Performance of prostate‐specific antigen mass in estimation of prostate volume in Japanese men with benign prostate hyperplasia

Objectives: Obese men with benign prostate hyperplasia might have lower serum prostate‐specific antigen because of hemodilution, resulting in underestimation of total prostate volume by serum prostate‐specific antigen. The aim of this study was to compare the performance of prostate‐specific antigen mass as the absolute amount of prostate‐specific antigen protein secreted into circulation with that of serum prostate‐specific antigen in the prediction of total prostate volume. Methods: A total of 1517 men with serum prostate‐specific antigen up to 10 ng/mL, including 1425 with biopsy‐proven benign prostate hyperplasia, were enrolled in this study. Height and weight were used to estimate body mass index, body surface area and plasma volume. Prostate‐specific antigen mass was calculated as serum prostate‐specific antigen multiplied by plasma volume. The association between serum prostate‐specific antigen or prostate‐specific antigen mass and transrectal ultrasound‐measured total prostate volume were evaluated by Pearson's correlation coefficient (Υ), linear regression analyses and receiver operating characteristic curves. Results: Serum prostate‐specific antigen had an inverse relationship with plasma volume, decreasing as plasma volume increased, after adjustment of total prostate volume. Larger total prostate volume per serum prostate‐specific antigen was found in men with higher body mass index or plasma volume. Among all participants, the correlation (Υ = 0.456) between prostate‐specific antigen mass and total prostate volume was apparently stronger than that (Υ = 0.442) between serum prostate‐specific antigen and total prostate volume. Prostate‐specific antigen mass outperformed serum prostate‐specific antigen at estimating total prostate volume cut‐off values of 30 and 40 mL. These findings were more significant in men aged ≥60 years. Conclusions: Prostate‐specific antigen mass performs better than serum prostate‐specific antigen in estimating TPV, especially in men aged ≥60 years.     

Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells

BACKGROUND: The expression of prostate-derived factor (PDF) is significantly elevated in human prostate tumors. We investigate the functional role and signaling of PDF in androgen receptor (AR)-positive human prostate cancer cells. METHODS: Transient or stable expression of PDF by cDNA transfection, antisense-mediated gene silencing, media conditioned by PDF-elevated cells, and antibody (Ab) neutralization were employed. RESULTS: Elevated endogenous and exogenous expression of PDF and treatment of PDF-enriched media were associated with increased proliferation and clonogenic growth of the cells. On the contrary, knockdown of PDF or addition of PDF neutralizing Ab resulted in diminished proliferation and reduced anchorage-independent growth. Further, ERK1/2 and p90RSK, but not Smad2/3, were activated in PDF-elevated cells as well as in cells treated with PDF-enriched media, while inhibition of ERK1/2 decreased the growth of those cells. CONCLUSION: PDF promotes AR-positive prostate tumor progression through upregulating cell proliferation via ERK1/2 signal pathway.     

Interpreting a rising prostate‐specific antigen after brachytherapy for prostate cancer

The aim of the present study was to review the English language literature on the topic of prostate‐specific antigen bounce after brachytherapy and present a summary of the current knowledge. Although ultimately prostate‐specific antigen is a reliable measure of success after prostate brachytherapy, it can be very misleading in the first 3 years because of the frequency with which temporary benign rises in prostate‐specific antigen occur. We have reviewed the English language literature on the topic of prostate‐specific antigen bounce under the following headings: prostate neoplasms, brachytherapy, biochemical definition of prostate‐specific antigen failure, “benign prostate‐specific antigen bounce” and “prostate‐specific antigen spike”. We included brachytherapy delivered as either low dose rate or high dose rate, and either as monotherapy or as a boost combined with external beam radiotherapy. A benign self‐limited rise in prostate‐specific antigen after prostate brachytherapy is seen in an average of 35% of patients, but increases in frequency with younger age. In patients aged less than 55 years, it is observed in up to 68%. Other factors, such as sexual activity, dose, prostate volume and the use of high dose rate versus low dose rate have been implicated in affecting the frequency of the benign bounce. Benign increases in prostate‐specific antigen are frequent after prostate brachytherapy. It is important to recognize and correctly diagnose this phenomenon in order to avoid unnecessary salvage treatment.     

Definition and preoperative predictors of persistently elevated prostate‐specific antigen after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

OBJECTIVES

To define a level of persistently elevated prostate‐specific antigen (PSA) after radical prostatectomy (RP) that equates with high‐risk for disease progression, and to identify preoperative predictors of PSA persistence among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

PATIENTS AND METHODS

A total of 901 men treated with RP between 2001 and 2008 were separated into groups based upon PSA nadir within 6 months after RP. We explored the association between nadir groups and time to biochemical recurrence (BCR) using multivariate Cox proportional hazards and determined the preoperative predictors of PSA persistence using logistic regression.

RESULTS

Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (hazard ratio [HR] 3.88, P < 0.001), 0.04 (HR 4.87, P < 0.001), 0.05–0.09 (HR 12.69, P < 0.001), 0.1–0.19 (HR 13.17, P < 0.001), and 0.2 ng/mL (HR 13.23, P < 0.001) were at increased risk of BCR while men with a nadir of 0.01 (HR 1.36, P = 0.400) and 0.02 (HR 1.64, P = 0.180) were not. Using the PSA persistence definition of a PSA nadir ≥0.03 ng/mL, 230 men (26%) had persistence. The independent preoperative predictors of PSA persistence were higher body mass index (BMI, P = 0.002), pathological Gleason score (relative to 2–6: 4 + 3–10, P = 0.001) and preoperative PSA level (P < 0.001).

CONCLUSIONS

Men with a PSA nadir ≥0.03 ng/mL after RP were at higher risk for BCR. Using a PSA persistence definition of a PSA nadir ≥0.03 ng/mL, persistence was predicted by known factors associated with aggressive disease (tumour grade, PSA level and BMI). Validation of the present definition in different populations using later end‐points remains necessary to assess its prognostic usefulness.     

Community‐based prostate cancer screening in Japan: Predicting factors for positive repeat biopsy

Objectives: To assess possible predictors in determining criteria for repeat biopsy in a prostate cancer screening population. Methods: A total of 50 207 men over 55 years‐of‐age have participated in a prostate cancer screening program in Otokuni, Kyoto, Japan for 12 years. Transperineal systematic biopsy was carried out in case of positive digital rectal examination (DRE) or positive transrectal ultrasonography (TRUS) or a prostate‐specific antigen (PSA) value greater than 10.0 ng/mL. For those with a PSA level from 4.1 to 10.0 ng/mL, and negative DRE and TRUS findings, biopsy was indicated only when PSA density (PSAD) was greater than 0.15. The same indication was applied for the repeat biopsy. Results: A repeat biopsy after an interval of more than 2 years was carried out in 140 patients and was positive in 50 (36%) patients. The PSA value at the diagnosis of cancer declined from the initial value in six (12%) patients. On multivariate logistic regression analysis, PSA velocity (PSAV) as well as PSAD and DRE findings at latest screening were independent predictors for positive repeat‐biopsy outcome. The odds ratio (95% confidence intervals) of PSAV >0.48, latest PSAD >0.33 and positive latest DRE were 4.17 (1.05–18.5), 4.15 (1.31–14.0), and 3.62 (1.06–13.2), respectively. A combination of three variables defined as positive if any of these were positive, reduced 31% of unnecessary biopsies while missing 8% of low volume, low grade cancers. Conclusions: A combination of latest PSAD, PSAV and positive DRE at latest screening might help to reduce unnecessary repeat biopsies in high‐risk patients with an initial negative biopsy.     

Prostate‐specific antigen velocity (PSAV): a practical role for PSA?

Background: Prostate cancer is a leading cause of morbidity and mortality in Australian men. Early detection and treatment are critical to patient outcome, but detection is often difficult because of the limited accuracy of available tests. This paper assesses whether the use of prostate specific antigen kinetics has a practical use in the contemporary urological setting. Methods: A Medline literature review was performed examining related articles on the commonly available tests for prostate cancer, what they mean, their limited accuracy in cancer detection, and how this accuracy can be improved. Discussion: Detection of significant organ‐confined prostate cancer should be the goal of general practitioners and urologists alike. Prostate‐specific antigen and digital rectal examination are commonly used but lack specificity and sensitivity, especially for small organ‐confined cancers. The additional use of prostate‐specific antigen velocity may enhance the specificity and sensitivity of detection.     

Second to fourth digit ratio: a predictor of prostate‐specific antigen level and the presence of prostate cancer

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? The Homeobox genes, Hox a and d, control urinogenital system differentiation and digit development. The patterns of digit formation may be related to gonad function and may be reflected in 2nd to 4th digit ratio (digit ratio). Digit ratio is negatively correlated with prenatal testosterone levels and androgen receptor activity which is related to the increased prostate cancer risk. Patients with a lower digit ratio have a higher risk of prostate biopsy due to high PSA level, and of prostate cancer. Digit ratio could be a predictor of high PSA level and the presence of prostate cancer.

OBJECTIVE

To investigate the relationships between the 2nd to 4th digit ratio (digit ratio) and prostate volume, prostate‐specific antigen (PSA) level, and the presence of prostate cancer.

PATIENTS AND METHODS

Of the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤40 ng/mL were prospectively enrolled. Right‐hand 2nd and 4th digit lengths were measured prior to the PSA determinations and transrectal ultrasonography (TRUS). Prostate volumes were measured by TRUS without information about digit length. Patients with a PSA level ≥3 ng/mL underwent prostate biopsy.

RESULTS

No relationship was found between prostate volume and digit ratio [correlation coefficient (r) =?0.038, P= 0.466]. But, significant negative correlations were found between digit ratio and PSA (r=?0.140, P= 0.007). When the patients were divided into two groups (Group A: digit ratio <0.95, n= 184; Group B: digit ratio ≥0.95, n= 182), Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P= 0.002) and had significantly higher risks of prostate biopsy [odds ratio (OR) = 1.75, 95% CI = 1.07–2.84] and prostate cancer (OR = 3.22, 95% CI = 1.33–7.78).

CONCLUSIONS

Patients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer.     

Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues

BACKGROUND: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured. METHODS: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k. RESULTS: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5). CONCLUSIONS: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.     

Over-diagnosis and under-diagnosis of screen- vs non-screen-detected prostate cancers with in men with prostate-specific antigen levels of 2.0-10.0 ng/mL

OBJECTIVES

To evaluate possible over‐ and under‐diagnosis of prostate cancer in a screened vs a referral population in the same range of prostate‐specific antigen (PSA).

PATIENTS AND METHODS

In all, 1445 patients undergoing radical prostatectomy and with a PSA level of <10 ng/mL were evaluated; 237 were from outside Tyrol (Austria) and represented the unscreened group, and 1208 were Tyrolean screening volunteers. Over‐diagnosis was defined as a pathological stage of pT2a and a Gleason score of <7 with no positive surgical margins. Under‐diagnosis was defined as a pathological stage of ≥pT3a or positive surgical margins. The chi‐square test was used to assess the differences, with P < 0.05 considered to indicate statistical significance.

RESULTS

There were no significant differences in patient age or PSA levels between the study groups. There was over‐diagnosis in the screening and referral groups in 17.4% and 8.9%, respectively, and under‐diagnosis in 18.6% and 42.2%, respectively.

CONCLUSION

This study suggests that patients with prostate cancer participating in a screening programme are less likely to be under‐diagnosed or have extracapsular disease than their counterparts in a referral population, even in the same PSA range, after radical prostatectomy. Furthermore, there was more under‐diagnosis in the referral group than over‐diagnosis in the screened group.