Is imiquimod a promising drug to treat oral mucosa diseases? A scoping review and new perspectives.

Imiquimod (IMQ) is a chemotherapeutic and immunostimulant drug that is applied topically, demonstrating antitumor and antiviral activities. The objective of this review was to compile data on the off-label use of IMQ in oral mucosal diseases. IMQ has exhibited effectiveness in the treatment of various oral mucosal conditions, including oral carcinogenic lesions, neoplasms, HPV-related lesions and autoimmune disorders. Although IMQ holds promise as a potential strategy for addressing oral mucosal lesions, it is important to note that significant side effects have been frequently reported. Nonetheless, it is crucial to develop and test new technological systems, such as the combination of nanotechnology with innovative drug delivery platforms. These advancements aim to minimize side effects and prolong the drug's contact time with the mucosa, preventing its removal by salivary flow.

Is vitamin D receptor (VDR) polymorphism associated with head and neck cancer risk? A systematic review and meta-analysis.

BACKGROUND: Head and neck cancer encompasses neoplasms affecting the oral cavity, pharynx, larynx, and thyroid. Identifying factors that modulate the carcinogenesis process can aid in identifying subgroups at higher risk of developing the disease, enabling implementation of prevention programs. Vitamin D receptor polymorphisms can affect the carcinogenesis of various tumors by altering vitamin D metabolism and cellular response. METHODS: To elucidate the role of vitamin D receptor polymorphisms in head and neck cancer, a systematic review was performed, searching the Embase, PubMed, Scopus, and Lilacs databases. A total of 19 articles met the inclusion criteria. The frequency of vitamin D receptors polymorphism alleles (FokI, ApaI, BsmI, TaqI, Cdx2, rs2107301, rs2238135) was recorded and pooled to calculate the odds ratio in a meta-analysis using the Review Manager software. RESULTS: Subgroup analysis demonstrated significant associations in the anatomical site of cancer (oral cancer in ApaI and BsmI, and unspecified subsites of head and neck cancer in TaqI), genotyping method (FokI and BsmI), and continent of the study (ApaI, FokI, and BsmI). CONCLUSION: Our findings were heterogeneous, as with other evidence available in the literature. Therefore, more clinical studies with larger sample sizes are needed to obtain more accurate results on the relationship between vitamin D receptor polymorphism and head and neck cancer.

Systemic non-steroidal immunomodulators for oral lichen planus treatment-a scoping review.

OBJECTIVE: The aim of this scoping review was to evaluate the efficacy and safety of the use of systemic nonsteroidal immunomodulators (SNSI) for oral lichen planus (OLP) treatment. MATERIALS AND METHODS: This review was conducted according to PRISMA-ScR guidelines and registered at PROSPERO (CRD42021243524). Consulted databases were Pubmed, Embase, Scopus, and Web of Science. The inclusion criteria was as follows: clinical trials, case series, prospective, and retrospective studies conducted with participants presenting OLP of any sex and age. RESULTS: Thirty-two studies were selected, assessing 9 different SNSI: methotrexate, dapsone, levamisole, hydroxychloroquine, thalidomide, metronidazole, azathioprine, mycophenolate mofetil, and colchicine. Methotrexate and dapsone were the drugs with the best evidence among the options included, regarding number and quality of studies. Methotrexate resulted in significant improvement in the clinical condition and remission of symptoms, ranging between 63 and 93% of cases. Dapsone presented a similar effect to the use of topical corticosteroids and tacrolimus CONCLUSION: Among SNSI therapeutic options, methotrexate, and dapsone showed promising efficacy and safety. However, large-scale randomized clinical trials are still needed. CLINICAL RELEVANCE: SNSI have been used in the treatment of recalcitrant OLP; however, so far, it is not clear which are the best options. This scoping review highlights the potential use of methotrexate and dapsone.

Clinical and immunological features of chronic ulcerative stomatitis: A systematic review.

Chronic ulcerative stomatitis (CUS) is a rare disease of the mucous membranes with characteristics similar to other autoimmune diseases. The aim of this study was to conduct a systematic review of the literature to recover all reported cases of CUS in order to summarize what are the clinical, demographic, microscopic, immunological features of CUS and its therapeutic response to different drugs. A systematic review of the literature was carried out following the statements of preferred reporting items for systematic reviews and meta-analyses (PRISMA). The searches were performed in the electronic databases PubMed, Scopus, EMBASE, LILACS, Opengrey, and Google scholar. Inclusion criteria were articles or abstracts reporting at least one case with a final diagnosis of CUS. A total of 696 records were identified through databases, and 25 studies were selected reporting 81 cases. CUS affects more females (92%), and a greater number of cases are reported in Caucasian patients (53%). The age of patients ranged from 20 to 86 years with a mean age of 60 years (±13.86), and 15% of cases reported concomitantly skin lesions. The clinical and histopathological characteristics of CUS are very similar to those of oral lichen planus. The direct immunofluorescence (DIF) remains the gold-standard diagnostic resource and was performed in 69 cases, revealing a dotted pattern of deposition of stratified epithelium-specific antibodies (SES-ANA). The serum of 38 patients was collected for the performance of the indirect immunofluorescence (IIF), and the use of epithelial substrates such as monkey and guinea pig esophagus often resulted in positive SES-ANA IgG. Most patients were treated with antimalarials, and the treatment of choice that proved to be effective is hydroxychloroquine (HCQ). This entity must be considered in the differential diagnosis of other autoimmune diseases, as it may be underreported.

Sun protection as a protective factor for actinic cheilitis: Cross-sectional population-based study.

OBJECTIVE: To determine whether sun protection is associated with lower occurrence of actinic cheilitis in adults living in a city from southern Brazil. MATERIALS AND METHODS: A multi-stage proportional sample of 404 individuals 18 years and older was obtained. Interviews and clinical examinations were conducted in participants' households. Four categories of self-reported use of sun protection were determined. Multivariable Poisson regression was used to assess the associations. RESULTS: Prevalence of actinic cheilitis was 47.1%. In the first main-effects multivariable model, AC was significantly associated with sex, age, skin colour and duration of sun exposure, but not with sun protection. However, the association between sun protection and actinic cheilitis was modified by the time of sun exposure. Among those exposed ≥4 hr/day to sun, individuals using physical protection or physical + chemical protection were 33% (prevalence ratio = 0.67, 95% confidence interval [CI] 0.47-0.94, p = .02) and 36% (PR = 0.64, 95% CI 0.47-0.94, p = .02), respectively, less likely to have actinic cheilitis than those who did not use any sun protection, adjusting for sex, age and skin colour. CONCLUSIONS: Physical and chemical sun protection were associated with lower occurrence of actinic cheilitis in individuals with greater exposure to sun.

Efficacy of topical non-steroidal immunomodulators in the treatment of oral lichen planus: a systematic review and meta-analysis.

OBJECTIVES: The aim of this systematic review was to assess the efficacy and safety of topical non-steroidal immunomodulators (TNSIs) for oral lichen planus (OLP) treatment. MATERIALS AND METHODS: A search strategy designed for this purpose retrieved 1156 references. After analysis of titles and abstracts, 75 studies were selected for full-text analysis. Only randomized controlled clinical trials were selected, resulting in 28 studies included for qualitative and quantitative analysis. RESULTS: The meta-analysis showed similar benefits in clinical response and symptom resolution between tacrolimus 0.1% and pimecrolimus 1% in comparison to topical steroids (TS). Pimecrolimus showed superior efficacy of clinical response but not for symptom resolution compared to placebo. Tacrolimus and pimecrolimus showed better performance preventing symptom relapse, while pimecrolimus also prevented clinical relapse better than TS. Cyclosporine was superior to placebo; however, TS showed better efficacy of clinical response. Thalidomide and retinoid were assessed in only one trial each, and both showed similar efficacy to TS. Rapamycin also presented similar clinical response to TS; however, the later showed greater reduction of symptoms. Mycophenolate mofetil 2% mucoadhesive was no better than placebo. No serious adverse effects have been reported. Cyclosporine showed a higher frequency and variety of adverse effects. CONCLUSIONS: Topical tacrolimus and pimecrolimus are safe and effective alternatives for OLP treatment. CLINICAL RELEVANCE: TS are usually the first choice for OLP treatment. Because some oral lesions may have a low response to treatment with TS, more topical therapeutic options, such as TNSIs, should be considered before systemic steroids are used.

The imaging role for diagnosis of idiopathic osteosclerosis: a retrospective approach based on records of 33,550 cases.

OBJECTIVE: The study aimed to describe the diagnostic imaging features of idiopathic osteosclerosis (IO) to aid in differential diagnosis of similar dentomaxillomandibular conditions. MATERIALS AND METHODS: An archive of 550 dentomaxillofacial radiographic (panoramic radiography (PR) and cone beam computed tomography (CBCT)) images and 33,000 histopathological records were reviewed to identify IO cases. Chi-square, Student's t test, and ANOVA tests, with a significance of p < 0.05, were applied for comparative analysis. In addition, we analyzed various studies to present a short review. RESULTS: After meticulous observation, 36 images of 34 patients revealed 60 IO lesions in 31 PR and 5 CBCT. Sex, age group, anatomical site, shape, regularity, and root relationship showed statistical significance: sex and age group (p = 0.046), sex and IO regularity (p = 0.007), age group and IO regularity (p = 0.014), anatomical site and IO shape (p = 0.010), anatomical site and IO regularity (p = 0.003), and IO shape and IO regularity (p = 0.002). We presented a short review from 26 articles, including retrospective, cross-sectional, and longitudinal studies, documenting 2307 patients with 2435 IO lesions from 51,160 imagiological examinations. CONCLUSIONS: A radiographic diagnostic profile of IO may guide the clinical practitioners in differentiating an incidental radiopacity. PR is a preliminary examination, with CBCT facilitating the IO diagnosis. CLINICAL RELEVANCE: Knowledge of imaging characteristics variability of idiopathic osteosclerosis is crucial for accurate diagnosis process when incidental radiopacities are found in the panoramic radiographs, thus avoiding unnecessary biopsies. CBCT scans facilitate the interpretation of idiopathic osteosclerosis overlapping the mandibular canal.

A Brazilian multicentre study of 2,497 isolated cases of odontogenic keratocysts.

We present the frequency of cases of isolated odontogenic keratocysts submitted to microscopic examination at 10 Brazilian referral centres in Oral and Maxillofacial Pathology. In a retrospective (1953-2017) analysis, data on clinicoradiographic features and treatment of these lesions were collected and analysed descriptively. Among the 258,867 cases retrieved, 2,497 (0.96%) were isolated odontogenic keratocysts. In summary, an overview of individuals affected with isolated odontogenic keratocysts is reported herein. This lesion showed predilection for the posterior mandible of young adult men.

Osteonecrosis of the jaw as a late complication of herpes zoster infection: a case report.

Occurrences of rare oral complications following herpes zoster (HZ) infection have been reported. In the present case, a 57-year-old man was referred for periodontal evaluation due to gingival bleeding. His medical history included diagnoses of chronic lymphocytic leukemia and HZ infection. Intraoral examination revealed necrosis and alveolar bone exposure around the mandibular left lateral incisor, and the patient reported spontaneous exfoliation of the maxillary and mandibular left central incisors. Conservative surgical and antibiotic therapies were provided to the patient, and a diagnosis of osteonecrosis of the jaw following HZ infection was established. There were no signs of recurrence in 17 months of follow-up. Clinicians should be aware of unusual complications related to a previous HZ infection.

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer.

Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalog of somatic mutations. However, the limited number of significant cancer-related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multiscale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort (n = 87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer-related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions.

Correction to: Treatment modalities for burning mouth syndrome: a systematic review.

The original version of this article contained two mistakes. First, in the subchapter "Alpha-lipoic acid (ALA)" page 1895, reference 4 is cited three times, however reference 42 is the correct one.

Treatment of actinic cheilitis: a systematic review.

OBJECTIVES: Actinic cheilitis is a potentially malignant disorder caused by excessive sun exposure. It affects the lower lip of individuals, mostly those with light skin color. Different treatments have been proposed for AC; however, no consensus has been reached on the best option available. MATERIALS AND METHODS: The present study describes the results of a computer-based systematic search conducted on electronic databases to identify the best therapies. RESULTS: A total of 29 journal articles were selected, and the results were divided according to the type of treatment employed: laser therapy, chemotherapy agents, surgical treatment, and application of anti-inflammatory agents. Clinically, photodynamic therapy showed positive results, with improvement in up to 100% of the patients; however, histopathological improvement varied greatly, from 16 to 100%. Among the chemotherapeutic agents assessed, imiquimod showed the best results: clinical improvement in 80 to 100% of the patients, and histopathological improvement in 73 to 100%. Regarding studies describing surgical approaches, the main focus was the search for the best technique, rather than the cure of AC. Finally, studies employing anti-inflammatory agents are sparse and have small samples, thus providing limited results. CONCLUSION: The scientific evidence available on the treatment of AC is scarce and heterogeneous, photodynamic therapy, and imiquimod application are promising. CLINICAL RELEVANCE: The study of the treatments for AC in the form of a systematic review allows us to evaluate the results against the different treatments. Being a potentially malignant lesion, it is important to seek evidence about the best results found.

Does Surgical Fragmentation of Odontogenic Keratocystic Capsule Interfere With the Recurrence Rate?

PURPOSE: We hypothesized that fragmentation of the cystic capsule during surgery would influence the recurrence rate of odontogenic keratocysts (OKCs) regardless of the treatment modality chosen. MATERIALS AND METHODS: We reviewed, in a retrospective study, cases diagnosed as OKCs on histopathologic examination at the oral pathology department between 1991 and 2013. Fragmentation data were obtained from the records of the oral surgical department. RESULTS: Fragmentation of the capsules of OKCs during surgery did not affect recurrence, irrespective of the chosen treatment modality. The addition of techniques such as cryotherapy lowered the risk of recurrence of OKCs (P = .013) compared with after enucleation alone. Furthermore, patients with associated nevoid basal cell carcinoma syndrome had a greater recurrence rate than that of those with no associated syndrome (P = .033). CONCLUSIONS: Fragmentation of the cystic capsule does not play an important role in the rate of OKC recurrence. The rate of recurrence can be modified by using additional strategies such as cryotherapy.

Treatment modalities for burning mouth syndrome: a systematic review.

OBJECTIVES: In the burning mouth syndrome (BMS), patients experience a burning sensation in the oral cavity with no associated injury or clinical manifestation. The etiology of this condition is still poorly understood, and therefore, treatment is challenging. The aim of this study is to perform a systematic review of treatment possibilities described in the literature for BMS. MATERIALS AND METHODS: PubMed, Embase, and SciELO databases were searched for randomized clinical trials published between 1996 and 2016. RESULTS: Following application of inclusion and exclusion criteria, 29 papers were analyzed and divided into five subcategories according to the type of treatment described: antidepressants, alpha-lipoic acid, phytotherapeutic agents, analgesic and anti-inflammatory agents, and non-pharmacological therapies. In each category, the results found were compared with regard to the methodology employed, sample size, assessment method, presence or absence of adverse effects, and treatment outcomes. CONCLUSIONS: The analysis revealed that the use of antidepressants and alpha-lipoic acid has been showing promising results; however, more studies are necessary before we can have a first-line treatment strategy for patients with BMS. CLINICAL RELEVANCE: To review systematically the literature about Burning Mouth Syndrome treatment may aid the clinicians to choose the treatment modality to improve patients symptoms based on the best evidence.

Low Doses of Curcuma longa Modulates Cell Migration and Cell-Cell Adhesion.

Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 µM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 µM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 µM of curcumin (50% and 40%, respectively, p < 0.05). Using spheroids, we observed that curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of Copaiba Oil Topical Administration on Oral Wound Healing.

The effects of topical copaiba oil extract and topical corticosteroid were assessed on oral wound healing in an in vivo model using 96 male Wistar rats. Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The animals were divided into: Control; Corticosteroid; Placebo and Copaiba oil Group. The animals received two daily applications of the products. The control group received only daily handling. Six rats in each group were euthanized at days 3, 5, 10 and 14. The animals were monitored daily to determine wound status. The weigh was assessed at day 0 and euthanasia day. The percentage of repair was calculated, and histopathological aspects were analyzed. The Kruskal-Wallis test was used to compare the results between groups and times of evaluation. Closing time was assessed through the log-rank test. The corticosteroid group lost more weight at days 10 and 14 than the control group (p < 0.05). Moreover, the healing time of corticosteroid group was longer than the control group (p = 0.007). No differences were observed between the copaiba oil group and the control group. We concluded that topical copaiba oil, in spite of being safe, did not accelerate the process of oral wound healing. Copyright © 2017 John Wiley & Sons, Ltd.

Topical Aloe Vera (Aloe barbadensis Miller) Extract Does Not Accelerate the Oral Wound Healing in Rats.

The effect of topical application of Aloe Vera (Aloe barbadensis Miller) extract was assessed on the healing of rat oral wounds in an in vivo model using 72 male Wistar rats divided into three groups (n = 24): control, placebo and Aloe Vera (0.5% extract hydroalcoholic). Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The Aloe Vera and placebo group received two daily applications. The animals were sacrificed after 1, 5, 10 and 14 days. Clinical analysis (ulcer area and percentage of repair) and histopathological analysis (degree of re-epithelialization and inflammation) were performed. The comparison of the differences between scores based on group and experimental period, both in quantitative and semi-quantitative analyses, was performed using the Kruskal-Wallis test. The significance level was 5%. On day 1, all groups showed predominantly acute inflammatory infiltrate. On day 5, there was partial epithelialization and chronic inflammatory infiltrate. On the days 10 and 14 total repair of ulcers was observed. There was no significant difference between groups in the repair of mouth ulcers. It is concluded that treatment using Aloe Vera as an herbal formulation did not accelerate oral wound healing in rats.

The importance of histopathologic analysis of pericoronal follicles for the early identification of ameloblastomas.

The objective of this study was to discuss the importance of performing histopathological examination of pericoronal follicles as a routine procedure, so as to enable the early identification of odontogenic lesions. We describe two clinical cases with histopathological diagnoses of ameloblastomas who did not show clinical or radiographic signs of disease before microscopic examination.

Relationship between the positions of impacted third molars and the presence of dentigerous cysts.

The objective of this study was to assess the association between the histopathological diagnoses of dentigerous cysts and pericoronal follicles and the positions of impacted third molars. The sample comprised 151 cases, diagnosed as dentigerous cysts and pericoronal follicles. Most patients were female (70.9%), white (90.1%), and age 20 years or older (63.6%). Ninety-eight cases (64.9%) were diagnosed as pericoronal follicles and 53 (35.1%) as dentigerous cysts. Teeth that developed dentigerous cysts were predominantly located in the mandible (84.9%), in a mesioangular position (49.1%), and in the 20- to 29-year age group (66.0%). The mandible seems to be the most frequent location of impacted teeth, probably because mandibular tooth eruption is more difficult, as well as dentigerous cysts, probably because the long duration of impaction increases the exposure to inflammatory stimuli and, thus, the potential for formation of dentigerous cysts. The findings also suggest that the incidence of dentigerous cysts tends to increase with age, especially for mandibular teeth in mesioangular positions.

Ki-67, TGF-ß1, and elastin content are significantly altered in lip carcinogenesis.

Epithelial changes observed in actinic cheilitis (AC) and lower lip squamous cell carcinoma (LLSCC) have been studied using different markers in order to observe diagnostic and prognostic factors for both lesions. The aim of the present study was to analyze Ki-67, TGF-ß1, and elastin content in AC and LLSCC to determine the possible role of these proteins in lip carcinogenesis. Medical records of 29 cases of AC and 53 cases of LLSCC were analyzed. Lesions were classified according histological pattern and submitted to immunostaining for Ki-67, TGF-ß1, and elastin. Different percentages of Ki-67-positive cells were found in AC depending on the degree of epithelial dysplasia (p < 0.01). An association was also found between the percentage of Ki-67-positive cells and tumor grade in LLSCC (p < 0.01). An inverse correlation was found between Ki-67 and TGF-ß1 in AC and LLSCC (p < 0.01). Elastosis was thinner and more discontinuous in LLSCC in comparison to AC, and this difference in the elastin immunolabeling pattern was statistically significant between groups (p < 0.01). The present findings indicate that changes in Ki-67 and TGF-ß1 content contribute to lip carcinogenesis. Furthermore, elastin content reflects changes in the extracellular matrix in both AC and LLSCC.