|Ahead of print publication
Prospective validation of %p2PSA and the Prostate Health Index, in prostate cancer detection in initial prostate biopsies of Asian men, with total PSA 4-10 ng ml -1
Lincoln GL Tan1, Yung Khan Tan2, Bee Choo Tai3, Karen ML Tan4, Vineet Gauhar5, Ho Yee Tiong1, Robert CW Hawkins6, Thomas P Thamboo7, Felicia SK Hong2, Edmund Chiong1
1 Department of Urology, National University Hospital, National University Health System, Singapore
2 Department of Urology, Tan Tock Seng Hospital, Singapore
3 Saw Swee Hock School of Public Health, National University of Singapore, Singapore
4 Department of Laboratory Medicine, National University Hospital, Singapore
5 Department of Urology, Alexandra Hospital, Jurong Health, Singapore
6 Department of Laboratory Medicine, Tan Tock Seng Hospital, Singapore
7 Department of Pathology, National University Hospital, Singapore
|Date of Submission||01-Apr-2015|
|Date of Decision||05-Aug-2015|
|Date of Acceptance||15-Oct-2015|
|Date of Web Publication||19-Feb-2016|
Lincoln GL Tan,
Department of Urology, National University Hospital, National University Health System, Singapore
Source of Support: None, Conflict of Interest: None
Despite its widespread use for prostate cancer screening, low specificity makes PSA a suboptimal biomarker, especially in the diagnostic "gray zone" of 4-10 ng ml -1 . False-positives lead to unnecessary biopsies with attendant morbidities. This is the first prospective validation study of %p2PSA and the Prostate Health Index (PHI) in Asian men presenting with a total PSA between 4.0 and 10 ng ml -1 . We studied 157 Asian men between 50 and 75 years old, with normal per rectal prostate examinations, undergoing their first prostate biopsy, using a standardized biopsy protocol, for PSA levels of 4-10 ng ml -1 . Thirty (19.1%) were found to have prostate cancer on biopsy. Statistically significant differences between patients with and without prostate cancer were found for total PSA, p2PSA, %p2PSA, and PHI. The areas under the curve of the receiver operating characteristic curve for total PSA, %fPSA, %p2PSA, and PHI were 0.479, 0.420, 0.695, and 0.794, respectively. PHI predicts prostatic biopsies results best. At a sensitivity of 90%, the specificity (95% CI) of PHI was 58.3%, more than triple the specificity of total PSA at 17.3%, potentially avoiding 77 (49%) unnecessary biopsies. Similar to studies in mainly Caucasian populations, we have prospectively shown that %p2PSA and PHI greatly outperform total and free to total PSA ratio, in the detection of prostate cancer at first biopsy. Higher PHI levels also correspond to increasing the risk of detecting GS ≥7 cancers. We have validated the use of PHI to aid decision-making regarding prostate biopsies in Asian men with serum PSA between 4 and 10 ng ml -1 .
Keywords: biological markers; prostate specific antigen; prostatic neoplasms
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|How to cite this URL:|
Tan LG, Tan YK, Tai BC, Tan KM, Gauhar V, Tiong HY, Hawkins RC, Thamboo TP, Hong FS, Chiong E. Prospective validation of %p2PSA and the Prostate Health Index, in prostate cancer detection in initial prostate biopsies of Asian men, with total PSA 4-10 ng ml -1. Asian J Androl [Epub ahead of print] [cited 2017 Apr 26]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=168687
| Introduction|| |
Globally, prostate cancer (PCa) is the 2 nd most frequently diagnosed cancer in men. Incidence rates vary by more than 25-fold worldwide and are highest in Australia/New Zealand, Northern America, Northern and Western Europe, and some Caribbean nations, and lowest in Asia.  Although the incidence is lower in Asia, PCa mortality rates are relatively higher. The 5-year survival rates for prostate cancer in Asia are generally much lower than the >95% rate reported in the United States, ranging from 40% in Mongolia to 87% in Japan.  Thus, although the incidence of PCa is lower in Asia, its early detection remains an important public health issue.
The advent of the PSA test has led to a dramatic reduction in the proportion of men diagnosed with metastatic disease and PCa death rates. Unfortunately, its low specificity has caused the problems of unnecessary biopsies with its associated morbidities, and overdiagnosis and overtreatment of indolent cancers.
Several approaches have been proposed to address the limitations of PSA, including the measurement of PSA molecular isoforms of free PSA (fPSA). Free PSA (fPSA) comprises proPSAs (pPSAs), benign PSA (BPSA), and intact PSA. Four different proPSA isoforms exist in serum, named as [-2]proPSA, [-4]proPSA, [-5]proPSA and [-7]proPSA, based on the length of the pro-leader peptide sequences, i.e., seven, five, four or two amino acids. The [-2]proPSA (p2PSA) is the most cancer-specific form of all, being preferentially concentrated in cancerous tissue on histochemical staining and  significantly increased in serum of men with PCa. 
The Prostate Health Index (PHI) developed by Beckman Coulter, Inc., in partnership with the NCI Early Detection Research Network was approved by the FDA in 2012. This is a mathematical formula of three biomarkers: -(p2PSA/fPSA) × √PSA. By use of this calculation, the clinician will be able to see each individual result as well as make a potentially better informed recommendation to the patient.
This is the first prospective evaluation of %p2PSA and PHI in a cohort of Asian men undergoing their first biopsy within the diagnostic gray zone of total PSA 4-10 ng ml -1 .
| Materials and Methods|| |
The current study is a two institutional observational prospective cohort study, carried out from August 2012 to October 2014.
The study included consecutive men undergoing their first outpatient prostate biopsy for suspected PCa. Inclusion criteria were the following: patients 50-75 years of age with normal digital rectal examination (DRE) in a total PSA range of 4-10 ng ml -1 .
Exclusion criteria were as follows: First, patients with bacterial acute prostatitis or untreated urinary tract infection. Second, patients subjected to previous endoscopic surgery of the prostate. Third, patients with prior history of prostate cancer or other urogenital cancers. Finally, patients subjected to previous prostate biopsy or patients being treated with dutasteride or finasteride. Patients who were under any of the conditions above were excluded.
Study end points
The primary end point was to evaluate the sensitivity, specificity, and diagnostic accuracy of p2PSA, %p2PSA and PHI (index tests) in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of free to total PSA ratio (standard tests). The number of prostate biopsies that could be spared if index tests were used in the prostate biopsy decision path was calculated.
Prior to prostate biopsy, blood was drawn to measure the prebiopsy total PSA (tPSA), fPSA, and p2PSA levels. Patients then underwent transrectal ultrasound-guided prostate biopsies according to a standardized extended scheme: at least 12 biopsy cores were taken, with additional cores taken if the performing clinician felt more cores were needed for adequate sampling. The specimens were processed and evaluated at each center by experienced genitourinary pathologists, who were blinded to the test results. PCa was identified and graded according to the 2005 consensus conference of the International Society of Urological Pathology  definitions. Patients diagnosed with high-grade intraepithelial neoplasia or suspicious lesions but not adenocarcinoma (atypical small acinar proliferation of prostate) according to the contemporary diagnostic criteria were not considered positive for the outcome of interest.
All laboratory analyses (free PSA, total PSA and p2PSA) were performed on serum samples (collected into Becton Dickinson SST II tubes) which were centrifuged at 2000 g for 4 minutes within 3 h of collection and subsequently stored at −70°C until analysis. Testing was performed on a Beckman Coulter DxI-800 immunoassay analyzer using manufacturer-supplied reagents, calibrators and controls in two analytical batches. All assays used chemiluminescent immunoenzymatic technology with Hybritech PSA standardization. The Beckman Coulter Prostate Health Index (PHI) was calculated by the formula: PHI = (p2PSA/fPSA) × √PSA.
We summarized the distribution of continuous normally distributed demographic and clinical characteristics of patients using mean and standard deviation, and the differences in mean between the prostate cancer and noncancer groups were compared using the independent sample t-test. For skewed continuous variables, the median and range were used for summarizing the distribution, with comparisons between groups made via the Mann-Whitney test. For categorical variables, the χ2 test was used for comparing differences in proportions.
The area under the receiver operating characteristic (ROC) curve was estimated for the various PSA derivatives and compared by assuming total PSA as the gold standard. The P value thus obtained were Bonferroni corrected. The specificity of the various PSA derivatives were also estimated at prespecified sensitivity of 90%.
All statistical analyses were carried out using STATA version 13.0 (StataCorp LP, College Station, TX, USA), assuming a two-sided test with a 5% level of significance.
The Institutional Review Board of the National Healthcare Group approved this study. Reagents for the study were supplied gratis by Beckman Coulter, but the sponsor had no input toward study design and were not given access to the study results nor had any input in the analysis of the results.
| Results|| |
The patient characteristics of the 157 men recruited, and values of the various PSA parameters for this cohort are described in [Table 1]. The positive biopsy rate was 19.1% (30/157). Among the 30 patients diagnosed with prostate cancer, 11 (36.7%) had Gleason score 6 disease, 17 (56.7%) had Gleason score 7 disease, and 2 (6.7%) had Gleason 8-10 disease.
Between the positive and negative biopsy groups, there was no statistically significant difference in the mean total PSA (P = 0.334), median free PSA (P = 0.148), and the free to total PSA ratio (P = 0.172). On the other hand, there was a statistical significant difference for the median p2PSA (P = 0.001), median %p2PSA (P = 0.001) and PHI (P < 0.001) between the two groups.
The area under the ROC of tPSA, free: total PSA ratio, p2PSA, %p2PSA and PHI were 0.4787, 0.4197, 0.6950, 0.6895, 0.7937, respectively ([Table 2] and [Figure 1]). Of the various parameters, the PHI showed the best performance in predicting the results of the initial biopsy in this cohort.
|Figure 1: Receiver operating characteristic (ROC) curves comparing various PSA derivatives.|
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|Table 2: Comparison AUC of various PSA derivatives assuming total PSA as gold standard|
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To assess the performance of the various parameters further, we analyzed the data at a preset sensitivity level of 90% ([Table 3]). The PHI had the best specificity of 58.27% (95% confidence interval: 49.19-66.95) compared to 17.32% for total PSA. At a cut-off for biopsy at PHI level 26.75, 77 patients or 49.0% of this cohort could have avoided undergoing a biopsy. Of the three cancers that would have been missed at this cut-off, two were GS 3 + 3 and one was GS 4 + 3.
|Table 3: Specificity of various PSA derivatives at prespecified sensitivity of 90%|
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Looking at the detection of GS ≥7 cancer at 90% sensitivity, we found that at the same PHI threshold of 26.75, there was a similar specificity of 55.1%. We also looked at how the PHI test would perform using the manufacturer's banding of PHI levels ([Table 4] and [Table 5]).
|Table 4: Performance of PHI test according to manufacturer banding of PHI levels|
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|Table 5: Avoidable biopsies at different PHI thresholds and probability of missed prostate cancers, or GS ≥7 cancers|
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The probability of cancer at the higher PHI levels was within the confidence intervals of that reported by the manufacturer. At the lowest risk level (PHI 0-26.9), 80 biopsies or 51% of all the biopsies could have been avoided, with a 5% risk of missing cancer. However, 2 of the 4 cancers detected in this lowest risk group were GS 4 + 3 cancers, one of which was later found to be stage pT3aN0M0 at radical prostatectomy.
As the PHI levels increased, the risk of detecting any cancer and GS ≥7 cancer corresponding increased. At the highest PHI risk group (PHI >55), there was a 42.9% chance of a positive biopsy, all of which were GS ≥7 cancers.
| Discussion|| |
There is a need for new biomarkers for early prostate cancer detection
Prostate cancer screening with the PSA test has led to a dramatic reduction in the proportion of men diagnosed with metastatic disease and prostate cancer death rates. Due to the poor specificity of the PSA test, these benefits have come at the cost of a high proportion of unnecessary biopsies and overdiagnosis and overtreatment of indolent cancers.
These problems led the USPSTF (U.S. Preventive Services Task Force) to recommend against prostate cancer screening in all age groups.  This highlights the need for a clinically more useful biomarker for the early detection of prostate cancer.
Validation of the PHI test
The PHI test was approved by the FDA in 2012. The intended use of PHI is to distinguish PCa from benign prostatic conditions in men aged 50 years and older with a total serum PSA between 2 and 10 ng ml -1 , and in whom the digital rectal examination is not suspicious for cancer.
A systematic review of studies to date by Abrate et al. and meta-analysis by Wang et al. showed that %p2PSA and PHI were consistently more accurate than standard reference tests in predicting prostate biopsy outcome and could guide prostate biopsy decision making.
Most of the data on %p2PSA and PHI have been based primarily in Caucasian populations, which have a higher incidence of prostate cancer. ,,,
Comparison with other Asian studies
Investigators from Hong Kong performed a retrospective evaluation of PHI in Asian men with negative digital rectal examinations, undergoing their initial biopsy with a total PSA of 4-10 ng ml -1 .  In comparison to our cohort, which had 19% positive biopsy rate, only 9% of their cohort had a positive biopsy. Nonetheless, similar to our findings, they found that the PHI test had the best performance in predicting the results of the initial biopsy, with an AUC of 0.781 versus 0.547 for total PSA.
Ito et al. performed another retrospective evaluation of %p2PSA and PHI in 239 Japanese men with total PSA 2-10 ng ml -1 . Abnormal digital rectal examination was not an exclusion criteria in this cohort. They found that at sensitivity levels of 70%-95%, PHI showed superior specificity in predicting prostate cancer compared to total PSA and %fPSA.
Na et al. prospectively evaluated p2pSA and PHI in a large hospital-based cohort of 636 Chinese men. However, almost 30% of this cohort had positive DRE, and the total PSA ranged from 0.04 to 2006 ng ml -1 . Not surprisingly, the positive biopsy rate was as high as 43.1%.
When they divided their cohort to those with total PSA 2-10 ng ml -1 , 10.1-20 ng ml -1 and more than 20 ng ml -1 , the AUC of total PSA versus PHI was 0.53, 0.58, 0.80 versus 0.73, 0.81, 0.90, respectively. Thus, while PHI was superior to total PSA at all total PSA levels, PHI showed the biggest advantage over PSA in the gray zone below 10 ng ml -1 .
Our results showed that PHI was the best performer in predicting prostate cancer in the initial biopsy. At 90% sensitivity, the specificity of PHI at 58.27% was 3 times better than that of total PSA at 17.32%. Together with the retrospective data provided by the Japanese and Hong Kong cohorts, our work validates the use of %p2PSA and PHI in Asian men with total PSA in the diagnostic "gray zone" of 4-10 ng ml -1 .
Avoiding unnecessary biopsies
In our cohort, a biopsy threshold at PHI ≥27.0, would have avoided 80 or 51% of biopsies in this cohort, at a 2.5% risk of missing a potentially aggressive cancer (GS ≥7 or more) ([Table 5]).
This should be taken in the perspective that the prostate cancer detection rate below the usual total PSA biopsy threshold of 4 ng ml -1 can be as high as 20%, with up to 24% having GS ≥7 cancer. 
This was also seen in an observational, prospective, multicenter European cohort  (PROMEtheuS Project). This study involved 646 patients from five European urology centers with total PSA of 2 to 10 ng ml -1 , who were subjected to initial prostate biopsy for suspected PCa. They found p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (P < 0.001). At 90% sensitivity, the PHI cut-off of 27.6 could result in the avoidance of 100 biopsies (15.5%), with 26 cancers (9.8%) being overlooked (23 with GS 6, 3 with GS 3 + 4).
Loeb et al. similarly showed that in a cohort of U.S men with total PSA 4-10 ng ml -1 , a PHI cut-off of 28.6, could avoid approximately 30% of biopsies, while missing 10% of GS ≥7 PCa.
Association with clinically significant prostate cancer
We looked at whether PHI could reliably detect clinically significant prostate cancer (GS ≥7) ([Table 4]). We found that as PHI levels increased, the detection of GS ≥7 cancers corresponding increased, with PHI level 36.0 and more detecting the majority of GS ≥7 cancers in the cohort. This has also been recently shown by de la Calle et al.  in a large multicenter European cohort.
Furthermore, there are studies that have shown that PHI selectively identifies clinically significant PCa in biopsies, , and can help predict for more aggressive pathological features at radical prostatectomies. ,
Cost-effectiveness of PHI in the early detection of prostate cancer
It would be expected that the three-fold greater specificity of PHI compared to PSA, with the resulting decrease in the cost of unnecessary biopsies, can lead to healthcare cost savings.
In two studies, Nichol et al. evaluated the cost-effectiveness of PHI. In the first study,  the authors constructed two budget impact models using PSA cut-off values of ≥2 ng ml -1 (model #1) and ≥4 ng ml -1 (model #2) for recommending a prostate biopsy in a hypothetical health plan with 100 000 male members aged 50-75 years old. The budgetary impact on the 1-year expected total costs for PCa detection was calculated. Adding PHI to the current PSA screening strategies increased the total costs of blood tests by $51 524 (model #1) and $13 611 (model #2). However the reduction of both true- and false-positive, which may reduce the number of office visits, laboratory tests and prostate biopsies, led to higher cost savings in model #1 ($356 647) than in model #2 ($94 219), with 92% of the savings realized by the reduction of unnecessary biopsies.
In the second study,  the same group evaluated the cost-effectiveness of early PCa detection with PHI associated with a PSA test compared with the PSA test alone from a United States of America societal perspective. Over 25 annual screening cycles, the strategy of PSA plus PHI was estimated to save $1199 or $443 with an expected gain of 0.08 or 0.03 quality-adjusted life years per person for PSA thresholds of ≥2 and ≥4 ng ml -1 , respectively. Because the strategy of PSA plus PHI was expected to increase the number of true-positive tests while reducing false-positives in men aged 50-75 years, the authors suggested that the increased total costs of adding PHI could be offset by reducing unnecessary prostate biopsies.
At first glance, this may not appear to be large savings, but if the cost of avoiding the attendant morbidities from prostatic biopsies, especially that of urosepsis, it can be expected that these savings will be increased.
PHI in clinical guidelines
The use of the PHI has been included in the National Comprehensive Cancer Network (NCCN, Beckman Coulter) guidelines on early detection of prostate cancer version 2.2015. Consistent with the current literature, they have recommended that biomarkers that improve the specificity of detection should not be used as first-line screening tests.
However, for patients who meet either PSA or DRE standards for consideration of biopsy, but for whom the patient and/or the physician wish to further define the probability of high-grade cancer, the guidelines have stated that PHI >35 (which provides an estimate of the probability of high-grade prostate cancer) is potentially informative in patients who have never undergone biopsy or after a negative biopsy.
The 2015 European Association of Urology (EAU) guideline for prostate cancer has stated that the PHI test may have a role in monitoring men under active surveillance. However, the guideline has not made a recommendation for its use in men not diagnosed with prostate cancer.
Our study also shows that PHI ≥36.0 was associated with a marked increase chance of detecting GS ≥7 prostate cancer compared to PHI <36.0, detecting 15/19 (79%) of the GS ≥7 cancers ([Table 5]), supporting the above recommendation by the NCCN.
Strengths and limitations of study
The strengths of our study include the prospectively enrolled source population from two centers. All blood samples were optimally managed according to the Semjonow et al. guidelines. All men had a histological diagnosis for endpoint assessment and in a direct comparison PHI was shown to outperform its individual components.
The limitations of our study are as follows. First, the relatively small sample size of the study may have limited the statistical significance of our findings. Second, we followed patients only through the index biopsy, and it is likely that some of the patients had false-negative prostate biopsies, given the known sampling error of a needle biopsy for the detection of cancer and the underdetection of high-grade prostate cancer. Finally, no correlation with pathologic outcome in patients who underwent RP after diagnosis was reported.
While we have shown that %p2PSA and PHI perform well as a reflex test in men in the PSA diagnostic gray zone, the potential role of %p2PSA and PHI as a screening test to replace PSA screening was not examined, as these findings do not extend to men who have not been prescreened by PSA. This is a flaw shared by all the other studies in the literature validating the use of %P2PSA and PHI.
To conclusively prove that %p2PSA and PHI are superior screening tools, prospective studies based on direct PCa screening by %p2PSA and PHI are needed.
| Conclusions|| |
Similar to studies in mainly Caucasian populations, we have prospectively shown that %p2PSA and PHI greatly outperform total and free to total PSA ratio, in the detection of prostate cancer at first biopsy in an Asian population with serum PSA between 4 and 10 ng ml -1 .
PHI is useful in reflex testing in men in the diagnostic gray zone of serum PSA between 4 and 10 ng ml -1 , aiding decision making about prostate biopsies, and can also avoid a significant proportion of unnecessary biopsies. Its potential to replace total PSA as a cost-effective prostate cancer screening tool needs to be validated in prospective trials in cohorts not selected by PSA.
| Authors Contributions|| |
LGT conceived and designed the study, drafted and revised the manuscript. YKT participated in the design of the study, data acquisition and critical review of the manuscript. BCT conducted statistical design of the study and data analysis. KMT, RCH and FSH participated in data acquisition. VG conceived and participated in the design of the study. TT performed the review of the prostate biopsies. HYT participated in data acquisition and critical review of the manuscript. EC participated in designing the study and critical review of the manuscript. All authors read and approved the final manuscript.
| Competing Interests|| |
None of the authors declare competing financial interests.
| Acknowledgments|| |
This work was supported by a grant from the National University Health System Leadership in Academic Medicine Program, Yong Loo Lin School of Medicine. We thank Dr. Lata Raman, Miss. Zin Mar and Miss. Hiliary Chua for their invaluable assistance in coordinating the study.
| References|| |
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, et al.
Global cancer statistics, 2012. CA Cancer J Clin
2015; 65: 87-108.
Allemani C, Weir HK, Carreira H, Harewood R, Spika D, et al.
Global surveillance of cancer survival 1995-2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet
2014; 385: 977-1010.
Chan TY, Mikolajczyk SD, Lecksell K, Shue MJ, Rittenhouse HG, et al.
Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen. Urology
2003; 62: 177-81.
Mikolajczyk SD, Catalona WJ, Evans CL, Linton HJ, Millar LS, et al.
Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem
2004; 50: 1017-25.
Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL, Committee IG. The 2005 international society of urological pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol
2005; 29: 1228-42.
Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med
2012; 157: 120-34.
Abrate A, Lazzeri M, Lughezzani G, Buffi N, Bini V, et al.
Clinical performance of Prostate Health Index (PHI) for prediction of prostate cancer in obese men: data from a multicenter European prospective study, PROMEtheuS project. BJU Int 2015
; 115: 537-45.
Wang W, Wang M, Wang L, Adams TS, Tian Y, et al.
Diagnostic ability of %p2PSA and Prostate Health Index for aggressive prostate cancer: a meta-analysis. Sci Rep
2014; 4: 512.
Guazzoni G, Nava L, Lazzeri M, Scattoni V, Lughezzani G, et al.
Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng ml -1
: results of a prospective study in a clinical setting. Eur Urol
2011; 60: 214-22.
Stephan C, Vincendeau S, Houlgatte A, Cammann H, Jung K, et al.
Multicenter evaluation of [-2]proprostate-specific antigen and the Prostate Health Index for detecting prostate cancer. Clin Chem
2013; 59: 306-14.
Jansen FH, van Schaik RH, Kurstjens J, Horninger W, Klocker H, et al.
Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol
2010; 57: 921-7.
Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, et al
. A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev
2010; 19: 1193-200.
Ng CF, Chiu PK, Lam NY, Lam HC, Lee KW, et al.
The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4-10 ng ml -1
. Int Urol Nephrol
2014; 46: 711-7.
Ito K, Miyakubo M, Sekine Y, Koike H, Matsui H, et al.
Diagnostic significance of [-2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0-10.0 ng ml -1
range. World J Urol
2013; 31: 305-11.
Na R, Ye D, Liu F, Chen H, Qi J, et al.
Performance of serum prostate-specific antigen isoform [-2]proPSA (p2PSA) and the Prostate Health Index (PHI) in a Chinese hospital-based biopsy population. Prostate
2014; 74: 1569-75.
Pelzer AE, Tewari A, Bektic J, Berger AP, Frauscher F, et al.
Detection rates and biologic significance of prostate cancer with PSA less than 4.0 ng ml -1
: observation and clinical implications from Tyrol screening project. Urology
2005; 66: 1029-33.
Lazzeri M, Haese A, de la Taille A, Palou Redorta J, McNicholas T, et al.
Serum isoform [-2]proPSA derivatives significantly improve prediction of prostate cancer at initial biopsy in a total PSA range of 2-10 ng ml -1
: a multicentric European study. Eur Urol
2013; 63: 986-94.
Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, et al.
The Prostate Health Index selectively identifies clinically significant prostate cancer. J Urol
2015; 193: 1163-9.
de la Calle C, Patil D, Wei JT, Scherr DS, Sokoll L, et al.
Multicenter evaluation of the Prostate Health Index (PHI) for detection of aggressive prostate cancer in biopsy-naive men. J Urol
2015; 194: 65-72.
Cantiello F, Russo GI, Ferro M, Cicione A, Cimino S, et al.
Prognostic accuracy of Prostate Health Index and urinary prostate cancer antigen 3 in predicting pathologic features after radical prostatectomy. Urol Oncol
2015; 163: e15-23.
Fossati N, Buffi NM, Haese A, Stephan C, Larcher A, et al.
Preoperative prostate-specific antigen isoform p2PSA and Its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol
2014; 68: 132-8.
Nichol MB, Wu J, An JJ, Huang J, Denham D, et al.
Budget impact analysis of a new prostate cancer risk index for prostate cancer detection. Prostate Cancer Prostatic Dis
2011; 14: 253-61.
Nichol MB, Wu J, Huang J, Denham D, Frencher SK, et al.
Cost-effectiveness of Prostate Health Index for prostate cancer detection. BJU Int
2012; 110: 353-62.
Semjonow A, Kopke T, Eltze E, Pepping-Schefers B, Burgel H, et al.
stability of [-2]proPSA in blood and serum. Clin Biochem
2010; 43: 926-8.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]