Molecular Markers and Diagnostic Model Specific for Barrett's Esophagus.

Biomarkers involved in the progression of Barrett's esophagus (BE) have not been extensively studied. We aimed to identify novel molecular markers for the early diagnosis of BE. The expression profiles of GSE100843 including BE segment and normal squamous mucosa samples before and after vitamin D3 supplementation were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using the limma package. Principal component analysis was performed using Minitab, and DEGs in the top three principal components were clustered into different gene sets by the mclust package. Pathways and functions enriched by these gene sets were evaluated by deregulation score analysis. Key genes associated with BE were identified by coexpression analysis and a genetic algorithm. Using the xgboost package, an XGBoost classifier specific for BE was further constructed based on the key genes. A total of 2598 DEGs were identified, which were further clustered into nine gene sets. According to the deregulation scores of pathways and functions enriched by these gene sets, nine functional and pathway terms were significantly deregulated in BE. Among the DEGs, CREB3L1, HNF1B, and IL35 were genes with high fitness levels and connectivity degrees, predicting that they were key genes associated with BE. The XGBoost classifier constructed using the key genes was efficient and robust in BE prediction. The accuracies for prediction were 93% and 87% for training and validation datasets, respectively. Key genes may serve as novel biomarkers of BE, and the XGBoost classifier may contribute to the diagnosis of BE in future clinical practice.

Multimodality evaluation of patients with gastroesophageal reflux disease symptoms who have failed empiric proton pump inhibitor therapy.

Patients with symptoms suggestive of gastroesophageal reflux disease (GERD), such as chest pain, heartburn, regurgitation, and dysphagia, are typically treated initially with a course of proton pump inhibitors (PPIs). The evaluation of patients who have either not responded at all or partially and inadequately responded to such therapy requires a more detailed history and may involve an endoscopy and esophageal biopsies, followed by esophageal manometry, ambulatory esophageal pH monitoring, and gastric emptying scanning. To assess the merits of a multimodality 'structural' and 'functional' assessment of the esophagus in patients who have inadequately controlled GERD symptoms despite using empiric PPI, a retrospective cohort study of patients without any response or with poor symptomatic control to empiric PPI (>2 months duration) who were referred to an Esophageal Studies Unit was conducted. Patients were studied using symptom questionnaires, endoscopy (+ or - for erosive disease, or Barrett's metaplasia) and multilevel esophageal biopsies (eosinophilia, metaplasia), esophageal motility (aperistalsis, dysmotility), 24-hour ambulatory esophageal pH monitoring (+ if % total time pH < 4 > 5%), and gastric emptying scanning (+ if >10% retention at 4 hours and >70% at 2 hours). Over 3 years, 275 patients (147 men and 128 women) aged 16-89 years underwent complete multimodality testing. Forty percent (n= 109) had nonerosive reflux disease (esophagogastroduodenoscopy [EGD]-, biopsy-, pH+); 19.3% (n= 53) had erosive esophagitis (EGD+); 5.5% (n= 15) Barrett's esophagus (EGD+, metaplasia+); 5.5% (n= 15) eosinophilic esophagitis (biopsy+); 2.5% (n= 7) had achalasia and 5.8% (n= 16) other dysmotility (motility+, pH-); 16% (n= 44) had functional heartburn (EGD-, pH-), and 5.8% (n= 16) had gastroparesis (gastric scan+). Cumulative symptom scores for chest pain, heartburn, regurgitation, and dysphagia were similar among the groups (mean range 1.1-1.35 on a 0-3 scale). Multimodality evaluation changed the diagnosis of GERD in 34.5% of cases and led to or guided alternative therapies in 42%. Overlap diagnoses were frequent: 10/15 (67%) of patients with eosinophilic esophagitis, 12/16 (75%) of patients with gastroparesis, and 11/23 (48%) of patients with achalasia or dysmotility had concomitant pathologic acid reflux by pH studies. Patients with persistent GERD symptoms despite empiric PPI therapy benefit from multimodality evaluation that may change the diagnosis and guide therapy in more than one third of such cases. Because symptoms are not specific and overlap diagnoses are frequent and multifaceted, objective evidence-driven therapies should be considered in such patients.

Pre-clinical evaluation of fluorescent deoxyglucose as a topical contrast agent for the detection of Barrett's-associated neoplasia during confocal imaging.

The availability of confocal endomicroscopy motivates the development of optical contrast agents that can delineate the morphologic and metabolic features of gastrointestinal neoplasia. This study evaluates 2-NBDG, a fluorescent deoxyglucose, the uptake of which is associated with increased metabolic activity, in the identification of Barrett's-associated neoplasia. Surveillance biopsies from patients with varying pathologic grades of Barrett's esophagus were incubated ex vivo at 37°C with 2-NBDG and imaged with a fluorescence confocal microscope. Images were categorized as neoplastic (high grade dysplasia, esophageal adenocarcinoma) or metaplastic (intestinal metaplasia, low grade dysplasia) based on the degree of glandular 2-NBDG uptake. Classification accuracy was assessed using histopathology as the gold standard. Forty-four biopsies were obtained from twenty-six patients; 206 sites were imaged. The glandular mean fluorescence intensity of neoplastic sites was significantly higher than that of metaplastic sites (p<0.001). Chronic inflammation was associated with increased 2-NBDG uptake in the lamina propria but not in glandular epithelium. Sites could be classified as neoplastic or not with 96% sensitivity and 90% specificity based on glandular mean fluorescence intensity. Classification accuracy was not affected by the presence of inflammation. By delineating the metabolic and morphologic features of neoplasia, 2-NBDG shows promise as a topical contrast agent for confocal imaging. Further in vivo testing is needed to determine its performance in identifying neoplasia during confocal endomicroscopic imaging.

[Clinical characteristics of gastroesophageal reflux disease with esophageal injury in korean: focusing on risk factors].

BACKGROUND/AIMS: Recent studies suggest that the prevalence of gastroesophageal reflux disease (GERD) is increasing in Korea. However, studies on risk factors for GERD have yielded inconsistent results. The aims of this study were to compare clinical features between symptomatic syndromes without esophageal injury (=non-erosive disease [NED]) and syndromes with esophageal injury (=erosive disease [ED]), and to determine risk factors associated ED. METHODS: A total of 450 subjects who visited gastroenterology clinics of six training hospitals in Daegu from March 2008 to April 2010 were consecutively enrolled. The subjects were asked to complete a questionnaire which inquired about gastroesophageal reflux symptoms. The questionnaire also included questions about smoking, alcohol drinking, consumption of coffee, use of drugs, exercise, and other medical history. The subjects were subdivided into NED and ED groups. RESULTS: The proportion of subjects in each NED and ED group was 172 (38.2%) and 278 (61.8%). Male gender, smoking, alcohol drinking, consumption of coffee, large waist circumference, infrequent medication of antacids, aspirin and NSAIDs, infrequent and mild GERD symptoms were all significantly associated with ED on univariate analysis. Age, hiatal hernia, diabetes mellitus, body mass index, change in weight during 1 year, and number of typical GERD symptoms were not independent risk factors for ED. However, the association between ED and alcohol drinking, infrequent medication of antacids, mild typical GERD symptoms remained as strong risk factors after adjustments on multivariate logistic analysis. CONCLUSIONS: Independent risk factors associated with ED were alcohol drinking, infrequent medication of antacids and mild typical GERD symptoms.

Diagnosing Barrett's esophagus: reliability of clinical and pathologic diagnoses.

BACKGROUND: The accuracy of a Barrett's esophagus diagnosis is not well studied. OBJECTIVE: Our purpose was to evaluate the accuracy of a clinical Barrett's esophagus diagnosis and the reproducibility of an esophageal intestinal metaplasia diagnosis. METHODS: All patients with a Barrett's esophagus diagnosis between 1994 and 2005 were identified by use of International Classification of Disease (ICD) and Systematized Nomenclature of Medicine (SNOMED) coding. Subsets received manual record review (endoscopy/pathology reports), slide review by a referral pathologist (interrater reliability), and 2 blinded reviews by the same pathologist (intrarater reliability). SETTING: An integrated health services delivery system. MAIN OUTCOME MEASUREMENTS: Accuracy of electronic clinical diagnosis and reproducibility of esophageal intestinal metaplasia diagnosis. RESULTS: A total of 2470 patients coded with Barrett's esophagus underwent record review; a subgroup (616) received manual pathology slide review. Review confirmed a Barrett's esophagus diagnosis for 1533 (61.9%) patients: 437 of 798 subjects (54.8%) with a SNOMED diagnosis alone, 153 of 671 subjects (26.8%) with an ICD diagnosis alone, and 940 of 1101 subjects (85%) who had both a SNOMED and an ICD diagnosis. The same metaplasia diagnosis occurred with 88.3% of subjects (original vs referral pathologist, interrater reliability; kappa = .42, 95% CI, 0.34-0.48). The referral pathologist made the same metaplasia diagnosis twice for a given patient for 88.6% of subjects (intrarater reliability, 2 reviews by same pathologist; kappa = 0.65, 95% CI, 0.35-0.93). LIMITATIONS: The accuracy of a Barrett's esophagus diagnosis likely represents the minimum number, given the strict criteria. CONCLUSIONS: A community pathologist's diagnosis of esophageal intestinal metaplasia is likely to be confirmed by a referral pathologist. Electronic diagnoses of Barrett's esophagus overestimate the prevalence, although they are usually confirmed in patients with both a SNOMED and ICD diagnosis of Barrett's esophagus.

Hernia paraesofágica gigante con riesgo de torsión en un paciente de 84 años / Large paraesophageal hernia at risk of torsion in an 84-year-old man

Se expone la vicisitud diagnóstica de una hernia paraesofágica de gran tamaño con riesgo de torsión en un varón de 84 años que gozaba de buen estado general y no tenía antecedentes clínicos de interés hasta la noche anterior, cuando se despertó sintiendo disnea y dolor mal localizado en el epigastrio, acompañado de un pico febril. Tras el breve interrogatorio con respuestas muy ambiguas que no resultaron concluyentes, con los datos de la exploración física, el electrocardiograma y los resultados de la analítica de urgencia y el nivel hidroaéreo que demostró la radiografía de tórax en bipedestación, se realizó el diagnóstico principal. Se descartó un infarto agudo de miocardio o una embolia pulmonar. Una vez estabilizado el paciente, se solicitó esofagogastroscopia; a las pocas horas se le sometió al resto de las exploraciones complementarias, tránsito intestinal, enema opaco y tomografía computarizada (TC), cuyos resultados motivan la discusión genérica del caso y la revisión bibliográfica desde una perspectiva geriátrica. Se constata la escasa publicación de artículos sobre hernias diafragmáticas gigantes en personas octogenarias y se comenta la aportación de las técnicas empleadas en el diagnóstico

We describe the diagnosis of a large paraesophageal hernia that showed a risk of torsion in an 84-year-old man who had good health status and no clinical antecedents of interest until the previous night when he woke up and felt dyspnea, some pain located in the epigastrium and a fever spike. After a short interview with ambiguous and inconclusive answers, the main diagnosis was based on the data obtained from the physical examination, the electrocardiogram, the results of the emergency blood tests, and the hydroaerial level that appeared on the standing chest x-ray; acute myocardial infarction and pulmonary embolism were excluded. Once the patient was stabilized, esophagogastroscopy was requested and some hours later the patient underwent the remaining examinations: intestinal transit, opaque enema and computed tomography scan, which are described in the text. The results of these examinations form the basis of a generic discussion about this case and a literature review from point of view of geriatrics. Few cases of large diaphragmatic hernias in octogenarians have been reported in the literature. We discuss the contribution of the techniques used in the diagnosis of this entity

New molecular concepts of Barrett's esophagus: clinical implications and biomarkers.

Barrett's esophagus (BE) represents the most serious histological consequence of gastroesophageal reflux disease (GERD) that develops in 5-10% of patients with GERD. Given that BE is the only known precursor to esophageal adenocarcinoma (EA), a systematic endoscopic biopsy protocol can detect EAs at an early stage. However, endoscopic and histopathological evaluation of BE are not adequate for effective screening of high risk patients. Therefore, molecular abnormalities associated with BE have been considered as surrogate markers and their use as such is proposed. Flow cytometry is the most useful adjunct to histology, and ploidy status of BE is an independent risk factor. Cyclin D1 overexpression is inversely correlated with survival in EA. C-erbB2 (+) patients have poorer prognosis. High plasma adenomatous polyposis coli levels correlate with reduced patient survival. p53 expression allows patient risk for EA stratification. Nuclear factor-kappaB overexpression inversely correlates with good response to adjuvant chemotherapy and radiotherapy in EA. Patients with cyclooxygenase-2 overexpression have reduced survival rates. Increased E-cadherin staining is associated with shorter survival in EA patients who received chemoradiotherapy. Finally, existing data cannot rule out a correlation between EA and colorectal tumors. Seventeen BE molecular alterations yielded noteworthy clinical implications. Apart from endoscopy and histology, these data allow for better risk stratification for patients with BE and for more efficient and timely therapeutic approaches.

Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett's esophagus.

BACKGROUND AND OBJECTIVES: Temporal and spectral fluorescence spectroscopy can identify adenomatous colonic polyps accurately. In this study, these techniques were examined as a potential means of improving the surveillance of high grade dysplasia (HGD) in Barrett's esophagus (BE). STUDY DESIGN/MATERIALS AND METHODS: Using excitation wavelengths of 337 and 400 nm, 148 fluorescence spectra, and 108 transient decay profiles (at 550 +/- 20 nm) were obtained endoscopically in 37 patients. Corresponding biopsies were collected and classified as carcinoma, HGD, or low risk tissue (LRT) [non-dysplastic BE, indefinite for dysplasia (IFD), and low grade dysplasia (LGD)]. Diagnostic algorithms were developed retrospectively using linear discriminant analysis (LDA) to separate LRT from HGD. RESULTS: LDA produced diagnostic algorithms based solely on spectral data. Moderate levels of sensitivity (Se) and specificity (Sp) were obtained for both 337 nm (Se = 74%, Sp = 67%) and 400 nm (Se = 74%, Sp = 85%) excitation. CONCLUSIONS: In the diagnosis of HGD in BE, steady-state fluorescence was more effective than time-resolved data, and excitation at 400 nm excitation was more effective than 337 nm. While fluorescence-targeted biopsy is approaching clinical usefulness, increased sensitivity to dysplastic changes-possibly through modification of system parameters-is needed to improve accuracy levels.

Impact of imprint cytology in detecting short segment Barrett's esophagus.

BACKGROUND: Short-segment Barrett's esophagus (SSBE) is defined by the presence of columnar-appearing mucosa in distal esophagus (involving less than 2 to 3 cm), with intestinal metaplasia on biopsy. Its potential to develop dysplasia and cancer may require a surveillance program with better diagnostic tools to detect intestinal metaplasia. GOALS: To investigate the role of imprint cytology as a diagnostic tool either alone or combined with histology in SSBE. STUDY: Seventy-nine patients (46 men, 33 women) with SSBE diagnosed during elective upper gastroscopy were included. Patients with serrated z-line with short tongues of pink mucosa and patients with a circular non-serrated z-line that extended less than 2 cm above the esophagogastric junction were biopsied on four quadrants just distal to z-line. Four slides of imprint preparation (including 1, 2, 3, and 4 touching of each biopsy specimen) was made for cytologic examination. Hematoxylin and eosin and Alcian blue staining for histologic examinations and Alcian Blue for cytologic evaluations were used to find evidence of intestinal metaplasia. RESULTS: Intestinal metaplasia was detected in 15 (19%), 21 (27%), and 30 (38%) patients by histologic examination with hematoxylin and eosin alone, by Alcian blue alone, and by histologic plus cytologic examination with Alcian blue, respectively. Nine patients with negative histologic but positive cytologic results were positive for intestinal metaplasia when they were reevaluated after further sectioning and staining. Sensitivity of imprint cytology alone was 53%. When imprint cytology was combined with the histologic evaluation, the prevalence of intestinal metaplasia increased from 27% to 38% (p < 0.05). CONCLUSION: Imprint cytology might be a complementary diagnostic tool for histology in detecting patients with SSBE.

Impact of esophageal acid exposure on the endoscopic reversal of Barrett's esophagus.

OBJECTIVE: Normalization of esophageal acid exposure had been assumed to be necessary for the reversal of Barrett's esophagus with endoscopic therapy. This assumption is examined by evaluating the esophageal pH in a group of patients undergoing reversal therapy with fixed high-dose proton pump inhibitor therapy and endoscopic multipolar electrocoagulation (MPEC). METHODS: Patients with Barrett's esophagus of 2-6 cm in length were treated with omeprazole (40 mg b.i.d.). They underwent 24-h esophageal pH monitoring 5 cm above the upper margin of the lower esophageal sphincter determined by a water-perfused catheter. They then underwent MPEC therapy to an endpoint of elimination of Barrett's (reversal) by both endoscopy and biopsy 6 months after the last MPEC session or failure to achieve visual (endoscopic) reversal after six treatment sessions. RESULTS: Twenty patients had 24-h pH testing and reached a reversal endpoint. Three patients had abnormal pH tests, two total and supine and one supine only. These patients had documented reversal. The remaining 17 patients had normal pH testing but five failed reversal therapy. CONCLUSION: Barrett's esophagus can be completely reversed with endoscopic therapy despite abnormal esophageal acid exposure. Also, patients can fail reversal even with normal esophageal acid exposure. The necessary reduction of esophageal acid exposure for reversal therapy has yet to be defined.

Comprehensive Cancer Centre Amsterdam Barrett Advisory Committee: first results.

BACKGROUND: Treatment and follow-up policy for Barrett's oesophagus are dependent on the grade of dysplasia. However, sampling error of random biopsy protocols and subjectivity of pathological grading may hamper endoscopic surveillance. METHODS: The Amsterdam Comprehensive Cancer Center Barrett Advisory Committee (BAC) is a regional multidisciplinary consultative working-group, offering revision of pathology, revision of pathology plus additional endoscopic diagnostics, or referral for treatment. RESULTS: Between July 1998 and July 1999 30 patients were referred to the B.A.C for advice; eighteen patients were referred because of suspicion of high grade dysplasia. Reassessment of biopsies, including additional quantitative pathology, with or without additional endoscopic diagnostics, led to adjustment of the grading of dysplasia in 15 patients (50%). A suspicion of low grade dysplasia was rejected in nine out of ten cases. Adjustment of the original diagnosis often influenced further therapy or follow-up. CONCLUSIONS: reassessment of conventional pathology, quantitative pathology, and additional diagnostic procedures might improve the accuracy of diagnosis and staging of malignant degeneration of Barrett's oesophagus, although experience is still limited. The complexity of the management of these patients demands a specialised multidisciplinary approach. A Barrett Advisory Committee can offer valuable contributions to the treatment of patients with Barrett's oesophagus.

Increased esophageal chemoreceptor sensitivity to acid in patients after successful reversal of Barrett's esophagus.

When compared to patients with erosive esophagitis, patients with Barrett's esophagus have demonstrated reduced chemo- and mechanoreceptor sensitivity to acid infusion and balloon distension, respectively. However, anecdotal clinical experience suggested an increase in symptom perception in patients after successful elimination of Barrett's epithelium, using multipolar electrocoagulation (MPEC) and high-dose proton pump inhibitor (PPI). To determine perception thresholds to acid infusion, we evaluated eight consecutive patients after a series of MPEC treatments resulted in complete elimination of Barrett's mucosa and compared them to 10 age-matched patients with nonreversed Barrett's esophagus and 10 patients with symptomatic, endoscopy-documented erosive esophagitis (Hetzel-Dent grade 2 or greater). Chemosensitivity was determined by a modified acid perfusion test, where acid perception thresholds were quantified by the lag time to initial typical symptom perception, sensory intensity rating, and an acid perfusion sensory score (APSS). While patients after successful elimination of Barrett's esophagus had similar sensory intensity ratings and APSS as patients with erosive esophagitis, the lag times differed significantly between the groups, and both groups had significantly higher sensory intensity ratings and APSS than patients with nonreversed Barrett's esophagus. In conclusion, patients after complete reversal of Barrett's mucosa are unexpectedly as sensitive to acid as symptomatic patients with erosive esophagitis.

Partial regression of Barrett's esophagus by long-term therapy with high-dose omeprazole.

BACKGROUND: Barrett's esophagus is mainly regarded as an acquired condition related to increased gastroesophageal reflux. Thus it is conceivable that abolition of acid reflux would lead to its regression. The aim of this study was to assess whether long-term treatment with high-dose omeprazole (60 mg/day) produces a consistent control of gastric acid production and normalizes the esophageal acid exposure, thus reducing the length of Barrett's epithelium. METHODS: Fourteen patients (8 men and 6 women, mean age 52 years) with histologic diagnosis of columnar epithelium longer than 3 cm in the distal part of the esophagus were enrolled and began receiving 60 mg of omeprazole in a single daily morning dose. Before therapy and after 6 and 12 months of therapy, all patients had endoscopy with four-quadrant biopsies at 2 cm intervals. A 24-hour esophagogastric pH recording was performed at entry and after 10 days, 6 months, and 12 months of treatment in all patients. RESULTS: The initial length of Barrett's epithelium (4.5 +/- 1.9 cm) was significantly reduced after 6 months (3.1 +/- 1.1; p < 0.01) and 12 months (2.1 +/- 1.6; p < 0.005) of treatment. Values were significantly lower at 12 than at 6 months (p < 0.03). The 24-hour mean gastric pH after 10 days (5.89 +/- 0.58), 6 months (5.71 +/- 0.55), and 12 months (5.54 +/- 0.76) of therapy was always higher (p < 0.001) than the basal level (1.9 +/- 0.49). No significant difference in gastric pH was seen over the treatment period. The 24-hour mean percent of time in which pH in the esophagus was below 4.0 decreased significantly (p < 0.001) from a basal rate of 29.4% to 3.5%, 3.0%, and 4.9% in the various time intervals of therapy. There was a normalization of esophageal acid exposure in all patients but two. CONCLUSIONS: It can be concluded that the antisecretory effect of 60 mg/day of omeprazole is consistent and is kept constant throughout the entire 1-year treatment period. The consequent normalization of esophageal acid exposure in almost all patients in our series led to a partial, but significant, regression in the length of Barrett's epithelium.

Early detection of neoplasia of the esophagus and gastroesophageal junction.

Recommendations for preventing adenocarcinoma: The standard definition of Barrett's epithelium should be the presence of intestinalized mucosa in the lower esophagus. Patients in this category should be considered for inclusion in a screening program for the detection of dysplasia or carcinoma. Those who are a poor operative risk should not be screened if the detection of an end-point such as high-grade dysplasia or intramucosal carcinoma will still not lead to resection. In some centers, however, alternative experimental methods of mucosal ablation may be available. The endpoint for screening is invasive or intramucosal carcinoma (or--in centers with a very low operative mortality--high-grade dysplasia). These should lead to consideration of surgery or, in specialized centers and as part of controlled studies, newer alternative modes of epithelial ablation. Intermediate markers, e.g., use of aneuploidy, gene markers, or their products, are at present experimental. Screening should be carried out annually or, possibly, biennially. This screening should utilize a standard protocol with an endoscope capable of obtaining large-particle biopsies. Four quadrant biopsies should be taken about every 2 cm, beginning 2 cm above the proximal limit of the gastric rugae, continuing until unequivocally in squamous mucosa, and following any tongues of glandular epithelium. Recommendations for prevention of squamous carcinoma: In high-risk populations, esophageal cytology, possibly supplemented by tests for blood in the stomach, appear most useful. Repeated screening may be necessary to detect early invasive or preinvasive (dysplastic) tumors. Although preliminary results from dietary intervention studies have yet to show a statistically significant decrease, if trends continue these will reach significance and may be the best overall method of cancer prevention. Measures to reduce smoking and drinking are to be encouraged, but their effectiveness is questionable. For patients who are positive on screening, endoscopy (possibly with Lugol's iodine) may provide the best indication of harboring underlying carcinoma or dysplasia. Endoscopic resection will play an increasing role in treatment. With the exception of tylosis, most other predisposing conditions are unlikely to be cost effective.