620 Injectable poly(DL-lactide-co-glycolide) microsphere: Preliminary study for endoscopic urological surgery

617 ATRASENTAN PRESENTING PROSTATE

DELAYS DISEASE WITH METASTATIC CANCER

Schulman C.‘, Deamaley A.O, Sleep D.h ‘HBpital Marsden Medical Pretoria, 6Abbott

D.2, Zonnenberg

PROGRESSION HORMONE

B.‘, Coetzee L.4, Hulting

IN MEN REFRACTORY S.‘, lsaacson J.5, Allen

Erasme Univ. Clinic Brussels: Department of Urology. Bmssels~ Belgium, 2Royal Hospital, Sutton - London, United Kingdom, 3UMCU Utrecht, Department of Oncology, Utrecht, The Netherlands, ‘Pretoria Hospital, Department of Urology, South Africa, iAbbott International, Department of Statistics, Illinois, United States, International, Department of Oncology, Illinois, United States

INTRODUCTION & OBJECTIVES: Atrasentan is a potent, selective endothehn A receptor (ET,R) antagonist under investigation for the treatment of men with hormone refractory prostate cancer (HRPC). In two double-blind placebo-controlled studies in men with metastatic HRPC, atrasentan has been shown to prolong disease progression on per-protocol analyses. Tumour-derived endothelin 1, acting via the ET,R, stimulates the osteoblast to proliferate and secrete growth factors that, in turn. drives local tumour cell proliferation. The objective of this analysis was to test the hypothesis that patients with metastases within bone respond better to atrasentan than those without bone metastases.

P35 FEMALEUROLOGY:FROMBENCHTO BEDSIDE Friday, 26 March, 15.45-17.15, Hall I/ Blue level RESTORATION OF SPHINCTER AUTOGRAFTS

OF FUNCTIONAL INJURY

Yiou R., Zini L., Hoznek Hospital

Henri

BY

A., Abbou

Mondor,

C., Chopin

Department

618

MOTOR MUSCLE

UNITS IN A RAT PRECURSOR

MODEL CELL

D., Atala A.

of Urology,

Crkteil,

France

INTRODUCTION & OBJECTIVES: Urinary incontinence is a debilitating condition that affects primarily elderly individuals. One major mechanism results from chronic denervation of the striated urethral sphincter with associated fibrosis. We investigated the fate of muscle precursor cells (mpc) injected into a model of striated urethral sphincter injury that reproduces the histopathological changes of sphincter insufficiency.

MATERIAL & METHODS: An exploratory analysis of data from a phase 111randomized, placebo controlled study of atrasentan in metastatic HRPC @=X09) was undertaken using Cox proportional hazard modelling in four subgroups of patients: 1) Panents with evidence of any metastases; 2) those with bone m&stases; 3) those with no bone metastases and 4) those with metastases exclusively to bone at baseline. Hazard ratios (HR) for the probability of progression on atrasentan relative to placebo were generated for each subgroup.

MATERIAL & METHODS: The striated urethral sphincter of older male rats was damaged by electrocoagulation. Mpc were isolated from limb myofibre explants, infected with an adenovirus carrying the transgene encoding fl-galactosidase, and injected into the sphincter of the same animal 37 days after injury. Animals were sacrificed 5 and 30 days after injection for assessment of sphincter function and the formation of motor units.

RESULTS: A total of 780 patients were included in the study with evidence of baseline mctastases. 1n this cohort, &as&an resulted in a statistically significant delay in time to disease progression (HR = 1.23, 95% confidence interval [CI] = 1.05 to 1.44, p = 0.013). In the subgroup of patients presenting with baseline bone m&stases evidenced by a positive bone scan (N=683), atrasentan treated patients were less likely to experience disease progression (HR = 1.24, 95% CI = 1.05 to 1.48, p = 0.013) whereas in patients with no evidence ofbone metastases (N=l19), there was no difference in disease progression between treatment groups (HR = 0.72, 95% CI = 0.47 to 1.12, p = 0.142). The beneficial effect of atrasentan on delayed disease progression was most apparent in the 473 patients with m&stases exclusive to bone at baseline (HR = 1.40, 95% CI = 1.14 to 1.72, P = 0.002). in whom the probability of remaining progression free at 6 months was 33.9% compared to 24.5% for placebo.

RESULTS: Electrocoagulation resulted in an irreversible destruction of both sphincteric myo’iibres and nerve endings, with a functional incapacity of the damaged sphincter to sustain an increase in bladder pressure; atrophy and fibrosis developed after one month. Injection of mpc resulted in the formation of p-galactosidase-expressing myotubes in the sphincter that persisted beyond 30 days. The regenerated myotubes carried acetylcholine receptors associated with a nerve ending, and were thus considered to form anatomic motor units. Urodynamic studies confirmed the restoration of 41% of sphincter function one month after mpc injection.

CONCLUSIONS: In men with demonstrable m&static HRPC, treatment with atrasentan resulted in a significant delay in disease progression. Patients presenting with bone m&stases achieved a significantly better response to atrasentan than those without bone metastases, and the greatest delay in disease progression resulting from atrasentan treatment was observed in men with only bone m&stases. These findings suggest that atrasentan may provide significant benefit to patients with HRPC metastatic to bone.

CONCLUSIONS: We showed that mpc isolated from limb muscles of an older animal can recapitulate a myogenic program when injected into an irreversibly injured

sphincter.

fimctional

The maturation

motor

of mpc activates

nerve

regeneration

and restores

units.

619 THE REGENERATION SPHINCTER INVOLVES CELLS

PROCESS OF AVTIVATION

Yiou R., Chopin

C., Atala A.

Hospital

Henri

D., Abbou Mondor,

Department

of Urology,

THE OF

STRIATED INTRINSIC

Crkteil,

URETHRAL SATELLITE

France

INTRODUCTION & OBJECTIVES: The regeneration of adult skeletal muscle is mediated by satellite cells (SC). These have been considered classically to be somitically derived cells that colonize the limbs during early embryogenesis. The striated urethral sphincter presents specific developmental characteristics that distinguish it from skeletal muscles, such as the non-somitic origin of its precursor cells and the late formation of its myofibres. This prompted us to determine whether the striated urethral sphincter can regenerate after injury according to the same mechanism as skeletal muscles. MATERIAL & METHODS: The single myofibre explant culture technique was used to investigate the presence of SC in the striated urethral sphincter of male mice and to evaluate their ability to recapitulate a myogenic program. In addition, a myotoxic substance (notexin) was injected into the sphincter in order to provoke a rapid destruction of the myofibres; the regeneration process was studied by means of electrophysiological and histological techniques. RESULTS: Satellite cells expressing pax7 were found attached to the sphincteric myofibres. They proliferated and expressed MyoD, Myf5 and desmin after two days in culture. After ten day, they formed multinucleated myotubes expressing alpha-actinin-2. In viva, complete recovery of the striated urethral sphincter, as assessed by normalization of muscle strength and of myofibre number and diameter, was observed after three weeks; and resulted from the fusion of myogenic cells. CONCLUSIONS: These results demonstrate that the striated urethral sphincter can regenerate according to a myogenic program involving intrinsic SC. The therapeutic implications of this knowledge and the possible origin of the sphincteric SC will be discussed.

620 INJECTABLE PRELIMINARY

POLY(DL-LACTIDE-CO-GLYCOLIDE) STUDY FOR ENDOSCOPIC

Cho Y.S.‘,

Moon

H.C.‘:

Park H.J.l,

Kwon

C.H.’

Cho U.R.‘,

MICROSPHERE: UROLOGICAL SURGERY

Kang S.U.2, Kim B.S.‘,

Han J.H.3, Joo K.J.',

‘Sungkyunkwan University School of Medicine, Department of Urology, Seoul, South Korea; 2Hanyang University. Department of Chemical Engineering, Seoul. South Korea, ?+nglcyunkwan University School of Medicine, Department of Pathology, Seoul, South Korea

INTRODUCTION collagen

or silicone

& OBJECTIVES: Injection of polytetrafluoroethylene has been used in the endoscopic treatment of urinary

or vesicoureteral reflux. Although the principle of endoscopic are concerns regarding the long-term safety and effectiveness

treatment

(Teflon), incontinence

is valid, there

of these substances human. We developed a composite of biomaterial, Poly(DL-lactide-co-glycolide) (PLGA) microsphere, and evaluated the possibility of applying PLGA microsphere human with animal model.

MATERIAL

& METHODS:

We made an injectable

form of PLGA composite

in in

mixed

with carboxymethyl cellulose gel. Six New Zealand White rabbits were used. Each rabbit was injected O.lml of PLGA composite, O.OSml of PLGA and 0.05ml of carboxymethyl cellulose gel, at five sites in the muscular layer of bladder. Rabbits were sacrificed two weeks and five weeks after injection and bladder, liver, spleen, lung, kidney were harvested. Each injection site was analyzed grossly and histologically.

RESULTS:

All rabbits

were healthy

after injection

and there were no complications

until being sacrificed. Histologically inflammatory reaction by eosinophils and lymphocytes infiltration at the injected sites was observed at 2 weeks after injection. At 5 weeks, ingrowth of smooth muscle cells was found with the degrading PLGA microsphere by anti-a-actin immunohistochemical staining (A, B). Volume of the PLGA decreased from initial 0. lml to 0.074ml at 2 weeks and 0.034ml at 5 weeks after injection but infiltrating cells substituted injected PLGA to bulk of tissue. There was no distant metastasis, tissue necrosis or calcification.

CONCLUSIONS: Injectable PLGA microsphere is a new attempt in urologic field. It shows reasonable maintenance of volume and neotissue growth into the injection site. Further investigation of long term follow-up will show the possibility of applications of PLGA for endoscopic treatment to vesicoureteral reflux or urinary incontinence.

European

Urology

Supplements

3 (2004)

No. 2, pp. 157