No abstract

In this study we evaluated the physiological variation of free and total prostatespeci®c antigen (PSA) levels to determine how the percent freeatotal PSA was affected. Twenty four patients had blood drawn for ten consecutive weekdays. The percent coef®cient of variation (%CV) of biological variation was calculated. The results were log-normally distributed with geometric means of 12.0% CV, 7.3% CV, and 8.8% CV for free, total, and percent freeatotal PSA, respectively. When applied, the percent freeatotal, PSA would need to¯uctuate by 31% to indicate that a signi®cant change (critical difference, P`0.05) between two measurements had occurred. Biological variation of PSA measurements is substantial.

All neoplasms require angiogenesis and resulting neovascularity for growth beyond 1 mm 2 . Quantitative microvessel density (MVD) has been shown to provide staging and prognostic signi®cance in human prostate cancer (CaP). recently, it has been demonstrated that loss of the wild-type allele of the p53 tumour suppressor gene results in reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. There is also an increased expression of vascular endothelial growth factor which promotes neovascularization. p53 gene mutation and MVD were investigated in men with prostate cancer. Sections from 103 radical prostatectomy cases were evaluated with immunohistochemistry to detect mutant p53 proteins. Quantitative MVD was performed on the cases exhibiting p53 positive staining and compared with negative ®elds of similar Gleason grade on the same histologic sections.Twenty of the 103 cases (19.4%) revealed positive p53 staining nuclei. In 19 of these 20 cases, the MVD in p53 positive areas was greater than corresponding control regions (overall P`0.0001). Extent of p53 abnormality, as well as MVD, correlated with pathologic stage.These data suggest that mutations of the p53 tumour suppressor gene may be associated with increased angiogenesis in CaP. In addition to providing staging and prognostic information, this relationship potentially has therapeutic implications.

Because prostate cancer has a long latency and high incidence, it is a good target for chemoprevention by agents such as retinoids, antiandrogens, antiestrogens, and vitamin D analogs. Phase II chemoprevention trials are frequently conducted on cohorts of patients with previous cancers or premalignant lesions who are scheduled for prostate cancer surgery; such trials are currently in progress with several agents. Prostatic intraepithelial neoplasia (PIN) can be used as a surrogate endpoint biomarker for prostate cancer incidence. Studies of men with highgrade PIN (HGPIN) are particularly useful in that they require a much smaller cohort of 200±400 patients instead of the 18 000 patients required for typical Phase III trials. Even with a smaller sample size, statistically signi®cant evidence of cancer prevention is achieved due to the high probability of HGPIN progressing to cancer (35±55%). A Bayesian sequential monitoring system allows interim analysis of biomarker modulation as early as the completion of 30 patients. Putting all these strategies together will help inhibit, delay, or modulate the natural history of prostate carcinogenesis.