Diagnostic Prostate-specific Antigen Research Articles

Negative first follow-up prostate biopsy on active surveillance is associated with decreased risk of upgrading, suspicion of progression and converting to active treatment.

To determine the risk of disease progression and conversion to active treatment following a negative biopsy while on active surveillance (AS) for prostate cancer (PCa). Men on an AS programme at a single tertiary hospital (London, UK) between 2003 and 2018 with confirmed low-intermediate-risk PCa, Gleason Grade Group <3, clinical stage <T3 and a diagnostic prostate-specific antigen (PSA) level of <20ng/mL. This cohort included men diagnosed by transrectal ultrasonography guided (12-14 cores) or transperineal (median 32 cores) biopsy. Multivariate Cox hazards regression analysis was undertaken to determine (i) risk of upgrading, (ii) clinical or radiological suspicion of disease progression, and (iii) transitioning to active treatment. Suspicion of disease progression was defined as any biopsy upgrading, >30% positive cores, magnetic resonance imaging (MRI) Likert score >3/T3 or PSA level of >20ng/mL. Conversion to treatment included radical or hormonal treatment. Among the 460 eligible patients, 23% had negative follow-up biopsy findings. The median follow-up was 62months, with one to two repeat biopsies and two MRIs per patient during that period. Negative biopsy findings at first repeat biopsy were associated with decreased risk of converting to active treatment (hazard ration [HR] 0.18, 95% confidence interval [CI] 0.09-0.37; P<0.001), suspicion of disease progression (HR 0.56, 95% CI: 0.34-0.94; P=0.029), and upgrading (HR 0.48, 95% CI 0.23-0.99; P=0.047). Data are limited by fewer men with multiple follow-up biopsies. A negative biopsy finding at the first scheduled follow-up biopsy among men on AS for PCa was strongly associated with decreased risk of subsequent upgrading, clinical or radiological suspicion of disease progression, and conversion to active treatment. A less intense surveillance protocol should be considered for this cohort of patients.

Long-term unmet supportive care needs of prostate cancer survivors: 15-year follow-up from the NSW Prostate Cancer Care and Outcomes Study.

To determine the prevalence, severity, and baseline associations of self-reported long-term unmet supportive care needs in a population-wide cohort of men with prostate cancer (PC), 15years post-diagnosis. Participants were drawn from the New South Wales (NSW) Prostate Cancer Care and Outcomes Study. Eligible men were diagnosed with PC between 2000 and 2002, aged less than 70years at diagnosis, and completed a 15-year follow-up survey. Demographic and clinical data were collected at baseline. The validated Cancer Survivors' Unmet Needs (CaSUN) Survey was administered to assess unmet needs. Of 578 eligible men, 351 completed CaSUN. Mean age was 75.8 (range 59-84) with a mean follow-up time of 15.2years post-diagnosis. Over a third of men (37.4%) reported at least one unmet need at 15years. Most frequently reported unmet needs pertained to the comprehensive cancer care (34.1%) domain. 87.2% of participants who reported problems with sexual function reported this need as moderate/severe. Higher diagnostic prostate-specific antigen (PSA) levels (20+ ng/mL) at diagnosis were associated with future unmet needs (PSA 20+: OR = 4.80, 95% CI [1.33-17.35]). Many PC survivors continue to report unmet needs 15years post-diagnosis. There is a pressing need for clinicians to work together to coordinate PC care, and to proactively, regularly, and openly enquire about men's sexual adjustment to PC. The needs of PC survivors could better be met with more coordinated approaches to multidisciplinary care and timely interventions and support for chronic sexual dysfunction.

When can active surveillance be less active? Prediction of long-term nonreclassification for men with low-risk prostate cancer.

140 Background: Active surveillance is endorsed as the preferred management strategy for most men with low-risk prostate cancer. However, nearly all active surveillance protocols entail prostate specific antigen (PSA) testing every 3-6 months, and prostate biopsies every 1-2 years. For many men with indolent tumors, this regimen is overly intense, and exposes men to the discomfort, risks, and costs of repeated biopsies. We aimed to determine if some men can be safely selected for a less intense surveillance regimen by predicting the probability of non-reclassification over the next 4 years of surveillance. Methods: Data were collected from men in the multicenter Canary Prostate Active Surveillance Study (PASS), in which PSAs are collected q3 months and biopsies performed 12 months of diagnosis and then every 2 years. For inclusion in this study, men had to have undergone ≤ 1 follow up biopsy, and have Gleason grade group 1 at diagnosis. Reclassification was defined as increase in Gleason grade group on subsequent biopsy; those without reclassification were censored at last study contact, treatment or 2 years after last biopsy. A dynamic risk prediction model based on a Cox regression with robust variance estimates was used to construct and test a model predicting non-reclassification. Results: Of 1082 men included, 362 (33%) reclassified and the remaining were censored. The final regression model included percent of biopsy cores involved, prior biopsy history, time since diagnosis, BMI, prostate size, diagnostic PSA, and PSAk (a measure of PSA kinetics). This dynamic risk prediction model was assessed at a measurement time of 1 year after diagnosis, predicting risk of reclassification at 4 years. Men at lowest and highest deciles of this model-based risk faced 6% (95%CI 0-12%) and 73% (55-84%) risks of reclassification within 5 years. For at least 10% of the men in the cohort, the negative predictive value (NPV) for reclassification was 95% or higher. Conclusions: A substantial proportion of men with low-risk prostate cancer can safely be followed with a de-intensified active surveillance protocol, which would improve both the tolerability and cost-effectiveness of this management strategy.

New prostate cancer grade grouping system predicts survival after radical prostatectomy

Summary Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy–treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively. Patients' all-cause and prostate cancer–specific mortality information was updated in November 2015 from the Finnish Cancer Registry. Secondary therapy information was also available from the patients' records at Helsinki. Univariate and multivariate statistical analyses were performed to assess predictive significance of the Grade Grouping system. Grade Grouping associated independently with increased risk of prostate cancer–specific mortality within 15 years of follow-up in a multivariable model containing age at operation, diagnostic prostate-specific antigen, pathological stage and lymph node status at operation. Additionally, the all-cause mortality-free survival time and time to secondary therapies were different between the Grade Groups, emphasized in the subanalysis of Grade Groups 1-2 versus Grade Groups 3-5. We can conclude that the new Grade Grouping system is feasible in predicting prostate cancer–specific survival after radical surgical treatment. Grade Grouping offers a simpler way to interpret the predicted course of the disease to individual patients and thus may help in justifying more conservative follow-up approaches, especially in the lower Grade Group patients.

Refined Analysis of Prostate-specific Antigen Kinetics to Predict Prostate Cancer Active Surveillance Outcomes

BackgroundFor men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial. ObjectiveTo develop prediction methods for utilizing serial PSA and evaluate frequency of collection. Design, setting, and participantsData were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels. Outcome measurements and statistical analysisThe association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models. Results and limitationsA total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 [95% confidence interval 1.2–2.1, p<0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions. ConclusionsPSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators. Patient summaryIn this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome.

Prognostic factors of prostate cancer mortality in a Finnish randomized screening trial.

To identify the prognostic factors of prostate cancer death among patients enrolled in a Finnish prostate cancer screening trial. Data on TNM stage, Gleason score, serum prostate-specific antigen at diagnosis, comorbidity and primary treatment were collected from medical records, as well as date and cause of death from Statistics Finland. Four prognostic risk groups were defined based on TNM stage, Gleason score and prostate-specific antigen at diagnosis. Hazard ratios and their 95% confidence intervals for prostate cancer death were calculated using Cox regression and competing-risk analysis with follow up from randomization. The differences in the effects of prognostic factors were assessed using interaction terms. The 15-year survival was significantly lower among cases in the control arm compared with the screening arm (0.90 vs 0.92). However, the survival advantage was limited to screen-detected cases (0.94 vs 0.91 in cases detected outside screening). The prognostic risk group was the strongest factor predicting survival in the control arm, but weaker in screen-detected cases. Advanced disease was associated with substantially poorer outcome in cases detected outside screening than in screen-detected disease. Primary treatment had a similar effect in all groups. Comorbidity had a small prognostic effect in the control arm only. Prognostic factors had a different effect on the outcome of cases detected through screening as those diagnosed otherwise. A high diagnostic prostate-specific antigen and advanced disease carried a poor prognosis, especially among the cases detected outside screening, even when lead-time was eliminated. This shows that the screening resulted in earlier treatment among the cases in the screening arm.

Outcomes of men on active surveillance for low-risk prostate cancer at a safety-net hospital

PurposeTo characterize demographic, disease, and cancer outcomes of men on active surveillance (AS) at a safety-net hospital and characterize those who were lost to follow-up (LTFU). MethodsFrom January 2004 to November 2014, 104 men with low-risk prostate cancer (PCa) were followed with AS at Zuckerberg San Francisco General Hospital (ZSFG). Criteria for AS have evolved over time; however, patients with diagnostic prostate-specific antigen (PSA) 10ng/mL or less, clinical stage T1/2, biopsy Gleason score 3 + 3 or 3 + 4, 33% or fewer positive cores, and 50% or less tumor in any single core were potentially eligible for AS. Men were longitudinally followed with a PSA or digital rectal examination or both every 3 to 6 months, and repeat prostate biopsy every 1 to 2 years. Clinical staging and grading were based on a physical examination and at least a 12-core biopsy, respectively. LTFU was defined as failure to successfully contact patients with 3 phone calls or any urology visit recorded within 18 months from a prior visit or biopsy. A secondary chart review was performed using the electronic medical record at ZSFG as well as EPIC Systems CareEverywhere which allows access to select non-ZSFG institutions to confirm that patients were truly LTFU. ResultsAmong the 104 men on AS at ZSFG, the median age at diagnosis of PCa was 61.5 years (range: 44–81). The median follow-up period was 29 months (range: 0–186 months) during which 18 (17.3%) men were LTFU and 48 (46%) remained on surveillance. Men underwent a median of 7 (1–21) serum PSA measurements and an average of 2 prostate biopsies (1–5). In total, 22 (20.6%) men had definitive treatment with the median time from diagnosis to active treatment being 26 (range: 2–87) months. Radiation therapy was more common than radical prostatectomy (12.5% vs. 7.7%). There was 1 PCa–related death and 3 noncancer deaths. Initial adherence to AS was poor; however, men committed to AS initially were ultimately more compliant over time. ConclusionAS for low-risk PCa is challenging among a vulnerable population receiving care in a safety-net hospital, as rates of LTFU were high. Our findings suggest the need for AS support programs to improve adherence and follow-up among vulnerable and underserved populations.

Extreme Gleason Upgrading From Biopsy to Radical Prostatectomy: A Population-based Analysis

To examine the risk factors associated with the odds of extreme Gleason upgrading at radical prostatectomy (RP) (defined as a Gleason prognostic group score increase of ≥2), we utilized a large, population-based cancer registry. The Surveillance, Epidemiologic, and End Results database was queried (2010-2011) for all patients diagnosed with Gleason 3 + 3 or 3 + 4 on prostate needle biopsy. Available clinicopathologic factors and the odds of upgrading and extreme upgrading at RP were evaluated using multivariate logistic regression. A total of 12,459 patients were identified, with a median age of 61 (interquartile range: 56-65) and a diagnostic prostate-specific antigen (PSA) of 5.5 ng/mL (interquartile range: 4.3-7.5). Upgrading was observed in 34% of men, including 44% of 7402 patients with Gleason 3 + 3 and 19% of 5057 patients with Gleason 3 + 4 disease. Age, clinical stage, diagnostic PSA, and % prostate needle biopsy cores positive were independently associated with odds of any upgrading at RP. In baseline Gleason 3 + 3 disease, extreme upgrading was observed in 6%, with increasing age, diagnostic PSA, and >50% core positivity associated with increased odds. In baseline Gleason 3 + 4 disease, extreme upgrading was observed in 4%, with diagnostic PSA and palpable disease remaining predictive. Positive surgical margins were significantly higher in patients with extreme upgrading at RP (P < .001). Gleason upgrading at RP is common in this large population-based cohort, including extreme upgrading in a clinically significant portion.

Ultra-sensitive protein detection via Single Molecule Arrays towards early stage cancer monitoring

The early diagnosis of cancers and continued monitoring of tumor growth would be greatly facilitated by the development of a blood-based, non-invasive, screening technique for early cancer detection. Current technologies for cancer screening and detection typically rely on imaging techniques or blood tests that are not accurate or sensitive enough to definitively diagnose cancer at its earliest stages or predict biologic outcomes. By utilizing Single Molecule Arrays (SiMoA), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA) technique, we were able to measure increasing levels of prostate specific antigen (PSA) within murine serum over time, which we attribute to tumor development. The measured concentrations of PSA were well below the detectable limits of both a leading clinical diagnostic PSA ELISA assay as well as a commercial ultra-sensitive PSA assay. Our work benchmarks the role of SiMoA as a vital tool in monitoring previously non-detectable protein biomarkers in serum for early cancer detection and offers significant potential as a non-invasive platform for the monitoring of early stage cancer.

The impact of PSA and digital rectal examination on the risk of prostate cancer specific mortality in men with a PSA level

IntroductionIt is unknown whether a normal range, diagnostic serum prostate specific antigen (PSA) level's influence on prostate cancer specific mortality (PCSM) is dependent upon digital rectal examination (DRE) findings. MethodsBetween 2004 and 2007, 9081 men diagnosed with non-palpable (T1c, N=1710) or palpable (T2–T4, N=7371) and non-metastatic prostate cancer (PC) were identified from surveillance, epidemiology, and end results data, selected based on pre-treatment PSA<2.5ng/ml. A multivariable competing risks regression model evaluated whether DRE findings interacted with PSA level in predicting risk of PCSM. ResultsAfter median follow-up of 2.83 years, 118 of 548 deaths (21.5%) were due to PC. Increasing diagnostic PSA was associated with increased risk of PCSM (AHR=3.52; 95% CI: 1.25–9.89; P=.017) in men with T1c, Gleason score 7–10 PC, but decreased PCSM risk (AHR=0.66; 95% CI: 0.52–0.83; P<.001) for men with T2–T4 PC and any Gleason score. DiscussionFor men with diagnostic PSA level <2.5ng/ml and palpable PC, risk of early PCSM increases by 34% for a 1 point decrease in PSA from 2. This suggests the existence of clinically detectable, low PSA secreting disease with an elevated risk of early PCSM, highlighting the importance of the DRE in men with PC and normal range, diagnostic PSA.

Racial Variation in Prostate Cancer Upgrading and Upstaging Among Men with Low-risk Clinical Characteristics

BackgroundAfrican American (AA) men suffer a higher prostate cancer (PCa) burden than other groups. ObjectiveWe aim to determine the impact of race on the risk of upgrading, upstaging, and positive surgical margins (PSM) at radical prostatectomy (RP) among men eligible for active surveillance. Design, setting, and participantsWe studied men with low-risk PCa treated with RP at two centers. Low clinical risk was defined by National Comprehensive Cancer Network criteria. Outcome variables were upgrading, upstaging, and PSMs at surgery. Associations between race and the outcomes were evaluated with logistic regression adjusted for age, relationship status, diagnostic prostate-specific antigen level, percentage of positive biopsy cores, surgical approach, year of diagnosis, and clinical site. Results and limitationsOf 9304 men diagnosed with PCa, 4231 were low risk and underwent RP within 1 yr. Men were categorized as AA (n=273; 6.5%), Caucasian (n=3771; 89.1%), or other racial/ethnic group (Other; n=187; 4.4%). AA men had a significantly younger mean age (58.7 yr; standard deviation: ±7.06), and fewer (85%) were married or had a partner. Upgrading (34%) and upstaging (13%) rates did not significantly differ among the groups. The PSM rate was significantly higher in AA men (31%) than in the Caucasian (21%) and Other (20%) groups (p<0.01). We found an association between race group and PSM rate (p<0.03), with higher odds of PSMs in AA men versus Caucasian men (odds ratio [OR]: 1.64; 95% confidence interval [CI], 1.08–2.47). No statistically significant associations between race and rates of upgrading and upstaging were found. This study was limited by the relatively low proportion of AA men in the cohort. ConclusionsAmong clinically low-risk men who underwent RP, AA men had a higher likelihood of PSMs compared with Caucasian men. We did not find statistically significantly different rates of upgrading and upstaging between the race groups. Patient summaryWe analyzed two large groups of men with what appeared to be low-risk prostate cancer based on the initial biopsy findings. The likelihood of finding worse disease (higher grade or stage) at the time of surgery was similar across different racial groups.

Androgen Pathway Related Gene Variants and Prostate Cancer Association in Auckland Men

Multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer (PC) have been reported in statistically robust studies in the past but these require an in-depth mechanistic understanding with respect to the biological pathways leading to disease. The current study was carried out to examine the PC and benign urology disease risk associations with lifestyle, demographic and genetic factors in a group of men between the ages 40-81 years from Auckland, New Zealand. The data presented herein support a significant positive association of PC risk with tobacco smoking, and a negative association with alcohol intake. The BMI was not associated with disease risk. The SRD5A2 rs632148 G allele was associated with PC compared to those with benign urology disease, after adjustments were made for the confounding variables. The Gleason score as well as disease aggressiveness of the PC group showed no association with lifestyle, demographic factors or the SNPs studied. The levels of prostate-specific antigen (PSA) significantly increased with age, smoking status and BMI, and decreased with alcohol consumption. The AKR1C3 rs12529 G allele was significantly associated with lower PSA levels in PC and benign urology disease groups compared to healthy controls. The G allele of the SRD5A2 rs632148 SNP has shown a significant interaction with PSA and a higher Gleason score outcome. Taken together, these findings show the utility of these gene variants and patient lifestyle history, together with the diagnostic serum PSA levels, to collectively enhance the understanding of the clinical-pathological variables of PC. Such information will support the selection of more personalised treatment options for this disease greatly impacting public health. Keywords: Androgen pathway related gene variants, Gleason score, personalised medicine, prostate cancer, PSA

PAGE4 Positivity Is Associated with Attenuated AR Signaling and Predicts Patient Survival in Hormone-Naive Prostate Cancer

Aberrant activation of the androgen receptor (AR) plays a key role during prostate cancer (PCa) development and progression to castration-resistant prostate cancer (CR-PCa) after androgen deprivation therapy, the mainstay systemic treatment for PCa. New strategies to abrogate AR activity and biomarkers that predict aggressive tumor behavior are essential for improved therapeutic intervention. PCa tissue microarrays herein reveal that prostate-associated gene 4 (PAGE4), an X-linked cancer/testis antigen, is highly up-regulated in the epithelium of preneoplastic lesions compared with benign epithelium, but subsequently decreases with tumor progression. We show that AR signaling is attenuated in PAGE4-expressing cells both in vitro and in vivo, most likely via impaired androgen-induced AR nuclear translocation and subsequently reduced AR protein stabilization and phosphorylation at serines 81 and 213. Consistently, epithelial PAGE4 protein levels inversely correlated with AR activation status in hormone-naive and CR-PCa clinical specimens. Moreover, PAGE4 impaired the development of CR-PCa xenografts, and strong PAGE4 immunoreactivity independently predicted favorable patient survival in hormone-naive PCa. Collectively, these data suggest that dysregulation of epithelial PAGE4 modulates AR signaling, thereby promoting progression to advanced lethal PCa and highlight the potential value of PAGE4 as a prognostic and therapeutic target.

Association between percentage of tumor involvement and Gleason score upgrading in low-risk prostate cancer

To find the predictors of Gleason score upgrading in a cohort of low-risk prostate cancer patients, data were analyzed comprising 1,632 consecutive men with low-risk prostate cancer who underwent radical prostatectomy between 1993 and 2009. Assessment focused on preoperative parameters including patient age, race, diagnostic prostate-specific antigen (PSA) levels, clinical stage and biopsy Gleason score, along with pathological parameters including percentage of tumor involvement (PTI), tumor laterality, pathological stage, extra-capsular extension, seminal vesicle invasion, and surgical margins. These parameters were analyzed using univariate and multivariate methods. Kaplan-Meier curves compared differences in biochemical disease-free survival in men having cancers with and without Gleason score upgrading. Cases involving pathological Gleason score upgrading were identified in 723 (44.3 %) of 1,632 patients. Kaplan-Meier PSA recurrence-free survival curves showed a difference in outcome between men with and without Gleason score upgrading (p < 0.001). Of Gleason score upgraded patients, 35 (4.8 %) men had PTI of <5 %, 237 (32.8 %) had PTI of 5-9.9 %, 177 (24.5 %) had PTI of 10-14.9 %, and 274 (37.9 %) had PTI ≥ 15 % (p < 0.001). PTI (p < 0.001) along with diagnostic PSA, patient age, diagnostic biopsy Gleason score, pathologic stage, and surgical margin status were independent predictors of pathological Gleason score upgrading on multivariate logistic regression. PTI correlates closely with Gleason score upgrading in a low-risk prostate cancer cohort. Low-risk prostate cancer patients with clinical findings suggestive of high PTI or large volume cancers should not benefit from active surveillance strategies.

Prostate cancer active surveillance and health‐related quality of life: results of the Finnish arm of the prospective trial

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Active surveillance is a management option in patients with localized prostate cancer. One concern is the possible psychological burden and quality-of-life effects caused by consciousness of living with untreated cancer. Previous studies have reported controversial results about the impact of active surveillance on patient's health-related quality of life. The data of the present study support the idea that patients with low-risk prostate cancer manage well on active surveillance and do not develop short-term mental or physical quality-of-life sequelae. To analyse longitudinal changes in general, mental and physical health-related quality of life (HRQL) and urinary and erectile function in patients with low-risk prostate cancer (PC) on active surveillance (AS). Patients comprised those (n= 124) enrolled in the Finnish arm of the Prostate Cancer Research International: Active Surveillance (PRIAS) study who were followed for at least 1 year (n= 80). All patients with PC received validated questionnaires at the start of surveillance and after 1 year of follow-up. General HRQL was assessed with the RAND 36-Item Health Survey (RAND-36), erectile function with the International Index of Erectile Function-5 (IIEF-5), and urinary symptoms with the International Prostate Symptom Score (IPSS) questionnaires. Results were also compared with an age-stratified general Finnish male population. A paired t-test served to compare results over time and a non-paired t-test or a corresponding non-parametric test, when applicable, served to compare the study group with the general population. Pearson and Spearman correlations were analysed between possible HRQL-affecting factors (demographic and clinical data) and HRQL data, followed by linear regression analysis to further evaluate any possible associations. Of the 124 patients, 105 (85%) returned the baseline RAND-36 questionnaire, and 75 (94%) of the 80 patients answered both the baseline and follow-up questionnaires; 15 patients (12%) had discontinued AS, all for protocol-based reasons, none due to anxiety or distress. No differences existed in the HRQL main categories at the 1-year follow-up (mental and physical: P= 0.142 and P= 0.154, respectively). When all the eight dimensions were analysed separately, the physical role showed statistically significant improvement from a mean of 81 to a mean of 89 (P= 0.010). No clinically significant correlations appeared between HRQL and age, diagnostic prostate-specific antigen (PSA), free PSA or PSA change during follow-up at any of the time points; in regression analysis, HRQL was not predictable by any of the variables available at diagnosis or during follow-up. No statistically significant changes occurred in urinary function as analysed by the IPSS (P= 0.121) or in erectile function by the IIEF-5 questionnaire (P= 0.583). Compared with an age-stratified Finnish general male population, patients with PC on AS had a significantly better general mental and physical HRQL at diagnosis and after 1 year of follow-up (P < 0.05). Active surveillance does not provoke short-term quality-of-life disturbances as assessed by standardized RAND-36, IIEF-5 and IPSS questionnaires. None of the patients changed treatment due to anxiety. Unexpectedly, PC patients on AS had significantly better general mental and physical HRQL than did a general age-stratified Finnish male population.

Copy number alterations in prostate tumors and disease aggressiveness

Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome-wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M single nucleotide polymorphism array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy-neutral), and 6q (copy-loss). Combined loss and copy-neutral events were associated with increasing disease grade (P = 0.03), stage (P = 0.01), and diagnostic prostate specific antigen (PSA) (P = 0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The "regulation of apoptosis" pathway was associated with stage of disease (P = 0.004), while the "reproductive cellular process" pathway was associated with diagnostic PSA (P = 0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (P = 0.007). These findings confirm known regions of CNAs in prostate cancer and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help to clarify the genetic basis of prostate cancer aggressiveness.

Factors Predicting Prostatic Biopsy Gleason Sum Under Grading

We determined clinical factors affecting the under grading of biopsy Gleason sum compared with prostatectomy pathology and developed a model predicting the probability of under grading. We analyzed a cohort of 1,701 patients treated for prostate cancer at our institution between 1988 and 2007 with complete biopsy and pathological data available. Patients with a biopsy Gleason sum of 7 or less were included in our analysis. Cases were categorized as under graded or not under graded by comparing biopsy and radical prostatectomy Gleason sums. Logistic regression was used to determine the predictors of under grading based on clinical variables (race, age at diagnosis, body mass index, prostate weight, diagnostic prostate specific antigen, biopsy positive-to-total core ratio, maximal cancer percent in positive cores and time from diagnosis to surgery). A nomogram was developed to calculate the probability of under grading. Results were validated using bootstrapping. Under grading occurred in 46.6% of our cohort. Significant variables predicting under grading were age at diagnosis, biopsy Gleason sum, diagnostic prostate specific antigen, prostate weight, biopsy positive-to-total core ratio and maximal percent of cancer in cores (p <0.05). Nomogram predictive accuracy was 72.4%. The risk of Gleason sum under grading can be predicted to a satisfactory level using our nomogram. Predicting under grading would improve patient consulting and identify those who should consider repeat biopsy, ultimately enhancing the accuracy of prostate cancer diagnosis.

Sociodemographic Predictors of Prostate Cancer Risk Category at Diagnosis: Unique Patterns of Significant and Insignificant Disease

We determined various sociodemographic predictors of prostate cancer risk category at presentation as assessed by serum prostate specific antigen, cancer grade and tumor stage. We performed a retrospective cohort study of 5,939 patients enrolled in the CaPSURE national disease registry database between 1995 and 2007. Prostate cancer risk category was assigned as low, intermediate or high based on diagnostic prostate specific antigen, clinical grade and biopsy Gleason grade. Additionally, a group of men with low grade, limited volume tumors were identified as having clinically insignificant disease. The primary outcome was prostate cancer risk category at presentation. Treatment received vs active surveillance was analyzed as a secondary end point. Patients who were older, had lower levels of education and had Medicare with or without a supplement instead of private or Veteran's Affairs insurance were more likely to have intermediate and high risk disease than low risk disease. Nonwhite race was associated with high risk disease at presentation. Clinically insignificant disease was more common in men younger than 60 years, those with higher education and income, and those with private insurance. Logistic regression analysis suggested that younger age, higher education and income, and private insurance were related to insignificant disease being detected. Among men with insignificant disease younger age and private insurance were associated with immediate treatment with curative intent. Unique sociodemographic variables are associated with the clinical risk of prostate cancer at diagnosis and they may influence treatment decisions and outcomes. Patients with insignificant disease may be susceptible to overtreatment due to the indolent nature of the disease. Intermediate and high risk groups, which are associated with poorer outcomes, may be further endangered by late detection of the disease.

Potentiometric enzyme immunoassay using miniaturized anion-selective electrodes for detection

An enzyme-linked immunosorbent assay (ELISA) for prostate specific antigen (PSA) detection in human serum was developed based on the potentiometric detection of 6,8-difluoro-4-methylumbelliferone (DiFMU). The assays were carried out in anti-human PSA capture antibody modified microtiter plates (150 microL volume). After incubation in the PSA-containing serum samples, beta-galactosidase-labeled PSA tracer antibody was added. The beta-galactosidase label catalyzed the hydrolysis of 6,8-difluoro-4-methylumbelliferyl-beta-D-galactopyranoside (DiFMUG) and the resulting DiFMU(-) anion was detected by potentiometric microelectrodes with anion-exchanger membrane. The selectivity of the anion-exchanger electrode is governed by the lipophilicity of the anions in the sample. Since DiFMU(-) is much more lipophilic (log P = 1.83) than any of the inorganic anions normally present in the working buffers and occurs in its anionic form at the physiological pH (pK(a) = 4.19), it was chosen as the species to be detected. The potentiometric ELISA-based method detects PSA in serum with a linear concentration range of 0.1-50 ng/mL. These results confirm the applicability of potentiometric detection in diagnostic PSA assays. Owing to simple methodology and low cost, potentiometric immunoassays seem to offer a feasible alternative to the development of in vitro diagnostic platforms.

TMPRSS2:ERG Fusion Identifies a Subgroup of Prostate Cancers with a Favorable Prognosis

Our aim was to assess the frequency of ERG overexpression and TMPRSS2:ERG rearrangement in prostate cancer and their association with clinicopathologic variables and outcome. The presence of the TMPRSS2:ERG rearrangement was studied by reverse transcription-PCR and fluorescence in situ hybridization in 19 prostate cancer xenografts and 7 prostate cancer cell lines. The expression of ERG was studied in the xenografts and cell lines and in 49 freshly frozen clinical prostate samples by quantitative reverse transcription-PCR. The frequency of the TMPRSS2:ERG fusion in clinical prostate cancer (n = 253) on tissue microarrays was assessed by three-color fluorescence in situ hybridization. Seven of 19 (37%) of the xenografts overexpressed ERG and had TMPRSS2:ERG rearrangement. Two xenografts, representing small cell carcinomas, also contained the fusion but did not express ERG. In clinical tumor specimens, the overexpression of ERG was associated with the rearrangement (P = 0.0019). Fifty of 150 (33%) of the prostatectomy specimens and 28 of 76 (37%) of the hormone-refractory prostate cancers on the tissue microarrays carried the TMPRSS2:ERG rearrangement. It was associated with longer progression-free survival in patients treated by prostatectomy (P = 0.019), and according to multivariate analysis, it was an independent predictor of favorable outcome (relative risk, 0.54; 95% confidence interval, 0.30-0.98). The fusion was not associated with Gleason score, pT stage, diagnostic prostate-specific antigen, or cell proliferation activity in prostatectomy specimens nor with the AR gene amplification in hormone-refractory tumors. The TMPRSS2:ERG rearrangement can be found in about one third of prostate cancers. A subgroup of prostate cancer patients with a good prognosis may be identified by the rearrangement.