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1.  Poor ‘real-life’ negative predictive value of cross-sectional imaging in obstructive jaundice 
Pancreatic cancer has a sizable incidence in the United States. Although some tumours are asymptomatic, others are too small to be detected despite recent technological advances in conventional imaging methods. This, however, does not appear to be a resolution problem but an inherent shortcoming of the imaging modalities themselves. This study investigated and compared the accuracy, diagnostic yield and predictive values of several imaging modalities in a series of consecutive patients in Charleston, South Carolina, USA.
Cross-sectional imaging remains the first-line test for obstructive jaundice despite high miss rates for pancreatobiliary tumours. Improvements in resolution and slice thickness of spiral computed tomography/magnetic resonance imaging/magnetic resonance cholangiopancreatography promised to increase accuracy.
To assess whether the post-test probability of neoplasm is truly altered by the presence or absence of a mass on computed tomography/magnetic resonance imaging in obstructive jaundice.
The institutional endoscopic ultrasound (EUS) database was retrospectively reviewed to stratify patients presenting to EUS over a two-year period for obstructive jaundice (suspicious for malignancy) according to their pre-EUS imaging results. The primary analysis involved the calculation of the positive predictive value and negative predictive value (NPV) of imaging with 95% binomial CIs. Test performance of EUS/fine-needle aspiration (FNA) was also calculated. Final diagnosis was determined by positive cytology/histology; negative EUS was supplemented by clinical follow-up.
The positive predictive value (n=51) and NPV (n=53) of pre-EUS imaging was 98% (95% CI 90% to 100%) and 9% (95% CI 3% to 21%), respectively (accuracy 53%), with post-test suspicion of malignancy similar between imaging-positive and -negative groups. EUS demonstrated a mass in 96% of imaging-positive cases versus 85% in imaging-negative cases (exact P=0.09). Malignant or suspicious FNA cytology was obtained with EUS in 92% of the imaging-positive group, and 62% of the imaging-negative group (75% of subgroup with FNA) (P<0.001).
Lack of a definite mass on pre-EUS imaging had low NPV, and was clearly not sufficiently accurate or reassuring in this clinical setting. In suspicious obstructive jaundice, EUS with FNA has a high diagnostic yield regardless of the findings of pre-EUS cross-sectional imaging and, as such, EUS may be a more reasonable first-line test in this high-suspicion setting.
PMCID: PMC4144457  PMID: 25157530
CT; Diagnostic test accuracy; EUS; MRI; Obstructive jaundice; Pancreatic cancer; Predictive value
2.  Spectrum of Use and Effectiveness of Endoscopic and Surgical Therapies for Chronic Pancreatitis in the United States 
Pancreas  2014;43(4):539-543.
This study aims to describe the frequency of use and reported effectiveness of endoscopic and surgical therapies in patients with CP treated at US referral centers.
Five hundred fifteen patients were enrolled prospectively in the North American Pancreatitis II Study 2, where patients and treating physicians reported previous therapeutic interventions and their perceived effectiveness. We evaluated the frequency and effectiveness of endoscopic (biliary or pancreatic sphincterotomy, biliary or pancreatic stent placement) and surgical (pancreatic cyst removal, pancreatic drainage procedure, pancreatic resection, surgical sphincterotomy) therapies.
Biliary and/or pancreatic sphincterotomy (42%) were the most commonly attempted endoscopic procedure (biliary stent, 14%; pancreatic stent, 36%; P<0.001). Endoscopic procedures were equally effective (biliary sphincterotomy, 40.0%; biliary stent, 40.8%; pancreatic stent, 47.0%; P=0.34). On multivariable analysis, the presence of abdominal pain (odds ratio, 1.82; 95% 95% confidence interval, 1.15–2.88) predicted endoscopy, whereas exocrine insufficiency (odds ratio, 0.63; 95% confidence interval 0.42–0.94) deterred endoscopy. Surgical therapies were attempted equally (cyst removal, 7%; drainage procedure, 10%; resection procedure, 12%) except for surgical sphincteroplasty (4%; P<0.001). Surgical sphincteroplasty was the least effective therapy (46%; P<0.001) versus cyst removal (76% drainage [71%] and resection [73%]).
Although surgical therapies were performed less frequently than endoscopic therapies, they were more often reported to be effective.
PMCID: PMC4122518  PMID: 24717802
3.  Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis 
PLoS Genetics  2014;10(7):e1004376.
CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.
Author Summary
Genetic disorders of ion channels can affect the body's ability to function properly in many ways. CFTR, an ion channel regulating movement of chloride and bicarbonate across cell membranes, is important for absorbing and secreting fluids. If the gene responsible for the CFTR channel is mutated severely, the result is cystic fibrosis, a hereditary disorder in which the patient develops thick mucus, especially in the lungs, as well as scarring (fibrosis) in the pancreas. Cystic fibrosis also affects the sweat glands, nasal sinuses, intestines, liver, and male reproductive system. Mutations to the CFTR gene that do not cause cystic fibrosis have been considered benign. However, we discovered 9 CFTR mutations that do not cause cystic fibrosis but do cause inflammation and scarring of the pancreas (chronic pancreatitis). These mutant CFTR channels secrete chloride, which is important in the sweat glands, lungs, and intestines, but not bicarbonate, which is important in the pancreas, sinuses, and male reproductive tract. We found patients with any of these 9 mutations had chronic pancreatitis, and often sinus infections, and male infertility, but not other symptoms of cystic fibrosis. Our computer models and data will help researchers develop better drugs and help physicians treating patients with chronic pancreatitis.
PMCID: PMC4102440  PMID: 25033378
4.  Clinical evaluation, imaging studies, indications for cytologic study and preprocedural requirements for duct brushing studies and pancreatic fine-needle aspiration: The Papanicolaou Society of Cytopathology Guidelines 
CytoJournal  2014;11(Suppl 1):1.
The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing and postbiopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed.
PMCID: PMC4153337  PMID: 25191515
Bile duct; cytology; fine-needle aspiration; guidelines; indications; pancreas; primary sclerosing cholangitis
5.  Does Rectal Indomethacin Eliminate the Need for Prophylactic Pancreatic Stent Placement in Patients Undergoing High-Risk ERCP? Post hoc Efficacy and Cost-Benefit Analyses Using Prospective Clinical Trial Data 
A recent large-scale randomized controlled trial (RCT) demonstrated that rectal indomethacin administration is effective in addition to pancreatic stent placement (PSP) for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. We performed a post hoc analysis of this RCT to explore whether rectal indomethacin can replace PSP in the prevention of PEP and to estimate the potential cost savings of such an approach.
We retrospectively classified RCT subjects into four prevention groups: (1) no prophylaxis, (2) PSP alone, (3) rectal indomethacin alone, and (4) the combination of PSP and indomethacin. Multivariable logistic regression was used to adjust for imbalances in the prevalence of risk factors for PEP between the groups. Based on these adjusted PEP rates, we conducted an economic analysis comparing the costs associated with PEP prevention strategies employing rectal indomethacin alone, PSP alone, or the combination of both.
After adjusting for risk using two different logistic regression models, rectal indomethacin alone appeared to be more effective for preventing PEP than no prophylaxis, PSP alone, and the combination of indomethacin and PSP. Economic analysis revealed that indomethacin alone was a cost-saving strategy in 96% of Monte Carlo trials. A prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP.
This hypothesis-generating study suggests that prophylactic rectal indomethacin could replace PSP in patients undergoing high-risk ERCP, potentially improving clinical outcomes and reducing healthcare costs. A RCT comparing rectal indomethacin alone vs. indomethacin plus PSP is needed.
PMCID: PMC3947644  PMID: 23295278
6.  Physical and Mental Quality of Life (QOL) in Chronic Pancreatitis(CP): A Case-Control Study from the NAPS2 cohort 
Pancreas  2013;42(2):293-300.
Define the Quality of Life (QOL) in chronic pancreatitis (CP) subjects
We studied 443 well phenotyped CP subjects and 611 controls prospectively enrolled from 20 US centers between 2000–2006 in the North American Pancreatitis Study 2 (NAPS2). Responses to the SF-12 questionnaire were used to calculate the Mental (MCS) and Physical component summary scores (PCS) with norm based scoring (normal ≥50). QOL in CP subjects was compared with controls after controlling for demographic factors, drinking history, smoking and medical conditions. QOL in CP was also compared with known scores for several chronic conditions.
Both PCS (38±11.5 vs. 52±9.4) and MCS (44±11.5 vs. 51±9.2) were significantly lower in CP compared with controls (p<0.001). On multivariable analyses, compared to controls, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. QOL in CP was similar to (heart, kidney, liver, lung disease) or worse than (non-skin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions.
The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions.
PMCID: PMC3618567  PMID: 23357924
Chronic pancreatitis; quality of life; SF12; prospective
7.  Predicting native papilla biliary cannulation success using a multinational Endoscopic Retrograde Cholangiopancreatography (ERCP) Quality Network 
BMC Gastroenterology  2013;13:147.
Success in deep biliary cannulation via native ampullae of Vater is an accepted measure of competence in ERCP training and practice, yet prior studies focused on predicting adverse events alone, rather than success. Our aim is to determine factors associated with deep biliary cannulation success, with/ without precut sphincterotomy.
The ERCP Quality Network is a unique prospective database of over 10,000 procedures by over 80 endoscopists over several countries. After data cleaning, and eliminating previously stented or cut papillae, two multilevel fixed effect multivariate models were used to control for clustering within physicians, to predict biliary cannulation success, with and without allowing “precut” to assist an initially failed cannulation.
13018 ERCPs were performed by 85 endoscopists (March 2007 - May 2011). Conventional (without precut) and overall cannulation rates were 89.8% and 95.6%, respectively. Precut was performed in 876 (6.7%). Conventional success was more likely in outpatients (OR 1.21), but less likely in complex contexts (OR 0.59), sicker patients (ASA grade (II, III/V: OR 0.81, 0.77)), teaching cases (OR 0.53), and certain indications (strictures, active pancreatitis). Overall cannulation success (some precut-assisted) was more likely with higher volume endoscopists (> 239/year: OR 2.79), more efficient fluoroscopy practices (OR 1.72), and lower with moderate (versus deeper) sedation (OR 0.67).
Biliary cannulation success appears influenced by both patient and practitioner factors. Patient- and case-specific factors have greater impact on conventional (precut-free) cannulation success, but volume influences ultimate success; both may be used to select appropriate cases and can help guide credentialing policies.
PMCID: PMC3882886  PMID: 24112846
8.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
9.  Effectiveness of disseminating consensus management recommendations for ulcer bleeding: a cluster randomized trial 
International guidelines for the management of nonvariceal upper gastrointestinal bleeding have not been widely adopted in clinical practice. We sought to determine whether a national, multifaceted intervention could improve adherence to guidelines, especially for patients at high risk of nonvariceal upper gastrointestinal bleeding.
In this randomized trial, we stratified hospitals by region and size and allocated sites to either the control or experimental group. Health care workers in the experimental group were given published guidelines, generic algorithms, stratification scoring systems and written reminders and attended multidisciplinary guideline education groups and case-based workshops. These interventions were implemented over a 12-month period after randomization, with performance feedback and benchmarking. The primary outcome of adherence rates to key guidelines in endoscopic and pharmacologic management, determined by chart review, was adjusted according to site characteristics and possible within-site dependencies. We also report the rates of adherence to other recommendations.
Forty-three sites were randomized to the experimental (n = 21) or control (n = 22) groups. In our primary analysis, we compared patients before (experimental group: n = 402 patients; control group: n = 424 patients) and after (experimental group: n = 361 patients; control group: n = 389 patients) intervention. Patient-level analysis revealed no significant difference in adherence rates to the guidelines after the intervention (experimental group: 9.8%; control group: 4.8%; p = 0.99) after adjustment for the rate of adherence before the intervention (experimental group: 13.2%; control group: 7.1%). The adherence rates to other guidelines were similar and decreased over time, varying between 5% and 93%.
This national knowledge translation–based trial suggests poor adherence to guidelines on nonvariceal upper gastrointestinal bleeding. Adherence was not improved by an educational intervention, which highlights both the complexity and poor predictability of attempting to alter the behaviour of health care providers (Trial registration:, no. MCT-88113).
PMCID: PMC3576461  PMID: 23318399
10.  A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis 
The New England Journal of Medicine  2012;366(15):1414-1422.
Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).
In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.
A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03).
Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; number, NCT00820612.)
PMCID: PMC3339271  PMID: 22494121
11.  Conventional versus Rosemont endoscopic ultrasound criteria for chronic pancreatitis: Comparing interobserver reliability and intertest agreement 
The Rosemont criteria (RC) were recently proposed by expert consensus to standardize endoscopic ultrasound (EUS) features and thresholds for diagnosing chronic pancreatitis (CP); however, they are cumbersome and are not validated.
To determine interobserver agreement between RC and conventional criteria (CC), and to assess intertest agreement in the diagnosis of CP.
Thirty-six consecutive patients who underwent EUS for abdominal pain or pancreatitis were retrospectively reviewed. Anonymized images were independently chosen as best representations of the pancreatic body and reviewed by three experts who recorded the presence of CC and RC features. Agreement (proportion and kappa statistic) between CC and RC was calculated. Interobserver agreement within the CC and RC was assessed. Secondary comparisons with endoscopic retrograde cholangiopancreatography were made where available.
Using CC, 60 readings (83.3%) were negative for CP, while 12 readings (16.7%) were positive. Using RC, 59 readings (81.9%) were negative for CP, while 13 (18.1%) were positive. The weighted kappa for interobserver agreement for CC (four categories: normal/low probability, indeterminate, high probability or calcific) was 0.50, with 80.0% overall agreement, versus 0.27 and 68.1% for the four RC categories (normal, indeterminate, suggestive of and consistent with). Agreement on a positive diagnosis with CC was 86.1% (P=0.38 [McNemar’s exact test]), with a kappa of 0.47; for RC, agreement was lower at 80.6% (P=0.016 [McNemar’s exact test]), with a kappa of 0.38. For patients who underwent endoscopic retrograde cholangiopancreatography (n=12), false-negative and false-positive rates between CC and RC did not appear to be different.
The RC do not appear to achieve the goals of improving accuracy and interobserver agreement for diagnosing CP.
PMCID: PMC3115006  PMID: 21647460
Accuracy; Chronic pancreatitis; Criteria; ERCP; EUS; Interobserver reliability
12.  Endosonographic Features Predictive of Malignancy on FNA in Lung Cancer-Associated Mediastinal Lymph Nodes 
Gastrointestinal endoscopy  2010;72(2):265-271.
Endoscopic ultrasonography (EUS) is useful in determining mediastinal lymph node (LN) metastases in patients undergoing staging for lung cancer. However, fine needle aspiration (FNA) of LNs is often performed only if suspicious features are present. The utility of individual LN features in predicting malignant cytology remains unclear.
To evaluate the utility of EUS LN features for predicting malignant cytology.
Prospective observational study.
Two tertiary care centers in USA.
425 patients with primary lung cancer underwent EUS. All mediastinal LNs were described according to size, shape, echogenicity, and edge characteristics. FNA was performed on LNs with any features suggestive of malignancy. EUS-FNA cytology was classified as benign or abnormal (suspicious/malignant). The utility of LN features in predicting malignant cytology were determined and further analyzed by logistic regression and a predictive model was established.
EUS detected 836 LNs in 425 patients, and FNA was obtained in 698. On multivariable analysis, only round shape, short axis >8.3 mm, and sharp margins were predictive of malignant cytology. According to the predictive model, the calculated probability of having malignancy is less than 4% (95% CI 0.022-0.064) when none of the LN features are present, and 63% (95% CI, 0.517-0.722) when all features were seen.
No surgical histology as gold standard.
Among patients with lung cancer, EUS features of round shape, sharp margins and short axis > 8.3 mm are significant predictors of malignancy. The probability of malignancy is low when none of the features are present.
PMCID: PMC2925200  PMID: 20541192
Endoscopic ultrasound (EUS); fine needle aspiration (FNA); LN (lymph nodes)
13.  Measuring episodic abdominal pain and disability in suspected sphincter of Oddi dysfunction 
AIM: To evaluate the reliability of an instrument that measures disability arising from episodic abdominal pain in patients with suspected sphincter of Oddi dysfunction (SOD).
METHODS: Although several treatments have been utilized to reduce pain and associated disability, measurement tools have not been developed to reliably track outcomes. Two pilot studies were conducted to assess test-retest reliability of a newly developed instrument, the recurrent abdominal pain intensity and disability (RAPID) instrument. The RAPID score is a 90-d summation of days where productivity for various daily activities is reduced as a result of abdominal pain episodes, and is modeled after the migraine disability assessment instrument used to measure headache-related disability. RAPID was administered by telephone on 2 consecutive occasions in 2 consenting populations with suspected SOD: a pre-sphincterotomy population (Pilot I, n = 55) and a post-sphincterotomy population (Pilot II, n = 70).
RESULTS: The average RAPID scores for Pilots I and II were: 82 d (median: 81.5 d, SD: 64 d) and 48 d (median: 0 d, SD: 91 d), respectively. The concordance between the 2 assessments for both populations was very good: 0.81 for the pre-sphincterotomy population and 0.95 for the post-sphincterotomy population.
CONCLUSION: The described pilot studies suggest that RAPID is a reliable instrument for measuring disability resulting from abdominal pain in suspected SOD patients.
PMCID: PMC2941064  PMID: 20845508
Sphincter of Oddi; Abdominal pain; Disability measurement; Reproducibility of results; Pain measurement; Episodic pain
15.  Bayesian Adaptation of the Summary ROC Curve Method for Meta-analysis of Diagnostic Test Performance 
Journal of data science : JDS  2009;7(3):349-364.
Meta-analytic methods for diagnostic test performance, Bayesian methods in particular, have not been well developed. The most commonly used method for meta-analysis of diagnostic test performance is the Summary Receiver Operator Characteristic (SROC) curve approach of Moses, Shapiro and Littenberg. In this paper, we provide a brief summary of the SROC method, then present a case study of a Bayesian adaptation of their SROC curve method that retains the simplicity of the original model while additionally incorporating uncertainty in the parameters, and can also easily be extended to incorporate the effect of covariates. We further derive a simple transformation which facilitates prior elicitation from clinicians. The method is applied to two datasets: an assessment of computed tomography for detecting metastases in non-small-cell lung cancer, and a novel dataset to assess the diagnostic performance of endoscopic ultrasound (EUS) in the detection of biliary obstructions relative to the current gold standard of endoscopic retrograde cholangiopancreatography (ERCP).
PMCID: PMC2790297  PMID: 20011624
Bayesian; biliary system; ERCP; EUS; SROC
16.  Primary squamous cell carcinoma of pancreas diagnosed by EUS-FNA: A case report 
Squamous cell carcinoma of the pancreas has been sparsely described since the 1940s, and generally has a poor prognosis. Herein, we present a case of primary squamous cell carcinoma of the pancreas with liver metastasis, both confirmed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). To the best of our knowledge, this is the first case report in literature utilizing EUS-FNA for a cell-type specific diagnosis of primary pancreatic squamous cell carcinoma with a liver metastasis.
PMCID: PMC2744195  PMID: 19750582
Computed tomography; Cytology; Endoscopic ultrasound
20.  Postprocedural interpretation of endoscopic retrograde cholangiopancreatography by radiology 
With the increase in the use of endoscopic retrograde cholangiopancreatography (ERCP) (necessitating real-time interpretation), it is unknown whether post-ERCP radiologist reporting is still necessary or helpful.
To determine the rate of discrepancy of results, and the rate of clinically relevant misses and additions, by the radiology report in a blinded setting.
A retrospective analysis of the procedure and blinded postprocedure radiology reports of 100 consecutive ERCP cases was performed. A list of clinically relevant pathology and subgroups was made a priori. Discrepancies are described as proportions, with 95% CIs. The radiology yield regarding pathology that was clearly demonstrated at ERCP (bile leaks and stones removed) was calculated. Clinical follow-up was used to clarify additional abnormalities reported by radiology.
Clinically relevant discrepancies in report pairs occurred in 29.0% of cases (95% CI 20% to 39%), or 40.0% if discrepancies regarding bile duct dilation are considered (95% CI 30% to 50%). In 15 of 30 cases (50.0% [95% CI 31% to 69%]) in which bile duct stones were removed, the radiologist did not report a stone. The radiologist did not report five of eight bile leaks (62.5% [95% CI 24% to 91%]). In seven cases (7.0% [95% CI 2.9% to 13.9%]), an additional abnormality was noted by radiology, including a biliary stricture, bile duct and pancreatic duct stones, as well as sclerosing cholangitis. However, during a mean follow-up period of 5.6 months, it appeared that these radiology interpretations were likely incorrect. Discrepancy rates did not vary among the ERCP attendings or by radiology volume.
Discrepancies between endoscopists’ and radiologists’ ERCP reports are common. Blinded radiology interpretation frequently misses important pathology, and falsely positive additional diagnoses may be made.
PMCID: PMC2659121  PMID: 18209782
Agreement; Bile leaks; CBD stone; Diagnostic test interpretation; ERCP; Radiologist
23.  Utility of endoscopic ultrasound, cytology and fluid carcinoembryonic antigen and CA 19-9 levels in pancreatic cystic lesions 
AIM: To assess the diagnostic accuracy of endoscopic ultrasound (EUS), fluid tumor markers and cytology in distinguishing benign from (pre)malignant pancreatic cystic lesions.
METHODS: 46 consecutive patients, referred to a gastroenterologist and surgeon for a symptomatic or incidental pancreatic cyst, were reviewed. EUS, cytology, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) levels were compared with the final diagnosis, based on surgical pathology and/or imaging follow-up of at least 12 mo. Cysts were classified as benign (pseudocyst, serous cystadenoma) or malignant/pre-malignant (mucinous cystic neoplasm). Receiver-operator characteristics (ROC) curve analysis was performed.
RESULTS: The mean age was 56 years; 29% were male and median cyst diameter was 3 cm. Final outcome was obtained in 41 (89%) patients. Twenty-three (56%) of these 41 had surgical pathology. Twenty-three (56%) had benign lesions and 18 (44%) had malignant/pre-malignant lesions. Sensitivity, specificity and positive and negative predictive value of EUS alone to distinguish benign from malignant/premalignant pancreatic cystic lesions were 50%, 56%, 36% and 54% and for cytology were 71%, 96%, 92% and 85%, respectively. The corresponding values for the ROC-derived ideal cutoffs were 75%, 90%, 75%, 90% for CA 19-9 (> 37 U/mL) and 70%, 85%, 79% and 78% for CEA (> 3.1 ng/mL). Subgroup analysis of those with surgical pathology yielded almost identical performance and cutoffs.
CONCLUSION: Cytology and cyst fluid tumor marker analysis is a very useful tool in distinguishing benign from (pre)malignant pancreatic cystic lesions.
PMCID: PMC4171168  PMID: 17663510
Endoscopic ultrasound; Carcinoembryonic antigen; CA 19-9; Pancreatic cystic lesions; Fine needle aspiration
24.  Cost-effectiveness of computerized tomographic colonography versus colonoscopy for colorectal cancer screening 
Computerized tomographic (CT) colonography is a potential alternative to colonoscopy for colorectal cancer screening. Its main advantage, a better safety profile, may be offset by its limitations: lower sensitivity, need for colonoscopy in cases where results are positive, and expense.
We performed an economic evaluation, using decision analysis, to compare CT colonography with colonoscopy for colorectal cancer screening in patients over 50 years of age. Three-year outcomes included number of colonoscopies, perforations and adenomas removed; deaths from perforation and from colorectal cancer from missed adenomas; and direct health care costs. The expected prevalence of adenomas, test performance characteristics of CT colonography and colonoscopy, and probability of colonoscopy complications and cancer from missed adenomas were derived from the literature. Costs were determined in detail locally.
Using the base-case assumptions, a strategy of CT colonography for colorectal cancer screening would cost $2.27 million extra per 100 000 patients screened; 3.78 perforation-related deaths would be avoided, but 4.11 extra deaths would occur from missed adenomas. Because screening with CT colonography would cost more and result in more deaths overall compared with colonoscopy, the latter remained the dominant strategy. Our results were sensitive to CT colonography's test performance characteristics, the malignant risk of missed adenomas, the risk of perforation and related death, the procedural costs and differences in screening adherence.
At present, CT colonography cannot be recommended as a primary means of population-based colorectal cancer screening in Canada.
PMCID: PMC1247700  PMID: 16217110

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