Impact of beta-tricalcium phosphate on preventing tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaw in rats.

Antiresorptive or antiangiogenic drugs can cause medication-related osteonecrosis of the jaw that is refractory. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be caused by procedures such as tooth extraction damage the alveolar bone, release bisphosphonates (BPs) and impede healing. This study investigated strategies for BRONJ prevention and molecular mechanisms of its onset. We assessed the effectiveness of filling extraction sockets with beta-tricalcium phosphate (ß-TCP). Rats were administered zoledronic acid (ZA) 1.2 mg/kg once per week for 2 weeks, and a molar was extracted. They were randomly assigned to the ß-TCP group (bone defects filled with 0.01 g of ß-TCP) or control group. Tissue content measurements indicated 2.2 ng of ZA per socket in the ß-TCP group and 4.9 ng in the control group, confirming BP distribution and BP adsorption by ß-TCP in vivo. At 4 weeks after extraction, the ß-TCP group had normal mucosal coverage without inflammation. Moreover, at 8 weeks after extraction, enhanced bone healing, socket coverage, and new bone formation were observed in the ß-TCP group. Connective tissue in the extraction sockets suggested that local increases in BP concentrations may suppress the local autophagy mechanisms involved in BRONJ. Filling extraction sockets with ß-TCP may prevent BRONJ.

Peri-operative hemostatic management of tooth extraction in patients with hemophilia A, with and without inhibitors, receiving emicizumab prophylaxis.

INTRODUCTION: Emicizumab treatment may allow patients with hemophilia A without (PwHA) and with inhibitors (PwHA-I) to undergo some minor surgeries, such as tooth extraction, without peri-operative factor infusions. However, criteria for determining the necessity of factor infusions before minor surgeries are unknown. AIM: We report the peri-operative hemostatic management and outcomes of emicizumab-treated PwHA and PwHA-I cases who underwent tooth extractions using our institutional protocol. METHODS: We retrospectively evaluated PwHA and PwHA-I who underwent tooth extraction with emicizumab prophylaxis at our institution. Local bleeding risk was assessed based on the method, number, and site of tooth extraction. Hemostasis was monitored peri-operatively by rotational thromboelastometry (ROTEM). Hemostatic agents and a mouth splint were used. RESULTS: Twenty-nine extractions (17 interventions) were performed in eight PwHA and two PwHA-I. Based on ROTEM, pre-operative factor infusions were used in ten PwHA and four PwHA-I interventions. Among nine low local bleeding risk interventions, three (33.3%) each received no infusions, one dose of factor infusion pre-operatively, and pre- and post-operative factor infusions. All eight high local bleeding risk interventions involved planned factor infusions. Absorbable hemostats were used in all extractions. A mouth splint was used in 21/25 (84.0%) PwHA and in 4/4 (100%) PwHA-I extractions. No post-extraction bleeding or thrombotic events occurred. CONCLUSIONS: Use of a systemic hemostatic treatment plan according to the local bleeding risk, peri-operative coagulation status assessment using ROTEM, filling the extraction socket with hemostats, and use of a mouth splint can achieve effective and safe hemostatic management in emicizumab-treated PwHA and PwHA-I.

Bevacizumab-Associated Implant Presence-Triggered Osteonecrosis: A Case Report and Literature Review.

The effect of bevacizumab-related osteonecrosis of the jaw on previously osseointegrated dental implants has not been adequately studied. Here, we report a case of osteonecrosis of the jaw detected around dental implants placed before bevacizumab therapy. A 66-year-old woman undergoing bevacizumab therapy for metastatic triple-negative breast cancer developed malocclusion after buccal gingival swelling and pain in the #18, #19, and #20 tooth region. The patient visited a local dental clinic, where existing implants in relation to #19 and #20 were removed. Subsequently, the patient visited our department, and intraoral examination revealed necrotic bone in the region corresponding to #19 and #20. Radiographic examination showed a pathologic fracture in this region that was considered to result from osteonecrosis of the jaw. Bevacizumab therapy was suspended temporarily until the acute inflammation had subsided. In addition, treatment with antibacterial agents and conservative surgery was considered. Complete soft tissue coverage was observed 14 days after surgery. In recent years, the number of patients receiving bevacizumab treatment has increased. Because bevacizumab-related osteonecrosis of the jaw could occur around previously osseointegrated dental implants as well, this case report suggests an effective treatment regimen based on a combination of antibacterial agents and conservative surgery.

Effect of smoking status and programmed death-ligand 1 expression on the microenvironment and malignant transformation of oral leukoplakia: A retrospective cohort study.

Tobacco smoking is associated with an increased risk of oral leukoplakia and head and neck cancer. Although it has recently been reported that the establishment of an immunosuppressive microenvironment in oral potentially malignant disorders may lead to malignant transformation, it is unclear whether the microenvironments of oral potentially malignant disorders differ according to smoking status. We examined differences in programmed death-ligand 1 (PD-L1) expression and subepithelial CD163+ TAM and CD8+ cell/lymphocyte counts in the microenvironment of oral leukoplakia of smoking and non-smoking patients and investigated their associations with malignant transformation. Pathology reports and original biopsy request forms from 1995-2015 were retrospectively reviewed. Lesions clinically characterized as white plaques/lesions of the oral mucosa and pathologically diagnosed as oral epithelial dysplasia were included. Immunohistochemistry was performed to evaluate PD-L1 expression and subepithelial CD163+/CD8+ cell counts. The significance of prognostic factors in predicting malignant transformation was determined using Cox regression analysis. Statistical significance was defined as P<0.05. In total, 200 patients with oral leukoplakia were selected. The mean age at diagnosis was higher in non-smoking patients (n = 141; 66.9 years) than in smoking patients (n = 59; 60.5 years). The 5-year cumulative malignant transformation rate was higher in non-smoking patients than in smoking patients (9.3% vs. 3.0%, respectively). Oral leukoplakia was associated with significantly higher PD-L1 expression and increased numbers of subepithelial CD163+ cells in the non-smoking group compared with the smoking group. Non-smoking-related oral leukoplakia with positive PD-L1 expression was associated with a 6.97-fold (95% confidence interval: 2.14-22.7) increased risk of malignant transformation. The microenvironment of oral leukoplakia differed according to smoking status. A combination of smoking status and PD-L1 expression may predict malignant transformation in oral leukoplakia patients. This study highlights the importance of understanding the interaction between smoking and the microenvironment in oral leukoplakia.

Risk factors for post-extraction bleeding in patients with haemophilia: a retrospective cohort study.

Many guidelines and studies describe haemostatic management protocols for patients with haemophilia, but few have evaluated the risk factors for post-extraction bleeding. This retrospective cohort study was performed to investigate these risks among this group of patients. We used medical records to identify patients with haemophilia who underwent tooth extraction(s) between April 2006 and April 2019 in the Department of Oral and Maxillofacial Surgery at Nara Medical University Hospital, Nara, Japan, and conducted logistic regression analyses to identify risk or protective factors for post-extraction bleeding in procedures involving factor replacement therapy. Post-extraction bleeding was defined as bleeding that could not be stopped by biting down on gauze, and that required medical treatment between 30min and 14 days after the extraction. A total of 151 extractions (84 interventions) in 55 patients fulfilled the inclusion criteria (130 extractions (72 interventions) in 48 patients with haemophilia A, and 21 extractions (12 interventions) in seven patients with haemophilia B). Post-extraction bleeding was observed in nine patients (16.3%), 10 interventions (11.9%), and 12 extractions (7.9%). On average, it occurred six days after the intervention, and on the fifth postoperative day after extractions. Use of mouth splints significantly reduced the risk (odds ratio: 0.13; p=0.01) in patients on factor replacement therapy. We will conduct a prospective study to investigate the optimal type of splint and optimal splint-wearing period.

Study of Treatment Methods for Surrounding Soft Tissues of Implants Following Mandibular Reconstructions with Fibula-Free Flaps.

In maxillofacial reconstruction implant treatment, unsatisfactory soft tissue treatment of the area around the implant may lead to inflammation. As a result, appropriate soft tissue treatment is critical. To the best of our knowledge, there are no studies that compare the different tissue treatment methods available. Hence, in this study, we compare three soft tissue treatment methods around implants after mandibular reconstruction is achieved with a fibula-free flap. Out of 33 patients who underwent mandible reconstruction using fibula-free flaps between 2006 and 2015, 5 were selected for this study. A total of 17 implants were used for treatment by the final prosthetics of the five patients. Three soft tissue treatment methods with free gingival graft (FGG) were evaluated, namely, installing a splint in a modified abutment to protect the wounded area during a palatal mucosa transplant (method 1), installing a splint or dentures to a locator abutment (method 2), and the use of screw-in fixed dentures (method 3). The method that could guarantee the widest keratinized mucosa was the screw-in fixed denture method. The results of our study indicated that employing screw-in fixed dentures for FGG may be a useful soft tissue treatment for mandible reconstruction implants.

Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats.

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 µg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.

Risks of postextraction bleeding after receiving direct oral anticoagulants or warfarin: a retrospective cohort study.

OBJECTIVE: The effect of direct oral anticoagulants (DOACs) on the risk of bleeding after tooth extraction remains unclear. This study aimed to evaluate the incidence of postextraction bleeding among patients who received DOAC and vitamin K antagonists (VKAs), such as warfarin. DESIGN: This study was a retrospective cohort analysis. Incidence rates and propensity score-matched regression models were used to compare the risks of bleeding after tooth extractions involving DOACs and VKAs. SETTING: The study took place in a single university hospital in Japan. PARTICIPANTS: Between April 2013 and April 2015, 543 patients underwent a total of 1196 simple tooth extractions. PRIMARY OUTCOME MEASURE: The primary outcome measure was the occurrence of postextraction bleeding, which was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 min and 7 days after the extraction. RESULTS: A total of 1196 tooth extractions (634 procedures) in 541 patients fulfilled the study criteria, with 72 extractions (41 procedures) involving DOACs, 100 extractions (50 procedures) involving VKAs and 1024 extractions (543 procedures) involving no anticoagulants. The incidences of postextraction bleeding per tooth for the DOAC, VKA and no anticoagulant extractions were 10.4%, 12.0% and 0.9%, respectively. The incidences of postextraction bleeding per procedure for DOACs, VKAs and no anticoagulants were 9.7%, 10.0% and 1.1%, respectively. In comparison to the VKA extractions, the DOAC extractions did not significantly increase the risk of postextraction bleeding (OR 0.69, 95% CIs 0.24 to 1.97; p=0.49). CONCLUSIONS: The risk of postextraction bleeding was similar for DOAC and VKA extractions.

Programmed death ligand 1 (PD-L1) expression and tumor microenvironment: Implications for patients with oral precancerous lesions.

OBJECTIVES: Cancer immunoediting represents a relatively novel concept attempting to explain the process of tumor escape from the host immune system response. Here, we attempted to elucidate the role of programmed death ligand 1 (PD-L1), the tumor microenvironment, and tumor escape mechanisms that allow malignant transformation of oral precancerous lesions. MATERIALS AND METHODS: Patients with oral precancerous lesions managed at the Nara Medical University Hospital, Japan, (n=120) were enrolled in this study. Epithelial dysplasias were graded by experienced pathologists, and subepithelial PD-L1-, CD163-, and CD8-positive cells were counted in the superficial lamina propria of oral mucosa. Epithelial PD-L1 expression was evaluated according to the staining intensity. The association of clinicopathological factors with epithelial dysplasia, malignant-free survival time, and significance of risk factors for malignant transformation were determined. RESULTS: Multivariate analysis showed that the subepithelial CD163-positive cell count was the only significant risk factor for high-grade epithelial dysplasia (P<0.001), while subepithelial CD163- and PD-L1-positive cell counts, and epithelial PD-L1 positivity were significantly associated with malignant-free survival (P=0.004, 0.04, and <0.001, respectively). Subepithelial PD-L1-positive cell count and epithelial PD-L1 positivity were significantly associated with malignant transformation (P=0.01 and 0.04, respectively). CONCLUSION: Our results indicate that PD-L1-expressing dysplastic epithelial and recruited subepithelial cells in oral precancerous legions may evade the host immune system, and that the inhibition of PD-1/PD-L1 pathway may potentially prevent malignant transformation of oral precancerous legions as well as can treat advanced cancers.

Maxillofacial bone regeneration with osteogenic matrix cell sheets: An experimental study in rats.

OBJECTIVE: Regeneration of maxillofacial bone defects, characterized by relatively small but complicated shapes, poses a significant clinical challenge. Osteogenic matrix cell sheets (OMCSs) have osteogenic ability and good shaping properties and may be ideal graft materials. Here, we assessed whether implantation of OMCSs could be used to repair maxillofacial bone defects. DESIGN: We adopted a rat mandibular symphysis model. The rat mandible is formed by a paired bone and the central portion consisting of fibrous tissue. There is no bone tissue at the site; accordingly, this site was interpreted as a physiological bone gap and was used for evaluation. Rat bone marrow cells were cultured in medium containing dexamethasone and ascorbic acid phosphate to create OMCSs. The OMCSs were implanted into the rat mandibular symphysis without a scaffold. Microcomputed tomography and histological analyses were conducted after 2, 4, and 8 weeks. RESULTS: Two weeks after implantation, microcomputed tomography images and histological sections showed some sparse granular calcification tissue within the bone gap at the mandibular symphysis. At 4 weeks, the calcification tissue spread, and the gap of the mandibles were continued. At 8 weeks, this continuous new bone tissue was matured. The experimental group showed abundant new bone tissue in the group with OMCS implantation, but not in the group with sham implantation. CONCLUSIONS: Our present results indicated that use of OMCSs may be an optimal approach towards achieving maxillofacial regeneration.