Patients with cirrhosis who have coronary artery disease treated with cardiac stents have high rates of gastrointestinal bleeding, but no increased mortality.

BACKGROUND: Patients with coronary artery disease (CAD) treated with stents require dual antiplatelet therapy (DAPT). For cirrhotics, who often have varices and coagulopathy, it is not clear if the risk of gastrointestinal bleeding (GIB) should preclude use of DAPT. AIM: To compare GIB and mortality rates in cirrhotics with CAD treated medically or with stents. METHODS: Using institutional databases, we identified patients with cirrhosis and CAD treated with stents or medical therapy between January 2000-September 2015. Primary outcomes were GIB and mortality. RESULTS: We identified 148 cirrhotics with CAD; 68 received stents (cases), 80 were treated with medical therapy (controls). Cases and controls had similar demographics, comorbidities, MELD scores and clinical presentation; DAPT was used in 98.5% of cases vs 5% of controls. The incidence of GIB was significantly higher in cases than controls (22.1% vs 5% at 1 year, P=.003; 27.9% vs 5% at 2 years, P=.0002), whereas all-cause mortality was similar (20.6% vs 21.3%). No patient required surgery or angiography for GIB, and no known patients died due to GIB. Multivariate analysis revealed use of a proton pump inhibitor (PPI) was highly protective against GIB (OR=0.26, 95%CI=0.08-0.79). CONCLUSIONS: CAD treatment with stents in our cirrhotics was associated with a significantly increased risk of GIB, but no adverse effects on survival. Although it remains unclear whether the cardiovascular benefits of stents outweigh the GIB risk, our findings suggest that DAPT should not be withheld from stented cirrhotics for fear of GIB. Moreover, the use of a PPI should be strongly considered.

Benchmarks for the interpretation of esophageal high-resolution manometry.

BACKGROUND: Competent interpretation of esophageal high-resolution manometry (HRM) is integral to a quality study. Currently, methods to assess physician competency for the interpretation of esophageal HRM do not exist. The aim of this study was to use formal techniques to (i) develop an HRM interpretation exam, and (ii) establish minimum competence benchmarks for HRM interpretation skills at the trainee, physician interpreter, and master level. METHODS: A total of 29 physicians from 8 academic centers participated in the study: 9 content experts separated into 2 study groups-expert test-takers (n=7) and judges (n=2), and 20 HRM inexperienced trainees ("trainee test-taker"; n=20). We designed the HRM interpretation exam based on expert consensus. Expert and trainee test-takers (n=27) completed the exam. According to the modified Angoff method, the judges reviewed the test-taker performance and established minimum competency cut scores for HRM interpretation skills. KEY RESULTS: The HRM interpretation exam consists of 22 HRM cases with 8 HRM interpretation skills per case: identification of pressure inversion point, hiatal hernia >3 cm, integrated relaxation pressure, distal contractile integral, distal latency, peristaltic integrity, pressurization pattern, and diagnosis. Based on the modified Angoff method, minimum cut scores for HRM interpretation skills at the trainee, physician interpreter, and master level ranged from 65-80%, 85-90% (with the exception of peristaltic integrity), and 90-95%, respectively. CONCLUSIONS & INFERENCES: Using a formal standard setting technique, we established minimum cut scores for eight HRM interpretation skills across interpreter levels. This examination and associated cut scores can be applied in clinical practice to judge competency.

The influence of Helicobacter pylori on the ethnic distribution of Barrett's metaplasia.

BACKGROUND: Environmental risk factors associated with ethnicity may contribute to the occurrence of Barrett's metaplasia. AIM: To investigate the interaction between ethnicity and Helicobacter pylori infection in the occurrence of Barrett's metaplasia among patients undergoing oesophago-gastro-duodenoscopy. METHODS: The Miraca Life Sciences Database is an electronic repository of histopathological patient records. A case-control study evaluated the influence of age, gender, ethnicity and histological diagnosis of H. pylori on the occurrence of Barrett's metaplasia. RESULTS: The total study population comprised 596 479 subjects, of whom 76 475 harboured a diagnosis of Barrett's metaplasia. Male sex, age and H. pylori infection in declining order exerted the strongest influence on the occurrence of BM. In comparison with the population comprising Caucasians and African Americans, Barrett's metaplasia was less common among subjects of African (OR = 0.09, 95% CI = 0.01-0.43), Middle Eastern (0.26, 0.20-0.34), East Asian (0.35, 0.31-0.40), Indian (0.39, 0.32-0.47), Hispanic (0.62, 0.59-0.64) or Jewish descent (0.50, 0.45-0.54), but more common among subjects of Northern European descent (1.14, 1.03-1.26). With the exception of Jews and Northern Europeans, all other ethnic subgroups were characterised by a higher prevalence of H. pylori than the comparison group. A low prevalence of H. pylori was significantly associated with a high prevalence of Barrett's metaplasia (R2 = 0.82, P < 0.001), as well as dysplasia or oesophageal adenocarcinoma (R2 = 0.81, P < 0.001). CONCLUSION: Our analysis reveals an inverse relationship between the prevalence of Barrett's metaplasia and H. pylori gastritis among different ethnic groups within the United States.

The role of bile acids in the neoplastic progression of Barrett's esophagus - a short representative overview.

Barrett's esophagus (BE) is an intestinal metaplasia of the distal esophagus in which squamous cells are replaced by a columnar epithelium. It is considered as a premalignant lesion, which can lead to esophageal adenocarcinoma, a very aggressive type of cancer, and can often be found in patients with gastro-esophageal reflux disease (GERD). In spite of the widespread use of acid-suppressing therapy with proton pump inhibitors, the incidence of adenocarcinoma has been steadily rising during the last 30 years. So, it can strongly be suggested that refluxed material other than acid might contribute to the progression of cancer within Barrett's esophagus. Along with gastric acid, bile acids enter the esophagus during an episode of reflux, and bile acids may be important in carcinogenesis. In their refluxates, patients with GERD and BE show high concentrations of the hydrophobic bile salt deoxycholic acid (DCA), which has cytotoxic effects and is able to induce DNA damage in different cell types. Other bile acids, like the hydrophilic urodeoxycholic acid (UDCA), have been therapeutically used to treat cholestatic liver diseases and to prevent colon carcinoma. This article reviews the effects of bile acids and points out new perceptions in the progression of Barrett's-associated carcinogenesis.

Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia.

BACKGROUND: Factors other than acid may play a role in gastro-oesophageal reflux disease (GERD) and its complications. AIM: To assessed the role of bile acids in the pathogenesis of GERD, Barrett's oesophagus and Barrett's-related neoplasia. METHODS: We conducted a systematic review of computerised bibliographic databases for original articles involving humans or human oesophageal tissue or cells that assessed exposure to or manipulation of bile acids. Outcomes assessed included GERD symptoms; gross oesophageal injury; Barrett's oesophagus and related neoplasia; and intermediate markers of inflammation, proliferation or neoplasia. RESULTS: Eighty-three original articles were included. In in vivo studies, bile acids concentrations were higher in the oesophageal aspirates of patients with GERD than controls, and bile acids infusions triggered GERD symptoms, especially in high concentrations or in combination with acid. In ex vivo/in vitro studies, bile acids stimulated squamous oesophageal cells and Barrett's epithelial cells to produce inflammatory mediators (e.g., IL-8 and COX-2) and caused oxidative stress, DNA damage and apoptosis. They also induced squamous cells to change their gene expression pattern to resemble intestinal-type cells and caused Barrett's cells to increase expression of intestinal-type genes. CONCLUSIONS: In aggregate, these studies suggest that bile acids may contribute to the pathogenesis of symptoms, oesophagitis and Barrett's metaplasia with related carcinogenesis in patients with GERD. However, all study results are not uniform and substantial differences in study parameters may explain at least some of this variation.

The Los Angeles and Savary-Miller systems for grading esophagitis: utilization and correlation with histology.

The aim of the study is to determine the proportion of patients who have esophageal biopsy specimens taken for an endoscopic diagnosis of reflux esophagitis in which an endoscopic grade of esophagitis (Los Angeles [LA] or Savary-Miller [SM]) is communicated to the pathologist, and to evaluate the correlation between those endoscopic grades and histopathologic findings. We searched the database of Caris Diagnostics (a large, gastrointestinal pathology practice that receives specimens from community-based endoscopy centers), and extracted data from all patients who had an endoscopy with esophageal biopsies submitted in a 12-month period. There were esophageal biopsy specimens from 49,480 patients obtained during 58,986 endoscopies. The LA grade was provided in 5513 cases (27.9% of 19,778 with endoscopic esophagitis); the SM grade was stated in only 2416 cases (12.2%). A histopathologic diagnosis of erosive or ulcerative esophagitis was made significantly less often in LA grade A patients (3.2%) than in those with LA grades C (20.0%) and D (23.3%); erosive or ulcerative esophagitis was found in only 1.4% of patients with SM grade I and in 35.5% of cases with grade IV. Endoscopists who biopsy the esophagus of patients with reflux esophagitis usually do not communicate the grade of esophagitis to the pathologist. Although both the LA and SM grading systems are based on the presence of esophageal mucosal breaks (erosions or ulcers), in practice such breaks are documented in only a minority of esophageal biopsy specimens taken from patients with reflux esophagitis of any grade.

Quality of life following radiofrequency ablation of dysplastic Barrett's esophagus.

BACKGROUND AND STUDY AIMS: The impact of the diagnosis and treatment of dysplastic Barrett's esophagus on quality of life (QoL) is poorly understood. This study assessed the influence of dysplastic Barrett's esophagus on QoL and evaluated whether endoscopic treatment of dysplastic Barrett's esophagus with radiofrequency ablation (RFA) improves QoL. PATIENTS AND METHODS: We analyzed changes in QoL in the AIM Dysplasia Trial, a multicenter study of patients with dysplastic Barrett's esophagus who were randomly allocated to RFA therapy or a sham intervention. We developed a 10-item questionnaire to assess the influence of dysplastic Barrett's esophagus on QoL. The questionnaire was completed by patients at baseline and 12 months. RESULTS: 127 patients were randomized to RFA (n = 84) or sham (n = 43). At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham). Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus. Of those randomized, 117 patients completed the study to the 12-month end point. Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer ( P=0.003) and esophagectomy ( P =0.009). They also had significantly reduced depression ( P=0.02), general worry about the condition of their esophagus ( P≤0.001), impact on daily QoL ( P=0.009), stress ( P=0.03), dissatisfaction with the condition of their esophagus ( P≤0.001), and impact on work and family life ( P=0.02). CONCLUSIONS: Inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life. This improvement appears secondary to a perceived decrease in the risk of cancer.

The prevalence of Barrett's esophagus in the US: estimates from a simulation model confirmed by SEER data.

Barrett's esophagus (BE) is the precursor and the biggest risk factor for esophageal adenocarcinoma (EAC), the solid cancer with the fastest rising incidence in the US and western world. Current strategies to decrease morbidity and mortality from EAC have focused on identifying and surveying patients with BE using upper endoscopy. An accurate estimate of the number of patients with BE in the population is important to inform public health policy and to prioritize resources for potential screening and management programs. However, the true prevalence of BE is difficult to ascertain because the condition frequently is symptomatically silent, and the numerous clinical studies that have analyzed BE prevalence have produced a wide range of estimates. The aim of this study was to use a computer simulation disease model of EAC to determine the estimates for BE prevalence that best align with US Surveillance Epidemiology and End Results (SEER) cancer registry data. A previously developed mathematical model of EAC was modified to perform this analysis. The model consists of six health states: normal, gastroesophageal reflux disease (GERD), BE, undetected cancer, detected cancer, and death. Published literature regarding the transition rates between these states were used to provide boundaries. During the one million computer simulations that were performed, these transition rates were systematically varied, producing differing prevalences for the numerous health states. Two filters were sequentially applied to select out superior simulations that were most consistent with clinical data. First, among these million simulations, the 1000 that best reproduced SEER cancer incidence data were selected. Next, of those 1000 best simulations, the 100 with an overall calculated BE to Detected Cancer rates closest to published estimates were selected. Finally, the prevalence of BE in the final set of best 100 simulations was analyzed. We present histogram data depicting BE prevalences for all one million simulations, the 1000 simulations that best approximate SEER data, and the final set of 100 simulations. Using the best 100 simulations, we estimate the prevalence of BE to be 5.6% (5.49-5.70%). Using our model, an estimated prevalence for BE in the general population of 5.6% (5.49-5.70%) accurately predicts incidence rates for EAC reported to the US SEER cancer registry. Future clinical studies are needed to confirm our estimate.

Clinical trial: intragastric acid control in patients who have Barrett's oesophagus--comparison of once- and twice-daily regimens of esomeprazole and lansoprazole.

BACKGROUND: Gastric acid control is important for treatment of gastro-oesophageal reflux disease associated with Barrett's oesophagus. Substantial indirect evidence suggests that gastric acid control may have a chemopreventive role in Barrett's oesophagus. AIM: To compare the pharmacodynamic efficacy of esomeprazole and lansoprazole at two dosages for intragastric pH control with Barrett's oesophagus. METHODS: Patients with Barrett's oesophagus received open-label consecutive treatment (a 15-day period of once-daily dosing followed by a 10-day period of twice-daily dosing) with esomeprazole (40-mg capsules) and lansoprazole (30-mg capsules) in random order with no washouts. Twenty-four-hour intragastric pH was recorded on the last day of each dosing period. The primary end point was the percentage of time with intragastric pH > 4.0. RESULTS: In the per-protocol once- (n = 46) and twice-daily (n = 41) analyses, the percentage of time with intragastric pH > 4.0 was significantly (P < 0.0001) longer after once- (67.1%) or twice-daily (81.2%) esomeprazole than after once- (50.8%) or twice-daily (64.3%) lansoprazole. The proportion of patients with intragastric pH > 4.0 for >12 h was significantly higher for esomeprazole than lansoprazole with once- (P = 0.004) and twice-daily (P = 0.016) dosing. CONCLUSION: Esomeprazole 40 mg is significantly more effective than lansoprazole 30 mg in controlling intragastric pH with Barrett's oesophagus.

Characterization of telomerase-immortalized, non-neoplastic, human Barrett's cell line (BAR-T).

Barrett's esophagus, a metaplasia predisposed to malignant transformation, has been studied in vitro using esophageal adenocarcinoma cell lines. However, findings in such transformed cells may not be applicable to the non-neoplastic cells of benign Barrett's esophagus. Therefore, we have developed and characterized a Barrett's cell line derived from a patient without malignancy or dysplasia. Human Barrett's epithelial cells were immortalized with the insertion of hTERT (human telomerase reverse transcriptase) using a Cre-lox recombination system. We then examined properties of this continuous cell line, such as in vitro tumorigenicity, growth patterns, histological differentiation characteristics, karyotype, and checkpoint arrest mechanisms (e.g., p16, p21, and p53). Non-neoplastic Barrett's epithelial cells infected with hTERT (BAR-T cells) have been sustained in culture beyond 200 population doublings. BAR-T cells maintain a diploid chromosome number and exhibit non-neoplastic properties, such as contact inhibition and anchorage-dependent growth. BAR-T cells express differentiation Barrett's epithelial markers, such as villin and cytokeratins 4, 8 and 18, and stain positive for Alcian blue, indicating the presence of mucin-producing cells. Expression of checkpoint arrest proteins p21 and p53 are intact, while p16 expression is lost. Thus, we have created a human Barrett's cell line that is not malignantly transformed, and yet can be maintained indefinitely in culture. BAR-T cells are diploid, have histological differentiation markers characteristic of benign Barrett's epithelium, and also maintain appropriate expression of p21 and p53. This cell line should be a useful model for the study of the early events in carcinogenesis in Barrett's esophagus.

Esophageal obstruction due to extensive intramural esophageal dissection: diagnosis and treatment using an endoscopic 'rendezvous' technique.

Intramural esophageal dissection is an uncommon condition which usually responds to conservative management. We report an unusual case of extensive dissection resulting in complete esophageal obstruction, and which required endoscopic therapy. Diagnosis was made using two endoscopes: the transoral endoscope was in the false esophageal lumen, while a second endoscope inserted through a pre-existing gastrostomy was in the true esophageal lumen. Endoscopic needle knife incision of the entire mucosal septum resolved the patient's symptoms, and was performed without complication. The literature is reviewed for current knowledge of this condition. We also propose that 'intramural esophageal dissection' should be the preferred name for this condition, which at present is known by many names.

Review article: what I do now to manage adenocarcinoma risk, and what I may be doing in 10 years' time.

This article summarizes the present recommendations for the screening, surveillance and treatment of Barrett's oesophagus, and identifies those areas in which change seems likely within the next decade. As a result of economic constraints and emerging data on ethnic variations in the frequency of Barrett's oesophagus, future screening programmes will probably focus on those individuals most likely to develop Barrett's adenocarcinomas: older white men whose gastro-oesophageal reflux symptoms are of long duration. The present surveillance strategy for patients with Barrett's oesophagus relies heavily on random biopsy sampling of the oesophagus to find dysplasia. In the future, biomarkers other than dysplasia may be used to identify patients at high risk for carcinogenesis, and physicians may use endoscopic techniques, such as fluorescence spectroscopy, to identify areas of dysplasia for biopsy sampling. Indirect evidence suggests that super-aggressive antisecretory therapy and treatment with non-steroidal anti-inflammatory drugs may reduce the risk of cancer in Barrett's oesophagus. Well-designed prospective studies will be needed to determine whether these treatments have sufficient efficacy in cancer prophylaxis to justify the large numbers needed to treat. Finally, recent data are reviewed, which suggest that the gastro-oesophageal junction is exposed repeatedly to concentrated acid and to potentially genotoxic concentrations of nitric oxide generated from dietary nitrate. Future studies on carcinogenesis in Barrett's oesophagus may well focus on the combined roles of nitric oxide and gastric acid.

Review article: screening and surveillance of Barrett's oesophagus: what is a cost-effective framework?

There is a strong association between symptomatic gastro-oesophageal reflux and oesophageal adenocarcinoma. With this in mind, the American College of Gastroenterology has recently revised its practice guidelines for the screening of patients with chronic gastro-oesophageal reflux disease (GERD) to identify those at risk of oesophageal adenocarcinoma, and recommends surveillance to identify curable oesophageal neoplasms in patients with established Barrett's oesophagus. Patients with chronic GERD symptoms, particularly those aged over 50 years, should undergo upper endoscopy. Patients found to have Barrett's oesophagus should be treated with acid suppression for GERD symptoms and then undergo regular surveillance endoscopy. Surveillance endoscopy every 3 years is recommended for those without dysplasia. For patients with verified low-grade dysplasia, yearly surveillance endoscopy is recommended. For those with focal high-grade dysplasia (defined as high-grade dysplastic changes involving fewer than five crypts), the condition may be followed with endoscopic surveillance performed at 3-month intervals. If there is verified, multifocal high-grade dysplasia, intervention (e.g. oesophagectomy) may be considered. Both observational and computer models suggest a benefit associated with screening and surveillance. Endoscopic screening and surveillance for Barrett's oesophagus compares favourably with mammography for the detection of breast cancer and other accepted medical practices.

Characterisation of telomerase immortalised normal human oesophageal squamous cells.

BACKGROUND AND AIMS: Oesophageal cell lines derived from malignancies have numerous genetic abnormalities and therefore are of limited value for studying the early events in carcinogenesis. Reported attempts to establish normal human oesophageal cell lines either have failed to achieve immortalisation or have achieved it by disrupting important cell functions. We have used telomerase technology to establish normal human oesophageal cell lines. METHODS: Endoscopic biopsy specimens of normal oesophageal squamous epithelium were trypsinised, dispersed into single cell suspensions, and cocultivated with ATCC Swiss 3T3 cells. Oesophageal cells were infected with the catalytic subunit of human telomerase (hTERT) using a defective retroviral vector. The integrity of cell cycle checkpoints was tested by measuring p53 response to UV irradiation, and p16 response to infection with H-RasGV12. Expression of a differentiation marker was tested by measuring involucrin response to calcium exposure. RESULTS: Cultures of uninfected oesophageal cells had weak telomerase activity at baseline but exhibited loss of telomerase activity and progressive telomere shortening before undergoing senescence between population doublings (PD) 40-45. In contrast, hTERT infected cells exhibited sustained telomerase activity and stabilisation of telomere length. These cells have reached PD 100 with no diminution in growth rate, while cell cycle checkpoint integrity and involucrin response to calcium exposure have remained intact. CONCLUSIONS: By introducing telomerase into normal human oesophageal squamous cells cocultivated with feeder layers, we have established a cell line that retains normal cell cycle checkpoints and normal differentiation markers. This cell line may be useful for studying the early events in oesophageal carcinogenesis.

Racial differences in the frequency of symptoms and complications of gastro-oesophageal reflux disease.

BACKGROUND: A number of reports have suggested that there are substantial racial differences in the frequency of gastro-oesophageal reflux disease and its complications, but few studies have compared directly the frequency of this disorder amongst different racial groups. AIM: To explore the racial differences in the frequency of gastro-oesophageal reflux disease and its complications. METHODS: We reviewed endoscopy reports and medical records for data on race and complications of gastro-oesophageal reflux disease in 2,477 consecutive patients who had endoscopic examinations at the general endoscopy unit of an academic hospital. In addition, we prospectively interviewed 129 out-patients attending general medical clinics in the hospital and in an Asian community health centre in Boston to obtain data on race and gastro-oesophageal reflux disease symptoms. RESULTS: One or more gastro-oesophageal reflux disease complications (peptic oesophageal ulcer, stricture or Barrett's oesophagus) were observed in 267 of 2,174 white patients (12.3%), seven of 249 black patients (2.8%), one of 21 West Asian patients (4.8%) and none of 33 East Asian patients seen at the general endoscopy unit (P < 0.001); 34.6% of whites, 46.1% of blacks and 2.6% of East Asian patients interviewed claimed that they had heartburn (P < 0.01), but the term 'heartburn' was understood by only 34.6%, 53.8% and 13.2% of whites, blacks and East Asians, respectively (P < 0.01). CONCLUSIONS: Asian patients in Boston infrequently complain of heartburn, whereas heartburn is commonly reported by both white and black patients. Many patients do not understand the meaning of the term heartburn, however, and so physicians should be cautious when using the term during patient interviews. Complicated gastro-oesophageal reflux disease appears to be predominantly a disorder of whites.

Screening and surveillance for complications related to gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) and columnar-lined esophagus with intestinal metaplasia (Barrett's esophagus) are the major recognized risk factors for adenocarcinoma of the esophagus. The American College of Gastroenterology recommends that patients with long-standing GERD symptoms (particularly those 50 years of age or older) undergo endoscopic screening to identify Barrett's esophagus and that those patients who have Barrett's esophagus undergo regular endoscopic surveillance. These recommendations are made with the expectation that screening and surveillance will decrease mortality from esophageal cancer, although this association is unclear. Nonetheless, retrospective studies have shown that endoscopic surveillance can detect some early, curable neoplasms in patients with Barrett's esophagus. Dysplasia in Barrett's esophagus is widely regarded as the precursor of invasive malignancy. Although grading dysplastic changes is largely subjective, dysplasia remains the most appropriate biomarker for clinical evaluation of Barrett's esophagus. Flow-cytometric and p53 abnormalities may be earlier and more specific markers for cancer development, but application of these abnormalities is not yet recommended for clinical practice. Endoscopic surveillance also is adversely affected by biopsy sampling error. Techniques that may minimize biopsy sampling error include chromoendoscopy, endosonography, optical coherence tomography, and fluorescence detection techniques. Further studies are needed to clearly define the role of these techniques in surveillance, and none is practical for routine clinical use at this time. Although not specifically recommended, experimental ablative therapies, such as photodynamic therapy, can be considered by physicians for their patients with high-grade dysplasia in Barrett's esophagus, if they are provided as part of an established, approved research protocol.