Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus.

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.

Nationwide analysis of survival after radical cystectomy for bladder cancer in Finland.

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.

MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.

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 .).

Nephrectomy improves the survival of metastatic renal cell cancer patients with moderate to good performance status-results from a Finnish nation-wide population-based study from 2005 to 2010.

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.

Multiparametric MRI prior to radical prostatectomy identifies intraductal and cribriform growth patterns in prostate cancer.

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.

Urinary Sample Collection Methods in Ileal Conduit Urinary Diversion Patients: A Randomized Control Trial.

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.

Treatment of renal angiomyolipoma: pooled analysis of individual patient data.

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.

The impact of metastasectomy on survival of patients with synchronous metastatic renal cell cancer in Finland: A nationwide study.

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.

Sacral nerve stimulation lead implantation using the O-arm.

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.

Changing trends in symptomatology, diagnostics, stage and survival of prostate cancer in Northern Finland during a period of 20 years.

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.

HuR expression is a marker of poor prognosis in renal cell carcinoma.

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.

Sacral neuromodulation in urological indications: the Finnish experience.

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.

Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer.

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.

Expression of toll-like receptor-9 is increased in poorly differentiated prostate 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.

Is the incidence of urinary bladder endometriosis increasing? Figures from Finland.

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.

Myosin VI is a modulator of androgen-dependent gene expression.

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.

Increased BTB-Kelch type substrate adaptor protein immunoreactivity associates with advanced stage and poor differentiation in renal cell carcinoma.

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.

The interaction of CYP3A5 polymorphisms along the androgen metabolism pathway in prostate cancer.

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.

The androgen receptor CAG repeat length polymorphism associates with prostate volume in Finnish men with benign prostatic hyperplasia.

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.

Lesion size on prostate magnetic resonance imaging predicts adverse radical prostatectomy pathology.

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.