Optimizing prostate biopsy.

Prostate biopsy (PBx) techniques have changed significantly since the original Hodge's scheme. Although the use of transrectal ultrasound (TRUS) guided (PBx) is considered the gold standard for the diagnosis of prostate cancer (Pca), the strategies for initial and repeat biopsies remain controversial. Even with the widespread application of extended prostate biopsy (ePBx) protocols, the false negative rate remains substantial and early PCa detection remains limited. Optimization of the PBx procedures reduce the likelihood of facing a "repeat biopsy dilemma". The aim of this review is to provide an evidence-based update on current methods of PBx and discuss the strategies to optimise biopsy procedures.

Detecting prostate cancer by intracellular macrophage prostate-specific antigen (PSA): a more specific and sensitive marker than conventional serum total PSA.

BACKGROUND: Serum prostate-specific antigen (PSA) is a standard method and a widely used marker for prostate cancer, but it has a poor specificity for early detection. Herein we demonstrate that intracellular macrophage PSA (imPSA) enables screening and differentiation between benign and malignant prostate disease. MATERIALS AND METHODS: The efficacy of intracellular macrophage PSA in circulating and tissue macrophages was therefore investigated in a double-centre study of 38 prostate cancer patients and 36 healthy controls by fluorescent-activated cell sorting analysis and immunohistology. RESULTS: Both methods uncovered the existence of PSA-positive macrophages specific for patients with prostate cancer. In addition, we demonstrate the superiority of our new test over standard serum total PSA in a blinded double-centre trial. ImPSA had a marked higher sensitivity and specificity than serum total PSA (imPSA: sensitivity 92%, specificity 92%, positive predictive value 92%; serum total PSA: sensitivity 79.5%, specificity 87.5%, positive predictive value 26.8%). CONCLUSION: In this study, we demonstrate that imPSA is a new prostate cancer screening method that is highly sensitive and more specific than standard PSA testing.

Biomarkers for early prostate cancer detection.

In the 1990s the discovery of prostate-specific antigen (PSA) revolutionized early prostate cancer detection. Since that time, PSA has become an indispensable marker for diagnosis and follow up of prostate cancer patients. Despite its remarkable performance, PSA is not cancer specific. High PSA levels are found in both cancerous and healthy tissue, particularly in benign prostate disease, resulting in significant numbers of false positive cases. Hence, there is a need for new markers that better differentiate benign from malignant lesions and indolent from aggressive cancers to decrease the potential over treatment of prostate cancer. With recent advances in biotechnology, many promising blood biomarkers have been identified and are currently under investigation. This article reviewed the literature searching for emerging biomarkers for early prostate cancer detection.

[Artificial neural networks for decision making in urologic oncology]. / Réseaux neuronaux artificiels pour la prise de décision en cancérologie urologique.

This chapter presents a detailed introduction regarding Artificial Neural Networks (ANNs) and their contribution to modern Urologic Oncology. It includes a description of ANNs methodology and points out the differences between Artifical Intelligence and traditional statistic models in terms of usefulness for patients and clinicians, and its advantages over current statistical analysis.

[Biological markers of prostate cancer]. / Marqueurs biologiques du cancer de la prostate.

Screening for prostate cancer is currently based on the assessment of blood prostate specific antigen (PSA). Although PSA was shown to be an adequate tool in prostate cancer screening, beginning from 4.0 ng/mL, its specificity is less significant. In men with a PSA between 4.0 and 10 ng/mL its predictive value is low. Therefore, there is a need for new instruments likely to improve the specificity of blood PSA levels between 4.0 and 10 ng/mL and the screening for prostate cancer in subjects with low PSA. Recent data are reviewed.

[Prostate cancer in the elderly patient]. / Cancer de la prostate du sujet âgé.

Although malignant tumours occur at all ages, cancer disproportionately strikes individuals in the age group 65 years and older. The increasing statistical life expectancy of men together with the introduction of prostate specific antigen (PSA) as a screening tool have both contributed to a rising number of elderly men with a diagnosis of prostate cancer. Age is generally considered to be a key prognostic factor in terms of therapeutic decision making, perhaps as important as PSA level and Gleason score. Even in men over 70 years, treatment without curative intent may deprive frail patients of years of life. When considering local treatment, strong consideration should be given to radical surgery. Modern radical prostatectomy is associated with low perioperative morbidity, excellent clinical outcomes as well as long term disease control. Besides, overdiagnosis has led to the concept of expectant management for screening-detected small-volume, low grade disease, with intention of providing therapy for those men experiencing disease progression.

Postradical prostatectomy TRUS-guided anastomotic biopsy. Where do we stand today?

The issue of performing tissue sampling from the vesicourethral anastomotic area postradical prostatectomy (transrectal ultrasound-guided biopsy) after radical surgical treatment of local disease has failed, still remains controversial. We review a selection of articles that evaluate this procedure as well as newer diagnostic modalities and we discuss how this technique may have a position in our treatment dilemmas in cases with biochemical failure of undetermined origin.

[Chemoprevention of prostate cancer]. / Chemoprävention des Prostatakarzinoms.

Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, i.e., the administration of agents that inhibit one or more steps in the natural course of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. A variety of chemoprevention studies have focused on the role of dietary factors, vitamins, and trace elements in prostate cancer. Some of these studies have been prospective, randomized, and double-blinded, while others have used retrospective or epidemiological approaches. Large-scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from two studies, one examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5a-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.

Can total and transition zone volume of the prostate determine whether to perform a repeat biopsy?

OBJECTIVES: To compare the ability of total prostate (TP) and transition zone (TZ) volume to predict the outcome of a repeat prostate biopsy in patients with serum prostate-specific antigen (PSA) levels of 4 to 10 ng/mL. METHODS: A total of 1137 patients were included and underwent transrectal ultrasound-guided needle sextant and two transition zone biopsies of the prostate. All patients with a prior negative biopsy (benign prostatic tissue) underwent a repeat biopsy after 6 weeks. The TP and TZ volumes of the prostate were measured by transrectal ultrasonography. RESULTS: Of the 1137 patients, prostate cancer was diagnosed in 364 (32%), in 276 (24.2%) after the first biopsy and in 88 (7.7%) after the repeated biopsy. The TP and TZ volumes were larger in the patients with prostate cancer detected on the repeated biopsy (P <0.0001). Using a cutoff for TP volume of less than 20 cm3 and greater than 80 cm3 and for TZ volume of less than 9 cm3 and greater than 41 cm3 would have spared 7.1% and 10% of repeated biopsies, respectively. CONCLUSIONS: The probability for a positive repeat prostate biopsy increases in a logarithmic function for larger prostates, as well as for larger TP and, especially, for larger TZ volumes. The probability of finding prostate cancer on a repeat biopsy in prostates with small (less than 20 cm3) and large (greater than 79 cm3) TP, as well as in small (less than 9.3 cm3) and large (greater than 41 cm3) TZ volumes, was very low. Therefore, a repeat prostate biopsy within 6 weeks is unnecessary. These patients should be followed up by serial PSA determination.

Heat versus drugs in the treatment of benign prostatic hyperplasia.

The improvement in symptoms and voiding function is greater with transurethral microwave thermotherapy than with drug therapy, and the associated morbidity is low. Transient urinary retention necessitating catheterization is of short duration after targeted microwave thermotherapy. The short-term effect of microwave thermotherapy can be improved by neoadjuvant and adjuvant alpha-blockade. Microwave treatment offers greater versatility than drug therapy, allowing patients with severe baseline symptoms and small prostates to be treated successfully. Medical management improves symptoms to a more modest extent than does microwave treatment. Finasteride gives comparatively small symptom and flow rate improvements and requires several months for the maximum responses. With alpha-blockers the onset of action is fast and side-effects reversible, although they limit their utility. Finasteride or alpha-blockers must be continued indefinitely to maintain improvements in patients with BPH, but they have a favourable safety and tolerability profile.

Prostate biopsy.

Transrectal ultrasound guided (TRUS) prostate biopsies is the standard method in the diagnosis of prostate cancer. The use of prostate specific antigen (PSA) and digital rectal examination for prostate cancer screening has led to a dramatic increase in the number of TRUS guided biopsies. Frequently urologists are faced with the dilemma of treating a patient with a high suspicion of prostate cancer, but an initial set of negative biopsies. In this review we focus on the current knowledge of prostate biopsies, the indication to perform a biopsy, the impact of prostate volume in the number of cores taken, the technique of an initial and repeat biopsies and when to stop.

[Androgen substitution in men from the urologic point of view]. / Androgensubstitution des Mannes aus der Sicht des Urologen.

Androgen substitution has been intensively debated due to major concerns with respect to unknown interactions with prostate cancer initiation and progression. Certainly, androgen substitution should be considered in men with symptomatic hypogonadism (< 1% of men) in whom prostate cancer has been excluded. Serum PSA values should not exceed the currently employed age specific reference values (40-50 years: 2.5 ng/ml, 50-60 years: 3.5 ng/ml, 60-70 years: 4.5 ng/ml and over 70 years: 6.5 ng/ml). A family history of prostate cancer and/or prostatic intraepithelial neoplasia (PIN) should be considered as relative contraindications. If androgen substitution is to be initiated, serum PSA should be monitored at 3 month intervals including digital rectal examinations (DRE). In case of abnormal results (PSA and/or DRE) substitution therapy should be terminated and random prostate biopsies performed. In addition, major issues regarding the optimal substitution pathway (transdermal versus intramuscular versus implants versus oral) remain unclarified and require further investigation. Furthermore, little is known about the precise type and dosage of androgens to be substituted. Lastly, only 10%-18% of men with hypogonadism are symptomatic, reducing the number of patients in whom substitution therapy may be an option significantly. Although substitution therapy is valuable in selected men, unclear issues related to prostate cancer initiation and progression, timing, type and dosage of androgen substitution raise major concerns and need further investigation. Meanwhile patients need to be counselled and advantages balanced against disadvantages, side effects and potential risks.

The urologist view of BPH progression: results of an international survey.

OBJECTIVES: To assess the opinion amongst the international urological community on whether benign prostatic hyperplasia (BPH) is a progressive disease. METHODS: A 15-item questionnaire was distributed to the mailing list of the publication European Urology Today as well as being accessed through the website of the European Association of Urology (EAU). The survey included questions on: whether BPH was a progressive disorder; what evidence there was to support this, including clinical parameters that could be identified; risk factors for progression; and prevention of progression. RESULTS: A total of 472 completed questionnaires from 47 countries were evaluated. Overall, the urologists surveyed agreed that BPH was a progressive disease, and that some patients were more prone to this than others. Increased post-void residual urine, reduced flow rate, increased urinary symptoms and urodynamic evidence of obstruction were considered to be the most significant risk factors for progression. Half of the urologists surveyed considered that current medical therapies could prevent progression of BPH, while a significant proportion thought that surgery was an effective preventative measure. CONCLUSIONS: BPH, although a benign disease, has a considerable impact on the patient's quality of life. Its progressive nature and the identification of risk factors for progression warrant further investigation. In the future, there is likely to be a shift in the paradigm from treatment of BPH complications to include the prevention of BPH progression.

Morbidity of transrectal ultrasound-guided prostate needle biopsy in patients receiving immunosuppression.

OBJECTIVES: To prospectively evaluate the safety and early and delayed morbidity of transrectal ultrasound-guided needle biopsies in patients receiving immunosuppressive therapy. METHODS: A total of 59 men receiving immunosuppressive agents after kidney transplantation, with a total prostate-specific antigen level between 4 and 10 ng/mL, were prospectively studied. All patients underwent transrectal ultrasound (TRUS)-guided sextant biopsy plus two additional transition zone biopsies. Biopsy samples were also obtained from suspicious areas identified during TRUS and digital rectal examination. The immediate and delayed morbidity, patient satisfaction, and complication rates were recorded and compared with the morbidity data recorded in the same period from 1051 men in the European Prostate Cancer Detection study. RESULTS: Of the 59 subjects, prostate cancer was detected in 17; 231 men were found to have cancer in the European Prostate Cancer Detection Study. Minor or no discomfort was observed in 88% and 92% of the transplant recipients and controls, respectively (P = 0.31). Twelve percent versus 8% experienced pain. Early morbidity included rectal bleeding (2.6% versus 2.1%, P = 0.19), severe hematuria (0.8% versus 0.7%, P = 0.08), and moderate to severe vasovagal episodes (1.9% versus 2.8%, P = 0.04). Late morbidity included fever (3.5% versus 2.9%, P = 0.1), hematospermia (11.0% versus 9.8%, P = 0.1), recurrent mild hematuria (17.4% versus 16.8%, P = 0.08), persistent dysuria (6.4% versus 7.2%, P = 0.2), and urinary tract infections (12.0% versus 10.9%, P = 0.08). Major complications were rare: urosepsis (0% versus 0.1%). CONCLUSIONS: The results of our study demonstrate that TRUS-guided biopsy of the prostate is generally well tolerated, with minor morbidity, in patients receiving immunosuppression. No differences were noted in pain apprehension or early and delayed morbidity, suggesting that TRUS-guided biopsies can be performed safely in these patients.

Human accessory cells activate fresh, normal, tumor-distant T lymphocytes but not tumor-infiltrating T lymphocytes to lyse autologous tumor cells in a primary cytotoxic T lymphocyte assay in renal cell carcinoma.

OBJECTIVES: Search for an ideal responder T-lymphocyte source for adoptive T-lymphocyte therapy in renal cell carcinoma (RCC). METHODS: Cytotoxic T-lymphocyte (CTL) activity of (a) normal, tumor-distant, renal T lymphocytes, (b) tumor-infiltrating T lymphocytes and (c) peripheral blood T lymphocytes against autologous tumor epithelial cells (EC) of 10 patients with organ-confined, primary RCC was analyzed in a primary CTL assay. Freshly enriched T lymphocytes were cultured with or without autologous, mitomycin-C-treated normal or tumor EC in the presence or absence of antigen-presenting cells (APC) for 7 days. RESULTS: Both tissue T-lymphocyte populations displayed a similar CD4:CD8 ratio (1:1). Elevated CD62L coexpression of CD4+ T lymphocytes in normal, tumor-distant, renal tissue resulted in a significantly higher transient T-cell activation than that seen in renal tumor tissue (46 vs. 27%; p = 0.002). All trials to induce significant lysis of autologous, renal tumor EC in tumor-infiltrating and peripheral blood T lymphocytes failed. Only when normal, tumor-distant, renal T lymphocytes were stimulated by autologous APC and tumor EC was significant autologous tumor EC lysis obtained (mean 14%; p<0.05). Costimulation by anti-CD3 (mean 21%; p<0.05) or interleukin-2 (mean 31%; p<0.05) further increased tumor EC lysis significantly. CONCLUSIONS: Increased turnover of T lymphocytes in normal, tumor-distant, renal tissue was associated with a higher yield of pre-CTL which can be transformed into a functionally active effector T-cell pool by stimulation via antigen plus APC. Thus, tumor-distant renal tissue has to be included in the tissue-sampling procedure for adoptive immunotherapy.

Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop?

PURPOSE: We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. MATERIALS AND METHODS: In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS: Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p = 0.009) and cancer location (p = 0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p = 0.2), Gleason score (p = 0.3), percent Gleason grade 4/5 (p = 0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p = 0.001 and 0.001), lower rate of grade 4/5 (p = 0.02), and lower volume (p = 0.001 and 0.001) and stage (p = 0.001), respectively. CONCLUSIONS: Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies 1 and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.

Insulin-like growth factors and prostate cancer.

Prostate cancer is one of the most common malignant tumors in Western countries. The etiology of prostate cancer is currently unknown, but it has been suggested that growth factor abnormalities may be involved in initiation and progression of this disease. Insulin-like growth factors (IGFs), including IGF-1 and IGF-2, are mitogenic peptides involved in the regulation of cell proliferation, differentiation and apoptosis. Studies have shown that IGFs are potent mitogens for a variety of cancer cells including prostate cancer since they stimulate cancer cell growth and suppress programmed cell death. This review outlines elements of IGF pathophysiology, reviews recent evidence that circulating IGF-1 levels are related to prostate cancer risk and discusses the clinical implications of these lines of research with respect to prevention and treatment.

Safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective European prostate cancer detection study.

PURPOSE: We prospectively evaluate the safety, morbidity and complication rates for first and repeat transrectal ultrasound guided prostate needle biopsies. MATERIALS AND METHODS: In this prospective European Prostate Cancer Detection Study 1,051 men, with total prostate specific antigen between 4 and 10 ng./ml., underwent transrectal ultrasound guided sextant biopsy plus 2 additional transition zone biopsies. Biopsy samples were also obtained from suspicious areas identified during transrectal ultrasound and digital rectal examination. All 820 patients with biopsy samples negative for prostate cancer underwent re-biopsy after 6 weeks. Immediate and delayed (range 1 to 7 days) morbidity, patient satisfaction and complication rates were recorded. RESULTS: Of the 1,051 subjects the initial biopsy was positive for prostate cancer in 231 and negative, including benign prostatic hyperplasia or benign tissue, in 820. Of these 820 patients prostate cancer was detected in 10% (83) on re-biopsy. Minor or no discomfort was observed in 92% and 89% of patients at first and re-biopsy, respectively (p = 0.29). Immediate morbidity was minor and included rectal bleeding (2.1% versus 2.4%, p = 0.13), mild hematuria (62% versus 57%, p = 0.06), severe hematuria (0.7% versus 0.5%, p = 0.09) and moderate to severe vasovagal episodes (2.8% versus 1.4%, respectively, p = 0.03). Delayed morbidity of first and re-biopsy was comprised of fever (2.9% versus 2.3%, p = 0.08), hematospermia (9.8% versus 10.2%, p = 0.1), recurrent mild hematuria (15.9% versus 16.6%, p = 0.06), persistent dysuria (7.2% versus 6.8%, p = 0.12) and urinary tract infection (10.9% versus 11.3%, respectively, p = 0.07). Major complications were rare and included urosepsis (0.1% versus 0%) and rectal bleeding that required intervention (0% versus 0.1%, respectively). Furthermore, an age dependent pattern of pain apprehension during biopsy was observed with the highest scores in patients younger than 60 years. CONCLUSIONS: Transrectal ultrasound guided biopsy is generally well tolerated with minor morbidity only rarely requiring treatment. Re-biopsy can be performed 6 weeks later with no significant difference in pain or morbidity. Patients younger than 60 years should be counseled in regard to a higher level of discomfort, and local and topical anesthesia if desired.