Adolf Lukanovi M D Ph D Mija Blaganje

Adolf Lukanović, M. D. , Ph. D. Mija Blaganje, M. D. , Department of Gynecology and Obstetrics University Medical Centre, Ljubljana, Slovenia VI hrvatsko-slovenski simpozij o menopauzi i andropauzi, Hotel Neptun, Brijuni, 10. 09. 2011

Stress Urinary Incontinence Is the Most Common Type in Women Based on Literature Review Mixed Urge Stress Hampel C, et al. Urology. 1997; 50(suppl 6 A): 4 -14.

Urinary incontinence affect at least one in every 4 women LITERATURE REVIEWS LARGE-SCALE SURVEYS Minassian VA, et al. Int J Gynecol Obstet 2003; 82: 327 -38; Hunskaar S, et al. BJU Int 2004; 93: 324 -30; Kinchen KS, et al. J Womens Health 2003; 12: 687 -98; Hannestad YS, et al. J Clin Epidemiol 2000; 53: 1150 -7

Urinary incontinence is prevalent, bothersome …but underreported: only 31 - 45% seek help Overall rate 31% Hunskaar S, et al. BJU Int 2004; 93: 324 -30; O’Donnell M, et al. Eur Urol 2005; 47: 385 -92; Diokno AC, et al. Am J Manag Care 2004; 10: 69 -78; Diokno AC, et al. J Urol 2003; 170: 507 -11

Prevalence of urinary incontinence increases with age Hannestad YS, et al. J Clin Epidemiol 2000; 53: 1150 -7; Hunskaar S, et al. BJU Int 2004; 93: 324 -30

Next 20 years 18% increase of women > 75 years 38% increase of women > 80 years Urinary incontinence: 11. 6% > 65 years 8. 5 % < 65 years

AGE RELATED CHANGES OF PELVIC FLOOR MUSCLE Koelbl et al 1987 Obstet Gynecol

BULKING EFFECT Before application 6 o’clock after application 3 o’clock 9 o’clock

THE IDEAL BULKING AGENT PROPERTIES: Non-immunogenic Non long term side effect Permanent High safety profile Non-migratory Non-erosive Non-inflammatory Easily stored Easily injected Painless

BULKING AGENTS Teflon (Berg 1973, Politano 1974) Purified bovine collagen (Contigen) (Shortliffe 1989) Autologuos fatty tissue (Gonzales de Gariby 1989) Silicon mikroimplants (Macroplastique) (Buckley 1992) Mikrobaloons (Pycha 1998) Copolymer of non-animal stabilised hyaluronic acid and dextranomer microspheres (Zuidex/Deflux) (Sternberg 1999) Autologuos chondrocites (Bent 2000) Pyrolitic carbon coated beads (Durasphere) (Calvosa 2000) Acellular porcine collagen (Permacol) (Lightfoot 2001) Polyacrylamid gel (97, 5% water+2, 5% cross-linked polyacrylamide) Bulkamid (Chancellor 2001) Adjustable balloons (ACT) (Sauter 2002)

SYNTHETIC BULKING AGENTS IN URETHRAL TISSUE Urethral sphincter muscle augmented with Contura’s hydrogel (violet). Picture taken 3½ months after injection. Scattered macrophages appear in the gel, no surrounding foreign-body reaction - no fibrosis.

SYNTHETIC BULKING AGENTS IN URETHRAL TISSUE Bladder augmented with Bulkamid hydrogel (violet). Picture taken 14 months after injection. Gel appears as an irregular mass containing scattered macropgages which formed minute islands or a fine network within a homogeneous gel

The Bulkamid® Kit 1 optic 0˚ Light cable (not included in the kit) 1 irrigation set 2 needles 23 G 2 prefilled 1 cc. Bulkamid® syringes Bulkamid ® Cystoscope

DURASPHERE Migration after 6 months 250 -300 um Pannek , J Urol 2001: 166, 1350

Lecce 2005

CULTIVATION AND CHARACTERISATION OF MYOBLASTS Single myoblasts were manually collected with a micropipette, then clones of pure myoblasts with 100% of desmin positive muscle cells could be cultured.

MUSCLE BIOPSY ULTRASOUND GUIDED INJECTION

Skeletal muscle portion was obtained from a small open cut biopsy of the non–dominant biceps muscle

Myoblast isolation and expansion was performed in GMP cerified cell-processing laboratory Innovacell Biotechnologie AG, Innsbruck, Austria

Autologus myoblast suspension was injected under transurethral ultrasound device

THE IMPACT OF LOCALLY INJECTED STEM CELLS FOR THE TREATMENT OF FEMALE STRESS URINARY INCONTINENCE PROSPECTIVE RESEARCH TRIAL DEPARTEMENT OF GYNECOLOGY UCC LJUBLJANA INCLUSION CRITERIA v Urodinamic proven pure SUI (standard ICS protocol) v Age 50 -70 v Normal US examination v Normal status gyn. v 38 patients EXCLUSION CRITERIA v Urge incontinence v Descensus or prolaps v Any sign of inflamation v Serious sistemic diseases v Previous antiincontinence surgery

Ø UIS- amount of leaked urine measured semiquantitative Ø UIE- UI episodes count from a 3 day voiding diary Ø QOL- quality of life questionnaire Ø VAS- visual analog scale of the degree of suffering Ø PGI-I – modified patient global impression scale

Characteristics of patients treated with autologous myoblasts at baseline, at completion of preoperative ES cycle and at 6 weeks postoperatively (Myoblasts + ES) Preoperative Postoperative p Baseline ES Myoblasts + ES 38 38 37 UIE 13 (4 -41) 12 (1 -35) 5 (0 -33) <0. 0001 UIS 24 (4 -67) 18. 5 (2 -49) 5 (0 -33) <0. 0001 Stress test negative 0 1 29 <0. 0001 PGI-I cured improved unchanged 0 0 38 0 7 31 5 29 3 <0. 0001 56. 5 (28 -92) 63 (29 -99) 78 (41 -105) <0. 0001 8 (3 -10) 7 (4 -10) 3 (0 -9) <0. 0001 No. of patients I-QOL VAS The numeric variables are presented as median values (range). P values are for ES vs. Myoblasts + ES

IMPROVEMENT FROM BASELINE VAS QOL Myoblast+ES ES UIE UIS 0% 10% 20% 30% 40% 50% VAS- visual analog scale of the degree of suffering QOL- quality of life questionnaire UIE- 3 -day bladder diaries for urinary incontinence episodes UIS- amount of leaked urine measured semiquantitative 60% 70% 80%

ü The use of embrionic stem cells is limited due to unresolved medicolegal questions ü When using stem cells of adult human being there are no medicolegal dilemas

Ø TO WHAT EXTEND THE MYOBLASTS SHOULD PROLIFERATE ? Ø HOW TO PREVENT URETHRA OBSTRUCTION ? Ø WHAT WILL BE THE EFFECT OF URETHRAL HIPERMOBILITY ON THE SUCCESS OF STEM CELL THERAPY ? Ø DANGER OF MALIGNANT ALTERATION Ø ETHICAL ASPETSC AS THIS IS EXPERIMENTAL SURGERY Ø MEDICOLEGAL ASPECTS IN CASE OF FAILURE Ø COSTS Ø LEARNING CURVE FOR APLICATION

WILL STEM CELLS PRODUCE BETTER RESULTS THAT CURRENTLY AVAILABLE MEDICAL OR SURGICAL THERAPY? WHAT MORBIDITY WILL IT CAUSE ? STEM CELL THERAPY IS PROMISING. BUT BEFORE ADOPTING IT LET’S BE SURE IT WORKS WHEN COMPARED TO CURRENTLY AVAILABLE PROCEDURES AND THAT IT WON’T HARM OUR PATIENTS. WE ARE THE ONLY ONES WHO CAN PROTECT OUR PATIENTS DON OSTERGARD, IUGA ANNUAL MEETING CANCUN 2007

TAKE HOME MESSAGE URINARY INCONTINENCE should not be viewed as a normal part of aging it should be viewed as treatable

Thank you for the attention