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Fig. 1. Photograph of a nitinol stent consisting of covered part and bare part. 234
대한영상의학회지 2005;52:233-240 후 밀대를 고정하고 외피관을 잡아당겨 스텐트의 하연이 carina에서 3-cm 상방에 위치하도록 하였다. 스텐트가 설치되고 나면 외피관과 밀대를 제거하였으며 스텐트의 피복된 부분은 기관의 하방에 위치하도록 하였다(Fig. 2). 모든 개에서 스텐트 삽입 후 8주 후에 투시조영 하에서 스 텐트의 이동 유무를 확인하였으며 12주 동안 스텐트를 삽입 한 상태를 유지하였다. 분의 염증세포 밀도를 경도(mild)로 보았을 때의 상대적인 침 윤 정도를 경도(mild)에서 고등도(severe)로 5등급으로 나누 어 측정하였다. 상피세포층의 미란/궤양, 염증세포의 침윤 정 도는 100배 비율에서, 육아조직의 두께는 40배 비율에서 관 찰하여 DS와 CS 간의 차이를 비교하였다. 각각의 스텐트가 삽입되었던 부위에서 얻은 절편의 세 부위에서의 측정치의 평 균치를 스텐트의 조직학적 소견의 값으로 하였다. 조직병리학적 검사 실험 동물은 스텐트 삽입 12주 후 xylazine hydrochloride 를 과량으로 정맥 주사하여 희생시켰고 스텐트가 삽입된 기관 을 분리한 후 기관의 종축으로 절개하였다(Fig. 3). 절개된 기 관에서 삽입된 스텐트를 조심스럽게 기관에서 제거한 후 10% 포르말린 용액에 고정하였다. 10% 포르말린에 하루 동안 고 정된 표본은 각 스텐트의 피복 부위와 비피복 부위가 위치하 였던 부분의 중앙을 횡단 절편하여 얻어 파라핀 포매시켰다. 포매된 블록은 4-10- 두께로 박절한 다음 hematoxylineosin 염색을 하여 광학현미경에서 관찰하였다. 측정 항목은 상피세포층의 미란/궤양(epithelial erosion/ulcer), 육아조직의 두께(granulation tissue thickness), 염증세포의 침윤 정도 (inflammatory cell infiltration)였다. 상피세포층의 미란/궤양 은 전체 상피세포층의 원주에서 상피세포층의 미란이나 궤양 이 차지하는 부분을 백분율로 표시한 것으로 여기서 미란이란 단지 상피세포층의 탈락을 의미하며 궤양이란 상피세포층의 탈락뿐만 아니라 일부 점막하 조직의 탈락을 동반한 경우로 정의하였다. 육아조직의 두께는 기저막(basement membrane) 에서부터 염증세포와 새로 형성된 혈관이 분포되어 있는 부분 까지의 비정상적인 점막하 조직의 두께를 mm 단위로 측정하 였다. 염증세포의 침윤 정도는 스텐트가 삽입되지 않았던 부 Fig. 2. Fluoroscopic image obtained after stent (arrows) placement in a canine trachea. The lower margin of the stent is located 3-cm apart from the carina. Fig. 3. Gross findings and locations of tissue samples for histologic examinations. The longitudinally opened trachea matches the schematic figure showing the location of tissue samples obtained from the mid-portion of the bare part (1) and covered part (2). 235
Table 1. Pathologic Findings in the Trachea of 13 Sacrificed Dogs 12 Weeks Following Stent Placement Epithelial erosion/ulcer (%) DS CS p-value Bare part 66.4311.80 51.0028.81 0.28 Covered part 62.8619.76 45.0027.39 0.22 Granulation tissue thickness (mm) DS CS p-value Bare part 3.631.33 4.370.38 0.37 Covered part 1.750.59 2.780.13 0.17 Inflammatory cell infiltration (Grade 15)* DS CS p-value Bare part 4.430.53 3.800.45 0.06 Covered part 4.290.76 3.801.30 0.55 Note. Results are reported as mean standard deviation DS = drug stent (paclitaxel-eluting stent), CS = control stent. * Grade 1 = mild, Grade 2 = mild to moderate, Grade 3 = moderate, Grade 4 = moderate to severe, and Grade 5 = severe. 236 Fig. 4. Cumulative drug release curve from paclitaxel-eluting covered stent.
대한영상의학회지 2005;52:233-240 drugs; 약제를 스텐트 표면에 흡착시키는 것)과 약제방출성 코팅(eluting matrices; 각종 폴리머에서 방출) 방식을 이용한 국소적 약물 전달 방식은 표적 조직에서 부작용 없이 국소적 인 치료 목적의 약물 효과를 발휘하는 것으로 알려져 있고 관 상 동맥이나 말초 동맥에서 활발히 연구되고 임상적으로도 활 용되고 있다(15, 17). 이처럼 관상동맥이나 말초동맥에서 신생내막증식을 줄이기 위해 paclitaxel이 활용되고 있으나 비혈관 장기에서의 활용은 매우 제한적이었다. Kalinowski 등(18)은 human epithelial gallbladder cell, human fibroblasts, 그리고 pancreatic carcinoma cell을 이용하여 paclitaxel이 세포 증식에 용량 반응 저해(dose-dependent inhibition)를 유도하는 것으로 보고하 텐트 철선 사이에 생기는 조직과증식의 형성은 특히 양성 기 관 기관지 협착 환자에서 비교적 흔하며 스텐트 재협착을 쉽 게 조장하기도 한다(4, 6, 8, 13). Paclitaxel은 임상적으로 강력한 항암제로 쓰이고 있는 약제 이다. 항암 기전은 미세소관(microtubule)의 조립 (assembly) 을 증진시키고 일단 형성된 미세소관을 안정화시켜 중합 (polymerization) 상태로 남아있게 하는 역할을 하여 결과적 으로 세포 분열이 세포 주기의 특히 G2 / M기에서 방해를 받 는 것으로 난소암, 유방암 및 폐암에서 주로 쓰이고 있다(1416). 전신적으로 paclitaxel을 투여하게 될 때 골수 억제, 심혈 관계 문제 또는 말초 신경병증 등과 같은 가능한 부작용 등이 보고되었다(15). 반면 스텐트를 통한 고정 코팅 (immobilized A B C D Fig. 5. Microscope findings of representative pathologic specimens (H & E, 40). A. Bare part of the paclitaxel-eluting stent. B. Bare part of the control stent. C. Covered part of the paclitaxel-eluting stent, and (D) Covered part of the control stent. The granulation tissue thickness (calibers) of the paclitaxel-eluting stents is slightly less than that of the control stents in either bare part or covered part. 237
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2002;105:1883-1886 12. Shin JH, Song HY, Choi CG, Yuk SH, Kim JS, Kim YM, et al. Tissue hyperplasia: influence of a paclitaxel-eluting covered stent-- preliminary study in a canine urethral model. Radiology 2005; 234:438-444 13. Hwang JC, Song HY, Kang SG, Suh JH, Ko GY, Lee DH, et al. Covered retrievable tracheobronchial hinged stent: an experimental study in dogs. J Vasc Interv Radiol 2001;12:1429-1436 1. Miyazawa T, Yamakido M, Ikeda S, Furukawa K, Takiguchi Y, 14. Klauber N, Parangi S, Flynn E, Hamel E, D Amato RJ. Inhibition Tada H, et al. Implantation of ultraflex nitinol stents in malignant of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 1997;57:81-86 tracheobronchial stenoses. Chest 2000;118:959-965 2. Shin JH, Kim SW, Shim TS, Jung GS, Kim TH, Ko GY, et al. 15. Dhanikula AB, Panchagnula R. Localized paclitaxel delivery. Int J Malignant tracheobronchial strictures: palliation with covered retrievable expandable nitinol stent. J Vasc Interv Radiol 2003;14: Pharm 1999;183:85-100 16. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1525-1534 1995;332:1004-1014 3. Monnier P, Mudry A, Stanzel F, Haeussinger K, Heitz M, Probst R, 17. Herdeg C, Oberhoff M, Karsch KR. Antiproliferative stent coatings: Taxol and related compounds. Semin Interv Cardiol 1998;3: et al. The use of the covered Wallstent for the palliative treatment of inoperable tracheobronchial cancers. A prospective, multicenter 197-199 study. Chest 1996;110: 1161-1168 18. Kalinowski M, Alfke H, Kleb B, Durfeld F, Wagner JH. Paclitaxel 4. George PJ, Irving JD, Khaghani A, Dick R. Role of the Gianturco inhibits proliferation of cell lines responsible for metal stent obstruction: possible topical application in malignant bile duct ob- expandable metal stent in the management of tracheobronchial obstruction. Cardiovasc Intervent Radiol 1992;15:375-381 structions. Invest Radiol 2002;37:399-404 5. Song HY, Shim TS, Kang SG, Jung GS, Lee DY, Kim TH, et al. 19. Song D, Wientjes MG, Au JL. Bladder tissue pharmacokinetics of Tracheobronchial strictures: treatment with a polyurethane-covered retrievable expandable nitinol stent--initial experience. intravesical taxol. Cancer Chemother Pharmacol 1997;40:285-92 20. Coppit G, Perkins J, Munaretto J, Nielsen R, McKinney L, Ulnick Radiology 1999;213:905-912 K. The effects of mitomycin-c and stenting on airway wound healing after laryngotracheal reconstruction in a pig model. Int J Pediatr 6. Zakaluzny SA, Lane JD, Mair EA. Complications of tracheobronchial airway stents. Otolaryngol Head Neck Surg 2003;128:478-488 Otorhinolaryngol 2000;53:125-135 7. Filler RM, Forte V, Chait P. Tracheobronchial stenting for the 21. Rubin P, Soni A, Williams JP. The molecular and cellular biologic treatment of airway obstruction. J Pediatr Surg 1998;33:304-311 basis for the radiation treatment of benign proliferative diseases. 8. Kim JH, Shin JH, Shim TS, Hong SJ, Ko GY, Lim JO, et al. Results Semin Radiat Oncol. 1999;9:203-214 of temporary placement of Covered retrievable expandable nitinol 22. Mayoral W, Fleischer D, Salcedo J, Roy P, Al-Kawas F, Benjamin stents for tuberculous bronchial strictures. J Vasc Interv Radiol S. Nonmalignant obstruction is a common problem with metal 2004;15:1003-1008 stents in the treatment of esophageal cancer. Gastrointest Endosc 9. Hong MK, Kornowski R, Bramwell O, Ragheb AO, Leon MB. 2000;51:556-559 Paclitaxel-coated Gianturco-Roubin II (GR II) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model. 23. Kurkinen M, Vaheri A, Roberts PJ, Stenman S. Sequential appearance of fibronectin and collagen in experimental granulation tissue. Lab Invest 1980;43:47-51 Coron Artery Dis 2001;12:513-515 10. Park SJ, Shim WH, Ho DS, Raizner AE, Park SW, Hong MK, et al. 24. Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. A paclitaxel-eluting stent for the prevention of coronary restenosis. Determination of paclitaxel and metabolites in mouse plasma, tissues, urine and faeces by semi-automated reversed-phase high-per- N Engl J Med 2003;348:1537-1545 11. Liistro F, Stankovic G, Di Mario C, Takagi T, Chieffo A, Moshiri S, formance liquid chromatography. J Chromatogr B Biomed Appl. et al. First clinical experience with a paclitaxel derivate-eluting 1995;664:383-391 polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation 239
Influence of a Paclitaxel-eluting Expandable Metallic Stent on Tissue Hyperplasia: An Experimental Study in a Canine Tracheal Model 1 Ji Hoon Shin, M.D., Jung-Sun Kim, M.D. 2, Tae-Hyung Kim, M.S., Eun-Young Kim, M.S., Won-Chan Choi, B.S., Chul-Woong Woo, B.S., Soon Hong Yuk, Ph.D. 3, Yong-Seok Lee, M.D. 4, Zhenhai Di, M.D., Ho-Young Song, M.D. 1 Departments of Radiology, Asan Medical Center, University of Ulsan College of Medicine 2 Departments of Pathology, Asan Medical Center, University of Ulsan College of Medicine 3 Department of Polymer Science and Engineering, Hannam University, College of Engineering 4 Department of Radiology, Wonkwang University College of Medicine Purpose: To evaluate the efficacy of a paclitaxel-eluting expandable metallic stent in reducing tissue hyperplasia following stent placement in a canine tracheal model. Materials and Methods: Nine paclitaxel-eluting stents (drug stent, DS) consisting of a proximal bare part and a distal polyurethane-covered part were placed in the trachea of nine dogs and nine control stents (control stent, CS) were placed in the other nine dogs. The dogs were scheduled to be sacrificed 12 weeks after stent placement. Gross and histological factors, such as epithelial erosion/ulcer, granulation tissue thickness and inflammatory cell infiltration were evaluated after each dog was sacrificed. Results: There were no procedure-related complications or malpositioning of any of the stents. One CS migrated less than eight weeks following stent placement. Four dogs (one DS and three CS dogs) died between three and five weeks following stent placement. Therefore, pathologic specimens were obtained from eight DS and five CS dogs. Epithelial erosion/ulcer or inflammatory cell infiltration was slightly more prominent in the DS cases than in the CS cases, in both the bare part and the covered part. However, the data was not statistically significant. Granulation tissue thickness was lower in the DS cases than in the CS cases in both the bare part (mean, 3.63-mm vs. 4.37-mm) and the covered part (mean, 1.75-mm vs. 2.78 mm), but the data was also statistically insignificant. Conclusion: Although the data was not statistically significant, placement of paclitaxel-eluting expandable metallic stent demonstrates a tendency toward a decrease in granulation tissue thickness in canine tracheal models. Index words : Drug, effects Stents and prostheses Trachea, interventional procedure Address reprint requests to : Ho-Young Song, M.D., Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea. Tel. 82-2-3010-4370 Fax. 82-2-476-0090 E-mail: hysong@amc.seoul.kr 240