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Objective. This trial examined the use of 4-hydroxyphenylretinamide (4-HPR), demonstrated to be a potent inhibitor of carcinogenesis in vitro and in animal models, in patients with cervical intraepithelial neoplasia (CIN) grades 2 to 3. Quantitative pathology and chromosome 9 polysomy were used to understand the bi ology and quantify the clinical histopathologic changes observed. Methods. Patie nts were randomized to 4-HPR or placebo for 6 months and followed for six more months. Cervical biopsies were obtained at baseline, 6 months, and 12 months; th e biopsies were read blinded three times by the study pathologist. Feulgen-stai ned sections were also obtained and analyzed using computer-assisted image cyto metry. Chromosome 9 polysomy was performed on tissue slices using in situ hybrid ization and measured quantitatively. Statistical analyses were carried out in S -Plus (Insightful Corporation, Seattle, WA) and R. Results. The interim analysi s, planned for 40 patients, was carried out on 39. The 6-and 12-month analyses showed a statistically significant difference between the two study arms. When code was broken, the 4-HPR-treatment arm was found to have fared less well tha n placebo. Analyses of Feulgen-stained sections provided a quantitative measure of the increase of DNA content and texture features. Chromosome 9 polysomy was also measured using image analysis. The changes observedwere consistentwith those of cells displaying cancerous change s, indicating a lack of response. Conclusion. 4-HPR is not active at 200 mg/day . The interim analysis was helpful in directing the study; and, in this case, en ding it. The intermediate endpoint biomarkers of quantitative histomorphometry a nd chromosome 9 polysomy yielded quantitative and repeatable results consistent with the findings of the clinical pathologist.
Objective. This trial examined the use of 4-hydroxyphenylretinamide (4-HPR), demonstrated to be potent inhibitor of carcinogenesis in vitro and in animal models, in patients with cervical intraepithelial neoplasia (CIN) grades 2 to 3. Quantitative pathology and chromosome 9 polysomy were used to understand the biology and quantify the clinical histopathologic changes observed. Methods. Patie nts were randomized to 4-HPR or placebo for 6 months and followed for six more months. Cervical biopsies were obtained at baseline, 6 months, and 12 months; th e biopsies were read blinded three times by the study pathologist. Feulgen-stai ned sections were also obtained and analyzed using computer-assisted image cyto metry. Chromosome 9 polysomy was performed on tissue slices using in situ hybridization and measured quantitatively Statistical analyzes were carried out in S-Plus (Insightful Corporation, Seattle, WA) and R. Results. The interim analysis, planned for 40 patients, was carried o ut on 39. The 6-and 12-month analyzes showed a significant significant difference between the two study arms. When code was broken, the 4-HPR-treatment arm was found to have fared less well tha n placebo. Analyzes of Feulgen- stained sections provided a quantitative measure of the increase of DNA content and texture features. Chromosome 9 polysomy was also measured using image analysis. The changes observedwere consistentwith those of cells displaying cancerous change s, indicating a lack of response. Conclusion. 4-HPR is not active at 200 mg / day. The interim analysis was helpful in directing the study; and, in this case, en ding it. The intermediate endpoint biomarkers of quantitative histomorphometry a nd chromosome 9 polysomy yielded quantitative and repeatable results consistent with the findings of the clinical pathologist.