Kanako Matsuoka

Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign

Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment.

The impact of nerve‐sparing robot‐assisted radical prostatectomy on lower urinary tract function: Prospective assessment of patient‐reported outcomes and frequency volume charts

To elucidate the effects of a nerve‐sparing (NS) procedure on lower urinary tract symptoms (LUTS) and urinary function after robot‐assisted radical prostatectomy (RARP), the associations between the NS procedure and LUTS and urinary function were investigated.

Protective Effect of a Rho-kinase Inhibitor on Bladder Dysfunction in a Rat Model of Chronic Bladder Ischemia

OBJECTIVE To investigate the effect of fasudil, a Rho-kinase inhibitor, on chronic ischemia-related bladder dysfunction. MATERIALS AND METHODS Male Sprague-Dawley rats (16 weeks old) were divided into control, chronic bladder ischemia (CBI), and CBI with fasudil treatment (CBI-Fa) groups. The CBI and CBI-Fa groups underwent balloon endothelial injury of bilateral iliac arteries and received a 2% cholesterol diet for 8 weeks after the procedure to induce CBI. The CBI-Fa group was given oral fasudil (30 mg/kg/day) using zonde for 8 weeks after the procedure. The control group received a regular diet for 8 weeks. After cystometry in a conscious state, rats from each group were euthanized, and the bladders and common iliac arteries were harvested for pharmacologic and histologic examination. RESULTS Mean wall thickness of the common iliac arteries was significantly greater in the CBI group than in controls. Contractile responses of muscle strips were significantly lower in CBI group rats than in controls. In the CBI group, micturition interval was significantly shorter, and bladder capacity was significantly lower compared with those in controls. In the CBI-Fa group, arterial wall thickening was significantly suppressed compared with the CBI group. Significant improvements in muscle strip contractility and cystometric parameters were seen in the CBI-Fa group compared with the CBI group. CONCLUSION Our results suggest that chronic treatment with fasudil could prevent neointimal formation in arteries and bladder dysfunction in this rat model. Fasudil may be therapeutically useful in protecting bladder function in chronically ischemic bladders.

The association between local atherosclerosis of the prostatic artery and benign prostatic enlargement in humans: Putative mechanism of chronic ischemia for prostatic enlargement

To investigate the possible pathogenesis of the benign prostatic enlargement (BPE) induced by local atherosclerosis, the association between local atherosclerosis and prostatic enlargement was investigated, and molecular biological analyses were performed using human prostatectomy specimens.

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

Background Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer that is expressed in natural killer cells, whose cytotoxicity is activated by interferon (IFN). We investigated the effect of suppressor of cytokine signaling (SOCS) 3 on the expression of TRAIL receptors (DR4) and on TRAIL sensitivity in renal cell carcinoma (RCC) cells. Methods Vector expression, RNA interference and IL-6 receptor antibody tocilizumab were used to investigate the functional role of SOCS3 in DR4 expression. Immunoprecipitation was employed to detect the biochemical interaction between SOCS3 and DR4. The expression of DR4 induced by combination with IFN-α and tocilizumab was also examined by immunohistochemical staining using mice xenograft model. Results DR4 expression was up-regulated by IFN stimulation in RCC cells. 786-O cells were resistant to TRAIL and showed higher SOCS3 expression. ACHN cells showed higher DR4 expression and lower SOCS3 expression. Suppression of SOCS3 up-regulated DR4 expression and enhanced the TRAIL sensitivity in 786-O cells. In ACHN cells, DR4 expression was down-regulated by transfection with pCI-SOCS3, and the cells became resistant to TRAIL. Immunoprecipitation revealed the biochemical interaction between SOCS3 and DR4. A marked increase in IFN-induced DR4 protein expression after tocilizumab treatment was observed by immunohistochemical staining in the tumor from the mice xenograft model. Conclusions Our results indicate that IFN and SOCS3 regulate DR4 expression in RCC cells. Combination therapy with IFN-α, tocilizumab and an anti-DR4 agonistic ligand appears to effectively inhibit advanced RCC cell growth.

Interleukin-6 induces drug resistance in renal cell carcinoma

Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.

MP39-13 IDENTIFICATION OF ISYNA1 AS A POTENTIAL PROGNOSTIC BIOMARKER FOR RENAL CANCER

microenvironment including invasions of Treg and M2 macrophages and CRP in RCC patients to explore the mechanisms underlying the association between CRP level and prognosis. METHODS: Immunohistochemical (IHC) measurement of CD4, CD8, CD163 (M2 macrophages), and FOXP3 (Treg) was performed in clear-cell RCC (ccRCC) patients (n 1⁄4111) treated with radical or partial nephrectomy. CD4+, CD8+, and CD163+ cells were counted and the optimal cut-off scores for CD4, CD8 and CD163 were determined through receiver-operating characteristic (ROC) analysis. Patients were classified into groups according to FOXP3 positive or negative status. The association between IHC status and preoperative serum CRP level and cancer-specific survival (CSS) was analyzed. RESULTS: Median follow-up period was 8.5 years. pT stage was pT1 in 58%, pT2 in 5%, pT3 in 35% and pT4 in 2% of patients. Lymph node involvement and distant metastasis were seen in 4% and 20% of patients, respectively. Thirty-three patients (30%) had a high CRP level ( 5.0 mg/L), and the CSS rate was significantly worse among these patients than among the remaining patients (p <0.0001). In patients with strong invasion of CD8+, CD163+ or FOXP3+ cells, CRP levels were significantly higher (Figure 1) and CSS was significantly worse (Figure 2) compared to patients with weak invasion. CONCLUSIONS: Invasion of the immunosuppressive cells known as Tregs and M2 macrophages in the tumor microenvironment is associated with higher CRP and poor prognosis in ccRCC patients. CRP indicates an immunosuppressive microenvironment.

MP31-12 PREVALENCE AND PREDICTIVE FACTORS OF DE NOVO DETRUSOR UNDERACTIVITY AFTER ROBOT-ASSISTED RADICAL PROSTATECTOMY

and ultimately bladder pain and reduced bladder capacity. Pioglitazone has been shown in previous murine studies to increase bladder mucosal cell proliferation when given systemically. For patients with IC, where decreased mucosal cell proliferation is a likely etiologic factor in the disease process, this effect may prove therapeutic. METHODS: Using a previously described animal model for IC, 6-week-old female Sprague-Dawley rats were treated with biweekly cyclophosphamide injections (35mg/kg) to induce cystitis. Animals were divided into 4 groups (n1⁄46): IC plus daily sham saline gavage (IC), IC plus daily pioglitazone gavage (150mg/kg) (IC+P), normal rats with daily pioglitazone (PIO), and normal rats with neither IC nor pioglitazone (CTRL). At the end of four weeks, urinary frequency was measured via counting spots on filter paper, and bladder capacity was measured cystometrically. Histologic examination was also performed, after embedding the excised bladders in paraffin, staining with haematoxylin and eosin (H&E), PAS and with Mason’s trichrome stain. Slides were reviewed in a blinded fashion by a pathologist for inflammation, bladder wall thickness, collagen deposition, and local tissue structure. RESULTS: On voiding paper tests, average voids per hour were: IC rats 10 +/2.44 , IC+P 4 +/-1.87, PIO 6 +/1.41, and CTRL voided 6 times/hour+/1.52. Comparison between IC and IC+P groups using students T-test showed a significant difference in voids/hour (P<.01). On cytometry, bladder volumes were significantly higher in IC+P versus IC (0.945 +/-0.122 ml vs 0.588 +/-0.165 ml s., P1⁄4.01) Control capacities averaged 0.82 +/0.20 ml and PIO capacities were similar at 0.94 +/-0.19ml. On histology, a diminished glycosaminoglycan layer was appreciated on cystitis bladders, and this effect was mitigated, though not resolved, in the treatment group. CONCLUSIONS: Pioglitazone improved bladder function in rats with cyclophosphamide-induced cystitis with respect to both observed urinary frequency and measured cystometric capacity. Pioglitazone and other PPAR-gamma agonists, due to their propensity to cause bladder mucosal proliferation, may prove to be useful for treating interstitial cystitis, and deserve further study.

PD02-02 THE STUDY OF OVERACTIVE BLADDER ASSOCIATED WITH PELVIC ORGAN PROLAPSE.

INTRODUCTION AND OBJECTIVES: This study presents a new potentially useful three-dimensional (3D) non-invasive tool to determine the basic 3D models of the pelvic floor, static and dynamic, in patients with pelvic organ prolapse (POP) which help to identify the main types of pelvic floor defects and to create an individual approach to their reconstruction. METHODS: We scanned 42 patients who were suffering from POP (no less than Grade 2 by Pelvic Organ Prolapse Quantification (POP-Q)) at rest and during Valsalva maneuver by using an Artec 3D optic portable scanner. Pelvic floor 3D models were generated. We calculated the volume of the prolapsed vaginal wall using Dynamic prolapse increment (DPI). It was defined as an increase in the prolapse volume from the rest to its maximal Valsalva probe (DPI 1⁄4 (Vval e Vrest) / Vrest %). RESULTS: The average value of the DPI in women with POP was 648% (95% CI 194-1102%). It indicated the presence of an advanced mobility of the pelvic floor and the need to use mesh surgical correction of POP in some cases. According to generated pelvic floor 3D models, six basic types of pelvic defects were allocated. The central defects of an anterior vaginal wall along with mixed one (cystocele combined with uterine prolapse or rectocele) were the most common defects of the pelvic floor (in 24 and 26%, respectively). The lateral defect occurred in 7%, the asymmetric one in 10%, urethra cystocele in 19%, the isolated uterine defect 10% and enterocele 5% (Figure 1). CONCLUSIONS: The detection of types of pelvic floor defects in women with POP by 3D modeling may allow creating of synthetic implants for an individual pelvic floor reconstruction, taking into account patients’ reserves of pelvic floor mobility. It will contribute reducing the risk of possible functional complications of surgical correction of POP. The further investigations of the pelvic floor dynamic features in women are necessary.

MP17-04 COMPLEMENT ACTIVATION MECHANISM ACTIVATED BY AUTOANTIGEN RECOGNITION DURING GROWTH OF BENIGN PROSTATIC HYPERPLASIA

INTRODUCTION AND OBJECTIVES: The association between the pathogenesis of benign prostatic hyperplasia (BPH) and inflammation has recently received attention. We previously showed that not only the inflammation response pathway, but also the classical complement pathway is activated in BPH tissue from model rats with stroma-dominant BPH. The classical complement pathway is activated by autoantigens that recognize immune complexes and it is responsible for various diseases via a mechanism that amplifies inflammation. We postulated that immune complexes amplify inflammation through complement activation, which leads to prostatic proliferation. Therefore, we expressed complement factors, analyzed their functions, and identified autoantigens to understand the pathogenic mechanism of BPH. METHODS: Fetal urogenital sinus (UGS) isolated from male 20-day-old rat embryos was implanted into the ventral prostate of pubertal male rats to create rat models of BPH. Complement factors were expressed and functionally analyzed in BPH tissues, and then serum concentrations of IgG and the expression of complement factors in BPH tissues were assessed. We immunoprecipitated BPH protein using an anti-IgG antibody to identify antigens, and analyzed the protein by mass spectrometry after SDS-PAGE separation. The expression of complement factors in human BPH tissue was also analyzed. RESULTS: The expression of complement factors C1q, C3, MBL, factor B, and MAC was significantly up-regulated in tissues from BPH rats compared with those from normal rats (p<0.01). The classical complement pathway was initially activated, followed by an alternative complement pathway activated in BPH. These complement factors were also up-regulated mostly in stromal areas of human BPH. The serum IgG concentration was significantly increased (398.1 ng/mL, p<0.01) in rat BPH and IgG was deposited in stromal areas of the BPH. Mass spectrometry of IgG binding protein identified annexin, Hsp90, and b-actin as antigens of immunocomplexes. CONCLUSIONS: We clarified that the immune system is responsible for the development of BPH. Complement pathway activation by immunocomplexes recognizing annexin, Hsp90, and b-actin as autoantigens might be responsible for the pathogenesis of BPH.