Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation.

Bisphosphonates (BPs)-related osteonecrosis of jaw (BRONJ) is a severe complication of the long-term administration of BPs. The development of BRONJ is associated with the cell death of osteoclasts, but the underlying mechanism remains unclear. In the current study, the role of Zoledronic acid (ZA), a kind of bisphosphonates, in suppressing the growth of osteoclasts was investigated and its underlying mechanism was explored. The role of ZA in regulating osteoclasts function was evaluated in the RANKL-induced cell model. Cell viability was assessed by cell counting kit-8 (CCK-8) assay and fluorescein diacetate (FDA)-staining. We confirmed that ZA treatment suppressed cell viability of osteoclasts. Furthermore, ZA treatment led to osteoclasts death by facilitating osteoclasts ferroptosis, as evidenced by increased Fe2+, ROS, and malonyldialdehyde (MDA) level, and decreased glutathione peroxidase 4 (GPX4) and glutathione (GSH) level. Next, the gene expression profiles of alendronate- and risedronate-treated osteoclasts were obtained from Gene Expression Omnibus (GEO) dataset, and 18 differentially expressed genes were identified using venn diagram analysis. Among these 18 genes, the expression of F-box protein 9 (FBXO9) was inhibited by ZA treatment. Knockdown of FBXO9 resulted in osteoclasts ferroptosis. More important, FBXO9 overexpression repressed the effect of ZA on regulating osteoclasts ferroptosis. Mechanistically, FBXO9 interacted with p53 and decreased the protein stability of p53. Collectively, our study showed that ZA induced osteoclast cells ferroptosis by triggering FBXO9-mediated p53 ubiquitination and degradation.

Accuracy of Computer-Aided Design/Computer-Aided Manufacturing Surgical Template for Guidance of Dental Implant Distraction in Mandibular Reconstruction With Free Fibula Flaps.

PURPOSE: The direction and orientation of the osteotomized upper segments in dental implant distractor (DID) can be compromised due to an unpredicted vector of distraction. The present study aimed to evaluate the accuracy of computer-aided design/computer-aided manufacturing (CAD/CAM) surgical templates to precisely guide the distraction process in lengthening of the alveolar height for functional mandibular reconstruction. PATIENTS AND METHODS: This retrospective study included all consecutive patients who underwent digitally designed mandibular reconstruction using the fibular flap and DID with the help of CAD/CAM designed surgical templates in a single-stage procedure from 2011 to 2014. First, the preoperative digital planning was performed on 3-dimensional models. Afterward, simulation of the distraction process was made on the virtual model and the resulting new height of the fibula was evaluated. The preoperative simulation was applied to accurately define the exact location and path of the DID device to achieve the suitable vertical height. The preoperative digital planning was used to help the design of the CAD/CAM surgical template, which was then fabricated by means of the 3-dimensional printing technology. The manufactured surgical template-assisted both horizontal and vertical osteotomies of the fibular segments and defining the DID path to lead the distractor into the accurate position. The outcome evaluation was achieved through comparing both preoperative virtual planning with postoperative actual outcomes. RESULTS: This study included 14 subjects, 8 were males and 6 were females. The mean age at time of surgery was 31.07 years (range 18-47). All fibular flaps showed 100% success rate. The mean vertical bone height attained with the DID device was 11.35 mm. The vertical and horizontal osteotomies of the fibular segments were completed, then the DID devices were successfully positioned guided by the template. The mean values of the linear and angular deviations for the distractor position and upper segments were calculated and recorded. The maximum linear deviation between the virtual and the postoperative actual distractors was 0.93 mm in the anteroposterior direction, and the greatest in the horizontal plane was 4.64°. CONCLUSIONS: CAD/CAM surgical templates can accurately guide the direction and orientation of the DID device for functional mandibular reconstruction; therefore, helping to improve the outcomes by accurately transferring the preoperative virtual plan to real surgical procedure.

Improved accuracy of hemimandibular reconstructions involving the condyle by utilizing hydroformed reconstruction plates rather than hand-bent stock plates.

BACKGROUND: Computer-aided design/computer-aided manufacturing (CAD/CAM) surgical templates allow precise mandibular reconstructive surgery. However, their clinical accuracy is limited by manual plate bending. Digitally hydroformed plates maintain a digital workstream in virtual planning. METHODS: Twelve patients with Brown's class IIc mandibular defects were randomized into two groups: group I (experimental), the reconstruction plate was digitally hydroformed, and group II (control), surgeries were performed CAD/CAM guided with the reconstruction plate manually prebent. The linear and angular deviations of reconstruction outcomes were compared to surgical simulation in both groups. RESULTS: The mean linear and angular deviations of middle and posterior segments were 2.14 ± 0.79 mm, 3.71 ± 0.95 mm, 8.73° ± 1.91°, and 9.06° ± 0.96° in group I and 4.31 ± 0.78 mm, 6.74 ± 1.40 mm, 16.35° ± 0.72°, and 31.48° ± 3.38° in group II, respectively. Measurements in group I were significantly lower than group II (P < .005). CONCLUSION: Digital hydroforming for plate prebent is a reliable method that helps improving the clinical accuracy of CAD/CAM-guided mandibular reconstruction surgery.

Randomized control trial comparing the titanium osteosynthesis and the biodegradable osteosynthesis in mandibulotomy access.

BACKGROUND: The clinical degradation rate and strength of biodegradable implant exposed to postoperative radiotherapy (PORT) are unknown. METHODS: A prospective randomized control trial of 40 consecutive mandibulotomy patients randomly divided into titanium and biodegradable cohorts. All patients received PORT. The following parameters were compared: maximal mouth opening, occlusal force, center of force trajectory, occlusal status, radiographic evidence of bony union, mandibular function impairment questionnaire (MFIQ), overall satisfaction score, and complication rates. RESULTS: Both the mandibular function and occlusal status parameter of the biodegradable and the titanium groups were not significantly difference. Biodegradable cohort showed better MFIQ scores (P = .08) and overall satisfaction scores (P = .64) but was not statistically significant. Of note, 40% of patients in the titanium cohort complained of plate palpability/cold intolerance and required plate removal (P = .02); 10% of patients in the titanium cohort developed osteoradionecrosis. CONCLUSION: Biodegradable osteosynthesis is as reliable as titanium osteosynthesis for mandibulotomy fixation. PORT did not increase the complication rate in the biodegradable group.

WITHDRAWN: A Randomized Controlled Trial Comparing Between Titanium Osteosynthesis and Biodegradable Osteosynthesis in Access Mandibulotomy for Oral Malignancy.

Available online April 7, 2018. This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

PDGFRA mRNA overexpression is associated with regional metastasis and reduced survival in oral squamous cell carcinoma.

BACKGROUND: Platelet-derived growth factor alpha (PDGFRA) is a gene encoding tyrosine kinase receptor and both EGFR and PDGFRA activate tyrosine kinases. The implication of PGFRA in many cancers and its prognostic significance irrespective to EGFR status in spinal chordoma, gliomas, and uterine cancers have shown a need for its investigation in oral squamous cell carcinoma (OSCC). We investigated the prognostic value of PDGFRA mRNA expression in OSCC. PATIENTS AND METHODS: The study was conducted in the department of oral maxillofacial surgery-head and neck oncology, at a tertiary hospital. The data on PDGFRA mRNA expression and immunohistochemical staining status in primary OSCC patients treated for curative surgery from 2010 to 2012 were analyzed. Univariate and multivariate analyses were performed with other cofactors for survival. RESULTS: A total of 114 consecutive patients with primary OSCC who received treatment were studied. Thirty-one patients died of the disease. Strong PDGFRA immunohistochemical staining and high expression of PDGFRA mRNA were associated with positive pN status (P < .001), disease-free survival (P < .001), and overall survival (P < .001) in multivariate cox regression when all other factors such as pN status and histological grading were analyzed. Kaplan-Meier analysis revealed that the 2-year survival and 3-year survival of patients with PDGFRA mRNA low expression were 96.83%. However, 2-year survival for PDGFRA mRNA high expression level was 59.64%, which decreased to 45.57% by 3-years. CONCLUSION: PDGFRA overexpression in oral SCC, in respect to strong PDGFRA immunohistochemical staining and high PDGFRA mRNA expression, was positively associated with regional metastasis and reduced patient survival.

Modified maxillary reconstruction technique for Brown's class III defects by subdividing a rhomboid shaped iliac crest into 2 subunits.

BACKGROUND: Men and women share a common maxillary morphology with heterogeneity in size. This indicated that our technique of reconstruction with a rhomboid-shaped iliac crest bone flap incorporating a 30° vertical wedge osteotomy may be widely used for Brown's class III maxillectomy defect reconstruction among a population with class I skeletal profile. The reconstruction of Brown's class III maxillary defects is extremely challenging. The purpose of this study was to closely study the maxilla geometrically in order to establish a standardized maneuver, which facilitates conversion of the iliac bone flap into a natural maxilla's contours. METHODS: We evaluated the geometries of 40 adult maxillas. The perimeter lengths of perinasal and infraorbital subunits were analyzed, in addition to the intersecting angle (δ) of both subunits. Sex variation was evaluated using the Student's t test. RESULTS: In the 80 studied unilateral maxillas (40 maxillas from 18 men and 22 women), there were no significant sex differences for δ (P = .1527). In addition, both sexes shared common morphological features, hence, in surgical reconstruction, the δ can be constantly set at 150°. Perimeter of bone segments had a greater intersubject variability (coefficient of variation [CV] of approximately 4.5-11). From both cadaveric dissections and clinical applications, our results have shown that our standard maneuver was reproducible and reliable in reestablishing natural facial contours. CONCLUSION: Our standard maneuver can serve as a universal guideline, with individualized perimeter manipulations, to yield an aesthetically natural and functional outcome.

Justification of routine venous thromboembolism prophylaxis in head and neck cancer reconstructive surgery.

BACKGROUND: Venous thromboembolism (VTE) is a preventable complication in which early ambulation is expected after head and neck surgery. Thus, the role of VTE prophylaxis is questionable and needs further assessment. The purpose of this study was to specify the relative contributing risk factors for patients who underwent head and neck cancer ablation with immediate reconstruction. METHODS: A retrospective analysis was conducted of consecutive head and neck cancer ablations with immediate reconstructions between 2008 and 2013. Dextran and prostaglandin E2 (PGE2) were routinely given as flap thromboprophylaxis. Logistic regression was applied to analyze the potentially significant risk factors. RESULTS: Of 1953 subjects, the incidence of symptomatic VTE was 2.2% with 0.1% mortality rate. Prolonged surgery (>592.5 minutes; P = .048), immobilization (>4 days; P = .019), and subjects without postoperative flap thromboprophylaxis (P = .002) are significant risk factors for VTE development. CONCLUSION: Our flap thromboprophylaxis regime might have played a crucial role in keeping the incidence of VTE low. Despite prolonged immobilization in fibula flap reconstruction, the incidence of VTE remained low when flap thromboprophylaxis was given.

PDGFRA mRNA is overexpressed in oral cancer patients as compared to normal subjects with a significant trend of overexpression among tobacco users.

BACKGROUND: Platelet-derived growth factors alpha (PDGFA) is a tyrosine kinase receptor activator which is known to be amplified in the malignancies, and their expression levels are correlated to tumor progression and reduced overall survival. The expression of PDGFRA is different among the tumors and normal tissues; furthermore, their expression level is site specific. Under a physiological condition, PDGFRA and its ligand are expressed in distinct cell populations and activated in a paracrine manner. Nevertheless, heterodimer characteristic of PDGFRA allows it to be trans-activated by non-specific ligands or via autocrine manner. The future of cancer therapy can be based on PDGFRA receptor blockade and therefore warrants further investigation to determine the differing expression of PDGFRA between controls and patients with oral squamous cell carcinoma (OSCC). METHODS: We performed a case-control study of 111 patients with newly diagnosed tongue squamous cell carcinoma and 111 control subjects without a cancer diagnosis, matched for age and gender, to evaluate the association between PDGFRA expression levels in oral mucosa. We then performed smoking stratification in each cohort. Independent t test analysis was applied for case-control comparisons. RESULTS: Mean value of PDGFRA mRNA level (-ΔCt) for normal cohort is -30.242, whereas mean value of PDGFRA mRNA level for patients with OSCC is -11.516. PDGFRA mRNA level (-ΔCt) was significantly higher in oral cancer cohort, P<.001. Smokers have a significantly higher PDGFRA mRNA expression in comparison with non-smokers (P=.002) among the non-cancer group. Likewise, this trend is observed in cancer cohort too, P=.044. CONCLUSION: PDGFRA expression is significantly higher in oral cancer cohort with or without the establishment of tobacco risk factor.

In Situ Release of VEGF Enhances Osteogenesis in 3D Porous Scaffolds Engineered with Osterix-Modified Adipose-Derived Stem Cells.

Adipose-derived stem cells (ADSCs) can differentiate into various cell types and thus have great potential for regenerative medicine. Herein, rat ADSCs were isolated; transduced with lentiviruses expressing Osterix (Osx), a transcriptional factor essential for osteogenesis. Osx overexpression upregulated key osteogenesis-related genes, such as special AT-rich binding protein 2, alkaline phosphatase, osteocalcin, and osteopontin, at both mRNA and protein levels. In addition, mineral nodule formation and alkaline phosphatase activity were enhanced in Osx-overexpressing ADSCs. The expression of dickkopf-related protein 1, a potent Wnt signaling pathway inhibitor, was also increased, whereas that of ß-catenin, an intracellular signal transducer in the Wnt pathway, was decreased. ß-catenin expression was partially recovered by treatment with lithium chloride, a canonical Wnt pathway activator. The Osx-expressing ADSCs were then combined with 3D gelatin-coated porous poly(ɛ-caprolactone) scaffolds with a unique release prolife of entrapped recombinant human vascular endothelial growth factor (VEGF). The controlled release of VEGF promoted osteogenic differentiation capacity in vitro. When the scaffold-ADSC complexes were transplanted into rat calvarial critical-sized defects, more bone formed on the gelatin/VEGF-coated scaffolds than on other scaffold types. Taken together, the results indicate that, Osx-overexpression promotes ADSCs' osteogenesis both in vitro and in vivo, which could be enhanced by release of VEGF.

Low Pretreatment Lymphocyte-Monocyte Ratio and High Platelet-Lymphocyte Ratio Indicate Poor Cancer Outcome in Early Tongue Cancer.

PURPOSE: The white blood cell (WBC) indices have been reported to have a prognostic impact in cancer of multiple organs including head and neck cancer; however; site and stage stratification was not attempted, and compelling evidence has shown that early cancers have a different distribution and prognostic ability than late-stage cancers. We studied the prognostic importance of WBC indices in early oral tongue cancers. PATIENTS AND METHODS: The retrospective data of primary pT1N0 to pT2N0 oral tongue cancers treated between 2009 and 2013 were charted. WBC indices such as the neutrophil count, lymphocyte count (LC), platelet count (PC), and monocyte count, along with derived indices such as the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), were analyzed by multivariate analysis with other clinicopathologic prognostic factors. RESULTS: A total of 133 patients fulfilled the inclusion criteria; the minimum follow-up period for living patients was 36 months. A total of 22 patients reported disease relapse, and 11 patients died of disease. Multivariate analysis showed LC (hazard ratio [HR], 0.206; 95% confidence interval [CI], 0.092 to 0.46; P < .001), PC (HR, 1.011; 95% CI, 1.001 to 1.021; P = .026), PLR (HR, 1.012; 95% CI, 1.008 to 1.016; P < .001), and LMR (HR, 0.721; 95% CI, 0.596 to 0.872; P = .001) are significant independent prognostic factors for disease-free survival. Distant metastasis (HR, 9.014; 95% CI, 2.303 to 38.914; P = .004), LC (HR, 0.091; 95% CI, 0.015 to 0.558; P = .01), PC (HR, 1.023; 95% CI, 1.006 to 1.041; P = .009), PLR (HR, 1.016; 95% CI, 1.004 to 1.027; P = .002), and LMR (HR, 0.58; 95% CI, 0.387 to 0.868; P = .008) are significant independent prognostic factors for overall survival. CONCLUSIONS: Low pretreatment LMR and high PLR indicate poor survival in patients with early tongue cancer. We suggest close follow-up for this subgroup despite radical resection with clear margins.

Osteosarcoma of the Mandible: A Site-Specific Study on Survival and Prognostic Factors.

Osteosarcoma of head and neck is a rare condition comprising of <1% of all head and neck cancers, retrospective studies show difference in survival of mandibular osteosarcoma to other head and neck sites, necessitating investigation into site-specific survival and recurrence rates.

Post-operative hemimaxillectomy rehabilitation using prostheses supported by zygoma implants and remaining natural teeth.

OBJECTIVES:: This study aimed to evaluate the stability of prostheses supported by zygoma implants and remaining teeth for subjects who had undergone hemi-maxillectomy. METHODS:: Ten patients were included in the study. Oral rehabilitation was performed using a temporary prosthesis that was supported by remaining teeth for the first three months. Then, a zygoma implant was placed to provide support for a final prosthesis in addition to the remaining teeth. Each prosthesis was tailor-made according to biomechanical three-dimensional finite element analysis results. The patients were assessed using the prosthesis functioning scale of the Memorial Sloan-Kettering Cancer Center. In addition, retention and bite force were recorded for both the temporary prosthesis and the final prosthesis. RESULTS:: The mean bite force of the prosthetic first molar was increased to 69.2 N. The mean retentive force increased to 13.5 N after zygoma implant insertion. The bite force on the prosthetic first molar was improved to 229.3 N. CONCLUSION:: Bite force increased significantly with the support of a zygoma implant. The use of zygoma implants in the restoration of maxillary defects improved functional outcome and patient satisfaction.

Post-operative hemimaxillectomy rehabilitation using prostheses supported by zygoma implants and remaining natural teeth

OBJECTIVES: This study aimed to evaluate the stability of prostheses supported by zygoma implants and remaining teeth for subjects who had undergone hemi-maxillectomy. METHODS: Ten patients were included in the study. Oral rehabilitation was performed using a temporary prosthesis that was supported by remaining teeth for the first three months. Then, a zygoma implant was placed to provide support for a final prosthesis in addition to the remaining teeth. Each prosthesis was tailor-made according to biomechanical three-dimensional finite element analysis results. The patients were assessed using the prosthesis functioning scale of the Memorial Sloan-Kettering Cancer Center. In addition, retention and bite force were recorded for both the temporary prosthesis and the final prosthesis. RESULTS: The mean bite force of the prosthetic first molar was increased to 69.2 N. The mean retentive force increased to 13.5 N after zygoma implant insertion. The bite force on the prosthetic first molar was improved to 229.3 N. CONCLUSION: Bite force increased significantly with the support of a zygoma implant. The use of zygoma implants in the restoration of maxillary defects improved functional outcome and patient satisfaction.

Update on the surgical management of temporomandibular joint-centered tendon sheath giant cell tumor with intradural extension: introducing a cost-effective method in using temporal bone for skull base reconstruction in preventing brain hernia.

Tendon sheath giant cell tumor is an idiopathic proliferative and destructive disease of the synovium. It is rare and tends to arise in large joints, for example, knee and ankle, but it can also arise in temporomandibular joints (TMJs). Because of its destructive nature, immediate treatment upon diagnosis is recommended. Radical resection proved to be an excellent choice for superior local control. However, the unfavorable anatomic location of TMJ and infratemporal fossa tumor with intradural extension make such a resection impractical. Hereby, we reported a case of resection of a TMJ tendon sheath giant cell tumor with intradural extension using a transcranial approach. This involves a complex radical resection with subsequent reconstruction. Transposition of temporal bone flap is a novel state-of-the-art technique in reconstructing the middle fossa floor defect by providing a three-dimensional rigid architecture to support the brain. Temporal bone flap is a reliable plug for rigid support in preventing brain hernia and cerebrospinal fluid leak. Despite its complexity, this cost-effective technique is relatively straightforward to learn and is applicable across all socioeconomic groups.

The pedicled latissimus dorsi myocutaneous flap in head and neck reconstruction.

The pedicled latissimus dorsi myocutaneous flap (PLDMF) is not the first-line reconstructive option for most clinicians; however, when treating salvage patients or those with depleted neck vessels, the PLDMF provides a valuable armamentarium. Unlike the pectoralis major myocutaneous flap or the lower island trapezius flap, the PLDMF has greater versatility in soft tissue design and a longer arc of rotation. These advantages are of great importance in managing advanced reconstructive cases.

Le fort I osteotomy with bone grafts in preprosthetic surgery: technical note.

Background Being edentulous causes progressive bony resorption in maxillae, which can lead to altered maxillomandibular relationships. Discussion should consider Le Fort I osteotomy with inlay grafts for a better success rate. Thus, this article introduces a technical note in improving the success rate. Case Report The presented technical note permits transformation of the surgery in a conventional Le Fort I with a simple fixation not only of the grafts but also of the osteotomy. The surgical steps are explained as well as the follow-up results. Discussion Adding additional wire anchorage around bone grafts greatly improved our success rate and reduced our operative time. Bone grafting concurrently with Le Fort I osteotomy immediately improved the facial skeletal profile. Several in vitro studies have shown that galvanic corrosion does not play a significant role when combining stainless steel and titanium. Our novel technique is relatively simple and can be easily picked up by young surgeons.

Head and neck inflammatory myofibroblastic tumor (IMT): evaluation of clinicopathologic and prognostic features.

Owing to rarity and awareness deficiency towards inflammatory myofibroblastic tumor (IMT), we sought to review on its clinicopathological features; arising awareness to achieve early diagnosis; exploring prognostic factors and then establishing a treatment protocol. Retrospective study was performed on patients with histological proven IMT between January 2003 and December 2010. Their demographic data, clinical and histological presentations were recorded. Overall survival (OS) and progression-free-survival (PFS) were estimated via Kaplan-Meier method. Cox regression model was applied to determine the significant of prognostic factors. Logistic regression model was established to predict the probability of relapse. A total of 28 patients. Five-year PFS was 65%. Surgical margins primarily and independently determined the survival, followed by size, pseudocapsule of the lesion, intra-lesional necrosis and lastly Ki-67 and ALK overexpression. Logistic model in prediction of relapse was established, with the formula as probability of relapse = 1/(1 + e(-z)) where e = exponential function, z = constant value (3.9) + B*margin + B*size + B*immunohistochemical expression + B*pseudocapsule + B*intra-lesional necrosis. Immunohistochemical overexpression was significant if Ki-67 was strongly expressed with a conditioned ALK overexpression simultaneously. Staining intensity must be at least moderate for those ALK nuclear staining was less than 25%. Weak ALK staining intensity is only significant if nuclear staining was more than 25%. Diagnosis of IMT is achieved via exclusion. Radical resection and obtaining negative margins remains the mainstay of treatment. Both high and moderate-risk groups required post-operative radiotherapy. In low-risk group, post-operative radiotherapy was recommended if the lesion is larger than 5 cm in diameter with a conditioned ALK & Ki-67 overexpression.