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1.  Outcome of Prostate Biopsy in Men Younger than 40 Years of Age with High Prostate-Specific Antigen (PSA) Levels 
Korean Journal of Urology  2010;51(1):21-24.
Prostate cancer is rarely diagnosed in men younger than 40 years of age. At present, the available data show a low rate of cancer detection from prostate-specific antigen (PSA) screening of this group of young men. We analyzed the outcome of prostate biopsy results in patients of this age group with a high PSA.
Materials and Methods
Between October 1997 and August 2008, a total of 81 men less than 40 years of age were referred from the Health Care Promotion Center as the result of elevated PSA levels. Six men with prostatitis were excluded. The remaining 75 men were asymptomatic and had normal findings on the digital rectal examination (DRE) and were selected to have a transrectal ultrasound-guided prostate biopsy for suspected prostate cancer. The patients with sustained high PSA levels underwent repeat biopsies.
The median age of the 75 men was 33 years (range, 26-40 years) and the mean PSA level was 6.57 ng/ml (range, 4.32-13.45 ng/ml). The results of the primary biopsy was 1 (1.3%) case of prostate cancer, 70 cases (93%) with benign tissue, 2 cases (2.6%) with inflammation, and 1 case each (1.3%) with high grade intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP). Of the 10 men who underwent a second biopsy, all had benign findings. Three of the men who underwent a third biopsy all had benign tissue findings.
The prostate cancer detection rate in young men less than 40 years of age with high PSA levels and normal DREs was very low. Repeat biopsy for sustained high PSA levels in young men less than 40 years of age may not be indicated.
PMCID: PMC2855470  PMID: 20414405
Prostate-specific antigen; Digital rectal examination; Biopsy; Young adult; Prostatic neoplasms
2.  Characteristics of Prostate Cancers Detected at Prostate-Specific Antigen Levels Less than 2.5 ng/ml 
The Journal of urology  2009;181(6):2515-2519.
The Prostate Cancer Prevention Trial (PCPT) reported that 15% of men with a PSA value < 4 ng/ml and a normal digital rectal examination (DRE) have biopsy-detectable prostate cancer (PCa). However, limited published data describe the tumor features of PCa detected at very low PSA levels (< 2.5 ng/ml).
A total of 934 men underwent radical retropubic prostatectomy (RRP) by one surgeon between 2003 and 2007. Herein, we describe the clinico-pathological features of 77 patients with a preoperative PSA < 2.5 ng/ml.
Of the men with a low-PSA (<2.5 ng/ml) tumor, 51 (66%) had findings suspicious for PCa on DRE. Indications for prostate biopsy in the remainder included an elevated PSA velocity, hematospermia, and abnormal transrectal ultrasound findings. PCa was detected at transurethral resection of the prostate (TURP) in the remaining 8%. Despite their low PSA at diagnosis, 8 (10.4%) and 20 (26%), respectively, had a biopsy and RRP Gleason grade ≥7, while 7 (9%) and 6 (7.8%) had extracapsular tumor extension or positive surgical margins. Compared to men with a normal DRE, the mean tumor volume was significantly higher in those with a suspicious DRE (3.3 cc vs. 1.7 cc, p=0.018).
Despite PSA levels <2.5 ng/ml at diagnosis, a considerable proportion of men had aggressive pathology features at RRP. DRE remains an important component of early PCa detection.
PMCID: PMC3155762  PMID: 19371879
Prostate Cancer; PSA; Prostate Cancer Screening
3.  PSA Screening: Pro 
Current opinion in urology  2010;20(3):185-188.
Purpose of review
Prostate cancer is the most common noncutaneous malignancy in US men, and is most frequently diagnosed through prostate-specific antigen (PSA)-based screening. Nevertheless, PSA testing has become increasingly controversial. In this review, we will present the evidence supporting the role of PSA in prostate cancer screening.
Recent findings
Numerous studies have shown that the risk of current and future prostate cancer is directly related to the serum PSA level. Moreover, increasing PSA levels predict a greater risk of adverse pathologic features and worse disease-specific survival. Substantial epidemiologic evidence has suggested a reduction in advanced disease and improvements in prostate cancer survival rates since the introduction of PSA-based screening. Recently, evidence from a randomized trial further validated that PSA testing reduces both metastatic disease and prostate cancer-specific mortality.
PSA is a valid marker for prostate cancer and its aggressiveness. Level 1 evidence is now available that PSA-based screening reduces both the rate of metastatic disease and prostate cancer-specific mortality.
PMCID: PMC3572789  PMID: 20224413
prostate cancer; screening; prostate-specific antigen; detection
4.  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
5.  Differentiation of lethal and non lethal prostate cancer: PSA and PSA isoforms and kinetics 
Asian Journal of Andrology  2012;14(3):355-360.
Prostate-specific antigen (PSA) testing for the early diagnosis of prostate cancer has led to a decrease in cancer mortality. However, the high prevalence of low-grade prostate cancer and its long natural history, competing causes of death in older men and treatment patterns of prostate cancer, have led to dramatic overtreatment of the disease. Improved markers of prostate cancer lethality are needed to reduce the overtreatment of prostate cancer that leads to a reduced quality of life without extending life for a high proportion of men. The PSA level prior to treatment is routinely used in multivariable models to predict prostate cancer aggressiveness. PSA isoforms and PSA kinetics have been associated with more aggressive phenotypes, but are not routinely employed as part of prediction tools prior to treatment. PSA kinetics is a valuable marker of lethality post treatment and routinely used in determining the need for salvage therapy.
PMCID: PMC3720162  PMID: 22343493
benign PSA; human kallikrein 2; precursor form of PSA; prostate specific antigen; PSA kinetics; unbound or free PSA
6.  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
7.  Current strategies for monitoring men with localised prostate cancer lack a strong evidence base: observational longitudinal study 
British Journal of Cancer  2009;101(3):390-394.
The UK National Institute for Health and Clinical Excellence (NICE) guidance recommends conservative management of men with ‘low-risk' localised prostate cancer, monitoring the disease using prostate-specific antigen (PSA) kinetics and re-biopsy. However, there is little evidence of the changes in PSA level that should alert to the need for clinical re-assessment.
This study compares the alerts resulting from PSA kinetics and a novel longitudinal reference range approach, which incorporates age-related changes, during the monitoring of 408 men with localised prostate cancer. Men were monitored by regular PSA tests over a mean of 2.9 years, recording when a man's PSA doubling time fell below 2 years, PSA velocity exceeded 2 ng ml–1 per year, or when his upper 10% reference range was exceeded.
Prostate-specific antigen doubling time and PSA velocity alerted a high proportion of men initially but became unresponsive to changes with successive tests. Calculating doubling time using recent PSA measurements reduced the decline in response. The reference range method maintained responsiveness to changes in PSA level throughout the monitoring.
The increasing unresponsiveness of PSA kinetics is a consequence of the underlying regression model. Novel methods are needed for evaluation in cohorts currently being managed by monitoring. Meanwhile, the NICE guidance should be cautious.
PMCID: PMC2720224  PMID: 19603015
disease management; kinetics; PSA; prostatic neoplasms
8.  Genome-wide Association Study Identifies Loci at ATF7IP and KLK2 Associated with Percentage of Circulating Free PSA1 2 
Neoplasia (New York, N.Y.)  2013;15(1):95-101.
Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy.
To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10-5 were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml.
We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10-8). The first associated SNP was rs3213764 (P = 6.45 x 10-10), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10-12), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness.
These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
PMCID: PMC3556942  PMID: 23359319
9.  Development of a New Method for Monitoring Prostate-Specific Antigen Changes in Men with Localised Prostate Cancer: A Comparison of Observational Cohorts 
European urology  2009;57(3):446-452.
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
PSA level.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
PMCID: PMC2910432  PMID: 19303695
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
10.  Management of Biochemically Recurrent Prostate Cancer After Local Therapy: Evolving Standards of Care and New Directions 
Among men treated with prostatectomy or radiation therapy for localized prostate cancer, the state of an increasing prostate-specific antigen (PSA) level is known as biochemical recurrence (BCR). BCR can be predictive of the development of subsequent distant metastases and ultimately death, but BCR often predates other signs of clinical progression by several years. Although patients may be concerned about their rising PSA levels, physicians attempting to address patient anxiety must inform them that BCR is not typically associated with imminent death from disease, and that the natural history of biochemical progression may be prolonged. Misinterpretation of the significance of early changes in PSA may cause patients to receive androgen deprivation therapy (ADT) prematurely, especially in settings where the disease is unlikely to impact survival. In addition, knowledge of the morbidities associated with ADT (hot flashes, impotence, sarcopenia, metabolic syndrome, bone loss, and increased risk of vascular disease) has accelerated the search for alternative treatment options for these patients. Clinical trials investigating when and how to best use and supplement hormonal therapies in this patient population are under way, as are trials of novel nonhormonal targeted agents, immunotherapies, natural products, and other pharmaceuticals that have been approved by the US Food and Drug Administration (FDA) for other indications. This review will summarize the acceptable standards of care for the management of biochemically recurrent prostate cancer, and will also outline some novel experimental approaches for the treatment of this disease state.
PMCID: PMC3624708  PMID: 23416859
Prostate cancer; biochemical recurrence; PSA recurrence
11.  Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability 
Prostate-specific antigen (PSA) level is typically used as a dichotomous test for prostate cancer, resulting in overdiagnosis for a substantial number of men. The rate at which serum PSA levels change (PSA velocity) may be an important indicator of the presence of life-threatening disease.
PSA velocity was determined in 980 men (856 without prostate cancer, 104 with prostate cancer who were alive or died of another cause, and 20 who died of prostate cancer) who were participants in the Baltimore Longitudinal Study of Aging for up to 39 years. The relative risks (RRs) of prostate cancer death and prostate cancer–specific survival stratified by PSA velocity were evaluated in the three groups of men by Cox regression and Kaplan–Meier analyses. Statistical tests were two-sided.
PSA velocity measured 10–15 years before diagnosis (when most men had PSA levels below 4.0 ng/mL) was associated with cancer-specific survival 25 years later; survival was 92% (95% confidence interval [CI] = 84% to 96%) among men with PSA velocity of 0.35 ng/mL per year or less and 54% (95% CI = 15% to 82%) among men with PSA velocity above 0.35 ng/mL per year (P<.001). Furthermore, men with PSA velocity above 0.35 ng/mL per year had a higher relative risk of prostate cancer death than men with PSA velocity of 0.35 ng/mL per year or less (RR = 4.7, 95% CI = 1.3 to 16.5; P = .02); the rates per 100 000 person-years were 1240 for men with a PSA velocity above 0.35 ng/mL per year and 140 for men with a PSA velocity of 0.35 ng/mL per year or less.
PSA velocity may help identify men with life-threatening prostate cancer during a period when their PSA levels are associated with the presence of curable disease.
PMCID: PMC2645644  PMID: 17077354
12.  Screening for prostate cancer. 
Western Journal of Medicine  1995;162(3):235-242.
Prostate cancer is a serious health care problem in the United States. Whether or not to screen for it has become a timely issue. Although a large number of men have clinically important, asymptomatic, undetected prostate cancer, an even larger number have clinically unimportant cancer. To justify screening programs, not only must we avoid detecting biologically unimportant cancers, we must also detect and effectively treat that subset of tumors that, if undiagnosed, would progress, produce symptoms, and reduce life expectancy. Serum prostate-specific antigen (PSA) assay, or its variations such as PSA density, PSA velocity, and age-specific reference ranges, and the digital rectal examination are the best tests for detecting clinically important, asymptomatic, curable tumors. Recent data suggest that using serum PSA levels does not result in an overdetection of unimportant tumors. Highly effective, curative treatment of localized prostate cancer is available. These factors promote optimism that screening for prostate cancer will ultimately prove beneficial. Nonetheless, men should be informed regarding the benefits and possible risks before being screened for prostate cancer.
PMCID: PMC1022708  PMID: 7536993
13.  Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection among US men 
Cancer causes & control : CCC  2011;22(11):1483-1495.
Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection were evaluated among 3927 U.S. men, 40–85 years of age, who participated in the 2001–2006 National Health and Nutrition Examination Surveys. Five recommended definitions of prostate cancer detection were adopted using total and free prostate specific antigen (tPSA and fPSA) laboratory measurements. Men were identified as high-risk based on alternative cut-offs, namely, tPSA>10 ng/ml, tPSA>4 ng/ml, tPSA> 2.5 ng/ml, %fPSA<25% and %fPSA<15%. %fPSA was defined as (fPSA÷tPSA)×100%. Serum levels of vitamin A (retinol, retinyl esters) and carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein+zeaxanthin, lycopene) were defined as quartiles and examined as risk/protective factors for PSA biomarkers. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using binary logistic models. After adjustment for known demographic, socioeconomic and lifestyle confounders, high serum levels of retinyl esters (tPSA>10 ng/ml: Q4vs.Q1→OR=0.38, 95% CI: 0.14–1.00) and α-carotene (%fPSA<15%: Q4vs.Q1→OR=0.49, 95% CI: 0.32–0.76) were associated with a lower odds whereas high serum level of lycopene (tPSA>2.5 ng/ml: Q4vs.Q1→OR=1.49, 95% CI: 1.01–2.14) was associated with a greater odds of prostate cancer detection. Apart from the three significant associations observed, no other exposure-outcome association was significant. Monitoring specific antioxidant levels may be helpful in early detection of prostate cancer.
PMCID: PMC3443554  PMID: 21800039
vitamin A; carotenoids; prostate cancer; prostate-specific antigen
14.  The value of prostate-specific antigen in Asia 
One of the most important diagnostic tools used to detect prostate cancer is prostate-specific antigen (PSA), yet increased PSA alone does not reflect the presence of prostate cancer. Other pathological prostatic conditions such as prostatitis and benign prostatic hyperplasia (BPH) may also increase the level of PSA. However, unlike in other prostate diseases, PSA has a key role in the diagnosis and management of prostate cancer. The incidence of prostate cancer varies from country to country, with the highest incidence being found in the Western world and the lowest in Asian countries. Owing to the low incidence of prostate cancer, there could be different views regarding the use of PSA in Asian countries, especially for the early detection/screening of prostate cancer. The purpose of this article is to review the use and value of PSA in the diagnosis of prostate diseases (especially prostate cancer) in Asian countries/populations. A literature search was performed in ‘MEDLINE’ (PubMed) and Google Scholar using main keywords such as ‘PSA’, ‘PSA usage’, ‘PSA sensitivity and specificity’, ‘Asia’, and various countries in Asia. Articles that provide population/community-based PSA data, together with the characteristics, distribution, and indications for PSA testing in the respective countries, were selected. Eleven papers were finally selected for inclusion in this review. Five studies found that PSA, by its 95th percentile value, have an age-referenced tendency in Asian males, similarly to the West. The predictive values of PSA in detecting prostate cancer are also quite similar to those in Western countries. With the exponential growth of the aging population in the world, especially in Asia, the incidence of prostate cancer will follow this upward trend. Therefore, PSA testing for screening or diagnostic purposes would increase with time in Asia.
PMCID: PMC3126072  PMID: 21789085
predictive value; prostate cancer; prostate-specific antigen; screening
15.  The COMPASs Study: Community Preferences for Prostate cAncer Screening. Protocol for a quantitative preference study 
BMJ Open  2012;2(1):e000587.
Prostate cancer screening using prostate-specific antigen (PSA) testing remains controversial. Trade-offs between the potential benefits and downsides of screening must be weighed by men deciding whether to participate in prostate cancer screening; little is known about benefit:harm trade-offs men are willing to accept.
The Community Preferences for Prostate Cancer Screening (COMPASs) Study examines Australian men's preferences for prostate cancer screening using PSA testing. The aims are to (1) determine which factors influence men's decision to participate in prostate cancer screening or not and (2) determine the extent of trade-offs between benefits and harms that men are willing to accept in making these decisions. Quantitative methods will be used to assess men's preferences for PSA screening. Using data on the quantitative outcomes of PSA testing from the published literature, a discrete choice study will be designed to quantitatively assess men's preferences. A web-based survey will be conducted in approximately 1000 community respondents aged 40–69 years, stratified by family history of prostate cancer, to assess men's preferences for PSA testing. A mixed logit model will be used; model results will be expressed as parameter estimates (β) and the odds of choosing screening over no screening. Trade-offs between attributes will also be calculated.
Ethics and Dissemination
The COMPASs study has been approved by the University of Sydney, Human Research Ethics committee (Protocol number 13186). The results will be published in internal reports, in peer-reviewed scientific journals as well as via conference presentations.
Article summary
Article focus
To assess men's preferences for prostate cancer screening and determine the relative importance of various factors that influence men's decision to participate in prostate cancer screening or not.
To determine the extent of trade-offs between benefits and harms that men are willing to accept in making decisions about participation in screening.
Key messages
Prostate cancer screening may offer some benefit in terms of a reduction in prostate cancer-specific mortality. However, there is also evidence of substantial harms: screened men have a higher likelihood of being diagnosed as having prostate cancer, including the diagnosis of cancers that would not have become clinically apparent within the man's lifetime, meaning more men experiencing the attendant harms of diagnosis and treatment such as unnecessary biopsies from false-positive prostate-specific antigen tests or impotence and/or incontinence from treatments.
Trade-offs between the potential benefits and downsides of screening must be weighed by men deciding whether to participate in prostate cancer screening; little is known about benefit:harm trade-offs men are willing to make.
This study will use best practice quantitative methods for preference elicitation (discrete choice experiments) to assess men's preferences for prostate-specific antigen screening and the trade-offs they are willing to make decision whether to participate in screening.
Strengths and limitations of this study
The strengths of the study are that it is the first study to use discrete choice methods to examine men's preferences for prostate cancer screening, and the benefit:harm trade-offs men may be willing to make; it will consider the influence of age and family history on preferences in a large cohort of men, broadly representative of the Australian population aged 40 to 69 years.
The limitation is that it is conducted in one country, Australia, and thus its generalisability may be limited by the prevailing screening environment.
PMCID: PMC3253419  PMID: 22226686
16.  Reducing Unnecessary Biopsy During Prostate Cancer Screening Using a Four-Kallikrein Panel: An Independent Replication 
Journal of Clinical Oncology  2010;28(15):2493-2498.
We previously reported that a panel of four kallikrein forms in blood—total, free, and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (hK2)—can reduce unnecessary biopsy in previously unscreened men with elevated total PSA. We aimed to replicate our findings in a large, independent, representative, population-based cohort.
Patients and Methods
The study cohort included 2,914 previously unscreened men undergoing biopsy as a result of elevated PSA (≥ 3 ng/mL) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 807 prostate cancers (28%) detected. The cohort was randomly divided 1:3 into a training and validation set. Levels of kallikrein markers were compared with biopsy outcome.
Addition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the area under the curve from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P < .001 for both). Application of the panel to 1,000 men with elevated PSA would reduce the number of biopsies by 513 and miss 54 of 177 low-grade cancers and 12 of 100 high-grade cancers. Findings were robust to sensitivity analysis.
We have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA. Use of this panel would dramatically reduce biopsy rates. A small number of men with cancer would be advised against immediate biopsy, but these men would have predominately low-stage, low-grade disease.
PMCID: PMC2881727  PMID: 20421547
17.  Diagnosis of prostate cancer by detection of minichromosome maintenance 5 protein in urine sediments 
British Journal of Cancer  2010;103(5):701-707.
The accuracy of prostate-specific antigen (PSA) testing in prostate cancer detection is constrained by low sensitivity and specificity. Dysregulated expression of minichromosome maintenance (Mcm) 2–7 proteins is an early event in epithelial multistep carcinogenesis and thus MCM proteins represent powerful cancer diagnostic markers. In this study we investigate Mcm5 as a urinary biomarker for prostate cancer detection.
Urine was obtained from 88 men with prostate cancer and from two control groups negative for malignancy. A strictly normal cohort included 28 men with complete, normal investigations, no urinary calculi and serum PSA <2 ng ml–1. An expanded control cohort comprised 331 men with a benign final diagnosis, regardless of PSA level. Urine was collected before and after prostate massage in the cancer patient cohort. An immunofluorometric assay was used to measure Mcm5 levels in urine sediments.
The Mcm5 test detected prostate cancer with 82% sensitivity (confidence interval (CI)= 72–89%) and with a specificity ranging from 73 (CI=68–78%) to 93% (CI=76–99%). Prostate massage led to increased Mcm5 signals compared with pre-massage samples (median 3440 (interquartile range (IQR) 2280 to 5220) vs 2360 (IQR <1800 to 4360); P=0.009), and was associated with significantly increased diagnostic sensitivity (82 vs 60% P=0.012).
Urinary Mcm5 detection seems to be a simple, accurate and noninvasive method for identifying patients with prostate cancer. Large-scale prospective trials are now required to evaluate this test in diagnosis and screening.
PMCID: PMC2938246  PMID: 20648010
biomarker; DNA replication licensing; Mcm5; prostate cancer; PSA
18.  Nomogram for Prediction of Prostate Cancer with Serum Prostate Specific Antigen Less than 10 ng/mL 
Journal of Korean Medical Science  2014;29(3):338-342.
Although prostate-specific antigen (PSA) is a very useful screening tool, prostate biopsy is still necessary to confirm prostate cancer (PCA). However, it is reported that PSA is associated with a high false-positive rate and prostate biopsy also has various procedure-related complications. Therefore, the authors have devised a nomogram, which can be used to estimate the risk of PCA, using available clinical data for men with a serum PSA less than 10 ng/mL. Prostate biopsies were obtained from 2,139 patients from January 1998 to March 2011. Of them, 1,171 patients with a serum PSA less than 10 ng/mL were only included in this study. Patient age, PSA, free PSA, prostate volume, PSA density and percent free PSA ratio were analyzed. Among 1,171 patients, 255 patients (21.8%) were diagnosed as PCA. Multivariate analyses showed that patient age, prostate volume, PSA and percent free PSA had statistically significant relationships with PCA (P < 0.05) and were used as nomogram predictor variables. The area under the (ROC) curve for all factors in a model predicting PCA was 0.759 (95% CI, 0.716-0.803).
Graphical Abstract
PMCID: PMC3945127  PMID: 24616581
Biopsy; Nomograms; Prostate; Prostatic Neoplasms
19.  Circulating insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in PSA-detected prostate cancer: the large case control study ProtecT 
Cancer research  2011;72(2):503-515.
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression.
PMCID: PMC3272440  PMID: 22106399
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
20.  A simple computer program for calculating PSA recurrence in prostate cancer patients 
BMC Urology  2004;4:8.
Prostate cancer is the most common tumor in men. The most commonly used diagnostic and tumor recurrence marker is Prostate Specific Antigen (PSA). After surgical removal or radiation treatment, PSA levels drop (PSA nadir) and subsequent elevated or increased PSA levels are indicative of recurrent disease (PSA recurrence). For clinical follow-up and local care PSA nadir and recurrence is often hand calculated for patients, which can result in the application of heterogeneous criteria. For large datasets of prostate cancer patients used in clinical studies PSA measurements are used as surrogate measures of disease progression. In these datasets a method to measure PSA recurrence is needed for the subsequent analysis of outcomes data and as such need to be applied in a uniform and reproducible manner. This method needs to be simple and reproducible, and based on known aspects of PSA biology.
We have created a simple Perl-based algorithm for the calculation of post-treatment PSA outcomes results based on the initial PSA and multiple PSA values obtained after treatment. The algorithm tracks the post-surgical PSA nadir and if present, subsequent PSA recurrence. Times to PSA recurrence or recurrence free intervals are supplied in months.
Use of the algorithm is demonstrated with a sample dataset from prostate cancer patients. The results are compared with hand-annotated PSA recurrence analysis. The strengths and limitations are discussed.
The use of this simple PSA algorithm allows for the standardized analysis of PSA recurrence in large datasets of patients who have undergone treatment for prostate cancer. The script is freely available, and easily modifiable for desired user parameters and improvements.
PMCID: PMC441391  PMID: 15207005
21.  A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden 
BMC Medicine  2008;6:19.
Prostate-specific antigen (PSA) is widely used to detect prostate cancer. The low positive predictive value of elevated PSA results in large numbers of unnecessary prostate biopsies. We set out to determine whether a multivariable model including four kallikrein forms (total, free, and intact PSA, and human kallikrein 2 (hK2)) could predict prostate biopsy outcome in previously unscreened men with elevated total PSA.
The study cohort comprised 740 men in Göteborg, Sweden, undergoing biopsy during the first round of the European Randomized study of Screening for Prostate Cancer. We calculated the area-under-the-curve (AUC) for predicting prostate cancer at biopsy. AUCs for a model including age and PSA (the 'laboratory' model) and age, PSA and digital rectal exam (the 'clinical' model) were compared with those for models that also included additional kallikreins.
Addition of free and intact PSA and hK2 improved AUC from 0.68 to 0.83 and from 0.72 to 0.84, for the laboratory and clinical models respectively. Using a 20% risk of prostate cancer as the threshold for biopsy would have reduced the number of biopsies by 424 (57%) and missed only 31 out of 152 low-grade and 3 out of 40 high-grade cancers.
Multiple kallikrein forms measured in blood can predict the result of biopsy in previously unscreened men with elevated PSA. A multivariable model can determine which men should be advised to undergo biopsy and which might be advised to continue screening, but defer biopsy until there was stronger evidence of malignancy.
PMCID: PMC2474851  PMID: 18611265
22.  PSA velocity does not aid the detection of prostate cancer in men with a prior negative biopsy: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden and Rotterdam, Netherlands 
The Journal of urology  2010;184(3):907-912.
Prostate specific antigen (PSA) velocity has been proposed as a marker to aid detection of prostate cancer. We sought to determine whether PSA velocity could predict the results of repeat biopsy in men with persistently elevated PSA after initial negative biopsy.
Materials and Methods
We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer (ERSPC), and who had one or more subsequent prostate biopsies after an initial negative finding. We evaluated whether PSA velocity improved predictive accuracy beyond that of PSA alone.
There were a total of 2579 repeat biopsies, of which 363 (14%) were positive for prostate cancer, and 44 (1.7%) were high grade (Gleason score ≥7). Although PSA velocity was statistically associated with cancer risk (p<0.001), it had very low predictive accuracy (area-under-the-curve [AUC] of 0.55). There was some evidence that PSA velocity improved AUC compared to PSA for high grade cancer. However, the small increase in risk associated with high PSA velocity – from 1.7 % to 2.8% as velocity increased from 0 to 1 ng / ml / year - is of questionable clinical relevance.
Men with a prior negative biopsy have a lower risk for prostate cancer at subsequent biopsies, with high grade disease particularly rare. We found little evidence to support the use of PSA velocity to aid decisions about repeat biopsy for prostate cancer.
PMCID: PMC3412428  PMID: 20643434
23.  Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer 
The Prostate  2009;69(4):419-427.
Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels.
We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer.
Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P≤0.05) were found for six SNPs. These six SNPs had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend=3.4×10−14. In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients.
Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening.
PMCID: PMC3348520  PMID: 19116992
genetic; bias; KLK3
24.  Prostate-specific antigen in serum of women with breast cancer. 
British Journal of Cancer  1995;72(3):728-731.
Prostate-specific antigen (PSA) was recently found in 30% of female breast tumours. In this study we have examined if PSA circulates in the blood of breast cancer patients and if serum PSA has any clinical application. We have compared serum PSA levels between women with and without breast cancer, between women with PSA-positive and PSA-negative breast cancer and between women with breast cancer before and after surgical removal of the tumour. We found that for women > or = 50 years, there is no difference in serum PSA between normal or breast cancer patients. We also could not find any difference in presurgical or post-surgical serum PSA between women who have PSA-positive or PSA-negative breast cancer. We found no correlation between PSA concentrations in matched presurgical and post-surgical sera, between presurgical sera and tumour cytosols and between post-surgical sera and tumour cytosols. High-performance liquid chromatography has shown that PSA in normal male serum consists mostly of PSA bound to alpha 1-antichymotrypsin (molecular weight approximately 100,000), and PSA in breast tumours and presurgical and post-surgical serum consists mostly of free PSA (molecular weight approximately 33,000). These data suggest that female serum PSA is not associated with tumour PSA levels. We speculate that most of the circulating PSA in women originates from the normal breast. It appears that serum PSA in women does not have potential for breast cancer diagnosis or monitoring, but our previous data are consistent with the view that tumour PSA concentration is a favourable prognostic indicator in women with breast cancer.
PMCID: PMC2033864  PMID: 7545417
25.  Initial Biopsy Outcome Prediction in Korean Patients-Comparison of a Noble Web-based Korean Prostate Cancer Risk Calculator versus Prostate-specific Antigen Testing 
We developed and validated a novel Korean prostate cancer risk calculator (KPCRC) for predicting the probability of a positive initial prostate biopsy in a Korean population. Data were collected from 602 Koreans who underwent initial prostate biopsies due to an increased level of prostate-specific antigen (PSA), a palpable nodule upon digital rectal examination (DRE), or a hypoechoic lesion upon transrectal ultrasound (TRUS). The clinical and laboratory variables were analyzed by simple and multiple logistic regression analysis. The area under the receiver operating characteristic curve (AUC) was computed to compare its performance to PSA testing alone. Prostate cancer was detected in 172 (28.6%) men. Independent predictors included age, DRE findings, PSA level, and prostate transitional zone volume. We developed the KPCRC using these variables. The AUC for the selected model was 0.91, and that of PSA testing alone was 0.83 (P < 0.001). The AUC for the selected model with an additional dataset was 0.79, and that of PSA testing alone was 0.73 (P = 0.004). The calculator is available on the website: The KPCRC improved the performance of PSA testing alone in predicting the risk of prostate cancer in a Korean population. This calculator would be a practical tool for physicians and patients.
PMCID: PMC3012855  PMID: 21218035
Prostate Neoplasms; Biopsy; Forecasting; Asian Continental Ancestry Group

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