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Background and Objective: Most of the studies on metastasectomy in renal cell cancer are based on metachronous, often oligometastatic disease. Prior data on the impact of metastasectomy in synchronous metastatic renal cell cancer (mRCC) is, however, very scarce. We aimed to investigate the role of complete and incomplete metastasectomy in a large, nationwide patient population., Methods: We analyzed nationwide data, including all synchronous mRCC cases in Finland diagnosed during a 6-year period identified from the Finnish Cancer Registry, and complemented with patient records from the treating hospitals. We only included the patients who underwent removal of the primary tumor by nephrectomy. We performed univariate and multivariable adjusted analysis to identify the effect of metastasectomy on overall survival (OS) and cancer-specific survival (CSS)., Results: We included 483 patients with synchronous mRCC. Overall, 57 patients underwent complete and 96 incomplete metastasectomy, while 330 patients had no metastasectomy. The median OS was 17.9 and CSS 17.2 months for all patients. The median OS and the median CSS were 59.3 and 60.8 months for the complete, 21.9 and 25.1 for the incomplete, and 14.5 and 14.8 months for the no metastasectomy groups ( p  < 0.001 for differences). In both applied multivariable statistical models, the OS and CSS benefit from complete metastasectomy remained significant (hazard ratios (HRs) varied between 0.42 and 0.54, p  < 0.001) compared with the no metastasectomy group. However, there was no improvement in survival estimates in the incomplete metastasectomy group compared with the no metastasectomy group (HRs varied between 1.04 and 1.10, p  > 0.40)., Conclusions: Complete metastasectomy, when possible, can be considered as a treatment option for selected patients with synchronous mRCC who are fit for surgery. By contrast, we found no survival benefit from an incomplete metastasectomy suggesting that such procedures should not be performed for these patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.L. declares reimbursements from Orion Corp. for attending a scientific meeting, outside the submitted work. M.H.V., P.O., and H.R. declare that they have no competing interests.

Background: Population-based survival results after radical cystectomy (RC) are limited. Our objective was to report short and long-term survival results after RC for bladder cancer from Finland in a population-based setting., Materials and Methods: The Finnish National Cystectomy Database containing retrospectively collected essential RC data covering the years 2005-2017 was combined with the survival data from the Finnish Cancer Registry. Kaplan-Meier plots were used to estimate survival and the survival graphs were illustrated according to the final pathological staging. Centers were divided according to operational volume, and the results were then compared using Pearsons's Chi-squared test., Results: A total of 2047 patients were included in the study. 30-, and 90-day mortality was 1.3%, and 3.8%, respectively. The OS of the entire RC population at 5- and 10 years was 66% and 55%, and CSS was 74% and 72%, respectively. Center volume did not significantly associate with surgical mortality or long-term survival. The 5- and 10-year OS according to pT-category was 87% and 74% for pT0, 85% and 69% for pTa-pTis-pT1, 70% and 58% for pT2, 50% and 42% for pT3 and 41% and 30% for pT4. The corresponding 5- and 10-year CSS rates were 96% and 93% for pT0, 91% and 90% for pTa-pTis-pT1, 78% and 75% for pT2, 56% and 55% for pT3 and 47% and 44% for pT4. The 5- and 10-year OS rates in patients with no lymph node metastases (pN-) were 74% and 62%, and CSS 82% and 80%, respectively. If lymph nodes were positive (pN+), the corresponding OS rates were 44% and 34% and CSS 49% and 48%, respectively., Conclusion: RC survival results have improved in contemporary series and are associated with the pTNM-status. The nationwide results from Finland demonstrate outcome comparable to high volume single-center series.

Since the introduction of targeted therapies (TTs) for metastatic renal cell cancer (mRCC) in 2005, a limited amount of epidemiological data on efficacy of modern drug therapies for synchronous mRCC has been published. We present a comprehensive nationwide cohort including all cases of primarily metastasized renal cell cancer among adults diagnosed between 2005 and 2010, based on data from the Finnish Cancer Registry and patient records from treating hospitals. Applied treatment protocols and survival outcomes were analyzed. A total of 977 patients were included in the analysis; 499 patients were diagnosed between 2005 and 2007 and 478 patients were diagnosed between 2008 and 2010. The median overall survival (OS) was 8.80 months (95% confidence interval (CI): 7.60-10.02). The median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8-13.4 vs. 7.0; 95% CI: 5.7-8.3 months, p ≤ 0.001). A total number of 524 (53.8%) patients received drug therapy. Altogether, TTs including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTORi), and vascular endothelial growth factor inhibitor covered 331 (63.2%) of first-line treatments, whereas interferon and its combinations with chemotherapy were used for 186 (35.5%) patients. The median OS rates for TT and interferon as first-line therapy groups were 19.9 (16.9-22.8) and 14.9 (12.3-17.4) months, respectively. The OS for patients who did not receive drug therapy after cytoreductive nephrectomy was dismal. We found that the OS estimate of mRCC patients in Finland has improved since the introduction of tyrosine kinase inhibitors. However, the prognosis remains poor for frail, elderly patients with an impaired performance status., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Lauri Laru et al.)

Background: The purpose of this study was to evaluate the effects of cytoreductive nephrectomy (CN) and metastasectomies on the survival of patients with synchronous metastatic renal cell cancer (mRCC) using real-life, population-based national dataset., Methods: Nationwide data, including all cases of synchronous mRCC in Finland diagnosed on a 6-year timeframe, based on the Finnish Cancer Registry and complemented with patient records from the treating hospitals, were analyzed. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 3-4 were excluded. Univariate and adjusted multivariable survival analysis were performed, including subgroup analysis for patients with different medical therapies. Nephrectomy complications were also analyzed., Results: A total of 732 patients were included in the analysis. CN was performed for 389 (53.1%) patients, whereas 68 (9.3%) patients underwent nephrectomy and metastasectomies of all lesions (surgery with curative intent). Median overall survival (OS) for patients who did not undergo nephrectomy was 5.9 (95% confidence interval [CI] = 4.6-7.2) months. Patients who had a CN had a median OS of 16.6 (95% CI = 14.2-19.1, p < 0.001) months, whereas patients who had surgery with curative intent had a median OS of 51.3 (95% CI = 36.0-66.6, p < 0.001) months. The survival benefit of CN and metastasectomies remained significant in all medical therapy subgroups and in both of the applied multivariable statistical models., Conclusions: Surgical treatment of metastatic renal cell cancer is associated with a significant survival benefit in patients with good and moderate performance status, regardless of the chosen medical therapy.

Objectives: To evaluate the diagnostic value of multiparametric prostate magnetic resonance imaging (mpMRI) prior to radical prostatectomy with curative intent for the detection of cribriform architecture (CA) and intraductal prostate cancer (IDC), which have recently been demonstrated to be adverse pathological features., Patients and Methods: The study included 124 men who underwent mpMRI prior to radical prostatectomy at our centre. Preoperative mpMRI, prostatectomy histology and clinical follow-up details were reviewed retrospectively. The diagnostic value of mpMRI was evaluated on the basis of the detection rate. Secondly, the prognostic significance of CA/IDC among grade group (GG)2 cancers with regard to biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier analysis, with the log rank test and Fisher's exact test., Results: Pathological examination of radical prostatectomy specimens identified CA/IDC in 89 of 124 cases (71%) and mpMRI identified 86/95 of tumours including any CA/IDC with a sensitivity of 90.5% (95% confidence interval 82.8-95.6%). When localization of the lesions was compared, there was an association between the highest Prostate Imaging-Reporting and Data System classification and the highest pathological grade in 106 of the 124 cases (85.5%). In patients with GG2 lesions, BCR occurred in 11 of 31 (35.5%) with CA/IDC and two of 21 (9.5%) without CA/IDC (P = 0.034)., Conclusion: Multiparametric MRI has good sensitivity for detection of pathological primary prostate cancer, including most cases with CA/IDC; however, reliable prediction of GG2 tumours with CA/IDC for individual risk stratification remains challenging., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Background: Neoadjuvant chemotherapy (NAC) is underutilized in the treatment of bladder cancer (BC)., Objective: To investigate the effect of NAC on the risk of surgical complications for radical cystectomy (RC) in a population-based setting., Design, Setting, and Participants: All radical cystectomies performed in Finland during 2005-2014 were included in the study. Data were collected retrospectively using a web-based data collection platform. Complications were recorded for 90 d using the Clavien classification. Patients treated with NAC were compared to patients receiving RC alone using three cohorts and approaches: the entire cohort, a neoadjuvant period cohort, and a matched cohort., Outcome Measurements and Statistical Analysis: For all three cohorts, odds ratios (ORs) were estimated using simple binary logistic regression. In addition, a multivariable stratified logistic model with propensity score was used. For the matched cohort analysis, both univariate and adjusted analyses were carried out., Results and Limitations: During 2005-2014, 1427 RCs were performed in Finland, of which 1385 were included in the analyses. NAC was introduced in 2008, and 231 patients (16%) were assigned to NAC and 214 (15%) received two or more cycles of chemotherapy. Within 90 d, 61% of patients experienced complications and mortality was 4% (1.9% in the NAC group, and 4.4% in the RC-alone group). In simple binary logistic regression, NAC patients had significantly fewer complications, but this was not observed in multivariable or propensity score analyses. In the matched cohort analyses, no differences in complication rates could be observed. None of the analyses demonstrated higher complication rates in the NAC group., Conclusions: Our retrospective study reports on nationwide use of NAC for BC and demonstrates that NAC does not increase RC morbidity., Patient Summary: Chemotherapy given before radical surgery does not increase severe postoperative complications in the treatment of bladder cancer., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited., Methods: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer., Results: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001)., Conclusions: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Objectives: To investigate the value of the maximal lesion diameter on preoperative multiparametric/bi-parametric magnetic resonance imaging for estimating the risk of adverse radical prostatectomy pathology., Patients and Methods: Consecutive patients (n = 162) with prostate multiparametric or biparametric magnetic resonance images acquired before prostatectomy were retrospectively stratified into two groups: 65 patients with normal MRI (n = 18) or a suspicious lesion <15 mm in diameter (n = 47), and 97 patients with a lesion diameter ≥15 mm. The presence of extraprostatic extension, margin positivity, seminal vesicle invasion, and lymph node metastasis was examined in these groups using logistic regression analysis, including preoperative clinical parameters (prostate-specific antigen concentration, biopsy Gleason grade group, clinical T-stage, and D'Amico risk group)., Results: The prevalence of extraprostatic extension, margin positivity, and seminal vesicle invasion was 53.1% (86/162), 22.8% (37/162), and 17.9% (29/162), respectively. Lymphadenectomy was performed in 64 men, of whom 14 had lymph node metastasis. Lesion diameter ≥15 mm strongly predicted extraprostatic extension (Odds ratio: 7.94, 95% confidence interval: 3.87-16.28, p < 0.001), margin positivity (Odds ratio: 7.86, 95% confidence interval 2.63-23.51, p < 0.001), and seminal vesicle invasion (Odds ratio: 7.57, 95% confidence interval 2.18-26.22, p = 0.001). Lesion diameter ≥15 mm was an independent risk factor for adverse prostatectomy pathology. Lesion diameter ≥20 mm, but not ≥15 mm, was a significant risk factor for lymph node metastasis., Conclusion: Magnetic resonance imaging lesion diameter ≥15 mm is an independent risk factor for extraprostatic extension, margin positivity and seminal vesicle invasion.

Purpose: The purpose of this study was to compare bacteriological urinalysis findings using 3 urinary sample collection methods (clean stoma catheterization, urine dripping from the stoma, urine collected from the clean urostomy pouch) in ileal conduit urinary diversion patients., Design: Randomized controlled trial., Sample and Setting: Twenty-seven patients with ileal conduit urinary diversion from an outpatient urology clinic were enrolled; 9 patients were seen twice, for a total of 36 subjects and comparisons., Methods: Data were collected during a clinic visit by a trained research nurse. Patients were randomized into 2 groups: group A had the first urine sample collected by clean stoma catheterization, followed by sample collection by urine dripping from the stoma; group B had the first urine sample collection by urine dripping from the stoma, followed by sample collected by clean stoma catheterization. All patients had a third urine sample collected from a factory-clean urostomy pouch. Bacteriological urinalysis findings were compared among methods. Descriptive analyses were summarized using mean, percentage, and frequency. The mean ages of the patients between the groups were compared with the t test. Other between-group comparisons were performed using the Fisher exact test. Urinary culture finding differences among the same patients were evaluated using the McNemar test. Sensitivity and specificity of the different urine sample collection methods were calculated assuming urine sample collection by catheterization as a reference method., Results: Uropathogen bacteria were detected in urinary culture in 16 of 36 samples (44%) collected by clean stoma catheterization, 15 of 36 samples (42%) collected by urine dripping directly from the stoma, and 13 of 35 samples (37%) collected from the clean urostomy pouch. Significant differences among the urine collection methods were not detected. Assuming catheterization as the most reliable method of sample collection, the sensitivity and specificity of the urine dripping from stoma collection method were 81.3% and 90.0%, respectively. The sensitivity and specificity of the urostomy pouch collection method were 73.3% and 90.0%, respectively. Among the same patients, there were no significant differences in the incidence of uropathogen bacteria when clean stoma catheterization was compared with urine dripping from the stoma and urostomy pouch methods., Conclusion: This study provides clinically relevant information regarding urine collection methods in ileal conduit patients. Urinary sample collection by urine dripping directly from the stoma or collected from a clean urostomy pouch provided similar uropathogen bacteria findings compared with sample collection by clean stoma catheterization.

Patients who undergo early androgen-deprivation therapy for prostate cancer may eventually develop castration-resistant prostate cancer. However, no optimal treatment for non-metastasized castration-resistant prostate cancer has yet been established. In the present retrospective, single-institutional study, the radiotherapy (RT) outcomes were evaluated in patients who underwent androgen-deprivation therapy for non-metastatic prostate cancer and subsequently developed castration-resistant disease. Following a thorough chart review, the data of 21 patients with castration-resistant prostate cancer who were treated between 2000 and 2010 with external beam radiation therapy (EBRT) at a prostate radiation dose of >45 Gy were evaluated. Of the 21 patients, 16 (76%) developed biochemical recurrence after RT, with a mean time to biochemical recurrence of 17 months. A total of 18 patients succumbed to the disease during follow-up, with a mean survival of 3 years after RT. A radiation dose of >66 Gy was associated with a longer time to biochemical recurrence after RT (P=0.011) and a longer survival, compared with a dose of ≤66 Gy (P=0.028). The mean overall survival time after RT was 42 months and did not depend on the primary hormonal treatment. Prostate-specific survival time was negatively associated with the Gleason score at diagnosis. The prostate-specific antigen (PSA) concentration prior to RT was a prognostic factor for biochemical recurrence of prostate cancer after RT, as well as for prostate cancer-specific survival. Finally, the multivariate analysis revealed that age, PSA concentration prior to RT and a high Gleason score were independent prognostic factors for prostate cancer-specific survival. Overall, our study findings demonstrated that disease progression was common after EBRT for castration-resistant prostate cancer and that survival was limited. However, young patients and those with low-risk disease at the time of diagnosis may benefit from RT.

The aim of this study was to evaluate risk factors for biochemical failure (BF) following permanent prostate seed 125 I brachytherapy for prostate cancer. The study reviewed the medical records of 607 patients with biopsy-proven prostate adenocarcinoma who were treated at Oulu University Hospital between 2001 and 2014. Clinical characteristics at diagnosis, treatment-related data and follow-up data were collected to identify potential risk factors for BF, which was defined using the Phoenix criteria [prostate-specific antigen (PSA) increase >2 µg/l from the PSA nadir concentration, which defined as the lowest PSA concentration observed after BT]. The median follow-up was 81 months. BF was detected in 117 (19.3%) patients. The PSA nadir concentration was associated with BF. The mean times to BF were 114 [95% confidence interval (CI): 112-116] and 55 (95% CI: 47-63) months for patients with PSA nadir concentrations <0.5 and ≥0.5 µg/l, respectively (P<0.001). Patients with underlying hypertension or diabetes tended to develop BF more rapidly. For patients without and with hypertension, the mean times to BF were 104 (95% CI: 100-107) and 98 (95% CI: 93-103) months, respectively (P=0.035). For patients without and with diabetes, the mean times to BF were 103 (95% CI: 100-106) and 89 (95% CI: 77-102) months, respectively (P=0.006). The overall survival and prostate cancer-specific survival rates were 90.3 and 98.0%, respectively. The mean overall survival and prostate-cancer specific survival times were 147 and 158 months, respectively. Therefore, PSA nadir level was identified as a clear risk factor for BF. In addition, BF tended to develop more rapidly among patients with underlying hypertension or diabetes. These risk factors should be considered, and individually tailored follow-up may be useful for identifying patients requiring more intense follow-up for early BF detection.

Controversy exists regarding a possible association between prostatitis and prostate cancer. To further evaluate the incidence of prostate cancer following prostatitis, a study of prostate cancer incidence in a cohort of Finnish men was performed. The original survey evaluating self-reported prostatitis was conducted in 1996-1997. A database review was conducted focusing on prostate cancer diagnoses in the cohort. In 2012, there were 13 (5.2%) and 27 (1.8%) prostate cancer cases among men with (n=251) and without (n=1,521) prostatitis symptoms, respectively. There were no significant differences in age, primary therapy distribution, prostate-specific antigen levels, Gleason score, clinical T-class at the time of prostate cancer diagnosis, or time lag between the original survey and prostate cancer diagnosis. The standardized incidence ratio (SIR) of prostate cancer was 1.16 [95% confidence interval (CI), 0.62-1.99] and 0.44 (95% CI, 0.29-0.64) among men with and without prostatitis symptoms, respectively. After 15 years of follow-up subsequent to self-reported prostatitis, no evident increase in incidence of prostate cancer was detected among Finnish men with prostatitis symptoms. The higher percentage of prostate cancer among men with prostatitis symptoms appears to be due to coincidentally low SIR of prostate cancer among men without prostatitis symptoms, and may additionally be due to increased diagnostic examinations. Further research is required to confirm this speculation.

Background: Multiparametric magnetic resonance imaging (MP-MRI) may improve the detection of clinically significant prostate cancer (PCa)., Objective: To compare MP-MRI transrectal ultrasound (TRUS)-fusion targeted biopsy with routine TRUS-guided random biopsy for overall and clinically significant PCa detection among patients with suspected PCa based on prostate-specific antigen (PSA) values., Design, Setting, and Participants: This institutional review board-approved, single-center, prospective, randomized controlled trial (April 2011 to December 2014) included 130 biopsy-naive patients referred for prostate biopsy based on PSA values (PSA <20 ng/ml or free-to-total PSA ratio ≤0.15 and PSA <10 ng/ml). Patients were randomized 1:1 to the MP-MRI or control group. Patients in the MP-MRI group underwent prebiopsy MP-MRI followed by 10- to 12-core TRUS-guided random biopsy and cognitive MRI/TRUS fusion targeted biopsy. The control group underwent TRUS-guided random biopsy alone., Intervention: MP-MRI 3-T phased-array surface coil., Outcome Measurements and Statistical Analysis: The primary outcome was the number of patients with biopsy-proven PCa in the MP-MRI and control groups. Secondary outcome measures included the number of positive prostate biopsies and the proportion of clinically significant PCa in the MP-MRI and control groups. Between-group analyses were performed., Results and Limitations: Overall, 53 and 60 patients were evaluable in the MP-MRI and control groups, respectively. The overall PCa detection rate and the clinically significant cancer detection rate were similar between the MP-MRI and control groups, respectively (64% [34 of 53] vs 57% [34 of 60]; 7.5% difference [95% confidence interval (CI), -10 to 25], p=0.5, and 55% [29 of 53] vs 45% [27 of 60]; 9.7% difference [95% CI, -8.5 to 27], p=0.8). The PCa detection rate was higher than assumed during the planning of this single-center trial., Conclusions: MP-MRI/TRUS-fusion targeted biopsy did not improve PCa detection rate compared with TRUS-guided biopsy alone in patients with suspected PCa based on PSA values., Patient Summary: In this randomized clinical trial, additional prostate magnetic resonance imaging (MRI) before prostate biopsy appeared to offer similar diagnostic accuracy compared with routine transrectal ultrasound-guided random biopsy in the diagnosis of prostate cancer. Similar numbers of cancers were detected with and without MRI., Trial Registration: ClinicalTrials.gov identifier: NCT01357512., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: This study was performed to evaluate the impact of baseline characteristics and treatment methods on the outcome of sporadic renal angiomyolipoma (AML)., Methods: This was a pooled analysis of individual data of 441 patients with AML retrieved from 58 studies and 3 institutional series., Results: Ninety-three patients underwent nephrectomy, 163 partial nephrectomy/enucleation, 128 embolisation, 19 cryoablation, 6 radiofrequency ablation, and 32 conservative treatment. Their mean follow-up period was 44.5 months. Patients who experienced major bleeding at presentation had significantly larger tumours than did those without bleeding (mean diameter, 10.1 vs. 5.9 cm, respectively; p < 0.0001). A total of 9.4 % and 26.4 % of bleeding tumours had a diameter of <4 and <6 cm, respectively. A tumour diameter of ≥8.0 cm (hazard ratio, 2.07; 95 % confidence interval, 1.20-4.77) and the treatment method (p = 0.001) were independent predictors of re-intervention. The risk of re-intervention was significantly higher after embolisation, particularly for large tumours (5-year rate of freedom from re-intervention: diameter of ≥8.0 cm, 49.2 %; diameter of <8.0 cm, 74.8 %; p = 0.018). Conservatively treated AMLs had a mean baseline diameter of 3.2 ± 2.7 cm; after 41 months, their mean diameter was 3.7 ± 3.1 cm (p = 0.109)., Conclusions: The prevalence of major bleeding is high in sporadic AMLs with a diameter of >6 cm. These results suggest that conservative treatment can be considered in AMLs of <6 cm in diameter. Among current treatment methods, embolisation was associated with a significantly higher risk of re-intervention. Further studies are needed to define risk factors for bleeding and assess the relative benefits of different treatment modalities.

Toll-like receptor 9 (TLR9) is a cellular DNA-receptor of the innate immune system that is widely expressed in cancers. We demonstrated that low tumor TLR9 expression predicts poor disease-specific survival in triple negative breast cancer (TNBC) and renal cell carcinoma (RCC). We hypothesized that this is because TLR9 expression affects tumor immunophenotype. To begin to test this, we compared the number of tumor infiltrating CD8 + T lymphocytes with TLR9 expression in treatment naïve breast cancer ( n = 197) and RCC ( n = 94) cohorts with known TLR9 expression status. CD8 + T lymphocyte counts were assayed with image analysis after immunohistochemistry (IHC). Tumor TLR9 expression was not correlated with CD8 + T cell counts in breast cancer or RCC. CD8 + T cell counts were significantly associated with tumor proliferation index in TNBC, but not in non-TNBC. CD8 + T cell counts were also significantly associated with tumor grade in non-TNBC, but not in TNBC. In RCC, CD8 + T cell counts were significantly associated with tumor stage. CD8 + T cell counts were significantly associated with prognosis in TNBC and RCC, but the presence of CD8 + T cells in these tumors had opposite effects on disease-specific survival: High CD8 + counts were associated with better prognosis in TNBC and worse prognosis in RCC. Among TNBC patients, those with low tumor TLR9 and low CD8 + T cell counts had the poorest prognosis (log-rank p = 0.0002 vs. high tumor TLR9 and high CD8 + T cell count). In conclusion, pre-treatment tumor TLR9 status is not associated with tumor infiltrating CD8 + T lymphocytes in TNBC or RCC. The combination of TLR9 and CD8 + TIL count might be a novel composite prognostic marker in TNBC.

The purpose of this study was to evaluate the utility of off-label use of DuraSeal polyethylene glycol (PEG) gel in low-dose rate (LDR) prostate brachytherapy seed implantation to reduce rectal doses. Diluted DuraSeal was easy to use and, in spite of a clearance effect, useful in decreasing D₂cc rectal doses., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.

Background: Sacral neuromodulation operations have usually been performed based on 2D fluoro images. However, sacral nerve stimulation lead implantation may be challenging when the normal anatomy is confused by obesity or congenital anomalies. Thus the surgical navigation and intraoperative imaging methods could be helpful as those same methods have proven to be feasible methods for guiding other surgical operations. Our recent knowledge about the O-arm in trauma pelvic operations encouraged us to evaluate the usefulness of O-arm guided navigation in sacral neuromodulation. Similar navigation would be useful for complex sacral nerve stimulation lead implantations., Methods: In this preliminary article we report our experience of utilizing the orthopedically optimized O-arm to implant the S3 stimulation electrode in a patient. The 3D O-arm imaging was performed intraoperatively under surgical navigation control. General anesthesia was used. The obtained 3D image dataset was registered automatically into the patient's anatomy. The stimulation needle was guided and the tined lead electrode was implanted using navigation., Results: The bony sacral structures were clearly visualized. Due to automatic registration, the navigation was practicable instantly after the O-arm scanning and operation could be performed successfully under navigation control., Conclusions: To our knowledge, this is the first published tined lead implantation which was guided based on the surgical navigation and intraoperative O-arm images. In this case, the applied method was useful and helped the surgeon to demarcate the region of surgical interest. The method is slightly more invasive than the formal technique but could be an option in anatomically challenging cases and reoperations. However, further evaluation with larger patient series is required before definitive recommendations can be made.

Background: Prostate cancer is the most common cancer among men in many countries. The aim of the present study was to find out how the symptoms leading to a diagnosis, diagnostic procedures and stages of the disease among prostate cancer patients have changed over a period of 20 years., Methods: This retrospective chart review consisted of 421 prostate cancer patients whose treatment was started in the years 1982, 1987, 1992, 1997 and 2002 at the Oulu University Hospital. Earlier prostatic disorders, specific urological symptoms, diagnostic procedures, the TNM classification and histological grade were recorded., Results: The number of symptom-free prostate cancer patients increased over the 20 years, as did the number of men suffering from chronic prostatitis, although the latter increase was not statistically significant. A drop in the number of clinical T4 cases and increase of clinical T1 and clinical T2 cases was recorded but no clear change in the histological distribution occurred. The 5-year prostate cancer-specific survival improved significantly over the 20 years. The urologist was found to be the person who was contacted first most often., Conclusions: Our data indicate that the number of prostate cancer patients has increased hugely over the period from 1982 to 2002 and although the clinical T stage has moved towards earlier stages, the proportion of well differentiated cancers remains low, so that most patients have clinically significant cancer with the need of some form of therapy. Further, prostate cancer-specific survival improved significantly over the period.

Toll-like receptor-9 (TLR9) is a member of the innate immune system and recognizes bacterial and vertebrate DNA in cells. In addition to being expressed in cells of the immune system, it is widely expressed in various types of human cancer, including prostate cancer. We have previously demonstrated that synthetic TLR9 ligands induce invasion in TLR9-expressing prostate cancer cells in vitro . However, the role of TLR9 in the pathophysiology of prostate cancer is unclear. The expression of TLR9 in radical prostatectomy samples (n=186) was studied using immunohistochemistry. TLR9 staining scores were compared with tumor stage, Gleason score and prostate-specific antigen (PSA) concentration prior to treatment and progression-free survival. Results revealed that 124 (66.7%) of the tumors were strongly positive, 59 (31.7%) were weakly positive and 3 (1.6%) were negative, for cytoplasmic TLR9 immunostaining in cancer cells. There was no significant association between cytoplasmic TLR9 expression and distributions of pT-class, prostatectomy sample margin status, Gleason score and preoperative PSA value. Prostate cancer-specific progression-free survival was significantly longer for patients whose tumors were graded as negative for cytoplasmic TLR9 expression, as compared with patients whose tumors were strongly immunopositive for cytoplasmic TLR9 (P=0.009). In the Cox regression analysis, high TLR9 expression was an independent marker of poor prognosis in prostate cancer. Expression of TLR9 is associated with poor progression-free survival in prostate cancer patients who were treated by radical prostatectomy with curative intent.

Androgens are essential for the development of the prostate and prostate cancer. We examined androgen-regulated gene expression in the human prostate. Samples from benign and malignant prostate tissue and samples containing prostate tissue obtained from prostate cancer patients three days after surgical castration were further processed as probes for a GeneChip array. The comparison of gene expression profiles in castrated samples and in benign or malignant prostate tissue samples revealed androgen-regulated genes. We further evaluated the genes which were differentially expressed in benign and malignant prostate samples. The androgen-regulated expression of dual specificity phosphatase 1 (DUSP1) was confirmed in the LNCaP prostate cancer cell line, as the expression of DUSP1 increased with androgen treatment over the course of time. The expression of the genes CRISP3, PCA3, OR51E2, HOXC6, AGR3, AMACR and SLC14A1 was affected by castration in addition to differential expression in the benign and malignant prostate. These sample results require further investigation for the role of AGR3 and SLC14A1 in prostate cancer as these associations have not been reported previously.

Background: Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC., Methods: TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery. The TLR9 staining intensity was compared with clinical parameters., Results: Of the studied tumours, 112 (81%) exhibited cytoplasmic TLR9 immunostaining. No association was detected between cytoplasmic TLR9 immunoexpression intensity and stage, nuclear grade, histological subtype or tumour necrosis. Cytoplasmic TLR9 immunoexpression was, however, a marker of favourable RCC specific survival both in univariate analysis and in multivariate regression model., Conclusions: We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC.

The HuR protein is a nucleocytoplasmic protein which plays an important role in the regulation of mRNA stability, and dysregulation of its expression has been linked to carcinogenesis. We studied 152 patients with primary renal cell carcinoma (RCC) who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of HuR and cyclooxygenase-2 (COX-2) was determined by immunohistochemistry using monoclonal antibodies. The immunostaining results were associated with patient age, clinical stage, Fuhrman grade and patient outcome. Cytoplasmic expression of HuR and COX-2 was positive in 37 (25%) and 22 (15%) of the tumours, respectively. The expression of HuR was associated with stage. The expression of COX-2 was associated with stage and nuclear grade. The RCC-specific survival was reduced in patients whose tumours expressed HuR or COX-2. The hazard ratio (HR) of patients with HuR-expressing tumours was 2.18 (95% confidence interval (CI), 1.16-4.09; p = 0.015) and the HR of patients with COX-2-expressing tumours was 2.29 (95% CI, 1.15-4.54; p = 0.018). In the Cox regression analysis the only independent prognostic factor was stage (p < 0.001). Treatment of an RCC cell line (769-P) with HuR-targeted small interfering RNA resulted in the reduced expression of HuR and COX-2. We conclude that cytoplasmic HuR expression is associated with reduced RCC-specific survival. The HuR protein regulates the expression of COX-2 in RCC cells, which is one potential mechanism of action for the HuR-associated aggressive behaviour of RCC.

Oxidative stress markers and peroxiredoxins are connected to cancer. A large set of urinary bladder carcinomas were studied for the expression of nitrotyrosine and 8-hydroxydeguanosine (8OHdG), two markers indicating oxidative damage. Serum and urine 8-OHdG were assessed in a subset of patients. We also analysed immunohisto-chemically the expression of nrf2, keap1, all six peroxiredoxins (prx) and thioredoxin (trx) in these tumors. 15 % of the cases showed 8OHdG and 36 % nitrotyrosine positivity. Expression of nitrotyrosine and 8OHdG associated with a poor prognosis (p=0.050, p=0.011, respectively). Peroxiredoxin positivity ranged from 39 % to 84 % lowest expression being for prx 4 and highest for prx 3. Prx 4 expression associated with a poor prognosis (p=0.025) with high grade (p=0.044) and larger tumors (p=0.023). Cytoplasmic trx positivity was seen in 91 % and nuclear in 59 % of tumors. Nuclear and cytoplasmic trx associated with each other (p<0.001), and nuclear trx associated with prx 6 (p=0.001), prx 2 (p<0.001), and prx 5 (p<0.001). 8OHdG associated with nuclear trx positivity (p=0.002), inversely with prx 1 (p=0.025) and with keap1 (p=0.020). Nuclear nrf2 was associated with nitrotyrosine (p=0.042). The results show that the amount of oxidative stress in urinary bladder tumors affects the prognosis of the patients. Of antioxidative enzymes, prx4 associated with an unfavourable prognosis. Selective inhibition of prx4 expression might then be one additional option of treatment of bladder cancer.

Objective: Sacral neuromodulation is a treatment modality for voiding dysfunction that is resistant to conventional medical and surgical treatments. In Finland, sacral neuromodulation has been used for the treatment of urgency-frequency syndrome, non-obstructive urinary retention and painful bladder/interstitial cystitis since 1996., Material and Methods: The investigation retrospectively evaluated 180 tested patients, 74 of whom underwent permanent implantation of the InterStim device., Results: A positive test result leading to implantation was significantly more frequent among females than males. Among urinary retention patients, the patients with a positive test leading to implantation were significantly younger than those without implantation. The implantation operation time was significantly shorter when using a tined lead device compared with open electrode insertion (76 vs 122 min). The mean follow-up time was 41 months (range 0-143). Significant improvement after implantation was noted in the mean urinated volumes and number of daily urinations, as well as in the number of catheterizations in urgency-frequency syndrome and urinary retention, respectively. The subjective long-term outcome was similar in these indications. Surgical revision was required for 15 patients (20.3% of implanted patients)., Conclusions: The difference in gender distribution compared with earlier published series may be explained by a selection bias due to the limited referrals of female patients from gynaecologists. The results favour the use of a tined lead device because of the shorter operating room time. Furthermore, the outcome seems to be more favourable among patients with a staged implant procedure compared with a one-stage operation with a tined lead device.

The clinical course of renal cell carcinoma (RCC) can be difficult to predict. In this study we evaluated the prognostic value of anillin and Ki-67 in predicting survival in RCC. Immunohistochemical analysis using anillin and Ki-67 antibodies was performed on tissue microarrays constructed from paraffin-embedded specimens from 152 patients with primary RCC. The mean follow-up time was 90 months. Levels of anillin and Ki-67 staining were correlated with clinical factors, pathological features and survival. Anillin expression in cytoplasmic and nuclear fractions of the RCC cell line 786-O was examined using Western blot analysis. Cytoplasmic anillin immunopositivity was detected in 121 (83%) tumours. Nuclear anillin expression was present in 40 (27%) tumours and increased Ki-67 activity in 98 (66%) tumours. A positive association was found between nuclear anillin and Ki-67 proliferation activity (p=0.005). The mean RCC-specific survival times for anillin immunopositive and immunonegative tumours were 158 (95% CI 143-173) and 109 (78-141) months, respectively, with p=0.03. Increased Ki-67 activity showed a tendency towards a poorer prognosis, although this was not statistically significant. In the Cox regression analysis for cytoplasmic anillin, nuclear anillin or Ki-67 rate, and age, gender, stage and nuclear grade, the only significant factor in RCC-specific survival was stage (p<0.001). Western blot analysis showed anillin expression in both nuclear and cytosolic fractions of the RCC cell line. To conclude, anillin expression can be observed both in the cytoplasm and nuclei in patients with RCC. Cytoplasmic anillin expression is a marker of favourable prognosis in RCC patients.

Background: The CIP2A protein is a recently characterized oncoprotein which inhibits protein phosphatase 2A activity. Expression of CIP2A has been detected in several carcinomas, but its expression and significance in prostate cancer has not been examined so far., Methods: Expression of the CIP2A protein was studied using immunohistochemistry in prostate cancer (n = 59) and in benign prostatic hyperplasia (n = 20) specimens. The CIP2A staining scores were compared with several clinicopathological parameters., Results: Expression of CIP2A was increased in prostate cancer epithelium as compared with the benign hyperplastic epithelium (p < 0.001). The expression of CIP2A was associated with high Gleason scores (p < 0.001) and among patients treated with radical prostatectomy, CIP2A expression was associated with pre-treatment risk stratification (p = 0.011) and pathological T-class (p = 0.031). No statistically significant association was detected between CIP2A expression and prostate specific antigen concentrations., Conclusions: Expression of the CIP2A protein is increased in prostate cancer specimens and its expression is associated with poorly differentiated and high-risk tumors.

Background: Toll-like receptor-9 (TLR9) is a cellular receptor for bacterial and vertebrate DNA. In addition to cells of the immune system, it is also expressed in various human cancer cell lines, including prostate cancer. We demonstrated previously that synthetic TLR9 ligands induce matrix metalloproteinase-13-mediated invasion in TLR9-expressing prostate cancer cells in vitro. Other studies have suggested possible sex steroid regulation of the function of the various TLRs. The role of TLR9 in the pathophysiology of prostate or any cancer is, however, unknown., Methods: Expression of TLR9, androgen receptor (AR), or the estrogen receptors alpha (ERalpha) and beta (ERbeta) were studied with immunohistochemistry in prostate cancer (n = 62) and benign prostatic hyperplasia (n = 45) specimens. TLR9 staining scores were compared with tumor stage, Gleason score, prostate-specific antigen (PSA) concentrations before tissue sampling and with the staining scores of AR, ERalpha, and ERbeta., Results: TLR9 expression was statistically significantly increased in prostate cancer epithelium and stroma, as compared with the same cellular compartments in benign hyperplasia. Significantly increased (P = 0.04) TLR9 expression was detected in cancers with high Gleason score (>7, n = 23), as compared with lower Gleason scores (< or =7, n = 39). No statistically significant associations were detected between TLR9 expression scores and PSA concentrations or tumor staging. Prostate adenocarcinoma cells were all positive for TLR9, AR, and ERbeta but negative for ERalpha expression. In cancer stroma cells, increased TLR9 expression was associated with increased ERalpha expression., Conclusions: Expression of TLR9 is increased in prostate cancer specimens, especially in the most poorly differentiated forms.

Background: The purpose of the study was to examine serotonin, CD56, neurone-specific enolase (NSE), chromogranin A and synaptophysin by immunohistochemistry in renal cell carcinomas (RCCs) with special emphasis on patient outcome., Methods: We studied 152 patients with primary RCCs who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of neuroendocrine (NE) markers was determined by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, clinical stage, Fuhrman grade and patient outcome., Results: Eight percent of tumours were positive for serotonin, 18% for CD56 and 48% for NSE. Chromogranin A immunostaining was negative and only 1% of the tumours were synaptophysin immunopositive. The NSE immunopositivity was more common in clear cell RCCs than in other subtypes (p = 0.01). The other NE markers did not show any association with the histological subtype. Tumours with an immunopositivity for serotonin had a longer RCC-specific survival and tumours with an immunopositivity for CD56 and NSE had a shorter RCC-specific survival but the difference was not significant. There was no relationship between stage or Fuhrman grade and immunoreactivity for serotonin, CD56 and NSE., Conclusions: Serotonin, CD56 and NSE but not synaptophysin and chromogranin A are expressed in RCCs. However, the prognostic potential of these markers remains obscure.

Sorbitol is an intermediate in the polyol pathway, which converts from glucose to fructose by sorbitol dehydrogenase (SORD). Androgens are essential for the development of prostate cancer. We studied castration-induced gene expression changes in the human prostate using the GeneChip array, and identified SORD as being androgen-regulated in the human prostate. A putative androgen-responsive regulatory region at the SORD 5' promoter was identified using promoter deletion constructs in a luciferase reporter assay in COS-7 cells. Chromatin immunoprecipitation assay was used to assess the binding of androgen receptor to suggested androgen responsive regulatory region. Finally, the expression of SORD in the human prostate was evaluated in 29 prostate tissue samples by immunohistochemistry. The expression of SORD decreased after castration. Androgen supplementation to the LNCaP prostate cancer cell line led to a 7.5-fold increase in SORD mRNA expression. Furthermore, a chromatin immunoprecipitation assay proved that the androgen receptor can bind to this putative androgen-responsive regulatory region. Finally, the expression of SORD in the human prostate was localised to epithelial cells of both benign and malignant prostate tissue by immunohistochemistry. In prostate cancer, increased immunostaining was associated with high Gleason patterns and high serum prostate-specific antigen concentrations. These results show that SORD is a novel androgen-regulated gene in the human prostate and suggest the need for more detailed analysis of the physiological role of SORD in the prostate.

Background: Renal cell carcinoma (RCC) is a cancer of increasing incidence and mortality. Currently, there are no immunohistochemical prognostic markers for RCCs in routine use. The aim of this study was to examine for the first time the immunostaining of myosin VI in RCCs as well as its association with E-cadherin and beta-catenin immunostaining and the prognostic significance of these markers in RCCs., Methods: Our study population consisted of 152 patients who underwent surgery for RCCs between 1990 and 1999. The tumours were examined with three immunohistochemical markers: myosin VI, E-cadherin and beta-catenin., Results: The immunostaining for cytoplasmic myosin VI was common (72%). One-third of the tumours were immunopositive for nuclear myosin VI. Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades (p = 0.04 and p = 0.005, respectively), but not stages. There was no significant association between myosin VI immunostaining and the histological subtype of RCC. Nuclear myosin VI was associated with the nuclear expression of beta-catenin. A direct association could also be proven between membranous E-cadherin and cytoplasmic beta-catenin. Cytoplasmic myosin VI immunostaining was a marker of poorer prognosis in multivariate Cox regression model adjusted with stage and Fuhrman grade with hazard ratio 2.4 (95% confidence interval 1.1 to 5.0 with p = 0.024)., Conclusions: Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades, and there was a strong positive relationship between E-cadherin immunostaining and beta-catenin immunostaining in RCCs. Cytoplasmic myosin VI immunostaining was associated with poorer prognosis in RCCs.

Objective: Urinary bladder endometriosis is a severe form of endometriosis often requiring surgery. The several cases treated at our hospital in recent years has led us to evaluate the incidence of urinary bladder endometriosis in Finland., Methods: We performed a register-based analysis of incidence of urinary bladder endometriosis. The patients were identified according to registered diagnosis and operation codes., Results: Six urinary bladder endometriosis cases were diagnosed at Oulu University Hospital during 1991-2007. These cases have been presented. The annual incidence, as evaluated from The Finnish Care Register HILMO, increased from 3.6 to 9.4 cases/1,000,000 females aged 15-49 years per year during 1996-1999 and 2004-2007, respectively, in Finland., Conclusion: There is an apparent increase in incidence of urinary bladder endometriosis in Finland. The low number of cases detected at Oulu University Hospital, and the limitations of the incidence evaluation based on the HILMO register, exclude the presentation of an accurate incidence. The results presented warrant further and careful evaluation of potential increases in urinary bladder endometriosis elsewhere., (Copyright (c) 2010 S. Karger AG, Basel.)

Myosin VI, one of the so-called unconventional myosins, is an actin-based molecular motor involved in intracellular vesicle and organelle transport. In human prostate, myosin VI is expressed in prostate epithelium. We examined the effect of myosin VI downregulation in the LNCaP human prostate cancer cell line using an RNA interference approach. Further, the expression of myosin VI in human prostate tissue was examined using immunohistochemistry. The expression of androgen receptor (AR) and E-cadherin was examined in myosin VI knocked-down cells and control cells. We determined 3H-testosterone uptake in the myosin knocked-down LNCaP cells. Next, we cotransfected LNCaP cells with the myosin VI-specific small interfering RNA (siRNA) duplex and an androgen-responsive luciferase reporter construct and then measured luciferase activity after androgen induction. To clarify whether myosin VI and the AR are interacting proteins, we performed immunoprecipitation studies using myosin VI and AR polyclonal antibodies in androgen-induced LNCaP cells. We confirmed previous results of myosin VI overexpression in human prostate cancer tissue, as in some cases malignant epithelium was more intensively stained than benign epithelium. We found that the expression of AR decreased as a result of myosin VI knock-down. Decreased myosin VI levels did not significantly influence the testosterone uptake of the LNCaP cell line. Instead, we noted a decreased activity of the androgen-regulated mouse mammary tumor virus promoter-reporter vector construct in LNCaP cells cotransfected with myosin VI siRNA duplexes. Finally, we detected the interaction between AR and myosin VI by immunoprecipitation. We propose that myosin VI is a modulator of androgen-dependent gene transcription via interaction with the AR. Thus, myosin VI is a potential therapeutic target for prostate cancer as it could be used as a modulator of AR-dependent gene expression.

Renal cell carcinoma (RCC) is a malignancy with increasing incidence. Despite the well-known prognostic factors - the stage, grade and histological subtype - the clinical course of RCC can seem quite random. The aim of this study was to evaluate markers of the oxidative system as candidate prognostic factors for RCC. Our study population consisted of 152 patients who underwent operation for RCC between 1990 and 1999. The tumours were examined with three immunohistochemical markers of the oxidative system, thioredoxin (Trx), NF-E2-related factor (Nfr2) and BTB-Kelch type substrate adaptor protein (Keap1). Cytoplasmic Keap1 staining was related to poorer prognosis in renal cancer-specific survival. The difference was statistically significant (P=0.02). Keap1 staining was associated with a more advanced stage and a higher nuclear grade. Cytoplasmic Trx staining was associated with a trend of better prognosis in renal cancer-specific survival. Nfr2 staining was not a prognostic factor in renal cancer-specific survival. In RCC, Keap1 is associated with a more advanced disease, a higher grade and a poorer prognosis.

Background and Purpose: Endopyelotomy is an option for the management of ureteropelvic junction (UPJ) obstruction, but long-term outcome data are lacking. The purpose of this study was to evaluate the long-term outcome of endopyelotomy., Patients and Methods: We retrospectively collected data from all endopyelotomies performed in two low-volume hospitals in Finland between 1987 and 2007. The diagnosis was based primarily on urography results. We also conducted a patient survey during the fall of 2007 for the subjective outcome of the operation. There were 18, 17, and 29 patients with a mean follow-up time 152.2, 67.1, and 77.6 months treated by percutaneous antegrade endopyelotomy, Acucise endopyelotomy, and retrograde endopyelotomy, respectively., Results: Reoperation for recurrent UPJ obstruction was required for 0, 1 (6%) and 5 (17%) of the patients, the radiographic outcome of the operation was better in 17 (94%), 13 (76%), and 18 (62%) of the patients, and 0, 2 (12%), and 5 (17%) of the patients experienced no relief in pain after percutaneous antegrade endopyelotomy, Acucise endopyelotomy, and retrograde endopyelotomy, respectively. Complications necessitating intervention were recorded for 7 (38.9%), 4 (23.5%), and 4 (13.8%) patients after antegrade endopyelotomy, Acucise endopyelotomy, and retrograde endopyelotomy, respectively. According to the patient survey, 15 (100%), 11 (73%), and 19 (86%) of the respondents were satisfied with the results of the operation after antegrade endopyelotomy, Acucise endopyelotomy, and retrograde endopyelotomy, respectively. The patients were mainly monitored by radiologic examinations, not by renography., Conclusions: Endopyelotomy offers good and durable results in the long-term. Complications were common, however, and laparoscopic pyeloplasty may be a recommended option for management of primary UPJ obstruction.

Prostate cancer is a leading solid tumor among men in the Western world. Androgens play an important role in the carcinogenesis and treatment of prostate cancer. CYP3A5 is a cytochrome P450 superfamily member which also has activity in testosterone metabolism. In this study, we looked for two-gene interactions associated with clinical characteristics of prostate cancer in the Finnish population. We used multifactor-dimensionality reduction for the identification of the two-gene interactions in androgen metabolism pathway genes together with clinical characteristics of prostate cancer among 754 genotyped prostate cancer patients. The CYP3A5*3/*3 and SRD5A2 A49T GG genotype interaction was associated with the clinical tumor stage T2-T4 (T-stage, TNM classification) with odds ratio (OR) 2.14, 95% confidence interval (CI) 1.35-3.40. Patients with CYP3A5*3/*3 and KLK3 I179T CC/TC genotypes had increased OR 2.30, 95% CI 1.16-4.58 for metastatic disease. Further, two-gene interaction CYP3A5*3/*3 and KLK3 -252A > G AA was associated with Gleason scores >or=7 with OR 1.52, 95% CI 1.11-2.09. Prostate cancer patients with CYP3A5*3/*3 and KLK -252A > G GG/AG genotypes had decreased OR of 0.70 with 95% CI 0.50-0.98 for high prostate-specific antigen levels at diagnosis. For prostate cancer patients aged below 65 years, the OR for interaction of CYP3A5*1/*3 or *1/*1 and AKR1C3 Q5H CC genotypes was 1.84 with 95% CI 1.03-3.28. For prostate cancer, the best two-gene interaction included genotypes SRD5A2 V89L GG and AKR1C3 Q5H CC with OR 1.30, 95% CI 1.01-1.66. It remains to be clarified whether these polymorphism associations identified here are also present in other populations., ((c) 2008 Wiley-Liss, Inc.)

The development of benign prostatic hyperplasia requires the presence of testicular androgens during prostate development, puberty, and ageing. We thus examined the association of three polymorphisms, namely, CYP3A5 6986A>G, CYP19A1 1531C>T, and androgen receptor (AR) gene CAG repeat length, which have previously been linked to the androgen pathway and with clinical characteristics of benign prostatic hyperplasia. Tissue samples from 262 consecutive prostate operations were used for genotyping. Prostate volumes and prostate-specific antigen values were collected from patient records. Linear regression analysis was performed to study the polymorphisms in an age-adjusted model. We did not find any association between the CYP3A5 6986A>G polymorphism and clinical characteristics of benign prostatic hyperplasia. Further, the previously published CYP19A1 1531C>T polymorphism association with an enlarged prostate could not be confirmed with this material. However, we detected an association between short AR gene CAG repeat length and a small prostate volume, which confirms a previous finding in the Finnish population. The data presented suggest a negligible role for the CYP3A5 6986A>G polymorphism in benign prostate enlargement in the Finnish population. However, the results presented do provide further evidence for potentially different genetic mechanisms behind benign prostatic hyperplasia in Finnish and other Caucasian populations. This is based on the conflicting results for AR gene CAG repeat length associations with benign prostatic hyperplasia found in published works.

The expression of claudins 1, 2, 3, 4, 5 and 7 was studied in prostate adenocarcinoma and compared to that of non-neoplastic epithelium and Gleason score of the tumors. Additionally, RT-PCR was performed for claudins 2 and 5 in three cases. Strong immunoreactivity of claudins 1, 3, 4 and 7 was seen in prostate adenocarcinoma while expression of claudins 2 and 5 was weaker. In relation to non-neoplastic glands, expression of claudins 2 and 5 was diminished. There was a significant association between the Gleason score and claudin 1 and 5 expression, these claudins were more strongly expressed in tumours with a lower Gleason score. A combined lowered claudin expression was associated with a high Gleason score and a poor prognosis. According to the results, there is a strong claudin expression in prostate adenocarcinoma, especially for claudins 3 and 4. In contrast, claudin 2 was low in neoplastic cells compared to non-neoplastic epithelium, suggesting downregulation of synthesis or altered metabolism/assembly of this protein during carcinoma development. The association of lowered claudin 1 and 5 expression and lowered overall claudin expression with tumours of a higher Gleason score suggest that claudins may modulate the histologic features of these tumors and in this way influence their biological behaviour.

Testosterone is needed for the growth and development of the prostate. Androgen deprivation therapy is used for the treatment of prostate cancer. CYP3A5 is a human drug-metabolizing cytochrome P450 enzyme that metabolizes testosterone to the inactive 6beta-hydroxylated metabolite. We identified CYP3A5 as a novel androgen-regulated gene in human prostate by GeneChip analysis of human prostate tissues obtained from patients 3 days after therapeutic castration and from control patients. We further showed androgen induction of CYP3A5 messenger RNA (mRNA) in LNCaP prostate cancer cell line. Immunoblotting studies revealed CYP3A5 protein expression in all prostate samples studied. Immunohistochemistry and in situ hybridization was used for localization of CYP3A5 expression in prostate tissue. CYP3A5 was detected both in luminal and in basal epithelial cells of human prostate. Androgen response element was identified in the CYP3A5 proximal promoter and in electrophoretic mobility shift assay androgen receptor was found to bind this element. Androgen induction was abolished by mutation of the response element. We suggest that CYP3A5 is a part of an autoregulatory feedback loop controlling prostate cell exposure to androgens.

Background: This study aimed to explore the value of the Glasgow Aneurysm Score in predicting the immediate and long-term outcome after elective open repair of abdominal aortic aneurysm (AAA)., Methods: Some 403 patients underwent elective open repair of an infrarenal AAA and were classified retrospectively according to the criteria of the Glasgow Aneurysm Score (risk score = (age in years) + (7 for myocardial disease) + (10 for cerebrovascular disease) + (14 for renal disease))., Results: Fourteen patients (3.5 per cent) died after operation, 23 (5.7 per cent) had a myocardial infarction and six (1.5 per cent) had a stroke. One hundred and nine patients (27.0 per cent) experienced severe postoperative complications. The Glasgow Aneurysm Score was predictive of postoperative death (area under the receiver-operator characteristic curve (AUC) 0.80, 95 per cent confidence interval (c.i.) 0.71 to 0.90), severe postoperative complications (AUC 0.67, 95 per cent c.i. 0.61 to 0.73), myocardial infarction (AUC 0.72, 95 per cent c.i. 0.62 to 0.82), myocardial infarction-related postoperative death (AUC 0.78, 95 per cent c.i. 0.63 to 0.94) and stroke (AUC 0.84, 95 per cent c.i. 0.74 to 0.95). Univariate analysis showed that this risk index was also predictive of long-term survival., Conclusion: The Glasgow Aneurysm Score is a good predictor of outcome after elective open repair of AAA. Its simplicity and accuracy make it useful for preoperative risk stratification., (Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

The serine protease TMPRSS2 gene expression was studied by in situ hybridization using benign prostatic hyperplasia and prostate cancer tissue samples from 32 patients. Expression of TMPRSS2 gene was higher in cancer cells than that in benign cells in 84% of the specimens containing both benign and malignant tissues. The TMPRSS2 mRNA level was significantly increased in poorly differentiated (p = 0.014, n = 7) and untreated (p = 0.022, n = 13) primary prostate adenocarcinomas compared to benign tissues. In addition, androgen-deprivation therapy significantly decreased the expression of TMPRSS2 in benign prostate tissue (p = 0.07), which is in accordance with the androgen-inducible expression of the gene. The gene copy number of TMPRSS2, analyzed by competitively differential PCR, was duplicated in the malignant cells of about 38% of the prostate cancer patients analyzed. Thus, the increase in the gene copy number is probably not the primary reason for the detected overexpression of the TMPRSS2 gene. Mutations in the TMPRSS2 gene were screened using DNA isolated from paraffin-embedded prostate cancer tissues from 9 patients with aggressive prostate cancer and from 9 patients with nonaggressive disease. Thirteen exons covering the coding region were checked using enzymatic mutation detection and direct sequencing. One patient with aggressive prostate cancer carried a deletion and a stop codon in exon 11, leading to inactivation of the serine protease domain in TMPRSS2., (Copyright 2001 Wiley-Liss, Inc.)

The purpose of this study was to clarify the expression of TMPRSS2 in mice during development and to compare the tissue distribution of the transcripts in adult mouse and human tissues. Mouse TMPRSS2 cDNA was cloned; the predicted amino acid sequence contains 490 residues sharing 81.4% similarity with human TMPRSS2. According to northern blots, mouse TMPRSS2 is expressed mainly in the prostate and kidney, while human TMPRSS2 is expressed in the prostate, colon, stomach, and salivary gland. In situ hybridization analyses of mouse embryos and adult tissues revealed that TMPRSS2 was expressed in the epithelia of the gastrointestinal, urogenital, and respiratory tracts. Expression was very selective and constant after the gene was turned on during development. Expression of TMPRSS2 was localized in the luminal epithelial cells of the mouse and human prostate. The information presented here will be useful in further studies regarding the function and physiological significance of TMPRSS2.

This study was aimed at exploring the effect of finasteride, a non-steroidal competitive inhibitor of the enzyme 5alpha-reductase, on 5alpha-reductase type 2 at the mRNA level in human prostate, using an in situ hybridization technique. After randomization, 10 men with benign prostatic hyperplasia (BPH) received oral finasteride (5 mg daily) and five men with BPH received placebo daily. Careful clinical examination was carried out and 2 biopsy samples were taken transrectally before the treatment and after 3, 6, and 12 months of treatment. In situ hybridization was carried out and expression of 5alpha-reductase type 2 mRNA was measured. The results showed that finasteride treatment had no permanent effect on expression of 5alpha-reductase type 2 in prostatic epithelium, compared with placebo treatment. Expression varied during treatment, but there was no clear tendency in this expression. The signal was localized in the epithelial cells. We conclude that finasteride treatment had no clear effect on human 5alpha-reductase type 2 expression in the prostate.

Prostate cancer tends to become transformed to androgen-independent disease over time when treated by androgen-deprivation therapy. We used two variants of the human prostate cancer cell line LNCaP to study gene expression differences during prostate cancer progression to androgen-independent disease. Production of prostate-specific antigen was regarded as a marker of androgen-dependence and loss of prostate-specific antigen was regarded as a marker of androgen-independence. mRNA from both cell lines was used for cDNA microarray screening. Differential expression of several genes was confirmed by Northern blotting. Monoamine oxidase A, an Expressed Sequence Tag (EST) similar to rat P044, and EST AA412049 were highly overexpressed in androgen-dependent LNCaP cells. Tissue-type plasminogen activator, interferon-inducible protein p78 (MxB), an EST similar to galectin-1, follistatin, fatty acid-binding protein 5, EST AA609749, annexin I, the interferon-inducible gene 1-8U, and phospholipase D1 were highly overexpressed in androgen-independent LNCaP cells. All studied genes had low or no expression in PC-3 cells. The EST similar to rat P044, the EST similar to galectin-1, follistatin, annexin I, and the interferon-inducible gene 1-8U were also expressed in benign prostatic hyperplasia tissue. The Y-linked ribosomal protein S4, Mat-8, and EST AA307912 were highly expressed in benign prostatic hyperplasia tissue. Additionally, both confirmation of differential expression in Northern blots and in situ hybridization were carried out for monoamine oxidase A, the EST similar to rat P044, the EST similar to galectin-1, fatty acid-binding protein 5, and the interferon-inducible gene 1-8U. We identified several potential prostate cancer markers, indicating that the method used is a useful tool for the screening of cancer markers, but other methods, such as in situ hybridization, are needed to further investigate the observations.

A cDNA library specific for mRNA over-expressed in prostate cancer was generated by subtractive hybridization of transcripts originating from prostatic hyperplasia and cancer tissues. cDNA encoding ribosomal proteins L4, L5, L7a, L23a, L30, L37, S14 and S18 was found to be present among 100 analyzed clones. Levels of ribosomal mRNA were significantly higher at least in one of the prostate-cancer cell lines, LNCaP, DU-145 and PC-3, than in hyperplastic tissue, as determined by slot-blot hybridization. Furthermore, L23a- and S14-transcript levels were significantly elevated in PC-3 cells as compared with those in the normal prostate epithelial cell line PrEC. Generally, dramatic changes in the mRNA content of the ribosomal proteins were not detected, the most evident over-expression being that of L37 mRNA, which was 3.4 times more abundant in LNCaP cells than in hyperplastic prostate tissue. The over-expression of L7a and L37 mRNA was confirmed in prostate-cancer tissue samples by in situ hybridization. Elevated cancer-related expression of L4 and L30 has not been reported, but levels of the other ribosomal proteins are known to be increased in several types of cancers. These results therefore suggest that prostate cancer is comparable with other types of cancers, in that a larger pool of some ribosomal proteins is gained during the transformation process, by an unknown mechanism.