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Thread: New Circulating Biomarkers for Prostate Cancer

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    Default New Circulating Biomarkers for Prostate Cancer

    New Circulating Biomarkers for Prostate Cancer

    Abstract
    The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and α-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.

    Introduction
    Prostate cancer (PCa) is the most frequently diagnosed cancer among men in the United States, with a lifetime prevalence of one in six men.[1] PCa displays a range of clinical behavior, from a slow-growing tumor of no clinical significance to aggressively metastatic and lethal disease. The introduction of prostate-specific antigen (PSA) revolutionized PCa screening and ushered the PSA era. This has resulted in earlier PCa detection and an increase in incidence. However, its use as a screening tool remains controversial due to questions regarding survival benefit, cost effectiveness and clinical factors such as the optimal age and total PSA at which to recommend biopsy.[2] Recently, Thompson et al.[3] showed that there is no true PSA cutoff point for identifying PCa risk in that there are a significant number of men with PSA values <4.0 ng ml-1 who actually have PCa. In addition to the controversy surrounding PSA-based screening, there is considerable debate whether PSA remains an important prognostic marker among men with PCa.[4]

    The first and most important concern regarding the use of PSA is the lack of cancer specificity. A rise of the PSA level can reflect the presence of cancerous cells but can also be related to nonmalignant disorders such as benign prostatic hyperplasia (BPH), infection or chronic inflammation. All types of prostatic cells, whether normal, hyperplastic or cancerous, synthesize PSA, with highest levels found in the transitional zone of the prostate. Neoplastic cells produce lower levels of PSA compared to BPH cells but deliver a greater amount of PSA into the blood stream, presumably because of the disordered architecture of PCa. Therefore, it has been suggested that total PSA should be considered as a significant marker of BPH-related prostate volume, growth and outcome rather than a reliable marker of PCa.[5-7]

    Changes in the epidemiology of PCa have strongly limited the correlation between total PSA and the stage of PCa.[8-10] PSA can no longer be considered as a classical tumor marker whose levels are directly correlated with increasing stage of the disease. Moreover, the relationship with tumor grade remains unclear since it has been suggested that total PSA expression decreases with higher Gleason scores.[11,12] Classical prognostic tools based on pretreatment PSA levels, such as Partin tables[13] and Kattan nomograms[14-16] have become less reliable because of the continuous shift toward earlier stages of the disease at diagnosis. Consequently, the upper limit of normality of 4.0 ng ml-1, that was set in initial studies, may no longer be optimal since it has been proven that a significant number of cancers remained undetected in patients with PSA levels below this cutoff point.[3,17]

    Initial reports suggested that men with a slightly 'abnormal' value (4.0-9.9 ng ml-1) had a 22% chance of having PCa, and those with a significant rise of >10.0 ng ml-1 had a 67% risk.[18] However, it became quickly clear that these relative risks were in context of a sextant biopsy technique fraught with a high false-negative detection rate, and that the risk of harboring PCa in men with a PSA level above 4.0 was approximately twice as likely, in the 40-50% range.[19] Multiple studies have now demonstrated that significant numbers of men with 'normal' PSA values harbor PCa. The most definitive was the Prostate Cancer Prevention Trial, which determined that there is no PSA level below which PCa can be ruled out, and no cutoff above which PCa can be assured.[20] As a result, it is now clear that men with PSA values below the artificial 4.0 cutoff are inaccurately categorized as being normal, and those above the cutoff are mischaracterized as being abnormal. Moreover, PSA levels in men that have undergone prior treatment for PCa are completely independent of the reference ranges in widespread laboratory use, making such references and thresholds even more meaningless in this setting.

    Therefore, clinicians and researchers are still on a quest for novel approaches to improve our ability to detect PCa and foretell the course of the disease. New therapeutics, such as chemoprevention, gene therapy and adjuvant therapies, will need a more reliable set of markers for their development. Because the most useful clinical biomarkers will likely be those that can be assayed from blood, there is much interest in proteomics, which has recently emerged as a promising tool to better understand systems biology. In that setting, many potential PCa blood biomarkers have been identified and are currently under investigation. In this review, we discuss the importance of molecular forms of PSA and other promising candidate blood markers in the management of PCa.

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    Can We Improve PCa Screening Performance with PSA Derivatives?

    A PSA above 4 ng ml-1 is not systematically associated with cancer. A major concern is to enhance the specificity of the test to rule out patients without cancer and avoid unnecessary biopsies. For that purpose, several approaches based on PSA derivatives have been investigated including age-specific values, PSA density (PSAD), PSA density of the transition zone (PSAD-TZ), PSA velocity and assessment of various isoforms of PSA.

    Age-adjusted PSA
    The rationale for adjusting PSA levels with the age of the patient is that PSA correlates linearly with prostate size and the prostate grows with age. Based on this approach, a lower cutoff should be used in younger men whereas a higher upper normal limit may be used for older men.[21] This modification is meant to improve cancer detection (improve sensitivity) in younger men and decrease the rate of 'unnecessary' biopsies (increase specificity) in older men. However, Bassler et al.[22] reported a significant loss in sensitivity when the upper limit was increased to 4.5 ng ml-1 in men aged 60-69 years. Moreover, Etzioni et al.[23] found a lower diagnostic accuracy when using age-adjusted PSA compared to the normal cutoff of 4.0 ng ml-1. Thus, the utility of age-specific PSA values remains controversial.

    PSA Density
    The calculation of PSAD takes into account the volume of the prostate gland, since it is well established that men with larger prostates have higher PSA levels. In theory, selectively performing a biopsy in men with a higher PSAD would increase the specificity in case of a large prostate and the sensitivity in case of a small gland. While some studies reported that men with PCa had higher PSAD than men with BPH, thereby,[24,25] other studies did not confirm these results.[26,27] In healthy men, most of the serum PSA originates from the transition zone (TZ) epithelium. In addition, BPH occurs in the TZ that in itself is an infrequent site of adenocarcinoma. For this reason, some authors considered the PSAD-TZ as a better alternative to PSAD.[28] Nevertheless, because of the need for transrectal ultrasound to accurately measure volume, the assessment of PSAD and PSAD-TZ is cumbersome, costly and uncertain as volume results may vary. As such PSAD and PSAD-TZ are not routinely used for the screening of PCa, although they may be useful when considering a repeat biopsy.

    PSA Velocity
    PSA velocity refers to the serial evaluation of serum PSA concentration over time. Carter et al.[29] were the first to report longitudinal changes in PSA in 1992. Based on a population of PCa, BPH and healthy subjects, they found that a PSAV greater than 0.75 ng ml-1 per year was significantly associated with cancer. This PSAV cutoff was mainly useful in patients with a PSA level between 4 and 10 ng ml-1, yielding specificity greater than 90% . If the initial PSA serum concentration was below 4 ng ml-1, the sensitivity became too low for a reliable testing, and to date, appropriate cutoffs have not been determined. The use of PSAV is also limited by physiological fluctuations in PSA concentrations in an individual[30] and by differences among available PSA assays.[31] Infection and chronic inflammation can also be confounding factors as they can cause significant increases in PSA. It is therefore recommended that a minimum of three consecutive PSA measurements should be made over a 2-year period.[32] More recent studies evaluated the PSA velocity prior to PCa treatment to predict tumor stage, grade and time to recurrence after radical prostatectomy. D'Amico and associates[33] reported significantly shorter time to PSA relapse and death from PCa in patients with a pretreatment annual PSA velocity of more than 2.0 ng ml-1 among 1054 patients who underwent radical prostatectomy for localized PCa. Other studies confirmed that annual PSA velocity prior to diagnosis is a promising approach to identify candidates who may not benefit from local therapy.[34,35]

    Molecular Isoforms of PSA
    One of the most promising approaches to improve the diagnostic accuracy of the PSA test, especially below 10 ng ml-1, relies on the measurement of different molecular isoforms of the PSA in the serum, including free (unbound to proteins) and complexed (bound to protease inhibitors) PSA.

    Approximately 75% of serum PSA is bound to α-1-antichymotropsin to form an inactive enzymatic complex (PSA-ACT). PSA is also bound to other protease inhibitors, although in smaller proportions: 1-2% of total PSA forms a complex with α-1-proteinase inhibitor (PSA-API, also called α-1-antitrypsin) and 5-10% occurs in complex with α-2-macroglobulin (PSA-A2M). Concentration of PSA-API is difficult to quantify because its serum level is very low. PSA-A2M cannot be detected by conventional immunoassays because of chemical interactions between A2M and PSA epitopes that are targeted by antibodies used in available commercial PSA assays. PSA-ACT and PSA-API are both detected by standard assays. However, complexed PSA (which comprises both PSA-ACT and PSA-API) is of poor utility in clinical practice since PSA-ACT increases whereas PSA-API decreases in PCa patients.[36-38] Complexed PSA is either determined by specific immunoassays or calculated by subtracting free PSA from total PSA. One study suggests that complexed PSA may slightly enhance performance in early detection of PCa.[39] However, its diagnostic superiority over free PSA is not yet established and warrants further investigation.[40]

    The remainder of total PSA exists as a free, noncomplexed and enzymatically inactive form (free PSA). Catalona et al.[41,42] initially reported that the measure of the percentage of free PSA ((free PSA/total PSA) x 100) could improve the diagnostic accuracy of the PSA test in men with a PSA level between 4 and 10 ng ml-1. They found that with a free PSA greater than 25% , only 8% of patients had PCa on biopsy whereas if the free PSA was less than 10% , 56% of the men were diagnosed with PCa. On the basis of these findings, in 1998 the FDA (Food and Drug Administration) approved the use of free PSA as an adjunct to total PSA for PCa screening. More recently, the same team focused on the value of free PSA in the subset of patients with a PSA between 2.5 and 4 ng ml-1 and determined that using a free PSA cutoff of 27% , they were able to obtain a sensitivity of 90% and avoid 18% of unnecessary biopsies in men older than 50. In their study, 83% of the diagnosed cancers were significant. Nevertheless, while it is now recognized that free PSA can improve the diagnostic accuracy of total PSA in patients with a PSA between 4 and 10 ng ml-1, the optimal cutoff value remains subject to debate. In addition, since initial studies on free PSA were done in the era of classical sextant biopsies, it has recently been suggested that free PSA is not as effective in patients undergoing an extended 12 core biopsies scheme.[19]

    The role of free PSA for PCa prognostication remains controversial. For example, Catalona et al.[42] reported that 75% of men with a free PSA greater than 15% had favorable pathological features compared to only 34% of patients with a lower free PSA. In accordance with these findings, Shariat et al.[9] reported that lower preoperative free PSA is an independent predictor of advanced pathologic features and aggressive disease progression in 402 consecutive men treated with radical prostatectomy and with a PSA less than 10 ng ml-1. In contrast, Graefen[43] failed to detect an independent association between free PSA level and biochemical recurrence in 581 unscreened patients with localized PCa.

    Free PSA Isoforms
    There are three distinct forms of free PSA in the serum: BPH-associated PSA (BPSA), pro-PSA and intact free PSA.[44] BPSA is produced from the cleavage of amino-acid residues from intact free PSA. It can be found in the prostate, blood and semen.[44] BPSA seems to be a promising marker of BPH since it has shown a direct association between its secretion and the volume of the TZ.[45] In healthy men, BPSA is undetectable. As such, BPSA is a better predictor of prostate enlargement than total and free PSA.[46] In addition, BPSA is not affected by age and is significantly higher in the presence of BPH symptoms.

    PSA is synthesized as an inactive pro-PSA form that is activated by human glandular kallikrein 2 (hK2) upon removal of a short peptide sequence.[44] Cancerous prostate cells contain higher levels of truncated forms of pro-PSA with remaining amino acids that should have been removed during the activation process. Several studies have reported interesting results on pro-PSA in PCa. Sokoll and Catalona found that the percentage of pro-PSA could significantly decrease the number of unnecessary biopsies in men with a PSA between 2 and 4 ng ml-1.[47,48] Moreover, 2-pro-PSA, a truncated form of pro-PSA, had the highest specificity for PCa screening and was the most efficient predictor of PCa aggressiveness.[49]

    Intact free PSA is similar to native PSA, but enzymatically inactive. Nurmikko et al.[50] developed an assay to measure intact free PSA and found no associated increase in men with PCa although the ratio to free PSA was significantly higher (higher than what?).

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    Novel Biomarkers for PCa Detection and Prognostication

    In summary, this review of shortcomings of PSA and its derivatives highlights the need for more specific and sensitive biomarkers for the diagnosis of PCa, particularly markers that could predict the behavior of a tumor in an individual patient to avoid over treatment of PCa. Among all previously discussed PSA derivatives, free PSA is the only one that is currently commonly used in clinical practice, despite the absence of well-defined cutoff. With recent advances in the sequencing of human genome, the improvement in high-throughput analysis such as microarrays and the rapid emergence of proteomics, many new potential biomarkers of PCa are currently under investigation.

    Human Glandular Kallikrein 2
    Human glandular kallikrein 2 belongs to a family of 15 proteases, from which only 12 were recently characterized.[51] hK2 is a serine protease very similar to PSA (also known as hK3). They share an 80% sequence homology and are both primarily expressed in the prostate gland.[51] Despite these structural similarities, hK2 and PSA differ in their enzymatic activity. The levels of hK2 in prostate tissue, plasma semen and serum are less than 2% that of PSA, although hK2 mRNA transcript expression represents half that of total PSA. Similar to PSA, serum hK2 is present in two forms in the blood: one bound to various protease inhibitors, and the other (preponderant) free in the circulation. Several studies have shown that when used in conjunction with free and total PSA serum hK2 could improve the discrimination of men with PCa from men without cancer.[52-54] It has also been suggested that hK2 could predict poor differentiation, extracapsular extension and biochemical recurrence in patients treated with radical prostatectomy.[55-57] However, this finding was not validated by other authors.[58] The usefulness of hK2 for the preoperative staging of localized PCa therefore remains controversial.

    Early Prostate Cancer Antigen
    Early prostate cancer antigen (EPCA) is a nuclear matrix protein originally identified through protein profiling of rat prostate tissue.[59] Alterations of nuclear matrix proteins are considered to be associated with carcinogenesis. Immunohistochemical studies on prostate core biopsies using autoantibodies against EPCA showed a sensitivity and a specificity superior to 80% for the diagnosis of PCa.[60,61] Interestingly, positive staining was also observed in noncancerous tissue adjacent to the tumor. In addition, EPCA was expressed in the precursor lesions such as proliferative atrophy and prostatic intraepithelial neoplasia, which indicates that EPCA may be associated with nuclear matrix alterations that occur during the early steps of carcinogenesis. More recently, a blood-based assay for EPCA was able to detect patients with PCa in a cohort of 46 individuals (12 cancers and 34 controls) with high accuracy (92% sensitivity and 94% specificity).[62] Another recent study, using an EPCA serum enzyme-linked immunosorbent assay assay, found similar findings (94% sensitivity and 92% specificity) for PCa detection.[63] Interestingly, the EPCA-2 serum assay was effective in differentiating patients with localized disease versus those with extraprostatic extension (area under the curve of 0.89; P<0.0001).[63] These results are promising and suggest a potential role for EPCA as a PCa biomarker, although larger validation studies are warranted.

    Urokinase Plasminogen Activation System
    The urokinase plasminogen activation (uPA) system is involved in the degradation of the extracellular matrix thereby permitting cancer progression. The inactive precursor of the serine protease, uPA, binds a specific soluble cell-surface receptor (uPAR), promoting the transformation of plasminogen into plasmin. Plasmin subsequently degrades a wide spectrum of extracellular matrix proteins through activation of a cascade of proteases. Increased serum levels of different uPAR forms have been associated with a poor prognosis in various cancers.[64,65] Reports concerning the ability of circulating uPAR to detect PCa are conflicting. McCabe et al.[66] did not find any significant association between uPAR levels and the presence of PCa whereas Steuber et al.[67] recently showed that uPAR fragments were significant predictors of PCa on biopsy specimens of patients with an elevated PSA. uPA and uPAR might also have a prognostic value. Elevated circulating levels of uPA and uPAR have been linked to PCa stage and bone metastases.[68-70] In these studies, preoperative plasma uPA was a strong predictor of biochemical recurrence after surgery. Both preoperative uPA and uPAR were associated with features of aggressive biochemical recurrence such as development of distant metastasis suggesting an association with occult metastatic disease at time of local therapy. Larger multi-institutional studies are under way to validate the potential role of uPA and uPAR as markers of metastatic PCa.

    Transforming Growth Factor-b1 and Interleukin-6
    Transforming growth factor (TGF)-1 is a growth factor involved in the regulation of several cellular mechanisms including proliferation, immune response, differentiation and angiogenesis.[71] TGF-1 has promoted cell progression in PCa models[72] and its local expression has been associated with higher tumor grade, tumor invasion and metastasis in PCa patients.[73,74] Several studies have shown that increased levels of circulating TGF-1 were associated with cancer progression, occult and documented metastasis and biochemical progression in PCa patients.[74-76] However, other authors did not confirm such correlations.[77,78]

    Interleukin-6 (IL-6) is a cytokine with variable effects on immune and hematopoietic mechanisms.[79] In vitro and in vivo studies have shown that both IL-6 and its receptors (IL-6R) were expressed in PCa.[80,81] Several authors reported that elevated serum levels of IL-6 and IL-6R were associated with metastatic and hormone-refractory disease, and suggested that IL-6 could predict progression and survival of PCa patients.[82,83]

    On the basis of these findings, Kattan and associates[84] developed and internally validated a prognostic model that incorporates plasma (TGF)-1 and IL-6R into a standard nomogram for prediction of biochemical recurrence following radical prostatectomy. This combination of serum markers and classical clinical parameters improved the predictive accuracy by a statistically and prognostically substantial margin (increase in predictive accuracy from 75 to 84% ).

    Chromogranin A
    Chromogranin A is a peptide secreted by neuroendocrine cells in the prostate gland. While its function is unknown,[85,86] attention has been dedicated to the potential prognostic value of chromogranin A. Several investigators found that increased chromogranin A levels are associated with high-grade disease, advanced state disease and poor survival, particularly in the case of hormone-refractory cancer.[87-89] In addition, a number of studies showed that an elevation of serum chromogranin A preceded PSA increase as a marker of progression to hormone-refractory disease. As such, it may be possible to use chromogranin A to monitor metastatic PCa patients under androgen blockade.[90,91]

    Prostate Secretory Protein (PSP)
    PSP94 (also known as h-microseminoprotein) is one of the most abundant proteins in the semen. PSP94 exists in two forms in the serum: one free form and one complexed to a binding protein (PSBP). In a recent study, PSBP and the ratio of bound PSP94/free PSP94 were independent predictors of biochemical recurrence in patients who underwent radical prostatectomy, after adjustment for total PSA, Gleason sum and surgical margin status.[92] However, further large prospective studies are warranted to confirm these preliminary findings.

    Prostate-specific Membrane Antigen
    Prostate-specific membrane antigen (PSMA) is a glycoprotein highly expressed in normal and cancerous epithelial prostatic cells. High levels of PSMA have also been detected in the serum of PCa patients.[93] The exact function of PSMA remains unclear. The interest of PSMA, as a potential diagnostic and prognostic marker of PCa, has been evaluated by several authors with inconclusive results. Some studies reported a strong correlation between PSMA and the degree of tumor differentiation and the stage of disease,[94,95] whereas others did not.[58,96] In addition, PSMA has been used in conjunction with an indium-111-labeled monoclonal antibody as a radiodiagnostic marker for in vivo detection of PCa recurrence and metastasis (Prostascint, Cytogen, Princeton, NJ, USA). Elgamal et al.[97] showed that Prostascint is more sensitive and accurate than CT, MRI and ultrasound for the diagnosis of local or regional lymph node invasion.

    Prostate Cancer-specific Autoantibodies and A-methylacyl-CoA Racemase
    Autoantibodies, such as those detected in autoimmune and infectious diseases, can be produced by cancer patients in response to tumor-associated antigens overexpressed in cancerous cells. α-Methylacyl-CoA racemase (AMACR) is an enzyme involved in fat metabolism, which has a strong expression in PCa tissues.[98] Immunostaining, using monoclonal antibodies to AMACR, is routinely used for the diagnosis of PCa yielding high diagnostic accuracy (sensitivity 97% and specificity 92% ).[99] A humoral response to tumor-related autoantibodies can be detected in the serum through amplification with high-affinity antibodies and T cells. Autoantibodies to AMACR have been detected in the blood of PCa patients and a recent study showed that they could help distinguish cancerous from healthy patients with more accuracy than PSA, holding promises for a new diagnostic test.[100] Other autoantibodies to antigens expressed in PCa (huntington-interacting protein 1, protasomes) have also been detected and it has been reported that their combination could improve the screening performance reaching a specificity of 97% .[101] Recently, using a so-called 'immunomics' technique, Wang et al.[102] analyzed the overall humoral response against specific tumoral antigens in PCa and were able to identify multiple antigens. With this panel of autoantibodies, they could detect PCa with a sensitivity of 81.6% and a specificity of 88.2% , which was more accurate than PSA alone. Additional studies are needed to validate this complex technique and assess the potential prognostic value of autoantibodies in PCa.

    Insulin-like Growth Factors Family
    Epidemiological studies have found high circulating insulin-like growth factor-I (IGF-I) and low IGF-binding protein 3 (IGFBP-3) levels to be associated with an increased risk of PCa development.[103,104] However, in these studies, total PSA remained by far the best predictor of PCa. Moreover, there is no difference in circulating IGF-1 levels between men with PCa and cancer-free controls.[105] In addition, there was no relationship between IGF-I and established markers of aggressive disease, cancer progression or metastasis.[105]

    Conversely, plasma IGFBP-2 was significantly elevated in patients with PCa compared to men without PCa and were inversely correlated with the prostate volume and features of aggressive disease.[105] In the same study, serum level of IGFBP-3 (the main carrier of IGF-I) was lowest in patients with bone metastases but no difference was seen between nonmetastatic PCa and healthy subjects. Moreover, lower levels of IGFBP-2 and -3 could predict cancer progression when adjusting for preoperative PSA, Gleason score and clinical stage in patients with localized disease undergoing radical prostatectomy. Hence, it seems that the interest of IGF-1 is limited to its association with preclinical stages of PCa, whereas the IGFBPs appear to play a direct role in PCa detection and prognosis

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    Conclusions

    Early detection of PCa was made possible 20 years ago by the introduction of PSA in the clinical practice. However, PCa screening remains controversial, because of the risk of over diagnosis and over treatment and the inability to detect a significant proportion of dangerous tumors. Furthermore, to date, there is no conclusive evidence that the use of PSA has reduced mortality from PCa.

    Several new biomarkers have shown promises in preliminary studies. However, no single biomarker is likely to have the desired level of diagnostic accuracy and the appropriate degree of certainty to foretell the course of PCa. The future of cancer profiling might rely on the combination of a panel of markers that can give accurate molecular staging and indicate the likelihood of aggressive behavior.

    To achieve this, further refinement of available high-throughput technology platforms may be able to identify the specific molecular profile of PCa that discriminates patients with cancer from healthy subjects. With newly discovered genes and molecular markers reaching record levels, there is a need for appropriate clinical guidelines and protocols to ensure a systematic and critical evaluation of each potential test prior to their introduction in patient care. By doing so, there is great hope that a time will come when new biomarkers will be translated into simple diagnostic kits which are easy to use and improve detection, monitoring and management of PCa.

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    Edit the lengthy posts with presentable look before posting..

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    ok sure!!
    I was reading Ca prostate n came across zt. I liked it n posted z whole thng!!!

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