Early antitumor activity of oral Langerhans cells is compromised by a carcinogen.

Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here, we define the Langerhans cells (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αßT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and natural killer cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies, while dendritic cells (DCs), macrophages, and plasmacytoid DCs (pDCs) populate the epithelium. Single-cell RNA-sequencing analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDCs and precedes the formation of visible tumors. This suggests LCs play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.

Photobiomodulation alleviates Burning Mouth Syndrome pain: Immediate and weekly outcomes explored.

Burning Mouth Syndrome (BMS) is an intraoral chronic burning or dysesthetic sensation, without clinically evident causative lesions on clinical examination and investigation. AIM: To assess immediate and weekly effects of photobiomodulation (PBM) on BMS patients. METHODS: Thirty BMS patients were treated intra-orally with photobiomodulation 940(±10) nm (InGaAsP) 3 W, semi-conductor diode, weekly, for up to 10 weeks. Pain intensity, measured using the Visual Analogue Scale (VAS), and characteristics were recorded immidiately after each treatment, along with a weekly average VAS. RESULTS: Immediate mean VAS score decreased from a starting score of 7.80 ± 1.83 to 2.07 ± 2.55 (p < 0.001). The mean weekly VAS score for the week after the final treatment session was higher (5.73 ± 2.80, p < 0.001) than the immediate response, but still significantly lower than the starting score (p = 0.017). We observed a trend of pain improvement with more treatments, but this was only statistically significant up to the third treatment. Male gender and unilateral pain correlated with better PBM efficacy (p = 0.017, 0.022, respectively). CONCLUSION: PBM provides significant immediate pain relief for BMS patients after each treatment; however, the efficacy decreases notably over the following week. A trend of increasing pain relief across treatments was observed, statistically significant up to the third treatment.

Familial oral lichen planus: A new risk group for oral cancer?

OBJECTIVE: The familial type of oral lichen planus (OLP) is rare, with a paucity of data regarding its clinical significance. Our objective was to characterize patients with familial OLP. METHODS: Families with at least two members diagnosed with OLP were included. Clinical and demographic data and medical history were recorded. RESULTS: Twenty families, 19 Jewish and 1 Arab, were identified. Of the Jewish families, 57.8% were non-Ashkenazi, originating mainly from central Asia. Of those with OLP there were 14 males and 23 females with an average age of 49.1. Dyslipidemia, cardiovascular, and thyroid disorders (27.7%, 22.2%, and 16.6%, respectively) were the most common comorbidities. Five patients from five distinct families had oral cancer, two with second primary. CONCLUSIONS: To the best of our knowledge, this is the largest study describing familial OLP. The predominant and common ethnicity of the families with multiple members diagnosed with OLP may imply an ethnic tendency. The higher tendency of hypothyroidism and the high percentage of OSCC among familial OLP patients might be connected to familial OLP and the latter suggests that this population is predisposed to malignant transformation. Thus, this group should be considered as a high-risk group.

Factors important in the correct evaluation of oral high-risk lesions during the telehealth era.

BACKGROUND: Considering that early detection of squamous cell carcinoma (SCC) improves prognosis and clinical examination is the primary detection method, we identified factors related to the clinical evaluation of oral mucosal lesions. Due to the growing role of telehealth, our study was based on clinical image evaluation. SUBJECTS AND METHODS: Oral medicine specialists and dental students evaluated six images of benign, potentially malignant, or SCC lesions (18 images in total). We analyzed the role of personal factors of the examiners and the visual pathological features of the lesion upon which the participants based their evaluation. RESULTS: One hundred thirty-three subjects participated. Half of the benign images were correctly evaluated. On average 1.2 (±SD1.3) cancer pictures were recognized correctly and 3.66 (±SD1.42) images were considered potentially malignant. Potentially malignant lesions were correctly evaluated at an average of 4.08 (±SD1.48) images. For cancer and potentially malignant lesion images, there were significantly better results among clinicians with the worst results from the fourth-year students. Student results correlated significantly with years of study, number of weeks spent in the oral medicine clinic, and interest in oral pathology. Consideration of lesion irregularity yielded a correct diagnosis, whereas wrong answers were based on color changes. Lesion size and margins were considered equally important. CONCLUSIONS: Using clinical images as part of the diagnostic process provides good results, though increased clinical experience for graduates and undergraduates may be necessary to improve accuracy. Therefore, emphasizing the important visual parameters of malignancy may be valuable in the current telehealth era.

Clinical photography: Attitudes among dental students in two dental institutions.

INTRODUCTION: Clinical photography is an important tool in teaching, clinical practice and academia especially for mucosal pathologies. Our aim was to examine differences in attitude towards clinical photography for mucosal pathologies among students. METHODS: Questionnaires about clinical photography were completed by students in dental teaching hospitals in Birmingham (UK) and in Israel (ISR). The questionnaires focussed on the perceived value of clinical photography for a number of purposes and also explored perceived barriers to clinical photography and technology in general. The two departments have different access to clinical photography; in the United Kingdom a separate dedicated photography unit takes all the photographs, whereas in ISR the clinicians take their own photographs. Pearson Chi-squared tests determined statistical significance between categorical variables (P < 0.05). RESULTS: Among the 163 respondents, there were no significant differences in the value of photography between countries or genders. The participants felt that the aims of photography included: teaching (99.4%), monitoring premalignancy (97.6%) and clinician communication (95.8%). More than 90% thought photography should be used for dysplasia and erosive lichen planus cases. Respondents from ISR were more in favour of photographing pathologies including simple leukoplakia, reticular lichen planus, vesiculobullous or pigmented lesions (P < 0.001 compared to the UK). Overall, the main reasons for not using photography were time constraints (25.5%) and access (21.8%). CONCLUSIONS: This study highlights a favourable attitude towards clinical photography for various teaching and clinical indications thereby demonstrating its importance. In order to maximise the benefits of clinical photography, access should be simplified.

Comparison of the efficacy of a novel sustained release clotrimazole varnish and clotrimazole troches for the treatment of oral candidiasis.

OBJECTIVES: Candida albicans is a common fungal infection and is commensal in 40-65 % of healthy adults. The development and pharmacokinetics of a novel sustained release clotrimazole varnish (Clot-SRV) for topical oral use have been reported. The aim of this study was to compare the efficacy of this varnish with clotrimazole troche treatment of oral candidiasis. MATERIALS AND METHODS: Of the 12 patients with denture stomatitis treated for 14 days, six used Clot-SRV (study group) and six clotrimazole troches (control). The patients were instructed to use Clot-SRV (50 mg of clotrimazole) once a day, and the control group was instructed to use five troches of 10 mg clotrimazole/day. Microbiological samples were obtained from saliva, buccal mucosa, palate, and denture. The degree of erythema was recorded at three time points, and subjective opinions noted using a questionnaire. RESULTS: At the end of the study, the control group had relatively more cases of erythema on all examined surfaces; patients who applied the Clot-SRV had significantly lower levels of candida on the denture surfaces and in saliva, and had better compliance to the medication. CONCLUSIONS: The novel clotrimazole sustained release varnish may be an important part of a new protocol for oral candidiasis, with improved clinical outcomes.

Demographic and clinical factors associated with referrals and compliance to biopsy of oral and maxillofacial lesions.

BACKGROUND: The gold standard for diagnosing oral disease is tissue biopsy. Data regarding compliance with advised oral and maxillofacial (OMF) biopsy are scarce. PURPOSE: To quantify compliance and evaluate the demographics and clinical factors associated with referrals and compliance with OMF biopsy procedures. METHODS: Medical records of military personnel referred for a biopsy (RB; N = 669) of OMF lesions over a 4-year period were studied retrospectively. These patients were divided into performed the biopsy (PB; N = 386) and not perform biopsy (NPB; N = 283) groups. Demographic and clinical features were analyzed, and demographics were compared to a control group of general military personnel (N > 100,000). RESULTS: The RB group differed from the control group regarding age >21 (OR = 1.681, P < 0.001) and education >12 years of schooling (OR = 1.545, P < 0.001). Differences between the PB and NPB groups related to the clinical features of the lesion but not to demographic parameters. Exophytic and suspected potentially malignant/malignant lesions were positively associated with higher compliance to biopsy (OR = 1.75, P = 0.004 and OR = 2.18, P = 0.017, respectively). CONCLUSION: Referrals to biopsy of OMF lesions are significantly influenced by age and education, whereas compliance is influenced by clinical features or suspected malignancy. Clinicians and health authorities should be aware of non-compliance, enhance awareness to biopsy as the gold standard in the diagnostic workup of OMF lesions, and closely monitor compliance patterns of patients with clinical and demographic risk factors.

Diagnosis and management of oral leishmaniasis--case series and literature review.

The worldwide prevalence of leishmaniasis is increasing because of ecologic changes and increased medical profession awareness. Furthermore, solitary cases have been recently reported in Western countries. The authors describe the epidemiology, mode of transmission, and diagnosis of leishmaniasis and present 4 oral cases treated with systemic, localized, or combined therapy. The authors suggest that clinicians should maintain a high index of suspicion for atypical, resistant, oral and perioral lesions in individuals with a history of traveling in certain geographic regions. After diagnosis, treatment should be determined jointly by experts from the fields of oral and maxillofacial surgery, oral medicine, and dermatology based on leishmaniasis species and clinical presentation.

Overnight use of oral appliance with sirolimus sustained-release varnish delivery system: a clinical note and an observational study.

OBJECTIVE: Maintaining appropriate salivary levels of an active ingredient is challenging. Intraoral trays can be used to deliver medications for localized treatment. Based on previous successful daytime studies with a slow-release sirolimus varnish, the aim was to optimize intraoral appliances/trays for overnight use to deliver slow-release medications in a manner that maintains therapeutic salivary levels of the active ingredient to treat oral conditions. METHOD AND MATERIALS: An acrylic tray appliance containing 0.5 mg of sirolimus in a sustained-release varnish was placed on six anterior teeth for 12 hours, in ten healthy volunteers. Whole unstimulated saliva was collected at 1, 2, 10, and 12 hours after application. Blood was collected at the time of recruitment to confirm eligibility, and 12 hours after device removal to measure sirolimus levels. Drug levels in the blood and saliva were analyzed. Slow- and fast-release formulations, varnish position (buccal, palatal, or lingual), and tray placement (mandibular or maxillary) were qualitatively compared. Participants evaluated the varnish and tray. RESULTS: Moderate concentrations of sirolimus were detected in the saliva when the fast-release formulation was used. The highest levels were from the mandibular tray with lingual varnish application. Sialometry of all participants was within normal range, and the highest drug levels were detected when low flow was measured. No traces of the medication were found in the blood. CONCLUSIONS: Salivary concentrations of medications applied to an intraoral appliance are affected by the placement in the maxilla or mandible, varnish formulation, location of varnish, and salivation rate. These results may help optimize medication release following application to various oral devices. (Quintessence Int 2023;54:242-249; doi: 10.3290/j.qi.b3604821).

Evaluation of oral mucosal diseases: inter- and intra-observer analyses.

BACKGROUND: Essential to the diagnosis and management of oral mucosal diseases are visual evaluation and monitoring of the oral cavity. Digital photography has recently become an important clinical tool. The aims of this study were to (i) evaluate inter- and intra-observer differences between oral medicine and other dental specialists when assessing changes in oral mucosal pathology and (ii) assess the influence of calibration labels incorporated into the clinical images on the reliability and consistency of evaluation. METHODS: Ten oral medicine specialists (OM) and 10 other dental specialists (DS) participated in the study. Pairs of images captured with an intraoral camera at two time points from 17 cases of mucosal diseases were presented to the participants. Each pair of photographs was presented with a calibration label (showing length and white to black hues) and again without one. The participants were asked to respond to a questionnaire evaluating changes in size, color, location, and severity for each image pair. RESULTS: Oral medicine specialists had better absolute agreement and consistency than DS when evaluating the changes in the images; however, these parameters did not exceed 52% in either group. The incorporation of a calibration label in the images increased agreement and consistency of evaluations in both groups. CONCLUSIONS: Follow-up evaluations of oral mucosal lesions are performed better by oral medicine practitioners compared to other dental specialists. The incorporation of a calibration label in the clinical images seems to enhance evaluation.

Topical tretinoin treatment for burning mouth syndrome: a pilot study.

OBJECTIVES: Burning mouth syndrome is an intraoral chronic pain condition characterized by a moderate to severe sensation of burning from the oral mucosa. No clinical signs are found and there is no efficient treatment. METHOD AND MATERIALS: This pilot study included 10 women that were resistant to other previous treatments or noncompliant to systemic medications. Patients were asked to apply tretinoin gel 0.05% on their tongues twice daily for 14 days. Treatment effectiveness was assessed by completing a pre-study psychologic questionnaire and recording a daily wellbeing and pain log. RESULTS: Significant pain-score decrease in 50% of the patients (delta numerical rating score -3.15 ± 3.02, P value = .005) was recorded. This finding was in concordance with the verbal statements including major quality-of-life improvement (P value = .05), without any treatment positive or negative predictive factors. CONCLUSIONS: Topical tretinoin exhibits potential efficacy in patients with treatment resistant burning mouth syndrome and may also be used as a primary treatment modality.

Oral cancer over four decades: epidemiology, trends, histology, and survival by anatomical sites.

BACKGROUND: Oral cancer is one of the few life-threatening oral diseases. The subtypes and different sites of oral cancer has different etiology epidemiology and survival rate. Prevalence of the various anatomical oral sites provided potential baseline for improvement of clinical approach. METHODS: Incidence and survival rates were derived from the Israel National Cancer Registry and included all registered data between 1970 and 2006. Oral cancer included the lips, tongue, buccal mucosa, gums, vestibulum, floor of the mouth, and palate. RESULTS: Most prevalent oral cancer subtype was squamous cell carcinoma (SCC) among men above the age of 55 years. Females had a higher incidence of SCC in lateral border of tongue, gums and buccal mucosa. Lymphoma and sarcoma were the most prevalent under the age of 20. Melanomas and metastatic disease revealed the lowest survival rate, while invasive or infiltrating basal cell carcinoma in the lips had the highest rate. The highest oral survival rate was for the lip, and the lowest was for the tongue and gums. CONCLUSIONS: Early detection of oral cancer is important for all the medical health team. Decrease in lip carcinoma may be a result of occupational or awareness changes and should be studied. Non-epithelial tumors under the age of 20 should be considered as a differential diagnosis. A basic oral examination should be included in all routine medical examinations, with emphasis on high-risk patients and high-risk oral sites.

A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis.

The use of dental varnish for therapeutic purposes has been reported for fluoride or antibacterial drugs. Our objectives were to develop a sustained-release varnish containing an antifungal drug (clotrimazole) for topical application and to evaluate the release rate of the drug in human saliva in comparison with an available commercial troche and their acceptance by healthy volunteers. Following in vitro optimization of the release rate from the varnish, we have embarked on a crossover comparative study assessing the oral sensations and pharmacokinetics of a 10-mg clotrimazole oral troche versus a 10-mg sustained-release clotrimazole varnish in 14 human volunteers over a period of 5 h. Saliva samples were assessed for clotrimazole concentration by high performance liquid chromatography analysis. The volunteers' evaluation of the varnish and troche (taste, other sensory changes, convenience, and oral suitability) were recorded. At all time points, salivary clotrimazole concentrations were higher, and the terminal half-life was significantly prolonged in the varnish group in comparison to the control group. This can be attributed to continuous release of clotrimazole from the varnish formulation. The duration of the drug over the minimal inhibitory concentration, following application of the varnish, was more than threefold longer than following administration of the troche. The developed sustained-release varnish can be applied in patients at a lower frequency than troches, thus, achieving higher patient compliance and efficacy. This novel varnish application can serve as the basis for a new treatment approach to oral candidiasis, a very common chronic opportunistic infection with improved clinical outcome.

Evidence of chorda tympani dysfunction in patients with burning mouth syndrome.

BACKGROUND: More than two-thirds of patients with burning mouth syndrome (BMS) have altered taste sensation. The authors conducted a study to assess chorda tympani and trigeminal nerve function in these patients. METHODS: The study was composed of 48 patients; 22 were diagnosed as having BMS, 14 had burning symptoms related to other diseases and were diagnosed as having secondary burning mouth syndrome (SBMS), and 12 were healthy volunteers. The authors evaluated the electrical detection thresholds of the infraorbital and mental nerves and the electrical taste and electrical detection/tingling thresholds in the anterior two-thirds of the tongue for all patients. Electrical taste threshold is thought to be dictated by chorda tympani nerve function while electrical detection/tingling thresholds are regulated by trigeminal nerve function. RESULTS: The mean electrical taste/tingling detection thresholds ratio and the taste detection thresholds were significantly higher in patients with BMS than in patients with SBMS and in control subjects, indicating chorda tympani nerve dysfunction. Eighteen (82 percent) of the 22 patients with BMS demonstrated chorda tympani dysfunction (13 unilateral and five bilateral). CONCLUSIONS: Chorda tympani hypofunction may play an important role in BMS pathology. Unilateral hypofunction may be sufficient to produce generalized burning sensation exceeding the affected nerve area. CLINICAL IMPLICATIONS: Elevated taste detection threshold levels determined via electrogustatory testing and an elevated taste/tingling detection thresholds ratio may assist clinicians in the diagnosis of BMS. More studies are needed to validate these findings.

Epidemiology of oral, salivary gland and pharyngeal cancer in children and adolescents between 1970 and 2011.

OBJECTIVES: The age of oral and pharyngeal cancer patients has reportedly decreased over the last decade, but most of the peer-reviewed literature regarding oral and pharyngeal cancer in individuals 0-19years of age (Y) is limited to specific tumor sites and/or types, or a small number of cases. Our aim is to characterize oral, salivary gland and pharyngeal cancer (OSPC) in 0-19Y in order to improve knowledge of the disease in young individuals. METHODS: Data on OSPC between 1970 and 2011 was taken from the Israel National Cancer Registry, and included patient age, gender, tumor site and tumor type. Data analysis was performed by using IBM SPSS, Winpepi software and Joinpoint Regression Program. alpha<0.05 was deemed statistically significant. RESULTS: A total of 13,863 OSPC cases were diagnosed with 2.6% (N=357) of 0-19Y. The male to female ratio was 1.5:1. The rates of diagnosis decreased between 1991 and 2011 and were not significantly different between the genders. The nasopharynx was the leading tumor site (42.3%) followed by the salivary glands (20.5%), and both were more common in 14-19Y. The tonsils and other pharyngeal sites were common among 0-13Y. The main tumor types were lymphomas (20.7%) and carcinomas (19.9%). CONCLUSIONS: The general characteristics of OSPC remained unchanged over the last four decades. This may imply that environmental factors have not had any effect. Males are affected more than females and might have a genetic predisposition for nasopharyngeal malignancy. Health care providers should be aware of the common sites and tumor types among children and adolescents.

Protein S drives oral squamous cell carcinoma tumorigenicity through regulation of AXL.

The TAM family of proto-oncogenic receptor protein tyrosine kinases, comprising of TYRO3, AXL, and MERTK, is implicated in many human cancers. Their activation leads to cancer cell proliferation, enhanced migration, invasion, and drug resistance; however how TAMs are activated in cancers is less understood. We previously showed that Protein S (PROS1) is a ligand of the TAM receptors. Here we identify PROS1 as a mediator of Oral Squamous Cell Carcinoma (OSCC) in proliferation, cell survival and migration. We demonstrate that excess PROS1 induces OSCC proliferation and migration. Conversely, blocking endogenous PROS1 expression using shRNA significantly inhibits cell proliferation and migration in culture. This inhibition was rescued by the addition of purified PROS1. Moreover, PROS1 knockdown reduced anchorage-independent growth in-vitro, reduced tumor xenograft growth in nude mice and altered their differentiation profile. Mechanistically, we identify the downregulation of AXL transcripts and protein following PROS1 knockdown. Re-introducing PROS1 rescues AXL expression both at the protein and transcriptional levels. The anti-proliferative effect of the AXL inhibitor R428 was significantly reduced following PROS1 inhibition, indicating the functional significance of PROS1-mediated regulation of AXL in OSCC. Taken together, we identify PROS1 as a driver of OSCC tumor growth and a modulator of AXL expression. Our results point to PROS1 as a potential novel anti-cancer therapeutic target.

Oral squamous cell carcinoma around dental implants.

It is well documented that oral squamous cell carcinoma (OSCC) is related to risk factors such as smoking and alcohol consumption as well as premalignant lesions and conditions such as leukoplakia, oral lichen planus (OLP), and previous malignancy of the upper respiratory system and gastrointestinal tract. Osseointegrated dental implants are rarely reported in association with OSCC. This article presents 2 cases of OSCC adjacent to dental implants in patients at risk for oral cancer--1 was a heavy smoker with OLP; the other had a history of previous oral and colon cancer. Six additional cases of malignancy adjacent to dental implants were retrieved from the literature; the majority of cases had at least 1 recognized risk factor for oral cancer. Although such cases are rarely reported, patients at risk for oral cancer, especially those with multiple existing risk factors, that present with failing dental implants should be thoroughly evaluated to rule out the presence of malignancy disguised as peri-implant disease.