Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

The prognostic relevance of lymph node ratio in patients with oral squamous cell carcinoma treated with neoadjuvant therapy regimen and radical surgery.

BACKGROUND: This study aims at investigating the prognostic significance of lymph node ratio (LNR) in a cohort of patients with oral squamous cell carcinomas (OSCC), treated with neoadjuvant radiochemotherapy followed by radical surgery. METHODS: The study included 171 treatment-naive patients with biopsy-proven primary OSCC, being reviewed retrospectively. All patients received a concomitant neoadjuvant radiochemotherapy (RCT) followed by radical surgery of the primary tumor and neck dissection based on the pretreatment staging results. The Kaplan-Meier survival analysis method was used to estimate the events of interest for overall survival (OS). Prognostic factors were identified through univariate and multivariate analysis. RESULTS: The 5-year overall survival rate for all patients was 48 %. In univariate analysis, patient's age and data compiled from the histopathological examination as margin status, extracapsular spread, ypT, ypN, ypUICC, number of positive lymph nodes and lymph node ratio (LNR) had a statistically significant impact on overall survival. Multivariate analysis revealed an independent significant impact of patient age, ypT, margin status and LNR on OS. ypN showed no statistical significant impact on OS. CONCLUSION: Our results show that LNR is an important predictor for OS in patients with OSCC that were treated with neoadjuvant radiochemotherapy and radical surgery.

Ameloblastoma-Clinical, radiological, and therapeutic findings.

Ameloblastoma are the most common odontogenic tumor. As they usually do not form metastasis, they are considered as benign tumors with a locally invasive growth pattern and destruction of the jaws and the surrounding tissue (Oral Diseases, 23, 2017, 199). This article focuses on clinical, radiological, and therapeutic findings, which may influence diagnosis and treatment of ameloblastoma in the future.

Prediction of outcome by lymph node ratio in patients with parotid gland cancer.

OBJECTIVE: Lymph node ratio (LNR) has been shown to be an independent predictor of recurrence risk and survival in different entities of carcinoma. METHODS: In this retrospective chart review, 128 patients with parotid gland cancer (PGC) subsequently treated by primary surgery were included. About 64% (n = 82) of these patients were additionally treated with adjuvant radiotherapy. Five-year overall survival rates were determined by subgroups based on LNR value. RESULTS: Lymph node ratio was found to be significantly associated with overall survival rate (P < 0.001). Using univariate analyses, pathological tumour-node-metastasis (TNM)-stage, UICC-stage grouping and extracapsular spread were found to be significant predictors of overall survival (P < 0.001). However, with a multivariate analyses, LNR remained the only independent predictor of overall survival (P = 0.043). CONCLUSIONS: After surgery for PGC, evaluation of the neck using LNR was found to reliably stratify the overall survival rate.

Three-dimensional cone beam computed tomography analysis of maxillary sinus and alveolar bone anatomy in the restorative axis of dental implants using radiopaque drill guides.

The objectives were to assess the sinus anatomy and alveolar ridge dimensions and to identify clinical factors and morphological relationships that may predict the characteristics of the sinus anatomy. A total 336 edentulous molar and 168 edentulous premolar regions were analyzed. The mediolateral maxillary sinus (5mm and 10mm above alveolar bone), lateral maxillary sinus wall, ostium height, and alveolar ridges were measured. Measurement regions were defined by radiopaque simulation of the restoration goal. Mean molar mediolateral dimensions were >10mm: first molar, 11.8mm (range 3.8-21.1mm); second molar, 12.2mm (range 7.9-20.1mm). The extent of the sinus differed significantly between premolars and molars (P<0.001). The first molar region had the highest mean value for the lateral sinus wall (2.4mm, range 0.2-7.9mm) and the greatest distance between the alveolar crest and simulated restorative goal (8.1mm, range 1.1-16.3mm). Septum prevalence was 46% in the molar region and 27% in the premolar region. A lower alveolar ridge height was associated with a wider transverse extent of maxillary sinus and consequently longer distances between the crest and restorative goal. Systematic three-dimensional analysis of the maxillary sinus yields precise preoperative information about sinus configurations. There were significant variations and relationships among characteristics of the maxillary sinus, ridge, and the restorative goal.

Three-dimensional fracture pattern analysis of the Obwegeser and Dal Pont bilateral sagittal split osteotomy.

The Obwegeser and Dal Pont modification of the bilateral sagittal split osteotomy (BSSO) is a well-established procedure in orthognathic surgery. The purpose of this retrospective study was to analyze the actual fracture patterns achieved with BSSO by Obwegeser and Dal Pont modification using postoperative cone beam computed tomography (CBCT) datasets from 100 patients. A total of 200 split osteotomies were assessed, which could be categorized into nine different split patterns. Only one of the observed split fractures (0.5%) followed exactly the fracture line described by Obwegeser and Dal Pont, whereas 40% followed the fracture line according to the Hunsuck and Epker modification and 13.5% were seen as unfavourable splits mainly running over the buccal plate. A significant correlation was found between unfavourable buccal splits and both horizontal osteotomies reaching the buccal surface at the dorsal ramus (P=0.001) and a vertical caudal bone cut end at the corpus with a buccal position (P<0.001). These results show that a complete antero-posterior horizontal osteotomy at the mandibular ramus does not lead to the intended fracture pattern, which rebuts the argument of a greater amount of bony overlap using the Obwegeser and Dal Pont modification.

Prognostic Performance of Current Stage III Oral Cancer Patients After Curative Intent Resection: Evidence to Support a Revision of the American Joint Committee on Cancer Staging System.

BACKGROUND: The American Joint Committee on Cancer (AJCC) stage III classification of oral cavity squamous cell carcinoma (OCSCC) represents a heterogeneous group of patients with early local disease with regional metastases (T1N1 and T2N1) and advanced local disease with or without regional metastasis (T3N0 and T3N1). OBJECTIVE: The aim of this study was to evaluate prognostic heterogeneity in the stage III category. METHODS AND PATIENTS: An international retrospective multicenter study of 1815 patients who were treated for OCSCC from 2003 to 2011. RESULTS: Kaplan-Meier survival analysis and multivariate models of stage III patients revealed better overall survival (OS; HR 2.12, 95 % CI 1.03-4.15; p = 0.01) and disease-specific survival (DSS; HR 1.7, 95 % CI 1.16-4.12; p = 0.04) rates for patients with T1-2N1/T3N0 disease than for patients with T3N1 disease. The outcomes of patients with T3N1 and stage IVa disease were similar (p = 0.89 and p = 0.78 for OS and DSS, respectively). Modifying stage classification by transferring the T3N1 category to the stage VIa group resulted in a better prognostic performance [Harrell's concordance index, C index 0.76; Akaike's Information Criterion (AIC) 4131.6] compared with the AJCC 7th edition staging system (C index 0.65; AIC 4144.9) for OS. When DSS was assessed, the suggested staging system remained the best performing model (C index 0.71; AIC 1061.3) compared with the current AJCC 7th edition staging (C index 0.64; AIC 1066.2). CONCLUSIONS: The prognosis of T3N1 and stage IVa disease are similar in OCSCC, suggesting that these categories could be combined in future revisions of the nodal staging system to enhance prognostic accuracy.

Accuracy of peri-implant bone evaluation using cone beam CT, digital intra-oral radiographs and histology.

OBJECTIVES: The present study assesses the accuracy of three-dimensional (3D) cone beam CT (CBCT) and intra-oral radiography (CR) in visualizing peri-implant bone compared with histology. METHODS: 26 titanium dental implants were placed in dog jaws with chronic type vestibular defects. After a healing period of 2 and 8 weeks (n = 12 dogs) the animals were sacrificed. CBCT scans and CR of the specimen were recorded. Dissected blocks were prepared, and histomorphometric analysis was performed. Both modalities were measured twice by two observers and compared with histomorphometry regarding bone levels and thickness around implants as well as length and diameter of implants. RESULTS: Measurements of CBCT correlated well with histomorphometry of the vestibular bone level, oral bone thickness and implant length (all p-values <0.05). Compared with histomorphometry, the mean differences between CBCT and histomorphometry were between 0.06 and 2.61 mm. Mesial bone level (MBL) and distal bone level (DBL) were underestimated by both CR and CBCT. CR and histology measurements were only significantly correlated for implant length measurements. All intraclass correlations were highly significant. CONCLUSIONS: 3D CBCT provides usable information about bone in all dimensions around implants with varying accuracy. CR and CBCT perform similar in assessing MBL and DBL, but, within its limits, the CBCT can assess oral and buccal bone. Metallic artefacts limit the visualization quality of bone around implants and further research could elucidate the value of post-processing algorithms. When information about osseous perforation of implants is needed, CBCT may still provide clinically valuable information.

Histopathological assessment of tumour regression, nodal stage and status of resection margins determines prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy.

OBJECTIVES: In advanced oral squamous cell carcinoma (OSCC), tumour regression after neoadjuvant radiochemotherapy seems to be an important prognostic factor. In this study, we intended to compare regression grading according to two previously described regression models and to analyse the association of tumour regression and other tumour characteristics with patients' characteristics and overall survival. METHODS: The retrospective study included 63 treatment-naive patients with primary OSCC of stages II-IV, who were treated with a concomitant neoadjuvant radiochemotherapy followed by radical surgery. Assessment of histopathological features was performed, there under regression grading according to two previously described regression models. RESULTS: Both tumour regression models provided comparable results in terms of distribution of different regression grades. In univariate analysis regression gradings (P = 0.003 and P = 0.007), ypT-stage, ypN-stage and status of resection margins (P < 0.001) were significantly associated with the 5-year overall survival (OS). None of the pretreatment clinicopathological parameters showed association with histopathological tumour regression. Multivariate analysis revealed the status of resection margins and of lymph node metastasis as statistically significant features for OS (P = 0.020 and P = 0.003, respectively). CONCLUSION: Tumour regression grading, nodal stage and status of resection margins predict prognosis in patients after neoadjuvant treatment. Currently, there are no pretreatment clinicopathological parameters, which predicting good tumour response to therapy. Thus, identifying non-responding patients, which might benefit from an intensified systemic therapy, requires surgical resection and consecutive histopathological assessment. Therefore, further investigation and validation of new, especially, molecular predictors of tumour response to radiochemotherapy remains an unmet, future clinical need.

Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research.

BACKGROUND: Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC. METHODS: The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis. RESULTS: The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures. CONCLUSION: This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.

Clinical nodal stage is a significant predictor of outcome in patients with oral cavity squamous cell carcinoma and pathologically negative neck metastases: results of the international consortium for outcome research.

BACKGROUND: We aimed to study the importance of clinical N classification (cN) in a subgroup of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically negative neck nodes (pN-). METHODS: A total of 2,258 patients from 11 cancer centers who underwent neck dissection for OSCC (1990-2011) had pN- disease. The median follow-up was 44 months. 5-year overall survival (OS), disease-specific survival (DSS), disease free survival, local control, locoregional control, and distant metastasis rates were calculated by the Kaplan-Meier method. cN classification and tumor, node, metastasis classification system staging variables were subjected to multivariate analysis. RESULTS: A total of 345 patients were preoperatively classified as cN+ and 1,913 were classified as cN-. The 5-year OS and DSS of cN- patients were 73.6 and 82.2 %, respectively. The 5-year OS and DSS of cN+ patients were 64.9 and 76.9 %, respectively (p < 0.0001 each). A cN+ classification was a significant predictor of worse OS (p = 0.03) and DSS (p = 0.016), regardless of treatment, depth of invasion, or extent of neck dissection. cN classification was associated with recurrence-free survival (p = 0.01) and locoregional (neck and primary tumor) control (p = 0.004), but not with local (p = 0.19) and distant (p = 0.06) recurrence rates. CONCLUSIONS: Clinical evidence of neck metastases is an independent predictor of outcome, even in patients with pN- nodes.

Possibilities and limitations of implant placement by virtual planning data and surgical guide templates.

The use of computer-aided surgical systems for dental implant bed preparation and implant placement results in an average precision within 1 mm of implant position and within 5 degrees of deviation for implant inclination. The accuracy of axis and implant position is significantly more precise with the three-dimensional surgical guide than with the free-hand method. The three-dimensional assessment of the restorative goal (radiopaque simulation of prosthesis with scanning template) allows virtual planning of implants, which enables optimized positioning of implants with surgical guide templates in oral surgery. If there is a clear indication for three-dimensional diagnostics, it should always be checked whether the data can be used as planning data for a surgical guide template, otherwise the chance for guided surgery remains unused. Since uncertainties still exist despite the use of a drilling template, it is recommended that the minimum safety distance from adjacent structures be maintained. The successful use of surgical guide templates requires comprehensive knowledge of and experience in using three-dimensional information for the virtual planning of implant position.

Podoplanin expression in oral leukoplakia: prognostic value and clinicopathological implications.

OBJECTIVES: Current clinicopathological parameters cannot predict the risk of malignant transformation in oral leukoplakia sufficiently. Recent studies have shown that podoplanin is expressed in oral cancer and precancerous lesions. The aim of our study was to assess whether podoplanin expression in pretreatment biopsies could serve as a biomarker to predict the risk of malignant transformation in patients with oral leukoplakia. MATERIALS AND METHODS: In this retrospective study, podoplanin expression was analysed in 60 patients with previously untreated oral leukoplakia by immunohistochemistry. We investigated the associations between podoplanin expression and various clinicopathological variables including oral cancer-free survival (OCFS) and the SIN-classification. RESULTS: The chi-square-test revealed that high expression of podoplanin in pretreatment biopsies was associated with malignant transformation (P = 0.003) and increasing SIN-classification (P = 0.009). In univariate analysis, podoplanin expression in oral leukoplakia had a significant impact on OCFS (P = 0.009). The 5-year OCFS rate decreased from 100% for patients with no podoplanin expression to 41.7% for patients with the highest level of podoplanin expression. CONCLUSION: Although podoplanin expression and the SIN-classification served as factors to predict malignant transformation in patients with oral leukoplakia in univariate analysis, no significant impact was found for both factors in multivariate analysis.

Registration accuracy of three-dimensional surface and cone beam computed tomography data for virtual implant planning.

OBJECTIVE: Virtual wax-ups based on three-dimensional (3D) surface models can be matched (i.e. registered) to cone beam computed tomography (CBCT) data of the same patient for dental implant planning. Thereby, implant planning software can visualize anatomical and prosthetic information simultaneously. The aim of this study is to assess the accuracy of a newly developed registration process. MATERIAL AND METHODS: Data pairs of CBCT and 3D surface data of 16 patients for dental implant planning were registered and the discrepancy between the visualized 3D surface data and the corresponding CBCT data were measured on 64 teeth at seven points by two investigators in two iterations with a total of 1792 measurements. RESULTS: All data pairs were matched successfully and mean distances between CBCT and 3D surface data were between 0.03(±0.33) and 0.14(±0.18) mm. At two of seven measuring points, statistically significant correlations were determined between the measured error and the presence and type of restorations. Registration errors in maxilla and mandible were not statistically significantly different. CONCLUSION: According to the results of this study, registration of 3D surface data and CBCT data works reliably and is sufficiently accurate for dental implant planning. Thereby, barium-sulfate scanning templates can be avoided and dental implant planning can be accomplished fully virtual.

CAD/CAM-produced surgical guides: Optimizing the treatment workflow.

The increased availability of devices for 3D radiological diagnosis allows the more frequent use of CAD/CAM-produced surgical guides for implant placement. The conventional workflow requires a complex logistic chain which is time-consuming and costly. In a pilot study, the workflow of directly milled surgical guides was evaluated. These surgical guides were designed based on the fusion of an optical impression and the radiological data. The clinical use showed that the surgical guides could be accurately placed on the residual dentition without tipping movements. The conventional surgical guides were used as a control for the manual check of the deviation of the implant axis. The direct transfer of the digital planning data allows the fabrication of surgical guides in an external center without the need of physical transport, which reduces the logistic effort and expense of the central fabrication of surgical guides.

Intraoral molluscum contagiosum imitating a squamous-cell carcinoma in an immunocompetent person--case report and review of the literature.

A case of intraoral molluscum contagiosum involving the right distal alveolar bridge of an immunocompetent person is reported. A review of the literature, with only five previously published cases, revealed that involvement of the oral soft tissues is rare.

Biomechanical comparison of four different miniscrew types for skeletal anchorage in the mandibulo-maxillary area.

This study compared four miniscrew types for skeletal anchorage (Aarhus, FAMI, Dual Top and Spider) regarding their biomechanical properties contributing to primary stability. Insertion torque measurements and pull-out tests in axial (0 degrees ) as well as in the 20 degrees and 40 degrees direction were performed. Stiffness of the screw-bone construct was calculated from the load-displacement curve. Conic FAMI and Dual Top screws had higher insertion torques. Insertion torques were raised by drill-free insertion of FAMI and Dual Top screws. Statistically significant differences were found between the 4 screw types in pull-out tests. The highly significant differences between the four screws for peak load in the axial (0 degrees ) and 20 degrees direction were not apparent in 40 degrees angular loads. For the conical screws, peak load values increased in angular compared with axial load. The Dual Top screw achieved the highest values for peak load and stiffness. 12 Dual Top and 1 Spider screw heads fractured in the pull-out tests. A conical drill-free screw design achieves higher primary stability compared with cylindrical self-tapping screws. This effect was more obvious in insertion torque estimations rather than in pull-out tests. The Dual Top screws, although biomechanically superior to other screw types, were most prone to fractures.