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.
Prostate-specific antigen (PSA) has emerged as the most predictive test of whether or not a man has prostatic carcinoma. The free to total PSA ratio provides important enhancement in specificity, thus obviating unnecessary negative biopsies. In the absence of an international standard for total PSA, much less free PSA, variation between manufacturers may cause confusing results. We sought to compare three different manufacturer's free and total PSA assays in a population consisting of consecutive patients who had PSA testing in a reference laboratory in Germany. Between April 1994 and July 1996, serum specimens from 240 men were evaluated with three different free and total PSA assays. Indications for PSA determination were based on the referring physician, who also provided the clinical diagnosis. Total and free PSA were measured on the same freeze-thaw cycle with Chiron Diagnostics, Enzymun Boehringer Mannheim, and Hybritech Tandem-R assays. Seventy-nine men had carcinoma of the prostate, 120 had clinical evidence of benign prostatic hyperplasia and 27 were without evidence of prostatic disease. The Chiron ACS: 180 free to total ratio compared very well with the Tandem-R assay at the 95% sensitivity level, affording 17 and 22% specificity respectively. Using the range of total PSA of 4-10 ng/ml, the increase in specificity of the free to total PSA is quite significant, and the specificity of the Enzymun assays is greatly improved. (Specificity of 49%, 29% and 25% at 95% sensitivity for ACS, Enzymun and Tandem respectively.) This data, based on 'real world' clinical experience, shows significant variation between different manufacturers' assays. There was significant equivalence between the Chiron and Hybritech assays. The Enzymun assay performed well only when data from the total PSA range of 4-10 ng/ml was included. Clinicians must be aware of which manufacturers' assays for both the free and total PSA their laboratory staff is utilizing, and laboratory technicians must provide meaningful outcome data based on the patient population they serve with respect to the performance of these assays.
This session included ®ve presentations in the areas of pathology of precursor lesions and carcinoma of the prostate, the value of determining neovascularity in the diagnosis and staging of prostate cancer, new`molecular' markers, correlation between pre-and postoperative Gleason scores and a study dealing with transition zone PSA density. The abstracts and talks are summarized in the next few pages.Keywords: prostate cancer; prostatic intraepithelial neoplasia; pathology; molecular markers
Pathology of premalignant lesions and carcinoma of the prostate WA SakrWhile the presentation discussed the anatomy and normal histology of the prostate and the morphologic changes of nodular hyperplasia, metaplastic processes and the changes associated with therapy effects, the limited scope of this summary will restrict the discussion to the pathology of neoplastic changes: Premalignant lesions (high grade PIN in particular) and the diagnosis, grading and staging of prostate cancer.
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