Abstract

Materials & Methods

Patients In the present study, 9 patients with SUI following radical prostatectomy and 2 patient with SUI after HoLEP were enrolled. The inclusion criteria for the patients undergoing radical prostatectomy for prostate cancer was as follows: 1. Persistence of moderate to severe urinary incontinence for more than two years after surgery 2. Curable resection at radical prostatectomy with cap(-) and negative surgical margin 3. No evidence of recurrence or metastasis of prostate cancer with undetectable levels of prostate-specific antigen

Harvesting adipose tissue and isolation of ADRCs After liposuction of 250 ml of adipose tissue from the anterior abdominal wall, ADRCs were isolated from the harvested adipose tissue by using the CelutionTM system. Briefly, adipose tissue was introduced into the CelutionTM cell-processing device which automatically and aseptically extracts and concentrates the mononuclear fraction of adipose tissue and removes unwarranted or deleterious cells, cell and matrix fragments. It required around 1 hour to process 250 mL of liposuction tissue. The final concentrated cell output collected using the CelutionTM System was counted using a NucleoCounter (Chemometec, Denmark), which exclusively detected nucleated cells. By using the CelutionTM system, we could finally obtain a 5 mL solution containing concentrated ADRCs.

The present study was approved by the Ethics Committee of Nagoya University Graduate School of Medicine, and also by the Japanese Ministry of Health, Labor and Welfare. Written informed consent was obtained from the patients.

Outcome measures 1. amount of incontinence: The 24-hour pad test was consecutively repeated for

4 days for each evaluation period. The total daily leakage amount was calculated as mean during 4 days at each period.

2.Subjective symptoms and QOL: evaluated using a validated disease-specific

questionnaire—the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF)

3. The urethral sphincter function: objectively assessed by measuring the urethral

pressure profile; maximum urethral closing pressure (MUCP) and functional profile length (FPL).

4. Blood flow to the area where ADRCs were injected: assessed by contrast-enhanced transrectal ultrasonography by intravenously injecting perflubutane.

5.Morphological condition of the injected area: monitored by magnetic resonance imaging (MRI). 5.Adverse events 6.Uroflowmetry and measure of residual urine volume

Patients’ characteristics and outcomes on isolation and injection of ADRCs

HoLEP: holmium laser enucleation of the prostate, RP: radical prostatectomy, SD: Standard deviation

4 days

Before injection

Advantage Our treatment strategy has an important advantage over

the use of other stem cells. 1.Since adipose tissue contains abundant multipotent

regenerattive cells as well as key mature cells and progenitor cells, therapeutic levels of ADRCs can be obtained rapidly using the CelutionTM system.

2.Unlike other cell therapy strategies, the treatment is all autologous, requires no cell culture and is performed in the context of a single surgical procedure.

1.A bulking effect produced by the injected adipose tissue fraction mixed with ADRCs

(Persistent bulking effect indicates the survival and growth of the injected adipose tissue, which could also be attributed to the presence of ADRCs).

2.Differentiation of injectied cells into mature adipose tissue and possibly into contractile cells.

3. Increased blood flow due to angiogenesis effect of the cytokines secreted by the injected ADRCs. (The increased blood flow might have a positive effect on the regeneration of the injected adipose tissue and impaired intrinsic sphincteric function).

Possible mechanisms for the ADRC-mediated improvement of the sphincteric function

Conclusions

Our preliminary study demonstrated that periurethral injection of the autologous adipose-derived regenerative cells is a safe and feasible treatment modality for stress urinary incontinence.

265 Periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: Outcome of preliminary clinical trial

Gotoh M1, Yamamoto T1, Matsukawa Y1, Toriyama K2, Kamei Y2, Funahashi Y1 Department of Urology1 and Plastic & Reconstructive Surgery2, Nagoya University Graduate School of Medicine, Nagoya, Japan

Objectives: To assess the efficacy and safety of a novel cell therapy for male stress urinary incontinence consisting of periurethral injection of autologous adipose-derived regenerative cells, and to determine the 1-year outcomes. Methods: Eleven male patients with persistent stress urinary incontinence after prostate surgery were included in the study. The CelutionTM system was used to isolate adipose-derived regenerative cells from abdominal adipose tissue obtained by liposuction. Subsequently, these regenerative cells and a mixture of regenerative cells and adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. One-year outcomes were assessed using a 24-hour pad test, a validated patient questionnaire, urethral pressure profile, transrectal ultrasonography, and magnetic resonance imaging. Results: Stress urinary incontinence improved progressively in 8 patients during the 1-year follow-up, as determined by a 59.8% decrease in the leakage volume in the 24-hour pad test, decreased frequency and amount of incontinence, and improved quality of life. One patient achieved total continence. Mean maximum urethral closing pressure and functional profile length increased from 35.5 to 44.7 cmH2O and from 20.4 to 26.0mm, respectively. Magnetic resonance imaging showed the sustained presence of the injected adipose tissue, and enhanced ultrasonography demonstrated a progressive increase in blood flow to the injected area in all patients. No significant adverse events were observed peri- or postoperatively. Conclusion: The results of this preliminary study showed that periurethral injection of autologous adipose-derived regenerative cells is a safe and feasible treatment modality for male stress urinary incontinence.

To assess the efficacy and safety of a novel cell therapy for male stress urinary incontinence consisting of periurethral injection of autologous adipose-derived regenerative cells, and to determine the 1-year outcomes.

Objectives

Unimproved (n=3): 441.8 to 473.7g (+9.5%)

All (n=11): 288.1 to 202.3g (-40.9%)

Improved (n=8): 230.4 to 100.5g (-59.8%)

All (n=11) 35.5 to 44.7 cmH2O (+38.8%) Improved (n=8) 36.1 to 45.5 cmH2O (+41.3%) Unimproved (n=3) 34.0 to 42.7 cmH2 (+32.0%)

All (n=11) 20.0 to 26.0 mm(+46.1%) Improved (n=8) 19.4 to 26.8 mm (+53.1%) Unimproved (n=3) 23.0 to 24.0 mm (+5.5%)

MUCP

FPL

Changes in leakage amount: 24-hour pad test

Changes in MUCP and FPL

Changes in Subjective Symptoms and QOL (ICIQ-SF)

Blood flow at the injection site evaluated by transrectal enhanced ultrasonography

Changes in post-void residual urine

Changes in injected adipose tissue on MRI

Results

The bladder and urethra was visualized as a sagittal section. The blood flow around the injected area visualized as orange color was progressively increased after the injection of ADRCs up to 6 months

In 8 patients, leakage volume decreased progressively over time up to 12 months with a mean reduction rate of 59.8%; however, no change in leakage volume was achieved in 3 cases. In the 8 patients showing decreased leakage volume, urinary incontinence improved immediately after injection, deteriorated approximately 1 month after injection, and progressively improved thereafter up to 6 to 12 months. One patient achieved total continence.

Mean MUCP progressively increased both in the patients with improved and those with unimproved leakage volume on the 24-pad test. On the other hand, mean FPL increased in patients with improved leakage volume, but not in those with unimproved leakage volume.

MRI demonstrated that injected fatty tissue remained at the injection site even 12 weeks after the injection.

PVR was note increased

In patients with improved leakage amount, total score and all sub-scores of the ICIQ-SF such as frequency of incontinence, amount of leakage and QOL, improved. However, the patients without improvement of leakage amount had no improvement in the ICIQ-SF.