Consensus Report and Recommendations on the Management of Late-stage Internal Derangement of the Temporomandibular Joint.

Introduction: This report investigates late-stage internal derangement (ID) of the temporomandibular joint (TMJ) with the aim of establishing a more effective and personalized treatment protocol to improve patients' quality of life (QoL). Material and methods: A consensus was reached among maxillofacial surgeons specializing in LSID, based on a literature research and collective expert experience following the Delphi method. Consensus was considered to be achieved when a response received at least 80% of votes. Results: Four expert groups were established, respectively, focusing on diagnosis, minimally invasive surgery (MIS), open surgery and joint replacement. A comprehensive approach to late-stage ID of the TMJ requires a consensus report. This underscores the need for a personalized treatment plan, considering the variability in clinical presentations and progression of this pathology. Our recommendations aim to optimize clinical outcomes and enhance patient QoL.

Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1).

INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.

Remodeling dental anatomy vs sham therapy for chronic temporomandibular disorders. A placebo-controlled randomized clinical trial.

BACKGROUND: Evidence regarding the etiology or effective treatments for chronic orofacial pain, the majority diagnosed as temporomandibular disorder (TMD), is limited. PURPOSE: To investigate whether occlusal equilibration therapy (ET) and decreasing the (higher) angle of the lateral guidance on the nonworking-side leads to a reduction in chronic TMDs intensity. METHODS: It was conducted a randomized, explanatory, single blind with blinded assessment, placebo-controlled trial with strong protection against bias involving patients with chronic TMDs. Participants were randomly assigned to receive equilibration therapy or sham therapy. ET in this study consisted of minimal invasive occlusal remodeling to obtain balanced occlusion with reduction of the steeper angle of lateral mandibular movement with respect to the Frankfort plane. The primary outcome was a change in the pain intensity score (on a 0-10 point scale, with 0 indicating no pain and 10 the worst possible pain) at month 6. Secondary outcomes include maximum unassisted mouth opening and psychological distress. RESULTS: A total of 77 participants underwent randomization, 39 of whom received ET and 38 sham therapy. The trial was stopped early for efficacy, according to preestablished rules when 67 participants (n = 34, n = 33, respectively) had completed the analysis. At month 6, the mean unadjusted pain intensity score was 2.1 in the ET and 3.6 in the sham therapy group (adjusted mean difference, -1.54; 95% confidence interval [CI] -0.5 to -2.6; P = 0.004; ANCOVA model). The mean increase in maximum unassisted mouth opening (main secondary outcome) was significantly higher in the real therapy group (adjusted mean difference 3.1 mm, 95% CI 0.5-5.7, p = 0.02). CONCLUSION: ET significantly reduced the intensity of facial pain associated with chronic TMDs and increased maximum unassisted mouth opening, as compared with sham therapy, over the course of 6 months. There were no serious adverse events. Funded by the Instituto de Salud Carlos III from the Ministry of Science and Innovation of the Government of Spain and European Regional Development Fund, Grant nº PI11/02507; "una manera de hacer Europa".

Somatic mutations in tumor and plasma of locoregional recurrent and/or metastatic head and neck cancer using a next-generation sequencing panel: A preliminary study.

BACKGROUND: We explore the utility of TruSight Tumor 170 panel (TST170) for detecting somatic mutations in tumor and cfDNA from locoregional recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). METHODS: Targeted NGS of tumor DNA and plasma cfDNA was performed using TST170 panel. In addition, a set of somatic mutations previously described in HNSCC were selected for validating in tumor, plasma, and saliva by digital droplet PCR. RESULTS: The TST170 panel identified 13 non-synonymous somatic mutations, of which five were detected in tumoral tissue, other five in plasma cfDNA, and three in both tissue and plasma cfDNA. Of the eight somatic mutations identified in tissue, three were also identified in plasma cfDNA, showing an overall concordance rate of 37.5%. CONCLUSIONS: This preliminary study shows the possibility to detect somatic mutations in tumor and plasma of HNSCC patients using a single assay that would facilitate the clinical implementation of personalized medicine in the clinic.

Craniofacial and three-dimensional palatal analysis in cleft lip and palate patients treated in Spain.

Growth alterations have been described in patients operated on for oral clefts. The purpose of this work was to analyze the craniofacial and palate morphology and dimensions of young adults operated on for oral clefts in early childhood in Spain. Eighty-three patients from eight different hospitals were divided into four groups based on their type of cleft: cleft lip (CL, n = 6), unilateral cleft lip and palate (UCLP, n = 37), bilateral cleft lip and palate (BCLP, n = 16), and cleft palate only (CPO, n = 24). A control group was formed of 71 individuals. Three-dimensional (3D) digital models were obtained from all groups with an intraoral scanner, together with cephalometries and frontal, lateral, and submental facial photographs. Measurements were obtained and analyzed statistically. Our results showed craniofacial alterations in the BCLP, UCLP, and CPO groups with an influence on the palate, maxilla, and mandible and a direct impact on facial appearance. This effect was more severe in the BCLP group. Measurements in the CL group were similar to those in the control group. Cleft characteristics and cleft type seem to be the main determining factors of long-term craniofacial growth alterations in these patients. Prospective research is needed to clearly delineate the effects of different treatments on the craniofacial appearance of adult cleft patients.

Genome-wide DNA methylation profiling in tongue squamous cell carcinoma.

OBJECTIVES: To provide a comprehensive characterization of DNA methylome of oral tongue squamous cell carcinoma (OTSCC) and identify novel tumor-specific DNA methylation markers for early detection using saliva. MATERIAL AND METHODS: Genome-wide DNA methylation analysis including six OTSCC matched adjacent non-tumoral tissue and saliva was performed using Infinium MethylationEPIC array. Differentially methylated levels of selected genes in our OTSCC cohort were further validated using OTSCC methylation data from The Cancer Genome Atlas database (TCGA). The methylation levels of a set of tumor-specific hypermethylated genes associated with a downregulated expression were evaluated in saliva. Receiver operating characteristic (ROC) curves were performed to assess the diagnostic value of DNA methylation markers. RESULTS: A total of 25,890 CpGs (20,505 hypomethylated and 5385 hypermethylated) were differentially methylated (DMCpGs) between OTSCC and adjacent non-tumoral tissue. Hypermethylation of 11 tumor-specific genes was validated in OTSCC TCGA cohort. Of these 11 genes, A2BP1, ANK1, ALDH1A2, GFRA1, TTYH1, and PDE4B were also hypermethylated in saliva. These six salivary methylated genes showed high diagnostic accuracy (≥0.800) for discriminating patients from controls. CONCLUSIONS: This is the first largest genome-wide DNA methylation study on OTSCC that identifies a group of novel tumor-specific DNA methylation markers with diagnostic potential in saliva.

Integrity and quantity of salivary cell-free DNA as a potential molecular biomarker in oral cancer: A preliminary study.

BACKGROUND: Differences in cell-free DNA (cfDNA) fragments have been described as a valuable tool to distinguish cancer patients from healthy individuals. We aim to investigate the concentration and integrity of cfDNA fragments in saliva from oral squamous cell carcinoma (OSCC) patients and healthy individuals in order to explore their value as diagnostic biomarkers. METHODS: Saliva samples were collected from a total of 34 subjects (19 OSCC patients and 15 healthy controls). The total concentration of salivary cfDNA (scfDNA) was determined using a fluorometry method and quantitative real-time polymerase chain reaction (qPCR). To evaluate the scfDNA quantity and integrity, qPCR targeting Arthobacter luteus (ALU) sequences at three amplicons of different lengths (60, 115, and 247 bp, respectively) was carried out. ScfDNA integrity indexes (ALU115/ALU60 and ALU247/ALU60) were calculated as the ratio between the absolute concentration of the longer amplicons 115 bp and 247 bp and the total scfDNA amount (amplicon 60 bp). RESULTS: The total scfDNA concentration (ALU60) was higher in OSCC than in healthy donors, but this trend was not statistically significant. The medians of scfDNA integrity indexes, ALU115/ALU60 and ALU247/ALU60, were significantly higher in OSCC, showing area under the curve values of 0.8211 and 0.7018, respectively. CONCLUSION: Our preliminary results suggest that scfDNA integrity indexes (ALU115/ALU60 and ALU247/ALU60) have potential as noninvasive diagnostic biomarkers for OSCC.

Impact of the Presenting Symptom on Time Intervals and Diagnostic Routes of Patients with Symptomatic Oral Cancer.

This investigation was aimed at determining the time intervals from the presenting symptoms until the beginning of oral cancer treatment and their relative contribution to the total time, and to assess the impact of the presenting symptom on diagnostic timelines and patient referral routes. A cross-sectional, ambispective study was designed to investigate symptomatic incident cases. The Aarhus statement was used as a conceptual framework. Strategies for minimizing potential recall biases were implemented. A sample of 181 patients was recruited (power: 99.5%; α = 0.05). The patient interval reached 58.2 days (95% CI, 40.3-76.2), which accounted for 74% of the whole prereferral interval and for more than one third of the total time interval. The presenting symptom (trigger for consultation) influenced both the number of primary care consultations and the length of time to diagnosis. General dental practitioners generated longer intervals to diagnosis (p < 0.005) and needed more consultations before referring a patient (RR = 0.76; 95% CI, 0.61-0.93), than general medical practitioners. The current study identifies the patient as the main target for interventions to improve awareness and reinforces the need for increased alertness amongst healthcare professionals about presenting symptoms of oral cancer and to diminish the number of prereferral consultations in order to optimize the primary care interval.

Saliva Gene Promoter Hypermethylation as a Biomarker in Oral Cancer.

Oral carcinogenesis is a multistep process characterized by a summation of multiple genetic and epigenetic alterations in key regulatory genes. The silencing of genes by aberrant promoter hypermethylation is thought to be an important epigenetic event in cancer development and progression which has great potential as a biomarker for early diagnosis, tumor molecular subtyping, prognosis, monitoring, and therapy. Aberrant DNA methylation has been detected in different liquid biopsies, which may represent a potential alternative to solid biopsies. The detection of methylated genes in saliva may have clinical application for noninvasive oral cancer screening and early diagnosis. Here, we review the current evidence on gene promoter hypermethylation in saliva.

Cell-Free microRNAs as Potential Oral Cancer Biomarkers: From Diagnosis to Therapy.

Oral cavity cancer is the most frequent malignancy of the head and neck. Unfortunately, despite educational interventions for prevention and early diagnosis, oral cancer patients are often diagnosed in advanced stages associated with poor prognosis and life expectancy. Therefore, there is an urgent need to find noninvasive biomarkers to improve early detection of this tumor. Liquid biopsy has emerged as a valuable tool in medical oncology which provides new horizons for improving clinical decision making. Notably, cell-free microRNAs (miRNAs), a class of short non-coding RNAs, are emerging as novel noninvasive cancer biomarkers. Here, we provide an overview of the potential clinical application of cell-free miRNAs as diagnostic, prognostic, and therapeutic biomarkers in oral cancer.

Association between hospital interval and survival in patients with oral cancer: A waiting time paradox.

BACKGROUND: In early diagnosis studies on symptomatic cancer, survival was the most recommended outcome. The magnitude and impact of the patient interval and primary care interval is well-known in oral cancer; however, the hospital interval and its influence on surviving this neoplasia are not well known. AIMS: To quantify the interval between the first contact with the specialist and the start of treatment for patients with oral cancer and to evaluate whether there was a link between this interval and disease survival. METHODS: We designed a hospital-based study that included 228 patients diagnosed with oral/oropharyngeal squamous cell carcinoma between 1998 and 2008 at A Coruña University Hospital (Spain) who were followed up until 2016. The data were extracted retrospectively from hospital medical charts. The study interval was defined in the context of the "pathways to treatment" model as the interval from the first specialist visit (start point) to the start of treatment (end point). We calculated the total interval (from first symptom to treatment) to evaluate the relative length of the hospital interval, and we considered the variables age, sex, location, comorbidity and tumour classification stage. Survival time was defined as the interval from the first treatment to death or censoring. RESULTS: The median hospital interval was 20 days, with an interquartile range of 15-29.1 days. The most relevant prognostic variable was the tumour stage (III-IV: Exp. ß = 2.8, p = 0.001). The hospital interval was part of the multivariate model, and its association with mortality showed a V-shaped association, where patients with short hospital intervals (3-18 days) and those with long hospital intervals (26-55 days) had significantly higher mortality than those with medium hospital intervals (19-25 days). CONCLUSION: The hospital interval represents a relevant interval for the patient's path towards treatment, has prognostic implications and is subject to a severity bias (waiting time paradox) that should be avoided.

Facial tumor as a presenting complaint in a patient with primary Sjögren's syndrome.

Sjögren's syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. Up to one-half of affected individuals also develop extraglandular involvement in organs distinct from the salivary and lacrimal glands, including the joints, skin, lung, gastrointestinal tract, nervous system, and kidneys. The disease also occurs in conjunction with other autoimmune disorders, such as systemic lupus erythematosus and rheumatoid arthritis. We report a case of a 76-year-old woman who presented to our department with a swelling on the left cheek. Investigations revealed Sjögren's syndrome as the underlying cause of the facial tumor.

Surgical management of ameloblastoma. Review of literature.

BACKGROUND: Ameloblastoma is an odontogenic tumor that represents 1% of all tumors in the oral cavity and it is clinically classified in three types. Currently, solid and multi-cystic are considered locally aggressive, with high recurrence rates with conservative treatment. MATERIAL AND METHODS: Objective of the present review is to assess whether the surgical treatment should be conservative or radical. English articles published between 2009-2014, with available summary and in humans were included. RESULTS: 241 articles were found, 188 were excluded because analyzing. 53 articles were analyzed and finally 14 were selected for this review. CONCLUSIONS: The optimal surgical treatment of ameloblastoma should minimize recurrences, restore function and aesthetic and present a minimal morbidity in the donor area. Surgical planning must be performed based on the patient comorbidities, the size and location of the tumor, the techniques available for reconstruction and the surgeon's experience-Radical surgery appears to be the most recommended option in multicystic / solid and advanced unicystic tumors, along with long-term follow-up for the possibility of recurrence beyond 10 year. Conservative surgery combined with a support technique and long-term follow-up is reserved for the unicystic and multicystic / solid types if small extension. Prospective and randomized studies for ameloblastoma are recommended. Key words:Ameloblastoma, surgery, enucleation, radical.

Liquid Biopsy in Oral Cancer.

Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical significance of circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and exosomes for diagnosis and prognosis of oral cancer. We highlight the importance of liquid biopsy­using blood and saliva­which represents a potential alternative to solid biopsy for diagnosis and prognosis. Moreover, liquid biomarkers allow for the real-time monitoring of tumour evolution and therapeutic responses, initiating the era of personalized medicine. However, in oral cancer, the impact of liquid biopsies in clinical settings is still limited, requiring further studies to discover the best scenario for its clinical use.

Osteoblastoma of the Hard Palate in a Child: A Rare Case.

Benign osteoblastoma is a rare bone tumour characterised histologically by the production of woven bone spicules, which are bordered by prominent osteoblasts. It mainly affects young adults. We report a rare case of benign osteoblastoma of the maxilla in a 7-year-old boy who presented with a painful swelling on the left hard palate. An incisional biopsy was interpreted as osteoblastic neoplasm most suggestive of osteoblastoma. After excision of the tumour there has been no recurrence for 2 years.

Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway.

OBJECTIVES: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved. MATERIAL AND METHODS: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n = 243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n = 62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n = 91). RESULTS: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors. CONCLUSIONS: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.

Denosumab-related osteonecrosis of the jaw.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is a debilitating chronic illness that has become one of the literature's most discussed adverse events in relation to advanced malignancy. In 2010, the first case reports of ONJ linked with denosumab administration were published. CASE DESCRIPTION: The authors describe a case of denosumab-related ONJ in a 73-year-old man with a diagnosis of prostatic adenocarcinoma, the treatment for which included the antiresorptive agent denosumab and who experienced severe pain and delayed healing after a mandibular molar extraction performed six months after the cessation of denosumab therapy. The patient had not received radiotherapy to the head and neck, nor had he received any bisphosphonate treatment. RESULTS: Clinicians established a diagnosis of denosumab-related ONJ. Follow-up across 12 months revealed that the patient needed long-term courses of antibiotics and that he experienced progressive bone destruction requiring surgical debridement. CONCLUSIONS: and CLINICAL IMPLICATIONS: The authors suggest that in patients receiving denosumab therapy, the dosing interval, the cumulative dose or both may be important in terms of the development of denosumab-related ONJ. This allows the hypothesis that preventive dentistry may reduce the prevalence of ONJ in those receiving denosumab as it has in those receiving bisphosphonates.

Oral bisphosphonate-related osteonecrosis of the jaws: Clinical characteristics of a series of 20 cases in Spain.

OBJECTIVE: The objective of this study was to define the clinical characteristics of osteonecrosis of the jaws (ONJ) induced by oral bisphosphonates in a series of patients from a circumscribed area in northwest Spain. STUDY DESIGN: A retrospective multicentre study was undertaken in 3 hospitals in an area with a radius less than 100 km in the Autonomous Community of Galicia (Spain). The medical records were reviewed and an oral examination was performed of patients diagnosed with oral bisphosphonate-related ONJ in the previous 3 years. RESULTS: We detected 20 cases of ONJ (24 lesions) related to oral bisphosphonates (alendronate [16 patients] and ibandronate [4 patients]), which were mainly administered as treatment for osteoporosis (17 patients). The mean interval between initiation of treatment and confirmation of a diagnosis of ONJ was 66±43 months (range, 6-132 months); in 7 patients (35%) the interval was less than 36 months. The past history revealed hypertension in 13 cases (65%) and diabetes in 4 (20%); 7 patients (35%) were on corticosteroid treatment. Oral surgery had been previously performed in 13 patients (65%) and the remaining 7 patients (35%) had removable dental prostheses. The lesions most frequently affected the posterior mandible (62.5%). The majority of the lesions (75%) were classified as stage 2, although lesions were identified in all established clinical stages (including 2 stage 0 lesions). CONCLUSION: In conclusion, in the present series, ONJ induced by oral bisphosphonates typically develops in women around 70 years of age, taking alendronate, that underwent oral surgery. Most lesions are located in the posterior mandible and are classified as stage 2 at diagnosis. Some patients presented no known risk factors, suggesting that there may be risk factors still to be identified. There are well-defined patterns of clinical presentation that can facilitate early diagnosis of ONJ.

A sheep model for endoscopic treatment of mandible subcondylar fractures.

BACKGROUND: Mandible subcondylar fractures may be treated via a traditional visible access incision; however, with the advances in surgical endoscopy surgeons are transitioning to a minimally invasive approach in an effort to reduce surgical morbidity and external facial scarring. We sought to design a clinically applicable teaching tool in a large animal model that would allow the operator to gain experience treating mandible subcondylar fractures via an endoscopic approach. METHODS: A large animal model was developed using the Churra sheep. Subcondylar fractures were created, reduced, and internally plated in ten specimens via an extraoral, two-port endoscopic approach. Animals were monitored for surgical success during the intraoperative and immediate postoperative periods. RESULTS: Mandibles were reduced and fixated successfully in each of the animals. Operative time was reduced from 70 to 40 min as the surgeons became more familiar with the surgical procedure. Each of the ten Churra sheep used in the study tolerated the surgeries without postoperative complications. CONCLUSIONS: Capitalizing on a mandibular anatomy similar to humans, the Churra sheep successfully demonstrated utility for the extraoral, endoscopic approach in treating mandibular condyle fractures. This model offers surgeons the opportunity to gain surgical endoscopic experience before treating clinical patients.