Anne Marie Lennon

Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the TERRACE study

BACKGROUND Although colonoscopy is currently the optimal method for detecting colorectal polyps, some are missed. The Third Eye Retroscope provides an additional retrograde view that may detect polyps behind folds. OBJECTIVE To determine whether the addition of the Third Eye Retroscope to colonoscopy improves the adenoma detection rate. DESIGN Prospective, multicenter, randomized, controlled trial. SETTING Nine European and U.S. centers. PATIENTS Of 448 enrolled subjects, 395 had data for 2 procedures. INTERVENTIONS Subjects underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC). Subjects were randomized to SC followed by TEC or TEC followed by SC. MAIN OUTCOME MEASUREMENTS Detection rates for all polyps and adenomas with each method. RESULTS In the per-protocol population, 173 subjects underwent SC and then TEC, and TEC yielded 78 additional polyps (48.8%), including 49 adenomas (45.8%). In 176 subjects undergoing TEC and then SC, SC yielded 31 additional polyps (19.0%), including 26 adenomas (22.6%). Net additional detection rates with TEC were 29.8% for polyps and 23.2% for adenomas. The relative risk of missing with SC compared with TEC was 2.56 for polyps (P < .001) and 1.92 for adenomas (P = .029). Mean withdrawal times for SC and TEC were 7.58 and 9.52 minutes, respectively (P < .001). The median difference in withdrawal times was 1 minute (P < .001). The mean total procedure times for SC and TEC were 16.97 and 20.87 minutes, respectively (P < .001). LIMITATIONS Despite randomization and a large cohort, there was disparity in polyp prevalence between the 2 groups of subjects. CONCLUSION The Third Eye Retroscope increases adenoma detection rate by visualizing areas behind folds. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01044732.).

A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

BACKGROUND & AIMS The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Detection and localization of surgically resectable cancers with a multi-analyte blood test

SEEK and you may find cancer earlier Many cancers can be cured by surgery and/or systemic therapies when detected before they have metastasized. This clinical reality, coupled with the growing appreciation that cancers rapid genetic evolution limits its response to drugs, have fueled interest in methodologies for earlier detection of the disease. Cohen et al. developed a noninvasive blood test, called CancerSEEK that can detect eight common human cancer types (see the Perspective by Kalinich and Haber). The test assesses eight circulating protein biomarkers and tumor-specific mutations in circulating DNA. In a study of 1000 patients previously diagnosed with cancer and 850 healthy control individuals, CancerSEEK detected cancer with a sensitivity of 69 to 98% (depending on cancer type) and 99% specificity. Science, this issue p. 926; see also p. 866 A blood test that combines protein and DNA markers may allow earlier detection of eight common cancer types. Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts

Objective Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. Design Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ∼66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. Results GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. Conclusion Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors

BACKGROUND The role of EUS for detection of pancreatic neuroendocrine tumors (PNETs) is not clearly defined in institutions that use multidetector CT for pancreatic imaging. OBJECTIVE The aims of this study were to (1) compare the detection rates of EUS and CT by type and size of PNET and calculate the incremental benefit of EUS over CT, (2) evaluate the CT detection rate for PNETs adjusted for improved CT technology over time, and (3) determine the factors associated with CT-negative PNETs. DESIGN Retrospective single-center cohort study. SETTING Johns Hopkins Hospital. PATIENTS Patients with pathologically proven PNETs with preoperative CT. Incidentally found PNETs (resection specimens) and those without Johns Hopkins Hospital CT imaging were excluded. MAIN OUTCOME MEASUREMENT Detection rates of CT and EUS were compared by using pathology as the reference standard. RESULTS In 217 patients (with 231 PNETs) studied, CT detected 84% of tumors (54.3% of insulinomas). The sensitivity of CT for the detection of PNETs significantly increased with improvement in CT technology (P = .02; χ(2) for trend). CT was more likely to miss lesions <2 cm (P = .005) and insulinomas (P < .0001). In 56 patients who had both CT and EUS, the sensitivity of EUS was greater than CT (91.7% vs 63.3%; P = .0002), particularly for insulinomas (84.2% vs 31.6%; P = .001). EUS detected 20 of 22 CT-negative tumors (91%). LIMITATIONS Retrospective nonrandomized design and referral bias. CONCLUSIONS The detection rate of CT has significantly improved over time. CT-negative tumors are small and more likely to be insulinomas. A sequential approach of CT followed by EUS can detect most PNETs. EUS is a more sensitive initial test for the detection of suspected insulinomas.

The Early Detection of Pancreatic Cancer: What Will It Take to Diagnose and Treat Curable Pancreatic Neoplasia?

Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.

A comparative evaluation of single-balloon enteroscopy and spiral enteroscopy for patients with mid-gut disorders.

BACKGROUND Single-balloon enteroscopy (SBE) and spiral enteroscopy (SE) are recently described device-assisted techniques in endoluminal evaluation of the small bowel. No studies comparing SBE and SE in patients with suspected small-bowel disorders have previously been reported. OBJECTIVE The aims of this study were to compare SBE and SE in terms of diagnostic yield, procedure time, depth of maximal insertion, and complications. DESIGN Retrospective cohort study. SETTING Tertiary-care referral center. PATIENTS A retrospective analysis was performed on all patients at our institution undergoing anterograde SBE or SE between 2007 and 2009. Patients with altered anatomy or prior small-bowel surgery were excluded. INTERVENTION Deep enteroscopy. MAIN OUTCOME MEASUREMENT Diagnostic yield. RESULTS During the study period, 92 patients underwent 105 procedures (52 SBE, 53 SE). The most common indication for small-bowel endoscopy was obscure GI bleeding (n = 42). The diagnostic yield was not statistically different between SBE and SE (59.6% and 43.4%, respectively, P = .12). The overall diagnostic yield in patients with obscure GI bleeding was 67%. There was no significant difference between mean SBE and SE procedure times (53 minutes [range 15-99 minutes] vs 47 minutes [range 20-125 minutes], respectively; P = .2). The mean depth of maximal insertion beyond the ligament of Treitz for SE was significantly higher than that for SBE (301 cm [range 175-400 cm] vs 222 cm [range 110-400 cm], respectively; P < .001). Perforation occurred in one SBE procedure. LIMITATIONS Retrospective design and nonstandardized gas insufflation. CONCLUSION This is the first report comparing SE and SBE. Although SE yielded greater depth of maximal insertion than SBE, both techniques had similar diagnostic yields and procedure times. In addition, both techniques were safe and were particularly useful in patients with obscure GI bleeding.

A Systematic Review of Solid-Pseudopapillary Neoplasms: Are these rare lesions?

Objective The aim of the study was to determine if there had been any change in the number of solid-pseudopapillary neoplasm (SPN) cases detected and their evaluation or management over time. Methods A systematic review of SPN was performed of all articles published in English in PubMed and Scopus. Results A total of 2744 patients with SPN were identified in 484 studies published between 1961 and 2012; 87.8% of the cases were reported between 2000 and 2012. A total of 2408 (87.8%) were females, and the mean age was 28.5 (SD, 13.7) years. The most common symptom was abdominal pain in 63.6% of the cases and incidentally detected in 38.1% of the cases. There were 2285 patients who underwent pancreatic resection. The mean tumor size was 8.6 (SD, 4.3) cm. Follow-up was reported for 1952 (90.5%) patients, with a mean follow-up of 36.1 (SD, 32.8) months. Disease-free survival was documented in 1866 (95.6%) patients with recurrence in 86 (4.4%) patients; the median time to recurrence was 50.5 months. Conclusions The number of SPNs reported in the literature has seen a 7-fold increase in the number of cases reported since 2000 compared with before. Solid-pseudopapillary neoplasms continue to be primarily found in young women and present with nonspecific symptoms. Surgery remains the mainstay of treatment with an excellent long-term prognosis.

Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms.

Objectives To evaluate the performance characteristics of endoscopic ultrasonography (EUS) compared with computed tomography (CT) and magnetic resonance imaging (MRI) and determine the incremental diagnostic yield and accuracy of EUS with or without fine needle aspiration (FNA) over CT and MRI for prediction of neoplastic pancreatic cysts. Methods The EUS database was queried for procedures performed for pancreatic cysts between March 2006 and January 2010. Cystic pancreatic ductal adenocarcinoma, cystic pancreatic neuroendocrine tumor, mucinous cystic neoplasm, intraductal papillary neoplasm, and solid pseudopapillary neoplasm were categorized as neoplastic; pseudocysts and serous cysts were designated as nonneoplastic/low risk. Results Final diagnoses were established by surgery in 154 patients (mucinous cystic neoplasm/intraductal papillary neoplasm [69.4%], pancreatic neuroendocrine tumor [10%], pancreatic ductal adenocarcinoma [6.4%], solid pseudopapillary neoplasm [0.6%], nonneoplastic/low risk [13.6%]). Endoscopic ultrasonography with or without FNA was superior to CT and MRI in accurately classifying a cyst as neoplastic (P < 0.0001). After CT and MRI, EUS increased the rate of correctly predicting neoplastic cysts in 43 (36%) and 27 (54%) additional cases, respectively. Conclusions The incremental increase in diagnostic yield of EUS and fluid analysis over CT and MRI for prediction of a neoplastic cyst is 36% and 54%, respectively. The addition of EUS-FNA to abdominal imaging significantly increases overall accuracy for diagnosis of neoplastic pancreatic cysts.

Mutant TP53 in Duodenal Samples of Pancreatic Juice From Patients With Pancreatic Cancer or High-Grade Dysplasia

BACKGROUND & AIMS Imaging tests can identify patients with pancreatic neoplastic cysts but not microscopic dysplasia. We investigated whether mutant TP53 can be detected in duodenal samples of secretin-stimulated pancreatic juice, and whether this assay can be used to screen for high-grade dysplasia and invasive pancreatic cancer. METHODS We determined the prevalence of mutant TP53 in microdissected pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and invasive adenocarcinomas. TP53 mutations were quantified by digital high-resolution melt-curve analysis and sequencing of secretin-stimulated pancreatic juice samples, collected from duodena of 180 subjects enrolled in Cancer of the Pancreas Screening trials; patients were enrolled because of familial and/or inherited predisposition to pancreatic cancer, or as controls. RESULTS TP53 mutations were identified in 9.1% of intermediate-grade IPMNs (2 of 22), 17.8% of PanIN-2 (8 of 45), 38.1% of high-grade IPMNs (8 of 21), 47.6% of PanIN-3 (10 of 21), and 75% of invasive pancreatic adenocarcinomas (15 of 20); no TP53 mutations were found in PanIN-1 lesions or low-grade IPMNs. TP53 mutations were detected in duodenal samples of pancreatic juice from 29 of 43 patients with pancreatic ductal adenocarcinoma (67.4% sensitivity; 95% confidence interval, 0.52-0.80) and 4 of 8 patients with high-grade lesions (PanIN-3 and high-grade IPMN). No TP53 mutations were identified in samples from 58 controls or 55 screened individuals without evidence of advanced lesions. CONCLUSIONS We detected mutant TP53 in secretin-stimulated pancreatic juice samples collected from duodena of patients with high-grade dysplasia or invasive pancreatic cancer. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and high-grade dysplasia. Clinical Trial numbers: NCT00438906 and NCT00714701.