Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up.

BACKGROUND: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. METHODS: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. RESULTS: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963-0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929-0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956-0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980-0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947-0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. CONCLUSIONS: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.

Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer.

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.

The effects of Cernitin® on inflammatory parameters and benign prostatic hyperplasia: An in vitro study.

The pollen extract Cernitin® is widely used for treatment of benign prostatic hyperplasia (BPH) and non-bacterial chronin prostatitis. However, little is known about the underlying molecular mechanisms to explain the clinical effects of Cernitin®. In this study, we sought to investigate the cellular mechanisms by which Cernitin® induces its effects on human prostatic cell lines BPH-1 and WPMY-1 and primary human peripheral blood mononuclear cells (hPBMCs) in vitro. We examined the effects of Cernitin® formulas T60 and GBX on the protein expression, proliferation, and cytokines production. Results revealed that Cernitin® upregulated antiinflammatory cytokine interleukin (IL)-10 and its receptors IL-10RA and IL-10B in addition to the upregulation of tumour necrosis factor-related apoptosis-inducing ligand in hPBMC. Interestingly, the levels of proinflammatory cytokines IL-6 and IL-8 were also increased. Furthermore, Cernitin® had significantly increased the level of IL-10 in BPH-1 and WPMY-1 cells. The level of IL-6 was also significantly increased in these cells although both T60 and GBX inhibited STAT-3 phosphorylation. Moreover, Cernitin® formulas had significantly reduced androgen receptor and prostate-specific antigen protein expression in stromal cells (p < .05). Treatment with GBX and T60 had significantly inhibited proliferation of BPH (p < .001) and stromal cells (p < .05), in a dose-dependent manner. Taken together, treatment with Cernitin® showed to regulate cytokines level in both prostatic cell lines and hPBMCs and it was associated with decreased androgen receptor and prostate-specific antigen levels WPMY-1 cells.

Is intermittent androgen-deprivation therapy beneficial for patients with advanced prostate cancer?

Use of intermittent androgen-deprivation therapy (IADT) in patients with prostate cancer has been evaluated in several studies, in an attempt to delay the development of castration resistance and reduce side-effects associated with ADT. However it is still not clear whether survival is adversely affected in patients treated with IADT. In this review, we explore the available data in an attempt to identify the most suitable candidate patients for IADT, and discuss factors that may inform appropriate patient stratification. ADT is first-line treatment for advanced/metastatic prostate cancer and is also recommended for use with definitive radiotherapy for high-risk localised prostate cancer. The changes in hormone levels induced by ADT can lead to short- and long-term side-effects which, although treatable in most cases, can significantly reduce the tolerability of ADT treatment. IADT has been investigated in several phase II and phase III studies in patients with locally advanced or metastatic prostate cancer, in an attempt to delay time to tumour progression and reduce the side-effect burden of ADT. In selected patient groups IADT is no less effective than continuous ADT, ameliorating the impact of ADT-related side-effects, and, to a degree, their impact on patient health-related quality of life (HRQL). Further comparative study is required, particularly in relation to HRQL and long-term complications associated with ADT.

A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis.

BACKGROUND: Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. METHODS: An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. RESULTS: An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. CONCLUSIONS: The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.

Regional distribution of neuroendocrine cells in the urogenital duct system of the male rat.

BACKGROUND: Neuroendocrine (NE) cells are frequently present in the human prostate and urethra, whereas they are lacking in the other urogenital organs. This study was undertaken as there are only few detailed studies available on the distribution, form and function of NE cells and the structure of excretory ducts of the accessory sex organs in the male rat. METHODS: Systematic gross anatomical dissections were combined with immunohistochemical and electron microscopic studies of the excretory ducts of the urogenital glands in male rats, with particular focus on the distribution and ultrastructure of the NE cells. RESULTS: The topography and structure of the excretory ducts of the different glands were characterized in detail and analyzed for the distribution of NE cells. These are present (in falling frequencies) in the ducts of seminal vesicles and ventral and lateral prostate and are rare in ducts of coagulating gland, dorsal prostate, urethral epithelium, and excretory ducts of the (bulbo) urethral glands. They are absent in the respective glands proper, the deferent duct and ejaculatory ampulla. Approximately 40% of the NE cells of the ventral prostate ducts are of the "open" type, whereas these are less frequent (14%) in the seminal vesicle ducts, where the "closed" type prevails. CONCLUSIONS: NE cells are present in unequal quantities in the excretory ducts of the accessory sex glands, but they are absent in the glands proper and the deferent ducts. This distribution pattern points to a strictly localized function and differentiation potency of NE precursor cells.

Testosterone in prostate cancer: the Bethesda consensus.

OBJECTIVE: • Androgen stimulation of prostate cancer (PCa) cells has been extensively studied. The increasing trend of using serum testosterone as an absolute surrogate for castration state means that the diagnostic measurement of testosterone and the values potentially influencing prognosis must be better understood. This is especially important when PCa progresses from an endocrine to an intracrine status. PATIENTS AND METHODS: • We performed a literature review using the MEDLINE database for publications on: (i) hormonal changes with androgen deprivation therapy (ADT); (ii) monitoring hormonal therapy with testosterone measurement; (iii) the efficacy of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation; (iv) the underlying mechanisms of castration-resistance; and (v) novel treatments for castration-resistant PCa (CRPCa). RESULTS: • The optimum serum castration levels to be achieved with ADT are still debated. Recently, the 50 ng/dL threshold has been questioned because of reports indicating worse outcomes when levels between 20 and 50 ng/dL were studied. Instead, a 20 ng/dL threshold for serum testosterone after ADT in patients with advanced prostate cancer was recommended. CONCLUSION: • Understanding the mechanisms of androgen biosynthesis relating to PCa as well as prognostic implications might achieve a consensus regarding the role of ADT for both the androgen-sensitive and -insensitive disease state.

Androgen deprivation therapy and side effects: are GnRH antagonists safer?

Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function. This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not. GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques. Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.

Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients.

Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available. Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups. Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892-0.942) in the retrospective cohort (n = 520), AUC of 0.959 (95% CI 0.935-0.983) in the prospective cohort (n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort (n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1-3 cancer subgroups. Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.

HIF1alpha isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation.

BACKGROUND: Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1alpha (HIF1alpha), in both benign and malignant NE prostate cells. HIF1alpha and HIF1beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1alpha in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1alpha isoforms. METHODS: We studied the HIF1alpha isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization. RESULTS: We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1alpha1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1alpha immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1alpha present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1beta. CONCLUSION: Our results indicate that the cytoplasmic stabilization of HIF1alpha in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1alpha isoform, HIF1alpha1.2. Co-localization of this isoform with HIF1beta indicates that the HIF1alpha1.2 isoform might sequester HIF1beta in the cytoplasm.

PCA3 as a diagnostic marker for prostate cancer: a validation study on a Swedish patient population.

OBJECTIVE: Prostate cancer antigen 3 in urine (uPCA3) has been shown to perform better than total prostate-specific antigen in serum (tPSA) to predict prostate cancer (PCa) detection. The aim of this study was to validate the diagnostic precision of uPCA3 in a mixed set of patients with no previous history of PCa, including patients with previous negative biopsies. MATERIAL AND METHODS: The study included 62 men scheduled for prostate biopsy at Skåne University Hospital Malmö, Sweden. Urine samples were obtained according to the Progensa™ uPCA3 assay. Logistic regression and receiver operating characteristic curves were used to test associations between levels of biomarkers and prostate cancer. RESULTS: According to pathological examination of core needle biopsies, PCa was found in 18 out of 62 patients. A one-step increase in uPCA3 was associated with an increase in the odds of cancer of 1.026 (p = 0.005). Differences in the odds ratio between uPCA3 and tPSA were not statistically significant. A model using both markers did not increase prediction of event. Areas under the curve for uPCA3, tPSA and a model combining uPCA3 and tPSA did not differ significantly. No significant correlation was found between uPCA3 and tPSA or prostate volume. CONCLUSION: In this small set of mixed patients uPCA3 alone and tPSA performed equally well as diagnostic markers for PCa. A combination of the two markers did not improve the diagnostic performance. This study does not support a role for the uPCA3 urine test to replace or be added to tPSA in PCa detection.

Phase II study of the human anti-epithelial cell adhesion molecule antibody adecatumumab in prostate cancer patients with increasing serum levels of prostate-specific antigen after radical prostatectomy.

BACKGROUND: Rising serum levels of prostate-specific antigen (PSA) after radical prostatectomy are indicative of recurrent prostate cancer. This double-blind, placebo-controlled phase II study evaluated the anti-tumour activity of the anti-epithelial cell adhesion molecule (EpCAM) antibody adecatumumab in delaying biochemical disease progression. PATIENTS AND METHODS: Prostate cancer patients with increasing serum PSA levels following radical prostatectomy were randomized to low- (2 mg/kg) or high-dose adecatumumab (6 mg/kg) or placebo. The primary efficacy endpoint was the mean change from baseline in total serum PSA at week 24. Secondary endpoints included PSA response rate, prolongation of serum PSA doubling time and time to biochemical disease progression. RESULTS: The primary and secondary endpoints of the study were not met in the predefined analyses. In a retrospective analysis of patients with baseline PSA ≤ 1 ng/ml and a high EpCAM expression, both the mean increase in PSA from baseline to week 24 and the PSA doubling time at week 15 were significantly improved in the high-dose adecatumumab group compared with the placebo group. Most frequent treatment-related clinical adverse events were gastrointestinal (diarrhoea and nausea) or general events (chills), showing a dose dependency but no grade 3/4 intensity in any patient. CONCLUSION: In men with rising PSA levels after radical prostatectomy and no evidence of clinical relapse, adecatumumab delayed disease progression in a subgroup of patients with baseline PSA levels ≤ 1 ng/ml and high EpCAM-expressing tumours.

The expression of pluripotency marker Oct 3/4 in prostate cancer and benign prostate hyperplasia.

BACKGROUND: Oct 3/4 (Octamer 3/4), a member of POU family has been considered as an important stem cell marker and essential transcription factor during human embryogenesis. In recent years, there have also been reports on presence of Oct 3/4 in differentiated benign and malignant human cells. The objective of this study was to investigate the transcription and the protein expression of Oct 3/4 isoforms in prostate cancer and benign prostate tissue. METHODS: Thirty sex adenocarcinomas and eight cases of benign prostate hyperplasia were studied. The transcription of Oct 3/4 was analyzed using RT-PCR approach associated with restriction digestion analysis. Oct 3/4 protein expression was studied by immunohistochemistry on paraffin sections using two different antibodies. RESULTS: We identified only the transcript 2 of Oct 3/4 in prostate tumors and benign prostate hyperplasia. Immunohistochemistry verified these results, demonstrating only cytoplasmic localization of Oct 3/4. Transcription of type 1 of Oct 3/4 as well as protein expression with nuclear localization of Oct 3/4 isoform 1 were not detected. Oct 3/4 immunopositive tumors were also displayed neuroendocrine differentiation and showed androgen receptor immunopositivity. The stem cell markers CD44 and CD117 were not detected in Oct 3/4 immunopositive cells. CONCLUSION: Our results indicate that only the cytoplasmic isoform 2 of Oct 3/4 is present in prostate cancer and benign prostate hyperplasia. The malignant and benign prostate cells, which are immunopositive for variant 2 of Oct 3/4, lack other stem cell markers supporting previously published data that variant 2 of Oct 3/4 is not a pluripotency marker.

Preserving bone health in patients with hormone-sensitive prostate cancer: the role of bisphosphonates.

Men with prostate cancer initiating androgen-deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal-related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone-sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT-related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT-related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease.

Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study.

OBJECTIVE: To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5alpha-reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent. PATIENTS AND METHODS: An increasing serum prostate-specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre-dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double-blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3-24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase > or =4 weeks apart and each PSA level > or =0.2 ng/mL, and a final PSA level of > or =0.4 ng/mL (after RP) or > or =2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of < or =15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer). CONCLUSIONS ARTS: will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5alpha-reductase inhibition in prostate cancer.

Structured Population-based Prostate-specific Antigen Screening for Prostate Cancer: The European Association of Urology Position in 2019.

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55-69yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. PATIENT SUMMARY: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated.

Malignant lesions in the ventral prostate of alloxan-induced diabetic rats.

The aim of this study was to evaluate the changes caused by chronic diabetes in the rat ventral prostate and to establish a correlation between diabetes and the development of prostatic lesions. Male rats received alloxan (42 mg/kg b.w.) to induce diabetes. Ninety days after diabetes diagnosis, animals were sacrificed and the ventral prostate was removed and prepared for general and immunohistochemical analyses. The total area showing different types of lesions was estimated. Diabetes led to a decrease in the body and prostatic weights, as well as in testosterone levels. The prostate morphology and stereology showed high variation in the diabetic group. Some animals had light changes; the great majority had an intense epithelial atrophy; and other rats showed premalignant and malignant lesions in the prostate. Such epithelial atrophy was, in some samples, combined with chronic inflammation, similar to proliferative inflammatory atrophy (PIA). The diabetic group also presented high incidence of prostatitis, adenocarcinoma and prostatic intra-epithelial neoplasia (PIN). Samples with adenocarcinoma had poorly differentiated acini with high levels of cellular proliferation and nuclear atypia. These lesions exhibited an invasive feature showing Bcl-2-positive cells and interruptions in the basement membrane. An association of PIA, PIN and adenocarcinoma was detected in one sample. Reduced androgen levels have a synergic effect to insulin dysfunction promoting negative effects in the rat prostate. Diabetic individuals had a high incidence of prostatitis, and this inflammation could stimulate the incidence of other forms of prostatic pathology.

Management of advanced prostate cancer: can we improve on androgen deprivation therapy?

Gonadotrophin-releasing hormone (GnRH) agonists are currently the mainstay in the management of advanced prostate cancer. Used either as monotherapy or combined with antiandrogens, GnRH agonists suppress serum testosterone levels and thus slow the growth of the tumour cells that depend on testosterone for growth. GnRH agonists have largely replaced orchidectomy in the management of advanced prostate cancer, because patients are reluctant to undergo surgical castration. However, can we do better in androgen-deprivation therapy? There is some evidence to suggest that GnRH agonists do not achieve the level of testosterone suppression attained with orchidectomy, or as rapidly, factors which could be expected to affect overall survival. Together, these observations highlight the need to develop newer agents that can achieve rapid, profound and sustained testosterone suppression, equivalent to that with orchidectomy. Preliminary data for the GnRH blocker, degarelix, suggest that this new agent might overcome the shortcomings associated with GnRH agonists. Further clinical data are therefore awaited with much interest.

Prostate cancer and active surveillance.

This review outlines the different treatment options in localized prostate cancer. This information can be considered alongside other important factors, such as the individual patient's values and situation as well as the potential impact of treatment on his quality of life, in the treatment decision-making process. Taking all these factors into consideration, the data support active surveillance as an appropriate choice in patients with well or moderately differentiated, low-volume prostate cancer who have a life expectancy of less than 10 years. Men with higher-grade tumors and longer life expectancy may be at excess risk of death from prostate cancer managed with active surveillance.