***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Tobacco/betel nut chewers ( Kerala , India ) with well-developed oral leukoplakias were chosen for a short-term intervention trial of vitamin A therapy .  Participants were r and omly distributed into two groups , one receiving 200,000 IU vitamin A per week ( 0.14 mg/kg body wt/per day ) for 6 months , and the other receiving placebo capsules . Their cancer-causing habit , which can be quantitated ( an average of 13.1 betel quids/day , 26.1 min/quid ) , did not change during the trial period . The 6-month oral administration of vitamin A caused complete remission in 57.1 % of participants , and a total suppression of the development of new leukoplakias in all chewers receiving vitamin A ( n = 21 ) , as compared to 3 % and 21 % , respectively , in the placebo group ( n = 33 ) . The results were substantiated by examining the histological and cytological changes on small biopsies which were taken at the onset and at the completion of the trial period . Over the 6-month period of vitamin A administration , the number of layers of spinous cells decreased in 85 % of the participants , the loss of polarity of basal cells was reduced from 72.2 % to 22.2 % of chewers , subepidermal lymphocytic infiltration was greatly diminished from 66.7 % to 5.5 % of chewers , and nuclei with condensed chromatin disappeared from the epidermal layer ( 72.2 % before to 0 % at the end of the trial ) We conducted a double-blind placebo-controlled trial to evaluate the chemopreventive potential of either vitamin A alone or beta carotene alone in subjects with oral leukoplakia in Kerala , India . We r and omised 160 fishermen and women with oral precancerous lesions to receive oral vitamin A ( retinyl acetate 300,000 IU/week x 12 months , n = 50 ) , or beta carotene ( 360 mg/week x 12 months , n = 55 ) , or placebo ( n = 55 ) . Blood , saliva and urine sample s were collected at baseline and at exit to study serum micronutrients and mutagenicity assays . Biopsies of the mucosal lesions at entry were performed for histopathological exclusion of malignancy . The subjects were examined once every 2 months to establish clinical response of lesions and toxicity , if any . The results are based on 43 complaint subjects on placebo , 42 on vitamin A and 46 on beta carotene . The complete regression rates were : 10 % in the placebo arm , 52 % with vitamin A and 33 % with beta carotene ( P < 0.0001 ) . Homogeneous leukoplakias and smaller lesions responded better than non-homogeneous and larger lesions . No major toxicities were observed . Half of the responders with beta carotene and two thirds with vitamin A  relapsed after stopping supplementation . Serum beta carotene concentration increased substantially with beta carotene administration while with vitamin A supplementation there was no change in serum retinol levels . In the vitamin A treated group there was a significant decrease in serum alpha tocopherol .  Vitamin A administration result ed in a significant remission of oral leukoplakia without any side effects of prolonged vitamin A supplementation . The results of this study , as well as those from previous studies , appear to provide strong supporting evidence to justify long term trials with vitamin A in subjects with high-risk leukoplakias with oral cancer as an endpoint This paper analyses preliminary results of a r and omised chemoprevention trial in patients surgically treated for oral leukoplakia started in 1988 at the Istituto Nazionale Tumori of Milan with the synthetic retinoid N-(4-hydroxyphenyl)-retinamide ( 4-HPR ) .  To date 115 patients have been r and omised , after surgical excision of oral leukoplakia , to receive 200 mg 4-HPR daily for 52 weeks versus no intervention .  80 patients completed the 1-year intervention , 41 in the control group and 39 in the 4-HPR group . During this period 12 local relapses or new lesions occurred in the control group and three in the 4-HPR group . Only 5 patients interrupted the intervention because of toxicity . No impaired dark adaptation was observed . It is concluded that 4-HPR is well tolerated and seems efficacious in preventing relapses and new localisations during the treatment period . This promising trend needs further confirmation The blue-green microalgae Spirulina , used in daily diets of natives in Africa and America , have been found to be a rich natural source of proteins , carotenoids , and other micronutrients . Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina algae on oral carcinogenesis . Studies among preschool children in India have demonstrated Spirulina fusiformis ( SF ) to be an effective source of dietary vitamin A. We evaluated the chemopreventive activity of SF ( 1 g/day for 12 mos ) in reversing  oral leukoplakia in pan tobacco chewers in Kerala , India .  Complete regression of lesions was observed in 20 of 44 ( 45 % ) evaluable subjects supplemented with SF , as opposed to 3 of 43 ( 7 % ) in the placebo arm ( p < 0.0001 ) . When stratified by type of leukoplakia , the response was more pronounced in homogeneous lesions : complete regression was seen in 16 of 28 ( 57 % ) subjects with homogeneous leukoplakia , 2 of 8 with erythroplakia , 2 of 4 with verrucous leukoplakia , and 0 of 4 with ulcerated and nodular lesions . Within one year of discontinuing supplements , 9 of 20 ( 45 % ) complete responders with SF developed recurrent lesions . Supplementation with SF did not result in increased serum concentration of retinol or beta-carotene , nor was it associated with toxicity . This is the first human study evaluating the chemopreventive potential of SF . More studies in different setting s and different population s are needed for further evaluation AIMS The aim of this study was to investigate the effectiveness of acitretin in a new topical formulation ( mucoadhesive two-layer tablets ) for the treatment of oral leucoplakias . METHODS Twenty-one volunteers , 16 men , five women , with oral leucoplakia ( histologically diagnosed ) , were included in this double-blind placebo-controlled study . Patients were r and omized in three groups ( A , B , C ) of seven patients each . Groups A and B received tablets with different in vitro release profiles , and group C subjects ( controls ) received tablets without acitretin . The acitretin dose was 20 mg/day ( two 10 mg tablets daily ) . Serum aspartate aminotransferase , alanine aminotransferase , cholesterol and triglycerides were evaluated before and after treatment . At the end of therapy the concentrations of acitretin in plasma , saliva and tissue were measured by high-performance liquid chromatography . RESULTS At the end of the study 71 % ( groups A and B ) of patients showed clinical remission or marked improvement . No improvement was noted in the control subjects ( group C ) . These results were further confirmed by histological findings . There were no significant changes in laboratory values in the three groups . The  acitretin concentration in plasma and tissue ranged from 0 to 50 mg with no difference between groups A and B , and it was very high in saliva ( ranging from 4.9 to 43 mg ) with higher concentrations in group A than in group B ( due to a longer adhesion time in group A ) . Patients ' compliance was excellent . The results show that mucoadhesive tablets of topical acitretin are efficacious in the treatment of oral leucoplakia without systemic side-effects BACKGROUND Beta-Carotene has been reported to produce regressions in patients with oral leukoplakia , a premalignant lesion . However , previous studies have all been of short duration , with clinical response as the end point . OBJECTIVE To evaluate the duration of response and the need for maintenance therapy in subjects who respond to beta-carotene .  METHODS In this multicenter , double-blind , placebo-controlled trial , subjects were given beta-carotene , 60 mg/d , for 6 months . At 6 months , responders were r and omized to continue beta-carotene or placebo therapy for 12 additional months . RESULTS Fifty-four subjects were enrolled in the trial , with 50 being evaluable . At 6 months , 26 subjects ( 52 % ) had a clinical response . Twenty-three of the 26 responders completed the second , r and omized phase . Only 2 ( 18 % ) of 11 in the beta-carotene arm and 2 ( 17 % ) of 12 in the placebo arm relapsed . Baseline biopsies were performed in all patients , with dysplasia being present in 19 ( 38 % ) of the 50 evaluable patients . A second biopsy was obtained at 6 months in 23 subjects who consented to this procedure . There was improvement of at least 1 grade of dysplasia in 9 ( 39 % ) , with no change in 14 ( 61 % ) . Nutritional intake was assessed using food frequency question naires . There was no change in carotenoid intake during the trial . Responders had a lower intake of dietary fiber , fruits , folate , and vitamin E supplements than did nonresponders . Beta-carotene levels were measured in plasma and oral cavity cells . Marked increases occurred during the 6-month induction . However , baseline levels were not restored in subjects taking placebo for 6 to 9 months after discontinuation of beta-carotene therapy . CONCLUSIONS The activity of beta-carotene in patients with oral leukoplakia was confirmed . The responses produced were durable for 1 year Tobacco chewing and /or smoking are strongly related to several cancers , mainly of the upper aerodigestive tract . Several studies on diet and cancer links suggest that micronutrients , particularly antioxidant vitamins and minerals , are risk modifiers of cancers of epithelial origin . This study looks at the impact of micronutrients such as vitamin A , riboflavin , zinc and selenium as intervention agents in subjects with and without precancerous lesions in a high risk group ( reverse smokers of chutta-rolled tobacco leaf ) . Reverse smokers from four villages were enrolled in the study . 150 subjects were supplemented with four nutrients , namely vitamin A , riboflavin , zinc and selenium in the form of a capsule twice a week for 1 year . 148 controls received a placebo capsule containing lactose for the same period . Clinical history and anthropometric data were collected from all the subjects and a clinical photograph of the palate was taken . Micronutrients were estimated in r and om blood collected from a sub- sample before and after the study . Micronutrients improved the vitamin A , riboflavin and selenium nutriture in the supplemented group with a concomittant regression of precancerous lesions present on the palate . Clinical ly complete remission of white , red and combination lesions was seen in 57 % of subjects on supplements whereas 8 % on placebo showed a positive response . Further progression of these lesions was seen in 10 % of the supplemented group compared with 47 % in the placebo group ( P < 0.001 ) . In the non-lesion group , new lesions appeared in 12 % on supplements while more than 38 % on the placebo developed new lesions ( P < 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The aim of the current study was to evaluate , in an open trial , the clinical efficacy of topical calcipotriol compared with tretinoin in the therapy of hyperkeratotic oral lesions ( leukoplakia ) . The study group consisted of 40 patients with histologically proven oral leukoplakias , 20 treated with calcipotriol , the other 20 with tretinoin .  The treatment was for 5 weeks and follow-up at 4 months , with clinical assessment s at 2 , 4 and 5 weeks and regular laboratory assessment s. The results showed a significant reduction in lesions ( 80 % ) , in both calcipotriol and tretinoin groups , with no documented topical or systemic adverse reactions , results maintained at 4 months . Tretinoin however , potentially can induce erythema , angular cheilitis and xerostomia . The study suggests that topical calcipotriol is as effective in the therapy of oral leukoplakia as is topical tretinoin This intervention trial carried out in Uzbekistan ( former USSR ) in an area with a high incidence of oral and esophageal cancer involved r and om allocation of 532 men , 50 to 69 years old , with oral leukoplakia and /or chronic esophagitis to one of four arms in a double-blind , two-by-two factorial design , with active arms defined by the administration of ( a ) riboflavin ; ( b ) a combination of retinol , beta-carotene , and vitamin E ; or ( c ) both . Weekly doses were 100,000 IU of retinol , 80 mg of vitamin E , and 80 mg of riboflavin . The dose of beta-carotene was 40 mg/d . Men in the trial were followed for 20 months 
    Output:
    
Treatment with beta carotene and vitamin A or retinoids , was associated with better rates of clinical remission , compared with placebo or absence of treatment .
Whenever reported , a high rate of relapse was a common finding .
Side effects of variable severity were often described ; however , interventions were well accepted by patients , since drop-out rates were similar between treatment and control groups .
REVIEW ER 'S CONCLUSIONS To date there is no evidence of effective treatment in preventing malignant transformation of leukoplakia .
Treatments may be effective in the resolution of lesion , however relapses and adverse effects are common