Prediction of Overall Survival by Thymidine Kinase 1 Combined with Prostate-Specific Antigen in Men with Prostate Cancer.

Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988-1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.

A randomised, double-blind, dose-finding, phase II multicentre study of ODX in the treatment of patients with castration-resistant prostate cancer and skeletal metastases.

AIMS: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease. METHODS: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period. RESULTS: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety. CONCLUSIONS: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).

Serum thymidine kinase 1 concentration as a predictive biomarker in prostate cancer.

BACKGROUND: Thymidine kinase 1 (TK1) recycles DNA before cell division. We do not know if baseline blood concentrations of TK1 predict death in prostate cancer within 30 years. Our objective is to determine if there is an association between baseline levels of TK1 and future prostate cancer-specific mortality. METHODS: With a "proof of concept" approach, we performed a nested case-control study among 1782 individuals screened for prostate cancer between 1988 and 1989. The concentration of TK1 was measured in frozen serum from 330 men, 36 of whom have died of prostate cancer. The primary endpoint was prostate cancer-specific mortality and outcomes after 30 years were analyzed using logistic regression modeling odds ratios (Ors). RESULTS: The estimated OR (adjusted for age) for dying from prostate cancer among the men who had a TK1 value in the upper tertile was 2.39 (95% confidence interval 1.02-5.63). The corresponding OR, regardless of the cause of death, was 2.81 (1.24-6.34). CONCLUSIONS: High levels of TK1 predicts death in prostate cancer within 30 years of follow-up.

Association between one-time prostate-specific antigen (PSA) test with free/total PSA ratio and prostate cancer mortality: A 30-year prospective cohort study.

OBJECTIVES: To explore if there is a long-term association between baseline prostate-specific antigen (PSA), including free/total PSA ratio and long-term (30-year) risk for prostate cancer death. SUBJECTS AND METHODS: In all, 1782 men were screened for prostate cancer through PSA analysis. Some years later, frozen plasma samples were used to calculate the ratio of free to total PSA (f/t PSA). At 30-year follow-up, baseline PSA and f/t PSA were compared with recent data extracts from the Swedish Cause of Death Registry and Swedish Cancer Registry. PSA values and f/t PSA values were treated as continuous variables in a multivariable analysis and also stratified according to their distribution and useful clinical thresholds. RESULTS: Risk of death from prostate cancer after 30 years of follow-up was significantly increased with a higher baseline PSA level, with the hazard ratio being 1.04 (95% confidence interval 1.03-1.09) per increase of one unit of PSA. Adding f/t PSA increased the model's ability to discriminate (concordance index 0.84-0.88). Men with PSA levels <1.0 ng/mL had a very low long-term risk of prostate cancer death (1.2% risk). An f/t PSA ≥ 0.25 extended the low-risk range to PSA < 2.0 ng/mL (1.5% risk). CONCLUSION: Prostate-specific antigen testing can be carried out less frequently or can be discontinued in men aged 55-70 years if their PSA levels are <2.0 ng/mL and the f/t PSA is ≥0.25.

Association between dihydrotestosterone and long-term risk for prostate cancer mortality: A prospective cohort study.

BACKGROUND: The androgen metabolism plays an important role in the progression of prostate cancer. Contradictory to what one might assume given the androgenic potency of dihydrotestosterone (DHT) there are indications that high DHT levels protect from prostate cancer. We want to determine whether there is a long-term association between baseline levels of DHT and death from prostate cancer. METHOD: During the years 1988 and 1989, 1782 men out of 2400 invited were screened for prostate cancer. The invited men were randomly selected from a background population of more than 27 000 men. Serum levels of DHT were analyzed for all 65 men diagnosed in the trial and 130 controls from the same cohort without any signs of prostate cancer. In this study we evaluate outcomes for the whole cohort (n = 195), the men without clinical signs of prostate cancer at beginning of follow up (n = 130) and men with screening detected cancer (n = 65). The cohort was followed up after 30 years and data from the Swedish Cause of Death Registry and the Swedish Cancer Registry were extracted. Hazard ratios (HRs) were calculated using Cox regression models. RESULT: High DHT levels were positively correlated to a lower risk for prostate cancer death in the entire cohort: HR = 0.44 (0.25-0.77 95% confidence interval [CI]). The positive correlation remained significant for the subgroup analysis. HR for the men enrolled in the study without any clinical signs of prostate cancer was 0.25 (0.07-0.88 95% CI) and for the men with a prostate cancer diagnosis at time of inclusion: HR = 0.50 (0.26-0.94 95% CI). CONCLUSION: DHT is negatively associated with long-term prostate cancer death regardless of clinical presentation at time of inclusion.

Long-Term Outcome of a Single Intervention Population Based Prostate Cancer Screening Study.

PURPOSE: We evaluated the long-term effect of screening for prostate cancer. MATERIALS AND METHODS: In 1988 we randomly selected 2,400 men from a background population of 27,464 men. The 2,400 men were invited to undergo screening, of whom 1,779 (74%) accepted and were examined with digital rectal examination, ultrasound and prostate specific antigen measurement. Biopsy was performed if there were suspicious findings on ultrasound or digital rectal examination, or prostate specific antigen was greater than 10 ng/ml. The subpopulations have now been reassessed after 20 years. RESULTS: Participants had a decreased overall mortality rate compared to the source population (IRR 0.93, 95% CI 0.86-0.98). Nonparticipants had an increased overall mortality rate (IRR 1.25, 95% CI 1.14-1.37). There was no difference between the groups in prostate cancer specific survival. The incidence of prostate cancer remained higher in the screened population throughout followup. CONCLUSIONS: A single screening intervention in men 50 to 75 years old using prostate specific antigen, digital rectal examination and transrectal ultrasound, and a prostate specific antigen cutoff of 10 ng/ml for biopsy carried a significant risk of prostate cancer detection without a concomitant reduction in prostate cancer specific mortality after 20 years. This intervention should not be considered for public screening. Nonparticipants were at greater risk for death of all causes. In addition to being a single intervention trial, the limitations of this study include an outdated prostate specific antigen cutoff for biopsy. Despite the outdated screening method the source population failed to reach the same level of prostate cancer incidence as the screened population even after 20 years.

Comparison between normal saline and Ringer's acetate in bipolar transurethral resection of the prostate.

OBJECTIVE: The standard surgical treatment for benign prostatic hypertrophy (BPH) is transurethral resection of the prostate (TURP). The aim of this study was to compare normal saline (NS) (0.9% sodium chloride) and Ringer's acetate (RA) as irrigation fluid with regard to visibility, resection feasibility, coagulation and bleeding in bipolar TURP. MATERIALS AND METHODS: Twenty patients (mean age 70 years) who were diagnosed with BPH were recruited to the study. The first three 3 liter bags of irrigation fluid contained either NS or RA and were administered in a randomized fashion. The surgeon assessed visibility, bleeding, coagulation, resection efficacy and overall outcome after each 3 liter bag on a scale of 1-10. RESULTS: The results disclosed only marginal differences between the two fluids with regard to the recorded parameters. All of the differences lacked statistical significance (p > .05). CONCLUSION: RA can be used as an irrigation fluid in bipolar TURP with no obvious difference in comparison with NS.

15-year followup of a population based prostate cancer screening study.

PURPOSE: We evaluated long-term survival in attendees and nonattendees of a 1-time screening for prostate cancer. MATERIALS AND METHODS: A total of 2,400 men 55 to 70 years old in 1988 were randomly selected and invited to a screening for prostate cancer. Of the invited men 1,782 (74%) attended. Screening attendees were examined with digital rectal examination, transrectal ultrasound and prostate specific antigen analysis. When cancer was suspected, prostate biopsies were taken. A total of 65 men with prostate cancer were detected by this procedure. The entire source population comprising 27,204 men, including 618 nonattendees (26%), was followed for prostate cancer diagnosis and survival for 15 years. RESULTS: Incidence rate ratios were calculated using Poisson regression models. We found no effect of this screening procedure on the risk of death from prostate cancer and other causes of death (incidence rate ratio 1.10, 95% CI 0.83-1.46 and 0.98, 95% CI 0.92-1.05, respectively) when comparing all invited men with the source population. However, attending the screening program was associated with a significantly decreased risk of death from causes other than prostate cancer (vs source population incidence rate ratio 0.82, 95% CI 0.76-0.90). In contrast, the corresponding incidence rate ratio in nonattendees was 1.53 (95% CI 1.37-1.71). CONCLUSIONS: We found no evidence of a beneficial effect of this specific screening procedure but strong evidence of a difference in overall survival in screening attendees and nonattendees. These findings should be considered when interpreting previous and upcoming studies of the effect of screening programs.

Dihydrotestosterone levels and survival in screening-detected prostate cancer: a 15-yr follow-up study.

OBJECTIVES: It has been hypothesized that dihydrotestosterone (DHT), the main intracellular androgen in the prostate, affects prostatic tumour progression. In this study, we evaluated serum DHT levels at the time of prostate-cancer diagnosis in relation to survival. METHODS: Sixty-five screening-detected patients diagnosed in 1988-1989 were followed for 15 yr. DHT levels at the time of diagnosis were determined through radio-immuno assay. Subjects were followed up through the nationwide tax register. Medical records of all dead subjects were reviewed, and cause of death was established by an endpoint committee. Data were analyzed through Kaplan-Meier estimation and Cox proportional-hazards regression. RESULTS: Seventeen of 41 deaths in the cohort during follow-up were attributed to prostate cancer. Patients with DHT above the median had a significant better prostate-cancer-specific survival than those with DHT below the median (log rank p=0.0075). In the univariate analyses, one unit increase in DHT was associated with a hazard ratio (HR) of 0.14 (95% CI=0.02-0.93). In the multivariate model, including prostate-specific antigen level, the association between DHT and prostate-cancer-specific survival was not significant (HR=0.18; 95% CI=0.02-1.6). DHT level below the median remained significantly associated with decreased survival in the multivariate model (HR=0.23; 95% CI=0.06-0.90). No association was found between DHT level and hazard of dying from causes other than prostate cancer. CONCLUSIONS: Although the prognostic value of DHT levels at diagnosis remains unclear, these results provides evidence of an association between low DHT and decreased survival in prostate cancer patients.

Prognostic significance of homozygous deletions and multiple duplications at the CDKN2A (p16INK4a)/ARF (p14ARF) locus in urinary bladder cancer.

OBJECTIVE: The 9p21 locus is a major target in the pathogenesis of human urinary bladder cancer. This locus harbours the CDKN2A/ARF tumour suppressor gene, which encodes two cell-cycle regulatory proteins: p16INK4a and p14ARF. We studied how homozygous deletions and multiple duplications at this locus affect prognosis and survival in patients with bladder cancer. MATERIAL AND METHODS: Real-time quantitative polymerase chain reaction (QPCR), based on simultaneous amplification of ARF and a reference gene, glyceraldehyde-3-phosphate dehydrogenase, was used to measure homozygous deletions and multiple duplications in a population-based material consisting of 478 patients with urinary bladder cancer. Results from real-time QPCR were compared with clinico-pathological parameters and survival curves were generated using the Kaplan-Meier method. RESULTS: Real-time QPCR analysis showed 71 (15%) homozygous deletions and 8 (2%) multiple duplications. We were unable to find any association between either stage or grade and urinary neoplasms with homozygous deletions. However, although there were only a limited number of patients with multiple duplications, 7/8 of them had highly malignant tumours (G2b-G4 or > or = T1; p = 0.02). CONCLUSIONS: Urinary bladder cancers constitute a spectrum of neoplasms with varying clinical manifestations. We were unable to establish a prognostic relevance for patients with tumours harbouring homozygous deletions at the CDKN2A/ARF locus. However, our data did indicate that patients with multiple duplications at the CDKN2A/ARF locus had poor survival. This suggests that multiple duplications, in combination with other genetic changes, have cooperative effects which have a negative outcome on urinary bladder cancer prognosis.

Polymorphisms in DNA repair and metabolic genes in bladder cancer.

We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.

Lead time associated with screening for prostate cancer.

Screening serum levels of prostate-specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value >/=10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan-Meier) of PC in the 946 participants (ED) during 12 years of follow-up was compared to that of an age-matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values >/=3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the "catch-up" point). After 12 years of follow-up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow-up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow-up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection.

S-phase fraction in superficial urothelial carcinoma of the bladder--a prospective, long-term, follow-up study.

OBJECTIVE: To study, in addition to traditional tumor characteristics at diagnosis, the significance of DNA ploidy and S-phase fraction for tumor progression and tumor-related death in superficial carcinoma of the urinary bladder. MATERIAL AND METHODS: Newly detected superficial bladder carcinomas (stage Ta-T1), from 195 consecutive patients were characterized according to stage, grade, tumor size, multiplicity, growth pattern, cytologic evaluation and random mucosal biopsies, as well as DNA ploidy and S-phase fraction as determined by means of DNA flow cytometry. The outcome of disease was evaluated using hospital charts and death certificates. RESULTS: During a median follow-up period of 98 months (range 1-160 months), 28 patients (14%) progressed to muscle-invasive or metastatic disease and 24 (12%) died from disease. In univariate analysis all factors studied, with the exception of the size and number of tumors at diagnosis, were significantly related to progress and tumor-specific survival. In multivariate analysis, however, S-phase fraction was the most significant prognostic factor. When 21 high-risk patients with T1G3 tumors who underwent early cystectomy were excluded, S-phase fraction remained the most important prognostic factor. DNA ploidy failed as an independent predictor of survival. CONCLUSIONS: High S-phase fraction at diagnosis of superficial urothelial carcinoma of the bladder identifies patients at high risk of progression and death from disease.

Bladder neoplasms--regions at chromosome 9 with putative tumour suppressor genes.

OBJECTIVES: To investigate the prevalence of loss of heterozygosity (LOH) at 12 different loci on chromosome 9 in patients with bladder neoplasms using a newly developed fluorescent multiplex polymerase chain reaction. PATIENTS AND METHODS: In a population-based study, freshly frozen tissue was collected from all cases of newly detected bladder neoplasms in the Stockholm region during 1995 and 1996 (n = 538) and 156 representative cases were subsequently studied in the present series. RESULTS: In total, at one or more loci of chromosome 9, 89% (139/156) of the tumours showed LOH. Loss of heterozygosity in informative cases was in the range from 33.1% (41/124) at the 9p21 locus to 67% (77/115) at the 9q31.3-32 loci. When minor LOH was studied, representing a single LOH with retention of heterozygosity at both adjacent markers, relatively frequent losses were detected at 9q22.3 harbouring the PTCH gene (7.7%), at 9q32-33.1 (6.6%) and at 9q33.2 harbouring the DBCCR1 gene (7.5%). In relation to clinical information, LOH at 9p22.1 was statistically significantly correlated with tumour grade (p = 0.01), but not with tumour stage. Replication errors were observed in 14 of 156 (9%) tumours. CONCLUSIONS: Our observation of relatively frequent minor LOH at 9p22.1, 9q22.3 and 9q32-33.1 identifies regions within which putative tumour suppressor genes, including the PTCH and the DBCCR1 genes, may reside.

A population-based study of 538 patients with newly detected urinary bladder neoplasms followed during 5 years.

OBJECTIVE: To describe in detail the diagnosis and clinical course of an unselected population-based cohort of patients with newly diagnosed bladder neoplasms. MATERIAL AND METHODS: A total of 538 patients registered in the Stockholm region with newly diagnosed primary bladder neoplasms (transitional cell carcinomas) in 1995 and 1996 were followed for at least 5 years. All hospitals and urology units in the region participated in the study. Treatment and follow-up were performed according to a standard-of-care programme. Routine pathological reports were used. Original case records were scrutinized on location in 2001. In addition, a tumour bank of freshly frozen tumour tissue was established. RESULTS: The calculated 5-year cancer-specific survival rate for the 538 patients in the cohort was 78%. No patient (0/29) with TaG1 tumours showed progression or died of bladder cancer. Only 2/187 patients (1%) with stage Ta and grade 2A or 2B tumours died of bladder cancer. In contrast, after 5 years of follow-up, patients with TaG3 and T1G2B tumours had disease-specific death rates of 20% and 27%, respectively. The result of the first cystoscopy examination after the initial resection of non-invasive tumours was of prognostic value. Recurrent disease was present in 62% (248/402) of all patients with Ta and T1 tumours at diagnosis and patients with T1 tumours had recurrences earlier than those with Ta tumours. Moreover, 32% (35/110) of the patients who presented with T1 tumours at diagnosis progressed to muscle-invasive disease during the follow-up period. The overall prognosis for patients presenting with muscle-invasive tumours (T2+) was dismal, with 69% (80/116) of the patients dying of the disease. CONCLUSIONS: We analysed a population-based cohort of patients with urinary bladder neoplasms in order to establish a clearly defined and unselected clinical series, with the main aims of comparing and evaluating the clinical utility of new molecular biology techniques. In the present series, TaG1 tumours behaved benignly. The disease-specific mortality rate was low for initial TaG2 tumours, intermediate for initial TaG3 and T1 tumours and high for initial T2+ tumours.

Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR.

PURPOSE: 9p21 is a major target in the pathogenesis of human urinary bladder cancer. The locus harbors the CDKN2A/ARF tumor suppressor gene, which encodes two cell cycle regulatory proteins cyclin dependent kinase 2A (p16(INK4a)) and alternate reading frame (p14(ARF)). We have designed a real-time quantitative PCR (QPCR) application to study homozygous deletion (HD) of CDKN2A/ARF in 186 urinary bladder cancer patients. EXPERIMENTAL DESIGN: Real-time QPCR, based on simultaneous amplification of ARF and a reference gene, GAPDH, was developed and evaluated in three melanoma cell lines with HDs at the CDKN2A/ARF locus (IGR-1, SK-MEL-5, and WM-266-4). In addition, loss of heterozygosity was analyzed at the D9S942, D9S1748, and D12S99 markers. Mutation analysis of the CDKN2A/ARF gene was performed using single-strand conformational polymorphism and sequencing. Results from the present investigation were combined with previous p53 analysis of the same urinary bladder neoplasms. RESULTS: Real-time QPCR analysis showed 26 (14%) HDs, 22 (12%) hemizygous deletions, and 3 (2%) multiple duplications. Loss of heterozygosity was determined in 30 (22%) cases at the D9S942 locus, which is located between E1alpha and E1beta of the CDKN2A/ARF gene. No association was established between occurrence of genetic aberrations at 9p21 and tumor stage or grade, supporting previous suggestions that CDKN2A/ARF inactivation is an early event in bladder carcinogenesis. CONCLUSIONS: We have established a fast and efficient method for detection of HDs. Our data support the notion that inactivation, including HDs, of CDKN2A/ARF is an early event in transitional cell carcinoma. We observed separate and specific targeting of the CDKN2A and ARF genes, respectively, and that simultaneous inactivation of ARF and p53 occurs.

Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms.

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population-based series. An association was found between uPA and uPAR expression (n = 172; Spearman r(s) = 0.60, p < 0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer-specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0-3.3) for uPA (upper quartile cut-line), 2.2 (1.3-4.0) for uPAR (median quartile cut-line) and 2.5 (1.3-4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6-9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1-3.9) for uPA, 1.6 (0.8-3.3) for uPAR and 2.5 (1.1-5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies.