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Oral premalignant lesions are a useful model for developing chemoprevention trials involving lesions throughout the upper aerodigestive tract (1). These lesions most often develop in association with exposure to carcinogens, such as tobacco and alcohol, and frequently precede the development of invasive carcinoma (2,3). Although early oral premalignant lesions (hyperplasia and mild dysplasia) are particularly responsive to single-agent retinoid therapy (4– 8), advanced oral premalignant lesions (i.e., moderate to severe dysplasia) are known to be resistant to single-agent retinoid therapy (9,10). Since the combination of retinoids and interferons (IFNs) has been shown to have an enhancing effect on the induction of cell differentiation and on the suppression of cell proliferation as seen in preclinical (10– 14) and clinical (15–17) studies, we designed a biochemoprevention study for testing a combination of isotretinoin (13-cis-retinoic acid), IFN-a, and a-tocopherol for advanced premalignant lesions in the head and neck. The mutations in the p53 (also known as TP53) gene and alterations in the p53 protein resulting in its accumulation in cells may play a critical role in tumorigenesis (18–20), and both are common in human cancers, including premalignant lesions and cancers of the head and neck region (21–23). We conducted a prospective, nonrandomized phase II trial to assess the effect of biochemopreventive therapy on the responsiveness of lesions in the head and neck area, particularly consisting of mild to severe dysplasia in a laryngeal site or moderate to severe dysplasia in the oral cavity, and to compare laboratory findings involving p53 alterations. All eligible patients received highdose isotretinoin (80 mg/m per day), IFN-a (3 million U/m twice a week), and a-tocopherol (1200 IU/day) for 12 months, unless the lesions showed progressive disease. The patients were evaluated for clinical and pathologic responses at 6 and 12 months after beginning of therapy. All analyses were based on the outcome observed at 6 months unless otherwise specified. All participants had follow-up examinations without therapy for the following 6 months and then had a final biopsy at 18 months. These tissue samples were analyzed for pathologic response, p53 protein expression, and p53 gene mutations. Pathologic changes in tissue in response to the therapy were consistently evaluated according to the criteria previously described (24) by one pathologist (A. El-Naggar). All pathology slides were coded by numbers, and the pathologist was blinded to the time the biopsies were performed. Immunohistochemical staining was performed on tissue sections by use of monoclonal anti-p53 antibody (clone D07; BioGenex, Inc., San Ramon, CA) (22). The epithelial layer of each lesion was microdissected in three or four serial sections from each biopsy sample, as described previously (25). The p53 positivity was stratified as low or high, based on two different sets of cut points, i.e., labeling index (L.I.) of less than 0.2 as low and greater than or equal to 0.2 as high or L.I. of less than 0.1 as low and greater than or equal to 0.1 as high (see Fig. 1 legend). P values were determined with the use of both sets of cut points. Three separate fragments of the p53 gene encompassing exons 5–9 were amplified from the extracted DNA from these microdissections and directly sequenced, as described previously (26). The optimal two-stage design by Simon (27) was applied, and a 6-month pathologic response was used as the major end point. The pathologic complete response was described as the complete disappearance of dysplastic cells from the epithelium, and the pathologic partial response was described as a reduction in the degree of dysplasia by at least one degree (i.e., severe to moderate dysplasia). Absence of any response (no response) was described as no pathologic change or a minor change involving focal improvement within the same degree of dysplasia. Progressive disease indicated an increase in the severity of dysplasia by at least one degree (i.e., moderate dysplasia to severe dysplasia) or the development of invasive carcinoma. The standard and target response rates were chosen to be 10% and 30% of all patients, respectively. Both the type I and type II error rates were set at 10%. Associations between categorical variables were determined either by the x test or Fisher’s exact test. Differences between the two groups with respect to continuous variables, such as the differences in p53 protein expression in relation to pathologic progression in laryngeal lesions and in oral cavity lesions, were compared with the use of the Wilcoxon rank sum test. All statistical tests were two-sided; P values of <.05 were considered to be statistically significant. From June 1994 through August 1998, 35 eligible patients were assessed. The lesions were evaluated for histologic criteria, p53 protein expression, and p53 gene mutations; the results are described in Table 1. Four patients (11.4%) had mild dysplasia, 16 (45.7%) had moderate dysplasia, and 15 (42.9%) had severe dysplasia. Twenty-two patients (62.9%) had laryngeal lesions (three had mild dysplasia, 10 had moderate dysplasia, and nine had severe dysplasia), and 13 (37.1%) had oral cavity lesions (one had mild dysplasia, six had moderate dysplasia, and six had severe

Biochemopreventive Therapy for Patients With Premalignant Lesions of the Head and Neck and p53 Gene Expression