Jacques Van Dam

Diffuse reflectance spectroscopy of human adenomatous colon polyps in vivo.

Diffuse reflectance spectra were collected from adenomatous colon polyps (cancer precursors) and normal colonic mucosa of patients undergoing colonoscopy. We analyzed the data by using an analytical light diffusion model, which was tested and validated on a physical tissue model composed of polystyrene beads and hemoglobin. Four parameters were obtained: hemoglobin concentration, hemoglobin oxygen saturation, effective scatterer density, and effective scatterer size. Normal and adenomatous tissue sites exhibited differences in hemoglobin concentration and, on average, in effective scatterer size, which were in general agreement with other studies that employ standard methods. These results suggest that diffuse reflectance can be used to obtain tissue information about tissue structure and composition in vivo.

Risk factors for complications after performance of ERCP

BACKGROUND ERCP has become widely available for the diagnosis and treatment of benign and malignant pancreaticobiliary diseases. In this prospective study, the overall complication rate and risk factors for diagnostic and therapeutic ERCP were identified. METHODS Data were collected prospectively on patient characteristics and endoscopic techniques from 1223 ERCPs performed at a single referral center and entered into a database. Univariate and multivariate analyses were used to identify risk factors for ERCP-associated complications. RESULTS Of 1223 ERCPs performed, 554 (45.3%) were diagnostic and 667 (54.7%) therapeutic. The overall complication rate was 11.2%. Post-ERCP pancreatitis was the most common (7.2%) and in 93% of cases was self-limiting, requiring only conservative treatment. Bleeding occurred in 10 patients (0.8%) and was related to a therapeutic procedure in all cases. Nine patients had cholangitis develop, most cases being secondary to incomplete drainage. There was one perforation (0.08%). All other complications totaled 1.5%. Variables derived from cannulation technique associated with an increased risk for post-ERCP pancreatitis were precut access papillotomy (20%), multiple cannulation attempts (14.9%), sphincterotome use to achieve cannulation (13.1%), pancreatic duct manipulation (13%), multiple pancreatic injections (12.3%), guidewire use to achieve cannulation (10.2%), and the extent of pancreatic duct opacification (10%). Patient characteristics associated with an increased risk of pancreatitis were sphincter of Oddi dysfunction (21.7%) documented by manometry, previous ERCP-related pancreatitis (19%), and recurrent pancreatitis (16.2%). Pain during the procedure was an important indicator of an increased risk of post-ERCP pancreatitis (27%). Independent risk factors for post-ERCP pancreatitis were identified as a history of recurrent pancreatitis, previous ERCP-related pancreatitis, multiple cannulation attempts, pancreatic brush cytology, and pain during the procedure. CONCLUSIONS The most frequent ERCP-related complication was pancreatitis, which was mild in the majority of patients. The frequency of post-ERCP pancreatitis was similar for both diagnostic and therapeutic procedures. Bleeding was rare and mostly associated with sphincterotomy. Other complications such as cholangitis and perforation were rare. Specific patient- and technique-related characteristics that can increase the risk of post-ERCP complications were identified.

Endosonographic features predictive of lymph node metastasis

Endosonographic features that are thought to characterize lymph node metastasis were evaluated in 100 patients with esophageal carcinoma. Subjects underwent preoperative endoscopic ultrasonography to assess depth of tumor invasion (T stage) and lymph node metastasis (N stage). Endosonographically imaged lymph nodes were evaluated according to the following parameters: size, shape, border demarcation, and central echo pattern. Sensitivity and specificity of endosonography in detecting lymph node metastasis were 89.1% and 91.7%, respectively, when stringent criteria were used. When lymph nodes were imaged endosonographically, regardless of the specific features, the likelihood of N1 disease, was 86%, whereas when no lymph nodes were imaged, the chance of N0 disease was 79%. Endosonographic features predictive of malignancy in increasing order of importance were echo-poor (hypoechoic) structure, sharply demarcated borders, rounded contour, and size greater than 10 mm. Collectively, the EUS features produced an additive effect with respect to accuracy in the prediction of malignant lymph node involvement; malignancy could be predicted with 100% accuracy when all four features were present. These results demonstrate that a careful and systematic approach to the endosonographic assessment of lymph node metastasis can improve staging accuracy.

Detection of dysplasia at colonoscopy using laser-induced fluorescence: a blinded study

BACKGROUND Laser-induced fluorescence spectroscopy has the potential to detect colonic dysplasia in vivo. However, previous studies have limited their analyses to multivariate regression techniques and unblinded retrospective evaluation. The purpose of this study was to develop a probability-based algorithm to detect colonic dysplasia using laser-induced fluorescence spectroscopy and to evaluate it in a blinded manner. METHODS Fluorescence spectra were collected from normal mucosa and colonic polyps during colonoscopy using 370 nm excitation. Tissue was classified as normal, hyperplastic, or adenomatous by histologic examination. Preliminary data was used to devise an algorithm to differentiate tissue type based on probability distributions of the fluorescence intensity at 460 nm and the ratio of the intensity at 680 nm to that at 600 nm. The algorithm was then tested in a blinded fashion. RESULTS The algorithm correctly determined the tissue type in 88% of cases, equal to the agreement of independent pathologists. Sensitivity, specificity, and positive predictive value for the detection of dysplasia was 90%, 95%, and 90%, respectively. CONCLUSIONS Dysplasia was detected in vivo using fluorescence spectroscopy and a probability-based algorithm. This method may form the basis for a new surveillance technique for patients with increased risk for dysplastic transformation.

CDH1 Truncating Mutations in the E-Cadherin Gene: An Indication for Total Gastrectomy to Treat Hereditary Diffuse Gastric Cancer

Background:Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer. Methods:Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with d-2 node dissection and Roux-en-y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically. Results:Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51–57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality. Conclusions:CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.

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.

Accuracy and complication rate of brush cytology from bile duct versus pancreatic duct

BACKGROUND The accuracy and complication rates of brush cytology obtained from pancreaticobiliary strictures have not been fully defined. In this study we compared the accuracy and complications of brush cytology obtained from bile versus pancreatic ducts. METHODS We identified 148 consecutive patients for whom brush cytology was done during an ERCP from a database with prospectively collected data. We compared cytology results with the final diagnosis as determined by surgical pathologic examination or long-term clinical follow-up. We followed all patients and recorded ERCP-related complications. RESULTS Forty-two pancreatic brush cytology samples and 101 biliary brush cytology samples were obtained. The accuracy rate of biliary cytology was 65 of 101 (64.3%) and the accuracy rate of pancreatic cytology was 30 of 42 (71.4%). Overall sensitivity was 50% for biliary cytology and 58.3% for pancreatic cytology. Of 67 patients with pancreatic adenocarcinoma, sensitivity for biliary cytology was 50% versus 66% for pancreatic cytology. Concurrent pancreatic and biliary cytology during the same procedure increased the sensitivity in only 1 of 10 (10%) patients. Pancreatitis occurred in 11 (11%) patients (9 mild cases, 2 moderate cases) after biliary cytology and in 9 (21%) patients (6 mild cases, 3 moderate cases) after pancreatic cytology (p = 0.22). In 10 patients who had pancreatic brush cytology, a pancreatic stent was placed. None of these patients developed pancreatitis versus 9 of 32 (28%) patients in whom a stent was not placed (p = 0.08). Pancreatic cytology samples obtained from the head of the pancreas were correct in 13 of 18 (72%) cases, from the genu in 7 of 7 (100%) cases, from the body in 5 of 9 (55%) cases, and from the tail in 4 of 7 (57%) cases. CONCLUSION The accuracy of biliary brush cytology is similar to the accuracy of pancreatic brush cytology. The yield of the latter for pancreatic adenocarcinoma is similar to that of the former. Complication rates for pancreatic cytology are not significantly higher than the rates for biliary cytology. The placement of a pancreatic stent after pancreatic brushing appears to reduce the risk of postprocedure pancreatitis.

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.

Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States

BACKGROUND The aim of this study was to determine the frequency and the severity of pancreatitis after EUS-guided FNA of solid pancreatic masses. A survey of centers that offer training in EUS in the United States was conducted. METHODS A list of centers in which training in EUS is offered was obtained from the Web site of the American Society for Gastrointestinal Endoscopy. Designated program directors were contacted via e-mail. The information requested included the number of EUS-guided FNA procedures performed for solid pancreatic masses, the number of cases of post-procedure pancreatitis, and the method for tracking complications. For each episode of pancreatitis, technical details were obtained about the procedure, including the location of the mass, the type of fine needle used, the number of needle passes, and the nature of the lesion. RESULTS Nineteen of the 27 programs contacted returned the questionnaire (70%). In total, 4909 EUS-guided FNAs of solid pancreatic masses were performed in these 19 centers over a mean of 4 years (range 11 months to 9 years). Pancreatitis occurred after 14 (0.29%): 95% CI[0.16, 0.48] procedures. At two centers in which data on complications were prospectively collected, the frequency of acute pancreatitis was 0.64%, suggesting that the frequency of pancreatitis in the retrospective cohort (0.26%) was under-reported (p=0.22). The odds that cases of pancreatitis would be reported were 2.45 greater for the prospective compared with the retrospective cohort (95% CI[0.55, 10.98]). The median duration of hospitalization for treatment of pancreatitis was 3 days (range 1-21 days). The pancreatitis was classified as mild in 10 cases, moderate in 3, and severe in one; one death (proximate cause, pulmonary embolism) occurred after the development of pancreatitis in a patient with multiple comorbid conditions. CONCLUSIONS EUS-guided FNA of solid pancreatic masses is infrequently associated with acute pancreatitis. The procedure appears to be safe when performed by experienced endosonographers. The frequency of post EUS-guided FNA pancreatitis may be underestimated by retrospective analysis.

In vivo identification of colonic dysplasia using fluorescence endoscopic imaging.

BACKGROUND Previous in vitro studies showed that autofluorescence images of colonic mucosa collected endoscopically can be used to detect dysplasia with high sensitivity. This method is extended to the collection of fluorescence images of adenomatous polyps in vivo. METHODS Fluorescence images were collected during colonoscopy in 30 patients. A total of 12 adenomatous and 6 hyperplastic polyps were identified. A fiberoptic excitation probe, located in the instrument channel of the colonoscope, delivered 300 mW of near-ultraviolet light at lambdaex = 351 and 364 nm. Mucosal fluorescence in the spectral bandwidth between 400 and 700 nm was imaged, processed, and displayed with various likelihoods of associated dysplasia. RESULTS Adenomatous polyps exhibited decreased fluorescence intensity compared with adjacent mucosa with normal appearance. With the fluorescence threshold set to 80% of the average intensity of normal mucosa, a sensitivity of 83% for dysplasia identification was achieved. All hyperplastic polyps were correctly identified as being non-dysplastic. Optimal identification of dysplastic regions was obtained with the colonoscope oriented at a near-normal angle of incidence to the polyps. At higher angles of incidence, artifacts caused by illumination shadows were introduced. CONCLUSIONS The dysplasia associated with adenomatous polyps can be identified in vivo by fluorescence imaging with high sensitivity, thus demonstrating the potential to guide endoscopic procurement of biopsy specimens.