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1.  Lower Provider Volume is Associated with Higher Failure Rates for Endoscopic Retrograde Cholangiopancreatography 
Medical care  2013;51(12):10.1097/MLR.0b013e3182a502dc.
Among physicians who perform endoscopic retrograde cholangiopancreatography (ERCP), the relationship between procedure volume and outcome is unknown.
Quantify the ERCP volume-outcome relationship by measuring provider-specific failure rates, hospitalization rates and other quality measures.
Research Design
Retrospective Cohort
16,968 ERCPs performed by 130 physicians between 2001-2011, identified in the Indiana Network for Patient Care (INPC)
Physicians were classified by their average annual INPC volume and stratified into low (<25/year) and high (≥25/year). Outcomes included failed procedures, defined as repeat ERCP, percutaneous transhepatic cholangiography or surgical exploration of the bile duct ≤ 7 days after the index procedure, hospitalization rates, and 30-day mortality.
Among 15,514 index ERCPs, there were 1,163 (7.5%) failures; the failure rate was higher among low (9.5%) compared to high volume (5.7%) providers (p<0.001). A second ERCP within 7 days (a subgroup of failure rate) occurred more frequently when the original ERCP was performed by a low (4.1%) versus a high volume physician (2.3%, p=0.013). Patients were more frequently hospitalized within 24 hours when the ERCP was performed by a low (28.3%) vs. high volume physician (14.8%, p=0.002). Mortality within 30 days was similar (low – 1.9%, high – 1.9%). Among low volume physicians and after adjusting, the odds of having a failed procedure decreased 3.3% (95% CI 1.6-5.0%, p<0.001) with each additional ERCP performed per year.
Lower provider volume is associated with higher failure rate for ERCP, and greater need for post-procedure hospitalization.
PMCID: PMC3830424  PMID: 24226304
ERCP quality; outcomes; gastroenterology
2.  Role of endoscopic ultrasound fine-needle aspiration evaluating adrenal gland enlargement or mass 
World Journal of Nephrology  2014;3(3):92-100.
AIM: To report the clinical impact of adrenal endoscopic ultrasound fine-needle aspiration (EUS-FNA) in the evaluation of patients with adrenal gland enlargement or mass.
METHODS: In a retrospective single-center case-series, patients undergoing EUS-FNA of either adrenal gland from 1997-2011 in our tertiary care center were included. Medical records were reviewed and results of EUS, cytology, adrenal size change on follow-up imaging ≥ 6 mo after EUS and any repeat EUS or surgery were abstracted. A lesion was considered benign if: (1) EUS-FNA cytology was benign and the lesion remained < 1 cm from its original size on follow-up computed tomography (CT), magnetic resonance imaging or repeat EUS ≥ 6 mo after EUS-FNA; or (2) subsequent adrenalectomy and surgical pathology was benign.
RESULTS: Ninety-four patients had left (n = 90) and/or right (n = 5) adrenal EUS-FNA without adverse events. EUS indications included: cancer staging or suspected recurrence (n = 31), pancreatic (n = 20), mediastinal (n = 10), adrenal (n = 7), lung (n = 7) mass or other indication (n = 19). Diagnoses after adrenal EUS-FNA included metastatic lung (n = 10), esophageal (n= 5), colon (n = 2), or other cancer (n = 8); benign primary adrenal mass or benign tissue (n = 60); or was non-diagnostic (n = 9). Available follow-up confirmed a benign lesion in 5/9 non-diagnostic aspirates and 32/60 benign aspirates. Four of the 60 benign aspirates were later confirmed as malignant by repeat biopsy, follow-up CT, or adrenalectomy. Adrenal EUS-FNA diagnosed metastatic cancer in 24, and ruled out metastasis in 10 patients. For the diagnosis of malignancy, EUS-FNA of either adrenal had sensitivity, specificity, positive predictive value and negative predictive value of 86%, 97%, 96% and 89%, respectively.
CONCLUSION: Adrenal gland EUS-FNA is safe, minimally invasive and a sensitive technique with significant impact in the management of adrenal gland mass or enlargement.
PMCID: PMC4202496  PMID: 25332900
Adrenal gland neoplasms/diagnosis; Adrenal glands/pathology; Adrenal gland/ultrasonography; Adrenal gland neoplasms/secondary; Endosonography; Biopsy; Fine-needle
3.  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
4.  Increased fat in pancreas not associated with risk of pancreatitis post-endoscopic retrograde cholangiopancreatography 
A preliminary study has shown increased pancreatic fat in patients with idiopathic pancreatitis and sphincter of Oddi dysfunction. In this study, we aimed to determine if an increased quantity of pancreatic fat is an independent risk factor for pancreatitis post-endoscopic retrograde cholangiopancreatography (ERCP).
In this case control study, we retrospectively reviewed a local radiological and ERCP database to identify patients who had had abdominal magnetic resonance imaging (MRI) followed by ERCP no more than 60 days later between September 2003 and January 2011. Percentage of fat was determined by recording signal intensity in the in-phase (Sin) and out-of-phase (Sout) T1-weighted gradient sequences, and calculation of the fat fraction as (Sin − Sout)/(Sin) × 2 by an abdominal radiologist blinded to clinical history. Controls matched for age, gender, and other pancreatobiliary disease were selected from a group with no post-ERCP pancreatitis (before fat content of the pancreas was analyzed).
Forty-seven patients were enrolled. Compared with controls, subjects with post-ERCP pancreatitis were similar in terms of age (41.4 years versus 41.1 years), gender (21.2% versus 20.2% males), pancreatobiliary disease characteristics, and most ERCP techniques. Measurements of pancreatic head, body, and tail fat and body mass index were similar in patients and controls.
Increased pancreatic fat on MRI criteria is not an independent predictor of post-ERCP pancreatitis.
PMCID: PMC4061141  PMID: 24959090
magnetic resonance imaging; obesity; pancreatic fat; post-ERCP pancreatitis; sphincter of Oddi dysfunction
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.  Endoscopic Palliation of Pancreatic Cancer 
Cancer journal (Sudbury, Mass.)  2012;18(6):584-590.
Endoscopy has an increasingly important role in the palliation of patients with pancreatic ductal adenocarcinoma. Endoscopic biliary drainage is still requested in the majority of patients who present with obstructive jaundice, and the increased use of self-expandable metallic stents has reduced the incidence of premature stent occlusion. First-line use of metallic stents is expected to be utilized more frequently as neoadjuvant protocols are improved. The efficacy of endoscopy for palliating gastroduodenal obstruction has advanced with the development of through-the-scope, self-expandable gastroduodenal stents. There have been advances in pain management, with endoscopic ultrasound-guided celiac plexus neurolysis reducing opiate requirements and pain for patients with unresectable malignancy. Future applications of endoscopy in pancreatic cancer may include fine needle injection of chemotherapeutic and other agents into the lesion itself. This review will summarize the evidence of endoscopy in the management of patients with pancreatic cancer.
PMCID: PMC3551340  PMID: 23187846
pancreatic cancer; endoscopic retrograde cholangiopancreatography; endoscopic ultrasound; stent
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.  Multicenter Randomized Trial of 10-French versus 11.5-French Plastic Stents for Malignant Biliary Obstruction 
Background. There is little prospective data on whether bigger plastic stents are better for patients with malignant biliary obstruction with jaundice. Goals. Multicenter prospective study to compare technical success, clinical response, stent occlusion, and patient survival in patients with malignant biliary obstruction randomized to 10-French or 11.5-French plastic stent. Study. Patients with malignant biliary obstruction were randomized to 10-French or 11.5-French biliary stents. Patients were prospectively assessed for stent occlusion, stent-related interventions, hospital stay, and change in bilirubin. Main outcome measurements included technical success, clinical response, rates of stent occlusion, and survival. Results. 234 patients (47 hilar and 187 common bile duct strictures) were randomized. Outcomes were similar for the 10-French and 11.5-French groups (technical success 99.1% versus 97.4%, P = 0.37). Overall, median stent survival was 213 days, but there was no statistically significant difference in stent survival between 10-French and 11.5-French stents (149 versus 258 days, P = 0.16). Stent survival was significantly longer when placed for common bile duct versus hilar strictures (231 versus 115 days, P = 0.049). Conclusions. The theoretical advantage of improved bile flow for the 11.5-French stent does not translate into more prolonged patency, better clinical response, and longer patient survival than the 10-French stent.
PMCID: PMC3659511  PMID: 23737656
10.  The Proteome of Normal Pancreatic Juice 
Pancreas  2012;41(2):186-194.
The aims of this study were to characterize the proteome of normal pancreatic juice, to analyze the effect of secretin on the normal proteome, and to compare these results with published data from patients with pancreatic cancer.
Paired pancreatic fluid specimens (before and after intravenous secretin stimulation) were obtained during endoscopic pancreatography from three patients without significant pancreatic pathology. Proteins were identified and quantified by mass spectrometry-based protein quantification technology. The human RefSeq (NCBI) database was used to compare the data in normal patient samples with published data from three pancreatic cancer patients.
A total of 285 proteins were identified in normal pancreatic juice. Ninety had sufficient amino acid sequences identified to characterize the protein with a high level of confidence. All 90 proteins were present before and after secretin administration but with altered relative concentrations, usually by 1-2 folds, after stimulation. Comparison with 170 published pancreatic cancer proteins yielded an overlap of only 42 proteins.
Normal pancreatic juice contains multiple proteins related to many biological processes. Secretin alters the concentration but not the spectrum of these proteins. The pancreatic juice proteome of normal and pancreatic cancer patients differ markedly.
PMCID: PMC3288545  PMID: 22129531
pancreatic fluid; proteome; secretin; pancreatic adenocarcinoma
11.  Rescue Endoscopic Ultrasound (EUS)-Guided Trucut Biopsy Following Suboptimal EUS-Guided Fine Needle Aspiration for Mediastinal Lesions 
Gut and Liver  2013;7(2):150-156.
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and Trucut biopsy (TCB) are sensitive techniques for diagnosing mediastinal lesions, but it is unclear how either one or both should be used to obtain a pathologic diagnosis. The objective of our study was to evaluate whether EUS-TCB impacts the diagnosis of mediastinal lesions after the initial on-site review of EUS-FNA specimen suggests a suboptimal result.
We enrolled consecutive patients with mediastinal lesions who underwent EUS-TCB during the same procedure if the initial EUS-FNA demonstrated an inadequate FNA sample or suggested that histopathology was required for diagnosis. Diagnostic accuracies between procedures were compared as the main outcome.
Twenty-seven patients (14 men; median age, 56 years; range, 19 to 82 years) underwent EUS-FNA and EUS-TCB to evaluate a mediastinal lymphadenopathy or mass (n=17), to determine the cancer stage (n=3) or to exclude tumor recurrence or metastasis (n=7). The overall diagnostic accuracies of EUS-FNA and EUS-TCB were 78% and 67%, respectively (p=0.375). The combined diagnostic accuracy of EUS-FNA plus EUS-TCB was 82%. In six patients with nondiagnostic EUS-FNA, EUS-TCB provided a final diagnosis in one patient (17%).
In the current series of patients with mediastinal masses or adenopathy, the administration of EUS-TCB following suboptimal results for the on-site cytology review did not increase the diagnostic yield.
PMCID: PMC3607767  PMID: 23560149
Endoscopic ultrasound; Endoscopic ultrasound-guided fine needle aspiration; Endoscopic ultrasound-guided Trucut biopsy; Mediastinum
12.  Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis in Pancreatic Cancer: A Prospective Pilot Study of Safety Using 10 mL versus 20 mL Alcohol 
Background. The dose of alcohol used in EUS-CPN is not standardized. The objective was to compare the safety of 20 mL alcohol versus 10 mL alcohol during EUS-CPN for patients with pancreatic cancer-related pain. Methods. 20 patients were selected to receive 10 mL or 20 mL of alcohol during EUS-CPN. Followup was done at baseline, 24 hours, and weekly. Health-related quality of life (HRQoL) was assessed at baseline, week 2, week 4, and every 4 weeks thereafter until pain returned. Results. There were no major complications in both groups. Minor self-limited adverse effects were seen in 6 (30%) subjects and included lightheadedness in 1 (5%), transient diarrhea in 2 (10%), and transient nausea and vomiting in 3. Pain relief was similar in both groups: 80% in the 10 mL group and 100% in the 20 mL group (P = 0.21). The mean (± SD) duration of pain relief in the 10 mL and 20 mL groups was 7.9 ± 10.8 and 8.4 ± 9.2 weeks, respectively. 30% of patients in each group had complete pain relief. Conclusions. EUS-CPN using 20 mL of alcohol is safe. Similar clinical outcomes were seen in both groups. Further investigations to confirm these findings are warranted.
PMCID: PMC3556397  PMID: 23365492
13.  Current endoscopic approach to indeterminate biliary strictures 
Biliary strictures are considered indeterminate when basic work-up, including transabdominal imaging and endoscopic retrograde cholangiopancreatography with routine cytologic brushing, are non-diagnostic. Indeterminate biliary strictures can easily be mischaracterized which may dramatically affect patient’s outcome. Early and accurate diagnosis of malignancy impacts not only a patient’s candidacy for surgery, but also potential timely targeted chemotherapies. A significant portion of patients with indeterminate biliary strictures have benign disease and accurate diagnosis is, thus, paramount to avoid unnecessary surgery. Current sampling strategies have suboptimal accuracy for the diagnosis of malignancy. Emerging data on other diagnostic modalities, such as ancillary cytology techniques, single operator cholangioscopy, and endoscopic ultrasonography-guided fine needle aspiration, revealed promising results with much improved sensitivity.
PMCID: PMC3501767  PMID: 23180939
Indeterminate stricture; Bile duct; Single operator cholangioscope; Cholangioscopy; Endoscopic ultrasound; Endoscopic retrograde cholangiopancreatography; Bile duct stricture; Indeterminate biliary stricture; Confocal microscopy; Transpapillary biopsy; Cholangiocarcinoma; Primary sclerosing cholangitis; Spyglass
14.  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
15.  Moderate and severe postendoscopic retrograde cholangiopancreatography pancreatitis despite prophylactic pancreatic stent placement: The effect of early prophylactic pancreatic stent dislodgement 
Placement of prophylactic pancreatic stents (PPS) is a method proven to reduce the rate and severity of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk patients; however, PPS do not eliminate the risk completely. Early PPS dislodgement may occur prematurely and contribute to more frequent or severe PEP.
To determine the effect of early dislodgement of PPS in patients with moderate or severe PEP.
A total of 27,176 ERCP procedures from January 1994 to September 2007 for PPS placement in high-risk patients were analyzed. Patient and procedure data were analyzed to assess risk factors for PEP, and to evaluate the severity of pancreatitis, length of hospitalization and subsequent complications. Timing of stent dislodgment was assessed radiographically.
PPS were placed in 7661 patients. Of these, 580 patients (7.5%) developed PEP, which was graded as mild in 460 (6.0%), moderate in 87 (1.1%) and severe in 33 (0.4%). Risk factors for developing PEP were not different in patients who developed moderate PEP compared with those with severe PEP. PPS dislodged before 72 h in seven of 59 (11.9%) patients with moderate PEP and five of 27 (18.5%) patients with severe PEP (P=0.505). The mean (± SD) length of hospitalization in patients with moderate PEP with stent dislodgement before and after 72 h were 7.43±1.46 days and 8.37±1.16 days, respectively (P=0.20). The mean length of hospitalization in patients with severe PEP whose stent dislodged before and after 72 h were 21.6±6.11 and 22.23±3.13 days, respectively (P=0.96).
Early PPS dislodgement was associated with moderate and severe PEP in less than 20% of cases and was not associated with a more severe course. Factors other than ductal obstruction contribute to PEP in high-risk patients undergoing ERCP and PPS placement.
PMCID: PMC3088697  PMID: 21523263
Complications; ERCP; Pancreatic stent; Post-ERCP pancreatitis
16.  Smoking Is Underrecognized as a Risk Factor for Chronic Pancreatitis 
Pancreatology  2011;10(6):713-719.
Smoking is an established risk factor for chronic pancreatitis (CP). We sought to identify how often and in which CP patients physicians consider smoking to be a risk factor.
We analyzed data on CP patients and controls prospectively enrolled from 19 US centers in the North American Pancreatitis Study-2. We noted each subject's self-reported smoking status and quantified the amount and duration of smoking. We noted whether the enrolling physician (gastroenterologist with specific interest in pancreatology) classified alcohol as the etiology for CP and selected smoking as a risk factor.
Among 382/535 (71.4%) CP patients who were self-reported ever smokers, physicians cited smoking as a risk factor in only 173/382 (45.3%). Physicians cited smoking as a risk factor more often among current smokers, when classifying alcohol as CP etiology, and with higher amount and duration of smoking. We observed a wide variability in physician decision to cite smoking as a risk factor. Multivariable regression analysis however confirmed that the association of CP with smoking was independent of physician decision to cite smoking as a risk factor.
Physicians often underrecognize smoking as a CP risk factor. Efforts are needed to raise awareness of the association between smoking and CP.
PMCID: PMC3068562  PMID: 21242712
Chronic pancreatitis; Smoking; Alcohol; Risk factor
17.  Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis 
Background & Aims
Alcohol has been implicated in the development of chronic pancreatitis (CP) in 60%–90% patients, although percentages in the United States are not known. We investigated the frequency of alcohol-related CP at tertiary U.S. referral centers.
We studied data from patients with CP (n=539) and controls (n=695) enrolled in the North American Pancreatitis Study-2 from 2000 to 2006 at 20 U.S. referral centers. CP was defined by definitive evidence in imaging or histologic analyses. Subjects and physicians each completed a detailed study questionnaire. Using physician-assigned diagnoses, patients were assigned to the following etiology groups: alcohol (with/without other diagnoses), non-alcohol (any etiology of CP from other than alcohol), or idiopathic (no etiology identified).
The distribution of patients among etiology groups were: alcohol (44.5%), non-alcohol (26.9%), and idiopathic (28.6%). Physicians identified alcohol as the etiology more frequently in men (59.4% in men vs 28.1% in women), but non-alcohol (18% in men vs 36.7% in women) and idiopathic etiologies (22.6% in men vs 35.2% in women) more often in women (P<0.01 for all comparisons). Non-alcohol etiologies were equally divided among obstructive, genetic, and other causes. Compared with controls, patients with idiopathic CP were more likely to have ever smoked (58.6% vs 49.7%, P<0.05) or have a history of chronic renal disease or failure (5.2% vs 1.2%, P<0.01). In multivariate analyses, smoking (ever, current, and amount) was independently associated with idiopathic CP.
The frequency of alcohol-related CP at tertiary U.S. referral centers is lower than expected. Idiopathic CP and non-alcohol etiologies represent a large subgroup, particularly among women. Smoking is an independent risk factor for idiopathic CP.
PMCID: PMC3043170  PMID: 21029787
Pancreas; Inflammation; alcoholism; tobacco
18.  Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Are Associated with Chronic Pancreatitis in Patients without Cystic Fibrosis 
Gastroenterology  2010;140(1):162-171.
Background & Aims
Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor, SPINK1, further increase the risk of pancreatitis in these patients.
We screened patients with ICP (sporadic or familial) and controls for variants in SPINK1 associated with chronic pancreatitis (CP) risk (in exon 3) and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, and 150 unrelated controls, plus 503 controls for limited genotyping. CFTR wild-type (wt) and p.R75Q were cloned and expressed in HEK293 cells and relative conductances of HCO3− and Cl− were measured.
SPINK1 variants were identified in 36% of subjects and 3% controls (odds ratio [OR]=16.5). One variant of CFTR that has not been associated with CF, p.R75Q, was found in 16% of subjects and 5.4% controls (OR=3.4). Co-inheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.15% controls (OR=62.5). Patch-clamp recordings of cells that expressed CFTR p.R75Q demonstrated normal chloride currents but significantly reduced bicarbonate currents (P=0.0001).
The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk for pancreatitis. Co-inheritance of CF-associated, and some not associated, CFTR variants with SPINK1 variants significantly increase risk of ICP.
PMCID: PMC3171690  PMID: 20977904
NAPS2; pancreas; polygenic; risk factor; patch-clamp; epistasis
19.  Endoscopic Therapy in Chronic Pancreatitis 
Chronic pancreatitis (CP) is a debilitating disease that can result in chronic abdominal pain, malnutrition, and other related complications. The main aims of treatment are to control symptoms, prevent disease progression, and correct any complications. A multidisciplinary approach involving medical, endoscopic, and surgical therapy is important. Endoscopic therapy plays a specific role in carefully selected patients as primary interventional therapy when medical measures fail or in patients who are not suitable for surgery. Endoscopic therapy is also used as a bridge to surgery or as a means to assess the potential response to pancreatic surgery. This review addresses the role of endoscopic therapy in relief of obstruction of the pancreatic duct (PD) and bile du ct, closure of PD leaks, and drainage of pseudocysts in CP. The role of endoscopic ultrasound-guided celiac plexus block for pain in chronic pancreatitis is also discussed.
PMCID: PMC3245386  PMID: 22205838
Pancreatitis, chronic; Endoscopy; Cholangiopancreatography, endoscopic retrograde
20.  Fluid analysis prior to surgical resection of suspected mucinous pancreatic cysts. A single centre experience 
EUS-FNA cytology and fluid analysis are frequently utilized to evaluate pancreatic cysts. Elevated cyst fluid CEA is usually indicative of a mucinous pancreatic cyst but whether CEA or amylase values can subclassify various mucinous cysts is unknown. The purpose of this study is to determine whether cyst fluid CEA and amylase obtained by EUS-FNA can differentiate between mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs).
Using our prospective hospital EUS and surgical databases, we identified all patients who underwent EUS of a pancreatic cyst prior to surgical resection, in the last 10 years. Cysts were pathologically sub-classified as MCNs or IPMNs; all other cysts were considered non-mucinous. Values of cyst fluid CEA and amylase were correlated to corresponding surgical histopathology and compared between the two groups.
134 patients underwent surgery for pancreatic cysts including 82 (63%) that also had preoperative EUS. EUS-FNA was performed in 61/82 (74%) and cyst fluid analysis in 35/61 (57%) including CEA and amylase in 35 and 33 patients, respectively. Histopathology in these 35 cysts demonstrated nonmucinous cysts in 10 and mucinous cysts in 25 including: MCNs (n=9) and IPMNs (n=16). Cyst fluid CEA (p=0.19) and amylase (p=0.64) between all IPMNs and MCNs were similar. Between branched duct IPMNs and MCNs alone, cyst fluid CEA (p=0.34) and amylase (p=0.92) were also similar.
In this single center study, pancreatic cyst fluid amylase and CEA levels appeared to be of limited value to influence the differential of mucinous pancreatic cysts. Larger studies are recommended to evaluate this role further.
PMCID: PMC3397629  PMID: 22811854
pancreatic cysts; EUS; FNA; amylase; CEA
21.  Bedside Endoscopic Ultrasound in Critically Ill patients 
Background. The aim of this study was to evaluate the role and impact of EUS in the management of critically ill patients. Methods. We retrospectively identified all patients at our institution over a 68-month period in whom bedside inpatient EUS was performed. EUS was considered to have a significant impact if a new diagnosis was established and/or the findings altered subsequent clinical management. Results. Fifteen patients (9 male; mean age 58 ± 15 years) underwent bedside EUS without complications. EUS-FNA (median 4 passes; range 2–7) performed in 12 (80%) demonstrated a malignant mediastinal mass/lymph node (5), pancreatic abscess (1), excluded a pelvic abscess (1), established enlarged gastric folds as benign (1) and excluded malignancy in enlarged mediastinal (1) and porta hepatis adenopathy (1). In two patients, EUS-FNA failed to diagnose mediastinal histoplasmosis (1) and a hemorrhagic pancreatic pseudocyst (1). In three diagnostic exams without FNA, EUS correctly excluded choledocholithaisis (n = 1) and cholangiocarcinoma (1), and found gastric varices successfully thrombosed after previous cyanoacrylate injection (1). EUS was considered to have an impact in 13/15 (87%) patients. Conclusions. In this series, bedside EUS in critically ill patients was technically feasible, safe and had a major impact on the majority of patients.
PMCID: PMC3123909  PMID: 21747653
22.  What is the role of endotherapy in chronic pancreatitis? 
Chronic pancreatitis (CP) can have debilitating clinical course due to chronic abdominal pain, malnutrition and related complications. Medical, endoscopic and surgical treatment of CP should aim at control of symptoms, prevention of progression of the disease and correction of complications. Endoscopic management plays a specific role in carefully selected patients as primary interventional therapy when medical measures fail or in high-risk surgical candidates. Endotherapy for CP is utilized also as a bridge to surgery or to assess potential response to pancreatic surgery. In this review we address the role of endotherapy for the relief of obstruction of the pancreatic duct (PD) and bile duct, closure of PD leaks and drainage of pseudocysts in the setting of CP. In addition, endotherapy for relief of pancreatic pain by endoscopic ultrasound-guided celiac plexus block for CP is discussed.
PMCID: PMC3002595  PMID: 21180616
chronic pancreatitis; endotherapy; ERCP; pancreatic duct stricture; pancreatic duct stone; pseudocyst
23.  Multicenter Approach to Recurrent Acute and Chronic Pancreatitis in the United States: The North American Pancreatitis Study 2 (NAPS2) 
Pancreatology  2008;8(4-5):520-531.
Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are complex syndromes associated with numerous etiologies, clinical variables and complications. We developed the North American Pancreatitis Study 2 (NAPS2) to be sufficiently powered to understand the complex environmental, metabolic and genetic mechanisms underlying RAP and CP.
Between August 2000 and September 2006, a consortium of 20 expert academic and private sites prospectively ascertained 1,000 human subjects with RAP or CP, plus 695 controls (spouse, family, friend or unrelated). Standardized questionnaires were completed by both the physicians and study subjects and blood was drawn for genomic DNA and biomarker studies. All data were double-entered into a database and systematically reviewed to minimize errors and include missing data.
A total of 1,000 subjects (460 RAP, 540 CP) and 695 controls who completed consent forms and questionnaires and donated blood samples comprised the final dataset. Data were organized according to diagnosis, supporting documentation, etiological classification, clinical signs and symptoms (including pain patterns and duration, and quality of life), past medical history, family history, environmental exposures (including alcohol and tobacco use), medication use and therapeutic interventions. Upon achieving the target enrollment, data were organized and classified to facilitate future analysis. The approaches, rationale and datasets are described, along with final demographic results.
The NAPS2 consortium has successfully completed a prospective ascertainment of 1,000 subjects with RAP and CP from the USA. These data will be useful in elucidating the environmental, metabolic and genetic conditions, and to investigate the complex interactions that underlie RAP and CP.
PMCID: PMC2790781  PMID: 18765957
North American Pancreatitis Study 2; NAPS2 United States; Recurrent acute pancreatitis; Chronic pancreatitis
24.  The effect of biliary sphincterotomy on serum cholesterol levels in postcholecystectomy patients: A pilot study 
Cholesterol, in the form of bile salts, is reabsorbed from the small intestine via the enterohepatic circulation. Biliary sphincterotomy increases the delivery of bile to the terminal ileum. If the absorptive capacity is exceeded, cholesterol excretion may increase, resulting in a decrease in serum cholesterol levels and improvement in serum lipid profiles.
To determine the effect of biliary sphincterotomy on serum cholesterol levels in patients without biliary obstruction.
Postcholecystectomy patients with type III biliary sphincter of Oddi dysfunction (disabling pancreatobiliary-type pain with normal liver function tests and bile duct diameter) who underwent biliary sphincterotomy were identified retrospectively from the endoscopic retrograde cholangiopancreatography database. Baseline (pre-endoscopic retrograde cholangiopancreatography) laboratory investigations (including cholesterol) were obtained for all patients. The effect of sphincterotomy on total cholesterol levels was noted in all patients who returned for subsequent procedures (temporary pancreatic stent removal or evaluation of recurrent symptoms), and also in the subgroup of patients with baseline hypercholesterolemia (higher than 5.18 mmol/L).
In the present pilot study, the performance of biliary sphincterotomy was associated with a reduction in total serum cholesterol levels in postcholecystectomy patients without biliary obstruction. This was statistically significant in patients with a baseline cholesterol level higher than 5.18 mmol/L. A possible effect on low-and high-density lipoprotein concentrations was not evaluated. The influence of dietary changes and exercise were not accounted for.
A prospective, controlled study involving a larger series of patients is required to determine whether biliary sphincterotomy lowers cholesterol levels and improves lipid profiles.
PMCID: PMC2657665  PMID: 17299610
Biliary sphincterotomy; Cholesterol levels; Postcholecystectomy
25.  A Pilot Study to Develop a Diagnostic Test for Pancreatic Ductal Adenocarcinoma Based on Differential Expression of Select miRNA in Plasma and Bile 
Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.
We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models.
Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%.
Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.
PMCID: PMC4261139  PMID: 25350767

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