Severity of GERD and disease progression.

BACKGROUND: Many factors may play a role in the severity and progression of gastroesophageal reflux disease (GERD) since pathophysiology is multifactorial. Data regarding the progression of GERD are controversial: some reports of increased esophageal acid exposure (EAE) and mucosal damage were considered as evidence for a stable disease course, while others interprete these findings as disease progression. The aim of this study is to analyze a large patient-population with persisting symptoms indicative of GERD under protonpumpinhibitor-therapy and identify components characterizing disease severity and progression. METHODS: Patients with symptoms indicative of GERD were included in the study in a tertiary referral center (Frankfurt, Germany). All selected patients were under long-term protonpumpinhibitor-therapy with persistant symptoms. All patients underwent investigations to collect data on their physical status, EAE, severity of esophagitis, anatomical changes, and esophageal functional defects as well as their relation to the duration of the disease. Incidence over time was plotted as survival curves and tested with Log-rank tests for the four main disease markers. Multivariate modeling with COX-regression model was used to estimate the general impact of the four main disease markers on the time course of the disease. In order to elucidate possible causal relationships over time, a path analysis (structural equation model) was calculated. RESULTS: From the database with 1480 data sets, 972 patients were evaluated (542 males, 430 females). The mean age was 50.5 years (range18-89). The mean body mass index was 27.2(19-48). The mean time between the onset of symptoms and the diagnostic investigations was 8.2 years (1-50). A longer disease history for GERD was significantly associated with a higher risk for LES-incompetence. The mean duration from symptom onset to the time of clinical investigation was 9 years for patients with LES-incompetence (n = 563), compared to a mean of 6 years for those with mechanically intact LES (n = 95). A longer period from symptom onset to diagnostics was significantly associated with higher acid exposure. The pathway analysis was significant for the following model: 'history' (P < 0.001➔LES-incompetence & Hiatal Hernia➔(p < 0,001)➔pH-score (P < 0.001).Conclusion: LES-incompetence, the functional deterioration of the LES, and the anatomical alteration at the esophagogastric junction (Hiatal Hernia) as well as an increased EAE were associated with a long history of suffering from GERD. Path modeling suggests a causal sequence overtime of the main disease-parameters, tentatively allowing for a prediction of the course of the disease.

Proceedings from an international conference on ablation therapy for Barrett's mucosa: Brittany, France, 31 August - 2 September 1997.

The increasing incidence of adenocarcinoma of the lower esophagus and cardia arising in Barrett's metaplastic epithelium continues to be of great concern because medical and surgical efforts to reverse the process have been disappointing. A potential answer to the problem is removal of the metaplastic epithelium. Modern technology has introduced physical and chemical modalities which facilitate ablation of the neo-epithelium endoscopically. These techniques have been used in several centers, and preliminary results are encouraging. This report summarizes the proceedings of an international symposium on ablative therapy held in Brittany, France in August 1997.Twenty-eight speakers contributed to the talks on the pathology, pathogenesis, current therapy experimental studies and clinical experience of ablation of Barrett's esophagus.

Safety analysis of first 1000 patients treated with magnetic sphincter augmentation for gastroesophageal reflux disease.

Antireflux surgery with a magnetic sphincter augmentation device (MSAD) restores the competency of the lower esophageal sphincter with a device rather than a tissue fundoplication. As a regulated device, safety information from the published clinical literature can be supplemented by tracking under the Safe Medical Devices Act. The aim of this study was to examine the safety profile of the MSAD in the first 1000 implanted patients. We compiled safety data from all available sources as of July 1, 2013. The analysis included intra/perioperative complications, hospital readmissions, procedure-related interventions, reoperations, and device malfunctions leading to injury or inability to complete the procedure. Over 1000 patients worldwide have been implanted with the MSAD at 82 institutions with median implant duration of 274 days. Event rates were 0.1% intra/perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations. All reoperations were performed non-emergently for device removal, with no complications or conversion to laparotomy. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in one patient (0.1%). The safety analysis of the first 1000 patients treated with MSAD for gastroesophageal reflux disease confirms the safety of this device and the implantation technique. The overall event rates were low based on data from 82 institutions. The MSAD is a safe therapeutic option for patients with chronic, uncomplicated gastroesophageal reflux disease.

Home self-dilatation for esophageal strictures.

Esophageal strictures secondary to caustic ingestion, head and neck radiation and at the anastomosis post-esophagectomy tend to be refractory to one or several dilatations. One option for these strictures is home self-dilatation. The aim of this study was to assess the efficacy and safety of home self-dilatation for a refractory esophageal stricture. A retrospective chart review was performed of all patients from 1997 to 2009 that performed home self-dilatation for an esophageal stricture. Patients with proximal strictures without tortuosity or a shelf proximal to the stricture were selected for self-dilatation. The patients were taught self-dilatation by the surgeon and an experienced nurse, and an appropriate sized Maloney dilator was provided to the patient and returned when no longer needed. There were 16 patients (11 male and 5 female) with a median age of 60 years (range 38-78). The stricture was related to the anastomosis after esophagectomy in 12 patients, caustic injury in 3 patients and cervical chemoradiotherapy in 1 patient. Prior to initiation of self-dilatation patients had a median of four endoscopic dilatations. Self-dilatation was done with a Maloney dilator ranging in size from 45 to 60 French. The median duration of self-dilatation was 16 weeks. No patient had a perforation or complication related to self-dilatation. No patient required stenting or repetitive endoscopic dilatations because of failure of self-dilatation. Strictures recurred in two patients after cessation of self-dilatation and both responded to endoscopic dilatation followed by additional self-dilatation. Self-dilatation effectively resolves refractory esophageal strictures. It was well tolerated, and there were no complications in this series. Home self-dilatation should be considered the treatment of choice in appropriate patients with refractory esophageal strictures in the cervical esophagus.

Utilization of wireless pH monitoring technologies: a summary of the proceedings from the esophageal diagnostic working group.

Gastroesophageal reflux disease (GERD) can be difficult to diagnose - symptoms alone are often not enough, and thus, objective testing is often required. GERD is a manifestation of pathologic levels of reflux into the esophagus of acidic, nonacidic, and/or bilious gastric content. However, in our current evidence-based knowledge approach, we only have reasonable outcome data in regards to acid reflux, as this particular type of refluxate predictably causes symptoms and mucosal damage, which improves with medical or surgical therapy. While there are data suggesting that nonacid reflux may be responsible for ongoing symptoms despite acid suppression in some patients, outcome data about this issue are limited. Therefore, this working group believes that it is essential to confirm the presence of acid reflux in patients with 'refractory' GERD symptoms or extraesophageal symptoms thought to be caused by gastroesophageal reflux before an escalation of antireflux therapy is considered. If patients do not have pathologic acid reflux off antisecretory therapy, they are unlikely to have clinically significant nonacid or bile reflux. Patients who do not have pathologic acid gastroesophageal reflux parameters on ambulatory pH monitoring then: (i) could attempt to discontinue antisecretory medications like proton pump inhibitors and H2-receptor antagonists (which are expensive and which carry risks - i.e. C. diff, etc.); (ii) may undergo further evaluation for other causes of their esophageal symptoms (e.g. functional heartburn or chest pain, eosinophilic esophagitis, gastroparesis, achalasia, other esophageal motor disorders); and (iii) can be referred to an ear, nose, and throat/pulmonary/allergy physician for assessment of non-GERD causes of their extraesophageal symptoms.

Circular stapled pyloroplasty: a fast and effective technique for pyloric disruption during esophagectomy with gastric pull-up.

The necessity of pyloroplasty after esophagectomy and gastric pull-up is debated. Disadvantages of a standard pyloroplasty include the potential for leak, shortening of the length of the graft, and complexity when done during a minimally invasive procedure. The aim of this study is to report our experience with a novel internal pyloroplasty technique using a circular stapler (CS pyloroplasty), which is applicable for both laparoscopic and open esophagectomy. The records of all patients who underwent an esophagectomy with gastric pull-up and pyloroplasty between 2002 and 2007 were reviewed. The CS pyloroplasty was performed through a lesser curve gastrotomy with a 21-mm CS, while the standard pyloroplasty entailed a longitudinal full thickness incision through the pylorus with mucosal closure in the same direction and a Graham patch. A CS pyloroplasty was performed in 144 and a standard pyloroplasty in 133 patients. The median patient age was 66years, and the median follow-up was 17months, and was similar for both types of pyloroplasty. Routine postoperative videoesophagram was significantly more likely to show a delay in contrast transit through the pylorus after standard pyloroplasty (16% standard vs. 8% CS pyloroplasty, P= 0.03). Significantly more patients had postoperative endoscopy after standard pyloroplasty (40% standard vs. 24% CS pyloroplasty, P= 0.004), but the frequency of pyloric dilatation was similar. There were no leaks with either technique. A circular stapled pyloroplasty is as efficacious as a standard pyloroplasty after esophagectomy with gastric pull-up. Potential advantages include the ease and simplicity of the procedure along with virtually no risk of a leak and no graft shortening. The technique is amenable to both open and minimally invasive procedures.

The gene expression profile of cardia intestinal metaplasia is similar to that of Barrett's esophagus, not gastric intestinal metaplasia.

The etiology and significance of cardia intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus due to reflux or could reflect generalized gastric intestinal metaplasia due to Helicobacter pylori. The aim of this study was to utilize gene expression data to compare CIM to Barrett's and gastric intestinal metaplasia. Endoscopic biopsies were classified by endoscopic and histologic criteria as CIM (n= 33), Barrett's (n= 25), or gastric intestinal metaplasia of the antrum or body (n= 18). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients and patients with diffuse gastric intestinal metaplasia were excluded. H. pylori was tested for in the biopsies of all patients. After laser-capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of a panel of nine genes that has been shown to differentiate Barrett's from other foregut mucosa. Cluster analysis with linear discriminant analysis of the expression data was used to classify each sample into groups based solely on similarity of gene expression. Cluster analysis was performed for three groups (CIM vs. Barrett's vs. gastric intestinal metaplasia) and two groups (CIM + Barrett's vs. gastric intestinal metaplasia). There was no difference in H. pylori infection among groups (P= 0.66). Clustering into three groups resulted in frequent misclassification between CIM and Barrett's while misclassification of gastric intestinal metaplasia was uncommon. The CIM and Barrett's groups were then combined for two group clustering and linear discriminant analysis correctly predicted 95% of CIM and Barrett's samples and 83% of gastric intestinal metaplasia samples based on gene expression alone. In conclusion, the gene expression profiles of CIM and Barrett's esophagus were similar in 95% of biopsies and differed significantly from that of gastric intestinal metaplasia. The indistinguishable gene expression profile of CIM and BE suggests that they may share a common etiology in the majority of patients with a similar biology, and calls into question the perception that CIM is an innocuous process.

A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer.

OBJECTIVE: To evaluate 5-year survival of patients with locally advanced esophageal cancer (LAEC) who have undergone multimodality treatment with complete histopathologic response. BACKGROUND: Patients with LAEC may obtain excellent local-regional response to multimodality therapy. The overall benefit of a complete histopathologic response, when no viable tumor is present in the surgical specimen, is incompletely understood and existing data are limited to single-center studies with relatively few patients. The aim of this multicenter study was to define the outcome of patients with complete histopathologic response after multimodality therapy for LAEC. METHODS: The study population included 299 patients (229 male, 70 female; median age: 60 years) with LAEC (cT2N1M0, T3-4N0-1M0; 181 adenocarcinomas, 118 squamous carcinomas) who underwent either neoadjuvant radiochemotherapy (n = 284) or chemotherapy (n = 15) followed by esophagectomy at 6 specialized centers: Europe (3) and United States (3). All patients in the study had stage ypT0N0M0R0 after resection. RESULTS: Esophagectomy with thoracotomy (n = 255) was more frequent than with a transhiatal approach (n = 44). The median number of analyzed lymph nodes in the surgical specimens was 20 (minimum-maximum: 1-77). Thirty-day mortality rate was 2.4% and 90-day mortality rate was 5.7%. Overall 5-year survival rate was 55%. The disease-specific 5-year survival rate was 68%, with a recurrence rate of 23.4% (n = 70; local vs distant recurrence: 3.3% vs 20.1%). Cox regression analysis identified age as the only independent predictor of survival, whereas gender, histology, type of esophagectomy, type of neoadjuvant therapy, and the number of resected lymph nodes had no prognostic impact. CONCLUSION: Patients with histopathologic complete response at the time of resection of LAEC achieve excellent survival.

Surgical management of submucosal esophageal cancer: extended or regional lymphadenectomy?

INTRODUCTION: Radical esophagectomy is considered the standard therapy for tumors that infiltrate the submucosa of the esophagus (T1b), as the prevalence of lymph node metastases has been reported in up to 40% of these patients. It remains unclear whether radical esophagectomy with extended lymphadenectomy is needed or whether a surgical procedure with only regional lymphadenectomy suffices. The aim of this study was to compare outcomes of patients who underwent esophagectomy for T1b cancer through a transthoracic approach with extended lymphadenectomy (TTE) with those of patients in whom transhiatal esophagectomy (THE) was performed with a regional lymph node dissection. METHODS: Patients who underwent esophagectomy for T1b cancer between 1990 and 2004 and who did not receive (neo)adjuvant therapy were included. Data were collected from prospective databases of 4 centers. In Leuven, Belgium (n = 101), and Los Angeles, CA (n = 31), patients with T1b tumors had been operated on via TTE with extended lymphadenectomy, whereas in Amsterdam (n = 43) and Rotterdam (n = 47), the Netherlands, THE with regional lymphadenectomy had been performed. RESULTS: The 2 patient groups (TTE, n = 132; THE, n = 90) were comparable with regard to age, body mass index, and ASA classification. Operative time was longer in patients who underwent TTE (390 minutes) versus THE (250 minutes) (P < 0.001). The yield of lymph nodes resected was higher in the TTE group (median: 32) versus THE (median: 10) (P < 0.001). Overall morbidity, in-hospital mortality, and length of hospital stay were comparable between both the groups. In the TTE group, 27.3% of complications were classified as major versus 14.4% in the THE group (P < 0.001); however, the reoperation rate was higher after THE (12.2%) versus TTE (3.8%) (P = 0.01). There was no difference in pathological outcomes (infiltration depth, pN stage, pM stage, positive lymph node ratio) between both groups. Overall, 5-year survival (63.4% TTE vs 69.4% THE; P = 0.55) and disease-free 5-year survival (76.9% TTE vs 78.3% THE; P = 0.65) were comparable between both the groups. In patients with N1 disease, disease-free 5-year survival was 49.8% in the TTE group versus 40.0% in the THE group (P = 0.57). CONCLUSIONS: In patients with submucosal esophageal cancer (T1b), TTE with extended lymphadenectomy and THE with regional lymphadenectomy had similar short-term outcome and long-term survival. In the selected group of T1bN1 patients, TTE may be the preferred operative technique because of a potential disease-free survival benefit; in patients with T1bN0 disease, THE with en bloc dissection of the esophagus and regional lymph nodes offers an oncologically safe and less invasive treatment.

Esophagectomy for cancer in octogenarians.

Because of changes in life expectancy, there is an increasing number of elderly patients with esophageal cancer. The aim of this study was to assess the outcome of esophagectomy for cancer in patients 80 years or older. A retrospective review was performed of the records of all patients who underwent esophagectomy for cancer from 1992 to 2007. A cardiac and pulmonary evaluation was obtained on an individual basis in the younger patients and in all octogenarians. Among 560 patients with esophagectomy for cancer, 47 patients (8%) were octogenarians. The median age of the younger group (n= 513) was 63 years (interquartile range 56-71). Octogenarians had significantly more stage III disease (49% vs 31%, P= 0.02) but received less neoadjuvant therapy than younger patients (2% vs 21%, P= 0.0004). In octogenarians, the transhiatal resection was more common than in the younger group (79% vs 36%, P < 0.0001). Weight loss prior to surgery was similar in both groups, but body mass index was significantly lower in octogenarians (25 vs 28 kg/m(2) , P= 0.0002). Major complications occurred in 26% in octogenarians and 31% in the younger group (P= 0.51). Hospital mortality was similar (9% for octogenarians vs 4% in the younger group, P= 0.13). The median postoperative hospital stay was similar at 16 days (P= 0.69). There was no difference in cancer-related survival (median survival 48.9 vs 59.3 months, P= 0.31 log-rank test). Esophagectomy can be performed safely in carefully selected octogenarians with good cardiac and pulmonary function. Patients should not be denied an esophagectomy based only on their age.

A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold.

INTRODUCTION: Identifying gastroesophageal reflux disease as the cause of respiratory and laryngeal complaints is difficult and depends largely on the measurements of increased acid exposure in the upper esophagus or ideally the pharynx. The current method of measuring pharyngeal pH environment is inaccurate and problematic due to artifacts. A newly designed pharyngeal pH probe to avoid these artifacts has been introduced. The aim of this study was to use this probe to measure the pharyngeal pH environment in normal subjects and establish pH thresholds to identify abnormality. METHODS: Asymptomatic volunteers were studied to define the normal pharyngeal pH environment. All subjects underwent esophagram, esophageal manometry, upper and lower esophageal pH monitoring with a dual-channel pH catheter and pharyngeal pH monitoring with the new probe. Analyses were performed at 0.5 pH intervals between pH 4 and 6.5 to identify the best discriminating pH threshold and calculate a composite pH score to identify an abnormal pH environment. RESULTS: The study population consisted of 55 normal subjects. The pattern of pharyngeal pH environment was significantly different in the upright and supine periods and required different thresholds. The calculated discriminatory pH threshold was 5.5 for upright and 5.0 for supine periods. The 95th percentile values for the composite score were 9.4 for upright and 6.8 for supine. CONCLUSION: A new pharyngeal pH probe which detects aerosolized and liquid acid overcomes the artifacts that occur in measuring pharyngeal pH with existing catheters. Discriminating pH thresholds were selected and normal values defined to identify patients with an abnormal pharyngeal pH environment.

Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case report.

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.

En bloc esophagectomy reduces local recurrence and improves survival compared with transhiatal resection after neoadjuvant therapy for esophageal adenocarcinoma.

OBJECTIVE: Neoadjuvant therapy is commonly used for esophageal adenocarcinoma. We have reported reduced local recurrence rates and improved survival after an en bloc esophagectomy compared with a transhiatal resection as primary therapy for adenocarcinoma of the esophagus. The aim of this study was to determine whether the benefits of an en bloc resection would extend to patients after neoadjuvant therapy. METHODS: The charts of all patients with esophageal adenocarcinoma that had neoadjuvant therapy and en bloc or transhiatal esophagectomy from 1992-2005 were reviewed. Patients found to have systemic metastatic disease at the time of the operation or who had an incomplete resection were excluded. RESULTS: There were 58 patients: 40 had an en bloc resection and 18 had a transhiatal esophagectomy. A complete pathologic response occurred in 17 (29.3%) of 58 patients. Median follow-up was 34.1 months after en bloc resection and 18.3 months after transhiatal resection (P = .18). Overall survival at 5 years and survival in patients with residual disease after neoadjuvant therapy was significantly better with an en bloc resection (overall survival: 51% for en bloc resection and 22% for transhiatal resection [P = .04]; survival with residual disease: 48% for en bloc resection and 9% for transhiatal resection [P = .02]). Survival in patients with complete pathologic response tended to be better after an en bloc resection (en bloc, 70%; transhiatal, 43%; P = .3). CONCLUSION: An en bloc resection provides a survival advantage to patients after neoadjuvant therapy compared with a transhiatal resection, particularly for those with residual disease. Similar to patients treated with primary resection, an en bloc esophagectomy is the procedure of choice after neoadjuvant therapy.

Plasma DNA: a molecular marker of surgical insult and postoperative recovery in esophageal cancer.

AIM: To assess plasma DNA changes intraoperatively, to relate plasma DNA to the magnitude of the surgical insult and to monitor the changes during the postoperative recovery period. MATERIAL AND METHOD: Prospective study of 35 patients with esophageal cancer who had esophagectomy of different magnitudes: 19 esophagectomy without thoracotomy and 16 esophagectomy with thoracotomy. The plasma DNA was measured prior to surgery, throughout the course of the operation on four different intervals, and on postoperative days 1, 3, 5, and 7. RESULTS: A significant difference was seen in the median plasma DNA intraoperatively between the two groups: esophagectomy without thoracotomy, 507 ng/ml/min (range 211-2,708), esophagectomy with thoracotomy, median 1,098 ng/ml/min (range 295-22,284; p = 0.014). Postoperative complications were identified in 6 patients who demonstrated a significant elevation in plasma DNA on postoperative days 5 and 7. CONCLUSION: Plasma DNA increases during surgery as a result of cell damage and the rise correlates with the magnitude of surgery. The descent of plasma DNA postoperatively correlates with surgical recovery. Elevation of the plasma DNA during the postoperative period correlates with postoperative complications. Plasma DNA is an objective molecular marker of surgical insult and can be used to monitor postoperative recovery after esophagectomy.

Fibrovascular polyp of the esophagus requiring esophagectomy.

Fibrovascular polyps of the esophagus are rare, with only 110 cases reported in the world literature to date. Dysphagia is the most common symptom. The diagnosis is usually made by barium swallow or upper endoscopy, but almost a third of cases can be missed with these studies. Treatment is surgical. Only four cases in the literature underwent esophagectomy for removal. We present a female patient with a fibrovascular polyp of the esophagus who required a transhiatal esophagectomy to safely remove this mass.

Is intestinal metaplasia a necessary precursor lesion for adenocarcinomas of the distal esophagus, gastroesophageal junction and gastric cardia?

Adenocarcinoma of the distal esophagus and gastroesophageal junction are believed to arise in Barrett's esophagus with intestinal metaplasia. Whether adenocarcinoma can arise in columnar lined esophagus without intestinal metaplasia is in doubt. Whether adenocarcinoma of the gastric cardia arises in intestinal metaplasia of the gastric cardia is also in doubt. We aim to evaluate the relationship of size and stage of adenocarcinoma of the distal esophagus, gastroesophageal junction and gastric cardia to intestinal metaplasia and other types of columnar epithelium. Seventy-four patients who had esophagogastrectomy for adenocarcinomas in this region were examined histologically to assess the frequency of residual intestinal metaplasia in the surrounding epithelium. Tumors without residual intestinal metaplasia were evaluated for the presence of other columnar epithelia and correlated with tumor size and stage. Cardiac mucosa was present around all tumors. Residual intestinal metaplasia was present in 48 (65%) tumors, including 33/38 (87%) distal esophageal, 10/25 (45%) junctional and 5/11 (45%) gastric cardia tumors. The prevalence of intestinal metaplasia was 100% in all tumors that were less than 1 cm in maximum diameter and all intramucosal tumors. The prevalence of residual intestinal metaplasia decreased with increasing tumor size and stage. These data strongly support the contention that adenocarcinomas of this region, including those in the gastric cardia, arise in intestinal metaplastic epithelium. The absence of residual intestinal metaplasia in larger tumors is the result of tumor overgrowing the intestinal metaplasia from which it arose.

When are reflux episodes symptomatic?

Careful scrutiny of pH recordings and symptom diaries in patients having 24-hour pH-metry reveals that most reflux episodes are asymptomatic. Although this observation is well known and long recognized, the explanation for why one reflux episode leads to symptoms and others do not is incompletely understood. Forty-four patients with chronic typical gastroesophageal reflux disease (GERD) symptoms referred for ambulatory pH testing were studied. Antisecretory medication was stopped 2 weeks prior to the study. Two meals were taken during the study; one standardized (hamburger, fries, milk-shake) and one at the patient's discretion. A system onset marker noted the type, beginning and end of symptoms (heartburn, regurgitation, chest pain). Age, sex, upright/supine position, nadir pH, time pH < 4, and relationship to meals were compared for symptomatic/asymptomatic reflux episodes. An acid reflux event was defined as a drop in pH < 4 lasting > 5 seconds. The pH catheter detected 1464 reflux episodes. Only 93 (6.3%) were symptomatic. Forty-six of the 93 (49.4%) were associated with heartburn, 38 (40.9%) with regurgitation, and nine (9.7%) with chest pain. Nadir pH was significantly lower in symptomatic episodes. Nearly 50% of symptomatic reflux episodes occurred after meals, especially after non-standardized compared to standardized meal. Symptomatic episodes tended to be longer in duration and to occur in the supine position, while age/sex made no difference. Six percent of the reflux episodes were temporally associated with typical GERD symptoms. This association seems to be influenced by the acidity of the refluxate. Nearly half of the symptomatic reflux episodes occurred after eating.

Cdx-2 expression in squamous and metaplastic columnar epithelia of the esophagus.

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.