title: Computer-assisted image analysis-derived intermediate endpoints.
abstract: The development of prostatic lesions undergoes a slow progression. To establish efficacy of chemopreventive intervention it is therefore necessary to define surrogate endpoint biomarkers. Such biomarkers should be sensitive in their ability to indicate response. They should be objective, ie, the result of measurement, and numerically defined so that a statistical validation of response is possible. They should be able to indicate not only a halt of progression of a lesion, but also a reversal of progression. The spatial and statistical distribution of nuclear chromatin in the secretory and luminal cells in prostatic intraepithelial neoplastic lesions has been shown to be well defined. It can be represented by a set of features. These have been used to define a progression curve along which progression or regression of a lesion can be assessed. One could define a fixed endpoint, or one might choose to accept a statistically significant regression along the progression curve as criterion for chemopreventive efficacy. Expected difficulties could arise from lesion heterogeneity, as it would affect the sampling, and from multifocal lesions of differing progressions. Lesion heterogeneity thus limits the precision with which regression could be detected. These problems might be partially overcome by observations taken in histologically normal appearing regions of the prostate. The nuclear chromatin pattern of secretory cell nuclei measured in such tissue regions from prostates harboring intraepithelial or malignant lesions has been shown to exhibit distinctive changes from the chromatin pattern seen in secretory cell nuclei from prostates free from any such lesions. These changes appear to be expressed in the tissue up to a substantial distance from a lesion. The expression of changes in the nuclear chromatin suggests the existence of an intraepithelial preneoplastic lesion that can be detected by biomarkers, but which is not apparent from visual microscopic inspection. Since chemoprevention might be expected to be most effective at the earliest stages of lesion development, the assessment of such early alterations is seen as highly relevant to efforts to validate the efficacy of chemopreventive intervention.
authors: National Cancer Institute, Bethesda, Maryland, USA.
authors: C W
authors: CW
authors: Boone
authors: R
authors: R
authors: Lieberman
authors: T
authors: T
authors: Mairinger
authors: B
authors: B
authors: Palcic
authors: J
authors: J
authors: Bacus
authors: P
authors: P
authors: Bartels
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002843:Chromatin; D018450:Disease Progression; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008297:Male; D019048:Prostatic Intraepithelial Neoplasia / Q000473:pathology* / Q000517:prevention & control / Q000648:ultrastructure; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000517:prevention & control / Q000648:ultrastructure; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin