title: Nuclear morphometry as an intermediate endpoint biomarker in chemoprevention of cervical carcinoma using alpha-difluoromethylornithine.
abstract: The use of nuclear morphometry as an intermediate endpoint biomarker is described in a Phase I, dose-seeking trial of chemoprevention of cervical cancer, using the agent alpha-difluoromethylornithine (DFMO). Thirty patients with grade III cervical intraepithelial neoplasia (CIN III) were enrolled, and these received daily doses of DFMO at 0.06-1.0 mg/m(2) for a period of 1 month. Fifteen patients were observed to have a complete or partial regressive response to the agent, as assessed by histopathology. No significant differences in cell feature measurements were found between responders and nonresponders in specimens obtained before treatment, indicating that it may be difficult to predict response on the basis of these measurements. In specimens collected after treatment, large differences in morphometric features were observed between responders and nonresponders, indicating a differential effect of DFMO. Significantly modulated features were considered in terms of their correlations with CIN grade, which was determined from an independent set of measurements from archival tissue. Differences between features were consistent with a deletion of cells with high grade nuclei in the responders, and with the persistence of a more heterogeneous population of high grade cells in the nonresponders. Based on an independent set of measurements from archival material, a morphometric index of progression was derived, yielding a quantitative measure of the degree of nuclear atypia in these lesions. When applied to this trial, the morphometric index was seen to be specifically and consistently decreased in responsive lesions, and unchanged in nonresponders. The study indicates that morphometric features fulfill the requirements for an intermediate endpoint biomarker of cervical cancer chemoprevention.
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Poulin
authors.forename: I
authors.initials: I
authors.lastname: Boiko
authors.forename: C
authors.initials: C
authors.lastname: MacAulay
authors.forename: C
authors.initials: C
authors.lastname: Boone
authors.forename: K
authors.initials: K
authors.lastname: Nishioka
authors.forename: W
authors.initials: W
authors.lastname: Hittelman
authors.forename: M F
authors.initials: MF
authors.lastname: Mitchell
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002467:Cell Nucleus / Q000473:pathology*; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D019044:Image Cytometry / Q000379:methods; D007091:Image Processing, Computer-Assisted; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D000518:Eflornithine