Temporary placement of a fully covered self-expandable metal stent in the pancreatic duct for management of symptomatic refractory chronic pancreatitis: preliminary data (with videos)

Temporary placement of a fully covered self-expandable metal stent in the pancreatic duct for management of symptomatic refractory chronic pancreatitis: preliminary data (with videos) Bryan Sauer, MD, Jayant Talreja, MD, Kristi Ellen, RN, Jennifer Ku, MD, Vanessa M. Shami, MD, Michel Kahaleh, MD, FASGE Charlottesville, Virginia, USA

Background: Pancreatic duct (PD) stenting is beneficial for the treatment of pain in patients with PD strictures associated with chronic pancreatitis. Placement of metal stents has been reported but failed secondary to hyperplasia or migration. Objective: To investigate the outcome of patients with symptomatic and refractory PD strictures who had temporary placement of a covered self-expandable metal stent (CSEMS). Design: Patients with refractory PD strictures were offered temporary CSEMS placement. Pain scores were evaluated before and after CSEMS placement. Setting: A tertiary-care center. Patients: Six patients (4 men, mean age  SD 55  8 years) received a CSEMS, and 5 patients had removal of a CSEMS after a mean time of 92 days. Intervention: Placement of CSEMS (8-mm or 10-mm diameter VIABIL) in the PD, with removal after 3 months. Main Outcome Measurements: The pain score before and after stent placement and the sustained response after removal. Morbidity associated with stent placement and removal was also noted. Results: Pain scores after CSEMS placement significantly improved (P Z.024), from 6.4 to 1.6. Of the 5 patients who underwent CSEMS removal, 3 developed recurrent symptomatic pancreatic stricture, of whom 2 required repeat stenting with a larger-diameter CSEMS (10 mm) and 2 remained pain free. The CSEMS was not removed in 1 patient because pancreatic malignancy was diagnosed. There were no complications during placement or removal of CSEMSs. Limitation: This was a pilot study. Conclusion: Temporary placement of CSEMSs in patients with symptomatic refractory PD stricture offers transient relief of pain. Further investigation is needed to determine the optimal diameter and duration of placement.

Transpapillary pancreatic duct (PD) stent placement in symptomatic chronic pancreatitis associated with PD stricture has been shown, in multiple studies, to be effective, with long-term pain relief achieved in approximately two thirds of patients.1-10 A subset of patients is refractory to conventional plastic PD stenting because of persistent stricture and pain. In this patient population, the placement of multiple plastic stents (8.5F-11F) has been shown to be feasible and safe, with a high clinical success rate.11 Self-expandable metal stents (SEMSs) have been success-

fully placed in the PD for malignant conditions,12 whereas SEMS placement for benign pancreatic diseases was unsatisfactory because of epithelial hyperplasia and migration.13 However, fully covered SEMSs (CSEMSs) have not been extensively studied. With the recent arrival of CSEMSs on the market, we report our preliminary experience on their safety and efficacy in patients with refractory PD stricture caused by chronic pancreatitis.

PATIENTS AND METHODS Abbreviations: CSEMS, fully covered self-expanding metal stent; PD, pancreatic duct; SEMS, self-expanding metal stent; VAS, visual analog scale. Copyright ª 2008 by the American Society for Gastrointestinal Endoscopy 0016-5107/$34.00 doi:10.1016/j.gie.2008.06.011

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Patients Between February 2007 and December 2007, 6 patients with chronic pancreatitis and PD stricture refractory to conventional PD stenting were enrolled and prospectively followed. Inclusion criteria included (1) painful chronic Volume 68, No. 6 : 2008 GASTROINTESTINAL ENDOSCOPY 1173

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pancreatitis, with PD stricture and upstream PD dilation, and (2) failure of conventional placement of a plastic stent in the PD to relieve pain. Institutional review board approval was obtained, and all patients provided consent.

Materials and techniques Side-viewing endoscopes (TJF-140, TJF-160, and TJF160VF; Olympus America, Center Valley, Pa) were used for all procedures. Patients with obstructing intraductal calcific stone underwent extracorporeal shock wave lithotripsy before ERCP (Table 1). Pancreatic sphincterotomy was performed on all patients before CSEMS placement. The pancreatic stricture was dilated with a 4-mm or 6-mm wire-guided balloon catheter (MaxForce; Microvasive Endoscopy, Boston Scientific Corp, Natick, Mass), then, over a 0.035-inch guidewire, an 8-mm-diameter or 10-mm-diameter VIABIL stent (Conmed, Utica, NY) was placed in the main PD across the stricture (Figs. 1-3); the length of the stent was predicated by the length of the stricture. Approximately 1 cm of the stent was left in the duodenum (Fig. 4) (Video 1, available online at www.giejournal.org). After 3 months, the CSEMSs were removed with a snare or a rat-tooth forceps by grasping the stent in its most distal portion and pulling it through the working channel of the endoscope (Video 2, available online at www.giejournal.org), and a pressure injection was performed to confirm pancreatic drainage after stent removal (Figs. 5 and 6). All procedures were performed by one dedicated pancreaticobiliary endoscopist (M.K.).

Definition of events Successful therapy was defined by pain improvement on a visual analog scale (VAS). Complications related to ERCP were defined following consensus criteria.14

Evaluation and follow-up Pain scores were evaluated before and after CSEMS placement and after CSEMS removal, on a VAS, which was previously validated in chronic pain.15 At the office visit, each participant was asked to assess his or her pain intensity before CSEMS placement, at the follow-up visit approximately 4 weeks after CSEMS placement, and the follow-up visit approximately 4 weeks after CSEMS removal. The visual analog scale consisted of a 10-cm horizontal line with verbal anchors of ‘‘no pain’’ and ‘‘worst pain imaginable.’’ The participant placed a vertical line at the appropriate pain level that was considered ‘‘usual pain’’ over the preceding week. A score was obtained by measuring the distance from the start of the scale to the vertical line placed by the participant, to the nearest tenth of a centimeter. The VAS was administered by one of the researchers (K.E.) who did not perform the procedure. The outcomes evaluated were pain relief and sustained response after stent removal. Morbidity associated with stent placement and removal was also noted. 1174 GASTROINTESTINAL ENDOSCOPY Volume 68, No. 6 : 2008

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Capsule Summary What is already known on this topic d

d

Pancreatic duct (PD) stenting is beneficial for the treatment of pain in patients with strictures associated with chronic pancreatitis. Uncovered metal stents are associated with epithelial hyperplasia and tissue ingrowth.

What this study adds to our knowledge d

In 6 patients with symptomatic refractory PD strictures, temporary placement of covered self-expanding metal stents resulted in transient relief.

Statistical analysis The efficacy of CSEMS was prospectively examined. A paired t test was used to compare pain scores before and after CSEMS placement. A P value of!.05 was considered significant.

RESULTS CSEMSs were placed in 6 patients (4 men, 2 women; mean age  SD 55  8 years) and were removed from 5 patients (mean time of CSEMS placement 92 days, range 87-100 days) (Tables 1 and 2). There were no complications during placement or removal of CSEMSs. Pain scores after CSEMSs placement significantly improved (P Z.024), from (mean  SD) 6.4  2 (range 3-8) to 1.6  1.8 (range, 0-4) (Fig. 7). Of the 5 patients who underwent CSEMS removal, 3 developed recurrent symptomatic PD strictures, and repeated stenting with a larger-diameter CSEMSs (10 mm) was required in 2 patients after 1 and 4 months; the third patient declined further intervention. Two patients remained pain free at 4 and 8 months after CSEMS removal. The remaining patient with the CSEMS left in place was diagnosed with pancreatic cancer in the setting of previously diagnosed chronic pancreatitis. The 2 patients who received repeated stenting with a larger-diameter CSEMSs were scheduled for removal at 3 months and responded to treatment with resolution of the stricture. All CSEMSs were removed without particular difficulty, and no major ductal changes, beside stricture remodeling, were seen on ERCP after removal (Figs. 5 and 6). No immediate or late complications of the procedure were encountered.

DISCUSSION Transpapillary PD stenting for patients with chronic pancreatitis associated with a PD stricture has been shown, in multiple studies, to be effective in a majority of patients, with long-term pain relief achieved in www.giejournal.org

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Fully covered SEMS in chronic pancreatitis

TABLE 1. Patient characteristics PD diameter Obstructing downstream/ Case Age calcific Location upstream no. (y) Etiology stone stricture (mm) 1

64 Alcohol

No

Proximal

5/14

2

48 Idiopathic

Yes

Distal

3/9

3

57 Alcohol

No

Distal

3/11

4

56 Alcohol

Yes

Distal

3/12

5

62 Idiopathic

Yes

Distal

4/7

6

42 Alcohol

Yes

Proximal

3/7

Figure 2. Fluoroscopic image of advancement of the delivery system of the CSEMS into the main PD.

Figure 3. Fluoroscopic image of the deployed covered metal sent with decompression of the PD. Figure 1. Fluoroscopic image of wire placed across a distal pancreatic stricture into the main PD.

approximately 60% to 75% of patients. Single plastic stents that ranged in size from 5F to 11.5F have been placed in the main PD for ductal stricture, often replaced at regular intervals.1-10 A subset of patients who underwent PD stenting for chronic pancreatitis has continued pain and a persistent PD stricture. In this group of patients, multiple palliative treatments have been tried, including placement of multiple plastic stents and SEMSs in the PD. Costamagna et al11 reported results from 19 patients who had multiple 8.5F to 11F plastic stents placed in the main PD for 7 months to treat refractory chronic pancreatitis. All patients had resolution of pain while the stents were in place, and 18 of 19 had resolution of the main PD stricture. On long-term follow-up (mean 38 months), 2 patients developed recurrent symptomatic strictures.11 These results suggest that multiple plastic stents placed in the main PD for refractory chronic pancreatitis were effective in maintaining persistent dilation of the stricture and in preventing recurrent symptoms of chronic pancreatitis in a majority of patients. Placement of SEMSs in the PD may offer advantages over multiple plastic stents for patients with chronic pancreatitis with refractory PD stricture. One major advantage www.giejournal.org

of expandable metal stents is longer patency. In malignant biliary obstruction, uncovered expandable metal stents have been shown, in prospective studies, to have longer patency than plastic stents.16,17 For benign diseases, the mean stent patency for uncovered expandable metal stents (Wallstent [Schneider, Bulach, Switzerland], and Gianturco-Ro ¨sch ‘‘Z’’ metal stent [Wilson Cook, WinstonSalem, NC], 60-80 mm length, 8-10 mm diameter) in 15 patients with benign biliary stricture was longer than 30 months (range 7-120 months);18 whereas plastic stent patency is estimated at 2 to 12 months, depending on the diameter.13,19 In addition, a cost analysis showed that metal stents were advantageous in patients with malignant strictures of the common bile duct who survived longer than 6 months because of fewer hospitalizations and procedures compared with plastic stents.20 If effective, placement of SEMSs to treat pancreatic obstruction may reduce the number of procedures and hospitalizations, which results in a significant cost savings. Uncovered expandable metal stents have been effectively used in the PD for obstructive complications of pancreatic cancer (8-mm diameter, 40-mm to 60-mm long, uncovered Wallstent; Microvasive Endoscopy, Boston Scientific Corp, Natick, Mass). Three patients with Volume 68, No. 6 : 2008 GASTROINTESTINAL ENDOSCOPY 1175

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Figure 6. Fluoroscopic image of pancreatic drainage after stent removal after deflating the retrieval balloon.

Figure 4. Endoscopic image of the deployed metal stent with the distal end in the duodenum.

Figure 7. Boxplot of pain score on a VAS, before and during CSEMS placement.

obstructive complications of pancreatic malignancy because of smoldering pancreatitis or a disrupted PD had resolution of their symptoms after placement of SEMS. No adverse events were reported; however, 1 patient who had repeated endoscopy had evidence of PD stent occlusion. The estimated duration of patency was 10 months or longer.12 One study reported the use of uncovered expandable metal stents (10-mm-diameter, 68-mm to 80-mm long Wallstent; Microvasive) placed in the PD 2 weeks before lateral pancreaticojejunostomy for patients with refractory chronic pancreatitis and a nondilated PD. This technique resulted in ductal expansion and was well tolerated, with minimal adverse effects.21 However, uncovered metal stents in a normal dog PD were shown to cause ductal and parenchymal damage at 1 month, with stricture or obstruction of the main PD.22

The Brussels team13 reported the largest experience with SEMS for benign PD obstruction when using both uncovered and covered experimental metal stents (6-mm diameter, uncovered and covered Wallstents; Schneider, Bulach, Switzerland). SEMSs were placed in patients with severe chronic pancreatitis and pain, most of whom (80%) had previous plastic stenting of the PD. Twenty patients received uncovered metal PD stents, and all had immediate pain relief. However, 17 patients (85%) had a subsequent relapse of pain. Eleven of the 17 patients (65%) with pain relapse had evidence of PD obstruction and recurrent stricture. The investigators noted that epithelial hyperplasia was seen in those with uncovered metal stents.13 Based on these studies, uncovered metal stent placement in the pancreatic duct does not appear beneficial, because of the high percentage of epithelial hyperplasia and tissue ingrowth that results in subsequent duct obstruction. Partially or totally covered metal stents were placed in 16 patients in the series by the Brussels team. All patients had immediate pain relief; however, 12 (75%) had a relapse, and 2 were lost to follow-up. Of the 8 who received

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Figure 5. Fluoroscopic image of a pressure pancreatogram after stent removal with an inflated retrieval balloon.

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TABLE 2. CSEMS placed and response to therapy Case no.

CSEMS (mm)

Pain score

Final outcome

1

10  100

Unchanged

Developed pancreatic cancer

CSEMS left in place

2

8  60

Improved

No pain after removal

No intervention

3

10  40

Improved

Recurrent pain after removal

Declined any intervention

4

8  40

Unchanged

Persistent PD stricture

Placement of a 10 mm  40 mm CSEMS

5

8  40

Improved

Recurrent pain after removal

Placement of a 10 mm  60 mm CSEMS

6

8  40

Improved

No pain after removal

No intervention

totally covered metal stents, 2 (25%) remained pain free. Stent migration was observed in 8 patients, occurring more often in those without previous metal stent placement. Three cases of stent migration occurred with a partially covered Wallstent (Schneider), and 5 cases of stent migration were seen, with fully covered Wallstent (Schneider). Epithelial hyperplasia was seen particularly when an uncovered stent was placed before a covered stent.13 However, in that study, epithelial hyperplasia with fully covered metal stents cannot be accurately determined, because some patients had uncovered stents placed before placement of the fully covered metal stent. Initial placement of fully covered metal stents may not cause epithelial hyperplasia. A recent case report highlighted the use of a partially covered expandable metal stent in the PD for treatment of a refractory PD leak. A 10-mm internal diameter, 60mm-long Wallstent (Microvasive) was placed across a PD leak and resulted in resolution. The stent was left in place because of patient comorbidities, and no further pancreatic symptoms were reported after 18 months of followup.23 The same team commented on the successful use of the partially covered Wallstent (Microvasive) in the main PD for treatment of refractory PD stricture in 3 patients, without significant sequelae. All 3 patients had the stents subsequently removed; however, further details on outcomes have not been published.23 Our study shows that placement of a fully CSEMS in the PD for refractory PD stricture is feasible and safe. No complications occurred during PC stenting or removal. Currently, the VIABIL stents are approved by the U.S. Food and Drug Administration for use in malignant biliary strictures. However, it offers potential advantages for placement in the PD. First, it is fully covered, which may prevent epithelial hyperplasia typically seen with uncovered metal stents. In addition, its side holes allow drainage of the PD side branches. Also, the fins might prevent stent migration, although this needs to be confirmed by further studies. Most patients had improvement in their pain score while the CSEMS was in the PD (Table 1). However, after removal, www.giejournal.org

Final disposition

3 of 5 patients had a relapse of symptoms. Repeated stenting in 2 out of the 3 failures with larger-diameter CSEMSs resulted in relief of pain. The recurrence of pain after CSEMSs removal suggests that the PD stricture was not completely resolved or had recurred, or that there might be another cause of the pain besides PD obstruction. It should also be emphasized that some patients with chronic pancreatitis may harbor malignant strictures that are difficult to distinguish from benign strictures. Our patient who developed pancreatic cancer had many previous procedures with negative brushing and normal carbohydrate antigen 19-9; therefore, he most probably developed pancreatic cancer in the setting of chronic pancreatitis. Sustained efficacy may require a longer duration of stenting to induce sufficient remodeling of the distal PD. In our study, the CSEMS was left in place for 3 months, whereas Costamagna et al11 left multiple plastic stents in place for 7 months, which resulted in stricture resolution in all but 1 patient. Furthermore, the optimal diameter of CSEMS for PD placement needs further study. Previous studies by the Brussels team used 6-mm SEMS, and the recent report by Baron and Ferreira23 reported using 10-mm, partially covered SEMS.13 We initially placed 8mm-diameter CSEMSs in most patients, with upsizing to 10-mm CSEMSs, with symptom recurrence, and achieved stricture resolution in the 2 patients who were re-treated. Several recent studies suggest that surgery may provide better long-term results in chronic pancreatitis.24,25 However, the overall technical success rate for endoscopic therapy was only 53% in the most recent study,25 whereas most series report a success rate of 60% to 70%.1-10 Moreover, the placement of larger-diameter metal stents may result in better PD drainage and stricture resolution, this results in better outcomes when compared with plastic stents. Although metal stents are significantly more expensive than plastic stents, a cost benefit is still possible. Indeed, if CSEMSs are more effective at controlling pain and PD strictures in chronic pancreatitis, then fewer procedures may be needed. In malignant biliary strictures, a cost analysis showed that metallic stents were advantageous in patients who survived longer than 6 months, because of fewer hospitalizations and procedures compared Volume 68, No. 6 : 2008 GASTROINTESTINAL ENDOSCOPY 1177

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with plastic stents.20 Given the benign and chronic nature of chronic pancreatitis, placement of SEMSs may also reduce the number of procedures and hospitalizations, and thus may be more cost effective. A limitation of the current study is the evaluation of pain in patients with chronic pancreatitis. Although the VAS has been validated in chronic pain,15 it does not measure the use of pain medications, frequency of pain, hospitalizations for pain, or the myriad of other factors associated with pain perception. The Izbicki scoring system is a validated scoring system used in multiple studies of chronic pancreatitis that measures some of these additional factors.25-27 One of the 4 aspects of the Izbicki scoring system is the VAS. We recommend the use of a modified Izbicki scoring system for further prospective studies. Long-term studies are needed to further assess long-term safety and efficacy of temporary CSEMS placement for refractory PD stricture related to chronic pancreatitis before recommending its use on a larger clinical scale. ACKNOWLEDGMENTS We thank the technical staff of the endoscopy unit for the strong support. DISCLOSURES The following authors report that they have no disclosures relevant to this publication: B. Sauer, J. Talreja, K. Ellen, J. Ku, V. M. Shami. The following author has disclosed actual or potential conflicts: M. Kahaleh has received grant support from Boston Scientific Corp, Cook Medical, and Alveolus, and research support from Conmed. REFERENCES 1. Ro¨sch T, Daniel S, Scholz M, et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy 2002;34:765-71. 2. Delhaye M, Arvanitakis M, Verset G, et al. Long-term clinical outcome after endoscopic pancreatic ductal drainage for patients with painful chronic pancreatitis. Clin Gastroenterol Hepatol 2004; 2:1096-106. 3. Smits ME, Badiga SM, Rauws EA, et al. Long-term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc 1995;42:461-7. 4. Cremer M, Deviere J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991;23:171-6. 5. Gabbrielli A, Pandolfi M, Mutignani M, et al. Efficacy of main pancreaticduct endoscopic drainage in patients with chronic pancreatitis, continuous pain, and dilated duct. Gastrointest Endosc 2005;61:576-81. 6. Ishihara T, Yamaguchi T, Seza K, et al. Efficacy of s-type stents for the treatment of the main pancreatic duct stricture in patients with chronic pancreatitis. Scand J Gastroenterol 2006;41:744-50. 7. Ponchon T, Bory RM, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc 1995;42:452-6.

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Received January 29, 2008. Accepted June 9, 2008. Current affiliations: Digestive Health Center, University of Virginia Health System, Charlottesville, Virginia, USA. Reprint requests: Michel Kahaleh, MD, Digestive Health Center Box 800708, University of Virginia Health System, Charlottesville, VA 22908-0708.

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