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1.  Predictive value of prostate-specific antigen for prostate cancer: a nested case-control study in EuroSIDA 
Journal of the International AIDS Society  2014;17(4Suppl 3):19510.
Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV− men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV− men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men.
Men with PCa (n=21) and up to two matched controls (n=40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics.
Sixty-one men were included with a median six (IQR 2–9) years follow-up. Time between last sample and PCa was seven (4–11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48–57) and CD4 of 437 (243–610) cells/mm3. Median tPSA [2.8 (IQR: 1.6–4.6) and 0.8 (0.5–1.2) µg/L] and fPSA [0.4 (0.2–0.8) and 0.3 (0.2–0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7–9.5) and 0.9 (0.6–1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5–1.4) and 0.2 (0.2–0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2-fold higher 4.7 (CI: 1.7–12.9) and 5.4 (1.7–17.4)]. Elevated tPSA values in cases were detectable ≥5 years before PCa (p<0.01). Testosterone [overall median 19.4 (IQR 15.3–23.9) nmol/L at first sample) and SHBG [50.0 (34.0–66.0) nmol/L] levels were similar in cases and controls at first and last sample (all p>0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC = 0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%).
PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age-related cut-offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa.
PMCID: PMC4224942  PMID: 25394019
2.  Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer 
Prostate-specific antigen (PSA) has been widely used as a serum marker for prostate cancer (PCa) screening or progression monitoring, which dramatically increased rate of early detection while significantly reduced PCa-specific mortality. However, a number of limitations of PSA have been noticed. Low specificity of PSA may lead to overtreatment in men who presenting with a total PSA (tPSA) level of < 10 ng/mL. As a type of free PSA (fPSA), [-2]proPSA is differentially expressed in peripheral zone of prostate gland and found to be elevated in serum of men with PCa. Two p2PSA-based derivatives, prostate health index (PHI) and %p2PSA, which were defined as [(p2PSA/fPSA) × √ tPSA] and [(p2PSA/fPSA) × 100] respectively, have been suggested to be increased in PCa and can better distinguish PCa from benign prostatic diseases than tPSA or fPSA. We performed a systematic review of the available scientific evidences to evaluate the potentials of %p2PSA and PHI in clinical application. Mounting evidences suggested that both %p2PSA and PHI possess higher area under the ROC curve (AUC) and better specificity at a high sensitivity for PCa detection when compare with tPSA and %fPSA. It indicated that measurements of %p2PSA and PHI significantly improved the accuracy of PCa detection and diminished unnecessary biopsies. Furthermore, elevations of %p2PSA and PHI are related to more aggressive diseases. %p2PSA and PHI might be helpful in reducing overtreatment on indolent cases or assessing the progression of PCa in men who undergo active surveillance. Further studies are needed before being applied in routine clinical practice.
PMCID: PMC4297331  PMID: 25606581
PSA; prostate cancer; [-2]proPSA; %p2PSA; PHI; biopsy
3.  An examination of the dynamic changes in prostate-specific antigen occurring in a population-based cohort of men over time 
BJU international  2012;110(3):375-381.
To determine whether prostate-specific antigen velocity (PSA-V), PSA doubling time (PSA-DT), or PSA percentage change (PSA-PC) add incremental information to PSA alone for community-based men undergoing prostate cancer (PCa) screening.
A population-based cohort of 11 872 men from Olmsted County, MN undergoing PSA screening for PCa from 1993 to 2005 was analysed for PSA, PSA-DT, PSA-PC and PSA-V and subsequent PCa.Receiver-operating characteristics curves and logistic regression were used to calculate the area under the curve (AUC) and Aikaike’s information criterion.Reclassification analysis was performed and the net reclassification improvement and integrated discrimination improvement were measured.The method of Begg and Greenes was used to adjust for verification bias.
The single best predictor of future PCa was PSA (AUC = 0.773) with PSA-V (AUC = 0.729) and PSA-DT/PSA-PC (AUC = 0.689) performing worse.After age adjustment, combining PSA with PSA-V (AUC = 0.773) or PSA-DT/PSA-PC (AUC = 0.773) resulted in no better predictions than PSA alone.Reclassification analysis showed that adding PSA-V or PSA-DT/PSA-PC to PSA did not result in a meaningful amount of reclassification.
PSA is a better predictor of future PCa than PSA-V, PSA-DT, or PSA-PC.Adding PSA-V, PSA-DT, or PSA-PC to PSA does not result in clinically relevant improvements in the ability to predict future PCa.
PMCID: PMC3637967  PMID: 22313933
prostate cancer; prostate-specific antigen; PSA doubling time; PSA velocity; PSA percentage change
4.  Immunoassay for the discrimination of free prostate-specific antigen (fPSA) forms with internal cleavages at Lys145 or Lys146 from fPSA without internal cleavages at Lys145 or Lys146 
Journal of immunological methods  2011;369(0):74-80.
Total levels of circulating prostate-specific antigen (tPSA) are strongly associated with prostate cancer (PCa) risk and outcome but benign prostate disease is the most frequent cause of a moderately elevated PSA level. Free PSA (fPSA) forms are independently associated with PCa risk and contribute modest diagnostic enhancements above and beyond tPSA alone. We developed an immunoassay for fPSA subfractions containing internal cleavages at Lys145 or Lys146 (fPSA-N). The assay was based on blocking intact single-chain fPSA (fPSA-I) with antibody 4D4 which does not detect PSA containing internal cleavages at Lys145 or Lys146. We also measured fPSA-N in blood from healthy volunteers and in anti-coagulated plasma from 76 men with or without evidence of PCa at biopsy. The analytical and functional detection limits of this assay were 0.016 ng/mL and 0.10 ng/mL, respectively. The median recovery of male fPSA-N from female plasma was 95.0 %. All 12 female samples (average age 28 years) had fPSA-N concentrations at or below the analytical detection limit. The median fPSA-N concentration (0.050 ng/mL) in 9 healthy male volunteers (age < 40 years) was below the functional detection limit, 0.420 ng/mL in 27 patients with benign prostate conditions and 0.239 ng/mL in 49 patients with PCa. Deming regression analysis of the patient samples showed that the measured fPSA-N concentrations were generally 23% lower than the previously calculated (fPSA minus fPSA-I) concentrations, likely due to differences in the antibody combinations used. In conclusion, we have developed a sensitive, specific and direct immunoassay for fPSA-N which can be used to study the clinical relevance of this PSA isoform.
PMCID: PMC4273311  PMID: 21554885
prostate-specific antigen; free PSA isoform; internally cleaved PSA; nicked PSA; immunoassay; prostate cancer
5.  Outcomes and Trends of Prostate Biopsy for Prostate Cancer in Chinese Men from 2003 to 2011 
PLoS ONE  2012;7(11):e49914.
Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood.
Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a 10-year period, since the increasing use of PSA tests.
All men (n = 1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from 2003–2011 were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October 2007 or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data.
The overall positive rate of prostate biopsy for PCa was 47% and the rate decreased significantly over the years from 74% in 2003 to 33% in 2011 (P-trend = 0.004) . Age at diagnosis was slightly increased (P-trend = 0.04) while fPSA/tPSA was significantly decreased (P-trend = 1.11×10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results) (AUC = 0.93) statistically outperformed models that included only PSA (AUC = 0.85) or fPSA/tPSA (AUC = 0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than 20 ng/mL (AUC = 0.87, vs. AUC of tPSA  = 0.62, P<0.05).
Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past 10 years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy.
PMCID: PMC3506536  PMID: 23189170
The Journal of urology  2010;183(4):1355-1359.
Due to the limited specificity of prostate-specific antigen (PSA) for prostate cancer (CaP) screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme PSA called [−2] proPSA (p2PSA) may enhance the specificity of PSA-based screening. The objective of our study was to examine the utility of p2PSA in a prospective CaP screening study.
Materials and Methods
From a population of 2034 men undergoing CaP screening, we examined the relationship between p2PSA and CaP detection. Specifically, we compared the utility of total PSA, the ratio of free PSA (fPSA) to total PSA (%fPSA), the ratio of p2PSA to fPSA (%p2PSA) and a formula combining PSA, fPSA and p2PSA (called Beckman Coulter prostate health index or phi®) to predict CaP among men from the study undergoing prostate biopsy with PSA levels of 2.5–10 ng/ml and non-suspicious digital rectal examination (DRE).
Despite similar total PSA levels (p=0.88), both %fPSA (p=0.02) and %p2PSA (p=0.0006) distinguished between positive and negative biopsy results. On receiver operating characteristic (ROC) analysis, %p2PSA (AUC 0.76) outperformed both PSA (AUC 0.50) and %fPSA (AUC 0.68) for differentiating between CaP and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity, positive and negative predictive values. The Beckman Coulter phi® (AUC 0.77) had the best overall performance characteristics.
This is the first prospective study to demonstrate that p2PSA provides improved discrimination between CaP and benign disease in screened men with PSA levels from 2.5 to 10 ng/ml and negative DRE.
PMCID: PMC3537165  PMID: 20171670
prostate-specific antigen; PSA; free PSA; PSA isoforms; proPSA
7.  Detectable Prostate-Specific Antigen Nadir During Androgen-Deprivation Therapy Predicts Adverse Prostate Cancer Specific Outcomes: Results from the SEARCH Database 
European urology  2012;65(3):620-627.
A prostate-specific antigen (PSA) level <0.2 ng/ml on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT—specifically, <0.2 ng/ml—can be used for risk stratification is untested.
We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)–specific outcomes in men treated with early ADT after radical prostatectomy (RP).
Design, setting, and participants
We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir.
ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease.
Outcome measurements and statistical analysis
PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes.
Results and limitations
Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p < 0.001), metastases (HR: 3.98; p = 0.006), and PCa-specific mortality (PCSM) (HR: 5.33; p = 0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM was 0.88, 0.91, and 0.96, respectively.
A PSA nadir on ADT, even at a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials.
PMCID: PMC3634863  PMID: 23245686
Prostate cancer; Androgen-deprivation therapy; Prostate-specific antigen
8.  Screening for Prostate Cancer: An Update 
The Canadian journal of urology  2008;15(6):4363-4374.
The introduction of total prostate specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer (PCa). This review will highlight some of the exciting new developments in the field of PCa screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high-risk for PCa from men at low-risk or men with “significant” (high-grade, high-volume) cancer from those with low-grade, indolent cancer. Taken together with a man’s age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop PCa have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in PCa development and progression. tPSA measurements before age 50 could help risk-stratify men for intensity of PCa screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by PCa. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of PCa, evidence from large prospective clinical trials remain to be reported.
PMCID: PMC2742707  PMID: 19046489
prostate-specific antigen; human glandular kallikrein; prostate cancer; prognosis; detection
9.  Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: potential for rapid monitoring of treatment responses 
The utility of conventional prostate-specific antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by GnRH agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with degarelix (Firmagon®), a novel GnRH antagonist.
This study included 24 patients treated with degarelix. Blood was taken at 1, 3, 7, 14, 21, and 28 days after injection of degarelix. Free and total PSA were measured with a commercial dual-label assay, and with in-house research assays of intact PSA and hK2.
Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92%) reached castrate levels of testosterone within 24 hours of degarelix initiation, and all patients did so within 72 hours. All kallikrein forms declined in an exponential fashion after degarelix administration. The median time to 50% reduction in biomarker level was 8–9 days for tPSA or complexed PSA versus 2–4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p<0.02), while tPSA and complexed PSA were similar.
The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor,
PMCID: PMC3474140  PMID: 22718641
androgen deprivation therapy; human kallikrein-related peptidase 2; prostate cancer; prostate-specific antigen; tumor markers
10.  Age-Specific Cutoff Value for the Application of Percent Free Prostate-Specific Antigen (PSA) in Chinese Men with Serum PSA Levels of 4.0–10.0 ng/ml 
PLoS ONE  2015;10(6):e0130308.
The influence of age on the performance of percent free prostate-specific antigen (%fPSA) in diagnosing prostate cancer (PCa) in East Asians is controversial. We tested the diagnostic performance of %fPSA in a multi-center biopsy cohort in China and identified the proper age-specific cutoff values to avoid unnecessary biopsies.
Consecutive patients with a prostate-specific antigen (PSA) level of 4.0–10.0 ng/ml or 10.1–20.0 ng/ml who underwent transrectal ultrasound-guided or transperineal prostate biopsy were enrolled from 22 Chinese medical centers from Jan 1, 2010 to Dec 31, 2013. The diagnostic accuracy of PSA and %fPSA was determined using the area under the receiver operating characteristic (ROC) curve (AUC). Age-specific cutoff values were calculated using ROC curve analysis.
The median %fPSA was much lower in younger patients compared with older patients with a PSA level of 4.0–10.0 ng/ml or 10.1–20.0 ng/ml. The AUC of %fPSA was higher than PSA only in older patients. In patients aged 50 to 59 years, %fPSA failed to improve the diagnosis compared with PSA in these two PSA ranges. Age-specific cutoff values were 24%, 27% and 32% for patients aged 60–69, 70–79 and ≥80 years, respectively, to reduce unnecessary biopsies in men with PSA levels of 4.0–10.0 ng/ml to detect 90% of all PCa.
The effectiveness of %fPSA is correlated with age in the Chinese population. Age-specific cutoff values would help avoid unnecessary biopsies in the Chinese population.
PMCID: PMC4474838  PMID: 26091007
11.  Role of Prostate Volume in the Early Detection of Prostate Cancer in a Cohort with Slowly Increasing Prostate Specific Antigen 
Yonsei Medical Journal  2013;54(5):1202-1206.
To investigate the relationship between prostate volume and the increased risk for being diagnosed with prostate cancer (PCa) in men with slowly increasing prostate specific antigen (PSA).
Materials and Methods
A cohort of 1035 men who visited our hospital's health promotion center and were checked for serum PSA levels more than two times between January 2001 and November 2011 were included. Among them, 116 patients had a change in PSA levels from less than 4 ng/mL to more than 4 ng/mL and underwent transrectal ultrasound guided prostate biopsy. Median age was 55.9 years and 26 (22.4%) had PCa. We compared the initial PSA level, the last PSA level, age, prostate volume, PSA density (PSAD), PSA velocity, and follow-up period between men with and without PCa. The mean follow-up period was 83.7 months.
Significant predictive factors for the detection of prostate cancer identified by univariate analysis were prostate volume, follow-up period and PSAD. In the multivariate analysis, prostate volume (p<0.001, odds ratio: 0.890) was the most significant factor for the detection of prostate cancer. In the receiver operator characteristic curve of prostate volume, area under curve was 0.724. At the cut-off value of 28.8 mL for prostate volume, the sensitivity and specificity were 61.1% and 73.1% respectively.
In men with PSA values more than 4 ng/mL during the follow-up period, a small prostate volume was the most important factor in early detection of prostate cancer.
PMCID: PMC3743199  PMID: 23918570
Prostatic neoplasms; prostate-specific antigen; early diagnosis; organ size
12.  PSA density improves the rate of prostate cancer detection in Chinese men with a PSA between 2.5–10.0 ng ml-1 and 10.1–20.0 ng ml-1: a multicenter study 
Asian Journal of Andrology  2014;17(3):503-507.
Chinese men should have a higher prostate-specific antigen (PSA) “gray zone” than the traditional value of 2.5–10.0 ng ml−1 since the incidence of prostate cancer (PCa) in Chinese men is relative low. We hypothesized that PSA density (PSAD) could improve the rate of PCa detection in Chinese men with a PSA higher than the traditional PSA “gray zone.” A total of 461 men with a PSA between 2.5 and 20.0 ng ml−1, who had undergone prostatic biopsy at two Chinese centers were included in the analysis. The men were then further divided into groups with a PSA between 2.5–10.0 ng ml−1 and 10.1–20.0 ng ml−1. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of PSA and PSAD for the diagnosis of PCa. In men with a PSA of 2.5–10.0 ng ml−1 or 10.1–20.0 ng ml−1, the areas under the ROC curve were higher for PSAD than for PSA. This was consistent across both centers and the cohort overall. When the entire cohort was considered, the optimal PSAD cut-off for predicting PCa in men with a PSA of 2.5–10.0 ng ml−1 was 0.15 ng ml−1 ml−1, with a sensitivity of 64.4% and specificity of 64.6%. The optimal cut-off for PSAD in men with a PSA of 10.1–20.0 ng ml−1 was 0.33 ng ml−1 ml−1, with a sensitivity of 60.3% and specificity of 82.7%. PSAD can improve the effectiveness for PCa detection in Chinese men with a PSA of 2.5–10.0 ng ml−1 (traditional Western PSA “gray zone”) and 10.1–20.0 ng ml−1 (Chinese PSA “gray zone”).
PMCID: PMC4430959  PMID: 25475661
area under the receiver operating characteristic curve; prostate cancer; prostate-specific antigen; prostate-specific antigen density
13.  Effect of Histological Inflammation on Total and Free Serum Prostate-Specific Antigen Values in Patients Without Clinically Detectable Prostate Cancer 
Korean Journal of Urology  2014;55(8):527-532.
We are often confronted with patients in the "gray zone" (prostate-specific antigen [PSA]<10 ng/mL) whose biopsies reveal no malignancy but only inflammation. We investigated the relationship between histological inflammation and total PSA (tPSA), free PSA (fPSA), and percentage of free PSA (f/tPSA) levels in patients without prostate cancer (PC).
Materials and Methods
We studied 106 men with tPSA<10 ng/mL who had undergone biopsy that was negative for PC and who had no clinical prostatitis. Inflammation observed at biopsies was scored for inflammation type in each biopsy core by use of a four-point scale and was then correlated with tPSA, fPSA, and f/tPSA.
Different patterns of inflammation were found in each set of biopsies. Regression factor analysis was used to form two groups according to inflammation type: more chronic and more acute. Median tPSA, fPSA, and f/tPSA levels in the more chronic and more acute inflammation groups were 6.4 ng/mL, 1.09 ng/mL, and 15%, and 7.3 ng/mL, 0.79 ng/mL, and l2%, respectively. A significant difference was found in fPSA (p=0.003) and f/tPSA (p<0.001), whereas the difference in tPSA was not significant (p=0.200). Total PSA correlated with fPSA (r=0.4, p<0.001) but not with inflammation type (r=0.12, p>0.010). A correlation existed between inflammation type and fPSA (r=-0.31, p=0.001) and f/tPSA (r=-0.43, p<0.001) in that the fPSA and f/tPSA were lower in the group with more acute inflammation.
Subclinical inflammation has a significant influence on fPSA in patients with tPSA<10 ng/mL but without PC or clinical prostatitis. Subclinical inflammation is not characterized by elevated tPSA alone but also by a decreased fPSA, a tendency similar to that in PC.
PMCID: PMC4131081  PMID: 25132947
Biopsy; Inflammation; Prostate-specific antigen; Prostatic neoplasms; Prostatitis
14.  Assessment of Intra-Individual Variationin Prostate-Specific Antigen Levels in a Biennial Randomized Prostate Cancer Screening Program in Sweden 
The Prostate  2005;65(3):216-221.
The degree of variability in prostate-specific antigen (PSA) measurements is important for interpreting test results in screening programs, and particularly for interpreting the significance of changes between repeated tests. This study aimed to determine the long-term intra-individual variation for PSA in healthy men.
A randomly selected cohort of men in a biennial prostate cancer screening program (ERSPC) conducted in Sweden from 1995–1996 to 2001–2002. We studied men who had total PSA (tPSA) levels <2.0 ng/ml in 2001–2002. This included 791 men with tPSA ≤ 0.61 ng/ml (group A), 1,542 men with tPSA ≤ 0.99 ng/ml (group B), and 1,029 men with tPSA 1.00–1.99 ng/ml (group C). The intra-individual variability of free PSA (fPSA) and tPSA was assessed by calculating coefficients of variation (CV) for each individual’s PSA measurements from the first and second round of screening (1995–1996 and 1997–1998).
Intra-individual CV (geometric means) for tPSA were 13.7%, 12.7%, and 11.5% in groups A, B, and C, respectively. Corresponding CVs for fPSA were significantly lower, ranging from 12.1% to 10.4%. The estimated biological variation of tPSA and fPSA in groups A to C were 12.5%, 11.4%, 10.0% and 9.7%, 7.8%, 7.5%, respectively.
In healthy men with PSA levels less than 2 ng/ml, the natural long-term variability for tPSA was less than 14%, and with 95% probability, a change in tPSA greater than 30% indicates a change beyond normal random variation.
PMCID: PMC1951509  PMID: 15948137
PSA; biological variation; critical difference; screening
15.  Free Prostate-Specific Antigen Provides More Precise Data on Benign Prostate Volume Than Total Prostate-Specific Antigen in Korean Population 
To investigate the efficacy of total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) for the estimation of prostate volume (PV) in pathologically-proven benign prostatic hyperplasia (BPH) patients.
From January 2010 to March 2013, 165 Korean men with a PSA less than 10 ng/mL who were diagnosed without prostate cancer by prostate biopsy were enrolled. Patients were classified into three age groups: ≤60, 61-70, and >70 years old. The results were organized to estimate and compare the ability of serum tPSA and fPSA to assess the PV.
Enrolled patients had a median age of 63.5 years (44 to 80), a median tPSA of 5.72 ng/mL, a median fPSA of 0.98 ng/mL and a median PV of 53.68 mL, respectively. Among the associations between tPSA, fPSA, age, and PV, the highest correlation was verified between fPSA and PV (r=0.377, P<0.0001); the correlation coefficient between tPSA and PV was much lower (r=0.262, P<0.001). All stratified age cohorts showed the same findings. The ROC curves (for PV greater than 30, 40, and 50 mL) showed that fPSA (area under the curve [AUC]=0.781, 0.718, and 0.700) outperformed tPSA (AUC=0.657, 0.583, and 0.67) in its ability to predict clinically significant PV enlargement.
Both tPSA and fPSA significantly correlated with PV in Korean men, while the correlation efficiency between fPSA and PV was more powerful. fPSA may be a useful tool in making therapeutic decisions and follow-up management in BPH patients.
PMCID: PMC3713245  PMID: 23869271
Prostate-specific antigen; Prostatic hyperplasia; Organ volume
16.  Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen 
BMC Medicine  2014;12:26.
Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.
Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).
If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.
Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.
PMCID: PMC3922189  PMID: 24512643
Prostate cancer; Early detection; Overdiagnosis; PSA; Screening
17.  Age-Specific Prostate Specific Antigen Cutoffs for Guiding Biopsy Decision in Chinese Population 
PLoS ONE  2013;8(6):e67585.
Age-specific prostate specific antigen (PSA) cutoffs for prostate biopsy have been widely used in the USA and European countries. However, the application of age-specific PSA remains poorly understood in China.
Between 2003 and 2012, 1,848 men over the age of 40, underwent prostate biopsy for prostate cancer (PCa) at Huashan Hospital, Shanghai, China. Clinical information and blood samples were collected prior to biopsy for each patient. Men were divided into three age groups (≤60, 61 to 80, and >80) for analyses. Digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total PSA (tPSA), and free PSA (fPSA) were also included in the analyses. Logistic regression was used to build the multi-variate model.
Serum tPSA levels were age-dependent (P = 0.008), while %fPSA (P = 0.051) and PSAD (P = 0.284) were age-independent. At a specificity of 80%, the sensitivities for predicting PCa were 83%, 71% and 68% with tPSA cutoff values of 19.0 ng/mL (age≤60),21.0 ng/mL (age 61–80), and 23.0 ng/mL (age≥81). Also, sensitivities at the same tPSA levels were able to reach relatively high levels (70%–88%) for predicting high-grade PCa. Area (AUC) under the receive operating curves (ROCs) of tPSA, %fPSA, PSAD and multi-variate model were different in age groups. When predicting PCa, the AUC of tPSA, %fPSA, PSAD and multi-variate model were 0.90, 0.57, 0.93 and 0.87 respectively in men ≤60 yr; 0.82, 0.70, 0.88 and 0.86 respectively in men 61–80 yr; 0.79, 0.78, 0.87 and 0.88 respectively in men>80 yr. When predicting Gleason Score ≥7 or 8 PCa, there were no significant differences between AUCs of each variable.
Age-specific PSA cutoff values for prostate biopsy should be considered in the Chinese population. Indications for prostate biopsies (tPSA, %fPSA and PSAD) should be considered based on age in the Chinese population.
PMCID: PMC3692456  PMID: 23825670
The Journal of urology  2005;173(6):1930-1934.
We developed and validated a nomogram which predicts presence of prostate cancer (PCa) on needle biopsy.
Materials and Methods
We used 3 cohorts of men who were evaluated with sextant biopsy of the prostate and whose presenting prostate specific antigen (PSA) was not greater than 50 ng/ml. Data from 4,193 men from Montreal, Canada were used to develop a nomogram based on age, digital rectal examination (DRE) and serum PSA. External validation was performed on 1,762 men from Hamburg, Germany. Data from these men were subsequently used to develop a second nomogram in which percent free PSA (%fPSA) was added as a predictor. External validation was performed using 514 men from Montreal. Both nomograms were based on multivariate logistic regression models. Predictive accuracy was evaluated with areas under the receiver operating characteristic curve and graphically with loess smoothing plots.
PCa was detected in 1,477 (35.2%) men from Montreal, 739 (41.9%) men from Hamburg and 189 (36.8%) men from Montreal. In all models all predictors were significant at 0.05. Using age, DRE and PSA external validation AUC was 0.69. Using age, DRE, PSA and %fPSA external validation AUC was 0.77.
A nomogram based on age, DRE, PSA and %fPSA can highly accurately predict the outcome of prostate biopsy in men at risk for PCa.
PMCID: PMC1855288  PMID: 15879784
prostatic neoplasms; biopsy; nomograms; validation studies
The Journal of Urology  2011;187(1):92-96.
To provide cross-sectional normative data for [-2]pro-prostate-specific antigen ([-2]proPSA) from the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) and the Flint Men’s Health Study (FMHS) and to describe the associations with clinical urologic measures and risk of prostate cancer diagnosis.
Materials and Methods
Measurements of [-2]proPSA were obtained from n=420 white men from Olmsted County, Minnesota and n=328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proPSA and prostate enlargement / elevated PSA level were assessed. Cox proportional hazard models were used to assess associations between [-2]proPSA and incident diagnosis of prostate cancer.
Baseline [-2]proPSA level was slightly higher among black men (median (25th, 75th percentiles) =6.3 (4.1, 8.9) pg/mL) than among white men (median=5.6 (3.9, 7.7) pg/mL), p=0.01. Baseline [-2]proPSA level was highly predictive of biopsy-confirmed prostate cancer (CaP) in the OCS cohort. Relative to men in the lower quartile of [-2]proPSA, men in the upper quartile had almost an 8-fold increase in the risk of CaP (hazard ratio (HR): 7.8, 95% confidence interval (CI): 2.2, 27.8) after adjustment for age and baseline PSA.
Levels of [-2]proPSA in these cohorts of community-dwelling black and white men are much lower than seen in previous studies. These data suggest that levels of [-2]proPSA may help identify prostate cancer in men with serum PSA levels in an indeterminate range, although the reference ranges for white and black men may differ slightly.
PMCID: PMC3307097  PMID: 22093189
prostate enlargement; prostate cancer; biomarkers; proPSA
20.  Prostate-Specific Antigen Testing of Older Men 
Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection.
We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age.
All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%–100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%–100%) of the cancers would still be detected by age 75 years.
These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.
PMCID: PMC3474977  PMID: 10528023
21.  Free to total serum prostate specific antigen ratio in symptomatic men does not help in differentiating benign from malignant disease of the prostate 
Free to total prostate specific antigen ratio (f/t PSA) has been used to help improving specificity of PSA in the range of 4-10 ng/ml based on the data on population based screening. There is no data on test characteristics of f/t PSA in men presenting with clinical symptoms of benign prostatic hyperplasia (BPH). This study is aimed to determine the usefulness of f/t PSA in symptomatic men.
From January 2006 to June 2012, men of 50-75 years with lower urinary tract symptoms (LUTS), normal rectal examination and PSA between 4-20 ng/ml had free and total PSA assessment. Men with clinical evidence of prostatitis, retention, history of 5α blocker reductase inhibitors and those who had surgery or biopsy on the prostate in last 3 months were excluded. Receiver operating characteristic curves were derived for f/t PSA and total PSA. The effect of age, prostate volume and Gleason score on the f/t PSA was also analyzed. All statistical analyses were performed on SPSS 16 (Chicago, USA).
Out of 170 men with the mean age of 67.4 ± 6.6 years, 43 (25.3%) had cancer on biopsy. Area under the curve for predicting the presence or absence of prostate cancer in all the men with f/t ratio was 0.63 (confidence interval [CI]: 0.54-0.71). The median value of f/t PSA for men with cancer was 5.5% (1-25%) and 9.2% (1-63%) for those with no cancer. Cut-offs derived at 95% specificity at PSA between 4-10 ng/ml and 4-20 ng/ml were 0.5% and 1% respectively. The specificity of f/t PSA ratio at cut-off levels 7%, 10% and 15% was 73%, 60%, 45% for PSA range of 4-10 ng/ml and 63%, 47% and 35% for PSA range of 4-20 ng/ml PSA. Age, prostate volume and Gleason grade did not show any effect on f/t PSA.
In men with LUTS the specificity of various f/t PSA ratio cut-offs; described for population based screening, is too low to be used as an aid to defer the decision of biopsy in PSA ranges of 4-20 ng/ml.
PMCID: PMC3897049  PMID: 24497678
Free to total prostate specific antigen ratio; prostate cancer; screening
22.  Increase in percent free prostate-specific antigen in men with chronic kidney disease 
Nephrology Dialysis Transplantation  2008;24(4):1238-1241.
Background. Prostate-specific antigen (PSA) occurs in different molecular forms in serum: free PSA (fPSA) and complexed PSA (cPSA), the sum of which corresponds to total PSA (tPSA). In addition to tPSA, percent fPSA is widely used in the detection of prostate cancer. Free PSA, ∼28 kDa, is eliminated by glomerular filtration. Previous data showed that men with end-stage renal dysfunction requiring chronic dialysis have increased percent fPSA. In this study, we evaluated whether moderate-to-severe chronic renal dysfunction, but with no need for dialysis, also importantly affects percent fPSA.
Methods. The study group consisted of 101 men (median age 57 years, interquartile range 46–68) with chronic kidney disease and no diagnosis of prostate cancer. Their median glomerular filtration rate (GFR) was 23 mL/min/1.73 m2 (interquartile range 16–33; range 8–83), determined by iohexol clearance. Controls included 5264 men (median age 57 years, interquartile range 54–62) attending a prostate cancer screening program with no diagnosis of prostate cancer during 8 years of follow-up.
Results. With adjustment for age, median fPSA levels and percent fPSA were significantly higher (P < 0.001) in patients with renal dysfunction, 0.45 μg/L and 47.2%, respectively, compared to controls, 0.29 μg/L and 29.9%, respectively. Regression analysis in the study group showed a significant association between GFR and percent fPSA (P = 0.036).
Conclusions. The percent fPSA is importantly influenced by moderately impaired renal function in men with chronic kidney disease. For such men, use of the current clinical decision limits for percent fPSA could cause some men with prostate cancer to be misdiagnosed as having benign disease, and therefore fPSA should not be used to diagnose prostate cancer in these patients.
PMCID: PMC2721427  PMID: 19028756
diagnosis; glomerular filtration rate; chronic kidney disease; prostate cancer; prostate-specific antigen
23.  Cancer Screening: A Mathematical Model Relating Secreted Blood Biomarker Levels to Tumor Sizes  
PLoS Medicine  2008;5(8):e170.
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.
Methods and Findings
Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm3 and 3,610.14 mm3 for CA125 and between 0.21 mm3 and 131.51 mm3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm3 and 1.52 × 106 mm3 for CA125 and between 27 mm3 and 3.45 × 105 mm3 for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.
This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.
Sanjiv Gambhir and colleagues describe a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays.
Editors' Summary
Cancers—disorganized masses of cells that can occur in any tissue—develop when cells acquire genetic changes that allow them to grow uncontrollably and to spread around the body (metastasize). If a cancer (tumor) is detected when it is small, surgery can often provide a cure. Unfortunately, many cancers (particularly those deep inside the body) are not detected until they are large enough to cause pain or other symptoms by pressing against surrounding tissue. By this time, it may be impossible to remove the original tumor surgically and there may be metastases scattered around the body. In such cases, radiotherapy and chemotherapy can sometimes help, but the outlook for patients whose cancers are detected late is often poor. Consequently, researchers are trying to develop early detection tests for different types of cancer. Many tumors release specific proteins—“cancer biomarkers”—into the blood and the hope is that it might be possible to find sets of blood biomarkers that detect cancers when they are still small and thus save many lives.
Why Was This Study Done?
For most biomarkers, it is not known how the amount of protein detected in the blood relates to tumor size or how sensitive the assays for biomarkers must be to improve patient survival. In this study, the researchers develop a “linear one-compartment” mathematical model to predict how large tumors need to be before blood biomarkers can be used to detect them and test this model using published data on two established cancer biomarkers—CA125 and prostate-specific antigen (PSA). CA125 is used to monitor the progress of patients with ovarian cancer after treatment; ovarian cancer is rarely diagnosed in its early stages and only one-fourth of women with advanced disease survive for 5 y after diagnosis. PSA is used to screen for prostate cancer and has increased the detection of this cancer in its early stages when it is curable.
What Did the Researchers Do and Find?
To develop a model that relates secreted blood biomarker levels to tumor sizes, the researchers assumed that biomarkers mix evenly throughout the patient's blood, that cancer cells secrete biomarkers into the fluid that surrounds them, that 0.1%–20% of these secreted proteins enter the blood at a continuous rate, and that biomarkers are continuously removed from the blood. The researchers then used their model to calculate the smallest tumor sizes that might be detectable with these biomarkers by feeding in existing data on CA125 and on PSA, including assay detection limits and the biomarker secretion rates of cancer cells growing in dishes. When only tumor cells secreted the biomarker and 10% of the secreted biomarker reach the blood, the model predicted that ovarian tumors between 0.11 mm3 (smaller than a grain of salt) and nearly 4,000 mm3 (about the size of a cherry) would be detectable by measuring CA125 blood levels (the range was determined by varying the amount of biomarker secreted by the tumor cells and the assay sensitivity); for prostate cancer, the detectable tumor sizes ranged from similar lower size to about 130 mm3 (pea-sized). However, healthy cells often also secrete small quantities of cancer biomarkers. With this condition incorporated into the model, the estimated detectable tumor sizes (or total tumor burden including metastases) ranged between grape-sized and melon-sized for ovarian cancers and between pea-sized to about grapefruit-sized for prostate cancers.
What Do These Findings Mean?
The accuracy of the calculated tumor sizes provided by the researchers' mathematical model is limited by the lack of data on how tumors behave in the human body and by the many assumptions incorporated into the model. Nevertheless, the model predicts detection limits for ovarian and prostate cancer that broadly mirror the clinical performance of both biomarkers. Somewhat worryingly, the model also indicates that a tumor may have to be very large for blood biomarkers to reveal its presence, a result that could limit the clinical usefulness of biomarkers, especially if they are secreted not only by tumor cells but also by healthy cells. Given this finding, as more information about how biomarkers behave in the human body becomes available, this model (and more complex versions of it) should help researchers decide which biomarkers are likely to improve early cancer detection and patient outcomes.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides a brief description of what cancer is and how it develops and a fact sheet on tumor markers; it also provides information on all aspects of ovarian and prostate cancer for patients and professionals, including information on screening and testing (in English and Spanish)
The UK charity Cancerbackup also provides general information about cancer and more specific information about ovarian and prostate cancer, including the use of CA125 and PSA for screening and follow-up
The American Society of Clinical Oncology offers a wide range of information on various cancer types, including online published articles on the current status of cancer diagnosis and management from the educational book developed by the annual meeting faculty and presenters. Registration is mandatory, but information is free
PMCID: PMC2517618  PMID: 18715113
24.  Polygenic Risk Score Improves Prostate Cancer Risk Prediction: Results from the Stockholm-1 Cohort Study 
European urology  2011;60(1):21-28.
More than 1 million prostate biopsies are conducted yearly in the United States. The low specificity of prostate-specific antigen (PSA) results in diagnostic biopsies in men without prostate cancer (PCa). Additional information, such as genetic markers, could be used to avoid unnecessary biopsies.
To determine whether single nucleotide polymorphisms (SNPs) associated with PCa can be used to determine whether biopsy of the prostate is necessary.
Design, settings, and participants
The Stockholm-1 cohort (n = 5241) consisted of men who underwent a prostate biopsy during 2005 to 2007. PSA levels were retrieved from databases and family histories were obtained using a questionnaire. Thirty-five validated SNPs were analysed and converted into a genetic risk score that was implemented in a risk-prediction model.
Results and limitations
When comparing the nongenetic model (based on age, PSA, free-to-total PSA, and family history) with the genetic model and using a fixed number of detected PCa cases, it was found that the genetic model required significantly fewer biopsies than the nongenetic model, with 480 biopsies (22.7%) avoided, at a cost of missing a PCa diagnosis in 3% of patients characterised as having an aggressive disease. However, the overall genetic model does not discriminate between aggressive and nonaggressive cases.
Although the genetic model reduced the number of biopsies more than the nongenetic model, the clinical significance of this finding requires further evaluation.
PMCID: PMC4417350  PMID: 21295399
Diagnosis; Prostate cancer; Polygenic; Prediction model; SNP
25.  proPSA Measurements in Serum and Tissue are Associated with Treatment Necessity Among Men Enrolled in Expectant Management for Prostate Cancer 
We assessed the association of quantitative clinical and pathologic information, including serum and tissue proPSA, with outcomes among men with prostate cancer (PCa) managed expectantly.
Experimental Design
We identified 71 men enrolled in expectant management (EM) with frozen serum and tissue available from diagnosis. 39 subsequently developed unfavorable biopsies (Gleason score>=7, >=3 cores positive for cancer, >50% of any core involved with cancer), while 32 maintained favorable biopsies (median follow-up: 3.93 years). Serum tPSA, fPSA and [−2]proPSA were measured by the Beckman Coulter immunoassay. [−5/−7]proPSA was evaluated in cancer and benign adjacent tissue areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion.
The ratio [−2]proPSA/%fPSA in serum was significantly higher at diagnosis (0.87+/−0.44pg/mL vs. 0.65+/−0.36pg/mL, p=0.02) in men developing unfavorable biopsies. [−5/−7]proPSA tissue staining was more intense (4104.09+/−3033.50 vs. 2418.06+/−1606.04, p=0.03) and comprised a greater fractional area (11.58%+/−7.08% vs. 6.88%+/−5.20%, p=0.01) in BAA of these men. Serum [−2]proPSA/%fPSA [HR:2.53(1.18–5.41), p=0.02], BAA [−5/−7]proPSA %area [HR:1.06(1.01–1.12), p=0.02] and BAA [−5/−7]proPSA stain intensity [HR:1.000213(1.000071–1.000354), p=0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [−2]proPSA/%fPSA significantly correlated with BAA [−5/−7]proPSA %area (rho=0.40, p=0.002) and BAA [−5/−7]proPSA stain intensity (rho=0.33, p=0.016).
In a prospective cohort of men enrolled into EM for PCa, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/%fPSA might be driven by increased proPSA production from “pre-malignant” cells in the prostate BAA.
PMCID: PMC2787812  PMID: 19934305
Prostate cancer; expectant management; proPSA; serum; benign-adjacent; cancer; unfavorable biopsy conversion; prediction

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