Gene/Protein Disease Symptom Drug Enzyme Compound
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 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to characterize the pathological features of hereditary prostate cancer, a recently recognized variant of prostate cancer with an autosomal dominant inheritance of a rare highly penetrant gene associated with early onset of disease. We compared the histology at radical prostatectomy of clinical stage T2 prostate cancer, including its relationship to prostatic intraepithelial neoplasia, in men with a family history of prostate cancer to those without a family history of prostate cancer. Three cohorts (hereditary, familial and sporadic) were identified based on pedigree analysis. A hereditary subgroup (28 patients) met 1 of the following 3 criteria: 1) cluster of greater than 3 affected relatives within the nuclear family, 2) occurrence of prostate cancer in each of 3 generations in either the proband paternal or maternal lineage, or 3) a cluster of 2 relatives affected at an early age of less than 55 years. This subgroup was compared to an age-matched subgroup with family history of prostate cancer (26 patients) yet the aforementioned conditions for inclusion within the hereditary subgroup were not met and to a sporadic subgroup without a family history of prostate cancer (27 patients). All parameters were statistically similar among the groups except that hereditary and familial group multifocal tumors were of lower grade (p = 0.0001), sporadic cases had a greater proportion of small multifocal cancers associated with prostatic intraepithelial neoplasia (p = 0.02) and the familial group had a weaker correlation between total tumor volume and grade. In conclusion, our analysis failed to demonstrate substantial pathological differences among hereditary, familial and sporadic forms of prostate cancer. Rather, our data are remarkable for the wide range of all parameters studied in each group. Even the sporadic cases had features, such as increased numbers of precursor lesions and tumor multifocality, which in other organs are commonly associated with either hereditary cancer or cancer arising in a field effect due to diffuse exposure to a carcinogen.
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PMID:Pathological features of hereditary prostate cancer. 785 89

Positive family history is a significant risk factor for prostate cancer. Improved knowledge of the epidemiology and molecular basis of hereditary prostate cancer has led to a need for counseling and clinical follow-up for men with a positive family history of prostate cancer. However, very little information is available on the efficacy of early screening procedures, such as serum prostate-specific antigen (PSA) measurements, in the management of genetically predisposed, high-risk individuals. In a nationwide study, we obtained family histories from 2099 Finnish prostate cancer patients and identified 302 families with two or more affected cases. Here, 209 asymptomatic 45-75-year-old males from these families were included in a study to determine the frequency of serum PSA positivity and the prevalence of subclinical prostate cancers. Serum PSA was elevated in 21 (10.0%) of these high-risk individuals. Seven prostate cancers (3.3%) and two high-grade prostatic intraepithelial neoplasia lesions were diagnosed, with three cancers occurring in men ages < or = 59 years. Men from prostate cancer families with an average age of onset of < 60 years had a significantly higher frequency of PSA positivity (28.6%, P = 0.01) as well as cancers (14.3%, P = 0.02) than those with a later age of onset. The results suggest that prostate cancer development in genetically predisposed individuals is preceded by a subclinical period when PSA detection is possible. Serum PSA screening may be particularly useful in men with a family history of early-onset prostate cancer.
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PMID:Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. 1038 9

A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life. Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention. The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. In summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic and acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention.
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PMID:Prostate cancer chemoprevention: Strategies for designing efficient clinical trials. 1129 33