Limits of Detection of Chemopreventive Efficacy: Karyometry of Skin Biopsies

Bartels, Peter H.; Yozwiak, Michael; Bartels, Hubert G.; Liu, Yun; Hess, Lisa M.; Alberts, David S.

doi:10.1158/1055-9965.epi-08-0313

Cited by 2 publications

(2 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These negative biomarker results match those observed in our prior positive skin cancer chemoprevention studies of oral vitamin A and topical difluoromethylornithine (18–20). On the other hand, karyometric analysis of nuclear chromatin abnormality in baseline and end-of-study sun-damaged skin once again has proven useful as an “integrating biomarker” of response to chemopreventive agent activity (13, 18–23).…”

Section: Discussionsupporting

confidence: 86%

A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Stratton

Alberts

Einspahr

et al. 2010

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

Chemopreventive and antitumor properties of perillyl alcohol (POH) studied preclinically indicate that topical POH inhibits both ultraviolet B (UVB)-induced murine skin carcinogenesis (squamous cell tumor models) and DMBA-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous Phase 1 clinical trial in participants with normal-appearing skin demonstrated that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here we performed a three month, double-blind, randomized, placebo-controlled Phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower dose of POH compared to placebo (p = 0.1), but this was not observed in the high dose group. However, in the high dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed using karyometric analysis (p< 0.01). There was no statistical significance demonstrated in the lower dose group. No changes were observed in p53 expression, cellular proliferation (by PCNA expression), or apoptosis in either treatment group compared to placebo. These results suggest that while our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary.

show abstract

Section: Discussionsupporting

confidence: 86%

A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Stratton

Alberts

Einspahr

et al. 2010

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our study builds upon numerous earlier efforts that have applied digital nuclear morphometry to questions involving risk and prognosis in cancer of the breast [10], cervix [2], oropharynx/lung [11], colon [12], skin [13] and prostate. In the prostate, nuclear morphometry has been shown to detect abnormalities in benign tissue adjacent to cancer and HGPIN [14], [15].…”

Section: Discussionmentioning

confidence: 99%

Development of a Nuclear Morphometric Signature for Prostate Cancer Risk in Negative Biopsies

et al. 2013

View full text Add to dashboard Cite

BackgroundOur objective was to develop and validate a multi-feature nuclear score based on image analysis of direct DNA staining, and to test its association with field effects and subsequent detection of prostate cancer (PCa) in benign biopsies.MethodsTissue sections from 39 prostatectomies were Feulgen-stained and digitally scanned (400×), providing maps of DNA content per pixel. PCa and benign epithelial nuclei were randomly selected for measurement of 52 basic morphometric features. Logistic regression models discriminating benign from PCa nuclei, and benign from malignant nuclear populations, were built and cross-validated by AUC analysis. Nuclear populations were randomly collected <1 mm or >5 mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3–5. Nuclei also were collected from negative biopsy subjects who had a subsequent diagnosis of PCa and age-matched cancer-free controls (20 pairs).ResultsA multi-feature nuclear score discriminated cancer from benign cell populations with AUCs of 0.91 and 0.79, respectively, in training and validation sets of patients. In prostatectomy samples, both nuclear- and population-level models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or from PCa-free glands. In negative biopsies, a validated model with 5 variance features yielded significantly higher scores in cases than controls (P = 0.026).ConclusionsA multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies.ImpactThis nuclear score shows promise as a risk predictor among men with negative biopsies and as an intermediate biomarker in Phase II chemoprevention trials. The results also suggest that subvisual disturbances in nuclear structure precede the development of pre-neoplastic lesions.

show abstract

Limits of Detection of Chemopreventive Efficacy: Karyometry of Skin Biopsies

Cited by 2 publications

References 2 publications

A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Development of a Nuclear Morphometric Signature for Prostate Cancer Risk in Negative Biopsies

Contact Info

Product

Resources

About