Stuart J. Salasche

Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers

A biomarker of skin cancer would be beneficial in evaluating the efficacy of potential cancer chemoprevention agents. To this end, we investigated the tumor suppressor gene p53 in precancerous actinic keratosis lesions (AK) and malignant squamous cell carcinomas (SCCs) using polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP) techniques. In addition, p53 protein expression was evaluated using immunohistochemistical analysis with the PAB 1801 monoclonal antibody. Nine out of 13 (69%) SCCs and 8 of 15 (53%) AKs were positive for p53 mutations. In contrast, normal skin samples were negative for p53 mutations. Sequence analysis of AKs and SCCs showed primarily C to T transition mutations. Nuclear immunochemical staining for p53 was observed in 12/15 (80%) AK and 12/13 (92%) SSCs. These results suggest that p53 mutations may be involved in the malignant conversion of AKs to SCCs and that p53 may be useful as a biomarker to study the potential modulatory effects of cancer chemopreventive agents against skin cancer.

Investigating Sun-damaged Skin and Actinic Keratosis with Optical Coherence Tomography: A Pilot Study

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.

Safety and Efficacy of Dose-Intensive Oral Vitamin A in Subjects with Sun-Damaged Skin

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 sun-damaged 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 α, retinoic acid receptor β, and retinoid X receptor α 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.

Skin Cancer as a Contraindication to Organ Transplantation

Skin cancer is the most common malignancy worldwide. When patients with a history of skin cancer present for organ transplantation, the vast majority are appropriate candidates. However, there is little guidance in the literature regarding the advisability of transplantation in patients with a history of high‐risk skin cancer. With limited allograft resources, it is important to allocate organs to patients who will derive the most benefit. Adverse outcomes that may be associated with prior skin cancer include recurrence, metastasis, or death from relapse or decreased quality of life from numerous new primary skin cancers. This review provides prognostic guidance to transplant physicians evaluating transplantation candidates who have a history of skin cancer.

Cross-validation of Murine UV Signal Transduction Pathways in Human Skin

Acute UVB irradiation of mouse skin results in activation of phospatidyinositol‐3 (PI‐3) kinase and mitogen‐activated protein kinase (MAPK) pathways leading to altered protein phosphorylation and downstream transcription of genes. We determined whether activation of these pathways also occurs in human skin exposed to 4× minimal erythemic dose of UVB in 23 volunteers. Biopsies were taken prior to, at 30 min, 1 and 24 h post‐UVB. In agreement with mouse studies, the earliest UV‐induced changes in epidermis were seen in phospho‐CREB (two‐ and five‐fold at 30 min and 1 h) and in phospho‐MAPKAPK‐2 (three‐fold at both 30 min and 1 h). At 1 h, phospho‐c‐JUN and phospho‐p38 were increased five‐ and two‐fold, respectively. Moreover, phospho‐c‐JUN and phospho‐p38 were further increased at 24 h (12‐ and six‐fold, respectively). Phospho‐GSK‐3β was similarly increased at all time points. Increases in phospho‐p53 (12‐fold), COX‐2 (four‐fold), c‐FOS (14‐fold) and apoptosis were not seen until 24 h. Our data suggest that UVB acts through MAPK p38 and PI‐3 kinase with phosphorylation of MAPKAPK‐2, CREB, c‐JUN, p38, GSK‐3β and p53 leading to marked increases in c‐FOS, COX‐2 and apoptosis. Validation of murine models in human skin will aid in development of effective skin cancer chemoprevention and prevention strategies.

Phase 1 Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Perillyl alcohol (POH) is a natural product derived from plants such as cherry and lavendin. Previous studies have indicated that topical POH inhibits ultraviolet (UV) B-induced skin carcinogenesis in vivo, and it may be an effective chemopreventive agent for skin cancer. We performed a 1-mo, first-in-man, Phase 1 trial of topically administered POH cream in human subjects. Endpoints included safety and evaluation of any histopathological changes in skin after 1 mo use of POH cream. We randomized 25 subjects with normal, healthy skin with little or no sun damage and no history of skin cancer in a double-blind fashion to receive topical POH (0.76% wt/wt) on 1 forearm with placebo cream applied to the other forearm twice daily for 30 days. Subjects were monitored for toxicity, and a 4 mm punch biopsy in the treated area was performed at the end of study for histopathological evaluation. The topical cream was well tolerated. No serious cutaneous toxicities, systemic toxicities, or histopathological abnormalities were observed. A total of 8 subjects (32%) reported mild adverse events possibly or probably related to use of cream including reversible appearance of 1 to 2 small papules. However, there was no significant difference between lesions appearing on the POH treated forearm vs. the placebo-treated forearm.

How to “Peer Review” a Medical Journal Manuscript

BACKGROUND The accuracy, validity, and appropriateness of what gets published in the medical literature depends upon a pool of competent peer referees. However, the requisite skills needed to become such a peer are not taught at the residency training program level or subsequently by the journals themselves, who offer no training and little written instruction. OBJECTIVE To outline a logical, orderly approach to the task of reviewing a “raw” medical manuscript. By breaking the overall endeavor down into smaller, step‐by‐step components, the novice reviewer should attain the direction and skills to complete a review with confidence. METHODS Explore the role of the reviewer, discuss the philosophy of review, identify the key elements to look for when reading and rereading the manuscript, and outline a orderly approach to the decision making process. CONCLUSIONS A “peer” is a physician with expertise on the subject under scrutiny who spends sufficient time and thought to fulfill two main obligations: to render an honest, unbiased decision on whether or not the manuscript should be published and, if it is acceptable, to help make it better. It is possible to perform the review process in a relatively simple, organized, and logical manner.

Recognition and management of the high-risk cutaneous squamous cell carcinoma

Abstract The incidence of cutaneous squamous cell carcinoma (SCC) has increased dramatically. Although the majority of these tumors are easily managed and cured using standard treatment, a certain percentage metastasize to regional nodes and subsequently to distant organs, resulting in death. This article reviews pertinent risk factors that cause these tumors to be more prone to metastasize and discusses available treatment choices for preventing metastases. Specific cases of metastasis are reviewed to illustrate various management principles.

Isotretinoin-basal cell carcinoma prevention trial: Design, recruitment results, and baseline characteristics of the trial participants

The Isotretinoin-Basal Cell Carcinoma Prevention Trial (ISO-BCC Study) is a double-masked, randomized, placebo controlled, multicenter clinical trial. It is the first intramural cancer chemoprevention trial sponsored by the Division of Cancer Prevention and Control of the National Cancer Institute. This trial was designed to evaluate the effectiveness of chronic administration of low dosage levels (10 mg) of a synthetic retinoid, isotretinoin, in reducing the incidence of basal cell carcinoma in a high-risk population and to determine the incidence and severity of side effects associated with this long-term treatment. Between 1984 and 1987, eight clinical centers enrolled 981 participants between the ages of 40 and 75, who had two or more biopsy proven basal cell carcinomas in the 5 years before trial entry. This article describes the trial design, recruitment results, and baseline characteristics of the participant population in the ISO-BCC Study.

Imiquimod 5% cream: a new treatment option for basal cell carcinoma.

The introduction of imiquimod 5% cream, the first member of the immune response modifiers (IRMs) has given clinicians a noninvasive, patient-administered, topical approach to anogenital warts. Equally exciting is the expanding number of conditions for which this option seems to be efficacious and is currently under study. These indications include nongenital warts, molluscum contagiosum, actinic keratoses, Bowen’s Disease, squamous cell carcinoma and the focus of this paper, basal cell carcinoma (BCC). There are many treatment modalities for BCC with proven efficacy, most of them involving local anesthesia and a surgical or destructive procedure. As there are so many BCCs in patients with a myriad of unique circumstances, a topical alternative would be a welcome addition to the current armamentarium. For instance, patients who have either a needle/ surgery phobia, are on blood thinners, or have implanted cardiac pacemakers/cardio-verters would all benefit from a noninvasive, self-administered topical modality. In order to understand the rationale for the use of IRMs as a monotherapy for BCC, a review of the salient aspects of the epidemiology, biology and immunology of this tumor is in order. Basal cell carcinomas are by far the most common skin cancer. Over a million new tumors are discovered each year in the USA alone. For the most part, they appear on the sun-exposed skin of the head and neck and the intermittently exposed skin of the trunk and extremities. There seems to be little doubt that solar-derived ultraviolet radiation damage to keratinocyte DNA is the main pathogenetic factor in tumor production. While there are several clinical subtypes of BCC, only two varieties account for the majority of the tumors. Nodular BCCs (nBCC), which appear mostly on the head and neck, account for approximately 80% of all BCC. Most of the remainder are superficial BCCs (sBCC), which occur most frequently on the trunk and extremities. Morpheaphorm, infiltrative, cystic, and other subtypes occur only infrequently. Nodular and superficial BCC may also be pigmented without altering their biologic potential. Over the last few years, several epidemiologic studies have detected a shift in the relative incidence of sBCC. There has been an increased incidence in sBCC, and because this subtype tends to occur predominantly on the trunk and extremities, there has been a relative shift in the anatomic distribution toward these areas. It has also been noted that this overall trend includes an increased incidence in younger people, particularly women, and an increased number of multiple sBCC of the trunk and extremities.