Martti Ala-Opas

Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trial

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non‐users of statins or other cholesterol‐lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996–2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate‐specific antigen (PSA) level was compared between current users and non‐users of cholesterol‐lowering drugs. Compared with medication non‐users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63–0.89]. The inverse association was dose‐dependent with cumulative amount of statin use, and strongest for low‐grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol‐lowering drugs (HR 0.62, 95% CI 0.28–1.38), but without dose‐dependence. Age‐adjusted median serum PSA tended to be lower among users of cholesterol‐lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non‐users was eliminated by systematical prostate cancer screening. Cholesterol‐lowering with statins seems beneficial for prostate cancer prevention.

Expression of cyclins A and D and p21 (waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival

SummaryWe have studied 118 renal cell carcinomas to analyse the expressions of cyclins A and D1 and p21(waf1/cip1), and their relationship to clinical and histopathological parameters as well as to clinical outcome. Cyclins A and D1 and cyclin-dependent kinase inhibitor p21(waf1/cip1) were not expressed in normal renal tissue. Staining signals of cyclin D1 and p21(waf1/cip1) were always nuclear but cyclin A was also expressed in the cytoplasm of the tumour cells. The mean (range) fractions of cyclin A, cyclin D1 and p21(waf1/cip1)-positive tumour cells were 2.2% (range 0–20%), 23.3% (range 0–90%) and 6.8% (range 0–70%) respectively. The expression of cyclin A was related to venous invasion, high nuclear grade, high mitotic rate, high Ki-67 and high PCNA expressions (P ≤ 0.006 for all). The expression of cyclin D1 was linked with age over 65 years, low nuclear grade and high p53 expression (P ≤ 0.05 for all). An inverse correlation was present between p21(waf1/cip1) and cyclin D1 (P = 0.011). Cyclin A predicted survival in the entire study group (P = 0.0014), in T1–4/N0–2/M0 (P = 0.0007) and in T1–2/N0/M0 tumours (P = 0.0007). Cyclin A was also a powerful predictor of disease-free survival in T1–4/N0/M0 (P = 0.0027) tumours (P = 0.0007). Cyclin D1 and p21(waf1/cip1) were not significantly related to survival or disease-free survival in any of the groups. In the entire material the independent prognostic factors were the presence of distant metastases (relative risk (RR) 5.16, P < 0.001), T category (RR 2.68, P < 0.001), Ki-67 expression (RR 1.02, P = 0.026) and cyclin A expression (RR 1.12, P = 0.001). The independent predictors in T1–4/N0/M0 tumours were T-category (RR 2.67, P = 0.001) and cyclin A (RR 1.21, P < 0.001), and in T1–2/N0/M0 tumours the only significant predictor was cyclin A (RR 1.19, P = 0.0002). In renal cell carcinoma, cyclin A is a powerful and independent prognostic factor in all clinical stages of the disease, whereas cyclin D1 and p21(waf1/cip1) have no prognostic value.

Parenteral Estrogen versus Combined Androgen Deprivation in the Treatment of Metastatic Prostatic Cancer - Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

Objective : In the mid-1980s, interest in parenteral estrogen therapy for prostate cancer was renewed when it was found that it influenced liver metabolism only marginally and had very few cardiovascular side-effects. In this study high-dose polyestradiol phosphate (PEP; Estradurin ® ) was compared to combined androgen deprivation (CAD) for the treatment of patients with metastatic prostate cancer. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular side-effects. Material and Methods : A total of 917 patients with T0-4, NX, M1, G1-3 prostate cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter once a month or flutamide (Eulexin ® ) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl ® ) 3.75 mg per month i.m. or, on an optional basis, bilateral orchidectomy. A total of 556 patients had died at the time of this analysis. Results : There was no difference between the treatment arms in terms of time to biochemical or clinical progression and overall or disease-specific survival. There was no increase in cardiovascular mortality in the PEP arm. The PEP group had a higher prevalence of cardiovascular disease prior to the study and a significantly higher incidence of non-fatal ischemic heart events and heart decompensation during the study. Conclusions : PEP has an equal anticancer efficacy to CAD and does not increase cardiovascular mortality. Final evaluation of cardiovascular morbidity is awaiting further analysis and follow-up. PEP is considerably cheaper than CAD.

The FinnProstate Study VII: Intermittent Versus Continuous Androgen Deprivation in Patients With Advanced Prostate Cancer

PURPOSE We conducted a randomized trial to compare intermittent and continuous androgen deprivation in patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. MATERIALS AND METHODS Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. RESULTS There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p=0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p=0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. CONCLUSIONS Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation.

Prognostic value of Ki-67 expression in renal cell carcinomas.

OBJECTIVE The aim of the study was to determine the prognostic power of Ki-67 immunostaining in renal cell carcinomas (RCC). METHODS Clinical follow-up data were reviewed in 111 RCC and the results of Ki-67 immunolabelling were correlated to standard prognostic factors and survival data of the patients. RESULTS Ki-67 expression correlated with tumor grade (p < 0.0001) and mitotic activity (p < 0.0001). In survival analysis Ki-67 expression could be used to divide patients into different prognostic groups (p = 0.0003). In separate analysis with M0 tumors Ki-67 immunolabelling was a powerful predictor of survival (p = 0.0016) as well as disease-free survival (DFS; p = 0.0067). In T1-2N0M0 tumors Ki-67 immunolabelling was superior (p = 0.0005) to other prognostic factors in survival analysis as well as in predicting DFS (p = 0.0006). Grade-2 tumors could be separated into distinct prognostic groups according to Ki-67 labelling (p = 0.0098). In Coxs multivariate analysis Ki-67 was an independent prognostic factor in all three subgroups of RCC. CONCLUSIONS The results show that Ki-67 expression is an independent prognostic factor in renal adenocarcinoma and could be applied in defining proper therapy for patients suffering from this malignancy.

Advanced Prostate Cancer Treated with Intermittent or Continuous Androgen Deprivation in the Randomised FinnProstate Study VII: Quality of Life and Adverse Effects

BACKGROUND Intermittent dosing may reduce the adverse events (AEs) of androgen-deprivation therapy (ADT). OBJECTIVE To compare intermittent androgen deprivation (IAD) and continuous androgen deprivation (CAD) with regard to health-related quality of life (QoL). DESIGN, SETTING, AND PARTICIPANTS A total of 852 men with advanced prostate cancer (PCa) were enrolled to receive goserelin acetate 3.6 mg every 28 d for 24 wk. A total of 554 patients whose prostate-specific antigen (PSA) decreased to <10 ng/ml or by ≥50% (<20 ng/ml at baseline) were randomised to IAD or CAD. INTERVENTION In the IAD arm, ADT was resumed for at least 24 wk whenever PSA increased >20 ng/ml or above baseline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS QoL was monitored with a validated Cleary 30-item questionnaire and analysed by the Mann-Whitney U test, 0.5 standard deviation rule, and repeated measures analysis of variance. AEs and adverse drug reactions (ADRs) were analysed by the chi-square test. RESULTS AND LIMITATIONS Median follow-up was 65 mo. Significant differences in QoL emerged in activity limitation, physical capacity, and sexual functioning, favouring IAD. No significant differences emerged in the prevalence of AEs: 87 patients in the IAD arm (31.8%) and 95 in the CAD arm (33.9%) had cardiovascular (CV) AEs (p=0.59), with 25 (9.1%) and 29 (10.4%) withdrawn (p=0.62), and 21 (7.7%) and 24 (8.6%) dying because of a CV event (p=0.70), respectively; bone fractures occurred in 19 (6.9%) and 15 (5.4%) patients (p=0.44), respectively. Hot flushes or night sweats were the most common ADRs (47.1% vs 50.4%; p=0.44). Erectile dysfunction (15.7% vs 7.9%; p=0.042) and depressed mood (2.2 vs 0%; p=0.032) were more common in the IAD arm. CONCLUSIONS IAD showed benefits in the treatment of advanced PCa with respect to QoL. The prevalence of AEs was not significantly lower with IAD. TRIAL REGISTRATION ClinicalTrials.gov, NCT00293670.

α-Catenin expression has prognostic value in local and locally advanced prostate cancer

SummaryNormally functioning cell–cell adhesion plays an important role in the maintenance of tissue architecture and cell cohesion. E-cadherin is an important adhesion molecule of epithelial cells. In many types of cancer the expression of E-cadherin is reduced leading to increased risk of disease progression. α-Catenin is one of the intracellular elements of the E-cadherin–catenin complex. The abnormalities in the expression of α-catenin seem to associate with malignant cellular features and disease progression in prostate cancer. To further analyse the significance of α-catenin expression, we studied 215 cases of prostate cancer by immunohistochemistry and the results were related to other known prognostic factors and patient survival during a mean follow-up period of 13 years. α-Catenin expression was down-regulated in 19% of the cases and 3% of the tumours were totally α-catenin-negative. The abnormal α-catenin expression and cytoplasmic signal were significantly linked with high T-category, metastatic disease, high Gleason score, perineural growth, high mitotic rate, high S phase fraction and DNA aneuploidy (P < 0.05 for all). In the survival analysis, reduced α-catenin expression (P = 0.06) and cytoplasmic signal (P = 0.04) were related to unfavourable patient outcome. In the multivariate analysis, including TM-classification and Gleason score, α-catenin expression had independent prognostic value in T1–2 M0 tumors. In the M0 tumours, abnormal α-catenin signal was independently associated with recurrence-free survival as well. The results indicate that down-regulation of α-catenin is related to several malignant cellular features, and it seems to have prognostic significance in the early phases of cancer progression. We suggest that α-catenin expression can provide prognostic information in early prostate cancer.

Expression and Prognostic Value of CD44 Standard and Variant v3 and v6 Isoforms in Prostate Cancer

Background: The adhesion molecule CD44 standard (CD44s), and its variant isoforms v3 and v6 are associated with cell–to–cell adhesion. The down–regulation of CD44 standard and its variant isoform CD44v6 is linked with early cancer cell dissemination, but the relationship between CD44v3 and malignant features of prostate cancer (PC) has not been established previously. Methods: The expression of CD44s and its CD44v3 and CD44v6 isoforms was analysed by immunohistochemistry in 209 archival PC biopsy specimens to establish their prognostic value. Results: Down–regulation of CD44s and CD44v6 was related to high T classification, metastasis, high Gleason score, DNA aneuploidy, high S–phase fraction, high mitotic index, perineural growth and dense amount of tumour infiltrating lymphocytes (p<0.03 for all). Down–regulation of CD44s and CD44v6 was related to poor survival in the entire cohort (p<0.0001), in M0 tumours (p<0.001) and in T1–2M0 tumours (p<0.05). In needle biopsies and TURP specimens, the prognostic impact of the investigated parameters was similar. In the multivariate analysis, T classification (p = 0.0009), presence of metastases (p<0.0001), Gleason score (p = 0.0060) and CD44v6 (p = 0.0220) expression were independent prognostic factors. In M0 tumours, T classification (p<0.0001) and CD44v6 (p = 0.003) independently predicted survival. Conclusion: Down–regulation of CD44s and its CD44v6 isoform is related to tumour malignancy and unfavourable prognosis in PC.

Expression of p21(waf1/cip1) protein in transitional cell bladder tumours and its prognostic value.

Objectives: p21(waf1/cip1) protein is a cyclin-dependent kinase inhibitor able to arrest the cell at the G1 phase by inhibiting DNA replication through interaction with proliferating cell nuclear antigen (PCNA). Experimental analyses of human bladder cancer cell lines show that p21 might be considered a tumour suppressor gene since it is able to induce apoptosis like p53. The prognostic value and expression of p21(waf1/cip1) is incompletely studied in bladder cancer at present. Methods: The expression of p21 protein was immunohistochemically analysed in paraffin-embedded specimens of 186 patients with primary transitional cell bladder tumours. The results of immunohistochemical analysis were related to known prognostic factors and complete long clinical follow-up data (over 11 years). Results: The expression of p21(waf1/cip1) protein was significantly related to DNA ploidy, S phase fraction, mitotic index, apoptotic index, morphometric nuclear factors, and the expression of p53 and PCNA proteins, whereas it was unrelated to grade or TNM classification. In univariate survival analysis, the expression of p21(waf1/cip1) protein was not significantly related to prognosis. Independent prognostic factors were T category, papillary status and mitotic index. Conclusion: The results indicate that although the expression of p21(waf1/cip1) protein is related to indicators of cell proliferation, apoptosis and p53 expression, it has no better prognostic value than already established prognostic factors in bladder cancer.

Treatment of prostate cancer with Ad5/3Δ24hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo

Hormone refractory metastatic prostate cancer is a deadly disease that currently lacks curative treatments. Conditionally replicating adenoviruses (CRAds) are promising new agents against cancer due to their innate capability to cause oncolysis of tumor cells. Their antitumor effect is determined in part by their capacity for infecting cancer cells. However, the respective primary receptor, the coxsackie-adenovirus receptor (CAR), is variably expressed in many cancer types. We created Ad5/3Δ24hCG, a novel CRAd retargeted to the adenovirus serotype 3 receptor, which has been reported to be highly expressed in tumors. Furthermore, we added a transgene for the β-chain of human chorionic gonadotropin (hCGβ), whose expression was tightly coupled to virus replication. Ad5/3Δ24hCG was found effective in killing prostate cancer cells, and oncolysis was seen in concordance with hCGβ production. In a s.c. in vivo model of hormone refractory prostate cancer, Ad5/3Δ24hCG treatment resulted in statistically significant tumor growth inhibition. Moreover, i.v. injection of Ad5/3Δ24hCG prolonged the survival of mice with hormone refractory prostate cancer metastatic to the lung. Detection of hCGβ in serum samples confirmed viral replication in vivo. Infection of human clinical samples of cancerous and normal prostatic tissue resulted in effective hCGβ production in cancer tissue, whereas it remained low in nonmalignant tissue, suggesting cancer-specific replication. These results suggest that Ad5/3Δ24hCG is a potent virus for the treatment of hormone refractory prostate cancer in vitro and in vivo. These preclinical data set the stage for translation into clinical studies. [Mol Cancer Ther 2007;6(2):742–51]