Digestive Endoscopy 2015; 27: 692–699
doi: 10.1111/den.12466
Original Article
Small cell- versus large cell-sized metal stent in endoscopic bilateral stent-in-stent placement for malignant hilar biliary obstruction Jae Min Lee,1,2 Sang Hyub Lee,1 Kwang Hyun Chung,1 Jin Myung Park,3 Woo Hyun Paik,4 Sang Myung Woo,5 Woo Jin Lee,5 Ji Kon Ryu1 and Yong-Tae Kim1 1
Departments of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul, Department of Internal Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, Jinju, 3Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, 4Department of Internal Medicine, Inje University Ilsan Paik Hospital and 5Center for Liver Cancer, National Cancer Center, Goyang, Korea 2
Background and Aim: Although the large cell-sized biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent for stent-in-stent (SIS) technique, there are concerns about its vulnerability to tumor ingrowth. The aim of the present study was to compare the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of a selfexpandable metallic stent (SEMS).
Results: There were no significant differences between the two
Methods: A total of 58 patients were enrolled who underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of cholangiocarcinoma or gallbladder cancer. Finally, 43 patients who underwent successful stent insertion were included in the analysis and divided into the small cell-sized stent (SCS; n = 21) and the large cell-sized stent (LCS; n = 22) groups. We retrospectively compared comprehensive clinical and laboratory data in both groups.
Conclusions: Endoscopic bilateral SIS placement for malignant hilar biliary obstruction shows no differences in stent patency, survival, complications and clinical course according to the cell size of SEMS.
INTRODUCTION
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NDOSCOPIC BILIARY DRAINAGE using a selfexpandable metallic stent (SEMS) can be considered palliative treatment for unresectable malignant hilar biliary obstruction.1,2 Although the choice of unilateral or bilateral drainage is still controversial,1,2 bilateral drainage theoretically provides more normal and physiological biliary flow through the biliary ductal system than unilateral drainage.3,4 In addition, recent studies reported that at least 50% drainage of liver volume is associated with a sufficient drainage
Corresponding: Sang Hyub Lee, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Email: [email protected] Received 29 September 2014; accepted 16 February 2015.
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groups in successful drainage (SCS vs LCS, 100% vs 100%, respectively), early complications (38.1% vs 18.2%), late complications (14.3% vs 22.7%), stent occlusion (42.9% vs 45.5%), tumor ingrowth (33.3% vs 45.5%) or overgrowth (9.5% vs 0%). Duration of stent patency and overall survival were not significantly different between the two groups (P = 0.086 and P = 0.320, respectively).
Key words: cell size, endoscopic retrograde cholangiopancreatography (ERCP), malignant hilar biliary obstruction, selfexpandable metallic stent (SEMS), stent-in-stent
effectiveness or longer survival in patients with malignant hilar obstruction.5,6 Nevertheless, endoscopic bilateral drainage using conventional SEMS is challenging and demands technical expertise, especially for the stent-in-stent (SIS) technique. For this reason, various new SEMS have recently been developed for the SIS technique to facilitate contralateral stent deployment through the mesh of the first metallic stent.7 The uniform large cell-sized biliary stent was newly designed as a SEMS with low axial force (AF) and sufficient radial force (RF) despite the large cell size.7–9 Mukai et al. reported that a SEMS with low AF is favorable for hilar biliary obstruction because of the acute bend in the bile duct at the hilar portion.10 Also, the large cell-sized stent (LCS) can be more easily used to carry out a reintervention than the small-sized stent (SCS) in cases where SEMS is occluded for the SIS technique.7,10 However, there are concerns about the
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
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Figure 1 Flowchart of patient selection in the present study. LCS, large cellsized stent; SCS, small cell-sized stent; SEMS, self-expandable metallic stent; SIS, stent-in-stent.
higher risk of tumor ingrowth because of the large cell size of this type of stent.7 But, as yet, there has been no study comparing the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of the SEMS. The primary endpoint of the present study was to compare stent patency and survival according to the cell size of the SEMS in patients after successful endoscopic bilateral SIS placement for malignant hilar biliary obstruction. Secondary endpoints were to compare the results of complications and clinical course.
METHODS Patients
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HIS RETROSPECTIVE STUDY initially included all patients (n = 58) with cholangiocarcinoma or gallbladder cancer who underwent endoscopic bilateral SEMS placement using a SIS technique for unresectable malignant hilar biliary obstruction at the Seoul National University Hospital between 2010 and 2013. SCS insertion was carried out in 30 patients from January 2010 to December 2011 and then LCS insertion was carried out in 28 patients from October 2011 to June 2013. Patients were excluded for the following reasons: Unsuccessful stent insertion (n = 7) and loss to follow up within 6 months after stent insertion (n = 8). A flowchart showing patient selection for the present study is shown in Figure 1. Histological and/or cytological confirmation of malignancy for all patients was established by endoscopic tissue sampling and/or brushing. Follow up continued from stent insertion until death of the patient or until December 2013. The study protocol was approved by the Institutional Review Board of the Seoul National University Hospital (IRB No. H-1303-105-475).
Figure 2 Stents used in the present study. (a) Small cell-sized stent. (b) Large cell-sized stent.
Stents The SCS (BONASTENT M-Hilar; Standard Sci. Tech Inc., Seoul, South Korea) uses nitinol wire with a high degree of flexibility and elasticity, a narrow stent mesh (cavity size 1.6 × 1.6 mm) and a thin delivery shaft (7 Fr) (Fig. 2a). The LCS (Niti-S large-cell D-type biliary stent; Taewoong Medical Co., Ltd, Seoul, South Korea) uses nitinol wire with a larger cell size (6 mm) and an 8-Fr delivery system (Fig. 2b).
Technique The technique of endoscopic bilateral SIS placement using SEMS was carried out as follows. The decision to carry out
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Figure 3 Procedure of endoscopic bilateral stent-in-stent placement for malignant hilar biliary obstruction. (a) Guidewires were initially introduced into both intrahepatic ducts bilaterally. (b, c) The 1st stent was inserted into the right intrahepatic duct. (d, e) The guidewire was placed in the left intrahepatic duct through the mesh of the 1st stent, and the 2nd stent then was inserted. (f) A Y-configured cholangiogram was obtained after bilateral stent placement.
bilateral stent insertion was based on imaging studies before the initial endoscopic retrograde cholangiopancreatography (ERCP) or during ERCP. Patients were sedated with i.v. midazolam (0.05 mg/kg) and pethidine under appropriate cardiopulmonary monitoring. Duodenoscopes used for this procedure were TJF-240 or 260V (Olympus Optical Co., Ltd, Tokyo, Japan) with large working channels (4.2 mm). An endoscopic small sphincterotomy was routinely done to insert the metallic stents. If possible, the left-sided guidewire was inserted first. In general, a contrast injection was done to enhance the bile duct and follow the passage of the guidewires, using small volumes of contrast in peripheral ducts. The first stent was inserted and slowly deployed into the left intrahepatic duct over the guidewire. The second stent was deployed through the mesh of the first stent, so that the two stents overlapped in the common hepatic duct and branched into the hepatic ducts, forming a Y-shape (Fig. 3).
Definition of events Successful stent insertion (technical success) was defined as passage of the stent across the stricture, along with flow of contrast medium and/or bile through the stent. Successful drainage (functional success) was defined as a decrease in
the total bilirubin level to less than 50% of the pretreatment value within the first month. Early and late complications were defined as those occurring within and after 30 days of stent placement, respectively. Definitions of complications were defined according to the criteria of Cotton et al.11 and Freeman et al.12 Stent occlusion was defined as recurrence of jaundice, increase in total bilirubin level and dilatation of the intrahepatic bile duct revealed by imaging. Stent patency was defined as the period until stent occlusion or the patient’s death after stent insertion. Clinical course included the result of reinterventions after stent occlusion.
Statistical analysis Mann–Whitney U-test was used for comparison of continuous variables and the chi-squared test with Fisher’s exact test was used for categorical variables. Wilcoxon signed-rank test was used for comparison of the total bilirubin level between baseline and 1 month after the procedure. Cumulative stent patency and patient survival were estimated by Kaplan–Meier analysis and curves were compared by log– rank test. P-values < 0.05 were considered statistically significant. All statistical analyses were done with SPSS 20.0 (SPSS Inc., Chicago, IL, USA).
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RESULTS
Table 1 Baseline characteristics of the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Clinical characteristics of patients
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TOTAL OF 58 patients underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of hilar cholangiocarcinoma or gallbladder cancer. Technical success was achieved in 26 of the 30 patients (86.7%) in the SCS group and in 25 of the 28 patients (89.3%) in the LCD group (P = 1.000). The main reason for unsuccessful stent insertion was that the second stent delivery system could not pass the mesh of the first SEMS. Finally, 43 patients were analyzed in the present study. Demographic and clinical characteristics of all 43 patients who underwent successful stent insertion are summarized in Table 1. Mean patient age was 69.7 ± 11.7 years. Causes of malignant hilar biliary obstruction were cholangiocarcinoma (n = 27) and gallbladder cancer (n = 16). According to the Bismuth classification, hilar obstructions were type II in 12 patients, type IIIa in nine, type IIIb in three and type IV in 19 patients. There were no significant differences in age, gender, diagnosis, Bismuth classification, TNM staging, antibiotic prophylaxis, adjuvant treatment and total bilirubin level between the two groups. Successful drainage was achieved in all 43 patients (100%). Total bilirubin level was significantly reduced from 6.0 ± 4.1 mg/dL to 2.1 ± 1.2 mg/dL in the SCS group (P = 0.000), and from 7.2 ± 6.4 mg/dL to 1.9 ± 1.3 mg/dL in the LCS group (P = 0.011). Procedure time was 34.4 ± 16.8 min in the SCS group and 27.9 ± 13.3 min in the SCS group (P = 0.293). Mean follow-up period was 145.7 ± 110.5 days in the SCS group and 198.1 ± 178.4 days in the LCS group (P = 0.593).
Primary outcomes There were no differences in cumulative stent patency and survival between the two groups (P = 0.086 and P = 0.320, respectively) (Figs 4,5). Median stent patency period was 83 days (range, 25–284 days) in the SCS group and 105 days (range, 27–376 days) in the LCS group. Median survival period was 109 days (range, 25–442 days) in the SCS group and 114 days (range, 27–595 days) in the LCS group.
Secondary outcomes There were no significant differences in early and late complications between the two groups as summarized in Table 2. A total of 12 early complications (cholangitis, n = 8 and pancreatitis, n = 4) were successfully treated with conservative treatments. Of the four patients in the SCS group with pancreatitis, two patients underwent precut sphincterotomy using a needle-knife as a result of difficult biliary cannulation, and one patient underwent transpapillary placement of
Age (years)† Gender Male Female Diagnosis Cholangiocarcinoma Gallbladder cancer Bismuth classification II IIIa IIIb IV TNM staging IIIA IIIB IVA IVB Antibiotic prophylaxis Precut sphincterotomy Transpapillary SEMS placement Adjuvant treatment‡ Chemotherapy Radiotherapy Chemoradiotherapy Total bilirubin level (mg/dL)†
SCS (n = 21)
LCS (n = 22)
P-value
71.0 ± 11.0
68.4 ± 12.4
0.466 0.443
9 (42.9) 12 (57.1)
12 (54.5) 10 (45.5)
12 (57.1) 9 (42.9)
15 (68.2) 7 (31.8)
8 (38.1) 2 (9.5) 1 (4.8) 10 (47.6)
4 (18.2) 7 (31.8) 2 (9.1) 9 (40.9)
3 (14.3) 2 (9.5) 1 (4.8) 15 (71.4) 13 (61.9) 3 (14.3) 2 (9.5)
0 (0.0) 2 (9.1) 2 (9.1) 18 (81.8) 16 (72.7) 2 (9.1) 0 (0)
11 (52.4) 10 1 0 6.0 ± 4.1
12 (54.5) 11 0 1 7.2 ± 6.4
0.454
0.206
0.433
0.449 0.664 0.233 1.000
0.981
† Values are presented as mean ± SD. Other values are presented as number or number (%). ‡ Adjuvant treatment is defined as treatment after stent insertion. LCS, large cell-sized stent; SCS, small cell-sized stent; SEMS, selfexpandable metallic stent; SIS, stent-in-stent.
SEMS. Late complications in the two groups occurred in eight patients (18.6%). In the SCS group, cholangitis with stent occlusion occurred in two patients and liver abscess in one. In the LCS group, cholangitis occurred in three patients, liver abscess in one and cholecystitis in one. Four patients with cholangitis were successfully treated with i.v. antibiotics and endoscopic reintervention using SEMS. In the LCS group, one patient with cholangitis underwent stent clearance by balloon sweeping, but there was no stent occlusion except for some sludge. All of the patients with liver abscess or cholecystitis were successfully treated with i.v. antibiotics and temporary percutaneous catheter drainage or percutaneous transhepatic gallbladder drainage. There were no significant differences in clinical course between the two groups (Table 3). One patient (4.8%) in the
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Figure 4 Cumulative stent patency curve by Kaplan–Meier analysis shows no differences between small cell-sized stent (SCS; ) and large cell-sized stent (LCS; ) (P = 0.086).
SCS group and one patient (4.5%) in the LCS group died of disease progression 25 and 27 days after the procedure, respectively. Stent occlusion occurred in nine (42.9%) of the patients in the SCS group and in 10 (45.5%) of the patients in the LCS group. Causes of stent occlusion were tumor ingrowth (n = 7) and tumor overgrowth (n = 2) in the SCS group. By comparison, stent occlusion was caused by tumor ingrowth in all patients (n = 10) in the LCS group. However, the difference of tumor ingrowth rates was not statistically significant between the two groups (P = 0.416). Reintervention was carried out in all 19 patients with stent occlusion during their follow up. Among them, endoscopic reintervention was done in six of the patients in the SCS group and in five of the patients in the LCS group (P = 0.650). Percutaneous reintervention was carried out in three of the patients in the SCS group and in five of the patients in the LCS group (P = 0.650). In the SCS group, we inserted a plastic stent
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Figure 5 Cumulative survival curve by Kaplan–Meier analysis shows no differences between small cell-sized stent (SCS; ) and large cell-sized stent (LCS; ) (P = 0.320). , LCScensored; , SCS-censored.
through the occluded SEMS in four patients and inserted a SEMS in two; the remaining three patients were treated by percutaneous transhepatic biliary drainage (PTBD). In the LCS group, we inserted a plastic stent through the occluded SEMS in two patients and inserted a SEMS in three; the remaining five patients were treated by PTBD.
DISCUSSION
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LTHOUGH THE SUCCESS rate of endoscopic bilateral SIS placement by experienced endoscopists has recently increased, contralateral stent deployment through the mesh of the first metallic stent is still a technical obstacle. The use of LCS can provide a high technical success rate in such cases, but there are concerns about the vulnerability to tumor ingrowth. However, there has been no study as yet comparing the clinical outcomes of endoscopic bilateral SIS
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Table 2 Early and late complications in the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Early complications Cholangitis Pancreatitis Bleeding Procedure-related mortality Late complications Cholangitis Cholecystitis Liver abscess
SCS (n = 21)
LCS (n = 22)
P-value
8 (38.1) 4 4 0 0 3 (14.3) 2 0 1
4 (18.2) 4 0 0 0 5 (22.7) 3 1 1
0.146
0.698
All values are presented as number or number (%). LCS, large cell-sized stent; SCS, small cell-sized stent; SIS, stent-in-stent.
Table 3 Clinical courses in the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Stent occlusion Tumor ingrowth Tumor overgrowth
SCS (n = 21)
LCS (n = 22)
P value
9 (42.9) 7 (33.3) 2 (9.5)
10 (45.5) 10 (45.5) 0 (0)
0.864 0.416 0.233
All values are presented as number or number (%). LCS, large cell-sized stent; SCS, small cell-sized stent; SIS, stent-in-stent.
placement according to the cell size of the SEMS. The current study showed that there was no significant difference in clinical outcomes according to the cell size of SEMS in patients who underwent an endoscopic bilateral SIS placement for malignant hilar biliary obstruction. Previous studies reported a multicenter experience with the use of SCS or LCS in patients with malignant hilar biliary obstruction.9,13 In the SCS study, median stent patency and survival were 150 days and 180 days, respectively.13 In the LCS study, median stent patency and survival were 157 days and 220 days, respectively.9 This study showed a longer median stent patency and survival period than our results. Those findings are explainable by the difference in baseline characteristics. Our patients had less Bismuth type II and more Bismuth type IV than the patients of previous studies.9,13 In addition, although related data have not been described in previous studies,9,13 there might be different factors including performance status, TNM staging and adjuvant treatment. In particular, our patients who underwent second-line chemotherapy were only 11.6% (n = 5) as a result of patient refusal.
As mentioned earlier, the efficacy of SCS or LCS has been reported in previous studies,8,9,13,14 but no direct comparison between the two stents has been done. In the current study, we compared the SCS and LCS groups using these two stents. As a result, there were no significant differences in clinical outcome between the two stents. In particular, LCS was not different from SCS in cumulative stent patency despite the large cell size. Moreover, in the analysis regarding causes of stent occlusion, the rate of difference of tumor ingrowth was not statistically significant between the two stents. These data suggest that stent characteristics including cell size may be less important factors in stent occlusion rates. In fact, the small cell size of SEMS is unlikely to impede tumor ingrowth because uncovered SEMS are rapidly embedded into a tumor and/or bile duct mucosa. Likewise, a previous randomized controlled study reported that stent diameter rather than design or material may be the more important feature in determining stent occlusion rates.15 That study showed no significant difference in stent occlusion between patients receiving a 10-mm Zilver stent (open-cell design; Cook Endoscopy, Winston-Salem, NC) or a 10-mm Wallstent (closed cell design; Boston Scientific, Watertown, MA).15 This finding is indirectly consistent with our results related to the cell size of SEMS. In the current study, there was no observed stent occlusion as a result of sludge formation. One possible explanation for this finding may be a low axial force (AF) of SEMS. The AF is the force required to keep stents straight.16 A lower AF is suitable for cases of hilar biliary obstruction as a result of the acute bend in the bile duct at the hilar portion, and confers a better conformability.10 If the AF is too high, the stent may exert forces to change its shape, which could result in adverse clinical events in the bile duct. Thus, late complications, especially related to biliary sludge may have been reduced by minimizing the damage to the bile duct wall through a low AF. Soon, survival periods may exceed the patency duration of SEMS with advances in anticancer therapies in cases of biliary malignancy. Therefore, SEMS are needed not only for better long-term patency but also for ease of endoscopic reintervention. The success rate of endoscopic reintervention varies from 44.4% to 100% after metallic stenting for malignant hilar biliary obstruction.13,17–23 However, these studies used various combinations of unilateral or bilateral stent placement and side-by-side or stent-in-stent techniques. Variations among these studies prohibit a direct comparison of the results. Mukai et al. recently reported that a large cell size is necessary for easy and safe reintervention in cases of SEMS occlusion with the SIS technique.10 In addition, it was reported that the LCS can easily be carried out as reintervention because of its uniform large cell size.7,9 However, our study showed no significant difference in endoscopic
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reintervention according to cell size of the SEMS. This finding may be explained by the structural features of the SCS which may facilitate a revisionary stent insertion as a result of the wider mesh by a cross-wired structure on the central portion. Park et al. reported a single-session success rate of 66.7% (16/24) for reinterventions by endoscopic bilateral placement in cases of SCS,13 which is consistent with our results. In our study, procedure time was slightly shorter in the LCS group. Although this difference was not statistically significant, we could not exclude the possibility that a lack of statistical power was caused by the relatively small sample size. Therefore, a further large prospective study is needed to identify these findings. Our study has some limitations. First, it was conducted in a non-randomized retrospective design without a predefined follow-up protocol. Second, the study was conducted in a highly experienced bilateral hilar stenting center with a high prevalence of malignant hilar biliary obstruction; technical and functional success rates may differ in non-specialist centers. Therefore, a further prospective multicenter randomized study is needed to confirm the current observations. Nevertheless, to the best of our knowledge, our work is the very first study comparing the clinical outcomes of endoscopic bilateral SIS placements according to the cell sizes of SEMS. In conclusion, our results showed no significant differences in clinical outcome, including stent patency and survival, according to the cell size of SEMS in patients who underwent endoscopic bilateral SIS placement for unresectable malignant hilar biliary obstruction.
CONFLICT OF INTERESTS
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UTHORS DECLARE NO conflict of interests for this article.
REFERENCES 1 Chang WH, Kortan P, Haber GB. Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage. Gastrointest. Endosc. 1998; 47: 354–62. 2 De Palma GD, Galloro G, Siciliano S, Iovino P, Catanzano C. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: Results of a prospective, randomized, and controlled study. Gastrointest. Endosc. 2001; 53: 547–53. 3 Polydorou AA, Cairns SR, Dowsett JF et al. Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion. Gut 1991; 32: 685–9. 4 Sherman S. Endoscopic drainage of malignant hilar obstruction: Is one biliary stent enough or should we work to place two? Gastrointest. Endosc. 2001; 53: 681–4.
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5 Bulajic M, Panic N, Radunovic M et al. Clinical outcome in patients with hilar malignant strictures type II Bismuth-Corlette treated by minimally invasive unilateral versus bilateral endoscopic biliary drainage. Hepatobiliary Pancreat. Dis. Int. 2012; 11: 209–14. 6 Vienne A, Hobeika E, Gouya H et al. Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: The role of liver volume assessment. Gastrointest. Endosc. 2010; 72: 728–35. 7 Kogure H, Isayama H, Kawakubo K et al. Endoscopic bilateral metallic stenting for malignant hilar obstruction using newly designed stents. J. Hepatobiliary Pancreat. Sci. 2011; 18: 653–7. 8 Kogure H, Isayama H, Nakai Y et al. Newly designed large cell Niti-S stent for malignant hilar biliary obstruction: A pilot study. Surg. Endosc. 2011; 25: 463–7. 9 Kogure H, Isayama H, Nakai Y et al. High single-session success rate of endoscopic bilateral stent-in-stent placement with modified large cell Niti-S stents for malignant hilar biliary obstruction. Dig. Endosc. 2014; 26: 93–9. 10 Mukai T, Yasuda I, Isayama H et al. Comparison of axial force and cell width of self-expandable metallic stents: Which type of stent is better suited for hilar biliary strictures? J. Hepatobiliary Pancreat. Sci. 2011; 18: 646–52. 11 Cotton PB, Lehman G, Vennes J et al. Endoscopic sphincterotomy complications and their management: An attempt at consensus. Gastrointest. Endosc. 1991; 37: 383–93. 12 Freeman ML, Nelson DB, Sherman S et al. Complications of endoscopic biliary sphincterotomy. N. Engl. J. Med. 1996; 335: 909–18. 13 Park DH, Lee SS, Moon JH et al. Newly designed stent for endoscopic bilateral stent-in-stent placement of metallic stents in patients with malignant hilar biliary strictures: Multicenter prospective feasibility study (with videos). Gastrointest. Endosc. 2009; 69: 1357–60. 14 Lee TH, Moon JH, Kim JH et al. Primary and revision efficacy of cross-wired metallic stents for endoscopic bilateral stent-instent placement in malignant hilar biliary strictures. Endoscopy 2013; 45: 106–13. 15 Loew BJ, Howell DA, Sanders MK et al. Comparative performance of uncoated, self-expanding metal biliary stents of different designs in 2 diameters: Final results of an international multicenter, randomized, controlled trial. Gastrointest. Endosc. 2009; 70: 445–53. 16 Isayama H, Nakai Y, Toyokawa Y et al. Measurement of radial and axial forces of biliary self-expandable metallic stents. Gastrointest. Endosc. 2009; 70: 37–44. 17 Kawamoto H, Tsutsumi K, Fujii M et al. Endoscopic 3-branched partial stent-in-stent deployment of metallic stents in high-grade malignant hilar biliary stricture (with videos). Gastrointest. Endosc. 2007; 66: 1030–7. 18 Chahal P, Baron TH. Expandable metal stents for endoscopic bilateral stent-within-stent placement for malignant hilar biliary obstruction. Gastrointest. Endosc. 2010; 71: 195– 9.
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19 Lee JH, Kang DH, Kim JY et al. Endoscopic bilateral metal stent placement for advanced hilar cholangiocarcinoma: A pilot study of a newly designed Y stent. Gastrointest. Endosc. 2007; 66: 364–9. 20 Kahaleh M. ‘Cross-wired’ biliary metal stents for malignant hilar strictures: A new window of opportunity? Gastrointest. Endosc. 2009; 69: 1361–2. 21 Chennat J, Waxman I. Initial performance profile of a new 6F self-expanding metal stent for palliation of malignant hilar biliary obstruction. Gastrointest. Endosc. 2010; 72: 632–6.
22 Dumas R, Demuth N, Buckley M et al. Endoscopic bilateral metal stent placement for malignant hilar stenoses: Identification of optimal technique. Gastrointest. Endosc. 2000; 51: 334–8. 23 Cheng JL, Bruno MJ, Bergman JJ, Rauws EA, Tytgat GN, Huibregtse K. Endoscopic palliation of patients with biliary obstruction caused by nonresectable hilar cholangiocarcinoma: Efficacy of self-expandable metallic Wallstents. Gastrointest. Endosc. 2002; 56: 33–9.
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doi: 10.1111/den.12466
Original Article
Small cell- versus large cell-sized metal stent in endoscopic bilateral stent-in-stent placement for malignant hilar biliary obstruction Jae Min Lee,1,2 Sang Hyub Lee,1 Kwang Hyun Chung,1 Jin Myung Park,3 Woo Hyun Paik,4 Sang Myung Woo,5 Woo Jin Lee,5 Ji Kon Ryu1 and Yong-Tae Kim1 1
Departments of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul, Department of Internal Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, Jinju, 3Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, 4Department of Internal Medicine, Inje University Ilsan Paik Hospital and 5Center for Liver Cancer, National Cancer Center, Goyang, Korea 2
Background and Aim: Although the large cell-sized biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent for stent-in-stent (SIS) technique, there are concerns about its vulnerability to tumor ingrowth. The aim of the present study was to compare the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of a selfexpandable metallic stent (SEMS).
Results: There were no significant differences between the two
Methods: A total of 58 patients were enrolled who underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of cholangiocarcinoma or gallbladder cancer. Finally, 43 patients who underwent successful stent insertion were included in the analysis and divided into the small cell-sized stent (SCS; n = 21) and the large cell-sized stent (LCS; n = 22) groups. We retrospectively compared comprehensive clinical and laboratory data in both groups.
Conclusions: Endoscopic bilateral SIS placement for malignant hilar biliary obstruction shows no differences in stent patency, survival, complications and clinical course according to the cell size of SEMS.
INTRODUCTION
E
NDOSCOPIC BILIARY DRAINAGE using a selfexpandable metallic stent (SEMS) can be considered palliative treatment for unresectable malignant hilar biliary obstruction.1,2 Although the choice of unilateral or bilateral drainage is still controversial,1,2 bilateral drainage theoretically provides more normal and physiological biliary flow through the biliary ductal system than unilateral drainage.3,4 In addition, recent studies reported that at least 50% drainage of liver volume is associated with a sufficient drainage
Corresponding: Sang Hyub Lee, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Email: [email protected] Received 29 September 2014; accepted 16 February 2015.
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groups in successful drainage (SCS vs LCS, 100% vs 100%, respectively), early complications (38.1% vs 18.2%), late complications (14.3% vs 22.7%), stent occlusion (42.9% vs 45.5%), tumor ingrowth (33.3% vs 45.5%) or overgrowth (9.5% vs 0%). Duration of stent patency and overall survival were not significantly different between the two groups (P = 0.086 and P = 0.320, respectively).
Key words: cell size, endoscopic retrograde cholangiopancreatography (ERCP), malignant hilar biliary obstruction, selfexpandable metallic stent (SEMS), stent-in-stent
effectiveness or longer survival in patients with malignant hilar obstruction.5,6 Nevertheless, endoscopic bilateral drainage using conventional SEMS is challenging and demands technical expertise, especially for the stent-in-stent (SIS) technique. For this reason, various new SEMS have recently been developed for the SIS technique to facilitate contralateral stent deployment through the mesh of the first metallic stent.7 The uniform large cell-sized biliary stent was newly designed as a SEMS with low axial force (AF) and sufficient radial force (RF) despite the large cell size.7–9 Mukai et al. reported that a SEMS with low AF is favorable for hilar biliary obstruction because of the acute bend in the bile duct at the hilar portion.10 Also, the large cell-sized stent (LCS) can be more easily used to carry out a reintervention than the small-sized stent (SCS) in cases where SEMS is occluded for the SIS technique.7,10 However, there are concerns about the
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Figure 1 Flowchart of patient selection in the present study. LCS, large cellsized stent; SCS, small cell-sized stent; SEMS, self-expandable metallic stent; SIS, stent-in-stent.
higher risk of tumor ingrowth because of the large cell size of this type of stent.7 But, as yet, there has been no study comparing the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of the SEMS. The primary endpoint of the present study was to compare stent patency and survival according to the cell size of the SEMS in patients after successful endoscopic bilateral SIS placement for malignant hilar biliary obstruction. Secondary endpoints were to compare the results of complications and clinical course.
METHODS Patients
T
HIS RETROSPECTIVE STUDY initially included all patients (n = 58) with cholangiocarcinoma or gallbladder cancer who underwent endoscopic bilateral SEMS placement using a SIS technique for unresectable malignant hilar biliary obstruction at the Seoul National University Hospital between 2010 and 2013. SCS insertion was carried out in 30 patients from January 2010 to December 2011 and then LCS insertion was carried out in 28 patients from October 2011 to June 2013. Patients were excluded for the following reasons: Unsuccessful stent insertion (n = 7) and loss to follow up within 6 months after stent insertion (n = 8). A flowchart showing patient selection for the present study is shown in Figure 1. Histological and/or cytological confirmation of malignancy for all patients was established by endoscopic tissue sampling and/or brushing. Follow up continued from stent insertion until death of the patient or until December 2013. The study protocol was approved by the Institutional Review Board of the Seoul National University Hospital (IRB No. H-1303-105-475).
Figure 2 Stents used in the present study. (a) Small cell-sized stent. (b) Large cell-sized stent.
Stents The SCS (BONASTENT M-Hilar; Standard Sci. Tech Inc., Seoul, South Korea) uses nitinol wire with a high degree of flexibility and elasticity, a narrow stent mesh (cavity size 1.6 × 1.6 mm) and a thin delivery shaft (7 Fr) (Fig. 2a). The LCS (Niti-S large-cell D-type biliary stent; Taewoong Medical Co., Ltd, Seoul, South Korea) uses nitinol wire with a larger cell size (6 mm) and an 8-Fr delivery system (Fig. 2b).
Technique The technique of endoscopic bilateral SIS placement using SEMS was carried out as follows. The decision to carry out
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Figure 3 Procedure of endoscopic bilateral stent-in-stent placement for malignant hilar biliary obstruction. (a) Guidewires were initially introduced into both intrahepatic ducts bilaterally. (b, c) The 1st stent was inserted into the right intrahepatic duct. (d, e) The guidewire was placed in the left intrahepatic duct through the mesh of the 1st stent, and the 2nd stent then was inserted. (f) A Y-configured cholangiogram was obtained after bilateral stent placement.
bilateral stent insertion was based on imaging studies before the initial endoscopic retrograde cholangiopancreatography (ERCP) or during ERCP. Patients were sedated with i.v. midazolam (0.05 mg/kg) and pethidine under appropriate cardiopulmonary monitoring. Duodenoscopes used for this procedure were TJF-240 or 260V (Olympus Optical Co., Ltd, Tokyo, Japan) with large working channels (4.2 mm). An endoscopic small sphincterotomy was routinely done to insert the metallic stents. If possible, the left-sided guidewire was inserted first. In general, a contrast injection was done to enhance the bile duct and follow the passage of the guidewires, using small volumes of contrast in peripheral ducts. The first stent was inserted and slowly deployed into the left intrahepatic duct over the guidewire. The second stent was deployed through the mesh of the first stent, so that the two stents overlapped in the common hepatic duct and branched into the hepatic ducts, forming a Y-shape (Fig. 3).
Definition of events Successful stent insertion (technical success) was defined as passage of the stent across the stricture, along with flow of contrast medium and/or bile through the stent. Successful drainage (functional success) was defined as a decrease in
the total bilirubin level to less than 50% of the pretreatment value within the first month. Early and late complications were defined as those occurring within and after 30 days of stent placement, respectively. Definitions of complications were defined according to the criteria of Cotton et al.11 and Freeman et al.12 Stent occlusion was defined as recurrence of jaundice, increase in total bilirubin level and dilatation of the intrahepatic bile duct revealed by imaging. Stent patency was defined as the period until stent occlusion or the patient’s death after stent insertion. Clinical course included the result of reinterventions after stent occlusion.
Statistical analysis Mann–Whitney U-test was used for comparison of continuous variables and the chi-squared test with Fisher’s exact test was used for categorical variables. Wilcoxon signed-rank test was used for comparison of the total bilirubin level between baseline and 1 month after the procedure. Cumulative stent patency and patient survival were estimated by Kaplan–Meier analysis and curves were compared by log– rank test. P-values < 0.05 were considered statistically significant. All statistical analyses were done with SPSS 20.0 (SPSS Inc., Chicago, IL, USA).
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RESULTS
Table 1 Baseline characteristics of the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Clinical characteristics of patients
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TOTAL OF 58 patients underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of hilar cholangiocarcinoma or gallbladder cancer. Technical success was achieved in 26 of the 30 patients (86.7%) in the SCS group and in 25 of the 28 patients (89.3%) in the LCD group (P = 1.000). The main reason for unsuccessful stent insertion was that the second stent delivery system could not pass the mesh of the first SEMS. Finally, 43 patients were analyzed in the present study. Demographic and clinical characteristics of all 43 patients who underwent successful stent insertion are summarized in Table 1. Mean patient age was 69.7 ± 11.7 years. Causes of malignant hilar biliary obstruction were cholangiocarcinoma (n = 27) and gallbladder cancer (n = 16). According to the Bismuth classification, hilar obstructions were type II in 12 patients, type IIIa in nine, type IIIb in three and type IV in 19 patients. There were no significant differences in age, gender, diagnosis, Bismuth classification, TNM staging, antibiotic prophylaxis, adjuvant treatment and total bilirubin level between the two groups. Successful drainage was achieved in all 43 patients (100%). Total bilirubin level was significantly reduced from 6.0 ± 4.1 mg/dL to 2.1 ± 1.2 mg/dL in the SCS group (P = 0.000), and from 7.2 ± 6.4 mg/dL to 1.9 ± 1.3 mg/dL in the LCS group (P = 0.011). Procedure time was 34.4 ± 16.8 min in the SCS group and 27.9 ± 13.3 min in the SCS group (P = 0.293). Mean follow-up period was 145.7 ± 110.5 days in the SCS group and 198.1 ± 178.4 days in the LCS group (P = 0.593).
Primary outcomes There were no differences in cumulative stent patency and survival between the two groups (P = 0.086 and P = 0.320, respectively) (Figs 4,5). Median stent patency period was 83 days (range, 25–284 days) in the SCS group and 105 days (range, 27–376 days) in the LCS group. Median survival period was 109 days (range, 25–442 days) in the SCS group and 114 days (range, 27–595 days) in the LCS group.
Secondary outcomes There were no significant differences in early and late complications between the two groups as summarized in Table 2. A total of 12 early complications (cholangitis, n = 8 and pancreatitis, n = 4) were successfully treated with conservative treatments. Of the four patients in the SCS group with pancreatitis, two patients underwent precut sphincterotomy using a needle-knife as a result of difficult biliary cannulation, and one patient underwent transpapillary placement of
Age (years)† Gender Male Female Diagnosis Cholangiocarcinoma Gallbladder cancer Bismuth classification II IIIa IIIb IV TNM staging IIIA IIIB IVA IVB Antibiotic prophylaxis Precut sphincterotomy Transpapillary SEMS placement Adjuvant treatment‡ Chemotherapy Radiotherapy Chemoradiotherapy Total bilirubin level (mg/dL)†
SCS (n = 21)
LCS (n = 22)
P-value
71.0 ± 11.0
68.4 ± 12.4
0.466 0.443
9 (42.9) 12 (57.1)
12 (54.5) 10 (45.5)
12 (57.1) 9 (42.9)
15 (68.2) 7 (31.8)
8 (38.1) 2 (9.5) 1 (4.8) 10 (47.6)
4 (18.2) 7 (31.8) 2 (9.1) 9 (40.9)
3 (14.3) 2 (9.5) 1 (4.8) 15 (71.4) 13 (61.9) 3 (14.3) 2 (9.5)
0 (0.0) 2 (9.1) 2 (9.1) 18 (81.8) 16 (72.7) 2 (9.1) 0 (0)
11 (52.4) 10 1 0 6.0 ± 4.1
12 (54.5) 11 0 1 7.2 ± 6.4
0.454
0.206
0.433
0.449 0.664 0.233 1.000
0.981
† Values are presented as mean ± SD. Other values are presented as number or number (%). ‡ Adjuvant treatment is defined as treatment after stent insertion. LCS, large cell-sized stent; SCS, small cell-sized stent; SEMS, selfexpandable metallic stent; SIS, stent-in-stent.
SEMS. Late complications in the two groups occurred in eight patients (18.6%). In the SCS group, cholangitis with stent occlusion occurred in two patients and liver abscess in one. In the LCS group, cholangitis occurred in three patients, liver abscess in one and cholecystitis in one. Four patients with cholangitis were successfully treated with i.v. antibiotics and endoscopic reintervention using SEMS. In the LCS group, one patient with cholangitis underwent stent clearance by balloon sweeping, but there was no stent occlusion except for some sludge. All of the patients with liver abscess or cholecystitis were successfully treated with i.v. antibiotics and temporary percutaneous catheter drainage or percutaneous transhepatic gallbladder drainage. There were no significant differences in clinical course between the two groups (Table 3). One patient (4.8%) in the
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Figure 4 Cumulative stent patency curve by Kaplan–Meier analysis shows no differences between small cell-sized stent (SCS; ) and large cell-sized stent (LCS; ) (P = 0.086).
SCS group and one patient (4.5%) in the LCS group died of disease progression 25 and 27 days after the procedure, respectively. Stent occlusion occurred in nine (42.9%) of the patients in the SCS group and in 10 (45.5%) of the patients in the LCS group. Causes of stent occlusion were tumor ingrowth (n = 7) and tumor overgrowth (n = 2) in the SCS group. By comparison, stent occlusion was caused by tumor ingrowth in all patients (n = 10) in the LCS group. However, the difference of tumor ingrowth rates was not statistically significant between the two groups (P = 0.416). Reintervention was carried out in all 19 patients with stent occlusion during their follow up. Among them, endoscopic reintervention was done in six of the patients in the SCS group and in five of the patients in the LCS group (P = 0.650). Percutaneous reintervention was carried out in three of the patients in the SCS group and in five of the patients in the LCS group (P = 0.650). In the SCS group, we inserted a plastic stent
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Figure 5 Cumulative survival curve by Kaplan–Meier analysis shows no differences between small cell-sized stent (SCS; ) and large cell-sized stent (LCS; ) (P = 0.320). , LCScensored; , SCS-censored.
through the occluded SEMS in four patients and inserted a SEMS in two; the remaining three patients were treated by percutaneous transhepatic biliary drainage (PTBD). In the LCS group, we inserted a plastic stent through the occluded SEMS in two patients and inserted a SEMS in three; the remaining five patients were treated by PTBD.
DISCUSSION
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LTHOUGH THE SUCCESS rate of endoscopic bilateral SIS placement by experienced endoscopists has recently increased, contralateral stent deployment through the mesh of the first metallic stent is still a technical obstacle. The use of LCS can provide a high technical success rate in such cases, but there are concerns about the vulnerability to tumor ingrowth. However, there has been no study as yet comparing the clinical outcomes of endoscopic bilateral SIS
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Table 2 Early and late complications in the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Early complications Cholangitis Pancreatitis Bleeding Procedure-related mortality Late complications Cholangitis Cholecystitis Liver abscess
SCS (n = 21)
LCS (n = 22)
P-value
8 (38.1) 4 4 0 0 3 (14.3) 2 0 1
4 (18.2) 4 0 0 0 5 (22.7) 3 1 1
0.146
0.698
All values are presented as number or number (%). LCS, large cell-sized stent; SCS, small cell-sized stent; SIS, stent-in-stent.
Table 3 Clinical courses in the two groups undergoing endoscopic bilateral SIS placement for malignant hilar biliary obstruction
Stent occlusion Tumor ingrowth Tumor overgrowth
SCS (n = 21)
LCS (n = 22)
P value
9 (42.9) 7 (33.3) 2 (9.5)
10 (45.5) 10 (45.5) 0 (0)
0.864 0.416 0.233
All values are presented as number or number (%). LCS, large cell-sized stent; SCS, small cell-sized stent; SIS, stent-in-stent.
placement according to the cell size of the SEMS. The current study showed that there was no significant difference in clinical outcomes according to the cell size of SEMS in patients who underwent an endoscopic bilateral SIS placement for malignant hilar biliary obstruction. Previous studies reported a multicenter experience with the use of SCS or LCS in patients with malignant hilar biliary obstruction.9,13 In the SCS study, median stent patency and survival were 150 days and 180 days, respectively.13 In the LCS study, median stent patency and survival were 157 days and 220 days, respectively.9 This study showed a longer median stent patency and survival period than our results. Those findings are explainable by the difference in baseline characteristics. Our patients had less Bismuth type II and more Bismuth type IV than the patients of previous studies.9,13 In addition, although related data have not been described in previous studies,9,13 there might be different factors including performance status, TNM staging and adjuvant treatment. In particular, our patients who underwent second-line chemotherapy were only 11.6% (n = 5) as a result of patient refusal.
As mentioned earlier, the efficacy of SCS or LCS has been reported in previous studies,8,9,13,14 but no direct comparison between the two stents has been done. In the current study, we compared the SCS and LCS groups using these two stents. As a result, there were no significant differences in clinical outcome between the two stents. In particular, LCS was not different from SCS in cumulative stent patency despite the large cell size. Moreover, in the analysis regarding causes of stent occlusion, the rate of difference of tumor ingrowth was not statistically significant between the two stents. These data suggest that stent characteristics including cell size may be less important factors in stent occlusion rates. In fact, the small cell size of SEMS is unlikely to impede tumor ingrowth because uncovered SEMS are rapidly embedded into a tumor and/or bile duct mucosa. Likewise, a previous randomized controlled study reported that stent diameter rather than design or material may be the more important feature in determining stent occlusion rates.15 That study showed no significant difference in stent occlusion between patients receiving a 10-mm Zilver stent (open-cell design; Cook Endoscopy, Winston-Salem, NC) or a 10-mm Wallstent (closed cell design; Boston Scientific, Watertown, MA).15 This finding is indirectly consistent with our results related to the cell size of SEMS. In the current study, there was no observed stent occlusion as a result of sludge formation. One possible explanation for this finding may be a low axial force (AF) of SEMS. The AF is the force required to keep stents straight.16 A lower AF is suitable for cases of hilar biliary obstruction as a result of the acute bend in the bile duct at the hilar portion, and confers a better conformability.10 If the AF is too high, the stent may exert forces to change its shape, which could result in adverse clinical events in the bile duct. Thus, late complications, especially related to biliary sludge may have been reduced by minimizing the damage to the bile duct wall through a low AF. Soon, survival periods may exceed the patency duration of SEMS with advances in anticancer therapies in cases of biliary malignancy. Therefore, SEMS are needed not only for better long-term patency but also for ease of endoscopic reintervention. The success rate of endoscopic reintervention varies from 44.4% to 100% after metallic stenting for malignant hilar biliary obstruction.13,17–23 However, these studies used various combinations of unilateral or bilateral stent placement and side-by-side or stent-in-stent techniques. Variations among these studies prohibit a direct comparison of the results. Mukai et al. recently reported that a large cell size is necessary for easy and safe reintervention in cases of SEMS occlusion with the SIS technique.10 In addition, it was reported that the LCS can easily be carried out as reintervention because of its uniform large cell size.7,9 However, our study showed no significant difference in endoscopic
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reintervention according to cell size of the SEMS. This finding may be explained by the structural features of the SCS which may facilitate a revisionary stent insertion as a result of the wider mesh by a cross-wired structure on the central portion. Park et al. reported a single-session success rate of 66.7% (16/24) for reinterventions by endoscopic bilateral placement in cases of SCS,13 which is consistent with our results. In our study, procedure time was slightly shorter in the LCS group. Although this difference was not statistically significant, we could not exclude the possibility that a lack of statistical power was caused by the relatively small sample size. Therefore, a further large prospective study is needed to identify these findings. Our study has some limitations. First, it was conducted in a non-randomized retrospective design without a predefined follow-up protocol. Second, the study was conducted in a highly experienced bilateral hilar stenting center with a high prevalence of malignant hilar biliary obstruction; technical and functional success rates may differ in non-specialist centers. Therefore, a further prospective multicenter randomized study is needed to confirm the current observations. Nevertheless, to the best of our knowledge, our work is the very first study comparing the clinical outcomes of endoscopic bilateral SIS placements according to the cell sizes of SEMS. In conclusion, our results showed no significant differences in clinical outcome, including stent patency and survival, according to the cell size of SEMS in patients who underwent endoscopic bilateral SIS placement for unresectable malignant hilar biliary obstruction.
CONFLICT OF INTERESTS
A
UTHORS DECLARE NO conflict of interests for this article.
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