CLIC4 Function in the Epithelial-Mesenchymal Transition of Epithelial Odontogenic Lesions.

BACKGROUND: Odontogenic lesions constitute a heterogeneous group of lesions. CLIC4 protein regulates different cellular processes, including epithelial-mesenchymal transition and fibroblast-myofibroblast transdifferentiation. This study analyzed CLIC4, E-cadherin, Vimentin, and α-SMA immunoexpression in epithelial odontogenic lesions that exhibit different biological behavior. METHODS: It analyzed the immunoexpression of CLIC4, E-cadherin, and Vimentin in the epithelial cells, as well as CLIC4 and α-SMA in the mesenchymal cells, of ameloblastoma (AM) (n = 16), odontogenic keratocyst (OKC) (n = 20), and adenomatoid odontogenic tumor (AOT) (n = 8). Immunoexpressions were categorized as score 0 (0% positive cells), 1 (< 25%), 2 (≥ 25% - < 50%), 3 (≥ 50% - < 75%), or 4 (≥ 75%). RESULTS: Cytoplasmic CLIC4 immunoexpression was higher in AM and AOT (p < 0.001) epithelial cells. Nuclear-cytoplasmic CLIC4 was higher in OKC's epithelial lining (p < 0.001). Membrane (p = 0.012) and membrane-cytoplasmic (p < 0.001) E-cadherin immunoexpression were higher in OKC, while cytoplasmic E-cadherin expression was higher in AM and AOT (p < 0.001). Vimentin immunoexpression was higher in AM and AOT (p < 0.001). Stromal CLIC4 was higher in AM and OKC (p = 0.008). Similarly, α-SMA immunoexpression was higher in AM and OKC (p = 0.037). Correlations in these proteins' immunoexpression were observed in AM and OKC (p < 0.05). CONCLUSIONS: CLIC4 seems to regulate the epithelial-mesenchymal transition, modifying E-cadherin and Vimentin expression. In mesenchymal cells, CLIC4 may play a role in fibroblast-myofibroblast transdifferentiation. CLIC4 may be associated with epithelial odontogenic lesions with aggressive biological behavior.

Central Pleomorphic Adenoma of Mandible Mimicking Ameloblastoma - A Rare Case Report.

Salivary gland neoplasms account for 3% of all head and neck tumours. Pleomorphic adenoma (PA) is the most common salivary gland tumour that mainly occurs in the parotid gland, followed by minor salivary glands of the oral cavity, however, the occurrence of PA inside the jaw bones is exceedingly rare and very few cases have been reported in the literature. Inside jaw bones these lesions tend to imitate large osteolytic lesions encompass a diagnostic challenge. An exhaustive review of the literature revealed only 10 cases of central pleomorphic adenoma. We present a rare case of primary PA that occurred inside the mandible and was provisionally diagnosed as ameloblastoma.

Molecular pathogenesis of ameloblastoma.

Ameloblastoma (AM) is a benign, although aggressive, epithelial odontogenic tumour originating from tooth-forming tissues or remnants. Its aetiopathogenesis remains unclear; however, molecular analysis techniques have allowed researchers to progress in understanding its genetic basis. The high frequency of BRAF p.V600E as a main driver mutation in AM is well established; nevertheless, it is insufficient to explain its tumourigenesis. In this review, we aimed to integrate the current knowledge about the biology of AM and to describe the main genetic alterations reported, focusing on the findings of large-scale sequencing and gene expression profiling techniques. Current evidence shows that besides BRAF mutation and activation of the MAPK pathway, alterations in Hedgehog and Wnt/ß-catenin pathway-related genes are also involved in AM pathogenesis. Recently, a tumour suppressor gene, KMT2D, has been reported as mutated by different research groups. The biological impact of these mutations in the pathogenesis of AM has yet to be elucidated. Further studies are needed to clarify the impact of these findings in the identification of novel biomarkers that could be useful for diagnosing, classifying, and molecular targeting this neoplasm.

Adenomatoid odontogenic tumor: A histopathologic profile of 43 cases with evidence supporting a mixed odontogenic origin.

BACKGROUND: Adenomatoid Odontogenic Tumor (AOT) accounts for 3% of all odontogenic tumors. It has been classified by WHO as an odontogenic tumor of purely epithelial origin. The current study attempts to establish the origin of the tumor along with detailed histopathological and clinicoradiographic analysis of 43 cases of AOT. MATERIAL AND METHODS: Forty-three cases were reviewed from the departmental archives for demographic data, radiographic features and histological features. Further, histopathological slides were stained with Picrosirius Red (PSR) and observed under polarised light. RESULTS: A majority of the cases were seen in the anterior jaws (76.7%), and were less than 3 cms (76.7%) in greatest dimension. Equal number of cases were of follicular and extra-follicular location while one was peripheral. Predominantly solid histological pattern was noted in 53.5%. Varied sub-patterns were observed with most cases exhibiting solid nodules and strands of tumor cells. Few cases showed melanin pigmentation. Over a third of cases (37.2%) showed dentigerous cyst like areas and one case each showed features of ossifying fibroma and focal cemento-osseous dysplasia. Tumor droplets, hyaline rings within duct-like structures, dentinoid material and osteodentin showed reddish yellow birefringence when observed under polarised microscopy post PSR staining. CONCLUSION: This study highlights the diverse histopathological variation of AOT with evidence to reclassify it as a mixed odontogenic tumor based on the polarising microscopic findings with PSR staining.

Proteomics study of bone tissue around ameloblastoma and the potential mechanism of CD36 in bone remodelling.

Ameloblastoma (AM) is characterised by local aggressiveness and bone resorption. To our knowledge, the proteomic profile of bone adjacent to AM has not previously been explored. We therefore looked at the differential proteins in cancellous bone (CB) adjacent to AM and normal CB from the mandible. CB proteins were extracted, purified, quantified, and analysed by liquid chromatography-mass spectrometry (LC-MS) using samples from five patients with AM. These proteins were further investigated using gene ontology for additional functional annotation and enrichment. Proteins that met the screening requirements of expression difference ploidy > 1.5-fold (upregulation and downregulation) and p < 0.05 were subsequently deemed differential proteins. Immunohistochemical staining was performed to confirm the above findings. Compared with normal mandibular CB, 151 differential proteins were identified in CB adjacent to the mandibular AM. These were mainly linked to cellular catabolic processes, lipid metabolism, and fatty acids (FA) metabolism. LC-MS and immunohistochemistry showed that CD36 was one of the notably decreased proteins in CB bordering the AM compared with normal mandibular CB (p = 0.0066 and p = 0.0095, respectively). CD36 expression in CB correlates with bone remodelling in AM, making CD36 a viable target for therapeutic approaches.

BRAF p.V600E Mutational Status Does Not Correlate with Biological Behavior in Conventional Ameloblastomas: A Disease-Free Survival Analysis.

BACKGROUND: Dysregulation of the MAPK pathway appears to exert a pivotal role in the pathogenesis of ameloblastomas, since BRAF p.V600E has been reported in over 65% of the tumors. Therefore, the purpose of this study was to investigate whether the BRAF p.V600E is related to biological behavior and disease-free survival in patients with conventional ameloblastomas. METHODS: This is a retrospective cohort study based on the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) recommendations. The study population consisted of individuals treated for conventional ameloblastomas. Clinical, imaging, histomorphological, immunohistochemical (Ki67 and CD138/syndecan-1), and molecular BRAF p.V600E mutation analyses were performed. Bivariate statistical analysis was performed through chi-square and Fisher's exact tests. Kaplan-Meier analysis with log-rank test and Cox proportional hazards regression were used to identify predictors of disease-free survival, with a significance level of 5%. RESULTS: Forty-one individuals were included, with a male-to-female ratio of 1.15:1. BRAF p.V600E mutation was identified in 75.6% of the tumors. No association between the BRAF mutational status and other clinical, imaging, histomorphological, and immunohistochemical variables was observed. Only the initial treatment modality was significantly associated with a better prognosis in univariate (p = 0.008) and multivariate (p = 0.030) analyses, with a hazard ratio of 9.60 (95%IC = 1.24-73.89), favoring radical treatment. CONCLUSION: BRAF p.V600E mutation emerges as a prevalent molecular aberration in ameloblastomas. Nevertheless, it does not seem to significantly affect the tumor proliferative activity, CD138/syndecan-1-mediated cell adhesion, or disease-free survival outcomes.

Rare Case of Recurrent Adamantinoma of the Tibia: Limited Efficacy of Pazopanib as a Standalone Treatment.

BACKGROUND Adamantinoma is a rare low-grade malignant bone tumor, usually found in the tibial diaphysis and metaphysis, with histological similarities to mandibular ameloblastoma. The most effective treatment of recurrent adamantinoma is not yet clear. This report is of a 22-year-old woman with recurrent tibial adamantinoma treated with the tyrosine kinase inhibitor pazopanib. CASE REPORT We report the case of a 22-year-old woman who was referred to our center for a suspicious bone lesion in the right tibia. Bone biopsy findings were consistent with an adamantinoma. En bloc resection was completed successfully, with no postoperative complications. Five years later, a positive emission tomography scan revealed mildly increased tracer uptake near the area of the previous lesion and in the right inguinal lymph node. Biopsies of the lesion and inguinal lymph node confirmed recurrence of the adamantinoma. Due to abdominal and pelvic metastasis, the patient underwent surgical debulking, along with an appendectomy, right salpingo-oophorectomy, intraoperative radiation therapy, and hyperthermic intraperitoneal chemotherapy. Subsequently, the patient was placed on pazopanib for 4 months; however, her tumor continued to worsen after 4 months of chemotherapy. Currently, the patient is receiving gemcitabine and docetaxel as second-line medical therapy. CONCLUSIONS This report showed that pazopanib as standalone treatment does not appear to have promising role on patient outcomes. To the best of our knowledge, this is the second report of pazopanib in the treatment of adamantinoma.

Single-cell transcriptomics reveals cell atlas and identifies cycling tumor cells responsible for recurrence in ameloblastoma.

Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.

Comparison of diagnostic methods for detection of BRAFV600E mutation in ameloblastoma.

BACKGROUND: Ameloblastoma is an aggressively growing, highly recurrent odontogenic jaw tumor. Its association with BRAFV600E mutation is an indication for BRAFV00E-inhibitor therapy The study objective was to identify a sensitive low-cost test for BRAFV600E-positive ameloblastoma. We hypothesized that immunohistochemical staining of formalin-fixed paraffin-embedded tissues for BRAFV600E mutation is a low-cost surrogate for BRAFV600E gene sequencing when laboratory resources are inadequate for molecular testing. METHODS: Tissues from 40 ameloblastoma samples were retrieved from either formalin-fixed paraffin-embedded blocks, RNAlater™ stabilization solution or samples inadvertently pre-fixed in formalin before transfer to RNAlater™. BRAFV600E mutation was assessed by Direct Sanger sequencing, Amplification Refractory Mutation System-PCR and immunohistochemistry (IHC). RESULTS: BRAFV600E mutation was detected by IHC, Amplification Refractory Mutation System-PCR and Direct Sanger sequencing in 93.33%, 52.5% and 30% of samples respectively. Considering Direct Sanger sequencing as standard BRAFV600E detection method, there was significant difference between the three detection methods (𝜒2 (2) = 31.34, p < 0.0001). Sensitivity and specificity of IHC were 0.8 (95% CI: 0.64-0.90) and 0.9 (95% CI: 0.75-0.99) respectively, while positive predictive value and negative predictive value (NPV) were 0.9 and 0.8 (Fischer's test, p < 0.0001) respectively. Sensitivity and specificity of Amplification Refractory Mutation System-PCR detection method were 0.7 (95% CI: 0.53-0.80) and 0.9 (95% CI = 0.67-0.98) respectively, while PPV and NPV were 0.9 and 0.6 respectively (Fischer's test, p < 0.0001). CONCLUSION: Low-cost and less vulnerability of IHC to tissue quality make it a viable surrogate test for BRAFV600E detection in ameloblastoma. Sequential dual IHC and molecular testing for BRAFV600E will reduce equivocal results that could exclude some patients from BRAFV600E-inhibitor therapies.

DNA content and clinicopathological features aid in distinguishing ameloblastic carcinoma from ameloblastoma.

BACKGROUND: Ameloblastoma and ameloblastic carcinoma are epithelial odontogenic tumors that can be morphologically similar. In the present study, we evaluated the DNA content and Ki-67 index in the two tumors. METHODS: The paraffin blocks of the tumors were selected to obtain sections for the immunohistochemical reactions and preparation of the cell suspension for acquisition in a flow cytometer. The Random Forest package of the R software was used to verify the contribution of each variable to classify lesions into ameloblastoma or ameloblastic carcinoma. RESULTS: Thirty-two ameloblastoma and five ameloblastic carcinoma were included in the study. In our sample, we did not find statistically significant differences in Ki-67 labeling rates. A higher fraction of cells in 2c (G1) was correlated with the diagnosis of ameloblastoma, whereas higher rates of 5c-exceeding rate (5cER) were correlated with ameloblastic carcinoma. The Random Forest model highlighted histopathological findings and parameters of DNA ploidy study as important features for distinguishing ameloblastoma from ameloblastic carcinoma. CONCLUSION: Our findings suggest that the parameters of the DNA ploidy study can be ancillary tools in the classification of ameloblastoma and ameloblastic carcinoma.

Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma.

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

Clinicoradiologic features of ameloblastomas: A single-centre study of 155 cases.

BACKGROUND: The purpose of the current study was to report on the clinical presentation and radiologic features of 155 cases of ameloblastoma (AB), representing a detailed, large, single-centre radiologic study. METHODS: Histologically confirmed cases were reviewed over 11 years. Demographic and clinical data were retrieved from the patient's records. Radiologic information was analysed from available radiographs. The radiologic features of ABs were assessed according to the mean age of presentation and the mean duration of the lesion. The distinguishing radiologic features between adults/children and sex were also evaluated. RESULTS: A statistically significant correlation existed between loss of border demarcation and advanced mean age. Multilocular lesions were markedly more common in adults compared to children. Multilocular ABs were associated with increased lesion duration and advanced mean age. Radiologic signs of reactive bony changes associated with the tumour presented at the highest mean duration of all bony effects. Bony expansion and cortical destruction were statistically correlated with lesion duration. Tooth impaction was more common in children. Some mandibular lesions reached a significant size, resulting in impingement of the maxillary sinus, zygoma, orbit and pterygoid plates. CONCLUSION: Due to unfortunate healthcare access constraints, ABs grow to significant sizes and exhibit features not often reported in the literature. The findings of this analysis highlighted the radiologic features of ABs expressed through the mean age and duration of the lesion. This emphasises the significance of timely management of these lesions.

Differential Profile of Primary and Recurrent Ameloblastomas Among Afro-descendants and Non-Afro-descendants-a Systematic Review.

Ameloblastoma is an aggressively growing jaw tumor with high recurrent properties. Reports on global and racial distribution of ameloblastoma are variable and inconclusive. The role of race and ethnicity on ameloblastoma growth characteristics, genetic mutational profile, and recurrence is also still unclear. The primary aim of this systematic review was to assess genetic, racial, and ethnic distribution of primary and recurrent ameloblastoma from published literature. The secondary aim was to assess potential correlations between ethnicity, genetic mutation, and disparities in ameloblastoma treatment outcomes in Afro-descendants and non-Afro-descendants. Twenty-three eligible articles were selected based on preferred reporting items for systematic review and meta-analysis (PRISMA), and a total of 169 ameloblastoma cases were evaluated. Data on patient demographics, ameloblastoma growth characteristics, and genetic status were collected for quantitative analysis. Among a total of 169 ameloblastoma cases, Afro-descendant patients had higher primary and recurrent ameloblastomas at 15.5% and 4.7% respectively compared to non-Afro-descendant at 10.7% and 1.8% respectively. Additionally, BRAF V600E was positively associated with 48.8% of all ameloblastomas and strong predilection for Afro-descendants. Despite the paucity of information on genetic profile of ameloblastomas in the Afro-descendant patient cohort, this ethnic group still accounted for 2.95% of all BRAF V600E-positive tumors. These suggest that Afro-descendants are understudied regarding ameloblastoma characteristics, genetic profile, and recurrence profile. Mutational analysis of ameloblastoma tumors in Afro-descendants should be promoted.

Recurrence and malignant risk of ameloblastoma: A demographic study of 1626 cases from east China.

BACKGROUND: Ameloblastoma is characterized by aggressive nature, high recurrence rate, occasional malignant transformation, but recurrence and malignant incidence of ameloblastoma are not yet addressed by a large-scale case series study. MATERIALS AND METHODS: This study provided a detailed description of the relationship between demographic characteristics and recurrence and malignant cases with different clinical types of ameloblastoma (n = 1626). RESULTS: The overall incidence of recurrence and malignancy was 17.2 % and 3.4 %, respectively. Notably, we observed that there were multiple recurrent episodes (mean time, 24.3-28.7 months) among ameloblastoma patients. Multivariate analysis revealed that age of > 45 years (odds ratios (OR), 2.10; 95 % confidence interval (CI), 1.17-3.76), male (OR, 3.24; 95 %CI, 1.49-6.99), maxilla (OR, 5.58; 95 %CI, 3.11-10.0), and pre-existing recurrence (OR, 3.79; 95 %CI, 2.05-7.01) as independent factors were associated significantly with increased risk of malignancy. CONCLUSION: Identification of the clinical factors responsible for increased risk of malignancy provides better insight in management planning for ameloblastoma.

Modifications of Gallego staining and its dental application.

BACKGROUND: The objectives of the study are to employ modified Gallego staining in pathology and to specifically evaluate the hard tissue apposed to odontogenic epithelium in order to aid in the diagnosis. METHODS: Lillie's modification of Gallego's stain was utilized as a reference to create a fresh batch of the stain. The archival and running cases of 2021-2022 was screened for odontogenic pathologies, yielding approximately 46 cases, among these four cases were selected which required evaluation of the hard tissue matrix apposed to odontogenic epithelium for its characterization. The modified Gallego staining was employed in the soft tissue sections of these cases under controlled environment. The staining results were evaluated. RESULTS: The stain was used in cases to stain dentinoid deposition as green color in hybrid ameloblastoma, archegonous cystic odontoma, dentinogenic ghost cell tumor and also in other cases like calcifying odontogenic cyst. Bone presented as green in color, cells as pink color and collagen as green-pink. This helped in the correct diagnosis of these cases facilitating the correct treatment modality. CONCLUSIONS: In the field of oral pathology, there are a multitude of lesions which are odontogenic with the diagnosis of few of them hinging on the characterization of hard tissue matrix found in close approximation to odontogenic epithelium implying an inductive capability to the odontogenic epithelium. This particular modified Gallego stain has been able to help in diagnosis of few such cases in our repertoire of cases.

Clinicopathologic Profile and Surgical Modalities in Mandibular Ameloblastoma: A Descriptive Study.

BACKGROUND: Ameloblastoma is a benign neoplasm composed of epithelial tissue with invasive and infiltrative behavior at the local level and a high recurrence rate, with various histopathologic patterns and clinical forms. Approximately 85% of conventional ameloblastomas occur in the mandible, most often in the body, angle, and ascending ramus area. The treatment modalities include both conservative and radical treatments. Postoperative follow-up is most important in the treatment of ameloblastoma. AIMS AND OBJECTIVES: To describe the clinicopathologic profile of mandibular ameloblastoma in patients undergoing different surgical modalities. The primary objective was to describe the clinicopathologic profile and surgical management of mandibular ameloblastoma in patients aged ≥18 years, who had reported to a tertiary dental care center for follow-up during the study period. The secondary objective was to describe the distribution of comorbidities associated with different surgical modalities and reconstructive methods. SUBJECTS AND METHODS: A total of 34 patients with mandibular ameloblastoma who underwent various surgical modalities between 2011 and 2021 were studied. Information was collected using a predesigned proforma and statistically analyzed. RESULTS: Thirty-four review cases of ameloblastoma were included in the study. The patients were analyzed concerning age, sex, site, size, clinical presentation, radiographic pattern, histopathologic subtype, type of surgery, and associated comorbidities. Most cases of mandibular ameloblastoma involve the age of 16 to 55 years. The mean age of occurrence was found to be 35.5±13.2. A female preponderance, a tumor size range of 2 to 4 cm, a multicystic variant, involvement of the mandibular body in the premolar-molar area, root resorption, cortical perforation, and a follicular type of histopathologic pattern were the common presentations. Isolated anterior tumors restricted to the incisor/canine region were not found. The common surgical modalities undertaken were conservative methods such as enucleation, and chemical cauterization, and radical methods such as marginal mandibulectomy and segmental resection. Reconstruction using a titanium plate or free fibular graft was performed in the indicated cases. The common comorbidities included difficulty in chewing and loss of facial contour. Recurrence after surgical treatment was rare. Only 9% of cases developed a recurrence within 5 years. No recurrence was noted in cases treated with radical treatment, whereas 50% of cases treated with conservative methods showed recurrence. CONCLUSION: The age of occurrence, site, and size of the tumor, cortical perforation, root resorption, histopathologic type, and radiographic patterns are widely considered factors in devising a treatment plan for mandibular ameloblastoma. However, there may be rare instances where these tumors behave differently regardless of their innocuous clinicopathologic presentation. Surgical procedures such as segmental resection and marginal mandibulectomy were found to be promising for the eradication of the tumor, and prevention of recurrences and metastasis. However, conservative measures such as enucleation and chemical cauterization were fraught with an increased risk of tumor recurrence and metastasis. Future studies with a larger sample size should focus on the clinicopathologic characteristics of ameloblastoma to elucidate its varied behavior and develop newer and advanced treatment modalities that would provide better surgical and postsurgical outcomes in affected patients.

Pediatric Odontogenic Tumors.

Odontogenic tumors are rare tumors of the jaws that arise from remnants of the tooth forming apparatus. Some odontogenic tumors demonstrate strong predilection for pediatric patients including the unicystic ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibro-odontoma, odontoma, and primordial odontogenic tumor. In this review, we discuss the clinical, radiographic, histopathologic, and molecular characteristics of select odontogenic tumors that demonstrate pediatric predilection and review management.

Does BRAF mutation status and related clinicopathological factors affect the recurrence rate of ameloblastoma? A systematic review, meta-analysis and metaregression.

OBJECTIVES: This review aims to analyse the recurrence rate in BRAFv600e+ and BRAFv600e- ameloblastomas and explore its association with clinicopathological variables. METHODS: A comprehensive search was conducted using databases including PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, Google Scholar and grey literature, without any limitation on start date or language up to 20 June 2023. A random effect meta-analysis was conducted and Metaregression analyses were performed based on available clinicopathological factors. RESULTS: Fifteen studies met the criteria for meta-analysis of outcomes. There was no significant difference in overall recurrence rates between the two groups (risk difference = 0.001, p-value = 0.987). Increasing male:female ratio in the BRAFv600e+ group was associated with a lower reported recurrence, suggesting a higher recurrence rate in females. The odds of having mandibular lesion were four times higher in BRAFv600e+ cases compared to BRAFv600e- cases (confidence interval: 2.121-7.870, p < 0.001, I2 = 28.37%). CONCLUSION: Within the BRAFv600e+ group, females showed a higher reported recurrence rate. This specific clinical group may benefit from BRAFv600e mutation investigation and potential upscaled surgical treatment and additional BRAF inhibitor therapy, which needs validation in future studies.

Current concepts in targeted therapies for benign tumors of the jaw - A review of the literature.

The aim of our study was to review current concepts in targeted therapies for benign tumors of the jaw. Benign odontogenic and maxillofacial bone tumors often require radical surgery, with consequent morbidity that impacts patients' postsurgical quality of life. Currently, targeted therapies and novel nonsurgical therapeutics are being explored for management of non-resectable tumors, with the aim of avoiding surgery or minimizing surgical scope. However, data on clinical applications of targeted therapies for benign tumors of the jaw remain sparse. Therefore, a literature review was conducted, based on the PubMed database, which included in vivo human clinical studies describing clinical application of targeted therapy for benign tumor of the jaw. The review assessed the outcomes of BRAF and MEK inhibitors for treatment of ameloblastoma, RANKL monoclonal antibody for treatment of giant cell tumor, cherubism, aneurysmal bone cyst, and fibrous dysplasia, and tyrosine kinase inhibitor for treatment of odontogenic myxoma and cherubism. Targeted therapies decreased tumor size, slowed down tumor progression, and reduced bone pain. Surgery remains the gold standard, but targeted therapies are promising adjuvant or alternative treatment options for reducing tumor progression and morbidity of tumor surgery.