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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-1β (IL-1β), 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-1β. 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-1β 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-1β 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-1β (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-1β expression in gingiva. The use of mono and combined clodronate and LDD administrations may significantly reduce levels of MMP-9 and IL-1β expression. However, drug administration did not affect alveolar bone levels during the study period. [ABSTRACT FROM AUTHOR]

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., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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, B‑RAF 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., (© 2022. The Author(s).)

Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (-) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV- OPSCC is expected. The purpose of this study was to analyze the expression of programmed cell death protein 1 ligand 1 (PD-L1) and its prognostic relevance in relation to CD8+ tumor infiltrating lymphocytes (TILs) and the major histocompatibility complex (MHC) I expression in OPSCC. We quantified PD-L1 expression on tumor cells (TC) and macrophages and MHC I expression in association to CD8 + TILs by immunohistochemistry on tissue microarray derived from 171 HPV+/-OPSCC. HPV-status was determined by p16 INK4a immunohistochemistry/HPV-DNA detection. Presence of CD8 + TILs, PD-L1 expression on TC, and a more frequent loss of MHC I in HPV+ compared to HPV- OPSCC was detected. A high amount of CD8 + TILs in the whole cohort and in HPV+ OPSCC and PD-L1 expression on TC in HPV- OPSCC was associated with favorable overall survival. There was a trend for an improved outcome according to PD-L1 expression (macrophages) in HPV+ OPSCC without reaching statistical significance. CD8 + TILs and PD-L1-expression have prognostic impact in OPSCC and might present useful biomarkers for predicting clinical outcome and personalized therapy concepts., Competing Interests: The authors declare no conflicts of interest.

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.

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.

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.

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.

Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16(INK4A) is often used as a surrogate marker for HPV-infection, although there is still controversy with respect its reliability. Our aim was to determine if p16(INK4A) overexpression can accurately predict both high-risk and low-risk-HPV-presence in (pre)malignant and benign head and neck lesions. P16(INK4A) immunohistochemistry was performed on paraffin-embedded tissue sections of 162 oropharyngeal squamous cell carcinomas (OPSCC), 14 tonsillar and 23 laryngeal dysplasias, and 20 tonsillar and 27 laryngeal papillomas. PCR, enzyme-immunoassay and FISH analysis were used to assess HPV-presence and type. Of the 162 OPSCC and 14 tonsillar dysplasias, 51 (31%) and 10 (71%) were HPV16-positive, respectively. All tonsillar papillomas were HPV-negative and four laryngeal dysplasias and 26 laryngeal papillomas were positive for HPV6 or -11. P16(INK4A) immunohistochemistry revealed a strong nuclear and cytoplasmic staining in 50 out of 51 HPV16-positive and 5 out of 111 HPV-negative OPSCC (p < 0.0001) and in all HPV16-positive tonsillar dysplasias, whereas highly variable staining patterns were detected in the papillomas and laryngeal dysplasias, irrespective of the HPV-status. In addition, the latter lesions generally showed a higher nuclear than cytoplasmic p16(INK4A) immunostaining intensity. In conclusion, our data show that strong nuclear and cytoplasmic p16(INK4A) overexpression is a reliable surrogate indicator for HPV16 in OPSCC and (adjacent) dysplasias. For HPV6 or -11-positive and HPV-negative benign and premalignant lesions of the tonsil and larynx, however, p16(INK4A) immunostaining is highly variable and cannot be recommended to predict HPV-presence., (© 2013 UICC.)

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.

Focal epithelial hyperplasia (FEH), or Heck's disease, is a benign proliferative viral infection of the oral mucosa that is related to Human Papil-lomavirus (HPV), mainly subtypes 13 and 32. Although this condition is known to exist in numerous populations and ethnic groups, the reported cases among Caucasians are relatively rare. It presents as asymptomatic papules or nodules on the oral mucosa, gingiva, tongue, and lips. Histopathologically, it is characterized by parakeratosis, epithelial hyperplasia, focal acanthosis, fusion, and horizontal outgrowth of epithelial ridges and the cells named mitozoids. The purpose of this case report was to present 3 cases of focal epithelial hyperplasia in a pediatric age group. Histopathological and clinical features of cases are discussed and DNA sequencing analysis is reported in which HPV 13, HPV 32, and HPV 11 genomes are detected.

The floor of the mouth is a rare location for fatty tissue lesions. These lesions could cause resorption of the adjacent bone and lead to a radiolucent appearance on radiographs. In this case report, a non-capsulated lesion composed of mature adipose tissue located on the floor of the mouth causing a well-circumscribed oval radiolucent lesion close to the roots of the molar teeth due to resorption of mandible in a 33-year-old woman is reported.

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.

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.

A study was conducted to evaluate the effects of local drug delivery on subgingival plaque flora using hydroxypropylmethylcellulose (HPMC) and methylcellulose (MC) base material containing 40% doxycycline (DOXY). Eleven patients who had at least four pockets exceeding 5 mm in depth associated with a single rooted tooth were selected from volunteers after an initial examination. Two of the pockets were chosen at random for insertion of the HPMC and MC strips twice a week for 6 w. One pocket received no treatment, and the other was debrided and root-planed only. Baseline and follow-up measurements at 0, 1, 3, 6, and 10w included probing depth, gingival shrinkage, bleeding on probing and crevicular fluid flow. Subgingival bacterial samples were also taken for dark-field microscopy. In vitro drug release from the HPMC strips was greater than that from MC. Significant improvements in many clinical parameters occurred in the pockets treated with HPMC or MC strips, or mechanical debridement. There was a marked decrease in the relative proportions of motile organisms during and after treatment.

A study was carried out to compare the effects of subgingival applications of resorbable hydroxypropylmethylcellulose (HPMC) membranes containing 20% chlorhexidine (CHx) and 40% doxycycline (DOXY) placed subgingivally in periodontal pockets greater than 5 mm in depth. Each of 11 patients had at least four pockets. HPMC strips containing CHx and DOXY were inserted into each pocket twice a week for 6 w. One pocket was kept as a control and the other received subgingival scaling and root planing at 0, 1, 3 and 6 w. The microbial flora of 44 pockets from the 11 patients was examined using dark-field microscopy at the baseline and at 1, 3, 6 and 10 w. Clinical parameters including probing depth, crevicular fluid flow, bleeding on probing and gingival shrinkage were also recorded. The CHx and DOXY-administered or root-planed pockets showed marked reduction of both pocket depth and the number of motile organisms. Less bleeding was also observed in CHx and DOXY-inserted pockets.