Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes.

INTRODUCTION: Testosterone treatment has evolved rapidly over the past 25 years as new, more effective and convenient methods have become available. This study reports experience with seven different methods, introduced on the market in the UK. AIM: To establish the symptom response when testosterone treatment was initiated on the basis of clinical features and symptoms of androgen deficiency, and the resulting endocrine, biochemical and physiological responses. METHODS: Of 2693 patients attending the 3 Men's Health Centers - The UK Androgen Study (UKAS), 2247 were treated. Treatments included pellet implants, oral testosterone undecanoate (Testocaps), mesterolone (Proviron), testosterone gel (Testogel), testosterone scrotal cream (Andromen) and scrotal gel (Tostran). RESULTS: There was no correlation between initial testosterone level, initial symptom score or the success of treatment as defined by adequate resolution of symptoms. Despite the diverse endocrine patterns produced, the testosterone preparations appear equally safe over prolonged periods, with either no change or improvement of cardiovascular risk factors, especially in lowering cholesterol and diastolic blood pressure. CONCLUSIONS: It is suggested that because of excessive reliance on laboratory measures of androgens and undue safety concerns, many men who could benefit from symptom relief, improvement in related clinical conditions and given preventive medical benefits remain untreated.

Is testosterone treatment good for the prostate? Study of safety during long-term treatment.

INTRODUCTION: For men with androgen deficiency on testosterone replacement therapy (TRT), clinical concern relates to the development of prostate cancer (PCa). AIM: An updated audit of prostate safety from the UK Androgen Study was carried out to analyze the incidence of PCa during long-term TRT. MAIN OUTCOME MEASURES: Diagnosis of PCa in men receiving TRT, by serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE), and its relation to different testosterone preparations. METHODS: One thousand three hundred sixty-five men aged 28-87 (mean 55) years with symptomatic androgen deficiency and receiving TRT have been monitored for up to 20 years. All patients were prescreened for PCa by DRE and PSA along with endocrine, biochemical, hematological, and urinary profiles at baseline and every 6 months. Abnormal findings or rising PSA were investigated by transrectal ultrasound and prostate biopsy. The data were compared for the four different testosterone preparations used in TRT, including pellet implants, Restandol, mesterolone, and Testogel. RESULTS: Fourteen new cases of PCa were diagnosed at one case per 212 years treatment, after 2,966 man-years of treatment (one case per 212 years). Time to diagnosis ranged from 1 to 12 years (mean 6.3 years). All tumors were clinically localized and suitable for potentially curative treatment. Initiating testosterone treatment had no statistically significant effect on total PSA, free PSA or free/total PSA ratio, and any initial PSA change had no predictive relationship to subsequent diagnosis of cancer. CONCLUSIONS: The incidence of PCa during long-term TRT was equivalent to that expected in the general population. This study adds to the considerable weight of evidence that with proper clinical monitoring, testosterone treatment is safe for the prostate and improves early detection of PCa. Testosterone treatment with regular monitoring of the prostate may be safer for the individual than any alternative without surveillance.

International web survey shows high prevalence of symptomatic testosterone deficiency in men.

INTRODUCTION: Though the clinical significance of testosterone deficiency is becoming increasingly apparent, its prevalence in the general population remains unrecognised. A large web-based survey was undertaken over 3 years to study the scale of this missed diagnosis. METHODS: An online questionnaire giving the symptoms characterising testosterone deficiency syndrome (Aging Male Symptoms-AMS-scale) was set up on three web sites, together with questions about possible contributory factors. RESULTS: Of over 10,000 men, mainly from the UK and USA, who responded, 80% had moderate or severe scores likely to benefit from testosterone replacement therapy (TRT). The average age was 52, but with many in their 40s when the diagnosis of 'late onset hypogonadism' is not generally considered. Other possible contributory factors to the high testosterone deficiency scores reported were obesity (29%), alcohol (17.3%), testicular problems such as mumps orchitis (11.4%), prostate problems (5.6%), urinary infection (5.2%) and diabetes 5.7%. CONCLUSIONS: In this self-selected large international sample of men, there was a very high prevalence of scores which if clinically relevant would warrant a therapeutic trial of testosterone treatment. This study suggests that there are large numbers of men in the community whose testosterone deficiency is neither being diagnosed nor treated.

Plexin-B1 mutations in prostate cancer.

Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.

Prostate cancer: diagnosis and staging.

Prostate cancer represents an increasing health burden. The past 20 years, with the introduction of prostate-specific antigen (PSA), has seen prostate cancer move increasingly from a condition that presented with locally advanced disease or metastases to one that is found upon screening. More is also known about the pathology of pre-malignant lesions. Diagnosis relies on trans-rectal ultrasound (TRUS) to obtain biopsies from throughout the prostate, but TRUS is not useful for staging. Imaging for staging, such as magnetic resonance imaging or computed tomography, still has a low accuracy compared with pathological specimens. Current techniques are also inaccurate in identifying lymph node and bony metastases. Nomograms have been developed from the PSA, Gleason score and clinical grading to help quantify the risk of extra-capsular extension in radical prostatectomy specimens. Improved clinical staging modalities are required for more reliable prediction of pathological stage and for monitoring of response to treatments.

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

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

Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guérin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guérin Therapy (HYMN): A Phase III, Open-label, Randomised Controlled Trial.

BACKGROUND: There is no effective intravesical second-line therapy for non-muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails. OBJECTIVE: To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.gov: NCT01094964]). INTERVENTION: Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42±2°C) or control following stratification for carcinoma in situ (CIS) status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment centre. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measures were DFS and complete response (CR) at 3 mo for the CIS at randomisation subgroup. Analysis was based on intention-to-treat. RESULTS AND LIMITATIONS: A total of 104 patients were randomised (48 RITE: 56 control). Median follow-up for the 31 patients without a DFS event was 36 mo. There was no significant difference in DFS between treatment arms (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.84-2.10, p=0.23) or in 3-mo CR rate in CIS patients (n=71; RITE: 30% vs control: 47%, p=0.15). There was no significant difference in DFS between treatment arms in non-CIS patients (n=33; RITE: 53% vs control: 24% at 24 mo, HR 0.50, 95% CI 0.22-1.17, p=0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n=71; HR 2.06, 95% CI 1.17-3.62, p=0.01; treatment-subgroup interaction p=0.007). Disease progression was observed in four patients in each treatment arm. Adverse events and health-related quality of life between treatment arms were comparable. CONCLUSIONS: DFS was similar between RITE and control. RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed. RITE patients with CIS with/without papillary had lower DFS than control. HYMN highlights the importance of the control arm when evaluating novel therapies. PATIENT SUMMARY: This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and standard of care treatment. Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment; however, more research is needed. Both treatments are similarly well tolerated.

Electromotive drug administration with mitomycin C for intravesical treatment of non-muscle invasive transitional cell carcinoma.

This article reviews the use and application of electromotive drug administration for the intravesical treatment of bladder cancer. Strong evidence supports the use of passive intravesical chemotherapy in the management of non-muscle invasive bladder cancer. More recently, two published randomised trials have shown therapeutic advantage with protocols that use electromotive drug administration to enhance urothelial penetration of intravesical mitomycin C. The results suggest that the passive intravesical administration of chemotherapeutic drugs may be suboptimal. Further studies are required to demonstrate the feasibility and advantage of electromotive intravesical mitomycin C in the wider uro-oncological community.

Allelic imbalance at 13q14.2 approximately q14.3 in localized prostate cancer is associated with early biochemical relapse.

Allelic imbalance (AI), particularly at chromosomes 8p, 10q, and 13q, is the most frequently observed genetic change in sporadic prostate cancer. AI at these sites may inactivate tumor suppressor genes that regulate normal cell growth. To establish the relationship between AI and progression, we analyzed loci on 8p, 10q, and 13q14 in archival prostate tumors matched for Gleason grade, pre-operative prostate-specific antigen levels, and pathologic stage, and they were paired on the basis of relapse status after 3 years. AI was identified in 66% of patients without relapse and in 73% with relapse. There was no statistically significant difference for AI at 8p21.3 and 10q23.2 between the two groups of patients, but significant differences between relapsers and nonrelapsers in the frequency of AI at D13S165 at 13q14.2 (P=0.006) and D13S273 at 13q14.3 (P=0.03). There was also a significantly higher incidence of AI at both loci in the relapsers compared to the nonrelapsers (P=0.03). In three relapsers, AI occurred at all three loci between 13q14.2 and 13q14.3, with no nonrelapsers demonstrating AI at all three loci. These findings show that AI at 13q14.2 approximately q14.3 is an important event in the progression of localized prostate cancer, and suggest a possible role for microRNAs.

Management of non-muscle invasive bladder cancer: A comprehensive analysis of guidelines from the United States, Europe and Asia.

Bladder cancer is the 8th most common cancer with 74,000 new cases in the United States in 2015. Non-muscle invasive bladder cancer (NMIBC) accounts for 75% of all bladder cancer cases. Transurethral resection and intravesical treatments remain the main treatment modality. Up to 31-78% of cases recur, hence the need for intensive treatment and surveillance protocols which makes bladder cancer one of the most expensive cancers to manage. The purpose of this review is to compare contemporary guidelines from Europe, (European Association of Urology), the United States (National Comprehensive Cancer Network), the United Kingdom (National Institute for Health and Care Excellence), Japan (Japanese Urological Association) and the International Consultation on Bladder Cancer (ICUD). We compare and contrast the different guidelines and the evidence on which their recommendations are based.

The vascular response to photodynamic therapy with ATX-S10Na(II) in the normal rat colon.

The mechanism of tissue damage from photodynamic therapy (PDT) may be cellular, vascular or both, depending on the photosensitising agent and the treatment conditions. Well established photosensitisers like porfimer sodium have an optimum drug light interval of two days and may cause skin photosensitivity lasting several weeks. ATX-S10Na(II) is a new photosensitiser that remains largely in the vasculature after systemic administration and clears from the body within a few hours. The present study looks at the factors controlling the extent of PDT necrosis using ATX-S10Na(II) and correlates these with changes in the circulation after PDT. Normal Wistar rats were sensitised with ATX-S10Na(II), 2 mg/kg. At laparotomy, a laser fibre was positioned just touching the colonic mucosa and 50 J light at 670 nm delivered varying the drug light interval (0.5-24 h) and light delivery regime (100 mW continuous, 20 mW continuous or 100 mW in five fractions). Some animals were killed at three days to document the area of necrosis, others received fluorescein shortly prior to death (from a few minutes to three days after PDT) to outline the zone of PDT induced vascular shutdown. Maximum necrosis was seen with the shortest drug light interval (0.5 h), with no effect by 6 h. Fractionating the light or lowering the power did not increase the necrosis. The area of fluorescein exclusion increased over the first 2 h after PDT (in contrast to the re-perfusion seen with other photosensitisers) and correlated with the area of necrosis. PDT with ATX-S10Na(II) is most effective with a drug light interval of less than one hour. It induces irreversible vascular shutdown that extends after completion of light delivery and which is largely independent of the light delivery regime.

Quantitative analysis of BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue.

Prostate carcinoma is the most common cancer in men with few, quantifiable, biomarkers. Prostate cancer biomarker discovery has been hampered due to subjective analysis of protein expression in tissue sections. An unbiased, quantitative immunohistochemical approach provided here, for the diagnosis and stratification of prostate cancer could overcome this problem. Antibodies against four proteins BTF3, HINT1, NDRG1 and ODC1 were used in a prostate tissue array (> 500 individual tissue cores from 82 patients, 41 case pairs matched with one patient in each pair had biochemical recurrence). Protein expression, quantified in an unbiased manner using an automated analysis protocol in ImageJ software, was increased in malignant vs non-malignant prostate (by 2-2.5 fold, p<0.0001). Operating characteristics indicate sensitivity in the range of 0.68 to 0.74; combination of markers in a logistic regression model demonstrates further improvement in diagnostic power. Triple-labeled immunofluorescence (BTF3, HINT1 and NDRG1) in tissue array showed a significant (p<0.02) change in co-localization coefficients for BTF3 and NDRG1 co-expression in biochemical relapse vs non-relapse cancer epithelium. BTF3, HINT1, NDRG1 and ODC1 could be developed as epithelial specific biomarkers for tissue based diagnosis and stratification of prostate cancer.

The clinical significance and therapeutic implications of extraprostatic invasion.

Invasion of the prostatic margin by cancer establishes a higher risk of disease progression and treatment failure depending upon its extent and other clinical factors. Pathological stage is the most important single prognostic indicator, but determined reliably only in patients having radical prostatectomy. Tumour beyond the prostatic margin or its invasion into the seminal vesicle defines the local stage category as T3, and when confirmed by pathological examination the extent of prostatic margin involvement has prognostic significance. Prediction of extraprostatic invasion may influence therapeutic decisions, but can be difficult to determine for the individual patient prior to treatment. In some individuals having radical prostatectomy, the finding of extraprostatic invasion is unsuspected, and fortunately for the majority of these men the treatment remains curative. On the other hand, when extraprostatic invasion is suspected prior to or at surgery, wide excision may be necessary to achieve negative surgical margins, with other factors contributing independently to the likelihood of subsequent progression. Radiotherapy is an effective alternative treatment for clinical stage T3 and high-risk clinically localized cancer. Recent technological advances and use of combination modality treatment with radiation and hormone manipulation have improved survival outcomes and reduced side-effects. Radiation also has its place as adjuvant treatment following radical prostatectomy in high-risk disease, or as salvage following PSA recurrence, with ongoing trials evaluating potential benefit and toxicity. For clinically localised stage T3 prostate cancer, treatment with surgery or radiotherapy may be highly effective, but multimodality interventions are increasingly being used for primary treatment where clinical assessment indicates that there would otherwise be a high risk for disease progression and therapeutic failure.

History of prostate cancer treatment.

The last two decades have seen great advancements in our understanding of the prostate anatomy and approach including laparoscopic and robotic techniques. One should not however, forget that the techniques evolved with time. The history of developments in prostate cancer surgery, radiotherapy and hormonal therapy is fascinating and urologists through the ages had the quest to find an ideal treatment for prostate cancer in spite of their limitations of resources and understanding. Surgeons have now practiced radical prostatectomy for prostate cancer for over 100 years. Initially feared because of its complications and difficulty, the operation can now be carried out safely owing principally to advances in our knowledge of the surgical anatomy. Refinements in surgical technique based on anatomical understanding have enabled morbidity to be progressively reduced to a widely acceptable level. Within the past 10 years, the same principles have been applied successfully in laparoscopic and robotic techniques of prostatectomy. There are constant improvements in the field of radiotherapy, evolution of cryotherapy and changes in the role of hormones. To the future, the matching of patients to the treatment modality most appropriate to their tumour, and quality of life outcomes are likely to become increasingly important in determining future practice. It is worth while to look at the evolution to plan for the future.

Prostate-specific antigen testing in hypogonadism: implications for the safety of testosterone-replacement therapy.

Hypogonadal men have lower prostate volumes and serum prostate-specific antigen (PSA) levels than age-matched controls. When present, prostate cancer in hypogonadal men is more aggressive than in eugonadal men, and given the lack of specificity of PSA for diagnosing prostate cancer, a more accurate test would be desirable in hypogonadal men. Once testosterone-replacement therapy is started in hypogonadal men, PSA levels should be measured regularly; however, there is often an initial rise 3-6 months after starting treatment. A rise of >0.5 ng/mL within this time requires further investigation.

Comparison of the zones of the human prostate with the seminal vesicle: morphology, immunohistochemistry, and cell kinetics.

BACKGROUND: The prostate contains three glandular zones (central, peripheral, transition) with widely differing susceptibilities to cancer and benign prostatic hyperplasia (BPH). Most of the prostate is derived from urogenital sinus, but the central zone may be derived from Wolffian duct, in common with the seminal vesicles (SV). The peripheral zone is the most frequent site of cancer and the transition zone is the almost exclusive site of BPH. METHOD: We compared the histology and immunohistochemistry of the SV with those of the prostate zones in order to identify differences associated with susceptibility to disease or different embryological origins. Sections from the prostates of nine organ donors (aged 15-36) were stained for tissue-specific markers, antigens previously shown to stain differentially between the zones and markers of cell proliferation and cell death. RESULTS: Neuroendocrine cells were absent from the SV and significantly fewer neuroendocrine cells were seen in the central zone compared to the peripheral zone. Most of the SV epithelium stained for lactoferrin, compared to approximately one-third of central zone and only 2% of peripheral zone epithelial cells. The proliferative index of the central zone was approximately 50% lower and the incidence of apoptotic cells approximately half that of the peripheral and transition zones. CONCLUSIONS: The central zone has features in common with both the SV and the other zones of the prostate. The higher incidence of proliferative diseases in the transition and peripheral zones may be associated with the higher rate of cell turnover observed in these zones.

Phased-array MRI of canine prostate using endorectal and endourethral coils.

A four-channel phased array consisting of one surface coil, two endorectal coils, and one flexible endourethral loop coil was designed for MRI of the canine prostate. The endorectal coils provide high signal in the posterior region of the prostate, while the endourethral and surface coils are sensitive to the central and anterior regions of the prostate. Gel phantom experiments indicate that the proposed phased-array configuration generates 15 times more signal-to-noise ratio (SNR) than a combination of two surface coils and one endorectal coil within the posterior region of the prostate; the performance of the two configurations is comparable near the anterior prostate surface. Ultimate intrinsic SNR (UISNR) analysis was used to compare the proposed phased array's performance to the best possible SNR for external coils. This analysis showed that the proposed phased array outperforms the best-case external coil within the posterior and central regions of the prostate by up to 20 times. In canine experiments in vivo, high-resolution fast spin-echo (FSE) images of the prostate were obtained with a pixel size of 230 microm obtained in 3 min 12 s. The proposed phased-array design potentially can be used to increase the accuracy of prostate cancer staging and the feasibility of MR-guided prostate interventions.