Transporter Associated With Antigen Processing (TAP) 1 Gene Polymorphisms and Risks of Urothelial Cell Carcinoma Among the Japanese Population.

Urothelial cell carcinoma is one of the costliest types of cancer because of its recurrence, lengthy course of therapy, and tendency to lead to further complications. Gene polymorphisms are one of many factors that are thought to cause the carcinogenesis of urothelial cell carcinoma. Two single-nucleotide polymorphisms (SNPs) of the transporter associated with antigen processing (TAP) 1 gene and their relationship with the risks of urothelial cell carcinoma in the Japanese population were examined in this study by using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) for genotyping and statistical analysis. The adjusted odd ratios with 95% confidence interval (CI) of the mutant types (A/G+G/G) in females for the I333V and D637G polymorphisms are 2.28 (1.11-4.66) and 2.50 (1.21-5.17), respectively. The findings showed that females with the (A/G+G/G) genotype are more likely to develop urothelial cell carcinoma than those with the A/A genotype. Any correlation between smoking and gene polymorphism was absent. Results indicate that TAP1 gene polymorphisms and the risk of urothelial cell carcinoma are related in females.

The Relationship Between CTLA-4 (-318 C/T) Polymorphism and Urothelial Cancer Carcinogenesis in Japanese Patients.

Background Urothelial cancer is one of the most common types of urinary system cancer and there are several factors that can influence its growth. One of the most prominent factors among these is genetics. The Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) gene is suspected to be a susceptibility gene in urothelial carcinoma. The aim of this study is to investigate polymorphism in the CTLA-4 gene (CTLA-4 -318 C/T) and whether it is associated with urothelial cancer. Methods The study population consisted of 253 cases and 272 controls. In this case-control study, DNA was extracted from peripheral blood cells, and the CTLA-4 -318C/T genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. Results C/T (adjusted OR (aOR) 3.37; 95%CI: 1.98-5.74) genotype, C/T + T/T (aOR 3.25; 95%CI: 1.96-5.39) genotype, and T allele (aOR 2.94 95%CI: 1.87-4.62) all indicated they are significant risk factors for urothelial cancer, with the effects of polymorphism being higher in the nonsmoker group than in the smoker group. Furthermore, the association between polymorphism and urothelial cancer carcinogenesis was similar among men and women. Conclusions This is the first study examining the association between CTLA-4 -318C/T polymorphism and urothelial carcinoma in Japanese patients. A significant association between CTLA-4 -318C/T polymorphism and urothelial cancer among Japanese patients was detected in this study. This supports the development of research on polymorphisms in urothelial cancer and is an important root of immunoreactions in cancer. We believe this study will be beneficial to clarify the relationship between CTLA-4 polymorphism and urothelial cancer.

The Relationship Between PD-1(rs2227981) and PD-L1(rs2890658) Polymorphisms and Urothelial Cell Carcinoma.

Background Urothelial cell carcinoma, which is believed to develop from the urothelium (transitional epithelium), is the most common aggressive tumor and accounts for the ten most prevalent cancers in the world. The risk factors for urothelial cell carcinoma are aging, smoking, gender, and genetic alternations. Programmed cell death1 (PD-1) has been widely described as a negative regulator of T-cells by sending inhibitory signals to the T-cell. Through PD-1 binding with PD-L1 (ligand for PD-1), an inhibitory signal is propagated to the T cell. The polymorphisms of PD-1 and PD-L1 lead to an efficient T-cell response and affect an anti-tumor reaction. The polymorphisms of PD-1 and PD-L1 could also affect the carcinogenesis of human cancer, including urothelial cell carcinoma. Therefore, in this study, we evaluated the relation between PD-1(rs2227981) and PD-L1(rs2890658) polymorphisms and the carcinogenesis of urothelial cell carcinoma. Materials and methods This study was conducted using 211 healthy controls and 256 cases of urothelial cell carcinoma among the Japanese population. The DNA samples were extracted from the peripheral white blood cells of each subject. The genotype was detected by using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results C/T (Adjusted OR 1.55, 95% CI:1.02-2.35) and C/T+T/T (OR 1.46, 95% CI:1.01-2.12) genotypes of PD-1 rs2227981 were significant and risk factors for urothelial cancer. Male with A/A genotype in PD-L1 and CT genotype in PD-1 has a significant higher risk factor compared with other genotypes (Adjusted OR 1.83, 95% CI:1.05-3.21). Conclusions and discussion We found that C/T(PD-1) and "A/A (PD-L1) and C/T(PD-1)" were predominant in urothelial cell carcinoma cases. This indicates that C/T(PD-1) and "A/A (PD-L1) and C/T(PD-1)" genotypes could increase susceptibility to urothelial cell carcinoma. However, since our findings indicated that the effects of PD-1 and PD-L1 polymorphisms included discrepancies, additional research will be needed to evaluate the relationship between human cancer and PD-1 and PD-L1 polymorphisms. This is the first study that seeks to find the relation between PD-1(rs2227981) and PD-L1(rs2890658) polymorphisms concerning urothelial cell carcinoma among the Japanese population.

Evaluation of sexual function after dutasteride treatment in patients with once-negative prostate biopsy and benign prostate hyperplasia.

INTRODUCTION: Patients with benign prostatic hyperplasia are usually treated with 5α-reduced inhibitors (5ARIs) such as finasteride and dutasteride. However, studies on the influence of 5ARIs on sexual function have been controversial. In this study, we evaluated the impact of dutasteride treatment for erectile function in patients with once-negative prostate biopsy and benign prostate hyperplasia. PATIENTS AND METHODS: 81 patients with benign prostate hyperplasia were enrolled in a one-armed prospective study. They were administrated 0.5 mg/day of dutasteride for 12 months. Patient characteristics and changes of International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF)-15 scores at baseline and 12 months after dutasteride administration were examined. RESULTS: The mean ± standard deviation (SD) age of the patients was 69.4 ± 4.9 years and the prostate volume was 56.6 ± 21.3 mL, respectively. The mean ± SD prostate volume and PSA levels were decreased 25.0 and 50.9%, respectively, after 12 months of dutasteride administration. IPSS total, voiding subscore, storage subscore, and quality of life score significantly improved after 12 months of dutasteride administration. No statistically significant change in IIEF-total score from 16.3 ± 13.5 to 18.8 ± 16.0 (p = 0.14), IIEF-EF score from 5.1 ± 6.9 to 6.4 ± 8.3 (p = 0.13) were observed. There was no decrease in erectile function severity. CONCLUSION: Twelve months administration of dutasteride for patients with BPH improved urinary function and did not increase the risk of sexual dysfunction.

Reclassification prediction of first-year protocol biopsy on active surveillance of prostate cancer by p2PSA-related parameters: from PRIAS-JAPAN.

BACKGROUND: There is no useful predictive marker for reclassification on active surveillance. Thus, we aimed to investigate thresholds of [-2] proPSA (p2PSA)-related parameters to predict reclassification of the first-year protocol biopsy (1-year PBx) and evaluate the influence of clinical decision-making. METHODS: This was an observational, prospective cohort study conducted at 19 Japanese institutes. The inclusion criteria included clinical stage T1c/T2, prostate-specific antigen (PSA) levels ≤10 ng/mL, PSA density <0.2 ng/ml/cc, one or two positive biopsy cores, and Gleason score (GS) ≤6 (GS ≦7 for patients aged ≥70 years) at diagnostic biopsy. All participants were required to receive a blood-sampling test on a protocol visit at inclusion and at the 1-year PBx. PSA and PSA isoforms (free PSA, p2PSA) were measured, and parameters (%free PSA, %p2PSA, phi) were calculated. Multivariable logistic regression models were used to predict the reclassification risk. To assess the predictive power and thresholds for reclassification, we plotted Receiver Operating Characteristic (ROC) curves. Decision curve analysis (DCA) was used to evaluate the variables that yielded a net clinical benefit. RESULTS: A total of 135 patients were included, and 36 patients were reclassified on the 1-year PBx. Multivariate analyses showed that %p2PSA and phi at inclusion and p2PSA, %p2PSA, and phi before the 1-year PBx were significant predictors of reclassification at the 1-year PBx. The ROC analysis showed an optimal cutoff point, sensitivity, and specificity of %p2PSA and phi before the 1-year PBx of 1.64, 86%, 49% and 35.92, 89%, 47%, respectively. The DCA showed that phi before the 1-year PBx had the highest net benefit. The study limitation was its single-arm observational design. CONCLUSIONS: %p2PSA and phi before the 1-year PBx had a good prediction power. phi is the most useful indicator for clinical decision-making on active surveillance. TRIAL REGISTRATION: This study is registered atthe Japan Trial Register with ID UMIN000009876 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000011573 ).

Prostate-specific antigen density during dutasteride treatment for 1 year predicts the presence of prostate cancer in benign prostatic hyperplasia after the first negative biopsy (PREDICT study).

OBJECTIVES: To prospectively evaluate the detection rate of prostate cancer, and to identify the risk factors of prostate cancer detection after a 1-year administration of dutasteride and first negative prostate biopsy. METHODS: Patients with benign prostatic hyperplasia who presented high prostate-specific antigen levels after the first negative prostate biopsy were administered 0.5 mg dutasteride daily for 1 year. They underwent a repeat prostate biopsy after 1 year. The primary end-point was the detection rate of prostate cancer. The secondary end-point was the ability of prostate-specific antigen kinetics to predict prostate cancer detection. Prostate-specific antigen was measured before the initial prostate biopsy and at 6, 9 and 12 months after starting dutasteride. Patients were classified into a prostate cancer and a non-prostate cancer group. RESULTS: Prostate cancer was detected in 15 of 149 participants (10.1%). The total prostate-specific antigen change between the prostate cancer and non-prostate cancer group at 1 year was significantly different (P = 0.002). Although prostate-specific antigen levels at baseline did not significantly differ between study groups (P = 0.102), prostate-specific antigen levels at 6, 9 and 12 months were significantly different (P = 0.002, P = 0.001 and P < 0.001, respectively). The mean reduction rate of prostate-specific antigen density between the prostate cancer and non-prostate cancer group at 1 year was significantly different (-4.25 ± 76.5% vs -38.0 ± 28.7%, P = 0.001). Using a multivariate analysis, a >10% increase of prostate-specific antigen density at 1 year post-dutasteride treatment was the only predictive risk factor for prostate cancer after the first negative prostate biopsy (odds ratio 11.238, 95% confidence interval 3.112-40.577, P < 0.001). CONCLUSION: In the present study cohort, >10% increase in prostate-specific antigen density represented the only significant predictive risk factor for prostate cancer diagnosis in patients with elevated prostate-specific antigen after the first negative prostate biopsy.

[Patient Background Factors Affecting Prescription Drugs for Male Lower Urinary Tract Symptoms: The Multicenter Study of Miyazaki Urological-Network Group].

The present multicenter study performed by the MIYAZAKI UROLOGICAL-NETWORK GROUP involving patients from 32 hospitals in Miyazaki Prefecture demonstrates that an association exists between the use of prescription drugs for male lower urinary tract symptoms (MLUTS) and patient characteristics. Men aged ≥40 years who were prescribed at least one drug for MLUTS between April 1, 2014 and March 31, 2015 were prospectively recruited. In total, 2,295 patients with a median age of 72 years were enrolled. The median prostate volume was 33 ml, the median International Prostate Symptom Score (IPSS) was 15, and the median quality-of-life score was 5. Prescribed drugs were α1-blockers alone in 1,661 patients, tamsulosin hydrochloride in 702, silodosin in 481, and naftopidil in 477. Multivariate analysis of the associations between use of α1-blockers and patient characteristics revealed use of tamsulosin hydrochloride to be more significantly associated with higher age (P=0.02), higher prostate volume (P=0.048), and higher IPSS score (P=0. 01) than silodosin. No significant associations between patient characteristics and naftopidil or tamsulosin hydrochloride ware revealed. We found that 369 patients received drug therapy for MLUTS plus overactive bladder (OAB). Multivariate analysis of the associations between patient characteristics and use of drugs for MLUTS or MLUTS plus OAB revealed higher age (P=0.001) and lower PSA value (P=0.04), lower prostate volume (P=0.01), and higher storage symptom score of IPSS (P< 0.001) to be more strongly associated with use of drugs for MLUTS plus OAB than drugs for MLUTS alone.

The efficacy and toxicity of cabazitaxel for treatment of docetaxel-resistant prostate cancer correlating with the initial doses in Japanese patients.

BACKGROUND: We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC). METHODS: We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated. RESULTS: PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9-4.4), 2.1 months (1.2-5.5), and 3.0 months (2.0-4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7-30.9), 30.9 months (11.8-47.4), and 10.2 months (8.6-20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose (hazard ratio 0.21, 95% CI 0.08-0.59, P = 0.002). CONCLUSIONS: CBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients.

Caveolin-1 and -2 regulate cell motility in castration-resistant prostate cancer.

BACKGROUND: Caveolin (Cav)-1 and Cav-2 are cell membrane proteins, which are structural proteins of caveolae and are reported to be positive regulators of cell survival and metastasis in prostate cancer (PC). In a previous study, we reported that elevated levels of Cav-1 and Cav-2 were significantly associated with PC progression. However, their functions in PC have not yet been clarified. In this study, we examined the function of Cav-1 and Cav-2 in PC cell invasiveness and motility. MATERIALS AND METHODS: We introduced Cav-1- and Cav-2-specific small interfering into PC3 cells to knock-down (KD) both molecules. We also performed cell proliferation assay, wound healing assay, migration assay, and invasion assay using PC3 cells and compared the results between Cav-1-KD, Cav-2-KD, and negative control PC3 cells. In addition, we performed real-time quantitative PCR (RT-qPCR) and RT2 Profiler PCR Array analysis to identify factors influencing migration. RESULTS: We observed no significant difference in the proliferative and invasive activities of Cav-1-KD and Cav-2-KD PC3 cells; however, the cell motility was significantly decreased compared with negative control PC3 cells. RT-qPCR revealed that the expression of vimentin and N-cadherin was downregulated in Cav-1-KD PC3 cells. In addition, PCR array revealed a decreased expression of MGAT5, MMP13, and MYCL in Cav-1-KD PC3 and ETV4, FGFR4, and SRC in Cav-2-KD PC3. CONCLUSION: Cav-1 and Cav-2 may positively contribute to the upregulation of castration-resistant PC cell migration. Cav-induced regulation of several molecules including vimentin, N-cadherin, MGAT5, MMP13, MYCL, ETV4, FGFR4, and SRC may have an important role in PC3 cell motility. However, further examination will be required.

Safe Resection of Renal Cell Carcinoma with Liver Invasion Using Liver Hanging Technique Supported by Preoperative Portal Vein Embolization.

In cases of RCC with liver involvement, partial hepatectomy is known to provide a better chance of survival for patients. For this reason, complete resection with clear surgical margin is thought to be necessary to achieve favorable outcome. Anterior liver hanging maneuver was extremely useful during hemihepatectomy in this rare type of RCC. A 63-year-old male was diagnosed with a large right renal cell carcinoma. The tumor measured 10 cm in diameter with tumor thrombus toward the inferior vena cava (IVC). In addition, we observed direct infiltration to the liver. We attempted a preoperative portal vein embolization (PVE) to preserve residual liver volume and function after right lobectomy. After PVE the resected volume decreased from 921 cm3 (71%) to 599 cm3 (53.4%). During the procedure, a nasogastric tube was placed in the retrohepatic space for liver hanging maneuver according to the original Belghiti's maneuver after dissection of the renal artery and vein. After hepatic parenchymal transection exposing vena cava, the right hepatic veins were safely transected using vascular stapler; right nephrectomy and hemihepatectomy were performed. The patient recovered without postoperative hepatic or urinary complications and has remained free of local recurrence and any de novo metastasis for 18 months.

Surgical intervention for renal cell carcinoma with inferior vena cava extension combined with laparoscopic procedure.

Clear cell renal cell carcinoma (ccRCC) shows extreme hypervascularity, which may cause significant bleeding during surgery. For this reason, control of arterial blood supply is an important factor in the choice of operative procedure and in avoiding perioperative complications. This case series reports the successful dissection of renal artery in the preliminary stage of laparoscopic procedure in three ccRCC patients with inferior vena cava (IVC) extension. Patient 1 had right renal cell carcinoma (RCC) with level I tumor thrombus through two renal veins, and the renal artery was successfully dissected by retroperitonealscopic approach. Patient 2 had right invasive, immobilized RCC with significant infiltration to IVC and liver. Ligation of renal artery was performed by transperitoneal laparoscopic procedure. Patient 3 had left RCC with level III tumor thrombus and lung metastasis. Ligation of left renal artery and mobilization of peritoneal organs and kidney were performed by transperitoneal laparoscopic surgery. These cases suggest that combined laparoscopic-open surgery for RCC with IVC extension may facilitate early control of arterial blood supply.

Myopericytoma in urinary bladder: a case report.

BACKGROUND: Myopericytoma is reported to occur mainly in the skin and superficial soft tissue of the extremities. In contrast, occurrence in the urinary bladder is extremely rare. CASE PRESENTATION: We describe a 75-year-old Japanese man who developed a submucosal tumor at the right trigone of his bladder that led to interference with the discharge of right ureteral calculus. No invasive growth was observed by magnetic resonance imaging. Transurethral resection was successfully performed; histopathological analysis revealed perivascular proliferation of spindle-shaped to oval-shaped, cytologically bland tumor cells with eosinophilic cytoplasm. On immunohistochemical examination, the tumor cells were positive for alpha-smooth muscle actin, desmin, CD34 and h-caldesmon. CONCLUSION: Cystoscopic and pathological findings were compatible with a diagnosis of myopericytoma of the urinary bladder.

Effective and Safe Administration of Low-Dose Estramustine Phosphate for Castration-Resistant Prostate Cancer.

UNLABELLED: Despite the favorable toxicity profile at the standard dose of 560 mg daily, the tolerability and toxicology of estramustine phosphate (EMP) have been a cause for concern at administration. Moreover, we do not know whether a lower dose of 280 mg of EMP daily can be administered with some efficacy and fewer side effects. The results of our phase II study suggest that low-dose EMP is a safe treatment option with the same efficacy in patients with castration-resistant prostate cancer. BACKGROUND: We evaluated the efficacy and safety of low-dose estramustine phosphate (EMP) in Japanese patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The present study was a single-arm, nonrandomized prospective study in which all patients received EMP orally twice daily for a total dose of 280 mg/day. A total of 31 patients with CRPC were enrolled from December 2009 to December 2012 at 5 institutions in Japan. The primary endpoint was the prostate-specific antigen (PSA) response, defined as a 50% decline in the serum PSA level, confirmed ≥ 3 weeks later. The secondary endpoints included the objective response rate, interval to PSA progression, PSA response duration, progression-free survival, disease-specific survival, overall survival, safety, and quality-of-life assessment using the Functional Assessment of Cancer Therapy-Prostate scores. RESULTS: Ten patients (32%) had a PSA response, and no patient had an objective response. The treatment was well tolerated, and the most frequent toxicities were grade 1 to 2 nausea/vomiting, anorexia, and gynecomastia. The median interval to PSA progression was 140 days (95% confidence interval [CI], 117-260 days). The PSA response duration was 119 days (95% CI, 49-219 days). The median progression-free survival was 213 days (95% CI, 167-422 days). The 3-year disease-specific survival and overall survival rates were 68.6% (median not reached; 95% CI, 33 months to not available) and 59.9% (median 42 months, 95% CI, 28 months to not available), respectively. CONCLUSION: Low-dose EMP seems to be a safe treatment option with some efficacy in patients with CRPC.

Plasma macrophage-stimulating protein and hepatocyte growth factor levels are associated with prostate cancer progression.

Hepatocyte growth factor (HGF) is a well-known multifunctional growth factor, and evidence has accumulated indicating that the HGF/MET (HGF receptor) signaling axis is involved in the progression of cancer. Macrophage-stimulating protein (MSP) is also known as a growth factor which activates not only macrophages but also cancer cells and osteoclasts through the activation of the specific Receptor d'origine nantais (RON). Pro-HGF and pro-MSP lack biological activity and, therefore, require proteolytic activation for conversion to an active two-chain form by HGF activator (HGFA). Although, there are several studies on HGF/MET signaling with castration-resistant prostate cancer (CRPC) and bone metastasis, reports on plasma protein are rare. In addition, the MSP/RON signaling axis in PC is not well understood. Here, we analyzed associations between PC progression and plasma HGF and MSP levels. We tested plasma samples from 58 patients with PC: 36 with castration-resistant (CR) PC and 22 with pretreatment for PC as control. We used enzyme-linked immunosorbent assay (ELISA) kit to determine plasma levels of HGF, MSP and HGFA, and examined correlations with clinicopathological characteristics such as Gleason grade and bone metastasis. PCR was used to evaluate HGF and MSP-related molecules in PC cell lines. Plasma levels of HGF, MSP and HGFA in the CRPC group were higher than in the control group (HGF: P < 0.001; MSP: P = 0.008; HGFA: P < 0.001). HGF and MSP levels were significantly correlated (P = 0.003). In the CRPC group, plasma HGF and MSP levels and Gleason score were not correlated; however, high plasma MSP level correlated with bone metastasis. (P = 0.016). In cell lines, PC3 expressed significantly more HGF, MET and RON than did LNCaP (P < 0.001), and both cell lines expressed MSP. Plasma concentrations of HGF, MSP and HGFA are significantly elevated in patients with CRPC. Also, as plasma MSP levels are significantly associated with bone metastasis in CRPC patients, MSP may be a candidate for serum marker of bone metastasis. Our results show the importance of the HGF/MET and MSP/RON signaling systems in CRPC.

Significant Association of Caveolin-1 and Caveolin-2 with Prostate Cancer Progression.

BACKGROUND/AIM: Up-regulation of caveolin (CAV)-1 is associated with aggressive prostate cancer. Recently, it has been inferred that CAV2, a co-factor sub-type of CAV1, cross-talks with CAV1 and promotes tumor growth. We previously reported that plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in hormone-sensitive prostate cancer (non-CRPC), implying that CAV1 may be a therapeutic target for CRPC. However, a correlation of CAV1 and CAV2 expression in PC has not yet been reported. Herein, we analyzed associations between PC progression and plasma CAV1 and -2 in Japanese men, and expression of CAV1 and -2 in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. MATERIALS AND METHODS: We investigated plasma samples from 36 patients with CRPC and 22 with non-CRPC. We used enzyme-linked immunosorbent assay (ELISA) to determine plasma levels of CAV1 and -2, and examined correlations with clinicopathological characteristics such as Gleason grade and clinical T stage. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate CAV1 and CAV2 mRNA in PC cell lines. We also introduced CAV1- and CAV2-specific small interfering (siRNA) into PC3 cells to knock-down (KD) both molecules, and examined its influence on the expression of these genes between PC3 CAV1 and -2 KD cells and control cells. RESULTS: Plasma CAV1 and -2 levels in patients with CRPC were significantly higher than in those with non-CRPC (CAV1, p=0.003; CAV2, p<0.001). Plasma levels of CAV1 and -2 were significantly correlated (p<0.001). However, we did not find any significant relationship between CAV1 or CAV2 expression and clinicopathological factors. ELISA and real-time qRT-PCR showed that both proteins and mRNAs in PC3 cells were significantly over-expressed compared to LNCaP cells (p<0.001). In PC3 CAV1 KD cells, expression of CAV2 was suppressed and confirmed the linkage of CAV2 KD and suppression of CAV1 expression. CONCLUSION: There was a significant correlation between plasma CAV-1 and -2 levels and progression of PC. CAV1 and -2 were highly expressed in the PC3 compared to the LNCaP cell line. Our findings support the potential of these molecules as therapeutic targets for CRPC.

Laparoscopic anterior pelvic exenteration for locoregionally advanced rectal cancer directly invading the urinary bladder: A case report of low anterior resection with en bloc cystectomy for sphincter preservation.

Laparoscopic multi-visceral resection in patients with T4 colorectal cancer remains controversial. A 73-year-old man was admitted to the hospital for rectosigmoid cancer directly invading the urinary bladder trigone without distant metastasis. We successfully performed complete resection by laparoscopic anterior pelvic exenteration while preserving the anus. After laparoscopic mobilization of the rectum, urinary bladder, and prostate, the urethra and urethral catheter were dissected to reveal the lower rectum. By pulling the urethral catheter toward the head, the prostate was excised retrogradely from the lower rectum anterior wall. The lower rectum was resected and anastomosed by the double stapling technique with a safe distal margin from the tumor. Pathological findings of the resected specimen indicated no residual tumor in the surgical margin. There was no evidence of recurrence 34 months after surgery. En bloc, R0, laparoscopic anterior pelvic exenteration for T4 rectal cancer is feasible. However, further studies with long-term follow-up are required to resolve oncological outcomes.

Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis.

Resistance to or relapse after androgen deprivation therapy (ADT) remains a significant problem in patients with prostate cancer. Several studies have hypothesized that the overexpression of MET and the activating signaling axis in prostate cancer cells are associated with castration-resistant prostate cancer (CRPC). On the other hand, the expression of human kallikrein 1-related peptidase (KLK) 4, which activates plasma HGF activator zymogen, in prostate cancer patients with bone metastasis or advanced stage has also been reported. In this study, we analyzed the expression and phosphorylation of MET along with KLK4 by immunohistochemistry in 62 formalin-fixed paraffin-embedded sections of prostate cancer collected by needle biopsy at our hospital between 2006 and 2011. As a result, the phosphorylation of MET was observed in 56% (35 of 62 cases) and positively correlated with worsening PSA relapse rate in a group of ADT-treated patients (P = 0.0445), suggesting significant correlation with CRPC. Overexpression of KLK4 was observed in patients with high T stage (P = 0.0001) and high Gleason score (P = 0.0146), and the expression was correlated with the phosphorylation of MET (P = 0.0002). Pathologically, strong MET phosphorylation observed in specific architectures in prostate cancer, such as cribriform structures, ill-defined glands or solid patterns, suggested the significance of MET activation in promoting the architectural formation of prostate cancer. In addition, high positivity rate (80%) of phospho-MET staining at high-grade prostatic intraepithelial neoplasia (HGPIN) may indicate the importance of the activating signaling axis in the carcinogenesis of prostate cancer.

Effect of dutasteride on microvessel density in benign prostatic hyperplasia.

AIM: Dutasteride, a dual 5α-reductase inhibitor, is used to treat benign prostatic hyperplasia (BPH). However, its histopathological effects on the morphometrics of blood vessels and glands are still controversial. This study aimed to assess the histopathological effects of dutasteride in cases of BPH in a retrospective manner. PATIENTS AND METHODS: Patients with BPH were administered 0.5 mg of dutasteride daily or left untreated prior to undergoing holmium laser enucleation of the prostate (HoLEP). After HoLEP, remaining prostatic peripheral tissue at the bladder neck and the apex was resected. Each specimen was subjected to hematoxylin/eosin and immunohistochemical staining for CD31, and microvessel density (MVD) was analyzed. RESULTS: In the dutasteride-treated group (n=14), the mean duration of administration was 7.07±2.46 weeks. MVD was significantly lower at the bladder neck side in the dutasteride-treated group than in the control group (p=0.018). CONCLUSION: The present study, to our knowledge for the first time, assessed MVD by evaluating the bladder neck and apex sides of the remaining prostatic peripheral tissue after HoLEP, allowing evaluation of MVD in more detail without intraoperative damage of the peripheral tissue, such as through heat denaturation. Dutasteride reduces MVD in the bladder neck side of the prostate among patients with BPH and may lead to decreased risk of perioperative prostatic urethral bleeding.

Cyclooxygenase 2 genotypes influence prostate cancer susceptibility in Japanese Men.

This study aims to evaluate the relationship between the cyclooxygenase 2 (COX2) G1195A (rs689465) polymorphism and the risk of prostate cancer in a Japanese population and the associations between COX2 polymorphisms and clinicopathological characteristics, including Gleason grade and prostate-specific antigen (PSA) grade. We recruited 134 patients with prostate cancer and 86 healthy controls matched for age and smoking status. The COX2 G1195A polymorphism status was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Genotype distributions (p = 0.028) and allelic frequencies (p = 0.014) differed significantly between prostate cancer and control groups in terms of the COX2 G1195A polymorphism (Pearson's χ (2) test). Logistic regression analysis of case and control outcomes showed an odds ratio between the GG and AA genotypes of 3.15 (95% confidence interval = 1.27-8.08, p = 0.014), indicating an increased risk of prostate cancer associated with the AA genotype. Subset analysis revealed no significant associations between this polymorphism and clinicopathological characteristics of prostate cancer. This study demonstrated a relationship between the COX2 G1195A variant and prostate cancer risk. This polymorphism may merit further investigation as a potential genomic marker for the early detection of prostate cancer. Our results support the hypothesis that rs689465 influences susceptibility to prostate cancer; however, prostate cancer progression was not associated with rs689465 in a Japanese population.

Increased plasma caveolin-1 levels are associated with progression of prostate cancer among Japanese men.

AIM: Up-regulation of caveolin-1 (CAV1) is associated with aggressive prostate cancer. Among Caucasian and African-American patients, plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in those with hormone-sensitive prostate cancer (non-CRPC), which implies that CAV1 could be a therapeutic target for CRPC. Here, we evaluated associations between plasma CAV1 levels and these types of cancer in Japanese men, and CAV1 expression in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. MATERIALS AND METHODS: Plasma samples were obtained from 58 patients with prostate cancer: 36 with CRPC and 22 with non-CRPC. Enzyme-linked immuno sorbent assay (ELISA) kits were used to determine CAV1 plasma levels; qRT-PCR and western blots were used to evaluate the expression of CAV1 mRNA and protein in cell lines. RESULTS: Plasma CAV1 levels in patients with CRPC were greatly higher than in those with non-CRPC (1.46±1.37 ng/ml in CRPC; 0.56±0.32 ng/ml in non-CRPC, p<0.004). Western blot and real-time qRT-PCR showed CAV1 protein and mRNA in PC3 cells to be significantly overexpressed compared to its expression in LNCaP cells (p<0.0001). CONCLUSION: Our results showed a relationship between CAV1 expression and prostate cancer progression, and support the possibility of CAV1 as a therapeutic target for CRPC.