Actinic Keratosis (AK) arises from sun-damaged skin and is the first clinical manifestation in the multistep process of skin carcinogenesis to invasive squamous cell carcinoma. Thus, it is an ideal target for chemopreventive efforts. Noninvasive measures of AK severity are needed to assess the efficacy of chemoprevention agents. We performed a pilot study on 20 participants to investigate the OCT appearance of sun-protected skin of the upper inner arm as well as sun-damaged skin and early AKs of the dorsal forearms, and to determine if features or quantitative measures in Optical Coherence Tomography (OCT) images could be used to reliably differentiate between these categories. OCT images of upper inner arm (normal appearing skin) showed skin layers and features (stratum corneum, epidermis, dermis, blood vessels) seen in previous studies; additionally in this participant group the subcutaneous fat layer was usually identified. Sun-damaged skin was characterized by increased signal in the epidermis and rapid attenuation of light. AKs were diverse in appearance but frequently characterized by high surface reflection, the presence of a low-signal band in the stratum corneum, and heterogeneous appearance in the epidermis/dermis. Significant differences were found between skin categories using measures of stratum corneum and epidermal/dermal depths and intensities. The presence of a dark band in the stratum corneum was 79% sensitive and 100% specific for AK. This study indicates that OCT holds promise as a useful technique for identifying and characterizing AKs and monitoring their response to chemoprevention agents.

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BACKGROUND. A considerable body of evidence supports the concept that a significant number of cutaneous malignant melanomas progress through a precursor lesion or dysplastic melanocytic nevi (DN). Tumor angiogenesis likely plays a critical role in early development of melanoma, and intermediate biomarkers of angiogenesis could be useful as chemoprevention and prognostic markers. METHODS. Markers of angiogenesis that included expression of the vascular endothelial growth factor A (VEGF-A) and microvessel density counts (MVD) were evaluated in 13 prospectively collected benign nevi (BN) and 19 DN from 16 individuals and in a comparison group of 17 primary melanomas (16 archival samples and 1 prospective melanoma). RESULTS. VEGF expression in melanocytic cells (mean AE standard error [SE]) was low or absent in BN (3.4 AE 1.4), increased significantly in DN (41.0 AE 10.1; P 5 .0003 for BN vs DN), and increased further in primary melanoma (119.9 AE 28.3; P 5 .06 for DN vs melanoma). MVD using CD31 (mean AE SE [percentage 3 intensity]) followed a similar pattern with similarity between BN (2.6 AE 0.7; N 5 13) and DN (2.2 AE 0.8; N 5 19; P 5 .4 for BN vs DN), whereas primary melanomas were significantly higher (39.4 AE 6.4; N 5 17; P 5 .0001 for BN or DN vs melanoma). CONCLUSIONS. In a prospective setting, the current data suggested that increased VEGF-A expression in DN may be a good indicator of preneoplastic change in melanocytic lesions with the potential for improving the understanding and prevention of the transformation of DN to melanoma.

Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU/ day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU/day would be both safe and more efficacious in skin cancer chemoprevention.Experimental Design: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25,000, 50,000, or 75,000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sundamaged skin.Results: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25,000 IU/day, 50,000 IU/day, and 75,000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22,600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25,000 and 50,000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor ␣, retinoic acid receptor ␤, and retinoid X receptor ␣ at the 50,000 IU/day vitamin A dose.Conclusions: The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.

Objectives: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. Methods: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. Results: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 F 1.2% for p53, 65.5 F 1.9 nmol/g for putrescine, and 187.7 F 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 F 2.3% for p53, P = 0.0001; 81.7 F 3.9 nmol/g for putrescine, P = 0.0001; 209.4 F 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. Conclusions: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1841 -8)