Endoscopic stenting of a fully covered self-expandable metal stent with a hole in each cavity in malignant hilar biliary obstruction: A preclinical proof-of-concept study and initial human experience

Endoscopic stenting of a fully covered self-expandable metal stent with a hole in each cavity in malignant hilar biliary obstruction: A preclinical proof-of-concept study and initial human experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endoscopic stenting of a fully covered self-expandable metal stent with a hole in each cavity in malignant hilar biliary obstruction: A preclinical proof-of-concept study and initial human experience Jungnam Lee, Seok Jeong, Don Haeng Lee, Jung-Hyun Lim, Makoto Kobayashi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5096366/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jan, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted 9 You are reading this latest preprint version Abstract Background and Aim Stent placement for biliary drainage in patients with malignant hilar biliary obstruction (MHBO) has been a topic of long-standing debate, and the best approach remains controversial. Therefore, we aimed to evaluate the efficacy, safety, and removability of multi-hole fully covered self-expandable metal stents (MH-FCSEMSs) in a preclinical experiment using swine hilar bile duct obstruction (HBDO) models and to assess the feasibility and safety of stent placement in patients with MHBO. Methods Three minipigs underwent endoscopic retrograde cholangiopancreatography (ERCP)-guided endobiliary-radio frequency ablation (EB-RFA) to establish Bismuth type II hilar bile duct stenosis models. Four weeks after EB-RFA, 10 mm-diameter and 4 cm-length MH-FCSEMSs were endoscopically inserted into the left intrahepatic bile duct of the models. Stent patency and migration, as well as adverse events including cholangitis and endoscopic stent removability, were assessed three months after stent placement. Additionally, clinical applications of MH-FCSEMS were performed in two patients with MHBO to determine feasibility, safety, and stent patency. Results MH-FCSEMSs were successfully inserted into the left main intrahepatic bile duct and common hepatic duct of the models under ERCP in all three animals without any technical difficulties. Cholangiograms performed 12 weeks after MH-FCSEMS placement showed no stent migration, and all were successfully removed from the animal models. The functional success rate, defined as a decrease in serum total bilirubin level of more than 50% at 12 weeks after stent placement, was 100%. Moreover, MH-FCSEMSs were successfully inserted in two patients with hilar cholangiocarcinoma. The procedures were technically feasible, and no major periprocedural complications were noted. Conclusion The preliminary long-term results of both preclinical and clinical pilot studies suggest that endoscopic biliary drainage using MH-FCSEMS may be a safe and effective treatment option for stenting and stent revision in the management of HBDO. Further studies comparing clinical outcomes to those of MH-FCSEMSwithout multi-hole in malignant hilar biliary obstruction will be needed to verify the clinical benefits. Fully covered self-expandable metal stent Hilar cholangiocarcinoma Malignant hilar biliary obstruction Radio-frequency ablation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Hilar cholangiocarcinoma (HC) is a biliary cancer involving the proximal extrahepatic bile duct. HC was first reported approximately 50 years ago and accounts for 50–70% of all biliary tract cancers.[1] Approximately 90% of patients have biliary tract symptoms, most commonly including painless jaundice, and up to 10% of patients have cholangitis.[2,3] Managing HC is particularly difficult considering its aggressive nature and complex anatomical relationships. Complete resection is the most effective treatment, but only a small number of patients are eligible for resection at the time of presentation.[4] HC is the most common disease that causes malignant hilar biliary obstruction (MHBO). Most patients present with jaundice, and the degree of hyperbilirubinemia is usually greater than that seen in benign obstructive cholelithiasis.[4] Almost all patients require biliary decompression before starting treatment.[2] Appropriate biliary drainage is particularly important before resection, given that long-term partial hepatectomy is often required and a healthy liver remnant is required. Despite advances in gastrointestinal endoscopy technology, managing MHBO remains a challenge even for advanced endoscopists.[4] Multiple debates about what stent is safer for patients with MHBO are still ongoing. Endoscopic stent placement for MHBO has been a topic of long-standing discussion, and the best approach is still controversial.[5,6] Plastic stents have been used; however, other stents have shown better efficacy in recent studies. Therefore, uncovered metal stents have been widely used for MHBO until recently due to the side branches and contralateral intrahepatic bile duct (IHD) occlusion risk. However, uncovered self-expandable metallic stents (SEMSs) have limited applicability in the case of recurrent biliary obstruction caused by inward growth of the tumor, and difficulties associated with endoscopic reintervention may occur. Moreover, advancements in chemotherapy have substantially improved the prognosis for patients with MHBO, but this has consequently resulted in an increased incidence of stent dysfunction following initial drainage treatment, thereby necessitating reintervention.[7] Overcoming these hurdles requires a covered metal stent that can be inserted into the hilar bile duct and endoscopically removed in the case of stent occlusion. Compared to uncovered SEMS, covered SEMSs are less susceptible to tumor internal growth and therefore show a longer time to recurrent biliary obstruction. Fully covered SEMS (FCSEMS) may increase tissue patency by preventing the internal growth of the tumor and can be removed as needed. Therefore, FCSEMS may improve the efficacy of endoscopic drainage in MHBO by increasing stent patency and the convenience of the procedure. Recent meta-analyses have shown that covered SEMSs are superior to uncovered SEMSs in preventing recurrent biliary obstruction in patients with malignant distal biliary obstruction.[8] However, FCSEMSs are more likely to migrate, and they are not recommended to treat MHBO due to concerns about obstruction of the intrahepatic bile duct branches, which connect to the main duct at the hilum. To address this problem, we used a stent with several holes in the FCSEMS membrane, positioned in the center of each cavity to maintain biliary drainage from the contralateral bile ducts and side branches. In this study, we aimed to evaluate the efficacy, safety, and removability of this multi-hole (MH) stent as a proof of concept for its utility in managing MHBO. A similar approach was taken in a study, where a multi-hole fully covered self-expandable metal stent (MH-FCSEMS) was developed and successfully used in patients with malignant biliary obstruction.[9] That study demonstrated that the MH-FCSEMS effectively prevented bile duct obstruction while minimizing complications such as stent migration.[9] Building on these findings, we conducted a 3-month follow-up preclinical study in a minipig model of hilar biliary obstruction. Additionally, we report on the human pilot application of the MH-FCSEMS, focusing on feasibility and early results. Methods Animal models Our in vivo experiments were conducted using three female minipigs ( Sus scrofa ; mean age 14 months, mean body weight 30 kg). All animal studies were performed in the National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders large animal endoscopy room. Animals fasted but had access to water for 24 h before the endoscopy was performed under general anesthesia. The procedures were conducted under general anesthesia with the animal in the left decubitus position on the fluoroscopy table. Approval was obtained from our institutional animal care committee before study commencement (MK-IACUC 150803-001). Preparation of MH-FCSEMSs Figure 1 shows the structure of the MH-FCSEMS (M.I. Tech Co., Ltd., Pyeongtaek, Korea), which was used in this study. The stents were 10 mm wide and up to 4 cm in length, with flare-free round margins on both ends. The stent is made of nitinol wire, and the inner surface is completely covered with silicone film. Uniquely, the stent has a 2.5-mm hole in the center of the membrane of each cavity to prevent side branch obstruction and stent migration due to the internal growth of tissue through the holes. In addition, the stent has a 9-cm-long lasso attached to the distal end for retrieval purposes. The primary endpoint of our study was the successful fixation of MH-FCSEMS under endoscopic procedures. Formation of hilar bile duct stricture in swine models Hilar bile duct stenosis was established using endobiliary radiofrequency ablation (EB-RFA). EB-RFA was performed in the left perihilar bile duct to create Bismuth type II hilar bile duct stenosis, assuming a stenosis length of approximately 10 mm. Three minipigs underwent endoscopic retrograde cholangiopancreatography (ERCP)-guided RFA using a high-frequency ablation catheter (electrode length 18 mm, diameter 7 F, working length 175 cm; STARmed Co., Ltd., Goyang, Korea) in the perihilar bile duct. High-frequency electrical energy was delivered for 120 s with a power of 7 W and a target temperature of 80 °C. The cholangiography was done right after the biliary RFA to assess the post-procedure adverse events, such as bile duct perforation. Four weeks after RFA, follow-up cholangiography under ERCP was performed to ensure the formation of hilar biliary stricture models. Bile duct stricture was defined as the presence of intrahepatic bile duct dilation with a luminal diameter reduction of >50% from baseline at the RFA application site. An expert biliary endoscopist performed all endoscopic procedures using a standard side-viewing duodenoscope (TJF-260; Olympus Optical Co. Ltd., Tokyo, Japan). Placement and removal of the MH-FCSEMS under ERCP Endoscopic insertion of MH-FCSEMS was performed under general anesthesia in well-prepared swine stricture models four weeks after RFA. Under fluoroscopic guidance, one MH-FCSEMS was inserted in the stricture segment. Technical success was defined as fluoroscopic confirmation that the stent was accurately inserted into the stricture segment as intended. After three months, follow-up ERCP with stent removal was performed to evaluate stent migration and removability. The MH-FCSEMS was removed by grabbing and pulling the lasso with a rat tooth forceps using the side-viewing duodenoscope. Laboratory tests and clinical complication evaluations Laboratory tests were performed before RFA (baseline), just before stent insertion (4 weeks after RFA), and just before stent removal (12 weeks after stent placement). Functional success was defined as a decrease in serum total bilirubin level of >50% at 12 weeks after stent placement compared to just before stent placement (4 weeks after RFA). Complications were assessed by daily monitoring of clinical signs, including weight change, daily food intake, and demeanor scores. Initial clinical experience with MH-FCSEMS Two patients with pathologically confirmed hilar cholangiocarcinoma with MHBO underwent FCSEMS-MS placement under ERCP for palliative biliary drainage. The procedures were performed on two patients by an experienced biliary endoscopist expert who performed at least 1,000 ERCPs after obtaining informed consent. A conventional side-viewing duodenoscope (TJF-260; Olympus Medical Systems) was used in this study. The 8.5-Fr stent introducers fitted with MH-FCSENSs (8-mm diameter, 6-cm length, 7-cm lasso; M.I. Tech Co., Ltd., Pyeongtaek, Korea) were inserted into both IHDs using the side-by-side technique. When placing the introducer, the radiopaque markers enabled stent position control to cover the stricture segment under fluoroscopy. This study was approved by the Institutional Review Board of Inha University Hospital (IRB No. 2022-06-004), and the need for informed consent was waived. Results Development of the biliary stricture model and feasibility of MH-FCSEMS insertion EB-RFA of the left main intrahepatic bile duct and common hepatic duct was successfully performed on all three animals (Fig. 2). Four weeks after EB-RFA, a cholangiogram was performed to confirm that Bismuth type II stricture was induced as intended. Cholangiograms showed that the stricture model was successfully prepared in all three pigs. Figure 3 shows the segmental stricture in the hilar bile duct and diffuse structure of both IHDs. MH-FCSEMSs were successfully inserted into the left perihilar bile duct under ERCP in all three animals without technical difficulties (Fig. 4). No technical difficulties were observed or major adverse events such as cholangitis, bleeding, perforation, or death. The mean serum level of total bilirubin at baseline was 0.14 mg/dL (range, 0.13–0.15) (Table 1). Evaluation of MH-FCSEMS migration and removability Cholangiograms were performed under ERCP at 12 weeks after MH-FCSEMS placement, and no noteworthy migration of the stent was observed (Figs. 5a and 5b). Although there was modest resistance, MH-FCSEMS was successfully removed with the lasso retrieval technique in all three pigs (Table 2). Functional success evaluation and safety profile at 12 weeks The functional success rate was 100%. At the time of MH-FCSEMS placement, the bilirubin level increased by 12 times (mean 1.62, range 0.19–4.31) compared to baseline values. However, at 12 weeks after stent placement, it decreased by 74% (mean 0.42, range 0.21–0.76). At this time point, there was no mortality or abnormal behavior that suggested a major adverse event in any animal (Table 2). Initial clinical experience MH-FCSEMSs were successfully inserted in two patients with confirmed unresectable hilar cholangiocarcinoma and MHBO (Fig. 6). The entire procedure was technically feasible, and no major periprocedural complications were noted. After MH-FCSEMS insertion, obstructive jaundice resolved in both patients and did not relapse during their remaining lifespan (90 and 303 days, respectively). During the remaining patient’s lifespan, stent patency was well maintained. Therefore, MH-FCSEMS removal or re-insertion of other stents was not required (Table 3). Discussion In this study, we demonstrated that the placement of MH-FCSEMS provides potentially effective palliative treatment for malignant hilar bile duct stenosis and cholangitis induced by FCSEMS placement for bile duct stricture. Stricture may therefore be prevented by creating multiple small holes in the stent to avert collateral obstruction. In our preclinical study, both the technical and functional MH-FCSEMS success rates were 100%. Moreover, there was no stent migration during the experiment, and the removability was 100% even after three months from the initial stent insertion. Furthermore, our clinical pilot study of two patients with hilar cholangiocarcinoma showed that MH-FCSEMSs were feasible, and stent migration did not occur. No evidence of obstructive jaundice, cholangitis, or pancreatitis in these patients was observed during their remaining lifespan (90 and 303 days, respectively). Biliary drainage is an important treatment for jaundice with liver dysfunction and allows for symptom recovery and extended survival duration in patients with malignant biliary obstruction.[1,2,10] Endoscopic or percutaneous biliary drainage is a technique that can be used to treat jaundice secondary to hilar cholangiocarcinoma. ERCP provides internal drainage by inserting stents, which provides a better quality of life compared to percutaneous drainage. Therefore, endoscopic bile duct stenting with biliary drainage is currently considered the first-line palliative treatment for relieving jaundice and preventing secondary cholangitis.[5,11] However, the best type of ERCP stent for hilar cholangiocarcinoma has been the subject of controversy for many years.[8,12] For example, uncovered SEMSs cannot be removed after placement.[13] Obstruction of uncovered SEMSs can generally be managed endoscopically by placing a second biliary stent within the first stent. However, second biliary stenting within the occluded stent is often technically more difficult than the first stenting, as the guidewire is often incorrectly inserted outside the stent lumen through the stent cavity and cannot pass through the stent lumen from the distal end to the proximal end. Compared to uncovered SEMS, FCSEMSs have a theoretically longer duration of patency since their covering membrane is resistant to tumor ingrowth. However, they are more likely to migrate. Stent migration is a major problem when using FCSEMS to treat biliary stenosis and has been reported to occur more frequently in patients receiving FCSEMS than other types of SEMS.[13,14] To address this problem, we have developed several holes in the MH-FCSEMS membrane at the center of each mesh to maintain bile flow between the contralateral bile duct and side branches. MH-FCSEMS was developed with the consideration that it can maintain drainage while having the advantages of covered stents.[9,15] Our newly modified MH-FCSEMS, used in the current study, features a non-flared end to minimize damage to the bile duct wall. The presence of holes reduces membrane tension, which allows the stent to become anchored to the surrounding tissues, thereby preventing migration. As a result of the reduced membrane tension associated with these small holes, no stent migration was observed in both the in vivo and in vitro conducted studies. This pilot study shows that MH-FCSEMS placement offers a potentially effective palliative treatment for malignant hilar biliary stricture. Technical and functional success rates were both 100%. In addition, the study demonstrates that cholangitis induced by FCSEMS placement in the hilar bile duct can be prevented by making multiple holes in the covering membrane of stent cavities to prevent side branch occlusion. The results of this study suggest that this FCSEMS modification is reasonable for the treatment of hilar biliary stricture. Furthermore, there were no clinical complications related to the stenting during the 3-month follow-up. Removal was possible after four weeks in a previous animal model study, and our current study demonstrated that stent removal is possible even after three months, which is thought to reflect actual clinical practice. Therefore, this new stent design is expected to be effective in treating hilar malignant biliary obstruction involving the hepatic duct confluence with unilateral biliary stenting by reducing the risk of obstructive cholangitis. Based on these results, it is expected that our MH-FCSEMS could be useful in malignant hilar biliary stricture, malignant common bile duct, and benign biliary stricture. In addition, the strengths of our stent, such as decreased side branch occlusion and stent migration risk and improved endoscopic removability during the re-intervention, are expected to significantly contribute to improving the quality of life as well as the clinical outcomes of patients with biliary obstruction. The limitations of our experimental study were as follows: First, we used a porcine hilar bile duct stenosis model, which was induced using intraductal RFA. Therefore, our results may not reflect results in a setting of malignant hilar bile duct stricture, as cholangiocarcinomas cause extensive microenvironment changes. Moreover, results from a human study may differ from those of our in vivo animal model experiment. Second, a pilot study was conducted on two patients with Klatskin tumors; however, since these patients did not develop cholangitis, in-stent obstruction, or stent migration until death, the removability of MH-FCSEMS in humans could not be evaluated. Third, a relatively small number of minipigs was used in our animal model study. Large-scale prospective comparative studies are required to confirm the effectiveness and safety of MH-FCSEMSs. Fourth, post-stenting pancreatitis was not evaluated due to anatomical differences, as a porcine model has a separate pancreatic and biliary ductal system. Our preliminary long-term outcomes suggest that biliary drainage of MHBO using MH-FCSEMS is a technically feasible, safe, and effective procedure for swine hilar biliary stricture models. No MH-FCSEMS migration, and the stents were movable in all cases. Further preclinical and clinical studies will be necessary to compare MH-FCSEMS with other fully covered SEMS without MH to demonstrate that MH-FCSEMS can reduce the need for stent reintervention while minimizing the risk of migration during stent placement. Abbreviations EB-RFA, endobiliary-radio frequency ablation; ERCP, endoscopic retrograde cholangiopancreatography; FCSEMS, fully covered self-expanding metal stent; HBDO, hilar bile duct obstruction; HC, hilar cholangiocarcinoma; IHD, intrahepatic bile duct; MH, multi-hole; MHBO, malignant hilar biliary obstruction; MH-FCSEMS, multi-hole fully covered self-expandable metal stent; SEMS, self-expanding metal stent Declarations Disclosure statement The authors have no conflict of interest to declare. Acknowledgment This work was supported by an INHA UNIVERSITY HOSPITAL Research Grant. References Soares KC, Kamel I, Cosgrove DP, Herman JM, Pawlik TM. Hilar cholangiocarcinoma: diagnosis, treatment options, and management Hepatobiliary surgery and nutrition . 2014;3:18. Mansour JC, Aloia TA, Crane CH, Heimbach JK, Nagino M, Vauthey J-N. Hilar cholangiocarcinoma: expert consensus statement Hpb . 2015;17:691-699. Jarnagin W, Winston C. Hilar cholangiocarcinoma: diagnosis and staging HPB . 2005;7:244-251. Soares KC, Jarnagin WR. The landmark series: hilar cholangiocarcinoma Annals of surgical oncology . 2021;28:4158-4170. Paik WH, Park YS, Hwang J-Het al. . Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach Gastrointestinal endoscopy . 2009;69:55-62; Dumonceau J-M, Tringali A, Papanikolaou ISet al. . Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline–Updated October 2017 Endoscopy . 2018;50:910-930. Lee TH, Park DH, Lee SSet al. . Technical feasibility and revision efficacy of the sequential deployment of endoscopic bilateral side-by-side metal stents for malignant hilar biliary strictures: a multicenter prospective study Digestive diseases and sciences . 2013;58:547-555; Park DH, Lee SS, Moon JHet 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) Gastrointestinal endoscopy . 2009;69:1357-1360; Naitoh I, Ohara H, Nakazawa Tet al. . Unilateral versus bilateral endoscopic metal stenting for malignant hilar biliary obstruction Journal of gastroenterology and hepatology . 2009;24:552-557. Takenaka M, Lee TH, Kudo M. Recent advances in metallic stents used in the stent‐in‐stent method for hilar malignant biliary obstruction Digestive Endoscopy . 2024;36:370-372 %@ 0915-5635. Yamashita Y, Tachikawa A, Shimokawa Tet al. . Covered versus uncovered metal stent for endoscopic drainage of a malignant distal biliary obstruction: Meta‐analysis Digestive Endoscopy . 2022. Kobayashi M. Development of a biliary multi-hole self-expandable metallic stent for bile tract diseases: A case report World Journal of Clinical Cases . 2019;7:1323. Qumseya BJ, Jamil LH, Elmunzer BJet al. . ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction Gastrointestinal endoscopy . 2021;94:222-234. e222. Tringali A, Boškoski I, Costamagna G. Endoscopic stenting in hilar cholangiocarcinoma: when, how, and how much to drain? Gastroenterology Research and Practice . 2019;2019; Bilal M, Freeman ML. Endoscopic Retrograde Cholangiopancreatography Stenting for Hilar Cholangiocarcinoma Techniques and Innovations in Gastrointestinal Endoscopy . 2022;24:190-199; Lin J, Wu A-L, Teng F, Xian Y-T, Xu X-J. Stent insertion for inoperable hilar cholangiocarcinoma: Comparison of radioactive and normal stenting Medicine . 2021;100. Tringali A, Hassan C, Rota M, Rossi M, Mutignani M, Aabakken L. Covered vs. uncovered self-expandable metal stents for malignant distal biliary strictures: a systematic review and meta-analysis Endoscopy . 2018;50:631-641. Li J, Li T, Sun Pet al. . Covered versus uncovered self-expandable metal stents for managing malignant distal biliary obstruction: a meta-analysis PloS one . 2016;11:e0149066. Tamura T, Yamaue H, Itonaga Met al. . Fully covered self-expandable metal stent with an anti-migration system vs plastic stent for distal biliary obstruction caused by borderline resectable pancreatic cancer: a protocol for systematic review Medicine . 2020;99. Park J-S, Jeong S, Kobayashi M, Lee DH. Safety, efficacy, and removability of a fully covered multi-hole metal stent in a swine model of hilar biliary stricture: a feasibility study Endoscopy International Open . 2019;7:E498-E503. Tables Table 1. Baseline characteristics of the swine hilar biliary stricture model Variables Values Liver enzyme, median (range) Total bilirubin, mg/dL 0.14 (0.2-4.3) Aspartate aminotransferase, IU/L 54.3 (28.3-97.8) Alanine aminotransferase, IU/L 36.7 (26.6-49.1) Alkaline phosphatase, IU/L 55.5 (31.0-81.2) Table 2. Overall outcomes at 12 weeks after MH-FCSEMS placement Variables Values Technical success, (%) 3/3 (100) Functional success, (%) 3/3 (100) Liver enzyme, median (range) Total bilirubin, mg/dL 0.4 (0.2–0.8) Aspartate aminotransferase, IU/L 58.0 (35.1–94.5) Alanine aminotransferase, IU/L 29.7 (20.8–45.2) Alkaline phosphatase, IU/L 101.6 (74.9–133.4) Adverse events Cholangitis (%) 0/3 (0) Stent migration (%) 0/3 (0) Stent occlusion (%) 0/3 (0) Success of stent removal (%) 3/3 (100) Table 3. Pilot study outcomes of two patients with MHBO after MH-FCSEMS placement Case Sex/Age Diagnosis Bismuth type Technical success Functional success Procedural-related complications Duration of stent patency (days) 1 65/Female Klatskin tumor II Yes Yes No 90 2 80/Female Klatskin tumor IV Yes Yes No 303 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Jan, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 06 Nov, 2024 Reviews received at journal 05 Nov, 2024 Reviews received at journal 29 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers agreed at journal 20 Oct, 2024 Reviewers invited by journal 21 Sep, 2024 Editor assigned by journal 18 Sep, 2024 Submission checks completed at journal 17 Sep, 2024 First submitted to journal 16 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5096366","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":374901078,"identity":"a5f30430-a279-42ee-8630-ad640a1a13ec","order_by":0,"name":"Jungnam Lee","email":"","orcid":"","institution":"Inha University Hospital, Inha University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jungnam","middleName":"","lastName":"Lee","suffix":""},{"id":374901079,"identity":"07dbca73-89ee-4c83-b906-c7c6efae864f","order_by":1,"name":"Seok 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University","correspondingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Takenaka","suffix":""},{"id":374901088,"identity":"870235cc-b77a-43be-aad3-440a1c41c0bb","order_by":6,"name":"Chang-Il Kwon","email":"","orcid":"","institution":"CHA University","correspondingAuthor":false,"prefix":"","firstName":"Chang-Il","middleName":"","lastName":"Kwon","suffix":""}],"badges":[],"createdAt":"2024-09-16 09:33:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5096366/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5096366/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-024-08810-1","type":"published","date":"2025-01-24T15:57:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70174724,"identity":"fa70f87f-ab2d-4c4f-9243-866d49ae9770","added_by":"auto","created_at":"2024-11-29 07:10:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8797973,"visible":true,"origin":"","legend":"\u003cp\u003eMH-FCSEMS has 2.5-mm holes at the center of each cell\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/72e61fc960c4e3c3d6b39ffb.png"},{"id":70174723,"identity":"7da0dd15-d8ff-47f4-ab81-32375e9ce817","added_by":"auto","created_at":"2024-11-29 07:10:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4549540,"visible":true,"origin":"","legend":"\u003cp\u003eEndobiliary-RFA in the hilar bile duct of minipigs\u003c/p\u003e\n\u003cp\u003e(a) Before endobiliary-RFA\u003c/p\u003e\n\u003cp\u003e(b) Endobiliary-RFA was applied to the left main IHD and common hepatic duct\u003c/p\u003e","description":"","filename":"Figure2aandb.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/f9deaf5ad9f22136568baeab.png"},{"id":70174720,"identity":"a3554766-8053-4d88-b70a-6b59554db0a8","added_by":"auto","created_at":"2024-11-29 07:10:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":136952,"visible":true,"origin":"","legend":"\u003cp\u003eFour weeks after endobiliary-RFA, the cholangiogram shows segmental stricture in the hilar bile duct and diffuse, severe dilation of both IHDs, suggesting Bismuth type II stricture\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/9e214021ef7f932b2e99da26.png"},{"id":70175087,"identity":"1503fa51-3c19-4a59-96f6-cb70ebad7b7b","added_by":"auto","created_at":"2024-11-29 07:18:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":157713,"visible":true,"origin":"","legend":"\u003cp\u003eMH-FCSEMS was inserted into the left IHD and common hepatic duct\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/700bca41256f38f907aec594.png"},{"id":70174722,"identity":"677f94d5-ec8a-4463-b116-5def86a4f7ab","added_by":"auto","created_at":"2024-11-29 07:10:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4504261,"visible":true,"origin":"","legend":"\u003cp\u003eRemoval of MH-FCSEMS after 12 weeks\u003c/p\u003e\n\u003cp\u003e(a) 12 weeks after stenting, MH-FCSEMS was located exactly where we inserted it without migration\u003c/p\u003e\n\u003cp\u003e(b) MH-FCSEMS was successfully removed with modest resistance from the hilar bile duct in a hilar stricture model\u003c/p\u003e","description":"","filename":"Figure5aand5b.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/a5c03d6b50ee8700cb76a860.png"},{"id":70174719,"identity":"e5a59f74-2bbf-4e11-a00f-435e28038729","added_by":"auto","created_at":"2024-11-29 07:10:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":3218898,"visible":true,"origin":"","legend":"\u003cp\u003ePilot study outcomes of MH-FCSEMS placement in two patients with MHBO\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/2e2994e3dcc25b63eb95066c.png"},{"id":74858437,"identity":"4658db70-71d8-4eea-8e39-fbf9a7f3afeb","added_by":"auto","created_at":"2025-01-27 16:09:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":23628764,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5096366/v1/21000163-e6b0-422f-91db-0c82aa711eae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endoscopic stenting of a fully covered self-expandable metal stent with a hole in each cavity in malignant hilar biliary obstruction: A preclinical proof-of-concept study and initial human experience","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHilar cholangiocarcinoma (HC) is a biliary cancer involving the proximal extrahepatic bile duct. HC was first reported approximately 50 years ago and accounts for 50\u0026ndash;70% of all biliary tract cancers.[1]\u0026nbsp;Approximately 90% of patients have biliary tract symptoms, most commonly including painless jaundice, and up to 10% of patients have cholangitis.[2,3]\u0026nbsp;Managing HC is particularly difficult considering its aggressive nature and complex anatomical relationships. Complete resection is the most effective treatment, but only a small number of patients are eligible for resection at the time of presentation.[4]\u0026nbsp;HC is the most common disease that causes malignant hilar biliary obstruction (MHBO). Most patients present with jaundice, and the degree of hyperbilirubinemia is usually greater than that seen in benign obstructive cholelithiasis.[4]\u0026nbsp;Almost all patients require biliary decompression before starting treatment.[2]\u0026nbsp;Appropriate biliary drainage is particularly important before resection, given that long-term partial hepatectomy is often required and a healthy liver remnant is required. Despite advances in gastrointestinal endoscopy technology, managing MHBO remains a challenge even for advanced endoscopists.[4]\u003c/p\u003e\n\u003cp\u003eMultiple debates about what stent is safer for patients with MHBO are still ongoing. Endoscopic stent placement for MHBO has been a topic of long-standing discussion, and the best approach is still controversial.[5,6]\u0026nbsp;Plastic stents have been used; however, other stents have shown better efficacy in recent studies. Therefore, uncovered metal stents have been widely used for MHBO until recently due to the side branches and contralateral intrahepatic bile duct (IHD) occlusion risk. However, uncovered self-expandable metallic stents (SEMSs) have limited applicability in the case of recurrent biliary obstruction caused by inward growth of the tumor, and difficulties associated with endoscopic reintervention may occur. Moreover, advancements in chemotherapy have substantially improved the prognosis for patients with MHBO, but this has consequently resulted in an increased incidence of stent dysfunction following initial drainage treatment, thereby necessitating reintervention.[7]\u0026nbsp;Overcoming these hurdles requires a covered metal stent that can be inserted into the hilar bile duct and endoscopically removed in the case of stent occlusion. Compared to uncovered SEMS, covered SEMSs are less susceptible to tumor internal growth and therefore show a longer time to recurrent biliary obstruction. Fully covered SEMS (FCSEMS) may increase tissue patency by preventing the internal growth of the tumor and can be removed as needed. Therefore, FCSEMS may improve the efficacy of endoscopic drainage in MHBO by increasing stent patency and the convenience of the procedure. Recent meta-analyses have shown that covered SEMSs are superior to uncovered SEMSs in preventing recurrent biliary obstruction in patients with malignant distal biliary obstruction.[8]\u0026nbsp;However, FCSEMSs are more likely to migrate, and they are not recommended to treat MHBO due to concerns about obstruction of the intrahepatic bile duct branches, which connect to the main duct at the hilum.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo address this problem, we used a stent with several holes in the FCSEMS membrane, positioned in the center of each cavity to maintain biliary drainage from the contralateral bile ducts and side branches. In this study, we aimed to evaluate the efficacy, safety, and removability of this multi-hole (MH) stent as a proof of concept for its utility in managing MHBO. A similar approach was taken in a study, where a multi-hole fully covered self-expandable metal stent (MH-FCSEMS) was developed and successfully used in patients with malignant biliary obstruction.[9] That study demonstrated that the MH-FCSEMS effectively prevented bile duct obstruction while minimizing complications such as stent migration.[9] Building on these findings, we conducted a 3-month follow-up preclinical study in a minipig model of hilar biliary obstruction. Additionally, we report on the human pilot application of the MH-FCSEMS, focusing on feasibility and early results.\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnimal models\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur \u003cem\u003ein vivo\u003c/em\u003e experiments were conducted using three female minipigs (\u003cem\u003eSus scrofa\u003c/em\u003e; mean age 14 months, mean body weight 30 kg). All animal studies were performed in the National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders large animal endoscopy room. Animals fasted but had access to water for 24 h before the endoscopy was performed under general anesthesia. The procedures were conducted under general anesthesia with the animal in the left decubitus position on the fluoroscopy table. Approval was obtained from our institutional animal care committee before study commencement (MK-IACUC 150803-001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePreparation of MH-FCSEMSs\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 shows the structure of the MH-FCSEMS (M.I. Tech Co., Ltd., Pyeongtaek, Korea), which was used in this study. The stents were 10 mm wide and up to 4 cm in length, with flare-free round margins on both ends. The stent is made of nitinol wire, and the inner surface is completely covered with silicone film. Uniquely, the stent has a 2.5-mm hole in the center of the membrane of each cavity to prevent side branch obstruction and stent migration due to the internal growth of tissue through the holes. In addition, the stent has a 9-cm-long lasso attached to the distal end for retrieval purposes. The primary endpoint of our study was the successful fixation of MH-FCSEMS under endoscopic procedures. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFormation of hilar bile duct stricture in swine models\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHilar bile duct stenosis was established using\u0026nbsp;endobiliary radiofrequency ablation (EB-RFA). EB-RFA was performed in the left perihilar bile duct to create Bismuth type II hilar bile duct stenosis, assuming a stenosis length of approximately 10 mm. Three minipigs underwent endoscopic retrograde cholangiopancreatography (ERCP)-guided RFA using a high-frequency ablation catheter (electrode length 18 mm, diameter 7 F, working length 175 cm; STARmed Co., Ltd., Goyang, Korea) in the perihilar bile duct. High-frequency electrical energy was delivered for 120 s with a power of 7 W and a target temperature of 80 °C. The cholangiography was done right after the biliary RFA to assess the post-procedure adverse events, such as bile duct perforation. Four weeks after RFA, follow-up cholangiography under ERCP was performed to ensure the formation of hilar biliary stricture models. Bile duct stricture was defined as the presence of intrahepatic bile duct dilation with a luminal diameter reduction of \u0026gt;50% from baseline at the RFA application site. An expert biliary endoscopist performed all endoscopic procedures using a standard side-viewing duodenoscope (TJF-260; Olympus Optical Co. Ltd., Tokyo, Japan).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlacement and removal of the MH-FCSEMS under ERCP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEndoscopic insertion of MH-FCSEMS was performed under general anesthesia in well-prepared swine stricture models four weeks after RFA. Under fluoroscopic guidance, one MH-FCSEMS was inserted in the stricture segment. Technical success was defined as fluoroscopic confirmation that the stent was accurately inserted into the stricture segment as intended. After three months, follow-up ERCP with stent removal was performed to evaluate stent migration and removability. The MH-FCSEMS was removed by grabbing and pulling the lasso with a rat tooth forceps using the side-viewing duodenoscope.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLaboratory tests and clinical complication evaluations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLaboratory tests were performed before RFA (baseline), just before stent insertion (4 weeks after RFA), and just before stent removal (12 weeks after stent placement). Functional success was defined as a decrease in serum total bilirubin level of \u0026gt;50% at 12 weeks after stent placement compared to just before stent placement (4 weeks after RFA). Complications were assessed by daily monitoring of clinical signs, including weight change, daily food intake, and demeanor scores.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInitial clinical experience with\u003c/em\u003e\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003eMH-FCSEMS\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo patients with pathologically confirmed hilar cholangiocarcinoma with MHBO underwent FCSEMS-MS placement under ERCP for palliative biliary drainage. The procedures were performed on two patients by an experienced biliary endoscopist expert who performed at least 1,000 ERCPs after obtaining informed consent. A conventional side-viewing duodenoscope (TJF-260; Olympus Medical Systems) was used in this study. The 8.5-Fr stent introducers fitted with MH-FCSENSs (8-mm diameter, 6-cm length, 7-cm lasso; M.I. Tech Co., Ltd., Pyeongtaek, Korea) were inserted into both IHDs using the side-by-side technique. When placing the introducer, the radiopaque markers enabled stent position control to cover the stricture segment under fluoroscopy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of Inha University Hospital (IRB No. 2022-06-004), and the need for informed consent was waived.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDevelopment of the biliary stricture model and feasibility of MH-FCSEMS insertion\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEB-RFA of the left main intrahepatic bile duct and common hepatic duct was successfully performed on all three animals (Fig. 2). Four weeks after EB-RFA, a cholangiogram was performed to confirm that Bismuth type II stricture was induced as intended. Cholangiograms showed that the stricture model was successfully prepared in all three pigs. Figure 3 shows the segmental stricture in the hilar bile duct and diffuse structure of both IHDs. MH-FCSEMSs were successfully inserted into the left perihilar bile duct under ERCP in all three animals without technical difficulties (Fig. 4). No technical difficulties were observed or major adverse events such as cholangitis, bleeding, perforation, or death. The mean serum level of total bilirubin at baseline was 0.14 mg/dL (range, 0.13–0.15) (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvaluation of MH-FCSEMS migration and removability\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCholangiograms were performed under ERCP at 12 weeks after MH-FCSEMS placement, and no noteworthy migration of the stent was observed (Figs. 5a and 5b). Although there was modest resistance, MH-FCSEMS was successfully removed with the lasso retrieval technique in all three pigs (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunctional success evaluation and safety profile at 12 weeks\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe functional success rate was 100%. At the time of MH-FCSEMS placement, the bilirubin level increased by 12 times (mean 1.62, range 0.19–4.31) compared to baseline values. However, at 12 weeks after stent placement, it decreased by 74% (mean 0.42, range 0.21–0.76). At this time point, there was no mortality or abnormal behavior that suggested a major adverse event in any animal (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInitial clinical experience\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMH-FCSEMSs were successfully inserted in two patients with confirmed unresectable hilar cholangiocarcinoma and MHBO (Fig. 6). The entire procedure was technically feasible, and no major periprocedural complications were noted. After MH-FCSEMS insertion, obstructive jaundice resolved in both patients and did not relapse during their remaining lifespan (90 and 303 days, respectively). During the remaining patient’s lifespan, stent patency was well maintained. Therefore, MH-FCSEMS removal or re-insertion of other stents was not required (Table 3).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we demonstrated that the placement of MH-FCSEMS provides potentially effective palliative treatment for malignant hilar bile duct stenosis and cholangitis induced by FCSEMS placement for bile duct stricture. Stricture may therefore be prevented by creating multiple small holes in the stent to avert collateral obstruction. In our preclinical study, both the technical and functional MH-FCSEMS success rates were 100%. Moreover, there was no stent migration during the experiment, and the removability was 100% even after three months from the initial stent insertion. Furthermore, our clinical pilot study of two patients with hilar cholangiocarcinoma showed that MH-FCSEMSs were feasible, and stent migration did not occur. No evidence of obstructive jaundice, cholangitis, or pancreatitis in these patients was observed during their remaining lifespan (90 and 303 days, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiliary drainage is an important treatment for jaundice with liver dysfunction and allows for symptom recovery and extended survival duration in patients with malignant biliary obstruction.[1,2,10]\u0026nbsp;Endoscopic or percutaneous biliary drainage is a technique that can be used to treat jaundice secondary to hilar cholangiocarcinoma. ERCP provides internal drainage by inserting stents, which provides a better quality of life compared to percutaneous drainage. Therefore, endoscopic bile duct stenting with biliary drainage is currently considered the first-line palliative treatment for relieving jaundice and preventing secondary cholangitis.[5,11]\u0026nbsp;However, the best type of ERCP stent for hilar cholangiocarcinoma has been the subject of controversy for many years.[8,12]\u0026nbsp;For example, uncovered SEMSs cannot be removed after placement.[13]\u0026nbsp;Obstruction of uncovered SEMSs can generally be managed endoscopically by placing a second biliary stent within the first stent. However, second biliary stenting within the occluded stent is often technically more difficult than the first stenting, as the guidewire is often incorrectly inserted outside the stent lumen through the stent cavity and cannot pass through the stent lumen from the distal end to the proximal end. Compared to uncovered SEMS, FCSEMSs have a theoretically longer duration of patency since their covering membrane is resistant to tumor ingrowth. However, they are more likely to migrate. Stent migration is a major problem when using FCSEMS to treat biliary stenosis and has been reported to occur more frequently in patients receiving FCSEMS than other types of SEMS.[13,14]\u0026nbsp;To address this problem, we have developed several holes in the MH-FCSEMS membrane at the center of each mesh to maintain bile flow between the contralateral bile duct and side branches. MH-FCSEMS was developed with the consideration that it can maintain drainage while having the advantages of covered stents.[9,15]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur newly modified MH-FCSEMS, used in the current study, features a non-flared end to minimize damage to the bile duct wall. The presence of holes reduces membrane tension, which allows the stent to become anchored to the surrounding tissues, thereby preventing migration. As a result of the reduced membrane tension associated with these small holes, no stent migration was observed in both the \u003cem\u003ein vivo\u003c/em\u003e and \u003cem\u003ein vitro\u003c/em\u003e conducted studies. This pilot study shows that MH-FCSEMS placement offers a potentially effective palliative treatment for malignant hilar biliary stricture. Technical and functional success rates were both 100%. In addition, the study demonstrates that cholangitis induced by FCSEMS placement in the hilar bile duct can be prevented by making multiple holes in the covering membrane of stent cavities to prevent side branch occlusion. The results of this study suggest that this FCSEMS modification is reasonable for the treatment of hilar biliary stricture. Furthermore, there were no clinical complications related to the stenting during the 3-month follow-up. Removal was possible after four weeks in a previous animal model study, and our current study demonstrated that stent removal is possible even after three months, which is thought to reflect actual clinical practice. Therefore, this new stent design is expected to be effective in treating hilar malignant biliary obstruction involving the hepatic duct confluence with unilateral biliary stenting by reducing the risk of obstructive cholangitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on these results, it is expected that our MH-FCSEMS could be useful in malignant hilar biliary stricture, malignant common bile duct, and benign biliary stricture. In addition, the strengths of our stent, such as decreased side branch occlusion and stent migration risk and improved endoscopic removability during the re-intervention, are expected to significantly contribute to improving the quality of life as well as the clinical outcomes of patients with biliary obstruction.\u003c/p\u003e\n\u003cp\u003eThe limitations of our experimental study were as follows: First, we used a porcine hilar bile duct stenosis model, which was induced using intraductal RFA. Therefore, our results may not reflect results in a setting of malignant hilar bile duct stricture, as cholangiocarcinomas cause extensive microenvironment changes. Moreover, results from a human study may differ from those of our \u003cem\u003ein vivo\u003c/em\u003e animal model experiment. Second, a pilot study was conducted on two patients with Klatskin tumors; however, since these patients did not develop cholangitis, in-stent obstruction, or stent migration until death, the removability of MH-FCSEMS in humans could not be evaluated. Third, a relatively small number of minipigs was used in our animal model study. Large-scale prospective comparative studies are required to confirm the effectiveness and safety of MH-FCSEMSs. Fourth, post-stenting pancreatitis was not evaluated due to anatomical differences, as a porcine model has a separate pancreatic and biliary ductal system.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur preliminary long-term outcomes suggest that biliary drainage of MHBO using MH-FCSEMS is a technically feasible, safe, and effective procedure for swine hilar biliary stricture models. No MH-FCSEMS migration, and the stents were movable in all cases. Further preclinical and clinical studies will be necessary to compare MH-FCSEMS with other fully covered SEMS without MH to demonstrate that MH-FCSEMS can reduce the need for stent reintervention while minimizing the risk of migration during stent placement.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEB-RFA, endobiliary-radio frequency ablation; ERCP, endoscopic retrograde cholangiopancreatography; FCSEMS, fully covered self-expanding metal stent; HBDO, hilar bile duct obstruction; HC, hilar cholangiocarcinoma; IHD, intrahepatic bile duct; MH, multi-hole; MHBO, malignant hilar biliary obstruction; MH-FCSEMS, multi-hole fully covered self-expandable metal stent; SEMS, self-expanding metal stent\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by an INHA UNIVERSITY HOSPITAL Research Grant.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSoares KC, Kamel I, Cosgrove DP, Herman JM, Pawlik TM. Hilar cholangiocarcinoma: diagnosis, treatment options, and management \u003cem\u003eHepatobiliary surgery and nutrition\u003c/em\u003e. 2014;3:18.\u003c/li\u003e\n\u003cli\u003eMansour JC, Aloia TA, Crane CH, Heimbach JK, Nagino M, Vauthey J-N. Hilar cholangiocarcinoma: expert consensus statement \u003cem\u003eHpb\u003c/em\u003e. 2015;17:691-699.\u003c/li\u003e\n\u003cli\u003eJarnagin W, Winston C. Hilar cholangiocarcinoma: diagnosis and staging \u003cem\u003eHPB\u003c/em\u003e. 2005;7:244-251.\u003c/li\u003e\n\u003cli\u003eSoares KC, Jarnagin WR. The landmark series: hilar cholangiocarcinoma \u003cem\u003eAnnals of surgical oncology\u003c/em\u003e. 2021;28:4158-4170.\u003c/li\u003e\n\u003cli\u003ePaik WH, Park YS, Hwang J-Het al. . Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach \u003cem\u003eGastrointestinal endoscopy\u003c/em\u003e. 2009;69:55-62; Dumonceau J-M, Tringali A, Papanikolaou ISet al. . Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline\u0026ndash;Updated October 2017 \u003cem\u003eEndoscopy\u003c/em\u003e. 2018;50:910-930.\u003c/li\u003e\n\u003cli\u003eLee TH, Park DH, Lee SSet al. . Technical feasibility and revision efficacy of the sequential deployment of endoscopic bilateral side-by-side metal stents for malignant hilar biliary strictures: a multicenter prospective study \u003cem\u003eDigestive diseases and sciences\u003c/em\u003e. 2013;58:547-555; Park DH, Lee SS, Moon JHet 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) \u003cem\u003eGastrointestinal endoscopy\u003c/em\u003e. 2009;69:1357-1360; Naitoh I, Ohara H, Nakazawa Tet al. . Unilateral versus bilateral endoscopic metal stenting for malignant hilar biliary obstruction \u003cem\u003eJournal of gastroenterology and hepatology\u003c/em\u003e. 2009;24:552-557.\u003c/li\u003e\n\u003cli\u003eTakenaka M, Lee TH, Kudo M. Recent advances in metallic stents used in the stent‐in‐stent method for hilar malignant biliary obstruction \u003cem\u003eDigestive Endoscopy\u003c/em\u003e. 2024;36:370-372 %@ 0915-5635.\u003c/li\u003e\n\u003cli\u003eYamashita Y, Tachikawa A, Shimokawa Tet al. . Covered versus uncovered metal stent for endoscopic drainage of a malignant distal biliary obstruction: Meta‐analysis \u003cem\u003eDigestive Endoscopy\u003c/em\u003e. 2022.\u003c/li\u003e\n\u003cli\u003eKobayashi M. Development of a biliary multi-hole self-expandable metallic stent for bile tract diseases: A case report \u003cem\u003eWorld Journal of Clinical Cases\u003c/em\u003e. 2019;7:1323.\u003c/li\u003e\n\u003cli\u003eQumseya BJ, Jamil LH, Elmunzer BJet al. . ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction \u003cem\u003eGastrointestinal endoscopy\u003c/em\u003e. 2021;94:222-234. e222.\u003c/li\u003e\n\u003cli\u003eTringali A, Bo\u0026scaron;koski I, Costamagna G. Endoscopic stenting in hilar cholangiocarcinoma: when, how, and how much to drain? \u003cem\u003eGastroenterology Research and Practice\u003c/em\u003e. 2019;2019; Bilal M, Freeman ML. Endoscopic Retrograde Cholangiopancreatography Stenting for Hilar Cholangiocarcinoma \u003cem\u003eTechniques and Innovations in Gastrointestinal Endoscopy\u003c/em\u003e. 2022;24:190-199; Lin J, Wu A-L, Teng F, Xian Y-T, Xu X-J. Stent insertion for inoperable hilar cholangiocarcinoma: Comparison of radioactive and normal stenting \u003cem\u003eMedicine\u003c/em\u003e. 2021;100.\u003c/li\u003e\n\u003cli\u003eTringali A, Hassan C, Rota M, Rossi M, Mutignani M, Aabakken L. Covered vs. uncovered self-expandable metal stents for malignant distal biliary strictures: a systematic review and meta-analysis \u003cem\u003eEndoscopy\u003c/em\u003e. 2018;50:631-641.\u003c/li\u003e\n\u003cli\u003eLi J, Li T, Sun Pet al. . Covered versus uncovered self-expandable metal stents for managing malignant distal biliary obstruction: a meta-analysis \u003cem\u003ePloS one\u003c/em\u003e. 2016;11:e0149066.\u003c/li\u003e\n\u003cli\u003eTamura T, Yamaue H, Itonaga Met al. . Fully covered self-expandable metal stent with an anti-migration system vs plastic stent for distal biliary obstruction caused by borderline resectable pancreatic cancer: a protocol for systematic review \u003cem\u003eMedicine\u003c/em\u003e. 2020;99.\u003c/li\u003e\n\u003cli\u003ePark J-S, Jeong S, Kobayashi M, Lee DH. Safety, efficacy, and removability of a fully covered multi-hole metal stent in a swine model of hilar biliary stricture: a feasibility study \u003cem\u003eEndoscopy International Open\u003c/em\u003e. 2019;7:E498-E503.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of the swine hilar biliary stricture model\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 80.7167%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80.7167%;\"\u003e\n \u003cp\u003eLiver enzyme, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80.7167%;\"\u003e\n \u003cp\u003eTotal bilirubin, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e0.14 (0.2-4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80.7167%;\"\u003e\n \u003cp\u003eAspartate aminotransferase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e54.3 (28.3-97.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80.7167%;\"\u003e\n \u003cp\u003eAlanine aminotransferase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e36.7 (26.6-49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80.7167%;\"\u003e\n \u003cp\u003eAlkaline phosphatase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.2833%;\"\u003e\n \u003cp\u003e55.5 (31.0-81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Overall outcomes at 12 weeks after MH-FCSEMS placement\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 74.2321%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eTechnical success, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e3/3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eFunctional success, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e3/3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eLiver enzyme, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eTotal bilirubin, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e0.4 (0.2\u0026ndash;0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eAspartate aminotransferase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u0026nbsp;58.0 (35.1\u0026ndash;94.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eAlanine aminotransferase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u0026nbsp;29.7 (20.8\u0026ndash;45.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eAlkaline phosphatase, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u0026nbsp;101.6 (74.9\u0026ndash;133.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eAdverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eCholangitis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e0/3 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eStent migration (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e0/3 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eStent occlusion (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e0/3 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 74.2321%;\"\u003e\n \u003cp\u003eSuccess of stent removal (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.7679%;\"\u003e\n \u003cp\u003e3/3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Pilot study outcomes of two patients with MHBO after MH-FCSEMS placement\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eCase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eSex/Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eBismuth type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eTechnical success\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eFunctional success\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2824%;\"\u003e\n \u003cp\u003eProcedural-related complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eDuration of stent patency (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e65/Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eKlatskin tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2824%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e80/Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003eKlatskin tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.6279%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2824%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.4585%;\"\u003e\n \u003cp\u003e303\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Fully covered self-expandable metal stent, Hilar cholangiocarcinoma, Malignant hilar biliary obstruction, Radio-frequency ablation","lastPublishedDoi":"10.21203/rs.3.rs-5096366/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5096366/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and Aim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStent placement for biliary drainage in patients with malignant hilar biliary obstruction (MHBO) has been a topic of long-standing debate, and the best approach remains controversial. Therefore, we aimed to evaluate the efficacy, safety, and removability of multi-hole fully covered self-expandable metal stents (MH-FCSEMSs) in a preclinical experiment using swine hilar bile duct obstruction (HBDO) models and to assess the feasibility and safety of stent placement in patients with MHBO.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree minipigs underwent endoscopic retrograde cholangiopancreatography (ERCP)-guided endobiliary-radio frequency ablation (EB-RFA) to establish Bismuth type II hilar bile duct stenosis models. Four weeks after EB-RFA, 10 mm-diameter and 4 cm-length MH-FCSEMSs were endoscopically inserted into the left intrahepatic bile duct of the models. Stent patency and migration, as well as adverse events including cholangitis and endoscopic stent removability, were assessed three months after stent placement. Additionally, clinical applications of MH-FCSEMS were performed in two patients with MHBO to determine feasibility, safety, and stent patency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMH-FCSEMSs were successfully inserted into the left main intrahepatic bile duct and common hepatic duct of the models under ERCP in all three animals without any technical difficulties. Cholangiograms performed 12 weeks after MH-FCSEMS placement showed no stent migration, and all were successfully removed from the animal models. The functional success rate, defined as a decrease in serum total bilirubin level of more than 50% at 12 weeks after stent placement, was 100%. Moreover, MH-FCSEMSs were successfully inserted in two patients with hilar cholangiocarcinoma. The procedures were technically feasible, and no major periprocedural complications were noted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe preliminary long-term results of both preclinical and clinical pilot studies suggest that endoscopic biliary drainage using MH-FCSEMS may be a safe and effective treatment option for stenting and stent revision in the management of HBDO. Further studies comparing clinical outcomes to those of MH-FCSEMSwithout multi-hole in malignant hilar biliary obstruction will be needed to verify the clinical benefits.\u003c/p\u003e","manuscriptTitle":"Endoscopic stenting of a fully covered self-expandable metal stent with a hole in each cavity in malignant hilar biliary obstruction: A preclinical proof-of-concept study and initial human experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-29 07:10:25","doi":"10.21203/rs.3.rs-5096366/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-06T14:27:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-06T03:47:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-29T15:11:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288496390731070137907990699434477603742","date":"2024-10-21T20:33:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234637993515358795620249066506456838460","date":"2024-10-20T15:42:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-21T16:19:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-18T20:01:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-18T03:36:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2024-09-16T09:31:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"39658700-f5b7-48c0-b267-d4c7bd9b102f","owner":[],"postedDate":"November 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:02:23+00:00","versionOfRecord":{"articleIdentity":"rs-5096366","link":"https://doi.org/10.1007/s10620-024-08810-1","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2025-01-24 15:57:43","publishedOnDateReadable":"January 24th, 2025"},"versionCreatedAt":"2024-11-29 07:10:25","video":"","vorDoi":"10.1007/s10620-024-08810-1","vorDoiUrl":"https://doi.org/10.1007/s10620-024-08810-1","workflowStages":[]},"version":"v1","identity":"rs-5096366","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5096366","identity":"rs-5096366","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}