Predictive Factors for Extracapsular Extension of Prostate Cancer to Select the Candidates for Nerve-sparing Radical Prostatectomy.

Nerve-sparing radical prostatectomy (NSRP) for prostate cancer (PC) enables better postoperative recovery of continence and potency but may increase the risk of positive surgical margins. This study aimed to investigate preoperative predictive factors for extracapsular extension (ECE) of PC to select patients for NSRP. We retrospectively evaluated 288 patients with PC (576 lobes) diagnosed with 12-core transrectal ultrasound-guided biopsy and magnetic resonance imaging (MRI) who underwent laparoscopic or robot-assisted radical prostatectomy at our institution. Surgical specimens and preoperative parameters (prostate-specific antigen, prostate volume, biopsy and MRI findings, preoperative therapy) were analyzed. Of 576 prostate lobes, the incidence Ipsilateral ECE was identified in 97 (16.8%) lobes. The higher number of unilateral positive biopsy cores, the highest Gleason score 8 or more and positive unilateral findings on MRI are significant higher in prostate sides with ECE in univariate analysis. In multivariate analysis, positive unilateral MRI findings (odds ratio [OR], 2.86; p < 0.001) and unilateral biopsy positive core ≥ 3 (OR, 3.73; p < 0.001) were independent predictors of unilateral ECE. The detection rate of unilateral ECE in those cases with two factors (side-specific positive biopsy core 2 or less and side-specific MRI findings negative) was 7.1% (19/269). Patients with fewer unilateral positive biopsy cores and negative unilateral MRI findings might be good candidates for NSRP.

[Role of Bone Scan Index (BSI) in the Prognosis and Treatment Efficacy in Castration-Sensitive Prostate Cancer Patients with Bone Metastasis].

Bone is the most common metastatic site in prostate cancer (PCa). Although the extent of disease (EOD) grade is used for evaluating burden of bone metastasis, the accuracy of bone metastasis classification needs improvement. Bone scan index (BSI) was developed as a quantitative tool to enhance the interpretability and clinical relevance of the bone scan. This study aimed to explore the role of BSI using BONENAVI® software in determining the prognosis and treatment efficacy in castration-sensitive PCa (mCSPC) patients with bone metastasis. We retrospectively reviewed 61 mCSPC patients with bone metastasis who had received primary androgen deprivation therapy (PADT) at our institution. All patients received PADT with luteinizing hormone-releasing hormone agonist or surgical castration accompanied by first-generation antiandrogen, bicalutamide. Bone scans were performed with 99[m]Tc-MDP. BSI (%) was divided into two groups (＜1.0 and ≧1.0), and BSI response rates(change at 0 months to after 6 months) were determined using thresholds of 45% decline. Castration-resistant prostate cancer (CRPC) -free survival (CRPC-FS) and Overall survival (OS) rates were analyzed using the Kaplan-Meier method. The median follow-up was 41. 9 months. Overall, 16 patients (26. 2%) died. Multivariate analysis on pretreatment factors revealed that hemoglobin (P＝0.03) and BSI (P＝0.04) were independent prognostic factors for OS. The 5-year OS rates in patients with low BSI and high BSI were 84.6% and 39.2%, respectively (P＝0.02). In 40 patients who had a bone scan before and after PADT, OS rates in patients with a good response (≧45%) were significantly higher than those with a poor response (＜45%) (P＝0.001). Nadir PSA titers within 6 months after the start of treatment (P＝0.005), Hb (P＝0.003), and BSI change (P＝0.014) were independent prognostic factors for OS. In mCSPC patients with bone metastases, BSI at diagnosis was an important predictor of CRPC progression and OS as a pre-treatment factor, and BSI change rate and PSA nadir as post-treatment factors.

Clinical Efficacy and Openness to New Challenges of Low Dose Rate Brachytherapy for Prostate Cancer.

Over a century ago, low-dose-rate (LDR) brachytherapy was introduced to treat prostate cancer (PCa). Since then, it has been widely applied worldwide, including in East Asia. LDR brachytherapy has been performed in 88 institutes in Japan. Beneficial clinical outcomes of LDR brachytherapy for intermediate-to-high-risk PCa have been demonstrated in large clinical trials. These clinical outcomes were achieved through advances in methods, such as urological precise needle puncture and seed placement, and the quantitative decision making regarding radiological parameters by radiation oncologists. The combined use of LDR brachytherapy with other therapeutic modalities, such as external beam radiation and androgen deprivation therapy, for the clinical risk classification of PCa has led to better anticancer treatment efficacy. In this study, we summarized basic LDR brachytherapy findings that should remain unchanged and be passed down in urology departments. We also discussed the applications of LDR brachytherapy for PCa in various clinical settings, including focal and salvage therapies. In addition, we highlighted technologies associated with brachytherapy that are under development.

Simple and reliable predictive factor for early recovery of urinary continence after non-nerve-sparing robot-assisted laparoscopic radical prostatectomy.

Post-prostatectomy urinary incontinence is one of the greatest concerns for both patients and urologists. The aim of this study is to elucidate simple and reliable factors contributing to early recovery of urinary continence (UC) and to develop a prediction model for early continence recovery after robot-assisted laparoscopic non-nerve-sparing radical prostatectomy (non-NS RARP). A retrospective analysis of 212 consecutive patients who underwent non-NS RARP by a single surgeon was carried out. Early recovery of urinary continence was defined as using no pads or one security pad per day within 1 month. Preoperative membranous urethral length (MUL) was measured on MRI, and the urinary continence at the standing position (UCSP) after removal of the catheter was examined during cystourethrography 6 days after surgery. Multivariable analysis was performed to detect predictive and postoperative factors associated with early recovery of urinary continence. The early continence recovery rate was 56.1%. Multivariable analysis revealed that MUL ≥ 13 mm, UCSP, and age ≤ 67 were the independent factors for early continence recovery. Early recovery rates were 97.1% for good risk, 76.3% for intermediate risk, and 28.4% for poor risk when divided into three risk groups by the sum score of three independent factors. Preoperative MUL, UCSP, and age are independent predictors of early recovery of UC in non-NS RARP, and our simple prediction model with the combination of the three factors could be a useful tool in clinical practice.

Prognostic Effect of Preoperative Psoas Muscle Hounsfield Unit at Radical Cystectomy for Bladder Cancer.

Radical cystectomy (RC) is the standard treatment for patients with advanced bladder cancer. Since RC is a highly invasive procedure, the surgical indications in an aging society must be carefully judged. In recent years, the concept of "frailty" has been attracting attention as a term used to describe fragility due to aging. We focused on the psoas muscle Hounsfield unit (PMHU) and analyzed its appropriateness as a prognostic factor together with other clinical factors in patients after RC. We retrospectively analyzed the preoperative prognostic factors in 177 patients with bladder cancer who underwent RC between 2008 and 2020. Preoperative non-contrast computed tomography axial image at the third lumbar vertebral level was used to measure the mean Hounsfield unit (HU) and cross-sectional area (mm2) of the psoas muscle. Univariate analysis showed significant differences in age, sex, clinical T stage, and PMHU. In multivariate analysis using the Cox proportional hazards model, age (hazard ratio (HR) = 1.734), sex (HR = 2.116), cT stage (HR = 1.665), and PMHU (HR = 1.758) were significant predictors for overall survival. Furthermore, using these four predictors, it was possible to stratify the prognosis of patients after RC. Finally, PMHU was useful as a simple and significant preoperative factor that correlated with prognosis after RC.

Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure.

The normal prostate epithelial structure is maintained by homeostatic interactions with smooth muscle cells. However, structural alterations of the stroma are commonly observed in prostatic proliferative diseases, leading to the abnormalities of prostate epithelial structure. A decrease in the androgen level experimentally induces stromal remodeling, i.e., replacement of smooth muscle cells with fibroblasts or myofibroblasts. In this study, we investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial-stromal interactions on the reconstituted human prostate-like epithelial structure. We performed in vivo experiments using the human prostate epithelial cell line BPH-1 and fetal rat urogenital sinus mesenchyme to generate heterotypic tissue recombinants that form human prostate-like epithelial structure (i.e., solid- and canalized-epithelial cords). Host mice were castrated at 12 weeks post transplantation (castration) and implanted with a dihydrotestosterone pellet at 14 days post castration (androgen replacement treatment; ART). In the castration group, the percentages of fibrotic area and disrupted prostate epithelial structure without the basement membrane (BM) increased proportionally in a time-dependent manner, but were suppressed by ART. In the castration group, tenascin-C (TNC)-positive fibroblasts were abundant in the stroma surrounding disrupted prostate epithelial structure without the BM. TGF-ß1 secretion from BPH-1 cells was increased by co-culturing with human primary cultured prostate fibroblasts. TNC mRNA expression was increased in fibroblasts co-culturing with BPH-1 cells and was suppressed by treatment with a TGF-ß RI kinase inhibitor. Moreover, in the castration group, the percentage of p-Smad2-positive cells was significantly higher in the stroma surrounding disrupted prostate epithelial structure without the BM. Our results demonstrate that castration-induced stromal remodeling disrupted the reconstituted human prostate-like epithelial structure and induced the appearance of TNC-positive fibroblasts accompanied by activation of TGF-ß signaling. The alteration of prostate stromal structure may be responsible for loss of the BM and epithelial cell polarity.

Predicting the tumorigenic phenotype of human bladder cancer cells by combining with fetal rat mesenchyme.

BACKGROUND: In nonmuscle invasive bladder cancer patients, prediction of pTa and pT1 bladder cancer recurrence and progression must be established. Micropapillary structures have been defined as small clusters of invasive cancer cells having features of the epithelial-mesenchymal transition. Since the stromal microenvironment helps to induce the epithelial-mesenchymal transition, interactions between cancer cells and stroma should be closely examined to predict the tumorigenic phenotype of human bladder cancer cells. MATERIALS AND METHODS: To investigate differences in the responsiveness of cancer cells to stroma, we combined 3 established human bladder cancer cell lines (high-grade T24 and UM-UC-3 cells, and low-grade papillary RT4 cells) with fetal rat mesenchyme. RESULTS: Among 3 bladder cancer cell lines, the expression profiles of p63 isoforms were distinct, i.e., p63γ in T24 cells, p63ß in UM-UC-3 cells, and p63α in RT4 cells. Tumors formed by T24 cells combined with fetal mesenchyme formed micropapillary-like structures, whereas those formed by T24 cells alone did not. T24 cells combined with fetal mesenchyme showed poor differentiation, e.g., innumerable chromatic atypia in the nuclei, higher levels of chromatic condensation, and increased nucleoli. In contrast, both UM-UC-3 and RT4 cells combined with fetal mesenchyme did not form micropapillary-like structures. Ki-67 and p63 labeling indices were significantly elevated by combining fetal mesenchyme with T24 cells but not with the others. CONCLUSIONS: By mixing cancer cells with fetal mesenchyme, our data demonstrated that formation of micropapillary-like structures may predict the tumorigenic phenotype of invasive bladder cancer cells. Taken together, distinct expression profiles of p63 isoforms may predict poor outcomes in invasive bladder cancer.

Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation.

BACKGROUND: The reduced androgen-sensitivity of prostate cancer (PCa) cells is an important clinical development because of its association with the cells' progression to castration-resistant prostate cancer (CRPC). During androgen deprivation therapy (ADT), stroma-derived growth factors and cytokines can activate the androgen receptor (AR). For example, IL-6 is a multifunctional cytokine that is involved in the malignancy of PCa cells through AR activation. In the present study, we used an androgen-sensitive human PCa cell line (LNCaP) and its sublines to investigate the relationship between the responsiveness of PCa cells to IL-6 treatment and the cellular AR signaling pathway. METHODS: The androgen-low-sensitive F10 and E9 cells were obtained from LNCaP cells by limiting dilution method in regular culture condition. In contrast, the androgen-insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone-depleted condition. Original carcinoma-associated fibroblasts (CAFs) PCaSC-8 and PCaSC-9 cells were isolated from needle biopsy samples of PCa patients. RESULTS: In fibroblasts derived from PCa patients, IL-6 secretion was generally higher than that observed with normal fibroblasts. In contrast, IL-6 secretion was not detected in LNCaP and its sublines. The soluble IL-6 receptor was detected in PCa cells but not in fibroblasts. IL-6 treatment suppressed cell growth of LNCaP, F10, and E9 cells but not AIDL cells and it was accompanied with neuroendocrine-like differentiation. Induction of PSA secretion was observed in IL-6-treated LNCaP and F10 cells. VEGF secretion was strongly induced in IL-6-treated LNCaP and AIDL cells. IL-6-induced VEGF secretion was significantly suppressed by a PI3K inhibitor (LY294002) and it was accompanied by inhibited phosphorylation of Akt. CONCLUSIONS: Our results suggest that IL-6 might induce VEGF secretion from PCa cells in a manner independent of AR activation. To prevent IL-6-induced VEGF secretion, inhibition of the PI3K/AKT signaling pathway could be an important pharmacological goal regardless of ADT.

Additive naftopidil treatment synergizes docetaxel-induced apoptosis in human prostate cancer cells.

PURPOSE: Docetaxel (DTX) is a standard chemotherapeutic drug for castration-resistant prostate cancer (CRPC), although adverse events are common. To overcome this problem, researchers have evaluated the efficacy of DTX treatment in combination with other drugs. Naftopidil is a tubulin-binding drug with fewer adverse events, implying the usefulness of this drug in clinical applications when combined with DTX. Here, we investigated the efficacy of additive naftopidil treatment in combination with DTX on prostate cancer (PCa) cells. METHODS: The effects of combination treatment with DTX plus naftopidil were analyzed using two animal models of LNCaP cells plus PrSC xenografts (sub-renal capsule grafting) and PC-3 xenografts (intratibial injection). RESULTS: Combination treatment with DTX plus naftopidil significantly inhibited cell growth in LNCaP cells compared with DTX alone. Analysis of the cooperativity index (CI) showed that combination treatment exhibited additive effects on DTX-induced growth inhibition in LNCaP cells. In contrast, combination treatment showed more than an additive (synergistic) effect on DTX-induced apoptosis in LNCaP and PC-3 cells. In LNCaP cells plus PrSC xenografts, combination treatment showed synergistic effects on DTX-induced apoptosis. The synergistic effects of naftopidil on DTX-induced apoptosis were also observed in PC-3 xenografts. CONCLUSIONS: Our results demonstrated that additive naftopidil treatment in combination with DTX increased the efficacy of DTX for the treatment of LNCaP and PC-3 tumors in vivo. Thus, additive naftopidil treatment showed a synergistic effect on DTX-induced apoptosis in PCa cells in vitro and in vivo, suggesting that this treatment approach may yield improved clinical benefits compared with DTX alone.

Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells.

PURPOSE: Clinically, radiotherapy (RT) often leads to the development of prostate cancer (PCa) resistance because of protective responses in cancer cells. One of the mechanisms includes the upregulation of RT-induced antioxidant enzymes. Thus, combination therapy with RT and certain pharmaceutical drugs targeting antioxidant enzymes may be ideal for increasing the efficacy of RT with minimum side effects. Naftopidil is a subtype-selective α1D-adrenoceptor antagonist used for the treatment of benign prostatic hyperplasia (BPH). In our drug repositioning study, naftopidil showed not only unique growth-inhibitory effects but also AKT phosphorylation-inhibitory effects in PC-3 human PCa cells. Here, we examined the efficacy of additive naftopidil treatment in combination with RT in PC-3 cells. METHODS: The effects of combination therapy with RT plus naftopidil were analyzed using an animal model of PC-3 xenografts in BALB/c nude mice. The expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was evaluated by western blotting. RESULTS: Combination therapy with RT plus naftopidil induced a more efficacious delay in PC-3 xenograft tumor growth as compared with monotherapy with naftopidil or RT. In PC-3 tumors, combination therapy with RT plus naftopidil suppressed the upregulation of RT-induced MnSOD expression. In vitro, neither AKT inhibitor IV nor naftopidil directly altered MnSOD expression. Upregulation of RT-induced MnSOD expression was markedly suppressed by combination treatment with RT plus AKT inhibitor IV or naftopidil. CONCLUSIONS: These results suggest that additive naftopidil treatment in combination with RT may increase the efficacy of RT for the treatment of PCa.

[A Case of Emphysematous Cystitis with Bladder Diverticulum].

Emphysematous cystitis (EC) is a rare form of acute complicated urinary tract infection (UTI). We report a case of EC with bladder diverticulum. A 77-year-old man who had a medical history of diabetes mellitus was admitted to our hospital with the chief complaint of macrohematuria and pneumaturia. Based on the findings of an abdominal computed tomography and cystoscopy, the diagnosis of EC and bladder diverticulum was made with its characteristic feature being gas within the bladder wall and lumen and a cystic lesion from the bladder. His condition improved immediately with a combination of bladder drainage and appropriate antibiotics. The cystography revealed a very large diverticulum causing incomplete bladder emptying and stagnation of urine. We considered diabetes mellitus and a large amount of residual urine after urination due to bladder diverticulum and neurogenic bladder as the possible causal factors of EC in this case.