Teuvo Tammela - Academia.edu (original) (raw)

Papers by Teuvo Tammela

Genome Medicine

Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as an... more Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. Methods We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and di...

European Urology Focus, 2022

Background: There is increasing interest in nonmorbid treatments for low-and intermediate-risk pr... more Background: There is increasing interest in nonmorbid treatments for low-and intermediate-risk prostate cancer with fewer side effects than surgery or radiotherapy. Objective: To investigate the tolerability, safety, and antitumor effects of the intraprostatic NanoZolid depot formulation Liproca Depot (LIDDS AB, Uppsala, Sweden) with antiandrogen 2-hydroxyflutamide (2-HOF) in men with low-or intermediate-risk localized prostate cancer managed with active surveillance. Design, setting, and participants: This clinical phase 2b trial, LPC-004, involved 61 patients. The 2-HOF-containing formulation Liproca Depot was injected transrectally into the prostate under ultrasound guidance. A single dose of 35% or 45% of the prostate volume (study part 1) and a fixed dose of 16 or 20 ml (study part 2) of the formulation were evaluated. Outcome measurements and statistical analyses: The primary endpoints were tolerability and the reduction in serum prostate-specific antigen (PSA) 5 mo after injection. Antitumor effects were evaluated with magnetic resonance imaging (MRI) and prostate biopsies. Quality of life was assessed using a validated questionnaire (International Prostate Symptom Score). Results and limitations: All doses were safe and well tolerated, without hormonal side effects. In part 2 of the study, the PSA reduction was greatest for the group receiving 16 ml, with an average decrease of 14%, and 95% of patients had a PSA reduction. Some 78% of patients showed a prostate volume decrease compared to baseline. Prostate MRI and biopsies confirmed stable or reduced lesion size. However, post treatment biopsies were performed at the discretion of the investigator, and not routinely. Most patients were amenable to a second injection. Conclusions: PSA and prostate volume decreased in most patients. Indications of efficacy were shown by post-treatment MRI and biopsies demonstrating stabilization or regression in the majority of cases.

European Journal of Cancer, 2021

Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus plac... more Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes.

European urology focus, Jan 11, 2017

A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and h... more A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether β-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. The predictive accuracy of prespecified prediction models was compa...

European Urology Focus, 2017

Background-The European Randomised Study of Screening for Prostate Cancer trial has shown a 21% r... more Background-The European Randomised Study of Screening for Prostate Cancer trial has shown a 21% reduction in prostate cancer (PC) mortality with prostate-specific antigen (PSA)based screening. Sweden used a two-year screening interval and showed a larger mortality reduction than Finland with a four-year interval and higher PSA cutoff. Objective-To evaluate the impact of screening interval and PSA cutoff on PC detection and mortality. Design, Setting, and Participants-We analysed the core age groups (55-69 years at entry) of the Finnish (N=31,866) and Swedish (N=5,901) screening arms at 13 and 16 years of follow-up. Sweden used a screening interval of two years and a PSA cutoff of 3.0 ng/ml, while Finland the screening interval was four years and the PSA cutoff 4.0 ng/ml (or PSA 3.0-3.9 ng/ml with free PSA<16%). Outcome Measurements and Statistical Analysis-We compared PC detection rate and PC mortality between the Finnish and Swedish centers and estimated the impact of different screening protocols. Results and Limitations-If the Swedish screening protocol had been followed in Finland, 122 additional PC cases would have been diagnosed at screening, 84% of which would have been low-risk cancers, and four leading to PC death. In contrast, if a lower PSA threshold had been applied in Finland, at least 127 additional PC would have been found, with 19 PC deaths.

European Journal of Epidemiology, 2017

The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific m... more The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55-67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA \ 1.5 ng/ml, 4 years with PSA 1.5-3.0 and 2 years if initial PSA [ 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.

Journal of Urology, 2017

Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic... more Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in Nano-ZolidÒ) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.

Urologic oncology, Sep 1, 2017

The aim of the present study was to investigate prognostic factors for long-term outcome of renal... more The aim of the present study was to investigate prognostic factors for long-term outcome of renal cell cancer (RCC) in a cohort of patients treated before new antiangiogenic therapy modalities were introduced. Our specific aim was to explore resistin and interleukin 6 (IL-6) levels to find out cytokines potential to predict recurrence and survival in patients with RCC. Our prospective study population consisted of 91 patients who underwent radical nephrectomy or partial resection for RCC at Tampere University Hospital between 1994 and 2001. At the time of surgery, 25 patients were diagnosed to have an advanced tumor and 66 patients a local tumor; 34 patients in the latter group developed a recurrence during the follow-up period of 15 years. Serum samples were collected preoperatively and at 3, 9, and 15 months and at 2, 3, 4, and 5 years postoperatively. IL-6 and resistin levels in serum were measured by immunoassay. Preoperative values of IL-6 (P = 0.006) and resistin (P<0.001) ...

European urology focus, Jan 27, 2017

Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen ... more Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen receptor antagonist ODM-201, in phase 1/2 studies. To evaluate the safety and antitumour activity of prolonged ODM-201 treatment in patients with CRPC. The ARADES trial was a multicentre phase 1 (dose escalation) and phase 2 (dose expansion) trial; 134 patients with CRPC were stratified by previous chemotherapy to receive ODM-201. This paper reports extended follow-up in CYP17 inhibitor (CYP17i)-naïve patients. Patients (n=77) received oral ODM-201 twice daily at daily doses of 200-1800mg. Safety, measured as the occurrence of adverse events (AEs), prostate-specific antigen (PSA), and radiographic progression. The safety profile of extended ODM-201 treatment (median treatment duration 8.2 mo, 95% confidence interval [CI] 5.6-11.0) was consistent with that reported at the time of the original data cutoff in the main ARADES trial, with no unexpected safety concerns over time. The majority ...

The Journal of urology, Jan 16, 2017

Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but le... more Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but leads to over diagnosis of indolent prostate cancer. The use of 5α-reductase inhibitors lowers prostate specific antigen and in theory could affect the performance of prostate specific antigen based screening. We evaluated the outcomes of prostate cancer screening in 5α-reductase inhibitors users. The study was performed in FinRSPC (Finnish Randomized Study of Screening for Prostate Cancer). Of 80,454 men 31,866 were randomized to be screened at 4-year intervals during 1996 to 2004. Information on 5α-reductase inhibitors reimbursements before prostate cancer during 1995 to 2009 was collected from the national prescription database for 78,615 men. We evaluated the effect of screening on prostate cancer risk and mortality by 5α-reductase inhibitors using Cox regression. Men receiving 5α-reductase inhibitors had higher median prostate specific antigen and were more often screen positive than ...

Cell reports, Jun 6, 2017

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcrip... more Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in sele...

The Journal of urology, Jan 16, 2017

Screening for prostate cancer (PCa) remains controversial even if the European Randomized Study o... more Screening for prostate cancer (PCa) remains controversial even if the European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% relative reduction in PCa mortality. The Finnish Randomized Study of Screening for Prostate Cancer is the largest component of the ERSPC and showed statistically non-significant 16% mortality benefit in a separate analysis. The purpose of this study was to estimate the degree of contamination in the control arm (CA) of the Finnish trial. Altogether 48,295 men were randomized to the CA and 31,872 men in the screening arm (SA). The screening period was 1996 - 2007. The extent of PSA testing was analyzed retrospectively using laboratory databases and incidence of T1c PCa (impalpable PCa detected by elevated PSA) was determined from the national Finnish Cancer Registry. Approximately 1.4% of men had been tested with PSA 1-3 years before randomization. By the first four, eight and twelve years of follow-up, 18.1%, 47.7% and 62.7% of the ...

Human Molecular Genetics, 2016

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive... more Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusionnegative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

Cancer Epidemiology, 2016

Background: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial t... more Background: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial to avoid bias from misclassification due to excessive recording of diagnosed cancer as a CoD in death certificates instead of non-cancer disease that actually caused death. We estimated whether there was bias in CoD determination between screening (SA) and control arms (CA) in a population-based prostate cancer (PCa) screening trial. Methods: Our trial is the largest component of the European Randomized Study of Screening for Prostate Cancer with more than 80,000 men. Randomly selected deaths in men with PCa (N = 442/2568 cases, 17.2%) were reviewed by an independent CoD committee. Median follow-up was 16.8 years in both arms. Results: Overdiagnosis of PCa was present in the SA as the risk ratio for PCa incidence was 1.19 (95% confidence interval (CI) 1.14-1.24). The hazard ratio (HR) for PCa mortality was 0.94 (95%CI 0.82-1.08) in favor of the SA. Agreement with official CoD registry was 94.6% (k = 0.88) in the SA and 95.4% (k = 0.91) in the CA. Altogether 14 PCa deaths were estimated as false-positive in both arms and exclusion of these resulted in HR 0.92 (95% CI 0.80-1.06). Conclusions: A small differential misclassification bias in ascertainment of CoD was present, most likely due to attribution bias (overdiagnosis in the SA). Maximum precision in CoD ascertainment can only be achieved with independent review of all deaths in the diseased population. However, this is cumbersome and expensive and may provide little benefit compared to random sampling.

Scandinavian Journal of Urology, 2016

Purpose Anticoagulants may reduce mortality of cancer patients, though the evidence remains contr... more Purpose Anticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death. Methods All anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2-and 3-year lag-time analyses were performed. Results During a median follow-up of 17.2 years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR = 2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories. Conclusion Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.

European urology, Jan 10, 2016

The multicenter European Randomized Study of Screening for Prostate Cancer has shown a 21% reduct... more The multicenter European Randomized Study of Screening for Prostate Cancer has shown a 21% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening, with substantial overdiagnosis. In the present study, we analyzed the incidence of PC after screening in relation to the number of screening rounds attended in the Finnish section of the trial. To evaluate the possible reduction in PC incidence following completed screening cycles in relation to the number of screening rounds attended. The participants in the screening arm of the Finnish screening trial (29 298 men) were divided into subgroups of men who had participated at one, two, or three screening rounds. A reference group was formed of the 43 151 men in the control arm by selecting age-matched controls for each subgroup of the screening participants. PC cases diagnosed after screening were identified from the Finnish Cancer Registry until the end of 2011. Follow-up of the screened men started 12 mo ...

Cancer medicine, 2015

Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed... more Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1 mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3'UTR of CC...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 19, 2015

The balance of benefits and harms in prostate cancer screening has not been sufficiently characte... more The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening. We analyzed the absolute mortality reduction expressed as number needed to invite (NNI=1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO=1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI 200-7000 and NNO 16-69. Extent of overdiagnosis and mortality reduction were closely associated (correlation coefficient r=0.76, weighted linear regression ...

Cancer Research, 2015

Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking th... more Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking therapies cause most of the deaths from prostate cancer, intensifying the need to fully understand CRPC pathophysiology. In this study, we characterized the transcriptomic differences between untreated prostate cancer and locally recurrent CRPC. Here, we report the identification of 145 previously unannotated intergenic long noncoding RNA transcripts (lncRNA) or isoforms that are associated with prostate cancer or CRPC. Of the one third of these transcripts that were specific for CRPC, we defined a novel lncRNA termed PCAT5 as a regulatory target for the transcription factor ERG, which is activated in approximately 50% of human prostate cancer. Genome-wide expression analysis of a PCAT5-positive prostate cancer after PCAT5 silencing highlighted alterations in cell proliferation pathways. Strikingly, an in vitro validation of these alterations revealed a complex integrated phenotype affecti...

Actas Urológicas Españolas, 2014

Cáncer de próstata resistente a castración no diseminado (CPRCM0), un viejo escenario con interés... more Cáncer de próstata resistente a castración no diseminado (CPRCM0), un viejo escenario con interés clínico renovado Non-metastatic castration-resistant prostate cancer (CPRCM0), an old scenario with renewed clinical interest * Autor para correspondencia.

Genome Medicine

Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as an... more Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. Methods We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and di...

European Urology Focus, 2022

Background: There is increasing interest in nonmorbid treatments for low-and intermediate-risk pr... more Background: There is increasing interest in nonmorbid treatments for low-and intermediate-risk prostate cancer with fewer side effects than surgery or radiotherapy. Objective: To investigate the tolerability, safety, and antitumor effects of the intraprostatic NanoZolid depot formulation Liproca Depot (LIDDS AB, Uppsala, Sweden) with antiandrogen 2-hydroxyflutamide (2-HOF) in men with low-or intermediate-risk localized prostate cancer managed with active surveillance. Design, setting, and participants: This clinical phase 2b trial, LPC-004, involved 61 patients. The 2-HOF-containing formulation Liproca Depot was injected transrectally into the prostate under ultrasound guidance. A single dose of 35% or 45% of the prostate volume (study part 1) and a fixed dose of 16 or 20 ml (study part 2) of the formulation were evaluated. Outcome measurements and statistical analyses: The primary endpoints were tolerability and the reduction in serum prostate-specific antigen (PSA) 5 mo after injection. Antitumor effects were evaluated with magnetic resonance imaging (MRI) and prostate biopsies. Quality of life was assessed using a validated questionnaire (International Prostate Symptom Score). Results and limitations: All doses were safe and well tolerated, without hormonal side effects. In part 2 of the study, the PSA reduction was greatest for the group receiving 16 ml, with an average decrease of 14%, and 95% of patients had a PSA reduction. Some 78% of patients showed a prostate volume decrease compared to baseline. Prostate MRI and biopsies confirmed stable or reduced lesion size. However, post treatment biopsies were performed at the discretion of the investigator, and not routinely. Most patients were amenable to a second injection. Conclusions: PSA and prostate volume decreased in most patients. Indications of efficacy were shown by post-treatment MRI and biopsies demonstrating stabilization or regression in the majority of cases.

European Journal of Cancer, 2021

Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus plac... more Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes.

European urology focus, Jan 11, 2017

A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and h... more A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether β-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. The predictive accuracy of prespecified prediction models was compa...

European Urology Focus, 2017

Background-The European Randomised Study of Screening for Prostate Cancer trial has shown a 21% r... more Background-The European Randomised Study of Screening for Prostate Cancer trial has shown a 21% reduction in prostate cancer (PC) mortality with prostate-specific antigen (PSA)based screening. Sweden used a two-year screening interval and showed a larger mortality reduction than Finland with a four-year interval and higher PSA cutoff. Objective-To evaluate the impact of screening interval and PSA cutoff on PC detection and mortality. Design, Setting, and Participants-We analysed the core age groups (55-69 years at entry) of the Finnish (N=31,866) and Swedish (N=5,901) screening arms at 13 and 16 years of follow-up. Sweden used a screening interval of two years and a PSA cutoff of 3.0 ng/ml, while Finland the screening interval was four years and the PSA cutoff 4.0 ng/ml (or PSA 3.0-3.9 ng/ml with free PSA<16%). Outcome Measurements and Statistical Analysis-We compared PC detection rate and PC mortality between the Finnish and Swedish centers and estimated the impact of different screening protocols. Results and Limitations-If the Swedish screening protocol had been followed in Finland, 122 additional PC cases would have been diagnosed at screening, 84% of which would have been low-risk cancers, and four leading to PC death. In contrast, if a lower PSA threshold had been applied in Finland, at least 127 additional PC would have been found, with 19 PC deaths.

European Journal of Epidemiology, 2017

The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific m... more The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55-67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA \ 1.5 ng/ml, 4 years with PSA 1.5-3.0 and 2 years if initial PSA [ 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.

Journal of Urology, 2017

Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic... more Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in Nano-ZolidÒ) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.

Urologic oncology, Sep 1, 2017

The aim of the present study was to investigate prognostic factors for long-term outcome of renal... more The aim of the present study was to investigate prognostic factors for long-term outcome of renal cell cancer (RCC) in a cohort of patients treated before new antiangiogenic therapy modalities were introduced. Our specific aim was to explore resistin and interleukin 6 (IL-6) levels to find out cytokines potential to predict recurrence and survival in patients with RCC. Our prospective study population consisted of 91 patients who underwent radical nephrectomy or partial resection for RCC at Tampere University Hospital between 1994 and 2001. At the time of surgery, 25 patients were diagnosed to have an advanced tumor and 66 patients a local tumor; 34 patients in the latter group developed a recurrence during the follow-up period of 15 years. Serum samples were collected preoperatively and at 3, 9, and 15 months and at 2, 3, 4, and 5 years postoperatively. IL-6 and resistin levels in serum were measured by immunoassay. Preoperative values of IL-6 (P = 0.006) and resistin (P<0.001) ...

European urology focus, Jan 27, 2017

Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen ... more Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen receptor antagonist ODM-201, in phase 1/2 studies. To evaluate the safety and antitumour activity of prolonged ODM-201 treatment in patients with CRPC. The ARADES trial was a multicentre phase 1 (dose escalation) and phase 2 (dose expansion) trial; 134 patients with CRPC were stratified by previous chemotherapy to receive ODM-201. This paper reports extended follow-up in CYP17 inhibitor (CYP17i)-naïve patients. Patients (n=77) received oral ODM-201 twice daily at daily doses of 200-1800mg. Safety, measured as the occurrence of adverse events (AEs), prostate-specific antigen (PSA), and radiographic progression. The safety profile of extended ODM-201 treatment (median treatment duration 8.2 mo, 95% confidence interval [CI] 5.6-11.0) was consistent with that reported at the time of the original data cutoff in the main ARADES trial, with no unexpected safety concerns over time. The majority ...

The Journal of urology, Jan 16, 2017

Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but le... more Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but leads to over diagnosis of indolent prostate cancer. The use of 5α-reductase inhibitors lowers prostate specific antigen and in theory could affect the performance of prostate specific antigen based screening. We evaluated the outcomes of prostate cancer screening in 5α-reductase inhibitors users. The study was performed in FinRSPC (Finnish Randomized Study of Screening for Prostate Cancer). Of 80,454 men 31,866 were randomized to be screened at 4-year intervals during 1996 to 2004. Information on 5α-reductase inhibitors reimbursements before prostate cancer during 1995 to 2009 was collected from the national prescription database for 78,615 men. We evaluated the effect of screening on prostate cancer risk and mortality by 5α-reductase inhibitors using Cox regression. Men receiving 5α-reductase inhibitors had higher median prostate specific antigen and were more often screen positive than ...

Cell reports, Jun 6, 2017

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcrip... more Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in sele...

The Journal of urology, Jan 16, 2017

Screening for prostate cancer (PCa) remains controversial even if the European Randomized Study o... more Screening for prostate cancer (PCa) remains controversial even if the European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% relative reduction in PCa mortality. The Finnish Randomized Study of Screening for Prostate Cancer is the largest component of the ERSPC and showed statistically non-significant 16% mortality benefit in a separate analysis. The purpose of this study was to estimate the degree of contamination in the control arm (CA) of the Finnish trial. Altogether 48,295 men were randomized to the CA and 31,872 men in the screening arm (SA). The screening period was 1996 - 2007. The extent of PSA testing was analyzed retrospectively using laboratory databases and incidence of T1c PCa (impalpable PCa detected by elevated PSA) was determined from the national Finnish Cancer Registry. Approximately 1.4% of men had been tested with PSA 1-3 years before randomization. By the first four, eight and twelve years of follow-up, 18.1%, 47.7% and 62.7% of the ...

Human Molecular Genetics, 2016

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive... more Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusionnegative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

Cancer Epidemiology, 2016

Background: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial t... more Background: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial to avoid bias from misclassification due to excessive recording of diagnosed cancer as a CoD in death certificates instead of non-cancer disease that actually caused death. We estimated whether there was bias in CoD determination between screening (SA) and control arms (CA) in a population-based prostate cancer (PCa) screening trial. Methods: Our trial is the largest component of the European Randomized Study of Screening for Prostate Cancer with more than 80,000 men. Randomly selected deaths in men with PCa (N = 442/2568 cases, 17.2%) were reviewed by an independent CoD committee. Median follow-up was 16.8 years in both arms. Results: Overdiagnosis of PCa was present in the SA as the risk ratio for PCa incidence was 1.19 (95% confidence interval (CI) 1.14-1.24). The hazard ratio (HR) for PCa mortality was 0.94 (95%CI 0.82-1.08) in favor of the SA. Agreement with official CoD registry was 94.6% (k = 0.88) in the SA and 95.4% (k = 0.91) in the CA. Altogether 14 PCa deaths were estimated as false-positive in both arms and exclusion of these resulted in HR 0.92 (95% CI 0.80-1.06). Conclusions: A small differential misclassification bias in ascertainment of CoD was present, most likely due to attribution bias (overdiagnosis in the SA). Maximum precision in CoD ascertainment can only be achieved with independent review of all deaths in the diseased population. However, this is cumbersome and expensive and may provide little benefit compared to random sampling.

Scandinavian Journal of Urology, 2016

Purpose Anticoagulants may reduce mortality of cancer patients, though the evidence remains contr... more Purpose Anticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death. Methods All anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2-and 3-year lag-time analyses were performed. Results During a median follow-up of 17.2 years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR = 2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories. Conclusion Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.

European urology, Jan 10, 2016

The multicenter European Randomized Study of Screening for Prostate Cancer has shown a 21% reduct... more The multicenter European Randomized Study of Screening for Prostate Cancer has shown a 21% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening, with substantial overdiagnosis. In the present study, we analyzed the incidence of PC after screening in relation to the number of screening rounds attended in the Finnish section of the trial. To evaluate the possible reduction in PC incidence following completed screening cycles in relation to the number of screening rounds attended. The participants in the screening arm of the Finnish screening trial (29 298 men) were divided into subgroups of men who had participated at one, two, or three screening rounds. A reference group was formed of the 43 151 men in the control arm by selecting age-matched controls for each subgroup of the screening participants. PC cases diagnosed after screening were identified from the Finnish Cancer Registry until the end of 2011. Follow-up of the screened men started 12 mo ...

Cancer medicine, 2015

Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed... more Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1 mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3'UTR of CC...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 19, 2015

The balance of benefits and harms in prostate cancer screening has not been sufficiently characte... more The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening. We analyzed the absolute mortality reduction expressed as number needed to invite (NNI=1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO=1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI 200-7000 and NNO 16-69. Extent of overdiagnosis and mortality reduction were closely associated (correlation coefficient r=0.76, weighted linear regression ...

Cancer Research, 2015

Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking th... more Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking therapies cause most of the deaths from prostate cancer, intensifying the need to fully understand CRPC pathophysiology. In this study, we characterized the transcriptomic differences between untreated prostate cancer and locally recurrent CRPC. Here, we report the identification of 145 previously unannotated intergenic long noncoding RNA transcripts (lncRNA) or isoforms that are associated with prostate cancer or CRPC. Of the one third of these transcripts that were specific for CRPC, we defined a novel lncRNA termed PCAT5 as a regulatory target for the transcription factor ERG, which is activated in approximately 50% of human prostate cancer. Genome-wide expression analysis of a PCAT5-positive prostate cancer after PCAT5 silencing highlighted alterations in cell proliferation pathways. Strikingly, an in vitro validation of these alterations revealed a complex integrated phenotype affecti...

Actas Urológicas Españolas, 2014

Cáncer de próstata resistente a castración no diseminado (CPRCM0), un viejo escenario con interés... more Cáncer de próstata resistente a castración no diseminado (CPRCM0), un viejo escenario con interés clínico renovado Non-metastatic castration-resistant prostate cancer (CPRCM0), an old scenario with renewed clinical interest * Autor para correspondencia.