e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3

avai lab le at www.sciencedi rect .com

journa l homepage: www.europeanurology.com

Endo-urology

Application of Paclitaxel-Eluting Metal Mesh Stents withinthe Pig Ureter: An Experimental Study

Evangelos N. Liatsikos a,*, Dimitrios Karnabatidis b, George C. Kagadis c,Kostantinos Rokkas a, Costas Constantinides d, Nikolaos Christeas b, Nikolaos Flaris e,Theodore Voudoukis a, Chrisoula D. Scopa f, Petros Perimenis a, Kriton S. Filos e,George C. Nikiforidis c, Jens-Uwe Stolzenburg g, Dimitrios Siablis b

aDepartment of Urology, University of Patras, School of Medicine, Patras, GreecebDepartment of Radiology, University of Patras, School of Medicine, Patras, GreececDepartment of Medical Physics, University of Patras, School of Medicine, Patras, Greeced First Department of Urology, University of Athens Medical School, ‘Laikon’ General Hospital, Athens, GreeceeDepartment of Anesthesiology and Critical Care Medicine, University of Patras, School of Medicine, Patras, GreecefDepartment of Pathology, University of Patras, School of Medicine, Patras, GreecegDepartment of Urology, University of Leipzig, Germany

Article info

Article history:Accepted May 31, 2006Published online ahead ofprint on June 14, 2006

Keywords:UreterHyperplasiaPaclitaxelMetal stents

Abstract

Objective: The purpose of the present study is to compare the standard bare metalstents (BMS) with the Paclitaxel-Drug Eluting Stent (DES) in the ureter of a pig model.Materials and methods: We report on an experimental study with ten female pigsweighing between 25 and 30 kg. The stents were randomly placed in either the right orleft ureter in each of 10 study animals, for a total of 20 stented ureters. Ten ureters werestented with an R-Stent (Orbus Medical Technologies, Hoevelaken Netherlands),and ten with a Paclitaxel-Eluting Coronary Stent (Boston Scientific, Natick, MA,USA). Patency was measured by radiograph of the nephrostomy tract, intravenousurography and virtual endoscopy at 24 hours and 21 days after the initial procedure,respectively.Results: Free flow of urine through the stents into the bladder was documented in allstented ureters 24 hours after stent insertion by radiograph of the nephrostomy tract.At the 21 day follow-up examination, 5 R-Stents were found to be completely occludedand two partially stenosed, whereas no occluded stent was detected in the Paclitaxel-DES group. Pathology examination of the stents at 21 days follow-up showed that theobstructed R-Stents generated severe inflammation with metaplasia of the urothe-lium. The Paclitaxel-Eluting MS generated a mild inflammatory response within theureteral lumen at the site of the stent, without hindering ureteral patency. R-stentsproved to develop more hyperplasia compared to the Paclitaxel-Eluting MS.

Conclusions: Paclitaxel-DES, when compared with the standard R- Stent BMS, generated less inflammation and/or hyperplasia of the surrounding tissues, thusmaintaining ureteral patency. Long-term animal trials are required to further validate our results.

# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, University of Patras Medical School, Rio,Patras, 26 500 Greece. Tel. +1130 2610 999386; Fax: +1130 2610 993981.E-mail address: Liatsikos@yahoo.com (E.N. Liatsikos).

0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.05.054

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3218

Fig. 1 – Radiograph of the nephrostomy tract at 24 hours

documenting ureteral patency of the TAXUS stent (right)

and the R-Stent (left). The white arrowheads show the

proximal and distal ends of the stents.

1. Introduction

Despite developments in endoscopic urology, thetreatment of extrinsic ureteral obstruction can createa great dilemma to the urologist. The methodscurrently used are transvesical as well as antegradeplacement of double pigtail stents, percutaneousnephrostomy and/or transluminal balloon dilationof the ureter.

The previous successful use of standard baremetal stents (BMS) in the vascular system and thebiliary tree, has led several investigators to proposetheir use for other applications such as the treat-ment of benign prostatic hyperplasia, urethralstrictures, and detrusor sphincter dyssynergia.BMS have also been used in the treatment ofmalignant and benign ureteral obstructions byothers and us with encouraging results, howeverurothelial hyperplasia through the stent meshresults in luminal occlusion in a significant numberof cases [1–6].

The ideal permanent stent for ureteral use hasnot been yet found. Metal mesh stents covered orcoated with various biocompatible materials, haverecently been introduced in vascular interventionfor the treatment of both aneurysmal and/orocclusive peripheral arterial diseases. The principleof covered stents to reduce tissue in-growth initiallyappeared promising but failed to demonstrate itsefficacy when used in the ureter due to a high rate ofmigration [7–9]. Drug Eluting Stents (DES) havebeen shown to minimize the restenosis rate afterstenting the coronary vessels due to a reductionof both inflammation and smooth muscle prolifera-tion [10,11]. The purpose of the present study wasto compare the standard BMS with the Paclitaxel-DES in the ureter of a pig model to test the conceptthat similar tissue effects will also reduce luminalocclusion in the stented ureter.

2. Materials and methods

We report on an experimental study with ten female pigs

weighing between 25 and 30 kg. The protocol was approved by

the Institutional Animal Care Committee of our institution. All

animals were allowed a minimum of 72 hours to recover from

the stress of transportation before the first procedure, and

food was withheld for 12 hours prior to anesthesia.

All interventions were performed in a standard operating

room equipped with a C-arm fluoroscope with the animals

under general anesthesia with a combination of ketamine

(20 mg/kg of body weight) and xylazine (2 mg/kg of body

weight). Thereafter, anesthesia was maintained with

inhaled isofluorothane (3–4%). Postoperative analgesia was

guaranteed with intramuscular administration of morphine

sulfate (0.1 mg/kg body weight) as necessary. Prophylactic

perioperative and postoperative antibiotics were administered

to all animals.

Balloon expanded metal stents were randomly placed in

either the right or left ureter at the level of the ureteropelvic

junction in each of 10 study animals, for a total of 20 stented

ureters. Ten ureters were stented with a 4 � 18 mm R-Stent

(Orbus Medical Technologies, Hoevelaken Netherlands), and

ten with a 4 � 32 mm TAXUSTM Express2TM Paclitaxel-Eluting

MS (Boston Scientific, Natick, MA, USA) which is currently

indicated for use in stenting coronary arteries. Both categories

of stents were coronary balloon expandable stents and thus

their diameters were the same. Their length was different

and not their diameter.

The TAXUSTM device consists of a stainless steel stent

coated with paclitaxel in a polymer carrier and premounted on

a balloon catheter. The TAXUSTM stent uses Translute

Polymer, a proprietary polymer carrier technology, to control

drug release. The durable Translute Polymer protects the drug

and maintains coating integrity during preparation, delivery,

and stent expansion. The polymer controls the release of

paclitaxel, and allows for a desired drug release and distribu-

tion [12–14]. The R-Stent is a stainless steel balloon expandable

vascular prosthesis, which is supplied mounted on a low

profile dilation catheter and has two radiopaque marker bands

that delimit the working length of the balloon.

The technique of stent insertion has been previously

described [5]. Briefly, percutaneous nephrostomy was per-

formed under ultrasonographic guidance and the collecting

system was visualized after injection of contrast material

through the nephrostomy sheath. Stents were positioned

and balloon inflated to maximum diameter. When the

deployment of the stent was finalized, the nephrostomy

tube was capped.

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3 219

Patency of the ureteral lumen was evaluated by radiograph

of the nephrostomy tract, intravenous urography and virtual

endoscopy at 24 hours and 21 days after the initial procedure,

respectively. In addition, conventional ureteroscopy of the

stented ureters was then undertaken in vivo at 21 days.

Following this, euthanasia and harvesting of the ureters took

place, and the specimens were sent for pathology examina-

tion. Pathology examination was blinded and performed by

the same pathologist minimizing possible bias.

3. Results

All stents were positioned successfully, and thepostoperative course was uneventful. All animalssurvived the entire follow up period of 3 weekswithout complications.

Free flow of urine through the stents into thebladder was documented in all stented ureters

Fig. 2 – Intravenous urography at 21 days depicts sufficient pat

the left ureter (R-Stent, (b)). In (b), an opacification pattern arou

This is certainly nonobstructive, and is probably due to the overd

muscular fibers of the adjacent ureteral segment. The white arr

24 hours after stent insertion by radiograph of thenephrostomy tract (Fig. 1). At the 21 day follow-upexamination, 5 R-Stents were found to be comple-tely occluded and two partially stenosed, whereasno occluded stent was detected in the Paclitaxel-DES group (Figs. 2 and 3). Two Paclitaxel-DES stentsmigrated distally within the ureter and were thuspartially stenosed jeopardizing ureteral patency,due to the limitation of the small size of thecoronary stent used in the ureter. Thus, 7 stentsin the R-group and 2 stents in the P-group were atleast partially stenotic, and when applying ChiSquare, the two groups differed significantly( p = 0.0246).

Ureteroscopic evaluation revealed extensivepolypoid hyperplastic response in the occludedR-Stents, while the lumen of the Pacitaxel-DESshowed homogeneous epithelial lining ascertaining

ency of the right ureter (TAXUS stent, (a)) as well as

nd the distal stent tip (trumpet-like configuration) is seen.

istension of the ureter and the resulting constriction of the

owheads show the proximal and distal ends of the stents.

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3220

Fig. 3 – Virtual endoscopy: View of patent stented ureter (T-Stent) (a). View of the stenotic segment within the stented

ureter (R-Stent) ( b).

patency. No stone formation or intraluminal encrus-tation occurred in any stent.

Mural inflammation was graded by using para-meters as previously reported by Nakada et al.(normal: grade 0-worst effect: grade 3) [15]. Pathologyexamination of the stents at 21 days follow-upshowed that the obstructed R-Stents generatedsevere inflammation (total grade 20) with metaplasiaof the urothelium. The sections of the remainingunobstructed R-Stents revealed the presence of apolypoid reaction adherent to the internal surface ofthe devices (Fig. 4a and b). The Paclitaxel-Eluting MSgenerated a mild inflammatory response (total grade6) within the ureteral lumen at the site of the stent,without hindering ureteral patency (Fig. 5a and b).

In order to check patency and inflammationdifferences between the ureters treated with R-Stents and/or Paclitaxel Stents (P-Stents) we appliedthe Wilcoxon signed-rank test. Two new variablescalled ‘‘D = difference in severity’’ and ‘‘E = differ-ence in inflammation’’ were calculated for every pigtaking as values the difference in hyperplasiaformation severity (D) and the difference in inflam-mation formation (E) (R-group score minus P-groupscore). Hyperplasia formation severity accordingto the radiologists measurements (intravenousurography and virtual endoscopy) was clusteredas ‘0 = patent’ when the stent had no stenosis or astenosis <50%, as ‘1 = stenosed’ when the stent had

a stenosis>50% and as ‘2 = occluded’ when the stentwas completely occluded. Inflammation formationaccording to the pathologists measurements wasclustered as described earlier. These measurementsare depicted in Table 1. All statistical tests were two-sided and the threshold of statistical significancewas set at 5% (a = 0.05). The SPSS v.11 statisticalsoftware package was employed for all data analysisand statistical calculations. Calculated median ofthe variable D (median = 1) proved to differ signifi-cantly ( p = 0.0156) from zero. Calculated median ofthe variable E (median = 1.5) proved also to differsignificantly ( p = 0.0117) from zero. These findingssupport that R-Stents developed more hyperplasiaand more inflammation compared to the TAXUSstents.

4. Discussion

The concept of BMS insertion is not new. They areused routinely in the cardiovascular and biliarysystems, and they also have been used for variousapplications in the urinary tract [1–6]. Milroy et al.first reported experience with BMS in the treatmentof urethral strictures [2]. Since then others haveused them for the treatment of benign prostatichyperplasia, detrusor-sphincter dyssynergia, and/orureteral obstruction [1–6].

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3 221

Fig. 4 – Gross pathology showing urothelial hyperplasia protruding through the stent mesh (a) and microscopic

histopathology (b) of an R-Stent with extensive inflammation (hematoxylin & eosin stain, magnification �40).

In previous reports we have showed our encoura-ging experience with the use of BMS in the treatmentof malignant ureteral obstruction, and in thetreatment of anastomotic strictures developed afterureteroileal diversion [5]. Nevertheless, there is a

Fig. 5 – Macroscopic image displaying constricted polypoid hyp

TAXUS stent (b) with a mild inflammatory response (hematoxy

concurrence among investigators that urothelialhyperplasia of the stent lumen has been theprincipal drawback with placement of BMS in theureter [3,4,6,16]. Thijssen et al. showed in anexperimental study that the grade of urothelial

erplasia of the urothelium (a) and microscopic images of a

lin & eosin stain, magnification �40).

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3222

Table 1 – Patency and inflammation correlation between the ureters treated with R-Stents and/or Paclitaxel (P) Stents

R-Stentpatency

R-Stentinflammation

P-Stentpatency

P-Stentinflammation

D = difference inseverity (R-group scoreminus P-group score)

E = difference ininflammation

(R-group score minusP-group score)

Pig 1 2 3 0 1 2 2

Pig 2 0 0 0 0 0 0

Pig 3 2 3 1 2 1 1

Pig 4 1 1 1 2 0 �1

Pig 5 2 3 0 0 2 3

Pig 6 2 3 0 0 2 3

Pig 7 0 1 0 1 0 0

Pig 8 0 1 0 0 0 1

Pig 9 1 2 0 0 1 2

Pig 10 2 3 0 0 2 3

Median 1.5 2.5 0 0 1 1.5

Range of the score 0 to 2 0 to 3 0 to 1 0 to 2 0 to 2 (�1) to 3

reaction is proportionally dependent on the extentof the ureteral overstreching and resulting urothe-lial trauma [16].

Drug eluting stents (or DES) have been widelyused in interventional cardiology in an attempt todecrease the restenosis rate after angioplasty andstenting [10,11]. Based on the existing vascularexperience we embarked upon their use withinthe ureter.

Paclitaxel is an anticancer agent that promotesthe polymerization of tubulin and inhibits thedisassembly of microtubules, thus causing the deathof the cell by interrupting the ordinary microtubuledynamics required for normal cell division. Inaddition it induces the expression of the gene fortumor necrosis factor a. These properties of thedrug led to the assumption that it could inhibitneointimal hyperplasia, and thus it was used in aplethora of trials that have shown a reduction inrestenosis in human coronary arteries [10–12].

Song et al. applied paclitaxel for intravesicalinstillations in an animal model and documentedits powerful antiproliferative effect upon the bladderurothelium [17]. In a recent report, Shin et al. havereported the use of paclitaxel-eluting polyurethanecovered stents in a canine urethral model. Theyshowed that there was a strong reduction of stentrelated tissue hyperplasia when compared to con-ventional polyurethane covered stents [18].

In the present study we assumed that Paclitaxel-Eluting MS would minimize urothelial hyperplasiaand/or ingrowth of tissue in the ureteral lumenalong the length of the treated segment therebyimproving patency as compared to the conventionalMS. We thus compared the standard MS with thePaclitaxel-Eluting MS in the ureter of a pig model.The results of the present study revealed that indeedthe Paclitaxel-Eluting MS offered the advantage of

minimal urothelial hyperplasia and/or limited intra-luminal tissue growth. The difference in length ofthe two-stent groups could be considered a limita-tion of our study. Even though there are commer-cially available 32 mm R-Stents, they wereunavailable to us. Nevertheless, the main purposeof this pilot experimental study was to depict theeffect of the stent on the ureteral wall and show if itcaused less ‘‘reaction’’ than the conventional stents.

In conclusion, Paclitaxel-Eluting metal meshstent, when compared with the standard R-Stent,generated less inflammation and/or hyperplasia ofthe surrounding tissues, thus maintaining ureteralpatency. To our knowledge this is the first report inthe literature applying drug eluting metal meshstents within the ureter of an animal model.Nevertheless, long-term animal and human trialsare deemed necessary to further validate our resultsincluding optimizing dose and duration of drugdelivery.

Acknowledgment

We would like to thank Boston Scientific Corpora-tion (Natick, MA, USA) for the invaluable helpprovided and the supply of the TAXUSTM Express2TM

Stents.

References

[1] Sigwart U, Puel J, Mirkovitch B, Joffre F, Kappenberger L.

Intravascular stents to prevent occlusion and restenosis

after transluminal angioplasty. New Engl J Med 1987;316:

701–6.

[2] Milroy EJ, Chapple CR, Cooper JE, Eldin A, Wallsten H,

Seddon AM, et al. A new treatment for urethral strictures.

Lancet 1988;1:1424–7.

e u r o p e a n u r o l o g y 5 1 ( 2 0 0 7 ) 2 1 7 – 2 2 3 223

[3] Flueckiger F, Lammer J, Klein GE, Hausegger K, Lederer A,

Szolar D, et al. Malignant ureteral obstruction: prelimin-

ary results of treatment with metallic self-expandable

stents. Radiology 1993;186:169–73.

[4] Pauer W, Lugmayr H. Metallic Wallstents: a new therapy

for extrinsic ureteral obstruction. J Urol 1992;148:281–4.

[5] Barbalias GA, Siablis D, Liatsikos EN, Karnabatidis D,

Yarmenitis S, Bouropoulos K, et al. Metal stents: a new

treatment of malignant ureteral obstruction. J Urol 1997;

158:54–8.

[6] Barbalias GA, Liatsikos EN, Kagadis GC, Karnabatidis D,

Kalogeropoulou C, Nikiforidis G, et al. Ureteropelvic junc-

tionobstruction: an innovativeapproachcombiningmetal-

lic stenting and virtual endoscopy. J Urol 2002;168:2383–6.

[7] Barbalias GA, Liatsikos EN, Kalogeropoulou C, Karnabati-

dis D, Zabakis P, Athanassopoulos A, et al. Externally

coated ureteral metallic stents: an unfavorable clinical

experience. Eur Urol 2002;42:276–80.

[8] Tekin MI, Aytekin C, Aygun C, Peskircioglu L, Boyvat F,

Ozkardes H. Covered metallic ureteral stent in the man-

agement of malignant ureteral obstruction: preliminary

experience. Urology 2001;58:919–23.

[9] Trueba Arguinarena FJ, Fernandez Del Busto E. Self-

expanding polytetrafluoroethylene covered nitinol stents

for the treatment of ureteral stenosis: preliminary report.

J Urol 2004;172:620–3.

[10] Grube E, Buellesfeld L. Paclitaxel-eluting stents: current

clinical experience. Am J Cardiovasc Drugs 2004;4:355–60.

[11] Wiskirchen J, Schober W, Schart N, Kehlbach R, Wersebe

A, Tepe G, et al. The effects of paclitaxel on the three

phases of restenosis: smooth muscle cell proliferation,

migration, and matrix formation: an in vitro study. Invest

Radiol 2004;39:565–71.

[12] Blabosklonny MV, Darzynkiewicz Z, Halicka HD, Pozar-

owski P, Demidenko ZN, Barry JJ, et al. Paclitaxel induces

primary and postmitotic G1 arrest in human arterial

smooth muscle cells. Cell Cycle 2004;3:8–14.

[13] Farmakis D, Pectasides M, Pectasides D. Recent advances

in conventional-dose salvage chemotherapy in patients

with cisplatin-resistant or refractory testicular germ cell

tumors. Eur Urol 2005;48:400–7.

[14] Johannsen M, Sachs M, Roigas J, Hinke A, Staack A,

Loening SA, et al. Phase II trial of weekly paclitaxel and

carboplatin chemotherapy in patients with advanced

transitional cell cancer. Eur Urol 2005;48:246–51.

[15] Nakada SY, Soble JJ, Gardner SM, Wolf Jr JS, Figenshau RS,

Pearle MS, et al. Comparison of Acucise endopyelotomy

and endoballoon rupture for management of secondary

proximal ureteral stricture in the porcine model.

J Endourol 1996;10:311–8.

[16] Thijssen AM, Millward SF, Mai KT. Ureteral response to

the placement of metallic stents: an animal model. J Urol

1994;151:268–70.

[17] Song D, Wientjes MG, Au JL. Bladder tissue pharmacoki-

netics of intravesical taxol. Cancer Chemother Pharmacol

1997;40:285–92.

[18] Shin JH, Song HY, Choi CG, Yuk SH, Kim JS, Kim YM, et al.

Tissue hyperplasia: influence of a paclitaxel-eluting cov-

ered stent—preliminary study in a canine urethral model.

Radiology 2005;234:438–44.