Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer.

Angiogenesis is required for tumour growth and is induced principally by vascular endothelial growth factor A (VEGF-A). VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer (PCa). In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by serine-arginine protein kinase 1 (SRPK1). Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared with benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in PCa may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knockdown (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small-molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC-3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of PCa. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies for the use of SRPK1 inhibition as a potential anti-angiogenic therapy in PCa.

Pathological analysis of lymph nodes in anterior prostatic fat excised at robot-assisted radical prostatectomy.

AIMS: To assess the lymph node content of anterior prostatic fat (APF) sent routinely at robot-assisted laparoscopic radical prostatectomy (RALP) and the incidence of positive nodes in the extended pelvic lymph node dissection. METHODS: Between September 2008 and April 2012, APF excised from 282 patients who underwent RALP was sent for pathological analysis. This tissue was completely embedded and lymph nodes counted. RESULTS: In total, 49/282 (17%) patients had lymph nodes in the APF, median lymph node yield in this tissue was 1 (range 1­5). In four patients, the lymph nodes contained metastatic deposits. These patients did not have positive nodes elsewhere in the extended lymph node dissection. CONCLUSIONS: APF contains lymph nodes in 1 in 6 patients and infrequently these may be malignant. APF should always be removed at radical prostatectomy. APF should be routinely sent for pathological analysis.

Ketamine-associated lower urinary tract destruction: a new radiological challenge.

AIM: Ketamine is a short-acting dissociative anaesthetic whose hallucinogenic side effects have led to an increase in its illicit use amongst club and party goers. There is a general misconception amongst users that it is a safe drug with few long term side effects, however ketamine abuse is associated with severe urinary tract dysfunction. Presenting symptoms include urinary frequency, nocturia, dysuria, haematuria and incontinence. MATERIALS AND METHODS: We describe the radiological findings found in a series of 23 patients, all with a history of ketamine abuse, who presented with severe lower urinary tract symptoms (LUTS). Imaging techniques used included ultrasonography (US), intravenous urography (IVU), and computed tomography (CT). These examinations were reviewed to identify common imaging findings. All patients with positive imaging findings had also undergone cystoscopy and bladder wall biopsies, which confirmed the diagnosis. The patients in this series have consented to the use of their data in the ongoing research into ketamine-induced bladder pathology. RESULTS: Ultrasound demonstrated small bladder volume and wall thickening. CT revealed marked, generalized bladder wall thickening, mucosal enhancement, and perivesical inflammation. Ureteric wall thickening and enhancement were also observed. In advanced cases ureteric narrowing and strictures were identified using both CT and IVU. Correlation of clinical history, radiological and pathological findings was performed to confirm the diagnosis. CONCLUSION: This case series illustrates the harmful effects of ketamine on the urinary tract and the associated radiological findings. Delayed diagnosis can result in irreversible renal tract damage requiring surgical intervention. It is important that radiologists are aware of this emerging clinical entity as early diagnosis and treatment are essential for successful management.

PSA recurrence following radical prostatectomy is comparable for all age groups in the UK.

UNLABELLED: Increasing numbers of men are being diagnosed with prostate cancer and undergo operative curative treatment. It has been suggested that outcome after radical prostatectomy (RP) may vary for different age groups. OBJECTIVE: To investigate whether PSA recurrence-free survival after RP is related to age at operation for a cohort of English men. METHODS: A total of 854 patients notes from four Urology units were audited for preoperative staging parameters and follow-up data obtained. The relationship of PSA, age, biopsy Gleason grade, clinical stage, era and institution on PSA recurrence-free survival was competitively assessed with a multivariate model. RESULTS: Only preoperative PSA (P<0.0001) and biopsy Gleason grade (P < 0.0001) were found to be strongly associated with PSA recurrence-free survival on multivariate analysis. PSA recurrence-free survival probabilities at 5 y for patients aged 45-55 y, 55.1-60 y, 60.1-65 y, 65.1-70 y and 70.1-75 y were 0.59 (CI 0.47-0.71), 0.74 (CI 0.64-0.784), 0.56 (CI 0.44-0.68), 0.61 (CI 0.53-0.69) and 0.60 (CI 0.46-0.74), respectively. No significant difference of PSA recurrence-free survival between any of the age groups was found (Log-rank, P = 0.8567). CONCLUSION: No significant difference of pathological variables or biochemical recurrence across the age groups was found. The widely held belief of poorer outcome in younger men selected for RP does not seem to be borne out by this study.

Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study.

OBJECTIVE: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer. PATIENTS AND METHODS: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points. RESULTS: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. CONCLUSION: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.

Contemporary update of cancer control after radical prostatectomy in the UK.

Despite a significant increase of the number of radical prostatectomies (RPs) to treat organ-confined prostate cancer, there is very limited documentation of its oncological outcome in the UK. Pathological stage distribution and changes of outcome have not been audited on a consistent basis. We present the results of a multicentre review of postoperative predictive variables and prostatic-specific antigen (PSA) recurrence after RP for clinically organ-confined disease. In all, 854 patient's notes were audited for staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. Median follow-up was 52 months for the remaining 705 patients. The median PSA was 10 ng ml(-1). A large migration towards lower PSA and stage was seen. This translated into improved PSA survival rates. Overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probability for PSA ranges <4, 4.1-10, 10.1-20 and >20 ng ml(-1) was 0.82, 0.73, 0.59 and 0.20, respectively (log rank, P<0.0001). PSA recurrence-free survival probabilities for pathological Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.84, 0.66, 0.55 and 0.21, respectively (log rank, P<0.0001). Similarly, 5-year PSA recurrence-free survival probabilities for pathological stages T2a, T2b, T3a, T3b and T4 were 0.82, 0.78, 0.48, 0.23 and 0.12, respectively (log rank, P=0.0012). Oncological outcome after RP has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic compared to quoted survival figures in the literature. Survival figures based on pathological stage and Gleason grade may serve to counsel patients postoperatively and to stratify patients better for adjuvant treatment.

Case selection for radical prostatectomy in the UK.

INTRODUCTION: Radical prostatectomy is an increasingly popular treatment option for clinically localised prostate cancer, yet PSA outcome figures are rare in the UK. This makes it difficult to establish appropriate criteria for case selection. We conducted an audit of PSA recurrence of 5 large centres in the south of England and investigated the use of pre-operative PSA to improve case selection and outcome. METHOD: 854 patients notes were audited for pre-operative staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. RESULT: Median follow-up was 52 months for the remaining 663 patients. Median PSA was 10 ng/ml. A large improvement of PSA recurrence free survival rates was observed from 1988 to 1998 as a result of change in case selection and stage migration. Overall Kaplan-Meier PSA recurrence free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. Five-year PSA recurrence free survival probability for PSA ranges <4 ng/ml, 4.1-10 ng/ml, 10.1-20 ng/ml and >20 ng/ml was 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, p < 0.0001). A simulation of biochemical recurrence free survival for patient cohorts with stepwise reduced inclusion PSAs suggests an improved outcome for patients with a pre-operative inclusion PSA of <12 ng/ml. Further reduction of the inclusion PSA does not improve outcome. CONCLUSION: Intermediate PSA recurrence free survival has improved over time in England. PSA recurrence free survival estimates are less optimistic compared to frequently quoted American figures. A reduced pre-operative PSA cut-off for case selection may be used to improve outcome.

Learning curve and stage migration of a radical retropubic prostatectomy series over a 10-y period.

OBJECTIVE: To show the impact of learning curve and patient selection on complication rate and biochemical recurrence-free survival of a UK radical prostatectomy series for localised prostate cancer and to model the influence of common preoperative variables on biochemical recurrence after controlling for learning curve. PATIENTS AND METHODS: From 1989 to 1999, 280 of 350 patients who underwent anatomical radical retropubic prostatectomy (RRP) at our institution had complete records and follow-up of at least 1 y. After exclusions of preoperative staging, factors reflecting the learning curve, early complications and prostate-specific antigen (PSA) outcome were recorded on 217 patients. Procedures before 1995 were compared with procedures after 1995. RESULTS: Comparison of the two groups showed a significant decrease in operating time (mean 152 vs 130 min), blood loss (mean 1500 vs 1000 ml), transfusion rate (83 vs 42%) and hospital stay (mean 7 vs 6 days). Median preoperative PSA changed significantly from 13.2 to 11.5 ng/ml. Only 17% were diagnosed by rectal examination compared to 27% in the early years. The number of clinical T1 tumours increased from 33 to 47%. This did lead to an increase of organ-confined tumours on pathological staging by 25%. Biochemical recurrence-free survival improved significantly after 1995. After controlling for the learning curve PSA and clinical stage were significant predictors of PSA recurrence. CONCLUSION: Time trends of case selection, stage migration and a steep learning curve are shown over a 10-y period. Factors associated with the learning curve as well as case selection have a significant impact on outcome. There may be other as yet not specified factors over time, which have a significant impact on PSA recurrence-free survival. Patients with a PSA of 20 ng/ml and above have a poor outcome and do not appear to be suitable candidates for RRP.

Time trends in case selection, stage and prostate-specific antigen recurrence after radical prostatectomy: a multicentre audit.

OBJECTIVES: To report an audit of preoperative staging variables, case selection, stage migration and prostate-specific antigen (PSA) recurrence at five large centres in the south of England. To establish PSA outcome values after radical prostatectomy for clinically localized prostate cancer in the UK, and enable appropriate patient counselling. PATIENTS AND METHODS: The notes of 854 patients were audited for preoperative staging variables and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment, and with incomplete data and follow-up, were excluded. RESULTS: The median follow-up was 52 months for the remaining 663 patients; the median PSA level was 10 ng/mL. There was a large migration towards lower PSA and stage; this translated into improved PSA survival rates. The overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probabilities for PSA levels of < 4, 4.1-10, 10.1-20 and > 20 ng/mL were 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, P < 0.001). The PSA recurrence-free survival probabilities for biopsy Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.70, 0.61, 0.55 and 0.21, respectively (Wilcoxon, P < 0.001). Similarly, the 5-year PSA recurrence-free survival probabilities for clinical stages T1a and 1b, T1c, T2a and T2b were 0.79, 0.62, 0.57 and 0.44, respectively (Wilcoxon, P = 0.0012). CONCLUSION: With better case selection the intermediate oncological outcome has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic than the frequently quoted American values. The present values may be used to help in counselling British patients before radical prostatectomy.

Prediction of prostate cancer in extended-field biopsies of the prostate.

OBJECTIVES: To assess the prediction of prostate cancer using extended-field prostatic biopsies (8-11 cores), as such biopsy protocols are recommended to increase the detection of prostate cancer, and as fewer cancers are missed this should improve the prediction of biopsy outcome from the patients' history, transrectal ultrasonography (TRUS) and serum markers. PATIENTS AND METHODS: In all, 260 patients were prospectively evaluated and 206 with a total prostate-specific antigen (PSA) level of < 20 ng/mL were included. All patients were evaluated for age, family history, lower urinary tract symptoms (LUTS), medication for LUTS, previous prostate biopsy, the presence of cysts, a digital rectal examination, calcifications or hypoechoic lesions on TRUS, total and transitional zone volume, total PSA (tPSA), PSA density (tPSAD), total PSA transition zone density (tPSATZD), complexed PSA (cPSA), cPSA density (cPSAD), cPSA transitional zone density (cPSATZD), free/total (f/t)PSA ratio and free/complexed PSA ratio (f/cPSA). Logistic regression was used to predict the outcome; 80% of the patients were used to generate the models and 20% to test the prediction. RESULTS: Two models were constructed; the most accurate contained family history, cPSA, cPSAD, cPSATZD, f/cPSA, PSAD and tPSATZD (sensitivity 91%, specificity 70%). A workable and concise model contained tPSATZD, cPSATZD and f/cPSA, and had a sensitivity of 93% and a specificity of 60%. The best single predictor was tPSATZD with a sensitivity of 92% and a specificity of 55%. Using regression models can produce considerable gains in specificity. This would allow unnecessary prostate biopsies to be avoided for a third of patients compared with tPSA alone. CONCLUSIONS: The present analysis for PSA indices appeared to be slightly more accurate than those in previously published studies. Most of this improvement in diagnostic accuracy was ascribed to the use of an extended-field biopsy protocol. Prostate cancer in a first-degree relative was the only variable that contributed significantly to the regression model. tPSATZD was the best volume-adjusted PSA index. The f/tPSA appeared to be the best test with no volume adjustment, followed by f/cPSA and cPSA. Although the models are cumbersome and expensive for use in general urological practice they could be used to optimize biopsy strategies on the basis of predicted cancer probabilities in screening studies. The cost of the models may compare favourably with tPSA because of the high specificity that can be achieved.

Lymphoedema in urological cancer.

OBJECTIVES: To review the evidence underlying the diagnosis, pathology and treatment of lymphoedema of the lower extremities and genitalia from or following the treatment for urological cancer, and to suggest possible underlying pathophysiological mechanisms that may explain its development. METHODS: Reviews of the epidemiological, surgical, and scientific literature and personal experience of treatment of patients are used to build a picture of clinical setting and the physiological principles underlying lymphoedema of the leg. RESULTS: Lymphoedema of the leg and genitals results in serious morbidity for the patient. The incidence is largely unknown, but varies according to the type and location of tumours and may be up to 50% in advanced stages of penile carcinoma, or following its treatment. Although the aetiology of the condition is either iatrogenic, or associated with malignancy, the underlying pathophysiology is not well understood. CONCLUSIONS: Recent studies in breast cancer related lymphoedema point to underlying vascular as well as lymphatic problems, but the parallels with lower limb lymphoedema are not known.

The effect of erectile dysfunction on the quality of life of men after radical prostatectomy.

OBJECTIVE: To report on the first use of a quality-of-life (QoL) measure specific for erectile dysfunction (ED), the 'ED effect on QoL' (ED-EQoL), to assess the effect of ED on QoL after radical prostatectomy (RP). PATIENTS AND METHODS: We retrospectively identified 89 patients who had undergone RP at one institution. Each was sent the ED-EQoL and a second questionnaire asking whether they had been counselled before RP about possible ED afterward. RESULTS: The response rate was 91% and the median time since RP 92 months; 76% of those who were potent before RP were impotent afterward. The overall results showed that the QoL of 72% of patients was moderately or severely affected. For each question, on average a third of the patients reported that their QoL was affected either 'quite a lot' or 'a great deal'. CONCLUSIONS: This study shows that ED after RP has a profound effect on QoL; it is therefore important when assessing ED to use an ED-specific QoL questionnaire such as the ED-EQoL to measure the psychosocial effect of ED, in addition to using an instrument such as the International Index of Erectile Function to measure the functional aspects of ED.

Use of bacille Calmette-Guérin in superficial bladder cancer.

Intravesical bacille Calmette-Guérin (BCG) has been used by urologists for several years after its first reported use as a cancer therapy in the 1930s. Morales in 1976 described the usage of BCG as a once weekly intravesical instillation for six weeks; this is a treatment regimen that still exists today. Its success as a treatment depends on it being used appropriately. It is employed: (1) to treat carcinoma in situ or occasionally residual papillary tumours; (2) to reduce the number and frequency of recurrent high grade superficial tumours; and (3) to prevent disease progression (although this remains a controversial point, on which there is no consensus view). Unfortunately, the more widespread use of BCG is often limited due its high side effect profile. Present research is directed towards reducing its side effect profile, improving its efficacy, and understanding its exact mechanism of action, which is not fully understood.

p53 and bcl-2 immunohistochemistry in preoperative biopsies as predictors of biochemical recurrence after radical prostatectomy.

OBJECTIVE: To evaluate p53 and bcl-2 immunohistochemistry in preoperative biopsies and radical prostatectomy specimens, as predictors of biochemical recurrence. PATIENTS AND METHODS: Preoperative biopsies from 73 men, and the radical prostatectomies from these men and from a further 47 men, were evaluated. The serum prostate specific antigen (PSA) level, Gleason score, pathological stage and margin involvement were recorded. The immunohistochemical expression of p53 and bcl-2 was studied on a representative area of tumour with the highest Gleason grade. The median follow-up was 53 months. RESULTS: During the follow-up 47 of the 120 patients had a biochemical recurrence. Capsular penetration was present in 63 (53%) and the surgical margins were positive in 47 (39%). The Gleason score was < 7 in 81 (68%) patients; p53 was positive in 40 (66%) of 61 biopsies and 84 (71%) of 118 prostatectomy specimens. Bcl-2 was positive in eight (13%) of 63 biopsies and 20 (17%) of 118 prostatectomies. On multivariate analysis the biopsy p53, Gleason score and serum PSA were significant predictors of recurrence. On multivariate analysis, capsular penetration, PSA and margin status at prostatectomy were significant predictors of recurrence. There was also a significant interaction between PSA and margin status. Although univariately significant, neither p53 nor bcl-2 featured in the final multivariate model. CONCLUSION: Biopsy p53 status significantly predicts recurrence after radical prostatectomy, but its low specificity and technical issues suggest that it will not be useful in the clinical setting. However, a patient with negative p53 on biopsy is likely to have a good prognosis on prolonged follow-up.

Her-2/neu oncogene amplification in clinically localised prostate cancer.

AIM: To examine the incidence of Her-2/neu oncogene amplification in clinically localised prostate cancer using in situ hybridisation. METHODS: One hundred and seventeen patients, who had undergone radical prostatectomy, were identified and in situ hybridisation was performed on formalin fixed, paraffin wax embedded tissue using the Quantum Appligene probe for Her-2/neu. The enzyme peroxidase was used to detect the probe because this enabled a permanent record to be kept. Tumours in which there were five or more signals in each nucleus in > 20% of the tumour cells were considered to have a significantly increased copy number. A serial section from these tumours was then hybridised with the chromosome 17 alpha satellite probe. The ratio of the percentage of cells showing an increase in Her-2/neu copy number to the number showing polysomy for chromosome 17 was calculated. A ratio above 2 was considered amplified. RESULTS: Biochemical recurrence occurred in 50 (43%) patients and 24 (21%) had clinical recurrence. In situ hybridisation for Her-2/neu was accessible in 114 (97%) patients. A significant increase in copy number was present in two patients (1.75 %), but chromosome 17 hybridisation showed that the increase was the result of polysomy rather than true amplification. Both these patients had a Gleason score of 7 and stage T3; they also had recurrent clinical disease with distal metastasis within two and 19 months. CONCLUSIONS: Increased Her-2/neu oncogene copy number appears to be rare in clinically localised prostatic adenocarcinoma and is related to chromosome 17 polysomy rather than true amplification. As a result, it would not be a useful biomarker for identifying those patients who will have recurrences after radical prostatectomy.

PC-SPES: a herbal therapy for the treatment of hormone refractory prostate cancer.

In this review the authors consider the commercially available herbal product PC-SPES. This is a combination of eight different herbs marketed for its effects of reducing prostate specific antigen (PSA) levels, improving pain, and enhancing the quality of life of those with hormone refractory prostate cancer. The evidence for these claims does not appear to be as conclusive as reported by the manufactures of this product. There also appears to be a significant risk of deep vein thrombosis (DVT) in those treated with PC-SPES. There have been 116 clinical and laboratory based studies of PC-SPES published to date, but there have been no randomised controlled trials conducted. Many of these studies contain very few patients, thus making the drawing of conclusions difficult. Despite this lack of information, there still remains a large patient group taking this supplement, therefore caution should be advised in the usage of PC-SPES in the treatment of hormone refractory prostate cancer.