Systematic review with meta-analysis: endoscopic retrograde cholangiopancreatography-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND: The accuracy of current endoscopic modalities for diagnosing cholangiocarcinoma in primary sclerosing cholangitis (PSC) is suboptimal. AIM: To evaluate the comparative effectiveness of endoscopic retrograde cholangiopancreatography (ERCP)-based modalities, independently or in combination, for the diagnosis of cholangiocarcinoma in patients with PSC-induced biliary strictures. METHODS: Searches of PubMed, EMBASE, Web of Science and the Cochrane Library databases were performed through December 2015. Measured outcomes included sensitivity and specificity of all diagnostic modalities independently or in combination. A bivariate model was used to compute the pooled sensitivity and specificity, and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence interval (95% CI). A logistic regression model was used to impute the incremental performance of combining two diagnostic tests. RESULTS: Twenty-one studies met inclusion criteria: 13 on bile duct brushing for cytology, 7 on fluorescence in situ hybridisation (FISH), 2 on probe-based confocal laser endomicroscopy, and 4 on single-operator cholangioscopy with targeted biopsies. Single-operator cholangioscopy with targeted biopsies was the most accurate diagnostic modality at 96% (95% CI, 94-97%). The pooled sensitivity and specificity of single-operator cholangioscopy for diagnosis of cholangiocarcinoma in patients with PSC was 65% (95% CI, 35-87%) and 97% (95% CI, 87-99%), respectively. The pooled diagnostic odds ratio to detect cholangiocarcinoma was 59 (95% CI, 10-341). CONCLUSIONS: Single-operator cholangioscopy with targeted biopsies appears to be the most accurate ERCP-based modality for diagnosing cholangiocarcinoma in primary sclerosing cholangitis. However, future large, well-designed comparative diagnostic studies are warranted to validate these findings.

Outcomes after implementing a tailored endoscopic step-up approach to walled-off necrosis in acute pancreatitis.

BACKGROUND: The aim of the study was to compare the outcomes of patients with pancreatic or peripancreatic walled-off necrosis by endoscopy using the conventional approach versus an algorithmic approach based on the collection size, location and stepwise response to intervention. METHODS: This was an observational before-after study of consecutive patients managed over two time intervals. In the initial period (2004-2009) symptomatic patients with walled-off necrosis underwent conventional single transmural drainage with placement of two stents and a nasocystic catheter, followed by direct endoscopic necrosectomy, if required. In the later period (2010-2013) an algorithmic approach was adopted based on size and extent of the walled-off necrosis and stepwise response to intervention. The main outcome was treatment success, defined as a reduction in walled-off necrosis size to 2 cm or less on CT after 8 weeks. RESULTS: Forty-seven patients were treated in the first interval and 53 in the second. There was no difference in patient demographics, clinical or walled-off necrosis characteristics and laboratory parameters between the groups, apart from a higher proportion of women and Caucasians in the later period. The treatment success rate was higher for the algorithmic approach compared with conventional treatment (91 versus 60 per cent respectively; P < 0·001). On multivariable logistic regression, management based on the algorithm was the only predictor of treatment success (odds ratio 6·51, 95 per cent c.i. 2·19 to 19·37; P = 0·001). CONCLUSION: An algorithmic approach to pancreatic and peripancreatic walled-off necrosis, based on the collection size, location and stepwise response to intervention, resulted in an improved rate of treatment success compared with conventional endoscopic management.

The presence of a cytopathologist increases the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration cytology for pancreatic adenocarcinoma: a meta-analysis.

OBJECTIVE: A meta-analysis has not been previously performed to evaluate critically the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solely pancreatic ductal adenocarcinoma and address factors that have an impact on variability of accuracy. The aim of this study was to determine whether the presence of a cytopathologist, variability of the reference standard and other sources of heterogeneity significantly impacts diagnostic accuracy. METHODS: We conducted a comprehensive search to identify studies, in which the pooled sensitivity, specificity, likelihood ratios for a positive or negative test (LR+, LR-) and summary receiver-operating curves (SROC) could be determined for EUS-FNA of the pancreas for ductal adenocarcinoma using clinical follow-up, and/or surgical biopsy or excision as the reference standard. RESULTS: We included 34 distinct studies (3644 patients) in which EUS-FNA for a solid pancreatic mass was evaluated. The pooled sensitivity and specificity for EUS-FNA for pancreatic ductal adenocarcinoma was 88.6% [95% confidence interval (CI): 87.2-89.9] and 99.3% (95% CI: 98.7-99.7), respectively. The LR+ and LR- were 33.46 (95% CI: 20.76-53.91) and 0.11 (95% CI: 0.08-0.16), respectively. The meta-regression model showed rapid on-site evaluation (ROSE) (P = 0.001) remained a significant determinant of EUS-FNA accuracy after correcting for study population number and reference standard. CONCLUSION: EUS-FNA is an effective modality for diagnosing pancreatic ductal adencarcinoma in solid pancreatic lesions, with an increased diagnostic accuracy when using on-site cytopathology evaluation.

Randomized trial comparing fanning with standard technique for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic mass lesions.

BACKGROUND AND STUDY AIMS: The fanning technique for endoscopic ultrasound-guided fine-needle aspiration (EUS - FNA) involves sampling multiple areas within a lesion with each pass. The aim of this study was to compare the fanning and standard techniques for EUS - FNA of solid pancreatic masses. PATIENTS AND METHODS: Consecutive patients with solid pancreatic mass lesions were randomized to undergo EUS - FNA using either the standard or the fanning technique. The main outcome measure was the median number of passes required to establish diagnosis. The secondary outcome measures were the diagnostic accuracy, technical failure, and complication rate of the two techniques. RESULTS: Of 54 patients, 26 were randomized to the standard technique and 28 to the fanning technique. There was no difference in diagnostic accuracy (76.9 % vs. 96.4 %; P = 0.05), technical failure or complication rates (none in either cohort). There was a significant difference in both the number of passes required to establish diagnosis (median 1 [interquartile range 1 - 3] vs. 1 [1 - 1]; P = 0.02) and the percentage of patients in whom a diagnosis was achieved on pass one (57.7 % vs. 85.7 %; P = 0.02) between the standard and fanning groups, respectively. CONCLUSIONS: The fanning technique of FNA was superior to the standard approach because fewer passes were required to establish the diagnosis. If these promising data are confirmed by other investigators, consideration should be given to incorporating the fanning technique into routine practice of EUS - FNA. Registered at Clinical Trials.gov (NCT 01501903).

A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer.

PURPOSE: (1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial-mesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment. METHODS: Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0-300 mg/m(2)/week) given concurrently with cetuximab (400 mg/m(2) loading dose, 250 mg/m(2) weekly maintenance dose) and abdominal irradiation (50.4 Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens. RESULTS: Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1-2 adverse events was 96%, and incidence of 3-4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5 months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients. CONCLUSIONS: Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300 mg/m(2)/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer.

The use of endoscopic ultrasound-guided gold markers in image-guided radiation therapy of pancreatic cancers: a case series.

While endoscopic ultrasound (EUS)-guided fiducial placement is technically feasible, its role in the delivery of image-guided radiation therapy (IGRT) is unclear. In this study, we evaluated the feasibility and safety of using EUS-guided fiducial markers for delivering IGRT in patients with pancreatic cancer. Following computed tomography (CT) simulation, a radiation therapy treatment plan was prepared for each patient. A kilovoltage (kv) image obtained before each treatment session was aligned with images generated during treatment planning, based on the position of fiducials. Radiation therapy was then delivered. Image analysis was also performed by alignment of bony landmarks (current standard of care). Daily shifts of fiducials between the two sets of images represented movement of the pancreas relative to the bony landmarks. EUS-guided fiducial placement was technically successful in all nine patients and no complications were encountered. The fiducials were easily identified for image fusion and IGRT was delivered successfully to all patients. The movement of the pancreas relative to bones was 0.2 cm (0.1-0.5 cm), 0.5 cm (0.2-1.5 cm), and 0.4 cm (0.2-0.9 cm) in the anterior-posterior, superior-inferior, and left-right axes, respectively. This technique may have significant clinical implications in terms of radiation dosimetry.

Endoscopic ultrasound-guided fine-needle aspiration for diagnosis of solid pseudopapillary tumors of the pancreas: a multicenter experience.

BACKGROUND AND STUDY AIMS: Solid pseudopapillary tumors of the pancreas are rare, low-grade, epithelial neoplasms that are usually discovered incidentally in young women. Distinguishing solid pseudopapillary tumors from other pancreatic tumors, especially pancreatic endocrine tumors, can be challenging. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in this context remains unclear. The purpose of this study was to describe the endoscopic ultrasound features of solid pseudopapillary tumors and the role of EUS-FNA in the preoperative diagnosis of these tumors. PATIENTS AND METHODS: Patients from five tertiary referral centers with surgically confirmed solid pseudopapillary tumors who had undergone preoperative EUS-FNA were included. The endoscopic ultrasound findings, cytologic descriptions, immunostaining results, operative records, surgical pathology, and results of the most recent clinical follow-up were reviewed. RESULTS: A total of 28 patients were identified (four men [14 %], 24 women [86 %], mean age +/- standard deviation [SD] 35 +/- 10 years). Solid pseudopapillary tumors had been found as incidental findings on cross-sectional imaging in 50 % of cases. The mean tumor size +/- SD was 42 +/- 19.5 mm and the majority were located in the pancreatic body and tail. The endoscopic ultrasound report described a well-defined, echo-poor mass in 86 %; the tumors were solid in 14 patients (50 %), mixed solid and cystic in 11 patients (39 %), and cystic in three patients (11 %). A preoperative diagnosis of solid pseudopapillary tumor was made in 21 patients (75 %) on the basis of EUS-FNA cytology. Surgical resection was performed in all cases. Laparoscopic resection was performed in eight of these patients (29 %). CONCLUSIONS: A solid pseudopapillary tumor should be included in the differential diagnosis of any well-demarcated, echo-poor, solid or mixed solid/cystic pancreatic lesion seen during endoscopic ultrasound, particularly in young women. The diagnostic accuracy of EUS-FNA for solid pseudopapillary tumors was 75 % in this study. A definitive preoperative diagnosis can guide the surgical approach in selected cases.

Prospective randomized trial evaluating ketamine for advanced endoscopic procedures in difficult to sedate patients.

BACKGROUND: Adequate patient sedation is mandatory for advanced endoscopic procedures such as ERCP and EUS. AIM: To evaluate the effectiveness and safety of ketamine in difficult to sedate patients undergoing advanced endoscopic procedures. METHODS: This was a prospective, randomized trial of all patients undergoing ERCP or EUS who were not adequately sedated despite administration of meperidine 50 mg, midazolam 5 mg and diazepam 5 mg. Patients during endoscopy were then randomized to receive either intravenous ketamine (20 mg) every 5 min or continue to receive standard sedation using meperidine and diazepam. RESULTS: Of 175 patients, 82 were randomized to receive ketamine and 93 standard sedatives. Compared with standard sedation, qualitative physician rating (P < 0.0001) and depth of sedation (P < 0.001) were superior in the ketamine group with shorter recovery times (P < 0.0001). Both patient discomfort and sedation-related technical difficulty were significantly less among patients randomized to receive ketamine (P < 0.0001). More patients in the standard sedation group were crossed-over to the ketamine group due to sedation failure (35.5 vs. 3.7%, P < 0.0001). Nine patients who received ketamine, developed adverse events that were managed conservatively. CONCLUSIONS: Ketamine is a useful adjunct to conscious sedation in patients who are difficult to sedate. Its use Results in better quality and depth of sedation with shorter recovery times than patients sedated using benzodiazepines and meperidine alone. Further prospective studies evaluating the effectiveness and safety of ketamine for endoscopic sedation are needed.

Cumulative sum procedure in evaluation of EUS-guided FNA cytology: the learning curve and diagnostic performance beyond sensitivity and specificity.

BACKGROUND: Using cumulative sum (CUSUM) chart, we address two questions: (i) Over time, how will an EUS-FNA (endoscopic ultrasound guided fine needle aspiration) service maintain an acceptable non-diagnostic rate defined as technical failures, unsatisfactory specimens and atypical and suspicious diagnoses? (ii) Over time, how will EUS-FNA maintain acceptable diagnostic errors (false-positives plus false-negative diagnosis)? METHODS: The study included all consecutive patients who underwent EUS-FNA at our institution from July 2000 to October 2003 and were followed up until December 2004. Using a simple spread sheet, we designed CUSUM charts and used them to track trends and assess performance at a preset acceptable rate of 10% and a preset unacceptable rate of 15% for non-diagnostic rate and diagnostic errors. We assessed all cases collectively and then in groups defined by site, size and cytopathologist. RESULTS: Of 876 patients undergoing EUS-FNA, 83 (9.5%) had non-diagnostic results: 43 (51%) of these diagnoses were 'atypical', 27(33%) were 'suspicious for malignancy', eight (10%) were 'insufficient material for diagnosis' and five (6%) were 'technical failure'. In 585 cases with adequate follow up, there were 26 (6.3%) diagnostic errors: three (0.5%) were false positive and 23 (3.1) were false negative. The overall CUSUM charts for both non-diagnostic rate and for diagnostic error rate start with a small period of learning then cross to a significantly acceptable level at case numbers 121 and 97 respectively. Our diagnostic performance was better in lymph nodes than in the pancreas and other organs and was not significantly different for lesions 25 mm in diameter. Performance was better for pathologists with prior experience than for pathologists without experience. CONCLUSION: In the current climate of proficiency testing, error tracking and competence evaluation, there is a great potential for the use of CUSUM charts to assess procedure failure and error tracking in quality control programs, particularly when a new procedure such as EUS-FNA is introduced in the laboratory. Additionally, the method can be used to assess trainee competency and to track the proficiency of practicing cytologists.

Evaluation of dextrose 50 % as a medium for injection-assisted polypectomy.

BACKGROUND AND STUDY AIMS: Injection-assisted polypectomy (IAP) is traditionally carried out by using normal saline as the submucosal fluid cushion. However, normal saline, being isotonic, does not maintain the elevation of the mucosa for prolonged periods. It was hypothesized that dextrose 50 %, as a hypertonic solution, might be an ideal medium for IAP. This study evaluated the efficacy and safety of dextrose 50 % for performing IAP. PATIENTS AND METHODS: All patients undergoing IAP during gastroscopy or colonoscopy were randomly assigned on a prospective basis to receive either normal saline or dextrose 50 % as the submucosal fluid cushion. The endoscopist was blinded to the type of solution injected. The volume of solution and number of sites injected to elevate the lesion, the number of times IAP was interrupted to inject more fluid to maintain elevation, the rates of en bloc and complete resections, and the complication rates were compared in the two groups. The mean follow-up period was 10 months. RESULTS: Fifty-two sessile lesions were removed in 50 patients. In comparison with normal saline, smaller volumes (median 7 ml vs. 5 ml; P = 0.02) and fewer injections (median 2 vs. 1; P = 0.003) were required to perform IAP when dextrose 50 % was used. The en bloc resection rate was higher with dextrose 50 % than with normal saline (82 % vs. 44 %; P = 0.01). Elevation of the submucosal area persisted even after completion of IAP in 96 % of the patients randomly assigned to dextrose 50 %, compared with 20 % of those receiving normal saline ( P < 0.001). There were no significant differences in the rates of complete resection or complications between the two groups. CONCLUSIONS: Dextrose 50 % is superior to normal saline as a submucosal fluid cushion, as it allows better en bloc resection during injection-associated polypectomy.

Transgastric endoscopic ultrasound-guided fine-needle aspiration biopsy and flow cytometry of suspected lymphoma of the spleen.

BACKGROUND AND STUDY AIMS: Masses in the spleen can be sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) but the diagnosis of lymphoma using EUS-FNA and flow cytometry has not been reported. We report our experience with transgastric EUS-FNA and flow cytometry in the investigation of patients with suspected lymphoma of the spleen. PATIENTS AND METHODS: All patients with splenic lesions that had been detected by computed tomography and who were referred for transgastric EUS-FNA over a 3-year period were enrolled in this study. The tissue obtained by EUS-FNA was evaluated by flow cytometry in all patients. RESULTS: Six patients with splenic masses were enrolled (four men, two women; median age 58.5 years, range 41 - 82 years). The mean size of the short axis of the lesions was 37.8 mm (SD 23.76 mm) and the mean size of the long axis was 45.6 mm (SD 31.72 mm). EUS-FNA was performed successfully in all patients and the tissue obtained was evaluated by flow cytometry. Two patients were diagnosed with lymphoma; no pathology was identified in the other four patients. Lymphoma of the spleen appeared as sharply demarcated echo-poor lesions; benign lesions appeared echo-rich in comparison with the surrounding splenic tissue. The two patients who were diagnosed with lymphoma underwent chemotherapy. Of the four patients in whom no pathology was identified, one patient subsequently underwent splenectomy for evaluation of persistent abdominal pain and was diagnosed with lymphoma; the three other patients had true-negative disease on the evidence of long-term follow-up (mean 8 months; range 6 - 12 months). No complications related to the EUS-FNA procedure were encountered in any patient. CONCLUSIONS: EUS-FNA of spleen masses is a safe technique that aids in the diagnosis of lymphoma when used in conjunction with flow cytometry.

Do all patients with abnormal intraoperative cholangiogram merit endoscopic retrograde cholangiopancreatography?

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is commonly used for postoperative evaluation of an abnormal intraoperative cholangiogram (IOC). Although a normal IOC is very suggestive of a disease-free common bile duct (CBD), abnormal studies are associated with high false-positive rates. This study aimed to identify a subset of patients with abnormal IOC who would benefit from a postoperative ERCP. METHODS: This prospective study investigated 51 patients with abnormal IOC at laparoscopic cholecystectomy who underwent postoperative ERCP at two tertiary referral centers over a 3-year period. Univariate and multivariate logistic regression analyses were performed to determine predictors of CBD stones at postoperative ERCP. RESULTS: For all 51 patients, ERCP was successful. The ERCP showed CBD stones in 33 cases (64.7%), and normal results in 18 cases (35.2%). On univariate analysis, abnormal liver function tests (p < 0.0001) as well as IOC findings of a large CBD stone (p = 0.03), multiple stones (p = 0.01), and a dilated CBD (p = 0.07) predicted the presence of retained stones at postoperative ERCP. However, on multivariable analysis, only abnormal liver function tests correlated with the presence of CBD stones (p < 0.0001). CONCLUSIONS: One-third of patients with an abnormal IOC have a normal postoperative ERCP. Elevated liver function tests can help to identify patients who merit further evaluation by ERCP. The use of less invasive methods such as endoscopic ultrasound or magnetic resonance cholangiopancreatography should be considered for patients with normal liver function tests to minimize unnecessary ERCPs.

Endoscopic ultrasound-guided FNA biopsy of bile duct and gallbladder: analysis of 53 cases.

OBJECTIVE: Endoscopic retrograde cholangiopancreaticography (ERCP)-guided brushing has been the standard of practice for surveillance and detection of carcinoma in the biliary tree. Few studies have evaluated the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in diagnosing clinically suspected cholangiocarcinoma. The role of this method in diagnosing clinically suspected gallbladder malignancies has not been extensively evaluated in the USA. This study investigates the role of EUS-FNA in the diagnosis of clinically suspected biliary tree and gallbladder malignancies in a large patient series. METHODS: EUS-FNAs were obtained from 46 bile duct and seven gallbladder lesions. On-site rapid interpretation was provided using air-dried Diff Quik stained smears. In addition, alcohol fixed Papanicoloau stained smears and Thin Prep preparations (Cytye Corp., Marlborough, MA, USA) were evaluated before providing a final cytological diagnosis. Tissue biopsies and/or clinical follow-up were used as the standards to determine operating characteristics for EUS-FNA. RESULTS: The mean ages for bile duct and gallbladder lesions were 66 years (range: 37-84 years), and 69 years (range 49-86 years), respectively. All cases diagnosed as suspicious/malignant on preliminary evaluation were confirmed on final cytological interpretation (27/27). The operating characteristics show that EUS-FNA is highly specific (100%) with sensitivity rates of 87% and 80% from clinically suspected malignancies of biliary tract and gallbladder, respectively. Sampling error in three cases and associated acute inflammation in two cases resulted in false-negative diagnoses. CONCLUSIONS: EUS-FNA of biliary tree and gallbladder carcinoma is highly specific and should be considered for evaluation of clinically suspicious lesions. Marked inflammation may result in false-negative diagnoses.

Endoscopic ultrasound-guided fine-needle aspiration in the evaluation of gallbladder masses.

BACKGROUND AND STUDY AIMS: There are very few data on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of gallbladder masses. The aim of this study was to assess the utility and safety of EUS-FNA in the evaluation of patients with gallbladder masses. PATIENTS AND METHODS: Six patients who underwent EUS-FNA of gallbladder masses over a 2-year period between 2002 and 2004 were studied retrospectively. Reports of endoscopic ultrasound (EUS) procedures, EUS images, cytology results, and clinical records were reviewed. Abdominal computed tomography (CT) prior to EUS had revealed a definitive gallbladder mass in only one of the six patients and no gallbladder masses were identified in any of the patients who had undergone prior transabdominal ultrasound. RESULTS: At EUS, all the patients were found to have an echo-poor mass arising from the gallbladder wall or within the lumen of the gallbladder. EUS-FNA of the gallbladder masses revealed adenocarcinoma in five patients and benign disease in one patient. After a mean follow-up period of 127 days (range 90 - 187 days), three patients had died, two were undergoing palliative chemoradiotherapy, and one had been confirmed as having chronic cholecystitis at surgery. No complications occurred. CONCLUSIONS: In patients with obstructive jaundice and equivocal ultrasound or CT findings, evaluation of the gallbladder for the presence of a primary malignancy by EUS is useful. In patients with gallbladder masses, EUS-FNA can be performed safely and can help to make a definitive diagnosis.