Efficiency of B-RAF-/MEK-inhibitors in B-RAF mutated Ameloblastoma: Case report and review of literature.

Background: Ameloblastoma is a benign but locally invasive and aggressive odontogenic tumor harboring activating BRAF V600E mutations in about two thirds of the cases. Case presentation: Neoadjuvant therapy with Dabrafenib and Trametinib was given to a 42-year-old male patient with recurrent ameloblastoma of the right mandible with a BRAF V600E mutation for 18 months. The patient manifested an excellent response to the therapy with remarkable reduction in tumor size from 72.6 mm to 55.9 mm. Histopathologically, the tumor underwent significant degenerative changes with only a few sparse vital residuals revealing 0 % Ki67 proliferative index. Conclusions: Neoadjuvant therapy with BRAF-inhibitors or BRAF-MEK-inhibitors is an effective means to reduce the size of mandibulary ameloblastomas. We propose the consideration of neoadjuvant therapy in future treatment modalities to minimize post-surgical morbidity and facial deformations.

Molecular diagnostics in odontogenic tumors.

BACKGROUND: Odontogenic tumors (OTs) are rare, with an estimated incidence rate of less than 0.5 cases per 100,000 per year. The causes of OTs remain unclear. Nonetheless, the majority of OTs seem to arise de novo, without an apparent causative factor. Although the etiopathogenesis of most OTs remains unclear, there have been some recent advances in understanding the genetic basis relating to specific histologies and clinical features. Molecular analyses performed by different techniques, including Sanger sequencing, next-generation sequencing, and allele-specific PCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway. Genetic mutations in these pathway genes have been reported in epithelial and mixed OTs, in addition to odontogenic carcinomas and sarcomas. Notably, B­RAF proto-oncogene serine/threonine kinase (BRAF) and KRAS proto-oncogene GTPase (KRAS) pathogenic mutations have been reported in a high proportion of ameloblastoma and ameloblastoma-related tumors and adenomatoid odontogenic tumors, respectively. OBJECTIVE: To discuss how molecular profiling aids in diagnostic classification of odontogenic tumors. CONCLUSION: Molecular profiling of odontogenic tumors helps to identify patients for neoadjuvant therapies and reduces postoperative morbidity.

Clinical and pathomorphological aspects of odontogenic tumors.

BACKGROUND: Odontogenic tumors (OTs) comprise a group of heterogeneous lesions ranging from hamartomatous or non-neoplastic tissue proliferation to benign or malignant neoplasms with metastatic potential. OTs are derived from epithelial, ectomesenchymal, and/or mesenchymal elements of tooth-forming ("odontogenic") tissues, which show variable clinical and histopathological features. OBJECTIVE: Herein, the authors summarize the World Health Organization (WHO) 2022 classification of OTs and further highlight diagnostic tips and differential clues for the most common OTs. CONCLUSION: OTs may not be commonly encountered in the daily practice of many pathologists. This makes their diagnosis challenging as there is little practice in understanding the features required for their classification. However, diagnosing the vast majority of these lesions is not difficult provided the following aspects are considered: 1) the general knowledge of tooth development; 2) a few key histological observations; 3) very basic knowledge of the clinical and especially the radiographic features with which they are associated.

The landscape of genetic alterations in ameloblastomas relates to clinical features.

Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey. In good agreement with previously published data, we observed BRAF mutations almost exclusively in mandibular tumors, SMO mutations predominantly in maxillary tumors, and single mutations in EGFR, KRAS, and NRAS. KRAS, NRAS, PIK3CA, PTEN, CDKN2A, FGFR, and CTNNB1 mutations co-occurred in the background of either BRAF or SMO mutations. Strikingly, multiple mutations were exclusively observed in European patients, in solid ameloblastomas and were associated with a very high risk for recurrence. In contrast, tumors with a single BRAF mutation revealed a lower risk for relapse. We here establish a comprehensive landscape of mutations in the MAPK and hedgehog signaling pathways relating to clinical features of ameloblastoma. Our data suggest that ameloblastomas harboring single BRAF mutations are excellent candidates for neo-adjuvant therapies with combined BRAF/MEK inhibitors and that the risk of recurrence maybe stratified based on the mutational spectrum.

Unusual Presentation of an Adenocarcinoma of the Lung Metastasizing to the Mandible, Including Molecular Analysis and a Review of the Literature.

Lung cancer is the most frequent cause of cancer-related death worldwide. Metastases of non-small cell lung carcinoma to the oral and maxillofacial region are rare. Thus, the diagnosis of a metastatic lesion in the oral cavity is challenging to the clinician and to the pathologist. This report presents a case of a 72-year-old man with metastatic lung adenocarcinoma located in the posterior mandibular region. Next-generation sequencing analysis showed no important mutations in the relevant genes except in the TP53 tumor suppressor gene.

Management of a Recurrent Pyogenic Granuloma of the Hard Palate with Diode Laser: A Case Report.

INTRODUCTION: Pyogenic granuloma (PG) is a prevalent inflammatory hyperplasia of skin and oral mucosa which is often caused by constant low-grade local irritation, traumatic injury or hormonal factors. In many cases, gingival irritation and inflammation due to poor oral hygiene are precipitating factors. Oral PG occurs predominantly on the gingiva, but it is also encountered on the lips, tongue, buccal mucosa and rarely on the hard palate. Although surgical excision is the first choice of treatment, many other treatment modalities could be counted such as cryosurgery, sodium tetradecyl sulfate sclerotherapy, intralesional steroids, flash lamp pulsed dye laser, neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, carbon dioxide (CO2) laser, erbium-doped yttrium aluminum garnet (Er:YAG) lasers and diode laser have been suggested. After surgical excision recurrence occurs up to 16% of these lesions. It is believed that recurrence ensues as a result of incomplete excision, failure to eliminate etiologic factors or repeated trauma. CASE REPORT: A 50-year-old female was referred to the Department of Oral Surgery, Gazi University, School of Dentistry, complaining of a swelling and growth on the right side of the hard palate for four months. Patient reported a similar growth in the same area about two years earlier, which had turned out to be a PG by histopathology. The treatment plan included surgical excision of the lesion using diode laser. RESULTS: The patient reported no pain after the surgery. She was discharged with a prescription of chlorhexidine mouthwash and necessary post-operative instructions. At 7 days follow up visit, immediate recurrence of the lesion was observed, and it was excised by diode laser with 2 mm margins at its clinical periphery, to a depth up to the periosteum, by the same operator. No recurrence or scarring was observed in 14 months follow-up. CONCLUSION: Although diode laser is a secure and efficient technique for the treatment of intraoral PG, in order to minimize its recurrence, the lesion should be excised with a wider margin down to the periosteum or to the causing agent. Also due to its high recurrence rate, long-term follow-up is recommended.

Lactobacillus rhamnosus could inhibit Porphyromonas gingivalis derived CXCL8 attenuation.

UNLABELLED: An increasing body of evidence suggests that the use of probiotic bacteria is a promising intervention approach for the treatment of inflammatory diseases with a polymicrobial etiology. P. gingivalis has been noted to have a different way of interacting with the innate immune response of the host compared to other pathogenic bacteria, which is a recognized feature that inhibits CXCL8 expression. OBJECTIVE: The aim of the study was to determine if P. gingivalis infection modulates the inflammatory response of gingival stromal stem cells (G-MSSCs), including the release of CXCL8, and the expression of TLRs and if immunomodulatory L. rhamnosus ATCC9595 could prevent CXCL8 inhibition in experimental inflammation. MATERIAL AND METHODS: G-MSSCs were pretreated with L. rhamnosus ATCC9595 and then stimulated with P. gingivalis ATCC33277. CXCL8 and IL-10 levels were investigated with ELISA and the TLR-4 and 2 were determined through flow cytometer analysis. RESULTS: CXCL8 was suppressed by P. gingivalis and L. rhamnosus ATCC9595, whereas incubation with both strains did not abolish CXCL8. L. rhamnosus ATCC9595 scaled down the expression of TLR4 and induced TLR2 expression when exposed to P. gingivalis stimulation (p<0.01). CONCLUSIONS: These findings provide evidence that L. rhamnosus ATCC9595 can modulate the inflammatory signals and could introduce P. gingivalis to immune systems by inducing CXCL8 secretion.

Lactobacillus rhamnosus could inhibit Porphyromonas gingivalis derived CXCL8 attenuation

ABSTRACT An increasing body of evidence suggests that the use of probiotic bacteria is a promising intervention approach for the treatment of inflammatory diseases with a polymicrobial etiology. P. gingivalis has been noted to have a different way of interacting with the innate immune response of the host compared to other pathogenic bacteria, which is a recognized feature that inhibits CXCL8 expression. Objective The aim of the study was to determine if P. gingivalis infection modulates the inflammatory response of gingival stromal stem cells (G-MSSCs), including the release of CXCL8, and the expression of TLRs and if immunomodulatory L. rhamnosus ATCC9595 could prevent CXCL8 inhibition in experimental inflammation. Material and Methods G-MSSCs were pretreated with L. rhamnosus ATCC9595 and then stimulated with P. gingivalis ATCC33277. CXCL8 and IL-10 levels were investigated with ELISA and the TLR-4 and 2 were determined through flow cytometer analysis. Results CXCL8 was suppressed by P. gingivalis and L. rhamnosus ATCC9595, whereas incubation with both strains did not abolish CXCL8. L. rhamnosus ATCC9595 scaled down the expression of TLR4 and induced TLR2 expression when exposed to P. gingivalis stimulation (p<0.01). Conclusions These findings provide evidence that L. rhamnosus ATCC9595 can modulate the inflammatory signals and could introduce P. gingivalis to immune systems by inducing CXCL8 secretion.

P16(INK 4a) and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions.

Human papilloma virus (HPV) is postulated as a risk factor in the etiology of some specific mucosal pathologies in the head and neck regions. Despite the frequent use of p16(INK4a) as a surrogate marker for HPV-infection, there is still controversy with respect to its reliability. This study has been undertaken to assess the potential role of p16(INK 4a) and Ki-67 expression in HPV-related lesions. The study was conducted on 71 specimens of oral, tonsillar and laryngeal lesions which comprised 25 dysplasia and 46 papilloma specimens. Specimens were immunohistochemically stained for p16(INK4A) and Ki-67 proteins. HPV DNA was determined by one step multiplex polymerase chain reaction. HPV DNA was detected in 33.8% of all lesions. Tonsil and larynx lesions showed significant differences with oral lesions for HPV positivity (p < 0.001). p16(INK 4a) over-expression was seen in 56.5% of papilloma and 60% of dysplasia specimens. HPV status showed a positive correlation with p16(INK 4a) expression in tonsillar dysplasias (p < 0.001). p16(INK 4a) expression may have a value as a marker in high risk HPV induced dysplasias, but not in low risk infected lesions. The proliferation index is not related to HPV-induced lesions and may be evaluated as an independent marker in head and neck premalignant lesions.

Oral mucosal lesions: a retrospective review of one institution's 13-year experience.

BACKGROUND/AIM: To investigate the relative frequency of biopsied nonneoplastic oral mucosal lesions in Ankara, Turkey. MATERIALS AND METHODS: Biopsy records of a single center from 2000-2012 were retrospectively collected. Diagnosis was recorded and evaluated with respect to patient demographics (age, sex) and location of the lesion. RESULTS: Of 11,980 biopsies, 1732 (14.5%) were mucosal nonneoplastic lesions. Hyperplastic lesions (n= 1000, 57.7%) with fibroepithelial hyperplasia in 30.9% of patients were the most common type of oral nonneoplastic lesions. The mean age of patients differed with respect to type of mucosal lesion, tending to be lower in patients with reactive lesions. Dermatoses showed a female predominance. CONCLUSION: Our ,findings revealed that hyperplastic lesions were the most common among nonneoplastic oral mucosa lesions. Geographic and ethnic.differences of patients with various types of oral mucosal lesions require further investigation.

p16INK 4a and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions / Expresión de p16INK 4a y Ki-67 en las lesiones de cabeza y cuello relacionados con el virus del papilloma humano

Human papilloma virus (HPV) is postulated as a risk factor in the etiology of some specific mucosal pathologies in the head and neck regions. Despite the frequent use of p16INK4a as a surrogate marker for HPV-infection, there is still controversy with respect to its reliability. This study has been undertaken to assess the potential role of p16INK 4a and Ki-67 expression in HPV-related lesions. The study was conducted on 71 specimens of oral, tonsillar and laryngeal lesions which comprised 25 dysplasia and 46 papilloma specimens. Specimens were immunohistochemically stained for p16INK4A and Ki-67 proteins. HPV DNA was determined by one step multiplex polymerase chain reaction. HPV DNA was detected in 33.8% of all lesions. Tonsil and larynx lesions showed significant differences with oral lesions for HPV positivity (p<0.001). p16INK 4a over-expression was seen in 56.5% of papilloma and 60% of dysplasia specimens. HPV status showed a positive correlation with p16INK 4a expression in tonsillar dysplasias (p<0.001). p16INK 4a expression may have a value as a marker in high risk HPV induced dysplasias, but not in low risk infected lesions. The proliferation index is not related to HPV-induced lesions and may be evaluated as an independent marker in head and neck premalignant lesions.

El virus del papiloma humano (VPH) se postula como un factor de riesgo en la etiología de algunas patologías de la mucosa, específicas en las regiones de cabeza y cuello. A pesar de usar con frecuencia el p16INK4A como un marcador sustituto para la infección por VPH, todavía existe controversia con respecto a su fiabilidad. Este estudio se ha llevado a cabo para evaluar el papel potencial de la expresión de p16INK 4a y de Ki-67 en las lesiones relacionadas con el VPH. El estudio se realizó en 71 muestras de lesiones orales, tonsilares y laríngeas que comprendían 25 displasias y 46 especímenes de papiloma. Los especímenes fueron teñidos inmunohistoquímicamente para p16INK4a y Ki-67. El ADN del VPH se determinó mediante una PCR multiplex de un paso. ADN del VPH se detectó en el 33,8% de todas las lesiones. Las lesiones de la amígdala y laringe mostraron diferencias significativas con lesiones orales para la positividad de VPH (p <0,001). Sobre-expresión de p16INK 4a se observó en 56,5% de las muestras de papiloma y 60% de las muestras de displasia. El estatus del VPH mostró una correlación positiva con la expresión de p16INK4a en displasias tonsilares (p <0,001). La expresión de p16INK4a puede tener valor como marcador en las displasias inducidas por VPH de alto riesgo, pero no en las lesiones infectadas de bajo riesgo. El índice de proliferación no está relacionado con las lesiones inducidas por VPH y puede ser evaluado como un marcador independiente en las lesiones premalignas de la cabeza y del cuello.

Parosteal osteochondrolipoma of the mandible.

Osteochondrolipoma is a rare benign soft tissue neoplasm. It is occasionally considered to be a variant of adipose tissue neoplasm 'lipoma' showing multiple differentiation pathways of pluripotent stem cells. As with the lipomas they can be seen at any location and show cartilagenous and osteoid differentiation when located parosteally. We present a case of osteochondrolipoma located at the symphysis of the mandible. To our knowledge, this is the first reported case of an oral osteochondrolipoma associated with parosteal localization.

Effects of low-dose doxycycline and bisphosphonate clodronate on alveolar bone loss and gingival levels of matrix metalloproteinase-9 and interleukin-1ß in rats with diabetes: a histomorphometric and immunohistochemical study.

BACKGROUND: Bisphosphonates (BPs) and low-dose doxycycline (LDD) have been shown to inhibit bone resorption and to improve the levels of proinflammatory mediators and destructive enzymes in gingival tissues, respectively. The purpose of this study is to evaluate the effect of mono and combined BP clodronate and LDD therapies in reducing gingival levels of matrix metalloproteinase-9 (MMP-9), interleukin-1ß (IL-1ß), and alveolar bone loss in rats with diabetes. METHODS: Fifty adult Wistar rats were divided into five study groups as follows: 1) group 1 = diabetes control; 2) group 2 = diabetes + periodontitis; 3) group 3 = diabetes + periodontitis + LDD; 4) group 4 = diabetes + periodontitis + clodronate; and 5) group 5 = diabetes + periodontitis + LDD + clodronate. LDD and clodronate were given as a single agent or as combination therapy during the 7 days of the post-experimental periodontitis period. On day 7, the rats were sacrificed, the mobility of the tooth was recorded, and block biopsies were removed. The gingival tissues were analyzed histologically and immunohistochemically for expression of MMP-9 and IL-1ß. Alveolar bone loss was evaluated morphometrically under a light microscope. Data analysis was performed statistically by Kruskal-Wallis and post hoc Tukey and Spearman correlation tests. RESULTS: Alveolar bone loss was significantly greater in groups 2 through 5 than group 1 (P <0.05) but was not significantly different among groups 2 through 5 (P >0.05). Animals with periodontitis (group 2) expressed significantly higher levels of MMP-9 and IL-1ß compared with those without periodontitis (group 1) (P <0.05). MMP-9 expression was significantly lower in group 3 than groups 1, 2, and 5 (P <0.05). IL-1ß expression was significantly lower in the groups 1, 3, 4, and 5 than 2 (P <0.01) but was not significantly different among groups 1, 3, 4, and 5. Positive correlations were found between alveolar bone loss and density of inflammation (ρ = 0.319, P = 0.021) and between MMP-9 and IL-1ß (ρ = 0.418, P = 0.002), respectively. CONCLUSION: Our findings suggest that ligature-induced periodontitis in animals with diabetes results in significantly higher levels of MMP-9 and IL-1ß expression in gingiva. The use of mono and combined clodronate and LDD administrations may significantly reduce levels of MMP-9 and IL-1ß expression. However, drug administration did not affect alveolar bone levels during the study period.

Effect of the topical use of the antioxidant taurine on the two basement membrane proteins of regenerating oral gingival epithelium.

BACKGROUND: The essential amino acid taurine has important physiologic and pathologic roles, and has been shown to have osmoregulatory, antioxidative, antiapoptotic, anti-inflammatory, and antilipid activities. However, the response of oral gingival epithelium to taurine during wound healing remains unclear. The goal of this study is to evaluate the expression of laminin 5 and Type IV collagen histologically in regenerating gingival epithelium after direct application of taurine on incised human gingival samples. METHODS: The study was conducted on 16 gingival samples obtained from gingivectomy specimens of eight adult patients with generalized gingival overgrowth. The samples were divided into two groups: gingiva with 1% taurine-hydrated collagen membrane (n = 8) and saline-hydrated collagen membrane (n = 8) applied specimens. The length of the newly formed epithelium on the wound surface and inflammation was assessed on hematoxylin and eosin-stained sections. Basement membrane formation was evaluated by detection of laminin 5 and Type IV collagen expressions on immunohistochemically stained samples. RESULTS: Complete new epithelial formation was observed in 1% taurine-treated gingivectomy specimens, whereas incomplete regeneration of the epithelium was observed in control gingivectomy specimens (P <0.05). The length of the newly formed epithelium showed a negative correlation with inflammation in the taurine group (P = -0.712; P <0.05). Immunoreactivity for both laminin 5 and Type IV collagen did not show any significant difference between groups. CONCLUSION: The local application of taurine-hydrated collagen membrane on human gingival wounds demonstrated the histologic evidence of rapid reepithelization with taurine.

Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid.

Intravenous bisphosphonates-the potent inhibitors of osteoclast-mediated bone resorption are among the most commonly prescribed drugs in the management of multiple myeloma (MM). Zoledronic acid (ZA) is a new generation potent intravenous bisphosphonate that has been approved for the treatment and prevention of bone lesions, and/or hypercalcemia associated with MM. Osteonecrosis of the jaw (ONJ) is an emerging serious side effect of the new generation bisphosphonates with a growing number of reports related to this pathological entity. ONJ usually appears following oral surgical and dental procedures but sometimes occur spontaneously. These cases are mostly seen and treated by dentists and oral surgeons. The aim of this study was to discuss the frequency, characteristics, risk factors, management and histopathological features of ZA induced ONJ based on the literature and illustrated with five own cases. Thirty-two patients with MM who received ZA for a median period of 26.5 +/- 18.7 months (min: 5 months, max: 76 months) were evaluated. ONJ was detected in five patients and mean drug duration time was 34 months. The frequency was 15% and the patients were usually symptomatic. There was no significant difference in terms of the duration of ZA in patients with and without ONJ. Management of these established cases were performed with medical treatment, minor debridement, sequestrectomy, and combining bone resection with autologous platelet rich plasma. Our data indicate that ZA therapy has a major role in the development of ONJ a fact that should be considered by physicians treating MM patients.

The effect of smoking on epithelial proliferation in healthy and periodontally diseased marginal gingival epithelium.

BACKGROUND: Smoking causes an increase in the thickness of gingival epithelium, which is the outcome of increased keratinocyte proliferation or loss. Smoking-related changes in the proliferative activity of the gingival epithelium are largely uncharacterized for periodontal diseases. The aim of the present study was to determine the effects of smoking on the proliferation of the epithelium in periodontally diseased marginal gingiva by comparing the expression patterns of two different proliferation markers. METHODS: Gingival biopsies (N=60) were obtained from smokers who had clinically healthy gingiva (n=10), smokers with gingivitis (n=10), smokers with periodontitis (n=10), non-smokers with clinically healthy gingiva (n=10), non-smokers with gingivitis (n=10), and non-smokers with periodontitis (n=10). The quantitative measurement of maximum epithelial thickness was performed on hematoxylin and eosin-stained sections. The expression patterns for proliferating cell nuclear antigen (PCNA) and Ki67 were evaluated immunohistochemically. RESULTS: The percentage of PCNA-positive cells was higher than the percentage of Ki67-positive cells in all groups (P<0.001). When the mean values of PCNA and Ki67 were compared in each group, a statistically significant difference was observed only in the healthy smoker group (P=0.003). Significant differences in PCNA proliferation indices were only found between the smoker group and the non-smoker healthy group (P=0.015). CONCLUSIONS: Smoking had an affect on the proliferation of cells in the oral gingival epithelium, regardless of periodontal status. The increase in thickness of the epithelium was not associated with smoking; periodontal status and inflammation seemed to be more important factors. Smoking induced the replication activity of gingival epithelium and induced DNA repair.

The early tissue response to titanium and LactoSorb screws.

Fractures of the maxillofacial region are common in the elderly people. Titanium and LactoSorb screws are the widely accepted materials for use in the maxillofacial fractures. This study was undertaken to evaluate the early tissue response following the insertion of both titanium and LactoSorb screws composed of 82% PLLA and 18% PGA in an elderly animal model. In this study, 22 titanium and 22 LactoSorb screws were applied to calvaria of 44 guinea pigs that were 10-11 months old. Animals were sacrificed on postoperative days 3, 7, 14, 30 and 60. Screws were retrieved with surrounding bone tissue and the specimens were prepared for routine histologic examination. All the specimens were evaluated by light microscopy. Histometric analysis revealed that there was no significant difference between LactoSorb and titanium screws for the new bone formation. The biodegradation of LactoSorb screws was not complete by the end of day 60. In conclusion, both materials were well tolerated and induced bone formation without causing adverse tissue response in an elderly animal model. Our results suggest that both LactoSorb and titanium miniplates and screws can be used safely, regardless of the increasing age. However, LactoSorb may be the first choice as it does not require a second operation for removal and has late biodegradation in elderly that keeps its support for a relatively longer time during fracture healing.