PSA screening for prostate cancer： why so muc ：ontroversy？

Since prostate cancer reaches the advanced and non curable stage in the absence of any specific symptom or sign, it seems reasonable to diagnose this cancer at an early and curable stage. Screening by prostate-specific antigen （PSA） has been the common technology used. The last follow-up of the first two prospective and randomized screening studies for prostate cancer, namely the Quebec and ERSPC （European Randomized Study of Screening for Prostate Cancer） clinical trials started in 1988 and 1991, respectively, have shown reductions of prostate cancer death of 62% （P〈0.002） and 21% （P〈0.001） （38% in the tenth and eleventh years of follow-up, P〈0.003）, respectively, while the PLCO （Prostate Lung Colorectal and Ovarian Cancer） screening trial reported no benefit. It has been estimated, however, that 85% of men in the planned ＇non-screened＇ group of the US study have been screened. With such a serious flaw, the PLCO study does not have the statistical power to reach any valid conclusion. In the Quebec study, only 7.3% of men were screened in the control arm. The important benefit observed in the ERSPC study was achieved using a less than optimal 4-year PSA screening interval which misses a significant number of cancers while the Quebec study used the optimal 1-year interval. With proper information obtained from their physicians or otherwise using data collected only from the clinical trials having the required statistical power, men should be in a good position to decide about being or not being screened for prostate cancer.     

Decreasing trend in prostate cancer with high serum prostate-specific antigen levels detected at first prostate-specific antigen-based population screening in Japan

To clarify the recent trends in prostate-specific antigen （PSA） distribution in men in Japan, we analyzed the PSA distributions of men undergoing PSA-based population screening. We summarized the annual individual data of PSA-based population screening in Kanazawa, Japan, from 2000 to 2011, and analyzed baseline serum PSA values of the participants at the first population screening. Serum PSA distributions were estimated in all participants and those excluding prostate cancer patients according to age. From 2000 to 2011, 19 620 men participated aged 54-69 years old in this screening program. Mean baseline serum PSA level of all participants at the first screening was 2.64 ng m1-1 in 2000, and gradually decreased to approximately 1.30 ng ml-I in 2006. That of participants excluding prostate cancer patients was 1.46 ng m1-1 in 2000, and there was no remarkable change during the study period. The 95t＂ percentiles in the participants excluding prostate cancer patients detected at the first population screening of men aged 54-59, 60-64, and 65-69 years old were 2.90, 3.60, and 4.50 ng m1-1, respectively. After the commencement of population screening, the proportion of prostate cancer patients with high serum PSA levels decreased. However, there were no changes in serum PSA levels in men without prostate cancer. Age-specific PSA reference level of men without prostate cancer in Japan was similar to that in China and Korea.     

Castrate-tolerant cells： what are the implications for the treatment of localized prostate cancer？

More effective treatment of prostate cancer relies on eliminating cellsthat survive androgen withdrawal therapy. The discovery that castrate-tolerant tumour cells pre-exist in localized prostate cancer, prior to androgen withdrawal or progres-sion to castrate-resistant disease, supports the notion that neo-adjuvant therapies might be considered in the management of early stage prostate cancer. Advances in our ability to xenograft human prostate cancer provides a unique model system to study individual patient responses and test the preclinical efficacy of novel compounds for men with localized disease.     

Efficacy of maximal androgen blockade versus castration alone in the treatment of advanced prostate cancer： a retrospective clinical experience from a Chinese medical centre

In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.     

Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer： the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors

A cure cannot be assured for all men with clinically localized prostate cancer undergoing radical treatment. Molecular markers would be invaluable if they could improve the prediction of occult metastatic disease. This study was carried out to investigate the expression of BCL-2, Ki-67, p53 and E-cadherin in radical prostatectomy specimens. We sought to assess their ability to predict early biochemical relapse in a specific therapeutic setting. Eighty-two patients comprising 41 case pairs were matched for pathological stage, Gleason grade and preoperative prostate-specific antigen （PSA） concentration. One patient in each pair had biochemical recurrence （defined as PSA ≥ 0.2 ng mL^-1 within 2 years of surgery） and the other remained biochemically free of disease （defined as undetectable PSA at least 3 years after surgery）. Immunohistochemical analysis was performed to assess marker expression on four replicate tissue microarrays constructed with benign and malignant tissue from each radical prostatectomy specimen. Ki-67, p53 and BCL-2, but not E-cadherin, were significantly upregulated in prostate adenocarcinoma compared with benign prostate tissue （P 〈 0.01）. However, no significant differences in expression of any of the markers were observed when comparing patients who developed early biochemical relapse with patients who had no biochemical recurrence. This study showed that expression of p53, BCL-2 and Ki-67 was upregulated in clinically localized prostate cancer compared with benign prostate tissue, with no alteration in E-cadherin expression. Biomarker upregulation had no prognostic value for biochemical recurrence after radical prostatectomy, even after considering pathological stage, whole tumour Gleason grade and preoperative serum PSA level.     

Fasting times in serum PSA assay

Prostate-specific antigen （PSA） test for prostate cancer is the only serum-based cancer screening test that is widely accepted. A large number of PSA tests are done in developed countries such as the United States due to the recommendation that men be screened annually starting at age 50. With the rapid economic development and increased access to healthcare, countries like China have also experienced a dramatic increase in the utilization of P SA test. This trend is unlikely to change significantly despite the recent recommendation against routine PSA screening by the US Preventive Health Task force.     

Long-term survival of participants in the prostate ：ancer prevention trial

The Prostate Cancer Prevention Trial （PCPT） is a seminal study in the field of urology. More than 10years after its initial publication, updated data from this trial continue to shape our understanding of prostate cancer. Among the major findings from the PCPT has been the demonstration that prostate cancer is common in men with prostate-specific antigen （PSA） once thought to be in the normal range,~ finasteride prevents the development of benign prostatic hypertrophy,2 it increases the sensitivity of PSA3 and digital rectal examination.4 Furthermore the PCPT helped to establish the link between erectile dysfunction and cardiovascular disease,5 and perhaps most importantly finasteride demonstrated a 25% relative risk reduction in the diagnosis of prostate cancer compared with placebo.     

The Xu＇s chart for prostate biopsy： a visual presentation of the added value of biomarkers to prostate-specific antigen for estimating detection rates of prostate cancer

Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,     

Molecular markers in prostate cancer Part Ⅱ： potential roles in management

Predicting treatment responses in advanced prostate cancer （PCa） currently centres on prostate-specific antigen （PSA） kinetics and on being able to visualize measurable changes in imaging modalities. New molecular markers have emerged as potential diagnostic and prognostic indicators; these were summarized in Part I of this review in the Asian Journal ofAndrology. A number of molecular markers are now being used to enhance PCa imaging and staging. However, management options for advanced and hormone-resistant PCa （HRPC） are limited and additional therapeutic options are needed. Molecular markers have been proposed as potential therapeutic targets using gene therapy and immunomodulation. Additionally, markers identified in early PCa and precursor lesions may offer novel targets for chemoprevention and vaccine development. This review summarizes the current advances regarding the roles of these markers in the management of PCa.     

Prostate calculi in cancer and BPH in a cohort of Korean men：presence of calculi did not correlate with cancer risk

Prostatic calculi are common and are associated with inflammation of the prostate. Recently,it has been suggested that this inflammation may be associated with prostate carcinogenesis. The aim of this study was to investigate the relationship between prostatic calculi and prostate cancer （PCa） in prostate biopsy specimens. We retrospectively analyzed 417 consecutive patients who underwent transrectal ultrasonography （TRUS） and prostate biopsies between January 2005 and January 2008. Based on the biopsy findings,patients were divided into benign prostatic hyperplasia and PCa groups. TRUS was used to detect prostatic calculi and to measure prostate volume.The correlations between PCa risk and age,serum total PSA levels,prostate volume,and prostatic calculi were analyzed. Patient age and PSA,as well as the frequency of prostatic calculi in the biopsy specimens,differed significantly between both the groups （P〈0.05）. In the PCa group,the Gleason scores （GSs） were higher in patients with prostatic calculi than in patients without prostatic calculi （P = 0.023）. Using multivariate logistic regression analysis,we found that patient age,serum total PSA and prostate volume were risk factors for PCa （P = 0.001）,but that the presence of prostatic calculi was not associated with an increased risk of PCa （P = 0.13）. In conclusion,although the presence of prostatic calculi was not shown to be a risk factor for PCa,prostatic calculi were more common in patients with PCa and were associated with a higher GS among these men.     

Global developments in prostate cancer research and clinical practice

The prostate cancer foundation （PCF） is committed to the facilitation of globalknowledge exchange as a mechanism for more rapidly discovering and developing new medicines and treatments for prostate cancer （PCa） patients worldwide. For the past 3 years, PCF has partnered with the Chinese Prostate Cancer Consortium and Shanghai Changhai Hospital to host a conference in China that brings together basic, translational, and clinical researchers from China and abroad to form new partnerships and exchange findings, insights, perspectives, and ideas toward improving the treatment of PCa. The seventh forum of prostate disease held in Shanghai, China, on July 26-28, 2013, focused on current and emerging developments and approaches in PCa diagnosis, prognosis, and treatment, and the discovery and targeting of disease mechanisms that drive metastasis and lethal subtypes of castrate-resistant PCa （CRPC）.     

α1 and β1 integrins enhance the homing and differentiation of cultured prostate cancer stem cells

CD133＋ prostate cancer stem cells （PCSCs） have recently been identified in human prostate cancer tissues. The present study reports the integrin profile of prostate cancer progenitor cells and the role of α1 and β1 integrins in the homing and differentiation of PCSCs in vitro. PCSCs were isolated from the tissue specimens of patients with prostate cancer and the expression of surface integrins and adhesion patterns were determined. Our analysis of the expression of surface integrins and their adhesion patterns of prostate cancer stem cells derived from prostate cancer tissues revealed that the levels of β1 and α2β1 integrins were significantly higher （P 〈 0.05） than those of the other integrins. By contrast, peripheral blood-derived CD 133＋ cells from prostate cancer patients showed a high level of expression （P 〈 0.01） of α2β1,αvβ3, αvβ5, β1 and α1 integrins and a minimal expression of α4β1 integrins. Moreover, CD 133＋ cells derived from both prostate cancer tissues and peripheral blood exhibited an increased degree of attachment to extraceUular matrix proteins （P 〈 0.001） and a high expression level of α2β1 integrin. In vitro experiments using blocking antibodies indicated that α1 and β1 integrins have a role in the homing and differentiation of PCSCs. This is the first report to suggest the importance of integrins in mediating the homing and differentiation of PCSCs.     

Prevalence of incidental prostate cancer in patients undergoing radical cystoprostatectomy： data from China and other Asian countries

The purpose of this study is to investigate the frequency of prostate cancer （Pca） discovered incidentally in radical cystoprostatectomy specimens in Asia and to determine the feasibility of prostate-sparing cystectomy （PSC） for Asian patients. Ninety-two male bladder cancer patients who underwent radical cystoprostatectomy at our center between January 2003 and January 2008 were included in this study. The mean age of patients was 67.1 years （range： 32-75 years）. Prostate-specific antigen （PSA） levels and digital rectal examination （DRE） results before surgery were obtained retrospectively. Prostates of all patients were embedded and sectioned at 5-mm intervals. The same pathologist examined the prostatic tissues from radical cystoprostatectomy specimens. Finally, a structured literature review was performed using MEDLINE and PUBMED to estimate the occurrence of incidental Pca in Asia. Of the 92 patients, 3 （3.3%） were found to have Pca; in one out of three （33.3%） patients the disease was clinically significant due to a Gleason grade 4 carcinoma. Eight articles were included in our review. The overall incidence of Pca discovered incidentally in radical cystoprostatectomy specimens in Asia was 9.9% （64/642）. When age was restricted to 〈 60 years, only 7 out of 222 （3.2%） patients were found to have synchronous Pca, and none of the cases was clinically significant. The occurrence of Pca in radical cystoprostatectorny specimens in Asia is much lower than that in Western countries. PSC might be feasible for Asian patients under a strict preoperative selection.     

Early and delayed castrations confer a similar survival advantage in TRAMP mice

The most appropriate time to introduce androgen deprivation therapy for prostate cancer remains controversial. Our aim was to evaluate the effects of early versus delayed surgical castration on prostate cancer progression and survival in the transgenic adenocarcinoma of the mouse prostate （TRAMP） model. TRAMP mice were randomly divided into three groups： the early castration group （on which castration was performed at the age of 4 weeks）, the delayed castration group （on which castration was performed when abdominal tumours could be palpated）, and the sham-castrated group. Mice were monitored daily throughout their lives until cancer-related death or the develop- ment of an obviously moribund appearance, at which time the individual mouse was killed. Androgen receptor expression in prostate tumours was also evaluated. The results shows that the average lifespan in early castration, delayed castration and sham-castrated groups were 54.1 weeks, 59.9 weeks and 39.1 weeks, respectively. Both early castration and delayed castration conferred a statistically significant survival advantage when compared with the sham-castrated group （P 〈 0.001）. However, the difference in lifespan between the early castration group and the delayed castration group was not statistically significant （P = 0.85）. The increase in lifespan in the TRAMP mice that received either early or delayed castration correlated with lower G/B value （genitourinary tract weight/body weight） at death than the sham-castrated mice. In conclusion, early and delayed castrations in TRAMP mice pro- longed survival to a similar extent. This finding may provide a guide for clinical practice in prostate cancer therapy.     

Targeted prostate biopsy： value of multiparametric magnetic resonance imaging in detection of localized cancer

Prostate cancer is the second most common cancer in men, with 1.1 million new cases worldwide reported by the World Health Organization in one recent year. Transrectal ultrasound （TRUS）-guided biopsy has been used for the diagnosis of prostate cancer for over 2 decades, but the technique is usually blind to cancer location. Moreover, the false negative rate of TRUS biopsy has been reported to be as high as 47%. Multiparametric magnetic resonance imaging （mp-MRI） includes T1- and T2-weighted imaging as well as dynamic contrast-enhanced （DCE） and diffusion-weighted imaging （DWI）. mp-MRI is a major advance in the imaging of prostate cancer, enabling targeted biopsy of suspicious lesions. Evolving targeted biopsy techniquesmincluding direct in-bore biopsy, cognitive fusion and software-based MRI-ultrasound （MRI-US） fusion--have led to a several-fold improvement in cancer detection compared to the earlier method. Importantly, the detection of clinically significant cancers has been greatly facilitated by targeting, compared to systematic biopsy alone. Targeted biopsy via MRI-US fusion may dramatically alter the way prostate cancer is diagnosed and managed.     

Targeted-cryosurgical ablation of the prostate with androgen deprivation therapy： quality of life in high-risk prostate cancer patients

Aim:To present preliminary results on health-related quality of life(QoL),prostate-associated symptoms and thera-peutic effects of targeted-cryosurgical ablation of the prostate(TCSAP)with androgen deprivation therapy(ADT)inhigh-risk prostate cancer(PCa)patients.Methods:Thirty-four men with high-risk PCa features underwent TCSAP,and ADT was added to improve the treatment outcomes.High-risk parameters were defined as either prostate-specific antigen(PSA)≥10ng/mL,or Gleason score≥8,or both.The Genito-Urinary Group of the European Orga-nization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30(EORTC QLQ-C30)withprostate-cancer-specific module(QLQ-PR25)was used for evaluating morbidities and PSA levels were recordedevery 3 months.PSA failure was defined as the inability to reach a nadir of 0.4 ng/mL or less.Results:Although itwas not statistically significant,the global health status scores increased after TCSAP with ADT.The scores for fivefunctional scales also became higher after treatment.The most prominent symptom after treatment was sexualdysfunction,followed by treatment-related and irritative voiding symptoms.Conclusion:TCSAP with ADT appearsto be minimally invasive with high QoL except for sexual dysfunction.Long-term follow-up of PSA data and survivalis necessary before any conclusions can be made on the efficacy of this promising new therapeutic modality in thetreatment of PCa.(Asian J Androl 2006 Sep;8:629-636)     

Molecular markers in prostate cancer. Part Ⅰ： predicting lethality

Assessing the lethality of ‘early,’ potentially organ-confined prostate cancer （PCa） is one of the central controversies in modem-day urological clinical practice. Such cases are often considered for radical ‘curative’ treatment, although active surveillance may be equally appropriate for many men. Moreover, the balance between judicious intervention and overtreatment can be difficult to judge. The patient＇s age, comorbidities, family history and philosophy of self-health care can be weighed against clinical features such as the palpability of disease, the number and percentage of biopsy cores involved with the disease, histological grade, presenting prostate-specific antigen （PSA） and possible previous PSA kinetics. For many years, scientists and physicians have sought additional molecular factors that may be predictive for disease stage, progression and lethality. Usually, claims for a ‘new’ unique marker fall short of true clinical value. More often than not, such molecular markers are useful only in multivariate models. This review summarizes relevant molecular markers and models reported up to and including 2008.     

The isolation and identification of apolipoprotein C-I in hormone-refractory prostate cancer using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry

Androgens play a central role in prostate cancer pathogenesis, and hence most of the patients respond to androgen deprivation therapies. However, patients tend to relapse with aggressive prostate cancer, which has been termed as hormone refractory. To identify the proteins that mediate progression to the hormone-refractory state, we used protein-chip technology for mass profiling of patients＇ sera. This study included 16 patients with metastatic hormone-refractory prostate cancer who were initially treated with androgen deprivation therapy. Serum samples were collected from each patient at five time points： point A, pre-treatment; point B, at the nadir of the prostate- specific antigen （PSA） level; point C, PSA failure; point D, the early hormone-refractory phase; and point E, the late hormone-refractory phase. Using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, we performed protein mass profiling of the patients＇ sera and identified a 6 640-Da peak that increased with disease progression. Target proteins were partially purified, and by amino acid sequencing the peak was identified as a fragment of apolipoprotein C-I （ApoC-I）. Serum ApoC-I protein levels increased with disease progression. On immunohistochemical analysis, the ApoC-i protein was found localized to the cytoplasm of the hormone-refractory cancer cells. In this study, we showed an increase in serum ApoC-I protein levels in prostate cancer patients during their progression to the hormone-refractory state, which suggests that ApoC-I protein is related to progression of prostate cancer. However, as the exact role of ApoC-I in prostate cancer pathogenesis is unclear, further research is required.