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Experimental Studies |
1 From the Departments of Radiology (J.H.S., H.Y.S., C.G.C., C.J.Y., T.H.K., J.Y.S.) and Pathology (J.S.K., Y.M.K.), Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea; Department of Polymer Science and Engineering, Hannam University, College of Engineering, Daejeon, Korea (S.H.Y.); and Department of Radiology, Nanjing First Hospital, Nanjing Medical University, China (X.H.). From the 2003 RSNA Scientific Assembly. Received January 3, 2004; revision requested March 4; revision received April 6; accepted May 19. Supported by a grant (R01-2003-000-11716-0) from the Korea Science and Engineering Foundation, Republic of Korea, and a grant (HMP-98-G-2-043) from the Highly Advanced National Project, Ministry of Health and Welfare, Republic of Korea. Address correspondence to H.Y.S. (e-mail: hysong@amc.seoul.kr).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Procedures were performed in accordance with the National Institutes of Health guidelines for humane handling of animals; approval of the committee of animal research was obtained. Twenty paclitaxel-eluting polyurethane-covered stents (drug stents) and 20 polyurethane-covered stents (control stents) were placed alternately between the proximal and distal urethra in 20 male dogs. The dose of paclitaxel was approximately 1800 µg in each drug stent but absent in each control stent. Dogs were sacrificed either 4 (n = 10) or 8 (n = 10) weeks after stent placement. The percentage diameter of stenosis was assessed with follow-up retrograde urethrography and histologic findings obtained after sacrifice and compared between drug stents and control stents and between the proximal and the distal urethra.
RESULTS: Two drug stents partially migrated during retrograde urethrography immediately after stent placement; they were removed and replaced with a second stent during the same procedure. There was a strong tendency toward a lower percentage diameter of stenosis and numeric mean values of the four histologic findings, which indicates less formation of tissue hyperplasia in the proximal urethra than in the distal urethra. In particular, thickness of the papillary projection denoting the entire thickness of hyperplastic reaction was significantly less in drug stents than in control stents in the proximal urethra in the 8-week group (P = .016, Mann-Whitney U test).
CONCLUSION: Local delivery of paclitaxel via covered stents has the potential to reduce tissue hyperplasia secondary to stent placement in a canine urethral model. With stent placement, there are distinct differences of tissue hyperplasia between the proximal and distal urethra.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Recently, self-expanding covered metallic stents have been successfully used to treat obstructive symptoms caused by stricture of nonvascular organs, such as the urethra, esophagus, and trachea (7–10). Formation of tissue hyperplasia at either end of the stent after covered stent placement is, however, not uncommon and can foster restenosis or stent blockage and make it difficult to remove the stent, thus requiring stent replacement or even surgical removal (7–10). Surely, the most fundamental way to solve the problemof tissue hyperplasia at either end of the covered stent is to reduce or prevent the development of tissue hyperplasia. There have been only a few studies, however, in which the antiproliferative characteristics of paclitaxel have been applied to nonvascular cells or organs to solve the problem of tissue hyperplasia. Kalinowski et al (11) and Song et al (12) suggested that paclitaxel would be a promising antiproliferative agent for use in nonvascular cells or organs.
The purpose of this study was to evaluate a paclitaxel-eluting covered stent for reduction of tissue hyperplasia after stent placement in a canine urethral model.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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A urethral stent introducer set includes a 9-F braided sheath (Cook, Bloomington, Ind), a dilator, and a pusher catheter. A guidewire was inserted through the urethra and advanced into the urinary bladder. A 9-F sheath and dilator, with the proximal portion lubricated with lidocaine jelly, were passed into the urethra over the guidewire and advanced until the proximal tip of the dilator reached the prostatic urethra. The sheath was left in place, and the dilator and guidewire were removed. A drug stent or control stent was then compressed until it fit into the distal end of the sheath and was advanced into the proximal or distal normal nonstrictured urethra with a pusher catheter and fluoroscopic guidance. The sheath was then withdrawn while the pusher catheter was held immobile. The sheath and pusher catheter were pulled out of the urethra after stent deployment. Stent placement was performed by one of two interventional radiologists (J.H.S., X.H.) with more than 5 years of experience with animal experiments. Follow-up retrograde urethrography was performed immediately after stent placement to document the position and apposition of the stent and patency of the urethra.
Follow-up.—We divided the 20 dogs into two groups according to the duration of the follow-up period; thus, we had a 4-week group and an 8-week group. Each group of 10 dogs was then divided into a group of five dogs in which drug stents and control stents were placed in the proximal and distal urethra, respectively, and a group of five dogs in which control stents and drug stents were placed in the proximal and distal urethra, respectively. In the 4-week group, follow-up retrograde urethrography was performed just before sacrifice to verify the stent position and evaluate the degree of urethral stricture. In the 8-week group, follow-up retrograde urethrography was performed 4 weeks after stent placement and before sacrifice. When there were stent-related complications, such as stent migration or obstruction, the stents were removed by using a retrievable hook, as described previously (8).
Information concerning urinary outlet obstruction and gross hematuria was obtained by means of daily examination of urine volume and color. On images obtained with retrograde urethrography, the percentage diameter of stenosis was measured (J.H.S., X.H.) at the point of maximum narrowing near both ends of the stent, as compared with the nearest normal urethral segment. The measurement was performed by using digital measurement (Photoshop 6.0; Adobe Systems, Palo Alto, Calif). Because relative measurements were used, correction for magnification was unnecessary. Percentage stenosis was calculated as (1 – MLD/N) · 100, where MLD is the measured minimum lumen diameter and N is the nearest normal diameter measurement. The nearest normal diameter immediately adjacent to the stent was chosen to minimize alteration of the diameter of the normal segment of the urethra. The expanded diameter of the stent and the lumen diameter of both the proximal and distal parts of each urethra were measured on retrograde urethrography images obtained 4 weeks after stent placement. The lumen diameter was measured from where the native urethra was not expanded by the inserted stents. The stent-to-lumen ratio was then calculated by dividing the stent diameter by the urethral lumen diameter for each stent.
Histologic examination.—Dogs in the 4- and 8-week groups were sacrificed with an overdose of xylazine hydrochloride (Rompun; Bayer, Seoul, Korea) 4 and 8 weeks after stent placement, respectively. Surgical exploration of the urethra, urinary bladder, both kidneys, and both ureters was performed (J.H.S., C.J.Y., T.H.K., X.H.). The urethra was incised longitudinally, and the stents were removed gently from the urethra (Fig 2). The remaining tissue samples were fixed in neutral buffered formalin for 24 hours. The fixed tissue samples were cross-sectioned at two locations (ie, the most proximal and distal portions of the area where each stent was present) (Fig 2). The sectioned tissue samples were stained with hematoxylin-eosin. At microscopic examination, the number of epithelial layers, thickness of granulation tissue (ie, the distance, measured in millimeters, between the basement membrane and the lower portion of the abnormal submucosa denoting the submucosa infiltrated with inflammatory cells), thickness of the papillary projection (ie, the length, measured in millimeters, of protruded tissue into the lumen), and degree of submucosal inflammatory cell infiltration (1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; 5, severe) were evaluated by two pathologists (J.S.K., Y.M.K.) in consensus. The thickness of the papillary projection includes the entire thickness of hyperplastic reaction induced by stent placement. The degree of submucosal inflammatory cell infiltration was determined subjectively according to the distribution and density of the inflammatory cells. The average value of each histologic item was obtained by adding the values of the two locations of sectioned tissue samples and dividing by two. Histologic analysis of the urethra was performed with a microscope equipped with magnification capabilities of x20 and x100. Measurements were obtained with Image-Pro Plus (Media Cybernetics, Silver Spring, Md).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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During follow-up, none of the dogs showed gross hematuria or died before sacrifice. No urinary outlet obstruction occurred during the follow-up period. As scheduled, the urethral specimens, urinary bladder, and both kidneys were successfully obtained in all dogs.
Retrograde Urethrography
The retrograde urethrography findings after stent placement are summarized in the Table.
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In the 8-week group, retrograde urethrography was performed 4 weeks after stent placement; retrograde urethrography images showed that there was significantly less tissue hyperplasia in the proximal urethra than in the distal urethra in dogs with control stents (P = .009). Retrograde urethrography images obtained just before sacrifice showed that there was significantly less tissue hyperplasia in the proximal urethra than in the distal urethra both in dogs with drug stents and in dogs with control stents (P = .047 for both) (Fig 3). There was no significant difference between drug stents and control stents in the proximal or distal urethra (P > .05).
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Histologic Findings
The histologic findings after sacrifice are summarized in Figures 4 –7. At autopsy, the urinary bladder, ureters, and kidneys showed no grossly abnormal findings.
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In the 8-week group, the thickness of the papillary projection was significantly less in drug stents than in control stents in the proximal urethra (P = .016) (Fig 6). Additionally, the thickness of the papillary projection was also significantly less in the proximal urethra than in the distal urethra in drug stents (P = .016) (Fig 6). The other comparisons between drug stents and control stents, as well as between the proximal and distal urethra, did not show significant differences. There was, however, a tendency toward less tissue response after stent placement in drug stents than in control stents in the proximal urethra but not in the distal urethra (Figs 4–7).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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In addition to antineoplastic application, the application of paclitaxel to coronary or peripheral arteries has been popular to reduce neointimal hyperplasia; however, to our knowledge, there have been few applications to nonvascular organs, with only two representative studies performed by Kalinowski et al (11) and Song et al (12). Kalinowski et al (11) reported that paclitaxel incubation results in a dose-dependent inhibition of cell proliferation of human epithelial gallbladder cells, human fibroblasts, and pancreatic carcinoma cells. Song et al (12) reported that intravesical administration of paclitaxel provides a bladder tissue targeting advantage (ie, the concentration in the urothelium was about 50% of the concentration in the urine) in animals, and that paclitaxel is a promising drug in intravesical bladder cancer therapy. These two reports suggest that paclitaxel has potent antiproliferative effects such as the inhibition of fibroblast proliferation in nonvascular cells or organs. In our study, the authors intended to combine the pharmacologic effects of paclitaxel with the mechanical advantages of a covered stent in nonvascular tubular organs because abnormal conditions in tubular organs are usually accompanied by stricture. Local delivery of paclitaxel via covered stents was feasible and effective in reducing the tissue hyperplasia secondary to stent placement in the canine urethra.
In our study, the antiproliferative effects of paclitaxel were more definite in the 8-week group than in the 4-week group in the proximal part of the urethra. That is, in the 8-week group, tissue response in drug stents was less than that in control stents in the proximal urethra at histologic examination. We postulate that the antiproliferative effects of paclitaxel were inadequate to overcome active tissue response after stent placement in the 4-week group; however, the antiproliferative effects were sufficient to overcome active tissue response in the 8-week group, as tissue healing was complete after 4 weeks. It is well known that the unique mode of action of rapid cellular uptake and microtubule stabilizing properties supports a long-lasting antiproliferative action, even after a brief single-dose application at very low concentrations (17). Kolodgie et al (19) reported that nanoparticle paclitaxel administered as a 10-minute intraarterial infusion (2.5–5.0 mg/kg) to rabbits receiving bilateral iliac artery stents showed substantial inhibition of neointimal growth at 4-week follow-up. Furthermore, an additional 3.5 mg/kg dose of nanoparticle paclitaxel administered 28 days after stent placement resulted in sustained suppression of neointimal thickness at 90-day follow-up. The blood concentration of nanoparticle paclitaxel was 0.1 µmol/L 48 hours after infusion. Theoretically, the duration of contact of paclitaxel with adjacent tissue in dogs with a paclitaxel-eluting stent in the urethra is longer than that in dogs who undergo intraarterial infusion because paclitaxel is slowly released over a longer period of time (ie, 29 days in the present study). Thus, we postulate that the slow-release characteristics of paclitaxel (ie, about 4 weeks) would be helpful in the delayed response of the antiproliferative effects in the 8-week group.
When we compared the results of drug stents and control stents between the proximal and distal parts of the urethra, we found that there was less tissue hyperplasia in the proximal urethra than in the distal urethra on retrograde urethrography images and in histologic findings. This difference was definite, even in the same urethra. On the basis of retrograde urethrography findings, we found that the diameter of the distal urethra was smaller than that of the proximal urethra; however, the expanded stent diameter was nearly the same in both the proximal and the distal urethra. Anatomically, a thick and somewhat rigid corpus cavernosum surrounds the distal penile urethra in dogs; however, this is absent in the proximal pelvic urethra (20). We surmise that the distal urethra has a smaller diameter, is less expandable, and shows more tissue response as a result of higher trauma than the proximal urethra as the stent of the same size expands over time. Although some investigators (21,22) reported that oversizing or high radial force did not result in increased neointimal hyperplasia in an animal arterial model, we surmise that the varying expansibility of surrounding tissues to inserted stents that have the same diameter and radial force could account for the varying results. Less expansibility of the distal urethra can be related to the lack of antiproliferative effects of paclitaxel in the 8-week group in the distal urethra, as the effects of paclitaxel are not strong enough to overcome the tissue response secondary to lesser expansibility in the distal urethra. In the present study, the lesser expansibility of the distal urethra can also be related to immediate migration of the two stents with manual injection of contrast material during postdeployment retrograde urethrography. Thus, we assume that comparison of the effect of eluted paclitaxel between the proximal and distal urethra will be erroneous because the surrounding milieu of the urethra is quite different in the proximal and distal urethra and because the smaller-diameter stents are necessary to place in the distal urethra.
To prevent excessive tissue ingrowth and to increase drug delivery efficacy, polyurethane-covered stents were used in the present study. For a covered stent to be useful as an intraluminal delivery device, compatibility at the tissue interface must be ensured (ie, the wire mesh and covering materials should not interfere with wound healing or induce excessive cell proliferation or chronic inflammation). Some investigators have reported that polyurethane-coated stents implanted in coronary or peripheral arteries showed a modest tissue reaction comparable with that of bare stainless steel stents (23,24); however, more investigators have reported intense inflammatory response to stents covered or coated with polyurethane and implanted in arteries or subcutaneous tissues (25–27). Although it is likely that the polyurethane used to cover stents may have promoted an inflammatory tissue reaction in the urethra in the present study, comparison with bare stents or polyurethane-coated stents should be performed to confirm this hypothesis.
This study has several limitations. First, the effective dose of paclitaxel was not quantified to suppress the tissue response secondary to inserted stents. Furthermore, approximately half of the released paclitaxel would be lost because paclitaxel released to the luminal side would be excreted with urine. To solve this problem, further experiments with stents that have various doses of paclitaxel should be performed, and quantitative assessment of local paclitaxel delivery on the basis of tissue concentrations of paclitaxel and in vitro release kinetics data should be followed. Second, retrograde urethrography results could be intrinsically inaccurate because the diameter of the urethra and quantification of tissue response could differ as a result of the degree of manual injection of contrast material.
In conclusion, local treatment with paclitaxel-eluting covered stents has the potential to reduce tissue hyperplasia secondary to stent placement in a canine urethral model. With stent placement, there are distinct differences of tissue hyperplasia between the proximal and distal urethra.
Practical application: Although our study has several limitations, paclitaxel-eluting covered stents showed the potential to reduce tissue hyperplasia, as compared with control stents in a canine urethral model. Thus, drug-eluting stents may have potential in the treatment of urethral stricture. Further study performed with an animal stricture model is needed. With a retrievable stent design, drug-eluting stents will be easier to remove because hyperplastic tissue growth at the ends of the stents will be reduced or prevented (7).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, H.Y.S.; study concepts, J.H.S., H.Y.S.; study design, J.H.S., H.Y.S., C.J.Y.; literature research, C.G.C., S.H.Y., C.J.Y., T.H.K., J.Y.S., X.H.; experimental studies, J.H.S., S.H.Y., C.J.Y., T.H.K., J.Y.S., X.H.; data acquisition, J.H.S., J.S.K., Y.M.K., J.Y.S.; data analysis/interpretation, J.H.S., H.Y.S., S.H.Y., J.S.K., Y.M.K.; statistical analysis, J.H.S., C.J.Y.; manuscript preparation, J.H.S., H.Y.S.; manuscript definition of intellectual content, J.H.S., H.Y.S., C.J.Y.; manuscript editing, J.H.S., H.Y.S., C.G.C., C.J.Y.; manuscript revision/review, all authors; manuscript final version approval, H.Y.S.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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