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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.

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.

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

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

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

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.

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.

Objective To evaluate prospectively the outcome of laparoscopic fundoplication in a large cohort of patients with typical symptoms of gastroesophageal reflux. Summary Background Data The development of laparoscopic fundoplication over the past several years has resulted in renewed interest in the surgical treatment of gastroesophageal reflux disease (GERD). Methods One hundred patients with typical symptoms of GERD were studied. The study was limited to patients with positive 24-hour pH studies and "typical" symptoms of GERD. Laparoscopic fundoplication was performed when clinical assessment suggested adequate esophageal motility and length. Outcome measures included assessment of the relief of the primary symptom responsible for surgery; the patient's and the physician's evaluation of outcome; quality of life evaluation; repeated upper endoscopy in 30 patients with presurgical esophagitis; and postsurgical physiologic studies in 28 unselected patients, consisting of 24-hour esophageal pH and lower esophageal sphincter manometry. Results Relief of the primary symptom responsible for surgery was achieved in 96% of patients at a mean follow-up of 21 months. Seventy-one patients were asymptomatic, 24 had minor gastrointestinal symptoms not requiring medical therapy, 3 had gastrointestinal symptoms requiring medical therapy, and 2 were worsened by the procedure. Eighty-three patients considered themselves cured, 11 were improved, and 1 was worse. Occasional difficulty swallowing not present before surgery occurred in 7 patients at 3 months, and decreased to 2 patients by 12 months after surgery. There were no deaths. Clinically significant complications occurred in four patients. Median hospital stay was 3 days, decreasing from 6.3 in the first 10 patients to 2.3 in the last 10 patients. Endoscopic esophagitis healed in 28 of 30 patients who had presurgical esophagitis and returned for follow-up endoscopy. Twenty-four-hour esophageal acid exposure had returned to normal in 26 of 28 patients studied after surgery. Lower esophageal sphincter pressures had also returned to normal in all patients, increasing from a median of 5.1 mmHg to 14.9 mmHg. Conclusions Laparoscopic Nissen fundoplication provides an excellent symptomatic and physiologic outcome in patients with proven gastroesophageal reflux and "typical" symptoms. This can be achieved with a hospital stay of 48 hours and a low incidence of postsurgical complications.

OBJECTIVE: The purpose of the study was to test the hypothesis that cardiac mucosa, carditis, and specialized intestinal metaplasia at an endoscopically normal-appearing cardia are manifestations of gastroesophageal reflux disease. SUMMARY BACKGROUND DATA: In the absence of esophageal mucosal injury, the diagnosis of gastroesophageal reflux disease currently rests on 24-hour pH monitoring. Histologic examination of the esophagus is not useful. The recent identification of specialized intestinal metaplasia at the cardia, along with the observation that it occurs in inflamed cardiac mucosa, led the authors to focus on the type and condition of the mucosa at the gastroesophageal junction and its relation to gastroesophageal reflux disease. METHODS: Three hundred thirty-four consecutive patients with symptoms of foregut disease, no evidence of columnar-lined esophagus, and no history of gastric or esophageal surgery were evaluated by 1) endoscopic biopsies above, at, and below the gastroesophageal junction; 2) esophageal motility; and 3) 24-hour esophageal pH monitoring. The patients were divided into groups depending on the histologic presence of cardiac epithelium with and without inflammation or associated intestinal metaplasia. Markers of gastroesophageal reflux disease were compared between groups (i.e., lower esophageal sphincter characteristics, esophageal acid exposure, the presence of endoscopic erosive esophagitis, and hiatal hernia). RESULTS: When cardiac epithelium was found, it was inflamed in 96% of the patients. The presence of cardiac epithelium and carditis was associated with deterioration of lower esophageal sphincter characteristics and increased esophageal acid exposure. Esophagitis occurred more commonly in patients with carditis whose sphincter, on manometry, was structurally defective. Specialized intestinal metaplasia at the cardia was only seen in inflamed cardiac mucosa, and its prevalence increased both with increasing acid exposure and with the presence of esophagitis. CONCLUSION: The findings of cardiac mucosa, carditis, and intestinal metaplasia in an endoscopically normal-appearing gastroesophageal junction are histologic indicators of gastroesophageal reflux disease. These findings may be among the earliest signs of gastroesophageal reflux and contribute to the authors understanding of the pathophysiology of the disease process.

Objective: Our aim was to compare outcome of vagal-sparing esophagectomy with transhiatal and en bloc esophagectomy in patients with intramucosal adenocarcinoma or high-grade dysplasia. Background Data: Intramucosal adenocarcinoma and high grade dysplasia have a low likelihood of lymphatic or systemic metastases and esophagectomy is curative in most patients. However, traditional esophagectomy is associated with significant morbidity and altered gastrointestinal function. A vagal-sparing esophagectomy offers the advantages of complete disease removal with the potential for reduced morbidity and a better functional outcome. Method: Retrospective review of outcome in patients with intramucosal adenocarcinoma or high grade dysplasia that had a vagal-sparing (n = 49), transhiatal (n = 39) or en bloc (n = 21) esophagectomy. Results: The length of hospital stay and the incidence of major complications was significantly reduced with a vagal-sparing esophagectomy compared with a transhiatal or en bloc resection. Further, postvagotomy dumping and diarrhea symptoms were significantly less common, and weight was better maintained postoperatively with a vagal-sparing esophagectomy. Recurrent cancer has developed in only 1 patient. Conclusion: Survival with intramucosal adenocarcinoma or Barrett's with high-grade dysplasia is independent of the type of resection. A vagal-sparing esophagectomy is associated with significantly less perioperative morbidity and a shorter hospital stay than a transhiatal or en bloc esophagectomy. Further, late morbidity including weight loss, dumping, and diarrhea are significantly less likely after a vagal-sparing approach. Consequently a vagal-sparing esophagectomy is the preferred procedure for patients with intramucosal adenocarcinoma or high grade dysplasia.

Objective To document what can be accomplished with surgical resection done according to the classical principles of surgical oncology. Methods One hundred consecutive patients underwent en bloc esophagectomy for esophageal adenocarcinoma. No patient received pre- or postoperative chemotherapy or radiation therapy. Tumor depth and number and location of involved lymph nodes were recorded. A lymph node ratio was calculated by dividing the number of involved nodes by the total number removed. Follow-up was complete in all patients. The median follow-up of surviving patients was 40 months, with 23 patients surviving 5 years or more. Results The overall actuarial survival rate at 5 years was 52%. Survival rates by American Joint Commission on Cancer (AJCC) stage were stage 1 (n = 26), 94%; stage 2a (n = 11), 65%; stage 2b (n = 13), 65%; stage 3 (n = 32), 23%; and stage 4 (n = 18), 27%. Sixteen tumors were confined to the mucosa, 16 to the submucosa, and 13 to the muscularis propria, and 55 were transmural. Tumor depth and the number and ratio of involved nodes were predictors of survival. Metastases to celiac (n = 16) or other distant node sites (n = 26) were not associated with decreased survival. Local recurrence was seen in only one patient. Latent nodal recurrence outside the surgical field occurred in 9 patients and systemic metastases in 31. Tumor depth, the number of involved nodes, and the lymph node ratio were important predictors of systemic recurrence. The surgical death rate was 6%. Conclusion Long-term survival from adenocarcinoma of the esophagus can be achieved in more than half the patients who undergo en bloc resection. One third of patients with lymph node involvement survived 5 years. Local control is excellent after en bloc resection. The extent of disease associated with tumors confined to the mucosa and submucosa provides justification for more limited and less morbid resections.

OBJECTIVE: The author's goal was to determine the role of duodenal components in the development of complications of gastroesophageal reflux disease. SUMMARY AND BACKGROUND DATA: There is a disturbing increase in the prevalence of complications, specifically the development of Barrett's esophagus among patients with gastroesophageal reflux disease. Earlier studies using pH monitoring and aspiration techniques have shown that increased esophageal exposure to fluid with a pH above 7, that is, of potential duodenal origin, may be an important factor in this phenomenon. METHODS: The presence of duodenal content in the esophagus was studied in 53 patients with gastroesophageal reflux disease confirmed by 24-hour pH monitoring. A portable spectrophotometer (Bilitec 2000, Synectics, Inc.) with a fiberoptic probe was used to measure intraluminal bilirubin as a marker for duodenal juice in the esophagus. Normal values for bilirubin monitoring were established for 25 healthy subjects. In a subgroup of 22 patients, a custom-made program was used to correlate simultaneous pH and bilirubin absorbance readings. RESULTS: Fifty-eight percent of patients were found to have increased esophageal exposure to gastric and duodenal juices. The degree of mucosal damage increased when duodenal juice was refluxed into the esophagus, in that patients with Barrett's metaplasia (n = 27) had a significantly higher prevalence of abnormal esophageal bilirubin exposure than did those with erosive esophagitis (n = 10) or with no injury (n = 16). They also had a greater esophageal bilirubin exposure compared with patients without Barrett's changes, with or without esophagitis. The correlation of pH and bilirubin monitoring showed that the majority (87%) of esophageal bilirubin exposure occurred when the pH of the esophagus was between 4 and 7. CONCLUSIONS: Reflux of duodenal juice in gastroesophageal reflux disease is more common than pH studies alone would suggest. The combined reflux of gastric and duodenal juices causes severe esophageal mucosal damage. The vast majority of duodenal reflux occurs at a pH range of 4 to 7, at which bile acids, the major component of duodenal juice, are capable of damaging the esophageal mucosa.