Transrectal sonography in prostate cancer detection--our 25 years experience of implementation

Prostate cancer is a leading public health problem of male population in developed countries. Gold standard for prostate cancer diagnosis is true cut biopsy guided by transrectal ultrasound. Aim of this study was to determine sensitivity, specificity, accuracy, positive and negative predictive value of transrectal sonography (TRUS) in prostate cancer detection. The analysis was made for two time periods, before and after routine implementation of prostate specific antigen (PSA) in prostate cancer diagnostics. From 1984 to 1993 TRUS guided prostate biopsy was performed in 564, and from 1994 to 2008 in 5678 patients. In the second period PSA was routinely used in prostate cancer diagnostics. In the first period by TRUS we have made an exact diagnosis of prostate cancer in 18.97% of patients what was confirmed by biopsy. 4.61% ware false positive and 11.34% ware false negative. In the second period prostate cancer was recognized in 30.34% of patients, confirmed by biopsy. False positive cases ware 6.11% and false negative 29.31%. Sensitivity of transrectal sonography in the first period was 62.57%, specificity 94.2%, accuracy 86.2%, positive predictive value 80.45% and negative predictive value 87.72%. In the second period sensitivity was 50.87%, specificity 91.93%, accuracy 73.84%, positive predictive value 83.24% and negative predictive value 70.39%. Based on our experience we can conclude that prostate cancer is mostly found in the peripheral zone. Smaller tumors are hypoechoic and bigger tumors are hyperechoic. Prostate cancer lesions are impossible to differentiate from chronic prostatitis only by TRUS. Implementation of PSA has significantly decrease sensitivity, accuracy and negative predictive value of TRUS in prostate cancer detection. TRUS guided true cut biopsy is a gold standard in prostate cancer diagnostics.     

Using Biopsy to Detect Prostate Cancer

Transrectal ultrasound-guided systemic biopsy is the recommended method in most cases with suspicion of prostate cancer. Transrectal periprostatic injection with a local anesthetic may be offered as effective analgesia; periprostatic nerve block with 1% or 2% lidocaine is the recommended form of pain control. On initial biopsy, a minimum of 10 systemic, laterally directed cores is recommended, with more cores in larger glands. Extended prostate biopsy schemes, which require cores weighted more laterally at the base (lateral horn) and medially to the apex, show better cancer detection rates without increasing adverse events. Transition zone biopsies are not recommended in the first set of biopsies, owing to low detection rates. One set of repeat biopsies is warranted in cases with persistent indication. Saturation biopsy (≥20 cores) should be reserved for repeat biopsy in patients who have negative results on initial biopsy but who are still strongly suspected to have prostate cancer.Key words: Prostate cancer, Biopsy, Transrectal ultrasound, Prostate-specific antigen, Anesthesia, NomogramsProstate cancer rarely causes symptoms until it is advanced. Thus, suspicion of prostate cancer resulting in a recommendation for prostatic biopsy is most often raised by abnormalities found on digital rectal examination (DRE) or by serum prostate-specific antigen (PSA) elevations. Although there is controversy regarding the benefits of early diagnosis, it has been demonstrated that an early diagnosis of prostate cancer is best achieved using a combination of DRE and PSA.Transrectal ultrasound (TRUS)-guided, systematic needle biopsy is the most reliable method, at present, to ensure accurate sampling of prostatic tissue in men considered at high risk for harboring prostatic cancer on the basis of DRE and PSA findings. In very rare circumstances, a biopsy of a metastatic site (bone lesion) or a suspicious lymph node may be easier and more advantageous. There are also circumstances in which the usual transrectal route is not feasible (eg, status post-anteroposterior resection of the rectosigmoid; see Tissue Diagnosis in Patients with No Rectal Access section, below). As nearly universal as the approach, as nearly universal is the technique, namely a TRUS-guided biopsy using an 18-gauge needle to obtain a tissue core. To be certain, the same biopsy device and needle may be used to perform a finger-guided biopsy, but this is reserved for unusual circumstances (eg, TRUS imaging not available, finger-guided directed biopsy of suspicious nodule not seen on TRUS). Last, whereas in decades past physicians in many countries performed fine-needle aspiration of the prostate, today this technique is less and less often used, although advocates claim that it is cheaper, faster, easier to perform, and results in lower morbidity than any other technique developed to date. Appropriate training in performing transrectal fine-needle aspiration of the prostate and in interpreting the smears is, of course, essential.¹ Fine-needle aspiration plays a major role in the aforementioned situations in which diagnosis is established from nonprostatic tissue sources, such as lymph nodes and others.^2,3Since the landmark study by Hodge and colleagues⁴ demonstrating the superiority of TRUS guidance compared with digitally guided biopsy, the TRUS-guided biopsy technique has become the worldwide accepted standard in prostate cancer diagnosis. Statistical performance (sensitivity, specificity, positive and negative predictive values) of all other diagnostic tests (eg, DRE and PSA assay) is calculated according to the assignment (cancer present vs absent) made by prostate biopsy. Recognizing the fact that all sampling procedures, including prostate biopsies, incur the risk of returning false-negative results (ie, cancer is present but missed by the biopsies), calculation of the statistical performance characteristics of all other tests using biopsy outcomes as the gold standard are inherently incorrect and biased. Similarly, when comparing the statistical performance of various biopsy strategies, usually the most extensive strategy is chosen as the gold standard to define disease presence or absence, and the performance of all other strategies is calculated on the basis of that particular strategy, again incurring a significant bias due to the remaining falsenegative rate of even the most extensive sampling strategy.     

Cancer de la prostate : la maladie localisée

Localized prostate cancer is characterized by a tumor confined to the prostate gland at clinical evaluation. Since the onset of PSA screening, the detection of localized prostate cancer has increased. Prognosis factors are clinical stadification, PSA value, PSA doubling time, tumor volume related to needle biopsy pathologic findings (Gleason score, percentage biopsies involved). Treatment depends on tumor prognosis, symptoms and performance status of the patient. Localized prostate cancer can be treated by surgery (radical prostatectomy, high intensity focused ultrasound) or radiotherapy (conformational radiation therapy, brachytherapy). Active follow-up can be proposed to very low risk patients.     

Developing a Follow-Up Strategy for Patients with PSA Ranging from 4 to 10 ng/ml via a New Model to Reduce Unnecessary Prostate Biopsies

Objective

The aim of this study was to develop a follow-up strategy based on the new model to reduce unnecessary prostate biopsies in patients with prostate specific antigen (PSA) ranging from 4 to 10 ng/ml.

Methods

A total of 436 patients with PSA ranging from 4 to 10 ng/ml who had undergone transrectal ultrasound (TRUS)-guided prostate biopsy were evaluated during the first stage. Age, PSA, free PSA (fPSA), digital rectal examination (DRE) findings, ultrasonic hypoechoic mass, ultrasonic microcalcifications, prostate volume (PV) and PSA density (PSAD) were considered as predictive factors. A multiple logistic regression analysis involving a backward elimination selection procedure was applied to select independent predictors. After a comprehensive analysis of all results, we developed a new model to assess the risk of prostate cancer and an effective follow-up strategy.

Results

Age, PSA, PV, fPSA, rate of abnormal DRE findings and rate of hypoechoic masses detected by TRUS were included in our model. A significantly greater area under the receiver-operating characteristic curve was obtained in our model when compared with using PSA alone (0.782 vs. 0.566). Patients were grouped according to the value of prostate cancer risk (PCaR). In the second stage of our study, patients with PCaR>0.52 were recommended to undergo biopsies immediately while the rest of the patients continued close follow-up observation. Compared with the first stage, the detection rate of PCa in the second stage was significantly increased (33.0% vs 21.1%, p = 0.012). There was no significant difference between the two stages in distribution of the Gleason score (p = 0.808).

Conclusions

We developed a follow-up strategy based on the new model, which reduced unnecessary prostate biopsies without delaying patients’ diagnoses and treatments.     

On the clinical usefulness of the free-to-total prostate-specific antigen ratio

The free-to-total prostate-specific antigen ratio (F/T PSA) is associated with the presence of prostate cancer and is thus used as an indicator for suspicion of prostate cancer and as a determinant for biopsy. We reviewed a recent retrospective series of 966 consecutive prostate biopsies where F/T PSA was blindly determined and did not influence biopsy indication. We simulated the association of F/T PSA with biopsy outcome and its impact as a biopsy determinant. When adopting an F/T PSA cutoff of 10%, 13%, 16% or 20% among random sextant biopsies in the 4-10 ng/mL total PSA range, the sensitivity was 15%, 37%, 55% and 72% and the specificity 89%, 80%, 64% and 44%, respectively. Using F/T PSA as a biopsy determinant, from 1.7 to 2.6 cancer biopsies would have been delayed to avoid 10 benign biopsies. As this balance is not acceptable, F/T PSA has no role as a biopsy indicator and its clinical use is questionable.     

The 4Kscore? Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices

There is significant concern regarding prostate cancer screening because of the potential for overdiagnosis and overtreatment of men who are discovered to have abnormal prostate specific antigen (PSA) levels and/or digital rectal examination (DRE) results. The 4Kscore® Test (OPKO Diagnostics, LLC) is a blood test that utilizes four kallikrein levels plus clinical information in an algorithm to calculate an individual’s percentage risk (< 1% to > 95%) for aggressive prostate cancer (Gleason score ≥ 7) on prostate biopsy. The 4Kscore Test, as a follow-up test after abnormal PSA and/or DRE test results, has been shown to improve the specificity for predicting the risk of aggressive prostate cancer and reduce unnecessary prostate biopsies. A clinical utility study was conducted to assess the influence of the 4Kscore Test on the decision to perform prostate biopsies in men referred to urologists for abnormal PSA and/or DRE results. The study population included 611 patients seen by 35 academic and community urologists in the United States. Urologists ordered the 4Kscore Test as part of their assessment of men referred for abnormal PSA and/or DRE test results. Results for the patients were stratified into low risk (< 7.5%), intermediate risk (7.5%–19.9%), and high risk (≥ 20%) for aggressive prostate cancer. The 4Kscore Test results influenced biopsy decisions in 88.7% of the men. Performing the 4Kscore Test resulted in a 64.6% reduction in prostate biopsies in patients; the actual percentage of cases not proceeding to biopsy were 94.0%, 52.9%, and 19.0% for men who had low-, intermediate-, and high-risk 4Kscore Test results, respectively. A higher 4Kscore Test was associated with greater likelihood of having a prostate biopsy (P < 0.001). Among the 171 patients who had a biopsy, the 4Kscore risk category is strongly associated with biopsy pathology. The 4Kscore Test, as a follow-up test for an abnormal PSA and/or DRE results, significantly influenced the physician and patient shared decision in clinical practice, which led to a reduction in prostate biopsies while increasing the probability of detecting aggressive cancer.Key Words: Prostate cancer, Prostate-specific antigen, Digital rectal examination, Biopsy rate, Gleason score, 4Kscore Test, Prostate cancer prognosisWidespread screening for prostate cancer with serum prostate-specific antigen (PSA) began in 1991, and subsequently a 45% decline in prostate cancer mortality has been observed.¹ A recent large European randomized clinical trial also reported a 29% reduction in death from prostate cancer in men undergoing routine screening.² However, because of a US study that showed no mortality benefits to organized PSA screening,³ and the net physical and psychologic burden of secondary adverse events triggered by PSA testing versus the number of lives saved, the United States Preventative Services Task Force (USPSTF) recently advised against routine PSA screening for prostate cancer.⁴ The concern of the USPSTF is based on the fact that most men diagnosed with prostate cancer have a tumor that is unlikely to pose a threat to life expectancy. A recent systematic analysis suggested that up to 60% of prostate cancers diagnosed in contemporary studies might be safely observed without a need for immediate intervention.⁵One of the primary challenges for urologists is the potential for under-grading of Gleason 6 prostate cancer due to biopsy sampling error; as a result, up to 90% of men with a Gleason 6 prostate cancer still proceed to prostate cancer treatment despite the advent of active surveillance programs. Approximately 66% of patients who are diagnosed with Gleason 6 disease at biopsy will be confirmed to have Gleason 6 cancer after radical prostatectomy.⁶ Some of these men are considered to have undergone overtreatment, because Gleason 6 cancer is not considered life threatening.⁷ This subset of men has the potential for developing complications following surgery, including erectile dysfunction, urinary incontinence, and changes in health-related quality of life with disruption of psychologic, sexual, and urinary function.^8–12The prostate biopsy procedure is invasive, and has significant costs and complications such as bleeding, urinary retention, and life-threatening infection. A recent population-based study from Ontario, Canada, revealed a fourfold increase to 4.1% for the rate of hospital admissions after prostate biopsy from 1996 to 2005, with 72% of admissions due to infection.¹³ These risks, combined with the anxiety involved in undergoing the procedure, present a significant burden to any man considering prostate cancer screening.The impact of the USPSTF has been a decrease in overall biopsy rates with a subsequent decline in the detection rate of Gleason 7 to 10 high-grade prostate cancers.¹⁴ The elimination of PSA screening means that the 20% to 30% of men who would have presented with an abnormal PSA level and been found to have high-grade prostate cancer may lose an opportunity for a possible cure.¹⁵ Clearly, there is a need for better risk-stratification tools for men presenting with an abnormal PSA level and/or digital rectal examination (DRE) result in order to both reduce the number of prostate biopsies performed and decrease the rate of Gleason 6 diagnosis and treatment.⁶The 4Kscore® Test (OPKO Diagnostics, LLC) incorporates measured blood levels of four kallikrein proteins: total PSA, free PSA, intact PSA, and human kallikrein 2 plus clinical information (age, DRE findings, and a history of prior negative biopsy result) into a proprietary algorithm to calculate an individual man’s percentage risk (< 1% to > 95%) of having Gleason score ≥ 7 if a prostate biopsy were to be performed. The 4Kscore Test has been extensively validated through a total of 12 prospective and retrospective studies published in peer-reviewed journals involving over 22,000 patients from both the United States and Europe.^16–23 These studies of men with elevated PSA levels involved cohorts of unscreened and screened men, and those with negative prior prostate biopsy results. Based on analyses published in these studies, the 4Kscore Test would have theoretically resulted in a 45% reduction in prostate biopsies while delaying the diagnosis of aggressive prostate cancer in only a few men (1.3%–4.7%).The 4Kscore Test is used to accurately determine percentage risk for aggressive prostate cancer (Gleason score ≥ 7) and provide additional information for men being considered for prostate biopsy because of abnormal PSA levels and/or DRE results. This allows urologists to better risk stratify men for biopsy and ultimately results in more selective treatment of those men with aggressive disease. Conversely, those men not harboring life-threatening disease are able to safely avoid prostate biopsy and overtreatment of indolent disease.With the introduction of any new diagnostic test such as the 4Kscore Test into clinical practice, it is important to assess whether its implementation, in this case as a follow-up test for an abnormal PSA and/or DRE result, influences and changes the physician-patient shared decision-making process and leads to an actual reduction in prostate biopsies. Herein we evaluated the influence of the 4Kscore Test on urologist-patient decisions about proceeding with biopsy in men who have an abnormal PSA and/or DRE result from multiple academic and community urology clinical practices in the United States.     

Prostate cancer association studies: pitfalls and solutions to cancer misclassification in the PSA era

Widespread screening of American men for elevated PSA has changed the characteristics of prostate cancer cases in the U.S. The influence of the changed nature of prostate cancer cases in the PSA era and the need for careful consideration of who is a "case" and who is a "control" on the ability to detect associations of risk factors with prostate cancer in etiologic epidemiologic studies merits discussion. Issue 1: prostate cancer cases diagnosed in the PSA era are enriched with a pool of early lesions, which may differ in etiology, and are deficient in advanced lesions, which are the most likely to be the product of promotion and progression events. By admixing the two types of cases (i.e., imperfect specificity), the associations previously detected using epidemiologic designs when the majority of cases were clinically detected may no longer be apparent in the PSA era when the majority of cases are now detected in the pre-clinical phase. Researchers must now tailor hypotheses such that they are testable using early stage cases or specifically augment the number of advanced cases when testing hypotheses related to extraprostatic growth and progression. Issue 2: even when controls are screened for elevated PSA to rule out the presence of prostate cancer, some proportion of those controls currently will have one or more foci of prostate cancer. The imperfect sensitivity of the PSA test coupled with diagnostic work-up may in part result from (a) lack of PSA elevation in some men with prostate cancer or (b) failure of biopsy to sample the tumor focus in men with elevated PSA. Misclassification of men with undetected prostate cancer as controls usually produces a bias that tends to deflate associations. Given this type of disease misclassification, whether an association still can be statistically detected depends on the extent of misclassification, the magnitude of the true association, the prevalence of the exposure in the true controls, and the sample size, although in general moderate nondifferential misclassification does not lead to profound attenuation. However, under the same scenario attenuation does not occur in cohort or case-cohort studies in which the rate or risk ratio (RR) is calculated. That prostate cancer cases diagnosed in the PSA era are enriched with early stage, minimally invasive disease in our opinion is likely to pose a far more serious obstacle to epidemiologic research on the etiology of clinically important prostate cancer than the issue of inclusion as controls some men who have undiagnosed prostate cancer because of imperfect sensitivity of PSA screening and biopsy sampling error.     

Predictors of random sextant biopsy outcome in screened men with PSA > 4 ng/mL and a negative sextant biopsy at previous screening. Experience in a population-based screening program in Florence

The aim of this study was to evaluate possible pedictors of the outcome of repeat random sextant biopsy of the prostate prompted by a rise in prostate-specific antigen (PSA). Random biopsies performed for PSA elevation (>4 ng/mL) in the course of a randomized study of screening efficacy were reviewed, and 87 consecutive biopsies (carcinoma = 13, high-grade prostatic intraepithelial neoplasia = 6, negative = 68) performed in subjects with a negative random biopsy at the previous screening round were considered. Findings at digital rectal examination or transrectal ultrasonography and total PSA value were not useful predictors of repeat biopsy outcome, whereas PSA velocity was significantly associated with biopsy outcome. The positive predictive value for a cancer biopsy was 2.7% (1/36), 28.5% (2/7), and 22.7% (10/44) for PSA velocity values of <0.1, 0.1-0.19, and >0.19 ng/mL/yr, respectively. A cutoff of 0.1 ng/mL/yr for PSA velocity would have allowed to avoid approximately half (35/74 = 47.2%) of the benign biopsies while decreasing the sensitivity by 7.6% (1/13), and is thus suggested as a possible criterion for the indication of repeat random biopsy for persistent PSA elevation.     

Predicting prostate biopsy outcome by findings at digital rectal examination, transrectal ultrasonography, PSA, PSA density and free-to-total PSA ratio in a population-based screening setting

The study offers a retrospective analysis of the positive predictive value (PPV) of several variables, i.e. digital rectal examination (DRE), transrectal ultrasonography (TRUS), PSA value, PSA density (PSAD), and free/total PSA ratio (F/T), for the histologic outcome of 179 prostate biopsies performed within a population-based screening trial. The ratio of spared benign biopsies to missed cancers (SBB/MC) if biopsy results had been decided on the basis of single variables was also evaluated. PPV was 82.9% for DRE, 56.3% for TRUS, 26.6% for PSA (cutoff > or =4 ng/mL), 47.4% for PSA (cutoff > or =10 ng/mL), 42.0% for PSAD (cutoff 0.15), 59.2% for PSAD (cutoff 0.20), 34.9% for F/T (cutoff 0.20) and 40.0% for F/T (cutoff 0.15). SBB/MC was 121/23 for DRE, 96/12 for TRUS, 11/10 for PSA (cutoff > or =4 ng/mL), 107/34 for PSA (cutoff > or =10 ng/mL), 87/23 for PSAD (cutoff 0.15), 109/26 for PSAD (cutoff 0.20), 45/8 for F/T (cutoff 0.20) and 70/14 for F/T (cutoff 0.15). Multivariate analysis of the association with biopsy outcome showed the highest odds ratio for TRUS (13.24, 95% CI=4.4-30.7), and considerably lower values for DRE (4.17, 95% CI=2.0-8-9), PSAD (cutoff 0.20: 3.24, 95% CI=-1.8-5.7) and F/T (cutoff <0.15: 3.16, 95% CI=1.7-1.8). None of the possible variable combinations was clinically useful: the highest PPV (83.3%) was obtained with a combination of suspicious DRE/TRUS, PSAD >0.20 and F/T <0.15, which nevertheless missed 20 of 52 cancers.     

Optimisation de l’utilisation du PSA

PSA is a tumor marker usually determined for prostate cancer at diagnosis for its pronostic value and at therapy follow-up. But lack of specificity of PSA for prostate cancer and variability between assays demonstrated by the quality program survey make this marker not valuable in mass screening program. Market control of Afssaps on analysis devices of PSA showed a correct harmonization for total PSA. Biological tools available and easy to perform could improve ability of PSA for early detection of prostate cancer at a curable stage without induction of unnecessary biopsies prescribed because elevated total PSA values.     

Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice

Orthotopic human prostate tumour models in athymic nude mice are regarded as being most suitable for fundamental and pre-clinical research on prostate cancer. The anatomic localization of the tumour in the pelvis, however, provides little possibility for monitoring tumour growth or regression. To assess time-related changes in orthotopic tumour volume, we applied transrectal ultrasonography (TRUS) to the murine prostate. This technique has the advantages of allowing accurate monitoring of tumours during therapeutic manipulations and a reduction of animal use due to a reduction of sacrificing endpoints. To validate the TRUS method, the mouse prostate reconstitution model, RM-9, and the prostate-specific antigen (PSA) producing human prostate cancer xenograft PC-346 were used. Volumetric calliper measurements were performed with a 30 MHz ultrasound probe designed for intra-arterial use in humans. Tumour weight, determined at various time-points, was found to be closely related to actual tumour weight (R = 0.99) and, in the PC-346 model, to the level of PSA in the plasma. Furthermore, the interobserver variation for TRUS was low for tumours above 50 mg. Thus, TRUS for murine prostate tumours proves to be an accurate, reproducible and sensitive method.     

UNINFORMED CONSENT: MASS SCREENING FOR PROSTATE CANCER

While medicine may agree in principle that cancer screening requires informed consent, such consent is not, in fact, common practice. In the case of prostate‐cancer screening this means that men in large numbers undergo PSA testing with little understanding of its liabilities – in particular, that it may or may not decrease mortality, often detects cancer of questionable significance, and may lead to unnecessary surgery. Given that prostate cancer is known to be overtreated and that family history is a risk factor, it follows that a man diagnosed with prostate cancer, even if it is of no clinical significance, automatically promotes his son into the high‐risk category; and given that those so categorized are subject to heightened medical surveillance and that the more diligently medicine searches for prostate cancer the more likely it is to find it, it follows that the sons of men diagnosed as a result of PSA testing are at risk of being overdiagnosed (and overtreated) precisely because their father was. Twenty years into the PSA revolution, its generational consequences have not been discussed in the medical literature.     

Newer potential biomarkers in prostate cancer

Prostate-specific antigen (PSA) screening has led to a significant rise in the number of men diagnosed with prostate cancer and an associated increase in biopsies performed. Despite its limitations, including a positive predictive value of only 25%-40%, PSA remains the only generally accepted biomarker for prostate cancer. There is a need for better tools to not only identify men with prostate cancer, but also to recognize those with potentially lethal disease who will benefit from intervention. A great deal of work has been done worldwide to improve our knowledge of the genetics behind prostate cancer and the specificity of PSA by developing assays for different PSA isoforms. Common genetic alterations in prostate cancer patients have been identified, including CpG hypermethylation of GSPT1 and TMPRSS2:ERG gene fusion. Serum and urine detection of RNA biomarkers (eg, PCA3) and prostate cancer tissue protein antibodies (eg, EPCA) are being evaluated for detection and prognostic tools. This article reviews some of the promising developments in biomarkers.     

Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice

A specific marker for early prostate cancer would fill an important void. In initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-à-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise. At the cellular level, PCA3 specificity for cancer is nearly perfect because of the gross overexpression of the gene by cancer cells. As a clinical test for early prostate cancer, heightened specificity is also seen in urine containing prostate cells from men with the disease. PCA3 gene testing holds valuable potential in PSA quandary situations: (1) men with elevated PSA levels but no cancer on initial biopsy; (2) men found to have cancer despite normal levels of PSA; (3) men with PSA elevations associated with varying degrees of prostatitis; and (4) men undergoing active surveillance for presumed microfocal disease.     

Prostate-specific antigen levels among cirrhotic patients

PURPOSE: The aim of this study was to determine serum prostate-specific antigen (PSA) levels in patients with liver cirrhosis. PATIENTS AND METHODS: Between January 1995 and August 2001, 216 men with cirrhosis were evaluated. The extent of their liver disease was classified according to the Child-Pugh classification. Serum PSA levels were measured with the Hybritech Tandem-R RIA method and matched with age-related reference PSA levels. Digital rectal examination (DRE) was performed in all patients. Patients with elevated PSA levels and/or abnormal DRE were recommended to undergo further assessment including transrectal ultrasonography (TRUS) and biopsy performed by an urologist. RESULTS: Two hundred and sixteen men (mean age 54.09 +/- 9.09 years, range 25-76) with cirrhosis were examined. Their mean PSA value was 0.57 +/- 0.84 ng/mL and tended to be lower than in the normal population. The degree of PSA decrease was found to parallel the severity of the liver disease (p=0.002). The mean serum PSA level increased with each age decade in a statistically significant manner (p<0.001). Four patients (three with elevated PSA values) underwent prostate biopsy. Three biopsies were positive for prostate cancer, the other showed evidence of benign prostatic hyperplasia (BPH). CONCLUSION: Serum PSA is influenced by the severity of liver disease and its levels tend to be lower in cirrhotic patients than in the normal population. However, serum PSA can still be considered a reliable marker in the clinical management of prostatic disease in patients with cirrhosis.     

An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs

Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.     

Finding the Wolf in Sheep’s Clothing: The 4Kscore Is a Novel Blood Test That Can Accurately Identify the Risk of Aggressive Prostate Cancer

Better biomarkers that can discriminate between aggressive and indolent phenotypes of prostate cancer are urgently needed. In the first 20 years of the prostate-specific antigen (PSA) era, screening for prostate cancer has successfully reduced prostate cancer mortality, but has led to significant problems with overdiagnosis and overtreatment. As a result, many men are subjected to unnecessary prostate biopsies and overtreatment of indolent cancer in order to save one man from dying of prostate cancer. A novel blood test known as the 4Kscore® Test (OPKO Lab, Nashville, TN) incorporates a panel of four kallikrein protein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2) and other clinical information in an algorithm that provides a percent risk for a high-grade (Gleason score ≥ 7) cancer on biopsy. In 10 peer-reviewed publications, the four kallikrein biomarkers and algorithm of the 4Kscore Test have been shown to improve the prediction not only of biopsy histopathology, but also surgical pathology and occurrence of aggressive, metastatic disease. Recently, a blinded prospective trial of the 4Kscore Test was conducted across the United States among 1012 men. The 4Kscore Test replicated previous European results showing accuracy in predicting biopsy outcome of Gleason score ≥ 7. In a recent case-control study nested within a population-based cohort from Västerbotten, Sweden, the four kallikrein biomarkers of the 4Kscore Test also predicted the risk for aggressive prostate cancer that metastasized within 20 years after the test was administered. These results indicate that men with an abnormal PSA or digital rectal examination result, and for whom an initial or repeat prostate biopsy is being considered, would benefit from a reflex 4Kscore Test to add important information to the clinical decision-making process. A high-risk 4Kscore Test result may be used to select men with a high probability of aggressive prostate cancer who would benefit from a biopsy of the prostate to prevent an adverse and potentially lethal outcome from prostate cancer. Men with a low 4Kscore Test result may safely defer biopsy.Key words: Prostate cancer, Biomarker, High-grade prostate cancer, ScreeningProstate cancer is the most common cancer in men in the United States, accounting for an estimated 27% of all newly diagnosed cancers in 2014.¹ Since the advent of screening for prostate cancer with serum prostate-specific antigen (PSA), we have seen a significant decline in prostate cancer mortality.¹ Randomized clinical trials have reported a 20% to 40% reduction in death from prostate cancer in men undergoing routine screening compared with those who are not screened.^2,3 However, these trials, and a trial showing little difference between opportunistic and systematic screening,⁴ have raised the concern for overdiagnosis and overtreatment of indolent prostate cancer. The fundamental concern is that an overwhelming number of men are subjected to interventions such as prostate biopsy in order to prevent one man’s death from prostate cancer.^2,3Prostate biopsy is an invasive procedure with significant complications, such as bleeding, urinary retention, and life-threatening infection. A recent population-based study from Ontario, Canada, revealed a fourfold increase to 4.1% for the rate of hospital admissions after prostate biopsy from 1996 to 2005, with 72% of admissions being due to infection.⁵ These risks, combined with the enormous anxiety involved in undergoing the procedure, present a significant burden to any man considering prostate cancer screening.Today, most men diagnosed with prostate cancer have a tumor that is unlikely to pose a threat to their life expectancies. A recent systematic analysis suggested that up to 60% of prostate cancers diagnosed in contemporary studies can be safely observed without a need for immediate intervention.⁶ However, in the United States, because of the concern for possible undergrading of prostate cancer due to biopsy sampling error, 90% of men diagnosed with prostate cancer undergo treatment and approximately 66% will be confirmed to have indolent Gleason score 6 prostate cancer,⁷ suggesting a significant problem with overtreatment. Although treatment for localized prostate cancer provides excellent cancer control,^8,9 it comes at a significant detriment to health-related quality of life (HRQoL). Previous studies have reported significant changes in HRQoL after primary treatment for prostate cancer, primarily in the domains of sexual and urinary function and bother.^10–12 Given the physical and psychological burden of these secondary adverse events, many government agencies and patients are beginning to question the risks and benefits of prostate cancer screening and treatment.¹³The United States Preventive Services Task Force recently advised against routine screening for prostate cancer, claiming that the risks of screening outweigh the benefits.¹³ However, 20% to 30% of men who are diagnosed with prostate cancer are found to have high-grade disease at presentation¹⁴; without screening, these men would lose their opportunity for cure. It is clear that new biomarkers or tests that promote the detection of both indolent and aggressive prostate cancer are unlikely to be helpful. We need tests that focus on the detection of aggressive tumors, not the indolent ones that are better left alone. Aggressive prostate cancer, for purposes of this review, is defined as cancer with a Gleason score ≥ 7 and tumors that are most likely to progress to metastatic disease and death. Targeted detection of aggressive prostate cancer would allow urologists to diagnose and treat those men most likely to benefit from aggressive intervention to avoid premature death. Conversely, those men harboring non-life-threatening disease would be able to avoid unnecessary interventions. The 4Kscore® Test (OPKO Lab, Nashville, TN) is a new blood test that accurately identifies the risk of aggressive prostate cancer. The 4Kscore Test plays an important clinical role as a reflex test prior to proceeding with initial prostate biopsy in men with an elevated PSA level or abnormal digital rectal examination (DRE) results, or after a prior negative biopsy and persistently abnormal PSA levels.     

Cancer de la prostate : les marqueurs biologiques

Normal prostate cells and prostate cancer cells produce prostate-specific antigen (PSA): thus, it is frequently increased in non-malignant conditions such as prostatitis and benign prostatic hyperplasia. Indeed, PSA is an excellent biomarker to monitor disease progression. The low diagnostic specificity of PSA leads to many false-positive and a large number of biopsies. These well-recognized limitations of PSA suggest that new prostate cancer biomarkers could play a useful role in reducing the number of unnecessary biopsies.     

前列腺特异性抗原在前列腺癌诊断中的应用进展

已经证明,前列腺特异性抗原（PSA）是一种有价值的前列腺癌（PCa)肿瘤标记物,血清PSA的广泛使用提高了前列腺癌的检出率,使晚期癌患得明显减少。然而,PSA对PCa的检测缺乏特异性,由于其高的假阳性率,引起许多不必要的活检。为了提高PSA对PCa诊断的特异性,降低不必要的活检,众多学正在探讨与PSA相关的几项参数的临床应用价值,本就此作一综述。     

Trends in Prostate Specific Antigen (PSA) testing and prostate cancer incidence and mortality in Australia: A critical analysis

BackgroundPopulation trends in PSA testing and prostate cancer incidence do not perfectly correspond. We aimed to better understand relationships between trends in PSA testing, prostate cancer incidence and mortality in Australia and factors that influence them.MethodsWe calculated and described standardised time trends in PSA tests, prostate biopsies, treatment of benign prostatic hypertrophy (BPH) and prostate cancer incidence and mortality in Australia in men aged 45–74, 75–84, and 85 + years.ResultsPSA testing increased from its introduction in 1989 to a peak in 2008 before declining in men aged 45–84 years. Prostate biopsies and cancer incidence fell from 1995 to 2000 in parallel with decrease in trans-urethral resections of the prostate (TURP) and, latterly, changes in pharmaceutical management of BPH. After 2000, changes in biopsies and incidence paralleled changes in PSA screening in men 45–84 years, while in men ≥85 years biopsy rates stabilised, and incidence fell. Prostate cancer mortality in men aged 45–74 years remained low throughout. Mortality in men 75–84 years gradually increased until mid 1990s, then gradually decreased. Mortality in men ≥ 85 years increased until mid 1990s, then stabilised.ConclusionAge specific prostate cancer incidence largely mirrors PSA testing rates. Most deviation from this pattern may be explained by less use of TURP in management of BPH and consequent less incidental cancer detection in TURP tissue specimens. Mortality from prostate cancer initially rose and then fell below what it was when PSA testing began. Its initial rise and fall may be explained by a possible initial tendency to over-attribute deaths of uncertain cause in older men with a diagnosis of prostate cancer to prostate cancer. Decreases in mortality rates were many fold smaller than the increases in incidence, suggesting substantial overdiagnosis of prostate cancer after introduction of PSA testing.