Mark R. Feneley

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.

PSA testing: an evolving relationship with prostate cancer screening

PSA testing has made prostate cancer screening a reality for men in many parts of the world, but its benefit for mens health continues to be debated. In men exposed to PSA testing, there has been a well-documented change in the presentation of prostate cancer with a shift towards earlier pathological stage, not without justifiable concern about over-diagnosis by prostate biopsy. Increasingly, men now diagnosed with early stage cancer have previous PSA exposure and are selected for biopsy based on PSA change in relation to cutoff values. Some recent observations suggest that PSA may no longer be an effective marker for early stage tumours, with PSA elevation failing to discriminate tumour-specific characteristics from benign gland enlargement. Traditionally, variation in pathological stage of clinically localised prostate cancer at diagnosis has related to clinical stage, PSA and biopsy Gleason grade, but with distinctions based upon these three assessments declining and an increasing proportion of organ-confined tumours at presentation, new methods of cancer detection and prognostic assessment are now required. Molecular technologies hold great promise in this respect, and in the future biomarker signatures are likely to overshadow total PSA for guiding early diagnosis and prognostic assessment. While arguments about prostate screening will continue, owing not least to its feasibility, future debate is likely to focus increasingly on technological advances and molecular profiling of these notoriously heterogeneous tumours.

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.

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.

Genome-wide screening for genetic changes in a matched pair of benign and prostate cancer cell lines using array CGH.

Copy number alterations in a matched pair of benign epithelial and prostate cancer cell lines derived from the same patient were assessed using array-based comparative genomic hybridisation (aCGH). The cancer cell line showed a gain of chromosome 7, deletion of chromosome 8, gains (including high level) and losses on chromosome 11, loss of 18p and gain of 20q. Deletions on chromosome 8 were confirmed with microsatellite markers. The aCGH results were compared to gene expression data obtained using DNA microarrays and suggested the involvement of caspases and ICEBERG on 11q and E2F1 on chromosome 20q.

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.

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.

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.

Neoadjuvant chemotherapy for muscle‐invasive bladder cancer: a new standard of care?

t has become fairly easy to accept the preventive medicine benefits of stopping smoking. Urologists have felt free to advise, cajole and sometimes bully their patients into a healthier lifestyle where the problem has been bladder cancer. Sadly, the same cannot be said in the area of erectile dysfunction (ED). It is abundantly clear that ED and vascular disease in general share many critical causal characteristics and the need for diligent attention to very influential lifestyle factors. Yet the link between lifestyle and ED has not become widely used therapeutically. Indeed, the issues of vascular disease and ED seem mainly to have focused on drug safety, which although important has been shown to be scarcely an issue with the phosphodiesterase inhibitors in most patients. In limiting the focus to prescriptions and drug safety, urologists are missing a major opportunity for preventive medicine that may have a significant effect on several areas of health. Urologists have an opportunity in ED to make significant and beneficial lifestyle changes that arguably may have an even greater health benefit (in terms of life years) than the lifestyle issues in prostate cancer, bladder cancer or stone disease.