External validation of blue light imaging (BLI) criteria for the optical characterization of colorectal polyps by endoscopy experts.

BACKGROUND AND AIM: Recently, the BLI Adenoma Serrated International Classification (BASIC) system was developed by European experts to differentiate colorectal polyps. Our aim was to validate the BASIC classification system among the US-based endoscopy experts. METHODS: Participants utilized a web-based interactive learning system where the group was asked to characterize polyps using the BASIC criteria: polyp surface (presence of mucus, regular/irregular and [pseudo]depressed), pit appearance (featureless, round/non-round with/without dark spots; homogeneous/heterogeneous distribution with/without focal loss), and vessels (present/absent, lacy, peri-cryptal, irregular). The final testing consisted of reviewing BLI images/videos to determine whether the criteria accurately predicted the histology results. Confidence in adenoma identification (rated "1" to "5") and agreement in polyp (adenoma vs non-adenoma) identification and characterization per BASIC criteria were derived. Strength of interobserver agreement with kappa (k) value was reported for adenoma identification. RESULTS: Ten endoscopy experts from the United States identified conventional adenoma (vs non-adenoma) with 94.4% accuracy, 95.0% sensitivity, 93.8% specificity, 93.8% positive predictive value, and 94.9% negative predictive value using BASIC criteria. Overall strength of interobserver agreement was high: kappa 0.89 (0.82-0.96). Agreement for the individual criteria was as follows: surface mucus (93.8%), regularity (65.6%), type of pit (40.6%), pit visibility (66.9%), pit distribution (57%), vessel visibility (73%), and being lacy (46%) and peri-cryptal (61%). The confidence in diagnosis was rated at high ≥4 in 67% of the cases. CONCLUSIONS: A group of US-based endoscopy experts have validated a simple and easily reproducible BLI classification system to characterize colorectal polyps with >90% accuracy and a high level of interobserver agreement.

Qualitative and Quantitative Contrast-enhanced Endoscopic Ultrasound Improves Evaluation of Focal Pancreatic Lesions.

BACKGROUND & AIMS: Endoscopic ultrasound (EUS) is a sensitive method to evaluate the pancreas but its diagnostic capability for several diseases is limited. We compared the diagnostic yield of unenhanced EUS with that of contrast-enhanced EUS for focal pancreas lesions and identified and tested quantitative parameters of contrast enhancement. METHODS: We performed a prospective tandem-controlled trial in which 101 patients with focal pancreas lesions (48 with masses, 28 with cysts, and 25 with pancreatitis) underwent conventional EUS followed by contrast EUS using intravenous perflutren microspheres. The diagnosis at each stage was scored and compared with a standard (findings from surgical pathology analysis, cytologic, and/or 6-month clinical follow-up evaluations). Quantitative parameters were generated by time-intensity curve analysis. Solid lesions were divided into derivation and testing cohorts for a crossover validation analysis of the quantitative parameters. The primary outcome was diagnostic yield of unenhanced vs contrast EUS in analysis of focal pancreas lesions. RESULTS: Contrast increased the diagnostic yield of EUS from 64% (65/101 lesions accurately assessed) to 91% (92/101 lesions accurately assessed); the odds ratio [OR] was 7.8 (95% CI, 2.7-30.2) for accurate analysis of lesions by contrast-enhanced EUS relative to unenhanced EUS. The contrast increased accuracy of analysis of pancreas masses (OR, 6.0; 95% CI, 1.8-31.8), improving assessment of neuroendocrine and other (non-carcinoma) tumors. Contrast increased the diagnostic yield for pancreas cysts to 96% (27/28) compared with 71.4% (20/28) for unenhanced EUS (P = .02), due to improved differentiation of mural nodules vs debris. Time-intensity curve analysis revealed distinct patterns of relative peak enhancement (rPE) and in-slope (rIS) for different lesions following contrast injection: for adenocarcinomas, values were low rPE and low rIS; for neuroendocrine masses, values were high rPE and normal IS; and for chronic pancreatitis foci, values were normal rPE and low rIS. In the validation cohort, these parameters correctly characterized 91% of lesions and improved yield relative to unenhanced EUS (OR, 10; 95% CI, 1.4-34.0). CONCLUSIONS: Contrast-enhanced EUS improves the accuracy of analysis of focal pancreas lesions, compared with unenhanced EUS. Integration of practical quantitative parameters, specifically relative peak enhancement and in-slope, might increase the diagnostic accuracy of contrast EUS. ClinicalTrials.gov no: 02863770.

Rectal Optical Markers for In Vivo Risk Stratification of Premalignant Colorectal Lesions.

PURPOSE: Colorectal cancer remains the second leading cause of cancer deaths in the United States despite being eminently preventable by colonoscopy via removal of premalignant adenomas. In order to more effectively reduce colorectal cancer mortality, improved screening paradigms are needed. Our group pioneered the use of low-coherence enhanced backscattering (LEBS) spectroscopy to detect the presence of adenomas throughout the colon via optical interrogation of the rectal mucosa. In a previous ex vivo biopsy study of 219 patients, LEBS demonstrated excellent diagnostic potential with 89.5% accuracy for advanced adenomas. The objective of the current cross-sectional study is to assess the viability of rectal LEBS in vivo. EXPERIMENTAL DESIGN: Measurements from 619 patients were taken using a minimally invasive 3.4-mm diameter LEBS probe introduced into the rectum via anoscope or direct insertion, requiring approximately 1 minute from probe insertion to withdrawal. The diagnostic LEBS marker was formed as a logistic regression of the optical reduced scattering coefficient [Formula: see text] and mass density distribution factor D. RESULTS: The rectal LEBS marker was significantly altered in patients harboring advanced adenomas and multiple non-advanced adenomas throughout the colon. Blinded and cross-validated test performance characteristics showed 88% sensitivity to advanced adenomas, 71% sensitivity to multiple non-advanced adenomas, and 72% specificity in the validation set. CONCLUSIONS: We demonstrate the viability of in vivo LEBS measurement of histologically normal rectal mucosa to predict the presence of clinically relevant adenomas throughout the colon. The current work represents the next step in the development of rectal LEBS as a tool for colorectal cancer risk stratification.

Massive pancreatic pseudocyst with portal vein fistula: case report and proposed treatment algorithm.

Pancreatic pseudocyst is a relatively common occurrence resulting from acute or chronic pancreatitis. However, a rare subset of these patients present with a pseudocyst fistulizing into the portal vein. We present the case of a 58 year-old woman with a rapidly expanding pancreatic pseudocyst with portal venous fistulization causing portal vein thrombosis, in addition to biliary and duodenal obstruction. The patient underwent surgical decompression with a cyst-gastrostomy and was well until one week post-operatively when she experienced massive gastrointestinal hemorrhage leading to her death. A review of the literature is presented and a treatment algorithm to manage patients with pancreatic pseudocyst to portal vein fistula is proposed.

Endoscopic treatment options for cholangiocarcinoma.

Cholangiocarcinomas are often locally advanced or have metastasized, and at the time of diagnosis individuals often have a poor prognosis. Endoscopic treatment options traditionally include biliary decompression via stenting to allow for systemic chemotherapy and radiotherapy, with self-expanding metal biliary stents being preferred. Recent developments in locoregional therapy delivered endoscopically, such as photodynamic therapy and radiofrequency abalation, have shown promising results in improving patient survival.

A Raman-based endoscopic strategy for multiplexed molecular imaging.

Endoscopic imaging is an invaluable diagnostic tool allowing minimally invasive access to tissues deep within the body. It has played a key role in screening colon cancer and is credited with preventing deaths through the detection and removal of precancerous polyps. However, conventional white-light endoscopy offers physicians structural information without the biochemical information that would be advantageous for early detection and is essential for molecular typing. To address this unmet need, we have developed a unique accessory, noncontact, fiber optic-based Raman spectroscopy device that has the potential to provide real-time, multiplexed functional information during routine endoscopy. This device is ideally suited for detection of functionalized surface-enhanced Raman scattering (SERS) nanoparticles as molecular imaging contrast agents. This device was designed for insertion through a clinical endoscope and has the potential to detect and quantify the presence of a multiplexed panel of tumor-targeting SERS nanoparticles. Characterization of the Raman instrument was performed with SERS particles on excised human tissue samples, and it has shown unsurpassed sensitivity and multiplexing capabilities, detecting 326-fM concentrations of SERS nanoparticles and unmixing 10 variations of colocalized SERS nanoparticles. Another unique feature of our noncontact Raman endoscope is that it has been designed for efficient use over a wide range of working distances from 1 to 10 mm. This is necessary to accommodate for imperfect centering during endoscopy and the nonuniform surface topology of human tissue. Using this endoscope as a key part of a multiplexed detection approach could allow endoscopists to distinguish between normal and precancerous tissues rapidly and to identify flat lesions that are otherwise missed.

Pre-ERCP imaging of the bile duct and gallbladder.

Advances in biliary imaging have improved making accurate diagnoses of the presence and causes of biliary obstruction. Abdominal ultrasound is a useful screening tool because it is highly specific for choledocholithiasis. New developments in CT and MRI have also been useful in the diagnosis of biliary disease. Although diagnosis of biliary disease can be achieved in a noninvasive manner, there are limitations to modern MRI and CT cholangiographic techniques; their use may not be necessary or cost effective. MRI and CT imaging of the biliary tract provides opportunities for less-invasive diagnostic techniques but should be used judiciously before interventional endoscopy.

Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts.

BACKGROUND: Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts. METHODS: A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed. RESULTS: Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (p = 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%). CONCLUSION: Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.

Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer.

PURPOSE: This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS: All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year. CONCLUSION: Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

A prospective study of total gastrectomy for CDH1-positive hereditary diffuse gastric cancer.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome. Up to 30% of families with HDGC have mutations in the E-cadherin gene, CDH1. The role of prophylactic versus therapeutic gastrectomy for HDGC was studied prospectively. METHODS: Eighteen consecutive patients with CDH1 mutations and positive family history were studied prospectively, including 13 without and 5 with symptoms. Proportions were compared by Fisher's exact test, and survival by the Breslow modification of the Wilcoxon rank-sum test. RESULTS: Each patient underwent total gastrectomy (TG), and 17 (94%) were found to have signet ring cell adenocarcinoma. Twelve of 13 asymptomatic patients had T1, N0 cancer, and only 2/12 (16%) had it diagnosed preoperatively despite state-of-the-art screening methods. Each asymptomatic patient did well postoperatively, and no patient has recurred. For five symptomatic patients, each (100%) was found to have signet ring cell adenocarcinoma (P = 0.002 versus asymptomatic) by preoperative endoscopy; three (60%) had lymph node involvement and two (40%) had distant metastases at time of operation. Two-year survival was 100% for asymptomatic and 40% for symptomatic patients (P < 0.01). CONCLUSION: The data show that asymptomatic patients with family history of HDGC and CDH1 mutation have high probability of having signet ring cell adenocarcinoma of the stomach that is not able to be diagnosed on endoscopy; when symptoms arise, the diagnosis can be made by endoscopy, but they have metastases and decreased survival. Surveillance endoscopy is of limited value, and prophylactic gastrectomy (PG) is recommended for patients with family history of HDGC and CDH1 mutations.

Determination of the relationship between gastric wall thickness and body mass index with endoscopic ultrasound.

BACKGROUND: The aim of this study was to determine the relationship between gastric wall thickness and BMI. METHODS: Bariatric surgery patients undergoing a pre-operative screening EGD and patients undergoing endoscopic ultrasound for non-gastric pathology were prospectively enrolled in the study. Patients underwent endoscopic ultrasound evaluation with measurements of gastric wall thickness at six areas of the stomach. The primary outcome was the correlation of BMI and mean gastric wall thickness. RESULTS: Twenty-four patients were enrolled in the study. Eight patients were excluded due to endoscopic abnormalities of the stomach (five) or intolerance to the procedure (three). Ten patients with a normal BMI and six obese patients were included in the analysis. BMI in the non-obese group was 23.8 ± 2.5 kg/m(2) compared to 54.7 ± 14.6 kg/m(2) in the obese population. The average gastric wall thickness amongst all subjects was 3.27 ± 0.42 mm. Mean gastric thickness in the non-obese group was 3.25 ± 0.45 mm compared to 3.30 ± 0.39 mm in the obese group (p = 0.41). When both groups were combined, there did not appear to be a linear relationship between mean thickness and BMI (R (2) = 0.005). There was no linear relationship between gastric wall thickness and waist circumference (R (2) = 0.02). CONCLUSION: There was no significant correlation between gastric wall thickness and BMI. Mean gastric wall thickness of endoscopically normal stomachs was in the range of 3-4 mm.

Determining scope position during colonoscopy without use of ionizing radiation or magnetic imaging: the enhanced mapping ability of the NeoGuide Endoscopy System.

BACKGROUND: Knowledge of the position and shape of the endoscope could overcome many challenges of performing colonoscopy, e.g., loop formation. A novel computer-assisted colonoscope (NeoGuide Endoscopy System) delivers a real-time, three-dimensional map of the tip position and insertion tube shape in addition to the video image of the colon lumen. The aim of this study is to evaluate the mapping capabilities of the NeoGuide Endoscopy System in terms of colonic looping, insertion depth, tip position, and tip angle formation. METHODS: Ten endoscopists with various levels of experience were each shown 70 map images generated by the NeoGuide endoscopy system in a benchtop anatomical colon model. First endoscopists were asked to determine the tip angle based on the map image and the system's corresponding tip positioning aid (20 images). In the second part they had to identify the scope-tip position in the colon model (40 images). In the third part ten images were presented for identification of colonic loops. RESULTS: The tip angle was correctly identified in 99% (198/200) of images. Using only the map images the scope position was accurately determined in 87.5% (350/400). Identification of colonic looping of the scope was appropriate in 99% (99/100). Overall accuracy was 92.4%, and overall positive predictive value was 94.9%. CONCLUSION: Three-dimensional map images generated by the NeoGuide endoscopy system provide accurate information regarding tip position, insertion tube position, and colonic looping.

EUS-guided gold fiducial insertion for image-guided radiation therapy of pancreatic cancer: 50 successful cases without fluoroscopy.

BACKGROUND: Image-guided radiation therapy (IGRT) accurately delivers a high dose of potentially tumoricidal radiation to its target while sparing adjacent healthy tissue. Application of IGRT to unresectable pancreatic cancer requires the use of fiducials to track the precise location of the tumor. Fiducial markers have been successfully placed endoscopically. OBJECTIVE: To determine the feasibility of EUS-guided gold fiducial placement for IGRT. DESIGN: Prospective case series. SETTING: Tertiary medical center. PATIENTS: Consecutively referred patients with locally advanced unresectable pancreatic adenocarcinoma for EUS-guided insertion of gold fiducials from December 2006 to February 2009. INTERVENTIONS: Under only EUS guidance, fiducial markers were deployed into or near the tumor by using a 19-gauge needle. In most cases, a sterile water injection technique was used to insert the fiducials. Fluoroscopy was not used in any case. MAIN OUTCOME MEASUREMENTS: Successful placement of an adequate number of fiducials to proceed with IGRT as determined by CT. RESULTS: Fifty-seven consecutive patients were included. Fifty cases (88%) were successful. Of the cases in which fiducial placement was attempted and follow-up was adequate, 94% (50 of 53) of cases were successful. LIMITATIONS: Single-center, nonrandomized study. CONCLUSIONS: EUS-guided fine-needle insertion was safe and effective in delivering gold fiducial markers for image-guided radiation therapy. Fluoroscopy was not required for successful fiducial placement.

Interfractional uncertainty in the treatment of pancreatic cancer with radiation.

PURPOSE: To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers. METHODS AND MATERIALS: Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)-right (-), anterior (-)-posterior (+), and superior (+)-inferior (-), and the overall interfractional tumor movement was calculated based on these values. RESULTS: A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0-9 mm), 1.8 mm (95th percentile, 7 mm; range, 0-13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0-19 mm) in the anterior-posterior, left-right, and superior-inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0-19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy. CONCLUSIONS: There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

Endoscopy is accurate, safe, and effective in the assessment and management of complications following gastric bypass surgery.

OBJECTIVES: Roux-en-Y gastric bypass (RYGB) is a common intervention for morbid obesity. Upper gastrointestinal (UGI) symptoms are frequent and difficult to interpret following RYGB. The aim of our study was to examine the role of endoscopy in evaluating UGI symptoms after RYGB and to assess the safety and efficacy of endoscopic therapy. METHODS: Between 1998 and 2005, a total of 1,079 patients underwent RYGB for clinically severe obesity and were followed prospectively. Patients with UGI symptoms after RYGB who were referred for endoscopy were studied. RESULTS: Of 1,079 patients, 76 (7%) who underwent RYGB were referred for endoscopy to evaluate UGI symptoms. Endoscopic findings included normal surgical anatomy (n=24, 31.6%), anastomotic stricture (n=40, 52.6%), marginal ulcer (n=12, 15.8%), unraveled nonabsorbable sutures causing functional obstruction (n=3, 4%) and gastrogastric fistula (n=2, 2.6%). Patients with abnormal findings on endoscopy presented with UGI symptoms at a mean of 110.7 days from their RYGB, which was significantly shorter than the time of 347.5 days for patients with normal endoscopy (P<0.001). A total of 40 patients with anastomotic strictures underwent 86 endoscopic balloon dilations before complete symptomatic relief. In one patient, a needle knife was used to open a completely obstructed anastomotic stricture. Unraveled, nonabsorbable suture material was successfully removed using endoscopic scissors in three patients. CONCLUSIONS: Patients presenting with UGI symptoms less than 3 months after surgery are more likely to have an abnormal finding on endoscopy. Endoscopic balloon dilation is safe and effective in managing anastomotic strictures. Endoscopic scissors are safe and effective in removing unraveled, nonabsorbable sutures contributing to obstruction.