry measurements. High-resolution manometry and conventional manometry did not differ in their measurement of LES resting pressure. LES overall and abdominal length were consistently overestimated by HRM. A variability up to 4 cm in overall length was observed and was greatest in patients with hiatal hernia (1.8 vs. 0.9 cm, p = 0.027). The current construction of the catheter and software analysis used in high-resolution manometry do not allow precise measurement of LES length. Errors in the identification of the upper border of the sphincter may compromise accurate positioning of a pH probe.

A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology.

ObjectiveThe Siewert classification system differentiates between adenocarcinoma of the gastroesophageal junction and that of the distal esophagus. The purpose of this study was to evaluate whether there were differences in the location and prevalence of lymph node metastases, type of recurrence, and survival with these tumors that warrant distinguishing between them in clinical practice.MethodsRecords of all patients who underwent resection for adenocarcinoma of the distal esophagus or gastroesophageal junction from 1987 to 2007 were retrospectively reviewed. Based on the endoscopic location of the epicenter of the tumor in relation to the gastroesophageal junction, tumors were categorized in 301 patients as being of the distal esophagus and in 208 as being of the gastroesophageal junction.ResultsThere were no significant differences in age, sex, or body mass index between patients with adenocarcinoma of the distal esophagus or gastroesophageal junction. Patients with adenocarcinoma of the distal esophagus were more likely to have reflux symptoms (75% vs 53%, P < .0001) and peritumoral intestinal metaplasia (73% vs 51%, P < .0001) and be in a surveillance program (54% vs 9%, P = .0005) compared with patients with adenocarcinoma of the gastroesophageal junction. However, the prevalence and location of nodal metastases was similar, and in node-positive patients mediastinal node involvement was present in more than 40% of the patients in each group (distal esophageal adenocarcinoma, 47%; gastroesophageal junction adenocarcinoma, 41%). Survival was similar (5 years: distal esophageal adenocarcinoma, 45%; gastroesophageal junction adenocarcinoma, 38%; P = .14), as was the prevalence and type of recurrence.ConclusionThe prevalence and distribution of lymph node metastases in patients with adenocarcinoma of the distal esophagus and gastroesophageal junction were similar, and after esophagectomy, there was no difference in overall survival or recurrence. Efforts to differentiate between these tumors are unnecessary, and both are effectively treated with esophagectomy.

Background Ischemia of the gastric conduit remains an important complication of esophagectomy and is associated with an increased risk of anastomotic leak and sepsis. We report a group of patients with multiple comorbid conditions and an ischemic gastric conduit that was successfully managed by a delayed esophagogastrostomy. Study Design Between 2000 and 2007, esophagectomy with gastric pullup was performed in 554 patients. In 37 patients (7%), the combination of an ischemic graft and substantial comorbid conditions prompted delayed reconstruction to avoid an immediate esophagogastrostomy. In these patients, the gastric conduit was brought up and secured in the neck, and a cervical esophagostomy was constructed. Subsequently, a delayed esophagogastrostomy was performed through neck incision. Outcomes were analyzed at a median of 22 months (interquartile range [IQR], 13 to 30 months). Results There were 29 male and 8 female patients, with a median age of 65 years (IQR, 58 to 75 years). Thirty-one patients had malignant disease; 12 received neoadjuvant therapy. All 37 patients recovered from their esophagectomy without evidence of ischemic necrosis or fistula from their gastric conduit. In 35 patients, a delayed esophagogastrostomy was performed at a median of 98 days (IQR, 89 to 110 days). At the time of reconstruction, all had well-perfused gastric conduits, and the anastomoses healed without leak, wound infection, or sepsis. A stricture developed in three patients and was treated with dilation. Delayed esophagogastrostomy was never performed in two patients because of development of recurrent malignant disease. Conclusions Delayed esophagogastrostomy is a safe strategy for management of patients with comorbidities and an ischemic gastric conduit at the time of esophagectomy.

Introduction Obesity and gastroesophageal reflux disease (GERD) are increasingly important health problems. Previous studies of the relationship between obesity and GERD focus on indirect manifestations of GERD. Little is known about the association between obesity and objectively measured esophageal acid exposure. The aim of this study is to quantify the relationship between body mass index (BMI) and 24-h esophageal pH measurements and the status of the lower esophageal sphincter (LES) in patients with reflux symptoms. Methods Data of 1,659 patients (50% male, mean age 51 ± 14) referred for assessment of GERD symptoms between 1998 and 2008 were analyzed. These subjects underwent 24-h pH monitoring off medication and esophageal manometry. The relationship of BMI to 24-h esophageal pH measurements and LES status was studied using linear regression and multiple regression analysis. The difference of each acid exposure component was also assessed among four BMI subgroups (underweight, normal weight, overweight, and obese) using analysis of variance and covariance. Results Increasing BMI was positively correlated with increasing esophageal acid exposure (adjusted R2 = 0.13 for the composite pH score). The prevalence of a defective LES was higher in patients with higher BMI (p

A rodent model of gastroduodenal–esophageal reflux can result in replacement of squamous esophageal mucosa with intestinal-type columnar mucosa and carcinoma. The validity of this model is debated, as it is unproven whether this mucosa is intestinal metaplasia due to reflux or represents migration of adjacent jejunal mucosa above the anastomosis. The aim of this study was to evaluate the esophageal intestinal-type mucosa in these animals by measuring expression of trefoil factor genes (TFF-1, -2, -3) and comparing it with adjacent jejunum in order to determine its etiology. Twenty-five rats underwent esophagojejunostomy at the ligament of Treitz to induce reflux of gastric and duodenal contents. The animals were sacrificed at 16 weeks (n = 14) and 30 weeks (n = 11). After sacrifice, the distal esophagus, jejunum, and colon were obtained. RNA was isolated, reverse transcribed, and messenger RNA (mRNA) expression of TFF-1, -2, and -3 was measured with real-time polymerase chain reaction (PCR). Linear discriminant analysis classified samples based on gene expression. Esophageal intestinal-type mucosa was present at sacrifice in 18 animals. Compared to jejunum, the expression of TFF-1 and TFF-2 mRNA in the intestinal mucosa of the distal esophagus was increased (p = 0.0007 and p

OBJECTIVE:: The aim of this study was to determine whether the risk of systemic disease after esophagectomy can be predicted by the number of involved lymph nodes. SUMMARY BACKGROUND DATA:: Primary esophagectomy is curative in some but not all patients with esophageal cancer. Identification of patients at high risk for systemic disease would allow selective use of additional systemic therapy. This study is a multinational, retrospective review of patients treated with resection alone to assess the impact of the number of involved lymph nodes on the probability of systemic disease. METHODS:: The study population included 1053 patients with esophageal cancer (700 adenocarcinoma, 353 squamous carcinoma) who underwent R0 esophagectomy with >/=15 lymph nodes resected at 9 international centers: Asia (1), Europe (5), and United States (3). To ensure a minimum potential follow-up of 5 years, only patients who had esophagectomy before October 2002 were included. Patients treated with neoadjuvant or adjuvant therapy were excluded. The impact of the number of involved lymph nodes on the risk of systemic disease recurrence was assessed using univariate and multivariate analyses. RESULTS:: Systemic disease occurred in 40%. The number of involved lymph nodes ranged from 0 to 26 with 55% of patients having at least 1 involved lymph node. The frequency of systemic disease after esophagectomy was 16% for those without nodal involvement and progressively increased to 93% in patients with 8 or more involved lymph nodes. CONCLUSIONS:: This study shows that the number of involved lymph nodes can be used to predict the likelihood of systemic disease in patients with esophageal cancer. The probability of systemic disease exceeds 50% when 3 or more nodes are involved and approaches 100% when the number of involved nodes is 8 or more. Additional therapy is warranted in these patients with a high probability of systemic disease

Gastric adenocarcinoma has a high recurrence rate. The goal of this study was to determine the timing and pattern of recurrence after gastrectomy. A retrospective review was performed of patients with gastric adenocarcinoma having curative partial or total gastrectomy with R0/D2 lymph node resection from 1999 to 2013. Follow-up included CT scans of the chest, abdomen, and pelvis at 3-month intervals for the first three years, at 6-month intervals for the next two years, and annually thereafter. There were 62 patients, 38 males and 24 females, with a median age of 65 years. Median follow-up was 29 months and recurrence was identified in 21 per cent of patients. Median time to recurrence was 12 months and 92 per cent of recurrences occurred within two years. The last recurrence was identified at 34 months. Abdominal CT scan identified all patients with recurrence, although some patients had disease elsewhere in addition to the abdominal disease. There were no extra-abdominal isolated recurrences. In conclusion, recurrence after complete resection for gastric adenocarcinoma typically occurs within the first two years, and can be found by abdominal CT scan. Close cancer follow-up appears unnecessary after three years because all recurrences were identified within 34 months of resection.

Esophageal adenocarcinoma is typically observed in the older non-Hispanic white population. Changing demographics are altering the epidemiology of the disease. The aim of this study is to review the presentation and outcomes of esophageal adenocarcinoma patients40 years old at our institution. A retrospective review was performed of patients diagnosed with esophageal adenocarcinoma between 1990 and 2013. Demographics, presentation, and outcomes were compared in those40 years old and those ≥40 years old. There were 772 total cases with 42 (5%)40 years old consisting of 37 (88.1%) males, five females and median age of diagnosis of 35 (interquartile range: 31-38). The two most common ethnicities were White non-Hispanic/Latino in 19 (45.2%), Hispanic /Latino in 18 (42.9%). Compared with patients 40 years and older, the younger group had more Hispanic/Latinos than the older group (43% vs 17%, P0.001), more frequently presented with stage IV disease (50% vs 29%) and had a shorter median survival. In conclusion, younger patients tend to present at a much later stage than the older counterparts, which may be due to a delay in diagnosis as well as more aggressive biology. Esophageal adenocarcinoma seems to be increasing in the Hispanic/Latino population.

The use of robotic-assisted surgery (RS) has rapidly increased, but public perceptions about RS are largely unknown. The aim of this study was to gain insight into public perceptions about RS, hospitals that have robots, and surgeons that use them. A Web-based survey was distributed worldwide. Surveys were collected from July to September 2014, and those with 50 % or greater completion were used for analysis. There were 789 surveys, and 747 (95 %) were used for analysis. The mean age of respondents was 38.5 years. Most (94 %) were from the USA. Over half (53 %) had a background in health care, and 13 % were physicians. The majority of respondents (86 %) had previously heard of RS, but almost 25 % indicated that RS was like open, laser, or scarless surgery. Over 20 % of respondents indicated that the robot had some degree of autonomy during surgery. Most respondents (72 %) indicated that RS was safer, faster, and less painful or offered better results, but when asked if they would choose to have RS, 55 % would prefer to have conventional minimally invasive surgery. Hospitals with a robot were thought to be better hospitals by 53 % of the respondents. Fewer physicians perceived advantages to RS (30 % physicians vs 78 % non-physicians p

Background Treatment of Zenker's diverticulum can be accomplished by use of a transcervical myotomy (TCM) with diverticulopexy/diverticulectomy or by the transoral endoscopic stapling (TOS) approach. Our aim was to evaluate the short-term and long-term outcomes of these two techniques. Methods A retrospective review was performed to identify all patients who had received either treatment for Zenker's diverticulum from July 1998 to August 2013. Telephone interviews were attempted of all surviving patients to assess long-term outcome. Results There were 77 patients, with a median age of 71 years (range, 37 to 97 years). All patients had dysphagia, and 33 (43%) had regurgitation. TCM was performed in 68 patients, and TOS was done in nine. The median size of the diverticulum was 2.5 cm in the TCM group and 4 cm in the TOS group ( p = 0.13). The operation was primary in 66 patients (86%) and a reoperation in 11 patients. The median hospital stay was 1 day for TOS and 3 for TCM ( p = 0.0005). The median time to oral intake for both groups was 1 day. There were three adverse events in the TCM group and none in the TOS group. Early outcome was assessed in all 77 patients at a median of 4 months (interquartile range [IQR], 1 to 13.5 months). Symptomatic improvement occurred in all patients, with 55 patients (71%) reporting complete resolution. Long-term symptoms were assessed at a median of 54 months (IQR, 34 to 77 months) in 38 of 59 (64%) surviving patients. Conclusions Cricopharyngeal myotomy with diverticulopexy/diverticulectomy and TOS are both safe and effective treatments for Zenker's diverticulum. All patients reported improvement in symptoms, with complete resolution in the majority of patients.

Background Mucosal ablation and endoscopic mucosal resection have been proposed as alternatives to surgical resection as therapy for intramucosal adenocarcinoma (IMC) of the esophagus. Acceptance of these alternative therapies requires an understanding of the clinical biology of IMC and the results of surgical resection modified for treatment of early disease. Study design Retrospective review of 78 patients (65 men, 13 women; median age 66 years) with IMC who were treated with progressively less-extensive surgical resections (ie, en bloc, transhiatal, and vagal-sparing esophagectomy) from 1987 to 2005. Results The tumor was located in a visible segment of Barrett's esophagus in 65 (83%) and in cardia intestinal metaplasia in 13 (17%). A visible lesion was present in 53 (68%) and in all but 4 the lesion was cancer. In those patients with visible Barrett's, the tumor was within 3 cm of the gastroesophageal junction in 66% and within 1 cm in 37%. Esophagectomy was en bloc in 23, transhiatal in 31, vagal-sparing in 20, and transthoracic in 4. Operative mortality was 2.6%. Vagal-sparing esophagectomy had less morbidity, a shorter hospital stay, and no mortality. Of the patients who had en bloc resection, a median of 41 nodes were removed. One patient had one lymph node metastasis on hematoxylin and eosin staining and two others, normal on hematoxylin and eosin staining, had micrometastases on immunohistochemistry. Actuarial survival at 5 years was 88% and was similar for all types of resections. Two patients died from systemic metastases and seven from noncancer causes. Conclusions IMC occurred in cardia intestinal metaplasia and in Barrett's esophagus. Two-thirds of patients with IMC had a visible lesion. Most tumors occurred near the gastroesophageal junction. Node metastases were uncommon, questioning the need for lymphadenectomy. A vagal-sparing technique had less morbidity than other forms of resection and no mortality. Survival after all types of resection was similar. Outcomes of endoscopic techniques should be compared with this benchmark.

The molecular pathogenesis of Barrett's esophagus is poorly understood. Evidence suggests that at a phenotypic level, the metaplastic process begins with the transformation of squamous epithelium in the distal esophagus to cardiac mucosa, which subsequently becomes intestinalized. The homeobox gene Cdx-2 has been shown to be an important transcriptional regulator of embryonic differentiation and maintenance of adult intestinal type epithelium. We hypothesized that Cdx-2 gene expression levels increase with the phenotypic transformation of normal squamous mucosa to the intestinalized columnar mucosa of Barrett's esophagus. Endoscopic biopsies were obtained at the gastroesophageal junction in patients with symptoms of gastroesophageal reflux disease and classified according to histology: normal squamous mucosa (n = 62), cardiac mucosa (n = 19), oxynto-cardiac mucosa (n = 14), and intestinal metaplasia (n = 15). Duodenal biopsies (n = 26) served as the columnar control. After laser capture microdissection and RNA isolation, gene expression levels of Cdx-2 were measured in each tissue type by quantitative reverse transcription polymerase chain reaction. Consistent with its known function, Cdx-2 gene expression levels were highest in duodenal mucosa and nearly absent in squamous epithelium. There was a stepwise increase in Cdx-2 gene expression from cardiac to Barrett's epithelium (P < 0.001). Expression levels of Cdx-2 in cardiac and oxynto-cardiac mucosa were 40-70 times higher and Barrett's mucosa 400 times higher than that found in squamous epithelium. Relative expression of the homeobox gene Cdx-2, known to induce differentiation of intestinal type epithelium, increases in a stepwise fashion during the phenotypic transformation of distal esophageal squamous mucosa to cardiac columnar mucosa and to the intestinalized columnar mucosa of Barrett's esophagus. Therefore, Cdx-2 may be a potential biomarker to detect the early transition to Barrett's esophagus.

Background Surgery, as the mainstay of treatment for localized esophageal cancer, is currently being challenged by the assumed high risk of esophagectomy and the poor longterm survival after resection. Epidemiologic and clinical changes over the past decade indicate that these assumptions should be reevaluated. The aim of this study was to assess the modern outcomes of esophagectomy for adenocarcinoma. Study design We studied 263 consecutive patients (215 men, 48 women), who had esophagectomy for adenocarcinoma from 1992 to 2002. Ninety-seven (37%) were stage I, 63 (24%) were stage II, 93 (35%) were stage III, and 10 (4%) were stage IV. Forty-five percent (119 of 263) had curative en bloc resection, 52% (138 of 263) had node involvement, and 18% (48) received neoadjuvant therapy. Results Seventeen percent (44 of 263) of the patients were identified in a Barrett's surveillance program. The frequency of T1N0 adenocarcinoma increased over the study period (p=0.024). The overall 5-year survival was 46.5%, and for the last 5 years of the study was 50.4%. The overall 5-year survival for stage I was 81%; for stage II, 51%; for stage III, 14%; and for stage IV, 0%. Complications occurred in 61% and there were 12 perioperative deaths (4.5%). Cox proportional hazard analysis identified tumor stage and type of resection as independent predictors of survival. Conclusions Nearly half of patients undergoing esophagectomy for adenocarcinoma survive ≥5 years. Improvements in survival are associated with increased detection of early stage disease, and a liberal use of en bloc resection. Nonsurgical treatments should be compared with these contemporary outcomes measures.

The presentation and management of esophageal cancer are changing, as more patients are diagnosed at an earlier stage of the disease in which endoscopic treatment methods may be contemplated. Therefore, we conducted a study to determine whether symptomatic and endoscopic findings can accurately identify node-negative early-stage adenocarcinoma. A total of 213 consecutive patients (171 men and 42 women) with resectable esophageal adenocarcinoma seen from 1992 to 2002 were evaluated. None of these patients received neoadjuvant chemotherapy or radiation therapy. Using a multivariable model, model-based probabilities of early-stage disease (T1 im/sm N0) were calculated for each combination of the following three features: no dysphagia as main symptom at presentation, tumor length ≤2 cm, and noncircumferential lesion. Eighty-two percent of the patients with all three characteristics presented with early-stage disease. Even in the setting of small, visible, noncircumferential tumors/nodules in patients without dysphagia, 14% of the patients harbored node metastasis. Simple clinical and endoscopic findings predicted early-stage disease in 82% of cases, whereas a small but significant percentage had node metastasis. Because node metastasis predisposes to local failure in nonresectional treatment options such as endoscopic mucosal resection and photodynamic therapy, such findings should have a significant bearing on treatment decisions.

Gastroesophageal reflux symptoms occur with similar frequency in males and females, yet Barrett's esophagus is less common in females. The reason for this disparity is unknown. The aim of this study was to determine the factors related to Barrett's in females.The records of 796 patients (462 male, 334 female) evaluated from 1990 to 2000 for symptoms of reflux were retrospectively reviewed. Physiologic abnormalities based on results of endoscopic, motility, pH, and Bilitec testing were identified, and factors related to the presence of Barrett's were determined using univariate and multivariate analysis.Females with reflux symptoms were significantly less likely to have a positive 24-h pH test, a defective lower esophageal sphincter, or a hiatal hernia than males with reflux symptoms. Further, females with reflux on the basis of an abnormal 24-h pH test had significantly less esophageal acid exposure than males with reflux. In contrast, esophageal exposure to refluxed acid and bilirubin was similar in females (n = 50) and males (n = 136) with Barrett's. On multivariable analysis increased esophageal bilirubin exposure was the only significant factor associated with the presence of Barrett's in male and female patients with reflux disease.Females with reflux symptoms have less esophageal acid exposure on average than males. However, females and males with Barrett's have a similar severity of reflux, and the female gender does not protect against the development of Barrett's in the setting of advanced reflux disease. Esophageal bilirubin exposure is the major risk factor for the presence of Barrett's in patients with reflux disease.

Endoscopic ultrasound (EUS) is an essential component of preoperative staging for esophageal cancer and is used to determine which patients should proceed to primary surgical resection or receive neoadjuvant therapy prior to surgery. However, when the EUS scope cannot traverse a tumor, the role of pre-dilatation is controversial due to the risk of perforation. A retrospective review was conducted of all patients with esophageal tumor stenosis that could not accommodate the EUS scope who then proceeded with primary esophagectomy. The pathology results were classified based on the revised seventh edition American Joint Committee on Cancer staging system. A total of 27 patients met inclusion criteria. The majority of tumors were T3 (24/27, 89 %). There were no stage I tumors, 15 % (4/27) were stage II, 81 % (22/27) were stage III, and 4 % (1/27) were stage IV due to a resected solitary lung metastasis. Tumors that cannot be assessed with an EUS scope due to tumor stenosis will have locally advanced disease in the majority of cases. In these situations, pre-dilatation of the tumor with EUS staging should be omitted when considering the risk of potential esophageal perforation and the patients should be referred for neoadjuvant therapy.

Proton pump inhibitors are the mainstay of medical management in gastroesophageal reflux disease. Although they provide relief from most symptoms, reflux may persist. We hypothesize that omeprazole does not reduce the total amount of gastroesophageal reflux but simply alters its pH characteristics. Six asymptomatic volunteers had combined 24-hour impedance pH monitoring before and after 7 days of omeprazole (20 mg BID). Multichannel intraluminal impedance was used to identify reflux episodes, which were classified as acid (pH 4 but decrease > 1 pH unit) and nonacid (pH > 4 and decrease < 1 pH unit) by pH measurements 5 cm above the lower esophageal sphincter (LES). A gastric pH sensor located 10 cm below the LES was used to verify the action of omeprazole. Impedance detected a total of 116 reflux episodes before and 96 episodes after omeprazole treatment. The median number of reflux episodes (18 versus 16, P = 0.4), median duration of reflux episodes (4.7 versus 3.6 minutes, P = 0.5), and total duration of reflux episodes (27.2 versus 42.4 minutes, P = 0.5) per subject were similar before and after omeprazole. Acid reflux episodes were reduced from 63% before to 2.1% after omeprazole (P < 0.0001), whereas nonacid reflux episodes increased (15% to 76%, P < 0.0001). Weak acid reflux episodes did not change (22.4% to 21.8%, P = 1.0). The proportion of reflux episodes greater than pH 4 increased from 37% to 98% (P < 0.0001). In normal subjects, omeprazole treatment does not affect the number of reflux episodes or their duration; rather it converts acid reflux to less acid reflux, thus exposing esophagus to altered gastric juice. These observations may explain the persistence of symptoms and emergence of mucosal injury white on proton pump inhibitor therapy.

The number or ratio of lymph node metastases detected by hematoxylineosin (HE) staining is the most important predictor of survival in esophageal cancer. The survival effect of lymph node metastases detected on immunohistochemistry (IHC) is controversial. My colleagues and I hypothesized that the extent of nodal disease determined by both HE and IHC examination would more accurately predict survival than either technique alone.The study population consisted of 37 patients who underwent en bloc esophagectomy as primary therapy for esophageal adenocarcinoma 5 or more years ago. All had mediastinal and upper abdominal lymphadenectomy. No patient received neoadjuvant or adjuvant therapy. Tissue blocks were sectioned for HE staining to confirm the initial histology, and a second slide was stained with monoclonal antibodies AE1 and CAM 5.2, which are directed at a number of cytokeratin antigens. The slides were reviewed by an investigator blinded to clinical outcome. The effect of IHC staining on prognosis was assessed by comparing 5-year survival based on HE and IHC findings.A total of 1,970 nodes were examined in the 37 patients. Routine HE staining detected metastases in 29 patients (78%); the remaining 8 with N0 disease all survived at least 5 years after operation (median not reached). In the 29 patients with N1 disease, survival was 41% at 5 years. In 20 of the 29 N1 patients, metastases were detected by HE in less than 10% of the nodes removed; 55% of the patients survived 5 years, and 39% survived 8 years. Nine of the 29 patients had metastases detected in more than 10% of the nodes removed, and all died at a median of 17 months. IHC staining was performed on the nodes from the 8 N0 patients and the 20 patients with less than 10% nodal involvement (a total of 28 patients). Additional nodal metastases, not identified on HE examination, were found in 51 nodes from 17 patients (60.7%). Of the 8 patients who were node negative on HE examination, 3 had metastases detected by IHC, and all survived 5 years or more free of disease. Of the 20 patients with less than 10% nodal metastases on HE, 14 (70%) had additional metastases detected by IHC (median, 2 nodes per patient). When combined with the results of HE staining, the node ratio remained less than 10% in 13 patients and exceeded 10% in 7. Survival in patients whose ratio remained less than 10% was significantly better than in those whose ratio exceeded 10% (actual 5-year survival, 77% vs 14%; chi2 = 4.662; p = 0.03).IHC staining techniques can identify nodal metastases missed by routine HE examination in a large number of patients. The combination of HE and IHC examination is useful in patients with less than 10% nodal involvement by HE examination in that IHC detection of micrometastases allows classification into low-risk (75% survival) and high-risk (15% survival) groups. IHC-detected micrometastases are not of prognostic importance in N0 patients or those with greater than 10% nodal metastases on HE.

The objective of this study was to assess the course over time of the Barrett's metaplasia-dysplasia-carcinoma sequence. The method used was a retrospective analysis of the medical records of a patient series with a median follow-up of 25 months. The study was undertaken in a university hospital foregut laboratory. The progress of seven patients was followed through the sequence of Barrett's esophagus, low-grade dysplasia and high-grade dysplasia to cancer. They all underwent subsequent esophagectomy and were found to have intramucosal adenocarcinoma. The main outcome measure was the time from the first diagnosis of intestinal metaplasia to the development of low-grade dysplasia, high-grade dysplasia and adenocarcinoma. Low-grade dysplasia developed in a median of 24 months, high-grade dysplasia after a median of 33 months and cancer after 36 months. All patients underwent esophagectomy with reconstruction and no patient has had a recurrence at a median follow-up of 25 months (range 10-204 months). Patients on Barrett's surveillance who develop early esophageal adenocarcinoma did so within approximately 3 years after the diagnosis of non-dysplastic Barrett's esophagus.

Hypertensive lower esophageal sphincter (LES) is an uncommon manometric abnormality found in patients with dysphagia and chest pain, and is sometimes associated with gastroesophageal reflux disease (GERD). Preventing reflux by performing a fundoplication raises concerns about inducing or increasing dysphagia. The role of myotomy in isolated hypertensive LES is also unclear. The aim of this study was to determine the outcome of surgical therapy for isolated hypertensive LES and for hypertensive LES associated with GERD. Sixteen patients (5 males and 11 females), ranging in age from 39 to 89 years, with hypertensive LES (>26 mm Hg; i.e., >95th percentile of our control population) who had surgical therapy between 1996 and 1999 were reviewed. Patients with a diagnosis of achalasia and diffuse esophageal spasm were excluded. All patients had dysphagia or chest pain. Eight of 16 patients had symptoms of GERD, four had a type III hiatal hernia, and four had isolated hypertensive LES pain. Patients with hypertensive LES and GERD or type III hiatal hernia had a Nissen fundoplication, and those with isolated hypertensive LES had a myotomy of the LES with partial fundoplication. Outcome was assessed as follows: excellent if the patient was asymptomatic; good if symptoms were present but no treatment was required; fair if symptoms were present and required treatment; and poor if symptoms were unimproved or worsened. All patients were contacted by telephone for symptom assessment at a median of 3.6 years (range 3 to 6.1 years) after surgery. Patients with hypertensive LES and GERD or type III hiatal hernia had significantly lower LES pressure than those with isolated hypertensive LES (29.9 vs. 47.4 mm Hg; P = 0.013). Dysphagia and chest pain were relieved in all patients at long-term follow up. Outcome was excellent in 10 of 16, good in 3 of 16, and fair in 3 of 16. All patients but one were satisfied with their outcome. Patients with hypertensive LES are a heterogeneous group in regard to symptoms and etiology. Treatment of patients with hypertensive LES should be individualized. A Nissen fundoplication for hypertensive LES with GERD or type III hiatal hernia relieves dysphagia and chest pain suggesting reflux as an etiology. A myotomy with partial fundoplication for isolated hypertensive LES relieves dysphagia and chest pain suggesting a primary sphincter dysfunction.

Three variants of Achalasia have been described using high-resolution esophageal manometry (HRM). While manometrically distinct, their clinical significance has yet to be established. Our objective was to compare the outcome after myotomy in patients with these Achalasia subtypes. A retrospective chart review was performed to identify patients with Achalasia who had HRM and who underwent Heller myotomy or Per oral endoscopic myotomy (POEM). Symptoms and esophageal clearance by timed barium study were compared before and after treatment. We identified 49 patients, 21 males and 28 females, with a median age of 52 years. The primary symptom in all patients was dysphagia, with a median duration of 4 years (range 4 months–50 years). By HRM, ten patients (20 %) were classified as Type I, 30 (61 %) as Type II, and 9 (18 %) as Type III. At a median follow-up of 16 months after myotomy (range 1–63 months), the median Eckardt score was zero and was similar across subtypes. Relief of dysphagia was also similar across subtypes (80 % of Type I, 93 % of Type II and 89 % of Type III). On pre-treatment timed barium study, no patient had complete emptying at 1 or 5 min. After myotomy, complete emptying occurred within 1 min in 50 % (20/40) and within 5 min in 60 % (24/40) and was similar across groups. Myotomy for Achalasia results in excellent symptomatic outcome and improvement in esophageal clearance. There was no difference among the described HRM Achalasia variants. This calls into question the clinical utility of Achalasia sub-classification and affirms the benefit of myotomy for this disease.

Objective To assess the long-term outcome of antireflux surgery in patients with Barrett's esophagus. Summary background data The prevalence of Barrett's esophagus is increasing, and its treatment is problematic. Antireflux surgery has the potential to stop reflux and induce a quiescent mucosa. Its long-term outcome, however, has recently been challenged with reports of poor control of reflux and the inability to prevent progression to cancer. Methods The outcome of antireflux surgery was studied in 97 patients with Barrett's esophagus. Follow-up was complete in 88% (85/97) at a median of 5 years. Fifty-nine had long-segment and 26 short-segment Barrett's. Patients with intestinal metaplasia of the cardia were excluded. Fifty patients underwent a laparoscopic procedure, 20 a transthoracic procedure, and 3 abdominal Nissen operations. Nine had a Collis-Belsey procedure and three had other partial wraps. Outcome measures included relief of reflux symptoms (all), patients' perception of the result (all), upper endoscopy and histology (n = 79), and postoperative 24-hour pH monitoring (n = 21). Results At a median follow-up of 5 years, reflux symptoms were absent in 67 of 85 patients (79%). Eighteen (20%) developed recurrent symptoms; four had returned to taking daily acid-suppression medication. Seven patients underwent a secondary repair and were asymptomatic, increasing the eventual successful outcome to 87%. Recurrent symptoms were most common in patients undergoing Collis-Belsey (33%) and laparoscopic Nissen (26%) procedures and least common after a transthoracic Nissen operation (5%). The results of postoperative 24-hour pH monitoring were normal in 17 of 21 (81%). Recurrent hiatal hernias were detected in 17 of 79 patients studied; 6 were asymptomatic. Seventy-seven percent of the patients considered themselves cured, 22% considered their condition to be improved, and 97% were satisfied. Low-grade dysplasia regressed to nondysplastic Barrett's in 7 of 16 (44%), and intestinal metaplasia regressed to cardiac mucosa in 9 of 63 (14%). Low-grade dysplasia developed in 4 of 63 (6%) patients. No patient developed high-grade dysplasia or cancer in 410 patient-years of follow-up. Conclusions After antireflux surgery, most patients with Barrett's enjoy long-lasting relief of reflux symptoms, and nearly all patients consider themselves cured or improved. Mild symptoms recur in one fifth. Importantly, dysplasia regressed in nearly half of the patients in whom it was present before surgery, intestinal metaplasia disappeared in 14% of patients, and high-grade dysplasia and adenocarcinoma were prevented in all.

The aim of this study was to test the hypothesis that gastric bacterial overgrowth is a side effect of acid suppression therapy in patients with gastroesophageal reflux disease (GERD) and that the bacteria-contaminated gastric milieu is responsible for an increased amount of deconjugated bile acids. Thirty patients with GERD who were treated with 40 mg of omeprazole for at least 3 months and 10 patients with GERD who were off medication for at least 2 weeks were studied. At the time of upper endoscopy, 10 ml of gastric fluid was aspirated and analyzed for bacterial growth and bile acids. Bacterial overgrowth was defined by the presence of more than 1000 bacteria/ml. Bile acids were quantified via high-performance liquid chromatography. Eleven of the 30 patients taking omeprazole had bacterial overgrowth compared to one of the 10 control patients. The median pH in the bacteria-positive patients was 5.3 compared to 2.6 in those who were free of bacteria and 3.5 in the control patients who were off medication. Bacterial overgrowth only occurred when the pH was >3.8. The ratio of conjugated to unconjugated bile acids changed from 4:1 in the patients without bacterial overgrowth to 1:3 in those with bacterial growth greater than 1000/ml. Proton pump inhibitor therapy in patients with GERD results in a high prevalence of gastric bacterial overgrowth. The presence of bacterial overgrowth markedly increases the concentration of unconjugated bile acids. These findings may have implications in the pathophysiology of gastroesophageal mucosal injury.

Laparoscopic Nissen flmdoplication has been applied with increasing frequency in the treatment of gastroesophageal reflux disease. The aim of this study was to determine the variables that predict outcome of laparoscopic Nissen fundoplication. A multivariate analysis was performed on data from 199 consecutive patients undergoing laparoscopic Nissen fundoplication. Variables included age, sex, body mass index, primary symptoms, clinical response to acid suppression therapy, erosive esophagitis, 24-hour esophageal pH score, and the percentage of time the esophageal pH was less than 4 on 24-hour pH monitoring, lower esophageal sphincter competence, status of the esophageal body motility, hiatal hernia, carditis, intestinal metaplasia of cardiac epithelium limited to the gastroesophageal junction, and Barrett's esophagus of any length. Clinical outcome was obtained from all patients at a median follow-up of 15 months (range 6 to 74 months) after surgery. One hundred seventy-three patients had an excellent or good outcome (87%) and 26 had a fair or poor outcome. Three factors were significantly predictive of a successful outcome: an abnormal 24-hour pH score (odds ratio = 5.4; 95% confidence interval [CI] = 1.9-15.3), a typical primary symptom (odds ratio = 5.1; 95% CI = 1.9-13.6), and a clinical response to acid suppression therapy (odds ratio = 3.3; 95% CI = 1.3-8.7). We conclude that 24-hour pH monitoring provides the strongest outcome predictor of laparoscopic Nissen fundoplication and that outcome is based more on the correct identification of the disease than on its severity. (J GASTROINTEST SURG 1999;3:292-300.)

Objective: Adenocarcinoma has replaced squamous cell as the most common esophageal cancer in the United States. The purpose of this study was to determine the prevalence and location of lymph node metastases, the feasibility of performing an R 0 resection, and disease recurrence and survival in patients with transmural adenocarcinoma of the lower esophagus and gastroesophageal junction. Methods: Forty-four patients with transmural adenocarcinoma underwent en bloc esophagectomy with systematic thoracic and abdominal lymphadenectomy. They were followed up for a median of 23 months. Results: Actuarial survival for the entire group was 26% at 5 years. The most important predictors of the likelihood of recurrent disease and 5-year survival were the presence and number of lymph node metastases and the ratio of involved to total removed nodes. Seven patients (16%) were found to have no lymph node metastases and had an 85% 5-year survival. In contrast, patients with more than 4 involved nodes or a node ratio greater than 0.1 had a high likelihood of recurrence and death. Location of involved lymph nodes did not predict the likelihood of recurrence or death. Despite all patients having transmural tumors, recurrence within the field of the en bloc resection occurred in only 1 patient (2%). Conclusions: En bloc esophagectomy in patients with transmural esophageal adenocarcinoma is required to obtain the survival benefit of an R 0 resection, to adequately assess lymphatic tumor burden, and to be able to predict the likelihood of recurrence and death and thereby guide the use of postoperative adjuvant therapy. (J Thorac Cardiovasc Surg 1999;117:960-8)

Objective: The purpose of this study was to characterize the prevalence and location of regional lymph node metastases in adenocarcinoma confined to the esophagal wall, to determine the extent of dissection required, and to investigate the applicability of nonoperative therapy. Methods: Histologic evaluation of the resected specimens after en bloc esophagogastrectomy with mediastinal and abdominal lymphadenectomy was performed on 37 patients with adenocarcinoma confined to the esophageal wall. Follow-up was complete in all patients (median 24 months). Results: Fifteen patients (41%) had intramucosal tumors. Twelve (32%) had submucosal tumors and 10 (27%) had muscular invasion. The prevalence of regional lymph node metastases (15/37 patients, 41%) increased progressively with depth of tumor invasion, with involved nodes identified in 80% of patients with muscular invasion. Lymph node metastases were also more common at distant node stations in intramuscular tumors (5/10, 50%). Actuarial survival for the entire group was 63% at 5 years. Recurrence was identified in 6 of the 37 patients (16%), with the risk of recurrence correlating with tumor depth. Conclusions: Tumor depth is a strong predictor of the probabilities of regional lymph node metastases, the likelihood of involvement of distant node groups, and the risk of recurrence. Patients with invasion of the muscular wall are at particularly high risk. En bloc esophagectomy with mediastinal and abdominal lymphadenectomy has the highest likelihood of achieving an R 0 resection. The long-term survival and low recurrence rate achieved with an en bloc esophagectomy emphasizes the importance of an aggressive lymph node dissection to remove all potentially involved nodes. (J Thorac Cardiovasc Surg 1999;117:16-25)

OBJECTIVE: The aim of this study was to determine whether antireflux surgery is more effective in producing loss of intestinal metaplasia located only at the gastroesophageal junction than it has been in patients with intestinal metaplasia extending up into the distal esophagus. SUMMARY BACKGROUND DATA: Biopsies of a normal appearing gastroesophageal junction will demonstrate cardiac mucosa containing goblet cells--the hallmark of intestinal metaplasia--in 10% to 15% of patients who are evaluated for symptoms of gastroesophageal reflux. The incidence of adenocarcinoma of the esophagus and cardia is rising faster than any other cancer in America, and most of these cancers are found adjacent to areas of intestinal metaplasia. Antireflux surgery in patients with Barrett's esophagus may provide protection from progression to dysplasia and cancer; however, it does not reliably cause regression of the intestinal metaplasia. Less is known about the potential for intestinal metaplasia limited to the cardia (CIM) to regress. METHODS: Sixty patients with intestinal metaplasia of the esophagus or cardia had antireflux surgery. Patients in the intestinal (CIM) group (n = 15) had no endoscopically visible segment of columnar epithelium. Patients in the Barrett's group (n = 45) had columnar epithelium visible within the esophagus. Median follow-up was 25 months in each group. RESULTS: Postoperative biopsies showed complete loss of intestinal metaplasia in 73% of the patients with CIM compared with 4.4% of the patients with Barrett's. Low-grade dysplasia, present in 10 patients preoperatively, regressed in 7 patients (70%). No patient progressed to high-grade dysplasia or cancer. CONCLUSIONS: Loss of intestinal metaplasia after antireflux surgery is rare in patients with Barrett's, but occurred in most patients with CIM. This suggests that cardiac epithelium is dynamic and that microscopic areas of intestinal metaplasia are able to regress much more frequently than longer, visible segments of intestinal metaplasia.

In the rat model, esophageal adenocarcinoma reproducibly develops following surgically induced duodenal reflux into the esophagus and administration of nitrosamine. In addition, decreasing gastric acid via partial or total gastrectomy increases the prevalence of adenocarcinoma in this model. We questioned whether carcinogen was necessary for cancer development in the gastrectomized model and whether esophageal acidification could reverse the effect of gastrectomy. Three groups of 26 rats each were randomized to a surgical procedure to produce one of the following reflux models: gastroduodenal reflux by esophagojejunostomy, duodenal reflux by total gastrectomy and esophagojejunostomy, or no reflux by Roux-en-Y reconstruction. In a second experiment, 42 rats were operated on to induce duodenal reflux. One week following surgery, they were randomized to receive acidified water (pH 1.8) or tap water. The animals were killed at 24 weeks of age, and the esophagus was evaluated histologically. All animals with reflux had severe esophagitis and 87% developed columnar lining of the distal esophagus. Nearly half (48%) developed adenocarcinoma at the anastomotic site 16 weeks postoperatively and without carcinogen administration. Cancer prevalence did not differ between animals with gastroduodenal or duodenal reflux but tended to be lower in animals receiving acidified water. Duodenoesophageal reflux is carcinogenic in the rat model. Exogenous carcinogen is not necessary for cancer development in gastrectomized rats.