Search

Oral leukoplakia (OLK) is the most representative oral potentially malignant disorder, with a high risk of malignant transformation and unclear mechanisms of occurrence. Recently, photodynamic therapy (PDT) has exhibited great potential in the treatment of OLK. However, the efficacy of PDT is difficult to predict and varies from person to person. Ferroptosis-related pathways are upregulated in many cancers, and ferroptosis induction is considered to be a potential synergistic strategy for various antitumor therapies, but its role in OLK treatment remains unclear. This study aimed to determine whether ferroptosis induction can enhance the efficacy of PDT in OLK treatment. Our study revealed that solute carrier family 7 member 11 (SLC7A11), a component of a crucial amino acid transporter and a key negative regulator of ferroptosis, was found to be highly expressed in OLK patients with no response to PDT. 5-Aminolevulinic acid (ALA)-PDT is known to cause apoptosis and necrosis, but ferroptosis also occurred under ALA-PDT in OLK cells in our study. Using erastin to induce ferroptosis enhanced the efficacy of ALA-PDT on OLK cells by disrupting the antioxidant system and further elevating intracellular reactive oxygen species levels, leading to increased apoptosis. Furthermore, this combined modality also enhanced the efficacy of ALA-PDT on 4-nitroquinoline-1-oxide (4NQO)-induced OLK lesions in mice. In summary, ferroptosis induction may serve as a potential strategy to enhance the efficacy of ALA-PDT for OLK treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Photodynamic therapy (PDT) has shown good short-term efficacy in the treatment of oral leukoplakia (OLK). However, the malignant transformation of OLK was seldom evaluated in most PDT studies. Therefore, this study evaluated the effect of PDT on the risk of malignant transformation of OLK., Methods: Kaplan-Meier survival analysis, COX regression, and sensitivity analysis were used to evaluate the effects of PDT on the risk of malignant transformation of OLK. Subgroup analyses were performed to explore the role of PDT in OLK patients with different clinical characteristics., Results: OLK patients with older age (HR=1.032, P = 0.018) and non-homogeneous lesion (HR=2.104, P = 0.044) had higher risk of malignant transformation. Patients who had finished a complete course of PDT (HR=0.305, P = 0.006) had a significant lower risk of malignant transformation, while those who hadn't finished a complete course of PDT (HR=0.692, P = 0.352) cannot be considered to have such a protective effect. In the subgroup analyses, complete PDT course showed a significant protective effect on malignant transformation of OLK in patients with female sex, no smoking or drinking habits, non-homogeneous lesions, lesions on oral mucosa outside the dangerous region, and any grade of epithelial dysplasia., Conclusions: A complete course of PDT could significantly reduce the risk of malignant transformation of OLK, especially in those patients with risk factors of malignant transformation., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The management of oral leukoplakia (OL) is challenging because of a high risk for recurrence and malignant transformation (MT), and recurrent OL is associated with a higher risk of MT than nonrecurrent OL. The present meta-analysis aimed to examine the association between OL recurrence and surgical techniques used for their management as well as their clinicopathological factors. Electronic searches were conducted in EMBASE, PubMed, Scopus, and Web of Science to retrieve studies reporting OL recurrence after surgery. The pooled proportion of OL recurrence after surgical excision was estimated. Subgroup analyses were conducted based on the surgical technique, data type, grades of epithelial dysplasia, anatomical subsites, clinical type and size of the lesion, surgical margin, and risk habits. Meta-regression analyses were conducted to identify the association between age, sex, and follow-up duration and OL recurrence. The risk of MT based on the recurrence status was also estimated. A network meta-analysis was performed to determine the surgical modality associated with the least OL recurrence. Eighty studies with a total of 7,614 samples and various surgical modalities (laser-based techniques, conventional scalpel surgery, cryosurgery, and photodynamic therapy) were included in the meta-analysis. A pooled proportion of recurrence of 22% was observed. Laser-based surgeries resulted in fewer OL recurrences than other surgical modalities, and the combination of laser excision and vaporization was identified to be the best treatment approach. OL in the retromolar area and multiple sites, nonhomogeneous OL, advanced age, female sex, inadequate surgical margin, retrospective data, and betel quid chewing habit were significantly associated with higher OL recurrence. Recurrent OL showed a 7.39 times higher risk of MT than nonrecurrent OL. These results suggest that the combination of laser excision and vaporization might reduce OL recurrence. Furthermore, OL in older patients, females, and nonhomogeneous OL need close monitoring after any surgical therapy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Chemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo., Methods: Normal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed., Results: In vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC., Conclusion: Expression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects., (© 2024. The Author(s).)

Background: The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT., Methods: The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model., Results: The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P: 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P: 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %., Conclusions: ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier B.V.)

Background: Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive., Purpose: To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action., Methods: In vitro, the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe 2+ , and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo, the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated., Results: CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety., Conclusion: This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: To investigate the clinical efficacy of aminovalerate hydrochloride photodynamic therapy (PDT) for oral potentially malignant disorder (OPMD),oral leukoplakia (OLK), along with identifying the influencing factors.Additionally, the study aims to detect the rates of recurrence and malignancy after PDT., Method: 60 patients with OPMD who received PDT at our hospital from 2006 to 2021 were included in this study. Relevant patient medical data were collected and analyzed using SAS 9.4 software.The Mann-Whitney U test was used to retrospectively analyze the factors influencing clinical efficacy, as well as recurrence rate and malignant transformation rate (MTR) after treatment., Result: Among the 60 OPMD patients receiving PDT, complete remission in 13 (21.67 %), partial remission in 39 (65.00 %), and no remission in eight (13.33 %), resulting in an overall effective rate of 86.67 %.Fifteen patients experienced relapse, leading to a recurrence rate of 25.00 %. Among these relapses,11 patients occurred within one year after treatment, corresponding to an 18.33 % recurrence rate during that period. Moreover, nine patients developed malignant transformation (MT), resulting in an MTR of 15.00 %. Out of these patients, six individuals developed MT within one year after treatment, resulting in a one-year MTR of 10.00 %., Conclusion: The study findings indicate that PDT shows promising clinical efficacy in the treatment of OPMD, with relatively limited and tolerable postoperative adverse reactions. However, there remains a certain rate of recurrence and malignancy after treatment. Therefore, close attention should be paid to postoperative monitoring, regular follow-up, and further expansion of the sample size to observe its long-term efficacy., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to compare the efficacy of Er:YAG and Er,Cr:YSGG laser in the treatment of oral leukoplakia refractory to conventional retinoid therapy. Materials and methods : The study sample consisted of 54 patients (16 men and 38 women) who were histopathologically diagnosed with oral leukoplakia that was refractory to conventional retinoid therapy. Patients were randomly allocated into two groups according to the type of the laser used for treatment of oral leukoplakia: Group 1. Er:YAG laser; Group 2. Er,Cr:YSGG laser. Patients were recalled at 6 months and 1 year after treatment to evaluate possible recurrence and assess the patients' postoperative quality of life. Results: After initial ablation, the degree of residual lesion was significantly greater in the Er:YAG laser group (74.1%), compared with the Er,Cr:YSGG group (18.5%) ( p  = 0.0001). Six months and 1 year after the second ablation, there was no lesion recurrence in either laser group. Fourteen days after the initial ablation, the visual analog scale (VAS) pain rating and the total oral health impact profile score fell significantly in both groups ( p  < 0.0001). However, in the Er,Cr:YSGG laser group, the average value of the VAS rating was significantly lower than in the Er:YAG laser group ( p  = 0.039). Conclusions : The Er:YAG and Er,Cr:YSGG lasers showed similar efficacy in the treatment of oral leukoplakia and resulted in full postoperative recovery without recurrence after 1 year of follow-up.

Oral leukoplakia (OLK) is one of the most common oral potentially-malignant disorders (OPMD) with complex causes, a long disease course and a high tendency for recrudescence. Although a variety of methods exist for treating this disease, canceration rates remain high. Herein, we described a case of 72-year-old male patient with OLK of the palatine mucous membrane who had achieved complete remission after being treated with five sessions of plum-blossom needle (PBN) assisted 5-aminolevulinic acid-photodynamic therapy (ALA-PDT). The patient had since been subsequently placed under close observation (>12 mo). To date, there has been no recurrence. PBN assisted PDT might be suitable for the treatment of OPMDs in patients presenting with epithelial hyperkeratosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The aim of the present study was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral leukoplakia (OLK)., Methods: This systematic review aimed to address the following focused question: "Is photodynamic therapy effective in the management of oral leukoplakia?'' PubMed/Medline, EMBASE, ISI Web of Knowledge, OVID, CNKI, and WANFANG DATA were searched up to and including June 2018 using different combinations of the following keywords: photodynamic therapy, leukoplakia, oral dysplasia, oral precancers, and oral premalignant lesions., Results: Sixteen studies were included in the present study. A total of 352 patients was included in this review, with age ranging from 20 to 79 years. Photosensitizers used were aminolevulinic acid, Photofrin, methylene blue, and chlorine-e6. Laser wavelength, duration of irradiation, and power density were 420-660 nm, 60-1000 s, and 100-150 mW/cm 2 , respectively. On the whole, the rates of complete response and partial response were 32.9% and 43.2%, and the sum was 76.1%. The follow-up period ranged from 1 month to 119 months. The recurrence rate of OLK was 0-60%., Conclusion: PDT appears to be a useful therapeutic strategy in the management of oral leukoplakia as a non-surgical treatment. Further RCTs with long follow-up period, standardized PDT parameters, and comparing efficacy of PDT with various other therapies are needed to acquire definite conclusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Photodynamic therapy (PDT) is a noninvasive method for the treatment of premalignant lesions, such as leukoplakia and lichen planus (LP). These lesions are very irregular. In the case of such irregular lesions, fractal dimension analysis (FDA) is very helpful. Photodynamic diagnosis (PDD) enables the visualization of irregular lesion shapes more precisely than a classical white-light examination., Objectives: In our study, we tried to distinguish oral leukoplakia and LP, using FDA in a classical examination with white light and PDD. Lesions treated using PDT were histopathologically verified., Material and Methods: We enrolled 35 patients in our study. Fractalyse software v. 2.4 (University of Franche-Comté, Besançon, France) was used to count fractal dimensions (FDs). Photodynamic therapy and PDD were mediated with 20% delta-aminolevulinic acid (5-ALA)., Results: Fractal dimensions of leukoplakia foci of the tongue in a white-light examination were significantly lower than in PDD. In the case of LP, a significant difference of FDs was observed between lesions in the cheek and in the alveolar ridge region. Differences in FDs were observed between leukoplakia foci of the alveolar ridge, tongue and palate. A complete response of leukoplakia foci to PDT was observed in 10 out of 34 lesions, partial remission occurred in 20 lesions and a total lack of response was noted in 4 lesions. Generally, LP was completely treated in 7 out of 14 cases, a partial response was observed in 5 lesions and a failure of PDT treatment was noted in 2 cases., Conclusions: Fractal dimension analysis may be a useful method in the comparison of complicated shapes of such lesions as LP or leukoplakia, but our study did not confirm that this method may be used to distinguish LP and leukoplakia without a histopathological examination. Photodynamic therapy is an effective treatment method in the case of LP and leukoplakia of the oral cavity.

Black raspberries (BRB) have been shown to inhibit carcinogenesis in a number of systems, with most studies focusing on progression. Previously we reported that an anthocyanin-enriched black raspberry extract (BE) enhanced repair of dibenzo-[a,l]-pyrene dihydrodiol (DBP-diol)-induced DNA adducts and inhibited DBP-diol and DBP-diolepoxide (DBPDE)-induced mutagenesis in a lacI rat oral fibroblast cell line, suggesting a role for BRB in the inhibition of initiation of carcinogenesis. Here we extend this work to protection by BE against DNA adduct formation induced by dibenzo-[a,l]-pyrene (DBP) in a human oral leukoplakia cell line (MSK) and to a second carcinogen, UV light. Treatment of MSK cells with DBP and DBPDE led to a dose-dependent increase in DBP-DNA adducts. Treatment of MSK cells with BE after addition of DBP reduced levels of adducts relative to cells treated with DBP alone, and treatment of rat oral fibroblasts with BE after addition of DBPDE inhibited mutagenesis. These observations showed that BE affected repair of DNA adducts and not metabolism of DBP. As a proof of principle we also tested aglycones of two anthocyanins commonly found in berries, delphinidin chloride and pelargonidin chloride. Delphinidin chloride reduced DBP-DNA adduct levels in MSK cells, while PGA did not. These results suggested that certain anthocyanins can enhance repair of bulky DNA adducts. As DBP and its metabolites induced formation of bulky DNA adducts, we investigated the effects of BE on genotoxic effects of a second carcinogen that induces bulky DNA damage, UV light. UV irradiation produced a dose-dependent increase in cyclobutanepyrimidine dimer levels in MSK cells, and post-UV treatment with BE resulted in lower cyclobutanepyrimidine dimer levels. Post-UV treatment of the rat lacI cells with BE reduced UV-induced mutagenesis. Taken together, the results demonstrate that BE extract reduces bulky DNA damage and mutagenesis and support a role for BRB in the inhibition of initiation of carcinogenesis.

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.

Objectives/hypothesis: To determine the utility of isotretinoin oral rinses as a method of chemoprevention for recurrent oral cavity squamous cell carcinoma (SCC), carcinoma in situ, and dysplasia., Study Design: Retrospective cohort study., Methods: One hundred forty-three patients were initially enrolled in the study; however, 18 were excluded due to inability to tolerate therapy. The included patients were classified into four groups. Group 1 included patients with multiple early stage oral cavity lesions following initial resection. Group 2 included patients with SCC in situ after excision. Group 3 included patients with multifocal dysplasia following initial CO 2 laser ablation. Group 4 included patients with a history of treated oral cavity SCC with new leukoplakia lesions proven to be dysplastic. Fifty-three patients in the control group did not use post-treatment isotretinoin rinses due to various reasons, whereas 72 patients completed therapy. Minimum use of isotretinoin rinses was 12 months, and minimum follow-up was 24 months. During the follow-up period, all recurrences of carcinoma, in situ disease, and dysplasia were noted and compared with a Fisher test of fit. A Bonferroni correction was applied to increase accuracy and strength of comparison., Results: Using a Bonferroni correction, the significance threshold was 0.0125. By that cutoff, isotretinoin rinses were found to be associated with lower recurrence in groups 1 and 3 (P = .00014, P = .00002, respectively) but not in groups 2 and 4 (P = .4, P = .3846, respectively)., Conclusions: Oral isotretinoin as chemoprophylaxis for patients treated for oral cavity squamous cell carcinoma, in situ disease, or dysplasia may be beneficial in decreasing recurrence rate., Level of Evidence: 4. Laryngoscope, 127:1595-1599, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Impairment of vascular functions after photodynamic therapy (PDT) is frequently associated with tumor remission and is considered one of the main antineoplastic PDT effects. Vascular alterations in oral leukoplakia (OL) treated with PDT have not yet been described. The aim of this study was to evaluate the effect of topical 5-ALA-mediated PDT on the vascular network of 4NQO-induced OL in rats. After applying 4NQO topically on the tongue during 16 weeks, there was induction of dysplastic lesions, which were treated with two PDT sessions (with an interval of 72 h between them), using topical application of 5-ALA and posterior irradiation with a laser (90 J/cm 2 fluency). Histological sections of the tongues were obtained and analyzed concerning plasmatic exudation and microvessel density after immunolabeling with CD31 and CD34 vessel markers. There was intense plasmatic exudation after 6 h of the first PDT session; at 6 h of the second PDT session, there was a significant reduction in the density of CD31- and CD34-positive microvessels in comparison to controls (p < 0.05). In the PDT intervals, there was an increase in the density of CD31 and CD34 microvessels, suggesting angiogenesis. Topical application of 5-ALA-mediated PDT caused an immediate deleterious effect on the vascular network, increasing vessel permeability and reducing vessel density, mainly after two sessions of the treatment. However, secondary angiogenesis emerged in these lesions during intervals of the PDT session. This fact may be considered during the adoption of a PDT protocol, to avoid OL resistance and recurrence after the treatment.

Objective: Requirements of an NCI contract examining a novel treatment for leukoplakia were to compare standard bi-dimensional measurement of oral lesions to examine for correlation with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and to examine the feasibility of digital image analysis for automated measurements., Study Design: Retrospective review., Methods: We examined 13 patients by bi-dimensional measurement and compared these measurements to 1) RECIST criteria, 2) scalar digital measurements using a standardized measuring device within the photograph, and 3) pixel number., Results: RECIST criteria correlated (r-squared=0.8535, p<0.0001) with bi-dimensional measurements. Digitized measures in photographs correlated with bi-dimensional measurements (r-squared=0.6661, p=0.0007), but were time consuming. There was minimal to no correlation between pixel number in Adobe Photoshop and the other measures., Conclusion: Bi-dimensional measurement of oral leukoplakia and RECIST criteria are highly correlated. Digital photography measurements, though highly correlative, are very cumbersome. We recommend bi-dimensional or longest length measurement and a simple photograph as standard of documentation for leukoplakia lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oral leukoplakia is a potentially malignant lesion of the oral cavity, for which no effective treatment is available. We investigated the effectiveness of curcumin, a potent inhibitor of NF-κB/COX-2, molecules perturbed in oral carcinogenesis, to treat leukoplakia. Subjects with oral leukoplakia (n = 223) were randomized (1:1 ratio) to receive orally, either 3.6 g/day of curcumin (n = 111) or placebo (n = 112), for 6 months. The primary endpoint was clinical response obtained by bi-dimensional measurement of leukoplakia size at recruitment and 6 months. Histologic response, combined clinical and histologic response, durability and effect of long-term therapy for an additional six months in partial responders, safety and compliance were the secondary endpoints. Clinical response was observed in 75 (67.5%) subjects [95% confidence interval (CI), 58.4-75.6] in the curcumin and 62 (55.3%; 95% CI, 46.1-64.2) in placebo arm (P = 0.03). This response was durable, with 16 of the 18 (88.9%; 95% CI, 67.2-96.9) subjects with complete response in curcumin and 7 of 8 subjects (87.5%) in placebo arm, demonstrating no relapse after 6 months follow-up. Difference in histologic response between curcumin and placebo was not significant (HR, 0.88, 95% CI, 0.45-1.71; P = 0.71). Combined clinical and histologic response assessment indicated a significantly better response with curcumin (HR, 0.50; 95% CI, 0.27-0.92; P = 0.02). Continued therapy, in subjects with partial response at 6 months, did not yield additional benefit. The treatment did not raise any safety concerns. Treatment of oral leukoplakia with curcumin (3.6 g for six months), thus was well tolerated and demonstrated significant and durable clinical response for 6 months. Cancer Prev Res; 9(8); 683-91. ©2016 AACR., (©2016 American Association for Cancer Research.)

Aim of the Study: Oral leukoplakia (OL) is the most common potentially malignant disorder that may transform into oral carcinoma. By treating leukoplakia in its incipient stage, the risk of occurrence of oral carcinoma can be prevented. In this aspect, photodynamic therapy (PDT) can serve as a useful treatment modality. The aim of the study is to treat patients with OL using PDT in which 5-aminolevulinic acid (ALA) is used as a photosensitizer., Materials and Methods: Five patients with OL were included in the study. They were treated with 10% ALA mediated PDT (light source: Xenon lamp, power: 0.1 W, wavelength: 630 ± 5 nm, total dose: 100 J/cm(2) per session) for 6-8 sessions. Follow-up was done for a period of 1 year., Results: One month (4 weeks) after ALA-PDT, the response was evaluated based on clinical examination. It was as follows: Complete response: Two patients; partial response: Two patients; and no response: One patient. There was no recurrence in any of the cases., Conclusion: There was satisfactory reduction in the size of the OL lesion without any side-effects. Thus, ALA mediated PDT seems to be a promising alternative for the treatment of OL.

Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day(-1) of beta-carotene and 500 mg day(-1) of vitamin C) or placebo arm (50 mg day(-1) of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p = 0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (p = 0.580) by the Cox proportional hazards model. No unfavorable side-effects were noted. Beta-carotene (10 mg day(-1) ) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia., (© 2014 UICC.)

The aim of the study was to prove the rationale for antiviral therapy combined with surgical procedures for treatment of severe oral leukoplakia. Complex clinical and laboratory evaluation and treatment was performed in 56 patients divided in 2 groups. Control group was presented by 13 patients receiving dental treatment, local and systemic keratoplastic formulations. Main group involved 43 patients in which conventional treatment protocol was completed by antiviral therapy and surgical procedures. Leukoplakia diagnosis was based on clinical findings, histological and immunohistochemical studies as well as optic coherent tomography data. The obtained results evidently prove the necessity for including antiviral therapy and surgical procedures in treatment scheme of severe oral leukoplakia.

Clinical morphological efficiency of local application of a new biopolymeric film was studied. The film was based on methylcellulose derivatives and contained shikonin (preparation of plant origin) and its esters isolated from Lithospermum erythrorhizon L. cell culture. Combined therapy of 30 patients (34-72 years) with erosive ulcerative lichen planus and leukoplakia of the buccal mucosa was carried out. Local application of the new drug led to more rapid pain relief, epithelialization of the inflammatory destructive foci in the buccal mucosa, and reduced the intensity of morphological signs of lesions in the studied patient population.

Background: Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia., Methods: Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585nm). Clinical, histologic, and biologic markers were assessed., Results: Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4J/cm(2). One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study., Conclusions: ALA PDT could be safely administered with a light dose up to 4J/cm(2) and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.

Armstrong and colleagues report the result of a large Phase IIb randomized trial evaluating the effectiveness of a preparation of the Bowman Birk Inhibitor compared with an oral placebo in reversing the extent of oral leukoplakia as measured visually by pathology or a battery of intermediate end points. In this editorial, we review the report of this negative clinical trials result to highlight the clinical trial process used in evaluating this previously promising chemoprevention agent. Publishing this report is important to address concerns with publication bias. The challenges in running a chemoprevention trial are reviewed with suggestions to enhance progress going forward. Conceptually, developing drugs to intercept the early stages of carcinogenesis is very attractive, but progress in this area has been slow. Two opportunities to overcome this reality are discussed. These measures include the broader use of neoadjuvant, window-of-opportunity trials with new candidate chemoprevention agents to get more textured information about the mechanistic impact of the drug exposure in previously untreated early tumor tissue. In addition, we discuss the use of new intermediate end point markers such as with optical imaging tools to obtain a more objective and quantitative assessment of drug response.

Chemoprevention, defined as the use of natural, synthetic, or biologic compounds to halt, reverse, or prevent the initial phases of carcinogenesis or the progression of neoplastic cells to cancer, has produced successes, but progress has been slow. Notably, in the field of oral cancer prevention and despite extensive clinical investigations, a standard systemic therapy for patients with oral premalignant lesions is yet to be developed. In view of safety concerns surrounding the use of pharmaceuticals, the use of phytochemicals derived from the diet has been considered but has not yet translated into clinical success. The Bowman Birk Inhibitor (BBI) is a serine protease inhibitor isolated from soybeans possessing domains with trypsin and chymotrypsin inhibitory activity. Encouraging results were previously reported in a phase IIa trial of BBI complex in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. In this issue of the journal, the less promising results of the randomized, placebo-controlled phase IIb trial are presented. In this commentary, the complexities involved in defining optimal biomarkers and endpoints for oral cancer prevention trials and the development of dietary chemoprevention agents are discussed.

Background: Our previous studies showed that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is very effective for oral verrucous hyperplasia (OVH) and relatively less effective for oral leukoplakia (OL) lesions. Nevertheless, there has been no report on the association of the expression of apoptosis-related proteins in OVH and OL biopsy tissues prior to PDT with PDT treatment outcomes., Methods: This study used immunohistochemistry to evaluate whether the expression of Bak, Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, or PCNA protein in biopsy specimens of OVH and OL lesions could be used to predict the clinical outcomes of 18 OVH and 40 OL lesions treated with topical ALA-PDT. The marker labeling score (LS) was defined as labeling index (positive cells/total cells) multiplied by staining intensity. The lesions after ALA-PDT treatment were divided into complete response (CR) group and partial or no response (PR/NR) group., Results: The mean Bak LS and the mean Bak/Mcl-1 LS ratio were significantly higher in the CR group than in the PR/NR group. However, there was no significant difference in the Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, or PCNA protein LS between the CR and PR/NR groups., Conclusion: We conclude that the Bak LS or Bak/Mcl-1 LS ratio may be a useful biomarker to predict the clinical outcomes of OVH and OL lesions treated with topical ALA-PDT. Pre-PDT epithelial cell levels of Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, and PCNA may not have a significant influence on the clinical outcome of OVH and OL lesions treated with topical ALA-PDT., (© 2012 John Wiley & Sons A/S. All rights reserved.)

Oral squamous dysplasia, which can usually be readily visualized as leukoplakia during an oral examination and confirmed by histology, is often considered a premalignant condition. Current treatments, however, focus on the final stages of disease, and treatments such as surgery can lead to postoperative disabilities. Hence, this study was designed to develop a noninvasive, mucoadhesive drug delivery system loaded with an immune response modifier, imiquimod, as a treatment for precancerous dysplastic lesions. Blends of polyvinylpyrrolidone and carboxymethylcellulose were used to prepare mucoadhesive films that were backed with poly(ethylene-co-vinyl acetate). Because of the hydrophobic nature of imiquimod, four loading methods (sonication, linoleic acid, 2-hydroxypropyl-β-cyclodextrin, and acetate buffer) were compared. The formation of imiquimod-cyclodextrin complexes and their solubility was studied by differential scanning calorimetry and phase solubility studies. All films achieved sustained release of drug for 3 h except those prepared by linoleic acid. The high solubility of imiquimod in acetate buffer facilitated high loading capacity and greater release (68%) of drug than did the other formulations (approximately 40%). In summary, a noninvasive and local approach with the potential to treat precancerous lesions may be achieved by this described mucoadhesive drug delivery system., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives/introduction: Clinical trial accrual for oral dysplasia is difficult in the United States and elsewhere. Patients with dysplastic oral leukoplakia progress to frank invasive carcinoma at a rate of 5-37% over 5 years. We compared two clinical trial screening efforts to hopefully devise better accrual strategies to these types of clinical trials., Methods: For the first trial, we identified 244 patients with dysplastic oral leukoplakia in our university database and a media campaign. Patients were notified and screened by examination and biopsy. For the second clinical trial, we established a preneoplastic lesions clinic and teaching and communications network with regional oral healthcare professionals., Results: Only one of 244 patients accrued to the first clinical trial through an organized screening effort based on database/medical records review. The second clinical trial accrued 16/30 screened patients through redirected efforts in teaching, communications, and a preneoplastic lesions clinic., Conclusion: We conclude that significant difficulties resulted from medical record/database review of leukoplakia patients as a screening method for leukoplakia clinical trial entry. We feel that persistent direct contact and education of healthcare professionals who are likely to examine leukoplakia patients improved accrual to the second clinical trial., (© 2012 John Wiley & Sons A/S.)

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK., Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies., Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre., Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555.

Objective: To determine the safety and efficacy of photodynamic therapy in the treatment of oral leukoplakia with 5-aminolevulinic acid and pulsed dye laser., Design: Nonrandomized, single-arm, single-site phase 1/2 pilot study., Setting: Academic referral center., Patients: A total of 23 patients, aged 37 to 79 years, having a confirmed diagnosis of leukoplakia with or without dysplasia measuring at least 10 mm in diameter., Interventions: Application of 5-aminolevulinic acid to lesions followed by activation with high-power 585-nm pulsed dye laser., Main Outcome Measures: Maximum tolerated dose of laser, postprocedure complications, objective response to treatment, and immunohistochemical changes in treated tissue., Results: No significant adverse events occurred; minor local adverse effects were observed during and following photodynamic therapy in the safety phase of the study. The maximum tolerated dose was 8 J/cm(2). Of 17 patients, 7 (41%) had more than 75% regression (significant response) and 9 (53%) had more than 25% regression (partial response), for an overall response rate of 94% at 90 days. This response rate was far higher than the null-hypothesis 20% rate (P < 10(-10)) and the alternative-hypothesis 50% rate (P = .0001) for which the study was powered. When compared with baseline levels immunohistochemically, p53 expression was increased in 8 of 11 available samples (73%) and Ki-67 expression was decreased in 7 of 12 available samples (58%)., Conclusions: Photodynamic therapy with 5-aminolevulinic acid and pulsed dye laser could be used to achieve regression of oral leukoplakia. The treatment is safe and well tolerated. An application time of 1.5 hours and laser radiant exposure of 8 J/cm(2) with 1.5-ms pulse time were found to be the optimal settings in this study. The high-power laser used in this study allows completion of laser therapy within 1 to 3 minutes. Further studies are necessary to determine the optimal laser radiant exposure and drug application to maximize the response rate.

Data from epidemiological studies have indicated that diets rich in fruits and vegetables are likely to benefit many aspects of the prevention of oral malignancy. Lycopene is a red-coloured carotenoid predominantly accumulated in tomatoes as well as other fruits and vegetables. It has been claimed to alleviate chronic diseases such as cancers and cardiovascular disease. Hence, the aim of this review is to summarize the features and its potential significance of lycopene in the development, prevention and treatment of oral premalignant lesions and oral cancer. Studies showed that lycopene might have beneficial effects in the management of some premalignant lesions in the oral cavity including oral submucous fibrosis and oral leukoplakia and may be an adjunct in the prevention and therapy of oral cancer. However, more mechanistic studies and randomized controlled trials of large sample size are necessary to further confirm these effects and to eventually make lycopene to be used in the community prevention and clinically routine management of these diseases., (© 2010 John Wiley & Sons A/S.)

Introduction: Photodynamic therapy (PDT) is a minimally invasive surgical intervention used in the management of tissue disorders. It can be applied before, or after, any of the conventional modalities, without compromising these treatments or being compromised itself., Materials and Methods: In this prospective study, a total of 147 consecutive patients with oral potentially malignant disorders were treated with surface illumination PDT, using 5-ALA or mTHPC as the photosensitizer. The average age was 53 ± 8.9 years. The patients' recovery was uneventful and no complications reported. Comparisons with the clinical and histopathological features and rate of recurrence as well as malignant transformation were made. The patients were followed-up for a mean of 7.3 years., Analysis and Results: Homogenous leukoplakias were identified in 55 patients, non-homogenous leukoplakias in 73 patients, whereas 19 patients had erythroplakias. Ex- and current lifelong smokers formed 84.4% of the recruited patients. While people who currently smoke and drink formed 38.1% (56 patients) of the cohort. Erythroplakias were mainly identified in heavy lifelong smokers. The most common identified primary anatomical locations were the lateral border of tongue, floor of mouth and retromolar area. Moderate dysplasia was identified in 33 patients while 63 patients had severe dysplasias; and 32 patients had a histopathological diagnosis of carcinoma in situ. The rate of recurrence in laser surgery was approximately 11.6%. Malignant transformation was observed in 11 patients (7.5%), in the tongue, floor of mouth and retromolar area. Recurrence and malignant transformation was mainly identified in erythroplakias and non-homogenous leukoplakias. The final outcome of the cohort showed that 11 (7.5%) suffered from progressive disease, 5 (3.4%) had stable disease, 12 (8.2%) were considered partially responsive to the therapy. Complete response was identified in 119/147 patients (81%)., Conclusion: 5-ALA-PDT and/or mTHPC-PDT offer an effective alternative treatment for oral potentially malignant disorders., (Copyright © 2011 Wiley-Liss, Inc.)

Pachyonychia congenita is a rare genetic disorder characterized mainly by hypertrophy of the nails and hyperkeratosis of the skin and mucosae. Fifty percent of all patients have oral leukokeratosis, which is often painful. The case reported here is of a 41-year-old patient who had white lesions in the form of irregular plaques; these affected multiple regions of the oral mucosa and were sensitive to touch. Histological examination revealed acanthosis, parakeratosis and ballooning of the epithelial cells, consistent with oral leukokeratosis. After therapy including topical steroids and prosthetic rehabilitation, the symptoms resolved.

Background: Oral verrucous hyperplasia (OVH) and oral erythroleukoplakia (OEL) are two oral precancerous lesions with relatively high malignant transformation potential. One of the best cancer prevention strategies is to use a conservative and effective treatment modality to eliminate oral precancers to stop their further malignant transformation. Our previous studies have shown that the topical 5-aminolevulinic acid-mediated photodynamic therapy (topical ALA-PDT) using the 635-nm light-emitting diode (LED) light is very effective for OVH and OEL lesions., Methods: Because the laser machine is a more-popular light source than the LED device in PDT clinics, in this study 40 OVH and 40 OEL lesions were treated once a week with the same PDT protocol but using the 635-nm laser light to evaluate whether this laser light-mediated topical ALA-PDT was also effective for OVH and OEL lesions., Results: We found that all the 40 OVH lesions exhibited complete response (CR) after an average of 3.6 PDT treatments. Of the 40 OEL lesions, 38 showed CR after an average of 3.4 PDT treatments and two showed partial response (PR). Better PDT outcomes were significantly associated with OVH and OEL lesions with the smaller size, pink to red color, epithelial dysplasia, or thinner surface keratin layer., Conclusion: This study indicates that the laser light-mediated topical ALA-PDT is also very effective for OVH and OEL lesions. Therefore, we suggest that topical ALA-PDT using either the LED or laser light may serve as the first-line treatment of choice for OVH and OEL lesions., (© 2010 John Wiley & Sons A/S.)

Objective: A study is made of the efficacy and adverse effects of retinoid therapy applied to the white lesions of proliferative verrucous leukoplakia (PVL)., Material and Methods: The results of retinoid therapy were evaluated in 17 patients diagnosed with PVL. Topical retinoids were used in 5 patients, in the form of two daily applications of 0.1% 13-cis-retinoic acid in orabase for an average of 6.17+/-3.13 months. Systemic retinoids were used in 11 patients, with the administration of 25 mg/day of acitretin in tablet form for an average of 5.41+/-2.02 months. One patient successively received the topical and systemic retinoid formulations. The course and results were evaluated on a blind basis by two investigators. The adverse effects of the medication were also assessed., Results: Clinical improvement was recorded for 7 lesions (38.8%) (six involving systemic treatment and one as a result of topical application). Clinical worsening was recorded in the same proportion (5 lesions with systemic therapy and two with topical treatment), while four lesions (22.4%) showed no changes (one lesion with systemic therapy and three with topical treatment). Adverse effects were documented in all the patients administered the systemic formulation, versus in only one patient administered topical retinoids. The most frequent problems were desquamation and pruritus., Conclusion: Although topical or systemic retinoic acid produces some improvement in about one-third of all patients with PVL, further studies are needed to assess the efficacy and safety of these products, in view of the important percentage of individuals who worsen despite therapy, and the frequent appearance of adverse effects.

Purpose: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. DeltaNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess DeltaNp63 expression in OPL and its role as a marker of oral cancer risk., Experimental Design: DeltaNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus beta-carotene with low-dose 13-cis-retinoic acid. The associations between DeltaNp63 expression as well as DeltaNp63 expression with other potential risk factors for oral cancer development were analyzed., Results: DeltaNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were DeltaNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive DeltaNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive DeltaNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001)., Conclusion: DeltaNp63 overepression in OPL is associated with increased oral cancer risk. Together, DeltaNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk.

We previously showed that low-dose fenretinide (200 mg/d) had limited activity in retinoid-resistant oral leukoplakia (34% response rate) possibly because serum drug levels were insufficient to induce retinoid receptor-independent apoptosis. Therefore, we designed the single-arm phase II trial reported here to investigate whether higher-dose fenretinide would improve leukoplakia response over that of our previous study. Leukoplakia patients received fenretinide (900 mg/m(2) twice daily) in four 3-week cycles (1 week on drug followed by 2 weeks off). At week 12, clinical responses were determined and blood samples were collected for serum drug level assessments. A planned interim futility analysis led to early trial closure after the initial 15 (of 25 planned) patients because only 3 (20%) had a partial response (stopping rule:

Objective: To evaluate the safety and efficacy of aminolevulinic acid photodynamic therapy (ALA-PDT) with the 585 nm pulsed dye laser., Methods: A 5-year prospective study was performed with 12 male patients with keratosis. Twenty percent ALA was sprayed into the larynx and activated with the 585 nm pulsed dye laser (PDL). Of the 12 patients, four were not included (one lost to follow-up, two developed cancer, one papillomatosis), which reduced the number to eight. Twenty-eight procedures were performed in these eight patients; 18 (64%) procedures were performed in the clinic setting., Results: There was a 78% reduction (range, 10% to 100%) in the keratosis. No major side effects were noted. Mean follow-up was 34.5 months (range, 12 to 50 months). There were no statistical differences between the outpatient and operating room treatments., Conclusions: ALA-PDL PDT is effective and safe in treating laryngeal keratosis in the awake clinic setting and reduces morbidity without sacrificing treatment efficacy.

Purpose: To test the hypothesis that the retinamide N-(4-hydroxyphenyl)retinamide (fenretinide) would be clinically active potentially via receptor-independent apoptosis and receptor-dependent effects in natural retinoid-resistant oral leukoplakia patients--the first test of this hypothesis in any in vivo setting., Experimental Design: A phase II trial of fenretinide (200 mg/d for 3 months) in oral leukoplakia patients who had not responded (de novo resistance) or who had responded and then relapsed (acquired resistance) to previous treatment with natural retinoids. We analyzed apoptosis via the terminal deoxynucleotidyl transferase-mediated nick end labeling in situ DNA fragmentation assay., Results: We accrued 35 evaluable patients with retinoid-resistant oral leukoplakia, 12 (34.3%) had partial responses to fenretinide (95% confidence interval, 19.2-52.4%), and response was associated with acquired resistance to natural retinoids (P = 0.015, Fisher's exact test). Nine responders progressed within 9 months of stopping fenretinide. Toxicity was minimal and compliance was excellent. Mean apoptosis values (SE) increased from 0.35% (0.25%) at baseline to 1.18% (0.64%) at 3 months (P = 0.001, sign test); this increase did not correlate with clinical response. The increases in 3-month mean serum concentrations of fenretinide (0.23 micromol/L) and N-(4-methoxyphenyl)retinamide (0.57 micromol/L) correlated with decreased retinol concentrations [Spearman correlation coefficient of -0.57 (P = 0.001) and -0.43 (P = 0.01), respectively]., Conclusions: Low-dose fenretinide was clinically active and produced a small increase in apoptosis in retinoid-resistant oral leukoplakia.

Various studies have evaluated the therapeutic effectiveness of vitamin A derivatives in the treatment of oral leukoplakia (OL). Not all the studies have shown concordant results. The aim of our study, which has a 10-year follow-up, was to test the effectiveness of topical therapy based on 0.18% isotretinoin by comparing it with that most frequently used, i.e., at 0.05% concentration. Forty patients with an established diagnosis of OL were involved in the study. The patients were randomly divided into two groups and the drug was administered topically at 0.05% and 0.18% concentrations. The drug was applied twice a day for 3 consecutive months; then it was suspended for 1 month, and the biopsy sample was repeated for the histological follow-up. The higher concentration of the drug, according to the same protocol, was administered to patients who did not benefit from the lower concentration. The results showed a significant reduction in lesions (85%), with no documented topical or systemic adverse reactions at 0.18% concentration. A significant reduction of the aggressiveness of the disease and the disappearance of dysplastic phenomena were observed histologically. The proposed therapeutic protocol was effective toward highly active oral leukoplakia with dysplastic phenomena, and therefore at higher risk of malignant progression., ((c) 2006 Prous Science. All rights reserved.)

Background and Objectives: Our recent studies showed that a new topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) protocol using a light-emitting diode (LED) light source is an effective and successful treatment modality for five cases of oral verrucous hyperplasia (OVH) and one case of verrucous carcinoma. In this study, we treated eight OVH lesions with the same topical ALA-PDT protocol to further confirm the efficacy of this protocol on OVH lesions. In addition, our recent study demonstrated an unsatisfactory clinical outcome for 24 oral leukoplakia (OL) lesions treated once a week by the same topical ALA-PDT protocol. Therefore, in this study 24 OL lesions were treated twice a week by the same protocol to compare whether the twice-a-week treatment modality could result in a better clinical outcome than the once-a-week treatment modality., Study Design/materials and Methods: In this study, 8 OVH and 24 OL lesions were treated by the same topical ALA-PDT once a week and twice a week, respectively., Results: All the former eight OVH lesions treated once a week showed complete response (CR) after 2-5 (mean, 3.8) treatments of ALA-PDT. The latter 24 OL lesions treated twice a week demonstrated CR in 8, partial response (PR) in 16, and no response in none. The present 24 OL lesions treated twice a week had a significantly better clinical outcome than the previous 24 OL lesions treated once a week (P = 0.000, chi-square test)., Conclusions: We conclude that complete regression of OVH lesions can be achieved by less than six treatments of topical ALA-PDT once a week. Although the response of OL lesions to the topical ALA-PDT is not as good as the response of OVH lesions to the same therapy, all OL lesions can have at least PR after eight treatments with the topical ALA-PDT twice a week. In addition, OL lesions treated twice a week have a significantly better clinical outcome than OL lesions treated once a week., ((c) 2005 Wiley-Liss, Inc.)

We assessed the efficacy of fenretinide at preventing relapses, new lesions and carcinomas after surgical excision of oral leukoplakia. In a controlled multicenter study, 170 patients operated on for oral leukoplakias with benign postoperative histology were randomized to 200 mg fenretinide daily for 1 year vs. no intervention. Preliminary analysis indicated that fenretinide had good tolerability and was effective at preventing relapses and new lesions during treatment. Analysis after 5-year follow-up suggested that fenretinide protected against relapses and new lesions up to 19 months after randomization, with both limits of the 95% hazard ratio CI for fenretinide vs. control below 1 for 7 months after randomization. There was also a protective effect against all first events, including cancer, for 25 months, with both limits of the 95% CI below 1 up to 11 months after randomization. Subsequently, risk ratio estimates were unstable. Fenretinide was well tolerated and effective at preventing relapses and new leukoplakias during treatment and after. The trial had to be stopped prematurely for very low recruitment and had insufficient power to reveal any protective effect against oral carcinoma; nevertheless, continuing studies on this promising chemopreventive are justified., (Copyright 2005 Wiley-Liss, Inc.)