Quantitative grading of rat esophageal carcinogenesis using computer-assisted image tile analysis.
ABSTRACT Our objective was to grade, by computer-assisted quantitative image tile analysis, the intraepithelial neoplasia (also called dysplasia) that develops in esophagi of rats given N-nitrosomethybenzylamine (NMBA) for 5 weeks. To perform image tile analysis, the computer divides the video image of the neoplastic epithelium into a row of contiguous small rectangular images, or "tiles," 84 x 292 microm in size, and quantitatively measures four selected tissue features within each image tile. The computer then calculates a tile grade for each image tile as the weighted sum of the four feature measurements, transformed into statistical Z-scores, the weights being determined by Fisher linear discriminant analysis of 300 tile grades of the neoplastic epithelium referenced to the mean tile grade (MTG) of 300 image tiles of normal epithelium. The two grading parameters, MTG and the percentage of tile grades exceeding the MTG of normal epithelium by >4 SD units (%TG>4SD), were validated as endpoints for screening chemopreventive agents in the rat NMBA-induced esophageal carcinogenesis model in two ways: (a) after NMBA treatment, %TG>4SD developed in parallel with tumor incidence and tumor multiplicity (number of papillomas/tumor-bearing rat); and (b) placing the chemopreventive phenethylisothiocyanate in the food of NMBA-treated rats produced parallel reductions in MTG, tumor incidence, and tumor multiplicity. Both MTG and %TG>4SD, measured by quantitative image tile analysis, are sensitive and objective continuous parametric response variables expressed to three significant figures, with wide dynamic range, that may be evaluated by t tests to compare tissue neoplastic changes before and after treatment with a chemopreventive agent.
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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.Urology 05/2001; 57(4 Suppl 1):129-31. DOI:10.1016/S0090-4295(00)00956-0 · 2.13 Impact Factor
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ABSTRACT: Squamous cell carcinoma (SCC) of the human esophagus has a multifactorial etiology involving several environmental and/or genetic factors. Current modalities of therapy for this disease offer poor survival and cure rates. Although a number of approaches could be undertaken to reduce the occurrence of esophageal SCC, including changes in lifestyle and improved nutrition, such approaches are not easily implemented. Chemoprevention offers a viable alternative that is likely to be effective against this disease. Clinical investigations in areas of high incidence of esophageal SCC have shown that primary chemoprevention of this disease is feasible, if potent inhibitors are identified. Studies in the Fischer 344 rat model of nitrosamine-induced tumorigenesis have proven valuable in understanding the biology of esophageal SCCs and help identify surrogate end-point biomarkers and putative agents that can be useful in human chemoprevention studies. Several compounds that inhibit tumor initiation by suspected human esophageal carcinogens have been identified using this model. These include diallyl sulfide, isothiocyanates and several polyphenolic compounds. Novel biomarkers, including nuclear/nucleolar morphometry using computer-assisted image analysis of preneoplastic lesions, have been developed to measure efficacy of chemopreventive agents against esophageal SCC. The identification of single agents that inhibit the progression of dysplastic lesions, however, has proven difficult. Results from a food-based approach suggest that the use of freeze-dried berry preparations can affect both initiation and promotion/progression of esophageal SCC in an animal model. These observations provide valuable information for future studies on chemoprevention of cancers of the esophagus in a clinical setting. Given the complex etiology of esophageal SCC, it is felt that the most effective chemoprevention strategies would include agents that reduce mutational events associated with carcinogen exposure in combination with agents that inhibit the progression of intraepithelial dysplasia to invasive cancer.Carcinogenesis 12/2001; 22(11):1737-46. DOI:10.1093/carcin/22.11.1737 · 5.27 Impact Factor
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ABSTRACT: Biomedical imaging with light-scattering spectroscopy (LSS) is a novel optical technology developed to probe the structure of living epithelial cells in situ without need for tissue removal. LSS makes it possible to distinguish between single backscattering from epithelial-cell nuclei and multiply scattered light. The spectrum of the single backscattering component is further analyzed to provide quantitative information about the epithelial-cell nuclei such as nuclear size, degree of pleomorphism, degree of hyperchromasia and amount of chromatin. LSS imaging allows mapping these histological properties over wide areas of epithelial lining. Because nuclear enlargement, pleomorphism and hyperchromasia are principal features of nuclear atypia associated with precancerous and cancerous changes in virtually all epithelia, LSS imaging can be used to detect precancerous lesions in optically accessible organs.Nature Medicine 12/2001; 7(11):1245-8. DOI:10.1038/nm1101-1245 · 28.05 Impact Factor