Antony C.P. Riddick

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

Extracellular proteases of the matrix metalloproteinase (MMP) and serine protease families participate in many aspects of tumour growth and metastasis. Using quantitative real-time RT–PCR analysis, we have undertaken a comprehensive survey of the expression of these enzymes and of their natural inhibitors in 44 cases of human prostate cancer and 23 benign prostate specimens. We found increased expression of MMP10, 15, 24, 25 and 26, urokinase plasminogen activator-receptor (uPAR) and plasminogen activator inhibitor-1 (PAI1), and the newly characterised serine proteases hepsin and matriptase-1 (MTSP1) in malignant tissue compared to benign prostate tissue. In contrast, there was significantly decreased expression of MMP2 and MMP23, maspin, and the protease inhibitors tissue inhibitor of metalloproteinase 3 (TIMP3), TIMP4 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the cancer specimens. The expression of MMP15 and MMP26 correlated positively with Gleason score, whereas TIMP3, TIMP4 and RECK expression correlated negatively with Gleason score. The cellular localisation of the expression of the deregulated genes was evaluated using primary malignant epithelial and stromal cell cultures derived from radical prostatectomy specimens. MMP10 and 25, hepsin, MTSP1 and maspin showed predominantly epithelial expression, whereas TIMP 3 and 4, RECK, MMP2 and 23, uPAR and PAI1 were produced primarily by stromal cells. These data provide the first comprehensive and quantitative analysis of the expression and localisation of MMPs and their inhibitors in human prostate cancer, leading to the identification of several genes involved in proteolysis as potential prognostic indicators, in particular hepsin, MTSP1, MMP26, PAI1, uPAR, MMP15, TIMP3, TIMP4, maspin and RECK.

180-W XPS GreenLight Laser Vaporisation Versus Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 6-Month Safety and Efficacy Results of a European Multicentre Randomised Trial—The GOLIATH Study

BACKGROUND The comparative outcome with GreenLight (GL) photoselective vaporisation of the prostate and transurethral resection of the prostate (TURP) in men with lower urinary tract symptoms due to benign prostatic obstruction (BPO) has been questioned. OBJECTIVE The primary objective of the GOLIATH study was to evaluate the noninferiority of 180-W GL XPS (XPS) to TURP for International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) at 6 mo and the proportion of patients who were complication free. DESIGN, SETTING, AND PARTICIPANTS Prospective randomised controlled trial at 29 centres in 9 European countries involving 281 patients with BPO. INTERVENTION 180-W GL XPS system or TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Measurements used were IPSS, Qmax, prostate volume (PV), postvoid residual (PVR) and complications, perioperative parameters, and reintervention rates. Noninferiority was evaluated using one-sided tests at the 2.5% level of significance. The statistical significance of other comparisons was assessed at the (two-sided) 5% level. RESULTS AND LIMITATIONS The study demonstrated the noninferiority of XPS to TURP for IPSS, Qmax, and complication-free proportion. PV and PVR were comparable between groups. Time until stable health status, length of catheterisation, and length of hospital stay were superior with XPS (p<0.001). Early reintervention rate within 30 d was three times higher after TURP (p=0.025); however, the overall postoperative reintervention rates were not significantly different between treatment arms. A limitation was the short follow-up. CONCLUSIONS XPS was shown to be noninferior (comparable) to TURP in terms of IPSS, Qmax, and proportion of patients free of complications. XPS results in a lower rate of early reinterventions but has a similar rate after 6 mo. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01218672.

The relevance of a hypoxic tumour microenvironment in prostate cancer

Research into the hypoxic tumour microenvironment is accelerating and the reversal of hypoxia is increasingly being suggested as a mechanism for improving cancer treatment. Recent studies have suggested that hypoxia is also a feature in prostate cancer and is associated with a poor prognosis. Hypoxia has been shown to cause radio‐resistance and hence hamper one of the major treatments for prostate cancer. However, unlike other solid tumours, such as cervical and head‐and‐neck cancer, there are inconsistencies and unanswered questions about the relevance of hypoxia in prostate cancer. This review outlines the role of low‐oxygen conditions in prostate cancer and the areas where further studies are required.

A European Multicenter Randomized Noninferiority Trial Comparing 180 W GreenLight XPS Laser Vaporization and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 12-Month Results of the GOLIATH Study

PURPOSE We present the 1-year results of the GOLIATH prospective randomized controlled trial comparing transurethral resection of the prostate to GreenLight XPS for the treatment of men with nonneurogenic lower urinary tract symptoms due to prostate enlargement. The updated results at 1 year show that transurethral resection of the prostate and GreenLight XPS remain equivalent, and confirm the therapeutic durability of both procedures. We also report 1-year followup data from several functional questionnaires (OABq-SF, ICIQ-SF and IIEF-5) and objective assessments. MATERIALS AND METHODS A total of 291 patients were enrolled at 29 sites in 9 European countries. Patients were randomized 1:1 to undergo GreenLight XPS or transurethral resection of the prostate. The trial was designed to evaluate the hypothesis that GreenLight XPS is noninferior to transurethral resection of the prostate on the International Prostate Symptom Score at 6 months. Several objective parameters were assessed, including maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen, in addition to functional questionnaires and adverse events at each followup. RESULTS Of the 291 enrolled patients 281 were randomized and 269 received treatment. Noninferiority of GreenLight XPS was maintained at 12 months. Maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen were not statistically different between the treatment arms at 12 months. The complication-free rate at 1 year was 84.6% after GreenLight XPS vs 80.5% after transurethral resection of the prostate. At 12 months 4 patients treated with GreenLight XPS and 4 who underwent transurethral resection of the prostate had unresolved urinary incontinence. CONCLUSIONS Followup at 1 year demonstrated that photoselective vaporization of the prostate produced efficacy outcomes similar to those of transurethral resection of the prostate. The complication-free rates and overall reintervention rates were comparable between the treatment groups.

Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate

The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers.

A Multicenter Randomized Noninferiority Trial Comparing GreenLight-XPS Laser Vaporization of the Prostate and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: Two-yr Outcomes of the GOLIATH Study

BACKGROUND The GOLIATH study is a 2-yr trial comparing transurethral resection of prostate (TURP) to photoselective vaporization with the GreenLight XPS Laser System (GL-XPS) for the treatment of benign prostatic obstruction (BPO). Noninferiority of GL-XPS to TURP was demonstrated based on a 6-mo follow-up from the study. OBJECTIVE To determine whether treatment effects observed at 6 mo between GL-XPS and TURP was maintained at the 2-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS Prospective randomized controlled trial at 29 centers in nine European countries involving 281 patients with BPO. INTERVENTION Photoselective vaporization using the 180-W GreenLight GL-XPS or conventional (monopolar or bipolar) TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the International Prostate Symptom Score for which a margin of three was used to evaluate the noninferiority of GL-XPS. Secondary outcomes included Qmax, prostate volume, prostate specific antigen, Overactive Bladder Questionnaire Short Form, International Consultation on Incontinence Questionnaire Short Form, occurrence of surgical retreatment, and freedom from complications. RESULTS AND LIMITATIONS One hundred and thirty-six patients were treated using GL-XPS and 133 using TURP. Noninferiority of GL-XPS on International Prostate Symptom Score, Qmax, and freedom from complications was demonstrated at 6-mo and was sustained at 2-yr. The proportion of patients complication-free through 24-mo was 83.6% GL-XPS versus 78.9% TURP. Reductions in prostate volume and prostate specific antigen were similar in both arms and sustained over the course of the trial. Compared with the 1(st) yr of the study, very few adverse events or retreatments were reported in either arm. Treatment differences in the Overactive Bladder Questionnaire Short Form observed at 12-mo were not statistically significant at 24-mo. A limitation was that patients and treating physicians were not blinded to the therapy. CONCLUSIONS Twenty-four-mo follow-up data demonstrated that GL-XPS provides a durable surgical option for the treatment of BPO that exhibits efficacy and safety outcomes similar to TURP. PATIENT SUMMARY The long-term effectiveness and safety of GLP-XLS was similar to conventional TURP for the treatment of prostate enlargement.

Endoscopic Versus Laparoscopic Management of Noninvasive Upper Tract Urothelial Carcinoma: 20-Year Single Center Experience

PURPOSE We compare the outcomes of endoscopic surgery to laparoscopic nephroureterectomy for the management of specifically noninvasive upper tract urothelial carcinoma. MATERIALS AND METHODS A retrospective database review identified consecutive patients with clinically noninvasive upper tract urothelial carcinoma who underwent endoscopic surgery (59, via ureteroscopic ablation or percutaneous resection) or laparoscopic nephroureterectomy (70) at a single center during 20 years (1991 to 2011). Overall survival, upper tract urothelial carcinoma specific survival, upper tract recurrence-free survival, intravesical recurrence-free survival, progression-free survival and renal unit survival were estimated using Kaplan-Meier methods, with differences assessed using the log rank test. RESULTS Median age and followup were 74.8 years and 50 months, respectively. Overall renal preservation in the endoscopic group was high (5-year renal unit survival 82.5%), although this came at a cost of high local recurrence (endoscopic surgery 5-year recurrence-free survival 49.3%, laparoscopic nephroureterectomy 100%, p <0.0001). For G1 upper tract urothelial carcinoma, endoscopic surgery 5-year disease specific survival (100%) was equivalent to that of laparoscopic nephroureterectomy (100%). However, laparoscopic nephroureterectomy demonstrated superior disease specific survival to endoscopic surgery for G2 disease (91.7% vs 62.5%, p = 0.037) and superior progression-free survival for G3 disease (88.9% vs 55.6%, p = 0.033). CONCLUSIONS For G1 upper tract urothelial carcinoma, endoscopic management can provide effective oncologic control and renal preservation. However, endoscopic management should not be considered for higher grade disease except in compelling imperative cases or in patients with poor life expectancy as oncologic outcomes are inferior to those of laparoscopic nephroureterectomy.

NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway

Nitric oxide‐donating non‐steroidal anti‐inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO‐NSAID called NO‐sulindac on the PC‐3 prostate cancer cell line under hypoxic conditions. NO‐sulindac was found to have pro‐apoptotic, cytotoxic, and anti‐invasive effect on PC‐3 cells under normoxia and hypoxia. NO‐sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO‐releasing subunits both contributed to the cytotoxic effects of NO‐sulindac. Resistance of PC‐3 cells to NO‐sulindac was induced as the oxygen concentration declined. Hypoxia‐induced chemoresistance was reversed by knocking‐down hypoxia‐inducible factor‐1α (HIF‐1α) mRNA using RNAi. Nuclear HIF‐1α levels were upregulated at 0.2% oxygen but reduced by treatment with NO‐sulindac, as was Akt phosphorylation. NO‐sulindac treatment of hypoxic PC‐3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co‐transfection of PC‐3 cells with the HRE promoter reporter construct and myr‐Akt (constitutively active Akt) plasmids reversed the NO‐sulindac induced reduction in HRE activation. Real‐time polymerase chain reaction analysis of hypoxic, NO‐sulindac treated PC‐3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO‐sulindac directly inhibits the hypoxia response of PC‐3 prostate cancer cells by inhibiting HIF‐1α translation via the Akt signalling pathway. The ability of NO‐sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC‐3.

Banking of fresh-frozen prostate tissue: Methods, validation and use

The question of banking of fresh frozen human prostatic tissue is addressed by a group of authors who have compared its value with what they call “pseudobanked” tissue. They then validate their methodology by a number of methods, including expression of hepsin, which they found to be significantly higher in malignant than in benign tissue. The theme of prostate cancer is continued by an English group looking at recent trends in the use of radical prostatectomy in England, and they make a number of interesting comments about this. Again in relation to prostate cancer, a group from Boston assess the use of steroids after prostate brachytherapy to reduce the risk of acute urinary retention.

Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years*.

BACKGROUND AND PURPOSE Open nephroureterectomy (ONU) rather than laparoscopic nephroureterectomy (LNU) is still regarded as the standard of care for extirpative surgical management of upper urinary tract urothelial-cell carcinoma (UUT-UCC). The longest published follow-up of LNU is 7 years. We report outcomes for patients having surgery ≥10 years ago. PATIENTS AND METHODS Consecutive patients with UUT-UCC who were treated with ONU (n=39) or LNU (n=23) between April 1992 to September 2000 were included. Preoperative, tumor, operative and postoperative characteristics, recurrence, and outcomes were collated. Survival was estimated using the Kaplan-Meier method. RESULTS Median follow-up of censored patients was 163 months (13.6 y). Estimated mean overall survival (OS) was 111 months for ONU and 103 months for LNU. Mean progression free survival (PFS) was 175 months for ONU and 143 months for LNU. Probability of PFS at 10 years was 79% for ONU and 76% for LNU and was unchanged at 15 years. There was no significant difference between ONU and LNU in terms of OS (P=0.51, log-rank test), PFS (P=0.70) or cancer-specific survival (CSS; P=0.43). There were no prognostic differences between ONU and LNU after correcting for confounding variables. There was no increase in the probability of a bladder cancer recurrence from 10 to 15 years postoperation. CONCLUSION Long-term follow-up of patients who were operated on more than 10 years ago suggests that LNU has oncologic equivalence to ONU because there were no significant differences in OS, PFS, or CSS between ONU and LNU patients followed for a median of 13 years.