Phase II Trial of Chemopreventive Effects of Levonorgestrel on Ovarian and Fallopian Tube Epithelium in Women at High Risk for Ovarian Cancer: An NRG Oncology Group/GOG Study.

A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO.

Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases.

This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded.

Classification in karyometry: performance testing and prediction error.

Classification plays a central role in quantitative histopathology. Success is expressed in terms of the accuracy of prediction for the classification of future data points and an estimate of the prediction error. The prediction error is affected by the chosen procedure, e.

Karyometry of nuclear phenotypes in cutaneous squamous cell cancer.

Objective: To establish the karyometric characteristics of the two main nuclear phenotypes in cutaneous squamous cell cancer (cSCC) lesions.

Study Design: The clinical materials comprised 75 cases of cSCC, 38 with aggressive lesions and 37 with nonaggressive lesions. High-resolution images of 100 nuclei per case were recorded.

Karyometry in atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

Objectives: Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC).

A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry.

Objective: Presurgical, window of opportunity trials have been proposed as a model to assess the activity of preventive and therapeutic interventions in a cost-effective manner in prostate cancer (CaP). The aim of the study was to explore karyometry as a method for monitoring the efficacy of intervention with preventive agents in patients with CaP.

Materials And Methods: The material used in this investigation was from the 2F study, i.

Nuclear morphometry identifies a distinct aggressive cellular phenotype in cutaneous squamous cell carcinoma.

By identifying aggressive cutaneous squamous cell carcinoma (cSCC) in patients who are at high risk for recurrences or second primaries after resection, intensive surveillance and therapy may decrease morbidity and mortality. We investigated the role of nuclear morphometry (karyometry) in differentiating between aggressive and nonaggressive cSCC. We retrospectively analyzed cSCC lesions from 40 male patients.

Discriminant analysis.

Objective: To present a fully worked numerical example for the derivation of a discriminant function in order to provide insight into the processing steps and origin of the function coefficients.

Study Design: The example begins with the reduction of a set of raw data to the values needed to calculate the variance/covariance matrix. Next the inversion of the covariance matrix by pivotal condensation is carried through.

A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer.

The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w).

Knowledge discovery processing and data mining in karyometry.

Objective: To present the rationale for applying different sequences of multivariate analysis algorithms to determine if and where, in the large and high-dimensional data space, events have led to change in karyometric features.

Study Design: Clinical materials and results from the analysis of 4 studies were used: the demonstration of chemopreventive efficacy of letrozole in a situation where only a small subset of cells is affected, the detection of a preneoplastic lesion in colorectal tissue, data processing to document clues that predict risk of recurrence of a bladder lesion and the use of metafeatures and second-order discriminant analysis in a study of efficacy of vitamin A in the chemoprevention of skin lesions.

Results: Evidence for chemopreventive efficacy was demonstrated in the first example only after processing identified the small subpopulation of affected nuclei in a study of breast epithelial cells.

Decision support systems for morphology-based diagnosis and prognosis of prostate neoplasms: a methodological approach.

Recent advances in computer and information technologies have allowed the integration of both numeric and non-numeric data, that is, descriptive, linguistic terms. This has led at 1 end of the spectrum of technology development to machine vision based on image understanding and, at the other, to decision support systems. This has had a significant impact on our capability to derive diagnostic and prognostic information from histopathological material with prostate neoplasms.

Karyometry: correction algorithm for differences in staining.

Objective: To describe an algorithm that allows the correction of differences in staining of histopathologic sections while preserving chromatin texture.

Study Design: In order to preserve the texture of the nuclear chromatin in the corrected digital imagery, it is necessary to correct the images pixel for pixel. This is accomplished by mapping each pixel's value onto the cumulative frequency distribution of the data set to which the image belongs, to transfer to the cumulative frequency distribution of the data set serving as standard and to project the intersection down onto the pixel optical density scale for the corrected value.

Progression of skin lesions from normal skin to squamous cell carcinoma.

Objective: To assess the changes in the nuclear chromatin pattern concomitant with progressive sun damage in skin biopsies ranging from sun-exposed, normal-appearing skin to squamous cell carcinoma (SCC).

Study Design: Biopsies were taken from 140 cases with sun-exposed but histopathologically normal skin, from 20 cases visually assessed as pre-actinic keratosis (pre-AK) or early AK, from 30 cases of AK, and from 21 cases of SCC. A total of 21,094 nuclei were recorded from these biopsies.

Actinic damage in histopathologically normal skin.

Objective: To establish measures of sun damage in histopathologically normal skin.

Study Design: Biopsies were taken from the upper inner arm, representing skin with presumably minimum sun exposure, from skin of the forearm with no visible sun damage, from skin of the forearm with visible sun damage and from normal-appearing skin from the forearm of individuals who had sun exposure that had resulted in actinic keratosis (AK) lesions. In addition, a data set of nuclei from AKs was recorded.

Digital image analysis of breast epithelial cells collected by random periareolar fine-needle aspirates (RPFNA) from women at high risk for breast cancer taking hormone replacement and the aromatase inhibitor, letrozole, for six months.

Aromatase inhibitors are currently being evaluated as preventive agents in post-menopausal women at high risk for breast cancer. A phase II trial of 42 women on hormone replacement therapy (HRT) treated with letrozole for 6 months showed Ki-67 was reduced by 66% but showed no change in cytomorphology or Masood score. Subsequent image analytical procedures (karyometry) conducted on a subset of the samples captured subvisual information that showed reduced cellular abnormality after 6 months of letrozole.

Limits of detection of chemopreventive efficacy: karyometry of skin biopsies.

Objective: This study was designed to establish estimates of the smallest effects due to chemopreventive intervention detectable by karyometry in skin biopsies.

Methods: Estimates of the smallest change of statistical significance and estimates of the power of the test were derived for several key features descriptive of the distribution of nuclear chromatin. Results from triplicate biopsies from the same case were used to provide estimates of the within-case, biopsy-to-biopsy variance.

Karyometry of the colonic mucosa.

Objective: The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma.

Methods: Karyometric analyses were done on high-resolution images of histologic sections from 48 patients with colorectal adenocarcinomas and 44 patients with adenomas and on images from matching normal-appearing mucosa directly adjacent to such lesions, at a 1-cm and 10-cm distance from the lesions or from the rectal mucosa of adenoma patients, as well as from 24 healthy normal controls with no family history of colonic disease.

Results: The nuclei recorded in the histologically normal-appearing mucosa of patients with either colorectal adenoma or adenocarcinoma exhibited differences in karyometric features in comparison with nuclei recorded in rectal mucosa from patients who were free of a colonic lesion.

Karyometry of breast epithelial cells acquired by random periareolar fine needle aspiration in women at high risk for breast cancer.

Objective: To establish whether karyometry was likely to detect change in the proportion of abnormal cells in random periareolar fine needle aspiration (RPFNA) specimens from high-risk women in a 6-month prevention trial with an aromatase inhibitor.

Study Design: Papanicolaou-stained ThinPrep slides of RPFNA samples from 11 of 42 women were digitally recorded at high resolution, with 200 cells measured per slide, at baseline (BL) and at the end of study (ES) after 6 months. The nuclear chromatin pattern characteristics were assessed by multivariate analytic techniques; determination of nuclear abnormalities was performed and cells that showed expression of abnormality were identified.

Chromatin phenotype karyometry can predict recurrence in papillary urothelial neoplasms of low malignant potential.

Background: A preceding exploratory study (J. Clin. Pathol.

Carcinogenesis and the hypothesis of phylogenetic reversion.

Chemoprevention must target early molecular events involved in malignant transformation. The sequence of events leading from a normally functioning interphase cell to an uncontrolled tumor cell is only partially understood, impeding systematic design of chemopreventive agents. The respective roles of mutagenic and epigenetic mechanisms have not been definitively established.

The evolution of scanning microphotometry: a historical review.

This article traces the evolution of scanning microphotometry from its beginning, with an emphasis on the developing technologies that have made feasible the rapid and detailed capture of high-resolution image information. Consideration is given to future directions that may prove fruitful to clinical practice.

Karyometry of infiltrating breast lesions.

Objective: To characterize nuclei from well-differentiated, moderately differentiated and poorly differentiated lesions of invasive breast cancer by karyometry and to test the hypothesis that these diagnostic categories form homogeneous sets.

Study Design: Histopathologic sections from 6 cases of well-differentiated, 11 cases of moderately differentiated and 17 cases of poorly differentiated ductal carcinomas were digitally recorded. From each case 100 nuclei were segmented and analyzed by karyometry.

Karyometry in rectal mucosa of patients with previous colorectal adenomas.

Objective: To determine whether karyometric measurements taken in biopsies from histologically normal-appearing rectal mucosa could serve as a biomarker for the risk of recurrence of polyps.

Materials And Methods: Biopsies were taken from the rectal mucosa of cases with a prior history of colonic polyps at the baseline of the study. In 57 cases recurrent polyps occurred (R cases); in 72 cases no recurrent disease was found at the end of the study (NR cases).