[Oral cavity changes in patients after kidney transplantation and preventive-treatment algorithms]. / Zmiany chorobowe w jamie ustnej u pacjentów po transplantacji nerki i algorytmy postepowania profilaktyczno-leczniczego.

Kidney transplantation is the best option of treatment for patients with end-stage renal failure. However, following kidney transplantation many stomatological abnormalities are frequently reported. It is mainly due to immunosuppressive therapy and subsequent impaired immune response. There is an increased risk of infections and malignancies. The most frequent findings in the oral cavity include: aphthae, erosions of bacterial, viral and fungal origin, lichen-like or leukoplakia-like changes. The another type of change is gingival hyperplasia and its periodontologial consequences. In this review etiology, clinical symptoms of periodontological changes are described together with algorithm of pre- and posttransplant management of oral healthy is provided.

Pilot phase IIA study for evaluation of the efficacy of folic acid in the treatment of laryngeal leucoplakia.

BACKGROUND: It has been previously observed that patients with head and neck squamous cell carcinoma or with laryngeal leucoplakia present a significant reduction in plasma folate levels. The current Phase IIA pilot study assessed the effectiveness of folic acid as a chemopreventive agent in patients affected by glottic laryngeal leucoplakia. METHODS: Forty-three untreated patients affected by glottic laryngeal leucoplakia were enrolled in the Ear, Nose, and Throat Department (Universita Cattolica del Saco Cuore, Rome, Italy). Glottic leucoplakia was initially diagnosed by indirect laryngoscopy and successively confirmed by diagnostic direct microlaryngoscopy with a biopsy for histologic assessment. Folic acid (Folina, Schwarz Pharma, Germany) was administered orally (5 mg every 8 hours) for 6 months. Patients were monitored every 30 days by videolaryngoscopy. RESULTS: Twelve (28%) patients had no response, 19 (44%) had a partial response, and 12 (28%) had a complete response. The mean increase in serum folate levels (10.06 +/- 0.53) and the mean decrease in homocysteine serum (3.65349 +/- 0.85526) at the end of the study were highly significant (P = .0001). CONCLUSIONS: The larynx is 1 of the sites of major interest and a good model for the development of chemopreventive agents, but so far the proposed agents have shown no clear efficacy on precancerous lesions or on the development of second malignancies.

Chemoprevention of head and neck and lung (pre)cancer.

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.

Leukoplakia: molecular understanding of pre-malignant lesions and implications for clinical management.

Oral leukoplakia is a white patch or plaque of the oral mucosa that cannot be characterized clinically or pathologically as any other diagnosable disease. Although oral leukoplakia is a well-known oral premalignant lesion with a high risk for development of oral cancer, little is known about its genetic basis. The development of oral cancer is a multistep process and it is believed that multiple genetic alterations are involved. Understanding this underlying genetic basis of oral cancer development will help us design better diagnosis and treatment plans in the cancer clinic. This review discusses recent progress in the identification of genetic and cytogenetic alterations in oral pre-malignant lesions and their potential clinical applications.

Accumulation of p53 protein and retinoic acid receptor beta in retinoid chemoprevention.

Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.

Positive impact of retinyl palmitate in leukoplakia of the larynx.

Laryngeal leukoplakia can be a premalignant precursor of squamous cell carcinoma, is often tobacco-related and can usually be readily monitored by indirect laryngoscopy. One of the main motivations for using retinyl palmitate in patients with persistent leukoplakia was to avoid general anesthesia for elderly patients, who are considered to be high-risk patients when direct larynoscopy is required for possible tissue biopsy. Our study was the first to investigate the effectiveness and toxicity of high-dose retinyl palmitate in the treatment of laryngeal leukoplakia. Treatment was divided into two phases. In the first phase, all patients underwent induction therapy with 300,000 IU/day of retinyl palmitate for the 1st week, which was then adjusted up to 1,500,000 IU/day in the 5th week in patients with resistant lesions. Patients whose lesions progressed during this period were withdrawn from the study. In the second phase, patients whose lesions responded to treatment or remained stable were assigned to a maintenance therapy of 150,000 IU/day. Complete remission was observed in 15 of 20 patients (75% of cases). Partial response was seen in the remaining 5 patients, with 3 of the patients relapsing. The median duration of treatment and follow-up was 18 months (range, 12-24 months). These results indicate that retinyl palmitate has substantial activity in laryngeal leukoplakias. Since only minor side effects were seen, the medication is an excellent candidate as a preventive agent for laryngeal cancer.

Levels of proteolytic activities as intermediate marker endpoints in oral carcinogenesis.

It is essential to identify intermediate marker endpoints of carcinogenesis for the evaluation of the effectiveness of cancer-chemopreventive agents. We have observed that levels of proteolytic activities (as detected by 4 different substrates) are increased 2-3-fold (P < 0.003) in oral buccal mucosa cells of smokers and patients with oral leukoplakia or erythroplakia as compared to a nonsmoking comparison group. In addition, proteolytic activity levels in the buccal cells were increased nearly 3-fold in patients with oral trauma (P < 0.01) or diabetes (P < 0.02), as well as pregnant women (P < 0.04). Excluding these subgroups of patients in epidemiological studies increase the differences in levels of proteolytic activities between both the nonsmoking comparison group and smokers and between the comparison group and patients with oral leukoplakia or erythroplakia. Evaluation of prerandomization levels of proteolytic activities of patients in cancer chemoprevention trials will increase the statistical power by allowing stratified randomization based on levels of proteolytic activities. The observed increases in levels of proteolytic activities in tissues at higher than normal risk of cancer development suggest that levels of proteolytic activities should be used as immediate marker endpoints in human cancer prevention trials using protease inhibitors as potential anticarcinogenic agents.

Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide.

Fenretinide or N-(4-hydroxyphenyl)retinamide is a vitamin A analogue synthesized in the United States in the late 1960s. This retinoid shows a preferential accumulation in breast instead of liver, is effective in the inhibition of chemically induced mammary carcinoma in rats, and has proved to be less toxic than many other vitamin A analogues. The Milan Cancer Institute has put a particular effort in this molecule in both the experimental and clinical fields. We have demonstrated, in animals and humans, that fenretinide induces a rapid reduction of retinol plasma concentration, that its blood levels remain constant during administration for as long as 5 years, and that the drug is able to accumulate in the human breast. To date, 2969 stage I breast cancer patients have been randomized to evaluate the efficacy of this retinoid to prevent contralateral new primaries, 709 subjects have been accrued in a prevention trial of basal cell carcinoma of the head and neck, and 153 patients entered a study the preliminary results of which already show the capability of fenretinide to prevent recurrences and new localizations of oral leukoplakia. Further studies on fenretinide will be aimed at evaluating its preventive efficacy in superficial bladder and prostate cancers and at exploring possible synergism with tamoxifen and interferons in breast cancer and skin cancer, respectively.

The effectiveness of a mixture of beta-carotene, alpha-tocopherol, glutathione, and ascorbic acid for cancer prevention.

Previous studies have shown that beta-carotene and alpha-tocopherol can act synergistically to inhibit the growth of experimentally induced oral cancer. The initial studies on the synergistic anticancer activity of antioxidants have been extended to include reduced glutathione and ascorbic acid. Sixty male hamsters (4-5 wks old) were divided into six equal groups. Groups 1-6 were treated with 7,12-dimethylbenz[a]anthracene (DMBA) (0.5% solution). Group 2 received a mixture containing equal amounts of beta-carotene, dl-alpha-tocopherol (vitamin E), glutathione, and l-ascorbic acid (vitamin C) (12.5 micrograms) delivered orally by pipette. Groups 3-6 were treated with beta-carotene alone (50 micrograms), vitamin E alone (50 micrograms), glutathione (50 micrograms) alone, and vitamin C alone (50 micrograms). Animals were euthanized at 12 and 14 weeks. Tumors were counted and measured, and tumor burden was calculated for each experimental group. The mixture of antioxidants significantly reduced tumor burden, whereas the beta-carotene, vitamin E, and reduced glutathione treatments also reduced tumor burden. beta-Carotene and glutathione provided greater levels of chemoprevention than vitamin E as single agents. In contrast, vitamin C treatment produced no antitumor effect but increased tumor burden by Week 14. This mixture of antioxidants produced a significant synergistic chemoprevention of oral cancer.

The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers.

Most biological reactions, including carcinogenesis, are complex processes involving thousands of compounds, their metabolites and intermediates. The separation of events which form part of a direct chain leading to neoplastic transformation from those which are mere by-products is a herculean task. In this study, we focused on the pros and cons of reactive oxygen species (ROS) being involved in the development of oral cancer among chewers of tobacco and areca nuts. The results revealed that bursts of ROS generation occur at different stages of carcinogenesis, and are caused by different mechanisms. This observation may have considerable practical implications. Different strategies will be required in the administration of chemopreventive agents in order to trap ROS formed in the alkaline (due to the addition of slaked lime) chewing mixture within the saliva of a chewer, to scavenge ROS within mucosal cells exposed to an array of tobacco- or areca nut-related carcinogens or tumour promoters, and to inhibit the action of ROS released from ROS-generating white cells during lymphocytic infiltration of the oral mucosa at a precancerous stage. The remission of oral leukoplakias following the administration of vitamin A (200,000 IU/week) or vitamin A (100,000 IU/week) plus beta-carotene (180 mg/week) for 6 months, the inhibition of new leukoplakias during this trial period, and the reduction of micronucleated oral mucosal cells in chewers treated with beta-carotene or vitamin A are indeed promising results. However, a better understanding of the role of ROS in various stages of carcinogenesis will provide the basis for selection of the proper chemopreventive agents and the design of a treatment regime which may either prevent the formation of precancerous lesions, induce their remission, or inhibit the progression of precancerous lesions into malignant cancers.

Smokeless Tobacco Reduction Program.

To reduce the incidence and prevalence of oral cancer, the Smokeless Tobacco Reduction Program will consist of a mass media campaign, public oral screening, and a week-long school health program for 350 students in the seventh, eighth, and ninth grades in Willows, Glenn County, CA. Mass media will include radio, television, newspapers, posters, and literature. The program will use resources of the public health department and junior high school; it will also depend on 8 teachers and 25 peer leaders, all trained in the program. Reducing the use of smokeless tobacco is the program's objective. If that goal is achieved, the program will reduce oral cancers in the target population by 75 percent within 10 years. The incidence of leukoplakia will be reduced by 50 percent within 3 years of the end of the program. By the end of the program, 90 percent of the target population will be able to identify warning signs of oral cancer and leukoplakia, and 85 percent of the students will no longer believe that use of smokeless tobacco is less harmful than smoking. As a result of the program, use of smokeless tobacco will not be viewed favorably by 80 percent of the target population; usage will be regarded as socially unacceptable.

Inhibition of hamster tongue carcinogenesis by selenium and retinoic acid.

The inhibitory effect of selenium, 13-cis-retinoic acid, and their combination was studied in an animal model in which squamous cell carcinoma of the tongue was induced by 0.5% 9,10 dimethyl-1,2 benzanthracene (DMBA). A controlled, blinded experiment was carried out using 60 Syrian hamsters divided into four groups of 15 each. When compared to controls, the mean day of carcinoma onset was delayed 3 weeks for animals given selenium, 6 weeks for animals given retinoic acid, and 5.5 weeks for animals given selenium plus retinoic acid. The differences between each experimental group and the control group are statistically significant. We conclude that both selenium and retinoic acid inhibit the development of DMBA-induced squamous cell carcinoma of the tongue in hamsters. The dose of retinoic acid used produces a stronger inhibitory effect, but is associated with significant toxicity. At the doses used, combined inhibitory effect is no greater than that for retinoic acid alone.