Accurate discrimination of pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration.

To augment cytological diagnosis of pancreatic ductal adenocarcinoma (PDAC) in tissue samples obtained by minimally invasive endoscopic ultrasound-guided fine needle aspiration, we investigated whether a small set of molecular markers could accurately distinguish PDAC from chronic pancreatitis (CP). Expression levels of 29 genes were first determined by quantitative real-time RT-PCR in a training set of tissues in which the final diagnosis was PDAC (n=20) or CP (n=10). Using receiver operator characteristic curve analysis, we determined that the single gene with the highest diagnostic accuracy for discrimination of CP vs. PDAC in the training study was urokinase plasminogen activator receptor (UPAR; AUC value = 0.895, 95% CI=0.728-0.976). In the set of test tissues (n=14), the accuracy of UPAR decreased to 79%. However, we observed that the addition of 6 genes (EPCAM2, MAL2, CEA5, CEA6, MSLN and TRIM29; referred to as the 6-gene classifier) to UPAR resulted in high accuracy in both training and testing sets. Excluding 3 samples (out of 44; 7%) for which results of the UPAR/6-gene classifier were "undefined," the accuracy of the UPAR/6-gene classifier was 100% in training samples (n=29), 92% in 12 test samples (p=0.004 that results were randomly generated; p=0.046 that the UPAR/6-gene classifier was comparable to UPAR alone; chi2 test), 100% in 3 samples for which the initial cytological diagnosis was "suspicious" and 98% (40/41) overall. Our results provide evidence that molecular marker expression data can be used to augment cytological analysis.

Accurate discrimination of Barrett's esophagus and esophageal adenocarcinoma using a quantitative three-tiered algorithm and multimarker real-time reverse transcription-PCR.

Esophageal adenocarcinoma (EA) is increasing faster than any other cancer in the U.S. In this report, we first show that EA can be distinguished from normal esophagus (NE) and esophageal squamous cell carcinoma by plotting expression values for EpCam, TFF1, and SBEM in three-dimensional Euclidean space. For monitoring progression of Barrett's esophagus (BE) to EA, we developed a highly sensitive assay for limited quantities of tissue whereby 50 ng of RNA are first converted to cDNA using 16 gene-specific primers. Using a set of training tissues, we developed a novel quantitative three-tiered algorithm that allows for accurate (overall accuracy = 61/63, 97%) discrimination of BE versus EA tissues using only three genes. The gene used in the first tier of the algorithm is TSPAN: samples not diagnosed as BE or EA by TSPAN in the first tier are then subjected to a second-tier analysis using ECGF1, followed by a third-tier analysis using SPARC. Addition of TFF1 and SBEM to the first tier (i.e., a five-gene marker panel) increases the overall accuracy of the assay to 98% (62/63) and results in mean molecular diagnostic scores (+/- SD) that are significantly different between EA and BE samples (3.19 +/- 1.07 versus -2.74 +/- 1.73, respectively). Our results suggest that relatively few genes can be used to monitor progression of BE to EA.

Is esophagoscopy alone sufficient for patients with reflux symptoms?

BACKGROUND: Unsedated esophagoscopy with ultrathin endoscopes is a valuable screening modality for Barrett's esophagus, but the stomach and the duodenum cannot be examined completely with the smallest and best tolerated of these endoscopes. There are no data as to how often disease in the stomach and the duodenum would be missed when using this screening strategy. Our hypothesis is that patients with reflux symptoms, in the absence of daily abdominal pain, nausea, or history of ulcer, were unlikely to have clinically significant gastroduodenal disease. METHODS: Patients scheduled for upper endoscopy at a single outpatient endoscopy unit in a tertiary referral center were screened. The inclusion criterion was reflux symptoms as the primary indication for upper endoscopy. Patients with another valid indication were excluded. A detailed history was recorded and symptom questionnaire completed for each patient before endoscopy; these data were compared with the endoscopy findings. RESULTS: A total of 175 patients were included. Indications for upper endoscopy were the following: worsening symptoms (n=74), ongoing reflux despite therapy (n=27), and long-standing reflux (n=74). Major esophageal findings were discovered in 95 patients. In 10 patients, major gastric or duodenal findings were detected as follows: erosive gastritis (n=8), gastric ulcer (n=2), duodenal ulcer (n=2), erosive duodenitis (n=2), and duodenal polyp (n=1). Daily abdominal pain (p=0.014) or possibly daily nausea (p=0.028 unadjusted, 0.197 adjusted) was associated with major gastric/duodenal disease. Patients without daily abdominal pain, nausea, or a history of gastric/duodenal ulcer were much less likely to have major disease (0.9%) than patients with one of these predictors (13.2%, p=0.00097). CONCLUSIONS: Daily abdominal pain and nausea, in combination with a history of ulcer disease, are strong predictors of major gastric or duodenal disease. Patients with reflux without these predictors are highly unlikely to have a major disease involving the stomach or duodenum, and are suitable candidates for esophagoscopy alone.

Tele-endoscopy: a way to provide diagnostic quality for remote populations.

BACKGROUND: Flexible endoscopy plays an important role in digestive health. However, access to endoscopy is limited in many rural areas throughout the world. Training non-physician personal to perform diagnostic endoscopy and to transmit images to a central hospital, where experienced endoscopists can review the procedures, may improve digestive health for patients in remote areas. The aim of this study was to evaluate the diagnostic quality and accuracy of upper-GI tele-endoscopy. METHODS: Fifty patients scheduled for EGD underwent upper-GI tele-endoscopy. The procedures were observed simultaneously by the endoscopist and a gastroenterologist observing from a remote station connected by 4 integrated services digital network telephone lines. The interpretation of the findings by both were compared and concordance for diagnosis of major and minor lesions was analyzed. RESULTS: Tele-endoscopic image quality was adequate to support diagnosis of abnormal lesions by the remote observer. Technical issues included worsening image quality caused by mild pixelation during rapid endoscope movement and rare loss of the telephone lines. The endoscopist identified 47 different major and 44 minor findings in the 50 patients. The observer missed one major lesion (columnar-lined esophagus) because of suspected inflammation and described 10 non-existing major lesions (sensitivity 98%: 95% CI[89%, 99%], specificity 80%: 95% CI[66%, 90%]). Some of the differences were because of interobserver variability. CONCLUSIONS: Upper-GI tele-endoscopy by using telephone lines has good diagnostic quality and is highly sensitive with regard to major findings. The misinterpretation of certain findings (esophageal ring, gastric erosions) may be caused by interobserver variability. The data strongly suggest that endoscopist and observer see similar endoscopic views.

A prospective, blinded study of diagnostic esophagoscopy with a superthin, stand-alone, battery-powered esophagoscope.

OBJECTIVES: A more widely available, well-tolerated, and cost-effective technique is needed to screen a broad population at risk for esophageal cancer. An ideal solution might be to perform unsedated esophagoscopy with an entirely self-contained, small-caliber endoscope. In a prospective, blinded study in three phases, we compared the feasibility, patient tolerance, and diagnostic accuracy of esophagoscopy performed with a prototype, superthin, battery-powered esophagoscope (BPE) with standard video esophagogastroduodenoscopy (SVE). METHODS: In phase I, 10 healthy volunteers underwent both peroral and transnasal esophagoscopy with BPE to evaluate the technical feasibility of the examination. For phases II and III, patients were recruited to have BPE before SVE. In phase II, both procedures were performed with conscious sedation. In phase III, the BPE was performed with only topical anesthesia. Two endoscopists assessed the technical performance of the endoscope and patient tolerance and recorded the esophageal findings independently. RESULTS: In phase I, all endoscopists reported adequate visualization of the esophagus in the 10 volunteers. A total of 181 patients were evaluated in phases II and III (89 in phase II, 92 in phase III). The sensitivity for detecting columnar lined esophagus was 94% in phase II and 95% in phase III. The sensitivity for all esophageal findings was 87% and 86% in phases II and III, respectively. The technical performance of the endoscope was significantly worse for BPE compared with the SVE. The patient tolerance as evaluated by the endoscopist was similar for both procedures. Ninety-five percent of the patients undergoing unsedated BPE were willing to have the procedure repeated under similar circumstances. CONCLUSIONS: Unsedated esophagoscopy with a 3.1-mm, battery-powered, stand-alone esophagoscope is feasible, well tolerated, and accurate in detecting esophageal pathologies. It might be an efficient and cost-effective screening tool for the detection of columnar lined esophagus.

Accuracy of esophagoscopy performed by a non-physician endoscopist with a 4-mm diameter battery-powered endoscope.

BACKGROUND: A cost-effective technique is needed for screening of a broad population at risk for esophageal cancer. A solution would be to have non-physician endoscopists perform esophagoscopy with small-caliber battery-powered endoscopes. METHODS: In a prospective blinded study, the diagnostic accuracy of sedated esophagoscopy performed by a trained nurse practitioner with a battery-powered 4-mm diameter endoscope was compared with that for a sedated standard video-endoscopy performed by a gastroenterologist. Patients were recruited to undergo peroral esophagoscopy by the nurse practitioner followed by sedated standard endoscopy by the supervising gastroenterologist, each blinded to the findings of the other. Major esophageal findings of nurse practitioner and gastroenterologist were compared. RESULTS: Findings in 40 patients were analyzed. In 4 patients both endoscopists could not assess the presence or absence of columnar-lined esophagus because of severe erosive esophagitis (n = 3) or severe candida-esophagitis (n = 1). By using sedated standard endoscopy as the standard, on a per finding basis, esophagoscopy by the nurse practitioner had a sensitivity for columnar-lined esophagus of 89%: 95% CI [75%, 97%] and specificity of 96%: 95% CI [84%, 99%]. The missed columnar epithelium was a 3 x 3-mm island. For all lesions, the sensitivity of endoscopy performed by the nurse practitioner with the battery-powered endoscope was 75%: 95% CI [67%, 82%] and specificity 98%: 95% CI [96%, 99%]. The nurse practitioner missed all of 4 rings (3 considered clinically irrelevant). CONCLUSION: Esophagoscopy with a battery-powered 4-mm diameter endoscope by a non-physician endoscopist is feasible and accurate in detecting esophageal pathologies. It may be an efficient screening method for the detection of columnar-lined esophagus. There was a distinct underestimate of the presence of esophageal rings.

Cost-effectiveness of screening a population with chronic gastroesophageal reflux.

BACKGROUND: Persons with chronic esophageal reflux are at increased risk for the development of Barrett's esophagus and adenocarcinoma. Recently developed ultrathin endoscopes are less expensive and better tolerated than standard endoscopes, they can be used without sedation, and are sensitive and specific for Barrett's esophagus. The cost-effectiveness of one-time screening strategies were evaluated for 50-year-old patients with chronic reflux: no screening, standard endoscopy, and screening by an ultrathin endoscope. METHODS: Markov models were created to simulate the clinical course for patients with chronic reflux. Costs and quality-adjusted life-years were estimated from cancer registry data, published medical data, and expert opinion. RESULTS: Under baseline assumptions, no screening resulted in average costs of $11,785 per person and 19.3226 quality-adjusted life-years. Ultrathin endoscopy screening resulted in costs of $12,119 per person and 19.3326 quality-adjusted life-years, yielding a marginal cost-effectiveness ratio of $55,764 per quality-adjusted life-year. Using standard endoscopy yielded costs of $12,332 with only slightly greater effectiveness, yielding a marginal cost-effectiveness ratio of $709,260 when compared with ultrathin endoscopy and $86,833 compared with no screening. Results were most sensitive to variation in the incidence of cancer in the population with Barrett's esophagus. CONCLUSIONS: Screening for Barrett's esophagus with ultrathin endoscopy is more cost-effective than standard endoscopy, and both strategies appear to improve quality-adjusted life-years among patients with chronic reflux at costs that are similar to those of other accepted preventive measures.