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Will Tissue-Engineered Urinary Bladders Change Indications for a Laparoscopic Cystectomy?

Tomasz Drewa, Piotr Chlosta and Rafal Czajkowski SURG INNOV 2010 17: 295 originally published online 23 July 2010 DOI: 10.1177/1553350610375092 The online version of this article can be found at: http://sri.sagepub.com/content/17/4/295

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Will Tissue-Engineered Urinary Bladders Change Indications for a Laparoscopic Cystectomy?

Tomasz Drewa, MD, PhD, FEBU,1,2 Piotr Chlosta, MD, PhD, FEBU,3 and Rafal Czajkowski, MD, PhD1

Surgical Innovation 17(4) 295299 The Author(s) 2010 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1553350610375092 http://sri.sagepub.com

Abstract Radical open cystectomy is a treatment of choice for muscle invasive urinary bladder cancer. Laparoscopic radical cystectomy (LapRC) is surgically advanced and is an extremely difficult technique but presents many advantages. Urinary diversion (conduit, pouch or neobladder) when performed during laparoscopy necessitates a conversion to open procedure. Urinary diversion using an autologous bowel is associated with longer operative times and complications. The authors have analyzed the LapRC procedure and its 2 main partsthat is, bladder resection and urinary diversion. The emphasis was on the operative time and complications related to the urinary diversion procedure. A urinary diversion created in vitro could make the LapRC totally intracorporeal, and it could be completed within an acceptable time. Tissue engineering techniques used for urinary diversion after cystectomy shorten the operative time and help avoid serious complications related to bowel surgery. LapRC with tissue-engineered urinary diversion could become a management of choice for muscle invasive bladder cancer. Keywords laparoscopic radical cystectomy, open radical cystectomy, bowel surgery, urinary diversion, tissue engineering

Introduction
Open radical cystectomy is a gold standard treatment of muscle invasive urinary bladder cancer.1 Laparoscopy is regarded as a standard operation access in almost all procedures in urology, that is, pyeloplasty, ligation of varicocele, uretherolithotomy, including oncology (radical nephrectomy, adrenalectomy, and radical prostatectomy), with one exceptionradical cystectomy. Laparoscopic radical cystectomy (LapRC) is surgically advanced and is an extremely difficult technique, which in spite of this, presents many advantages, such as good pathological and clinical outcomes. LapRC is a considerably less-invasive procedure compared with open radical cystectomy, but the operative time is still long, regardless of the kind of urinary diversion.2-4 The urinary diversion technique using autologous bowel is associated with substantial extension of the operative time and higher complication rates. On the other hand, tremendous development in the field of tissue engineering and techniques of in vitro construction of urological organs may help overcome this barrier. Recent clinical research demonstrated the feasibility of bladder wall regeneration supported using in vitro techniques.5,6

Laparoscopic Radical Cystectomy: The Technique

Procedures are comparable between authors.7-11 The technique used by our team begins with the creation of 5 ports for 2 trocars of 5 mm and 3 trocars of 10 mm.11

Bladder Resection Part

In men, the procedure starts with dissection of seminal vesicles and the posterior surface of the prostate. Ureters are divided, and bladder ligaments and vessels are supplied with clips. Then, the procedure is continued with sectioning
1 2

Nicolaus Copernicus University, Bydgoszcz, Poland Institute of Oncology, Bydgoszcz, Poland 3 Department of Urology, Institute of Oncology, Kielce, Poland Corresponding Author: Tomasz Drewa, MD, PhD, FEBU, Tissue Engineering Department, Nicolaus Copernicus University, ul. Karlowicza 24, 85-092 Bydgoszcz, Poland Email: tomaszdrewa@wp.pl

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296 of the Retzius space, incision of pelvic fascia, dissection of the apex, and sectioning of urethra. The postoperative specimen is removed together with lymph nodes. In women, the procedure starts with dissection of uterus ligaments and the peritoneum in the Douglas cavity. The bladder with the urethra, uterus, adnexes, and anterior vaginal wall is removed transvaginally. After closing the vagina, lymph nodes are removed.

Surgical Innovation 17(4) for humans.17 We are still waiting for the results of the phase II clinical trials on tissue-engineered human urinary bladders. The main drawbacks of tissue engineering are costs of cells expanding in vitro, cell senescence during culture, and appropriate cell amount for reconstruction of such a huge organ like the human bladder.16,18 Our experience is in line with the opinion of other scientific groups that small- and medium-sized animals are both models in which bladder reconstruction is feasible and reasonable from the economical point of view.19-21 The human model is still a challenge reserved only for teams with a lot of financial support, such as the Atala Group.16 We should keep in mind that hospital procedures are covered by insurance companies. LapRC is a very involved procedure, and in the case of tissue-engineered device implantation, it would probably be very expensive. On the other hand, clinical practice says that costs can be lowered only if the innovative technique works in properly selected patients.

Urinary Diversion Part

Two kinds of urinary diversions are preferable after radical cystectomy for bladder cancer: the first one is a urinary orthotopic neobladder sewed from the bowel segment, and the second is a bowel conduit. Ureters are anastomosed to an ileal conduit or the urinary neobladder, which are performed via an open laparotomy technique. The bowel segment for urinary diversion is divided. Bowel ends are anastomosed using staples or running sutures. The neobladder is formed using absorbable running sutures from the prepared bowel segment. It is created via laparotomy but grafted using a pure laparoscopic technique. Urinary conduit made from the bowel is connected to the abdominal wall.

Future Perspective
We have analyzed the time for the LapRC procedure and its 2 main partsthat is, the bladder resection part and urinary diversion part performed in our department.11 The emphasis was on the operative time and complications related to the urinary diversion procedure. We have established the potential benefits associated with an autologous urinary diversion ex vivo created for cystectomized patients. Future research should examine whether a tissue-engineered artificial conduit or artificial neobladder for urinary diversion could help shorten the operative time for LapRC. We think that LapRC would be a management of choice for muscle invasive bladder cancer, if the total operative time was shorter than that for the open procedure and the whole procedure could be performed intracorporeally.

Tissue-Engineered Urinary Diversion After Bladder Removal

It was shown that implantation of a polymer scaffold seeded with autologous bladder cells did not show significant local or systemic toxicity.12,13 This study suggests that such tissue-engineered neobladders are safe and effective for reconstructive surgery. Engineering (in vitro creation) of a neobladder from autologous urothelial and smooth muscle cells cultured on biocompatibleeither synthetic or naturally derivedsubstrates is now feasible.14,15 An artificial bladder wall created in vitro was used for the first time in patients needing cystoplasty.16 The development of an artificial neobladder would warrant the prevention of both the metabolic and neoplastic shortcomings of the intestinal neobladder as well as early complications after cystectomy and urinary diversion. Artificial conduits for urinary diversion in a small animal model were constructed.17 Alberti and colleagues suggested a creation of simple structures like tissue engineered conduit or continent pouch when waiting for success with complete tissue-engineered bladder with a trigone-shaped base.14 It is clear that there is a need to obtain such tissue-engineered artificial bladders, pouches, and conduits for urinary diversion after LapRC. It has to be emphasized that tissue engineering is a growing discipline, and therefore data are lacking, and only small clinical series can be found in the literature. Only 7 bladders were augmented in humans with the tissue-engineered bladder wall.16 No tissue-engineered conduits were prepared

Discussion
Radical cystectomy has become the best form of therapy for invasive bladder cancer, but this procedure remains complex with potential complications.22 Open radical cystectomy is still the fastest method of bladder removal for muscle invasive cancer (Figure 1).23 Bowel complications were the major source of early morbidity after primary and salvage cystectomy. Urinary leakage occurred in 3% following radical cystectomy and 8.7% after salvage cystectomy. Bowel complications were the major cause of death following salvage cystectomy.17,22,23 In the analysis by Bostrm and coworkers,24 the total complication rate was 34%, with minor and major complications in 26% and 11% of patients, respectively. Maffezzini et al25 have noticed in a group of 107 patients that 26% who underwent radical cystectomy with intestinal urinary reconstruction experienced complications, which

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Drewa et al.

297 and open radical cystectomy performed for bladder cancer, it has to be emphasized that the mean operative time for the laparoscopic procedure, even combined with extracorporeally created urinary diversion, was longer (Figure 1).2,23 Murphy et al8 presented a mean operative time of 6.1 1.4 hours for robotic-assisted LapRC and extracorporeal urinary diversion. The mean operative time of LapRC and extracorporeal urinary diversion was 5.2 hours, as reported by Hemal et al.4 They noticed that extracorporeal urinary diversion decreases the operating time while maintaining the benefits of laparoscopic surgery. Urinary diversions with robot-assisted radical cystectomy are performed extracorporeally via a small incision because the intracorporeal procedure involves a long operative time with associated morbidity and complications.8 Deger and collegues9 presented 12 patients who received rectosigmoid pouches for urinary diversion performed completely laparoscopically (entire procedure was intracorporeal). The median operating time was more than 8 hours (Figure 1).9 It should be mentioned that this study was undertaken by a leading center in laparoscopic surgery. We have analyzed the operative time for LapRC.11 The mean time of the surgery in our cases was 4.8 (4.5-5.7 hours). The time for cystoprostatectomy and lymphadenectomy (bladder resection part in men) was 1.8 hours (1.3-2.0). The time for cystohysterectomy and lymphadenectomy (bladder resection part in women) was 1.8 hours. The time for conduit creation (urinary diversion part) was 2.7 hours (2.3-3.0). The time for orthotopic neobladder creation (urinary diversion part) is almost 4 hours (3.5-4.2). Stress has to be laid on the fact that a short time of bladder resection does not guarantee a short time for the whole procedure of LapRC (Figure 2). We hypothesized that the tissue-engineered construct needs to be only sutured and because of this, the procedure time can be substantially shortened (Figure 2). LapRC is associated with morbidity largely resulting from the urinary diversion procedure, which, in fact, cannot be completed intracorporeally. The future of pure LapRC (including robot-assisted procedures) with intracorporeal reconstruction of the urinary tract using bowel segments does not look so optimistic.8,9,27 Our experience with open and LapRC techniques shows that the operating time is a crucial factor influencing the choice of method of treatment. The total operative time of LapRC is similar when comparing between centers, but it has to be shortened. We think, based on our experience, that the time taken for the bladder resection part is now as short as possible, and nothing revolutionary can be done regarding this part of the operation. One has to shorten the time for the urinary diversion procedure, and considering all aspects of the procedure, this appears to be feasible (Figure 2). Tissue-engineered constructs used for urinary diversion can really shorten the operative time and help omit bowel complications. An artificial bladder wall created in vitro was used in clinical experiments

Figure 1. The mean operative time of selected methods of cystectomies: an open procedure (open) according to Porpiglia et al,26 laparoscopic with extracorporeal creation of urinary diversion (laparoscopy [Lap] + open diversion) by Hemal et al,4 (robot assisted) by Murphy et al,8 and pure laparoscopic procedure (pure laparoscopy) where all parts of the procedure were performed intracorporeally by Deger et al9

led to relaparotomy in 10% of patients. The mortality rate was 3.7%.25 Anastomotic leak, bowel obstruction, or sepsis requiring reexploration developed in 29% of patients in the series presented by Haber and colleagues.10 Postoperative ileus was observed in 23% of patients who underwent radical cystectomy with urinary diversion in the study presented by Park and coworkers.26 In our series of 47 patients, 43 procedures were performed laparoscopically, but in 4 cases, because of technical difficulties, conversion to the standard, open technique was necessary. Sigmoid colon injury was found in 1 case but was treated by laparoscopic suturing. In 6 cases, a short-term paralytic ileus was found on the second day after surgery. One patient developed leakage of ileal anastomosis on the sixth day after the operation. The patient was operated successfully using the laparotomy technique.11 Ramani et al27 have stated that the contemporary standards for 1- and 2-month mortality rates for radical cystectomy are 0.4% and 2.6%, respectively.27 It can be concluded that bowel complications although not frequent should still be taken into consideration when cystectomy is offered as a treatment choice. Artificial and prepared in vitro conduit or neobladder allow spare bowel continuity, and because of this, the complication rate related to the bowel can be minimized theoretically to zero. In attempts to decrease the morbidity, minimally invasive techniques have been used for both the extirpative as well as the reconstructive portions of the procedure. Although a completely intracorporeal approach is technically feasible, it has been associated with significant increases in operative times and perioperative complications.7,9 The usual method is performing the urinary diversion portion of the procedure extracorporeally, after laparoscopic removal of the bladder.1,7,8,10,11,28 When comparing the results of laparoscopic

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Surgical Innovation 17(4)

Figure 2. Hypothetical shortening of the operative time if tissue-engineered (TE) urinary diversions were used in the cystectomy procedure (laparoscopy [Lap]+ conduit: laparoscopic cystectomy performed with extracorporeal conduit creation; laparoscopy + bladder: laparoscopic cystectomy performed with extracorporeal neobladder creation; laparoscopy + TE conduit: laparoscopic cystectomy performed with tissue-engineered conduit implantation; laparoscopy + TE bladder: laparoscopic cystectomy performed with tissue-engineered neobladder intracorporeal implantation). Operative times of laparoscopy + conduit and laparoscopy + bladder are real operating times. Laparoscopy + TE conduit and laparoscopy + TE bladder are both hypothetical

for cystoplasty. Conduits for urinary diversion can be constructed in a manner similar to that used for the artificial urinary bladder wall and can be used for laparoscopically cystectomized patients. It can be speculated that the procedure time could be reduced to 2.5 to 3 hours instead of 4.5 hours (Figure 2). Tissue-engineered autologous conduits or neobladders created in vitro have several advantages: they facilitate performing LapRC in an acceptable amount of time, help avoid early and late complications related to bowel surgery, and finally make the LapRC totally intracorporeal, within reach of the surgeon. All these advantages should prompt us to consider LapRC as a treatment of choice for muscle invasive bladder cancer in selected patients.

create a urinary conduit, pouch, or even the whole bladder and then used as a urinary diversion after LapRC. This strategy will shorten the operative time and make it possible to perform the whole operation intracorporeally within an acceptable time. A tissue-engineered urinary bladder wall when used to construct a urinary diversion after urinary resection should allow LapRC to be regarded as a treatment of choice for muscle invasive bladder cancer. Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The author(s) received no financial support for the research and/ or authorship of this article.

Conclusions
Open radical cystectomy is a method of choice in the management of muscle invasive bladder cancer, but LapRC is less invasive when compared with open radical cystectomy. The urinary diversion part is the main reason for converting the procedure into an open one because of bowel preparation and dissection. LapRC is surgically feasible, but the operative time is still too long for the urinary diversion part. The autologous urinary bladder wall was constructed in vitro and used in a human cystoplasty operation, and this artificial (in vitro constructed) bladder wall can be used to

References
1. Huang GJ, Stein JP. Open radical cystectomy with lymphadenectomy remains the treatment of choice for invasive bladder cancer. Curr Opin Urol. 2007;17:369-375. 2. Hemal AK, Kolla SB. Comparison of laparoscopic and open radical cystoprostatectomy for localized bladder cancer with 3-year oncological follow-up: a single surgeon experience. J Urol. 2007;178:2340-2343. 3. Guillotreau J, Gam X, Mouzin M, et al. Radical cystectomy for bladder cancer: morbidity of laparoscopic versus open surgery. J Urol. 2009;181:554-559.

Downloaded from sri.sagepub.com at CALIFORNIA DIGITAL LIBRARY on June 19, 2011

Drewa et al.
4. Hemal AK, Kolla SB, Wadhwa P, Dogra PN, Gupta NP. Laparoscopic radical cystectomy and extracorporeal urinary diversion: a single center experience of 48 cases with three years of follow-up. Urology. 2008;71:41-46. 5. Roth CC, Kropp BP. Recent advances in urologic tissue engineering. Curr Urol Rep. 2009;10:119-125. 6. Wood D, Southgate J. Current status of tissue engineering in urology. Curr Opin Urol. 2008;18:564-569. 7. Irwin BH, Gill IS, Haber GP, Campbell SC. Laparoscopic radical cystectomy: current status, outcomes, and patient selection. Curr Treat Options Oncol. 2009;10:243-255. 8. Murphy DG, Challacombe BJ, Elhage O, et al. Roboticassisted laparoscopic radical cystectomy with extracorporeal urinary diversion: initial experience. Eur Urol. 2008; 54:570-580. 9. Deger S, Peters R, Roigas J, Wille AH, Tuerk IA, Loening SA. Laparoscopic radical cystectomy with continent urinary diversion (rectosigmoid pouch) performed completely intracorporeally: an intermediate functional and oncologic analysis. Urology. 2004;64:935-939. 10. Haber GP, Campbell SC, Colombo JR Jr, et al. Perioperative outcomes with laparoscopic radical cystectomy: pure laparoscopic and open-assisted laparoscopic approaches. Urology. 2007;70:910-915. 11. Chlosta P, Drewa T, Dobruch J, et al. Is pure laparoscopic radical cystectomy still an attractive solution for the treatment of muscle-invasive bladder cancer? [published online ahead of print April 8, 2010]. Urol Int. doi:10.1159/ 000310349. 12. Kwon TG, Yoo JJ, Atala A. Local and systemic effects of a tissue engineered neobladder in a canine cystoplasty model. J Urol. 2008;179:2035-2041. 13. Jayo MJ, Jain D, Ludlow JW, et al. Long-term durability, tissue regeneration and neo-organ growth during skeletal maturation with a neo-bladder augmentation construct. Regen Med. 2008;3:671-682. 14. Alberti C, Tizzani A, Piovano M, Greco A. Whats in the pipeline about bladder reconstructive surgery? Some remarks on the state of the art. Int J Artif Organs. 2004;27: 737-743. 15. Frimberger D, Lin HK, Kropp BP. The use of tissue engineering and stem cells in bladder regeneration. Regen Med. 2006;1:425-435.

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16. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissueengineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241-1246. 17. Drewa T. The artificial conduit for urinary diversion in rats: a preliminary study. Transplant Proc. 2007;39:1647-1651. 18. Azzarello J, Kropp BP, Fung KM, Lin HK. Age-dependent vascular endothelial growth factor expression and angiogenic capability of bladder smooth muscle cells: implications for cell-seeded technology in bladder tissue engineering. J Tissue Eng Regen Med. 2009;3:579-589. 19. Drewa T, Sir J, Czajkowski R, Woniak A. Scaffold seeded with cells is essential in urothelium regeneration and tissue remodeling in vivo after bladder augmentation using in vitro engineered graft. Transplant Proc. 2006;38:133-135. 20. Drewa T, Adamowicz A, ysik J, Polasik J, Pielichowski J. Chitosan scaffold enhances nerve regeneration within the in vitro reconstructed bladder wall, an animal study. Urol Int. 2008;81:330-334. 21. Drewa T, Joachimiak R, Kaznica A, Sarafian V, Sir J. Primary cultures from rat vibrissae as potential cell source for in vitro construction of urinary bladder wall grafts. Transplant Proc. 2009;41. 22. Buscarini M, Pasin E, Stein JP. Complications of radical cystectomy. Minerva Urol Nefrol. 2007;59:67-87. 23. Porpiglia F, Renard J, Billia M, et al. Open versus laparoscopyassisted radical cystectomy: results of a prospective study. J Endourol. 2007;21:325-329. 24. Bostrm PJ, Kssi J, Laato M, Nurmi M. Risk factors for mortality and morbidity related to radical cystectomy. BJU Int. 2009;103:191-196. 25. Maffezzini M, Campodonico F, Canepa G, Gerbi G, Parodi D. Current perioperative management of radical cystectomy with intestinal urinary reconstruction for muscle-invasive bladder cancer and reduction of the incidence of postoperative ileus. Surg Oncol. 2008;17:41-48. 26. Park HK, Kwak C, Byun SS, Lee E, Lee SE. Early removal of nasogastric tube after cystectomy with urinary diversion: does postoperative ileus risk increase? Urology. 2005;65:905-908. 27. Ramani VA, Bromage SJ, Clarke NW. A contemporary standard for morbidity and outcome after radical cystectomy. BJU Int. 2009;104:628-632. 28. Hemal AK. Role of robot-assisted surgery for bladder cancer. Curr Opin Urol. 2009;19:69-75.

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