Evaluation of the strategies to reduce third-generation oral cephalosporins in dentistry at a Japanese academic hospital: An interrupted time series analysis.

WHAT IS KNOWN AND OBJECTIVE: Third-generation oral cephalosporins, especially cefcapene-pivoxil (CFPN-PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost-effectiveness of antibiotics. METHODS: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). RESULTS AND DISCUSSION: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN-PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). WHAT IS NEW AND CONCLUSION: After December 2014, prophylactic antibiotics were switched from CFPN-PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost-effectiveness perspective.

A giant peripheral ossifying fibroma of the maxilla with extreme difficulty in clinical differentiation from malignancy: a case report and review of the literature.

BACKGROUND: Peripheral ossifying fibroma is a nonneoplastic inflammatory hyperplasia that originates in the periodontal ligament or periosteum in response to chronic mechanical irritation. Peripheral ossifying fibroma develops more commonly in young females as a solitary, slow-growing, exophytic nodular mass of the gingiva, no more than 2 cm in diameter. While various synonyms have been used to refer to peripheral ossifying fibroma, very similar names have also been applied to neoplastic diseases that are pathologically distinct from peripheral ossifying fibroma, causing considerable nomenclatural confusion. Herein, we report our experience with an unusual giant peripheral ossifying fibroma with a differential diagnostic challenge in distinguishing it from a malignancy. CASE PRESENTATION: A 68-year-old Japanese male was referred to our department with a suspected gingival malignancy presenting with an elastic hard, pedunculated, exophytic mass 60 mm in diameter in the right maxillary gingiva. In addition to computed tomography showing extensive bone destruction in the right maxillary alveolus, positron emission tomography with computed tomography revealed fluorodeoxyglucose hyperaccumulation in the gingival lesion. Although these clinical findings were highly suggestive of malignancy, repeated preoperative biopsies showed no evidence of malignancy. Since even intraoperative frozen histological examination revealed no malignancy, surgical resection was performed in the form of partial maxillectomy for benign disease, followed by thorough curettage of the surrounding granulation tissue and alveolar bone. Histologically, the excised mass consisted primarily of a fibrous component with sparse proliferation of atypical fibroblast-like cells, partly comprising ossification, leading to a final diagnosis of peripheral ossifying fibroma. No relapse was observed at the 10-month follow-up. CONCLUSIONS: The clinical presentation of giant peripheral ossifying fibromas can make the differential diagnosis from malignancy difficult. Proper diagnosis relies on recognition of the characteristic histopathology and identification of the underlying chronic mechanical stimuli, while successful treatment mandates complete excision of the lesion and optimization of oral hygiene. Complicated terminological issues associated with peripheral ossifying fibroma require appropriate interpretation and sufficient awareness of the disease names to avoid diagnostic confusion and provide optimal management.

Evaluation of safety and efficacy of autologous oral mucosa-derived epithelial cell sheet transplantation for prevention of anastomotic restenosis in congenital esophageal atresia and congenital esophageal stenosis.

BACKGROUND: We performed the first autologous oral mucosa-derived epithelial cell sheet transplantation therapy in a patient with refractory postoperative anastomotic stricture in congenital esophageal atresia (CEA) and confirmed its safety. In this study, patients with CEA and congenital esophageal stenosis were newly added as subjects to further evaluate the safety and efficacy of cell sheet transplantation therapy. METHODS: Epithelial cell sheets were prepared from the oral mucosa of the subjects and transplanted into esophageal tears created by endoscopic balloon dilatation (EBD). The safety of the cell sheets was confirmed by quality control testing, and the safety of the transplantation treatment was confirmed by 48-week follow-up examinations. RESULTS: Subject 1 had a stenosis resected because the frequency of EBD did not decrease after the second transplantation. Histopathological examination of the resected stenosis revealed marked thickening of the submucosal layer. Subjects 2 and 3 did not require EBD for 48 weeks after transplantation, during which time they were able to maintain a normal diet by mouth. CONCLUSIONS: Subjects 2 and 3 were free of EBD for a long period of time after transplantation, confirming that cell sheet transplantation therapy is clearly effective in some cases. In the future, it is necessary to study more cases; develop new technologies such as an objective index to evaluate the efficacy of cell sheet transplantation therapy and a device to achieve more accurate transplantation; identify cases in which the current therapy is effective; and find the optimal timing of transplantation; and clarify the mechanism by which the current therapy improves stenosis. TRIAL REGISTRATION: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393 .

Oral and maxillofacial surgery with computer-assisted navigation system.

Intraoperative computer-assisted navigation has gained acceptance in maxillofacial surgery with applications in an increasing number of indications. We adapted a commercially available wireless passive marker system which allows calibration and tracking of virtually every instrument in maxillofacial surgery. Virtual computer-generated anatomical structures are displayed intraoperatively in a semi-immersive head-up display. Continuous observation of the operating field facilitated by computer assistance enables surgical navigation in accordance with the physician's preoperative plans. This case report documents the potential for augmented visualization concepts in surgical resection of tumors in the oral and maxillofacial region. We report a case of T3N2bM0 carcinoma of the maxillary gingival which was surgically resected with the assistance of the Stryker Navigation Cart System. This system was found to be useful in assisting preoperative planning and intraoperative monitoring.

In Vivo Periodontium Formation Around Titanium Implants Using Periodontal Ligament Cell Sheet.

Osseointegrated implants have been recognized as being very reliable and having long-term predictability. However, host defense mechanisms against infection have been known to be impaired around a dental implant because of the lack of a periodontal ligament (PDL). The purpose of our experimental design was to produce cementum and PDL on the implant surface adopting cell sheet technology. To this aim we used PDL-derived cells, which contain multipotential stem cells, as the cell source and we cultured them on an implant material constituted of commercially pure titanium treated with acid etching, blasting, and a calcium phosphate (CaP) coating to improve cell attachment. Implants with adhered human PDL cell sheets were transplanted into bone defects in athymic rat femurs as a xenogeneic model. Implants with adhered canine PDL-derived cell sheets were transplanted into canine mandibular bone as an autologous model. We confirmed that PDL-derived cells cultured with osteoinductive medium had the ability to induce cementum formation. The attachment of PDL cells onto the titanium surface with three surface treatments was accelerated, compared with that onto the smooth titanium surface, at 40 min after starting incubation. Results in the rat model showed that cementum-like and PDL-like tissue was partly observed on the titanium surface with three surface treatments in combination with adherent PDL-derived cell sheets. On the other hand, osseointegration was observed on almost all areas of the smooth titanium surface that had PDL-derived cell sheets, but did not have the three surface treatments. In the canine model, histological observation indicated that formation of cementum-like and PDL-like tissue was induced on the titanium surface with surface treatments and that the PDL-like tissue was perpendicularly oriented between the titanium surface with cementum-like tissue and the bone. Results demonstrate that a periodontal-like structure was formed around a titanium implant, which is similar to the environment existing around a natural tooth. The clinical application of dental implants combined with a cell sheet technique may be feasible as an alternative implant therapy. Furthermore, application of this methodology may play an innovative role in the periodontal, prosthetic, and orthodontic fields in dentistry.

Comparison of salivary cytokine levels in oral cancer patients and healthy subjects.

In order to find informative salivary biomarkers specific to oral cancer we examined expression of 4 kinds of cytokine in saliva. Levels of interleukins (IL-1beta, -6, -8) and osteopontin were measured by ELISA using whole saliva samples collected from 19 patients with oral cancer (9 men, 10 women; mean age, 60.9 years) and 20 healthy persons (15 men, 5 women; mean age, 32 years). Expression of the 4 cytokines was higher in patients with oral cancer than in healthy controls. The difference was significant in IL-6, in particular. The results suggest that saliva offers a potential target for a screening test aimed at detection of precancerous lesions.

Long-term outcomes after carbon-ion radiotherapy for oral mucosal malignant melanoma.

Oral mucosal malignant melanoma (OMM) is extremely rare and has a poor prognosis. Owing to its rarity, it has not yet been possible to establish an optimal treatment modality. The objective of this study was to evaluate the long-term efficacy of carbon-ion radiotherapy (C-ion RT) for OMM. Between 1997 and 2013, 19 patients with OMM were treated with C-ion RT alone. Patient ages ranged from 44 to 84 years (median, 69 years). Nine men and 10 women were included. OMMs were restaged in accordance with the seventh edition of the tumour/node/metastasis (TNM) Staging System of the International Union Against Cancer. Before treatment, 14 patients had T3 disease and 5 had T4a disease. Three patients were classified as having N1 disease. All patients were classified as having M0. The hard palate was the most frequently involved oral subsite. All patients were treated with 57.6 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 61 months (range, 8-190 months). The 5-year local control, overall survival and progression-free survival rates were 89.5%, 57.4% and 51.6%, respectively. For local control and overall survival, T classification was found to be a significant prognostic factor. Grade 2 and 3 osteoradionecrosis was observed in three and four patients, respectively. The presence of teeth within the planning target volume was a significant risk factor for developing osteoradionecrosis. C-ion RT was an effective treatment option with acceptable toxicity for OMM.

Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice.

PURPOSE: This study examined the mechanisms of osteoclast-mediated bone invasion in a model of oral squamous cell carcinoma (OSCC). C3H/HeN mice were inoculated with SCC VII cells into the masseter region to establish an animal model of mandibular invasion by OSCC. EXPERIMENTAL DESIGN: The mice were divided into three groups: a control group, given daily s.c. injections of saline; group 1, given 2 microg per mouse per day of the bisphosphonate YM529; and group 2, given 10 microg per mouse per day of YM529. After 3 weeks of treatment, the lesions were studied by micro-computed tomography. After tartrate-resistant acid phosphatase (TRAP) staining, the osteoclasts were easily identified, and the percentages of the area occupied by osteoclasts were calculated by computer for each sample. The tumors were analyzed by RT-PCR to determine the mRNA expression of interleukin-6 (IL-6), parathyroid hormone-related protein (PTHrP), tumor necrosis factor-alpha (TNF-alpha), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), and osteoprotegerin. RESULTS: SCC VII cells rapidly multiplied in the masseter muscle of the mice. Bone invasion was evident only in the control group on micro-computed tomography. On TRAP-stained slices, the percentages of osteoclasts in groups 1 and 2 were significantly lower than that in the control group. The mRNA expressions of IL-6, PTHrP, THF-alpha, and RANK decreased as the concentration of YM529 increased. CONCLUSIONS: We conclude that various cancer-derived cytokines play important roles in the invasion of bone by OSCC. YM529, a third-generation bisphosphonate, can suppress osteoclast-mediated bone invasion by OSCC. The mechanism of this effect might involve inhibition of cytokines such as IL-6, PTHrP, TNF-alpha, and RANK by YM529.

Allogeneic Transplantation of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets in Canine Critical-Size Supra-Alveolar Periodontal Defect Model.

Periodontitis is a chronic inflammatory disease that induces the destruction of tooth-supporting tissues, followed by tooth loss. Although several approaches have been applied to periodontal regeneration, complete periodontal regeneration has not been accomplished. Tissue engineering using a combination of cells and scaffolds is considered to be a viable alternative strategy. We have shown that autologous transplantation of periodontal ligament-derived multipotent mesenchymal stromal cell (PDL-MSC) sheets regenerates periodontal tissue in canine models. However, the indications for autologous cell transplantation in clinical situations are limited. Therefore, this study evaluated the safety and efficacy of allogeneic transplantation of PDL-MSC sheets using a canine horizontal periodontal defect model. Canine PDL-MSCs were labeled with enhanced green fluorescent protein (EGFP) and were cultured on temperature-responsive dishes. Three-layered cell sheets were transplanted around denuded root surfaces either autologously or allogeneically. A mixture of ß-tricalcium phosphate and collagen gel was placed on the bone defects. Eight weeks after transplantation, dogs were euthanized and subjected to microcomputed tomography and histological analyses. RNA and DNA were extracted from the paraffin sections to verify the presence of EGFP at the transplantation site. Inflammatory markers from peripheral blood sera were quantified using an enzyme-linked immunosorbent assay. Periodontal regeneration was observed in both the autologous and the allogeneic transplantation groups. The allogeneic transplantation group showed particularly significant regeneration of newly formed cementum, which is critical for the periodontal regeneration. Serum levels of inflammatory markers from peripheral blood sera showed little difference between the autologous and allogeneic groups. EGFP amplicons were detectable in the paraffin sections of the allogeneic group. These results suggest that allogeneic PDL-MSC sheets promoted periodontal tissue regeneration without side effects. Therefore, allogeneic transplantation of PDL-MSC sheets has a potential to become an alternative strategy for periodontal regeneration.

Evaluation of the safety and efficacy of carbon ion radiotherapy for locally advanced adenoid cystic carcinoma of the tongue base.

BACKGROUND: Most cases of adenoid cystic carcinoma (ACC) of the tongue base are radioresistant, and are diagnosed in the advanced stage. Therefore, we evaluated the safety and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced ACC of the tongue base. METHODS: Eighteen patients with ACC of the tongue base were treated with C-ion RT between May 2002 and April 2014. Seventeen patients had T4a disease and 1 patient had T2 disease before C-ion RT. RESULTS: The median follow-up period was 57 months (range, 10-132 months). The 5-year local control rate was 92%. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 72% and 44%, respectively. Regarding late reactions, 2 patients developed grade 3 mandible osteoradionecrosis, and 1 had grade 3 hemorrhage of the tongue base. CONCLUSION: C-ion RT was effective with acceptable toxicities for locally advanced ACC of the tongue base. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2122-E2126, 2016.

Brush biopsy of human oral mucosal epithelial cells as a quality control of the cell source for fabrication of transplantable epithelial cell sheets for regenerative medicine.

Autologous oral mucosal epithelial cell sheets have been used for treating epithelial defects such as cornea and esophagus. The cell source of patients' oral mucosal epithelial cell sheet should be examined in normality because it has individual difference. In this study, oral mucosal epithelial cells were less invasively collected by brush biopsy from the buccal, gingival, labial, and palate mucosa of four healthy volunteer donors without anesthesia, and analyzed the keratin expressions by western blotting and the obtained results were compared with those by immunohistochemistry of each of the native tissues. All of the oral mucosal epithelial cells expressed keratin 4 (K4) and K13, which were mucosal stratified squamous epithelial cell markers. K1 and K10, keratinized epithelial cell markers, were also detected in keratinized tissues such as gingival and palate mucosa. The markers of epithelial basal cells such as p63 and K15 were not detected by brush biopsy-western blotting. Although this method does not include basal layers of oral mucosa, protein expressions of upper layer of lesion area are different from normal. Therefore, brush biopsy-western blotting was extremely less invasive and would contribute to quality control of the fabrication of autologous oral mucosal epithelial cell sheets.

Fabrication of transplantable corneal epithelial and oral mucosal epithelial cell sheets using a novel temperature-responsive closed culture device.

Temperature-responsive culture surfaces make it possible to harvest transplantable carrier-free cell sheets. Here, we applied temperature-responsive polymer for polycarbonate surfaces with previously developed closed culture devices for an automated culture system in order to fabricate transplantable stratified epithelial cell sheets. Histological and immunohistochemical analyses and colony-forming assays revealed that corneal epithelial and oral mucosal epithelial cell sheets could be harvested with the temperature-responsive closed culture devices. The results were similar to those obtained using temperature-responsive culture inserts. These results indicate that the novel temperature-responsive closed culture device is useful for fabricating transplantable stratified epithelial cell sheets.

Effects of the dose-volume relationship on and risk factors for maxillary osteoradionecrosis after carbon ion radiotherapy.

BACKGROUND: Osteoradionecrosis (ORN) is a critical complication after carbon ion (C-ion) or photon radiotherapy (RT) for head and neck tumors. However, the risk factors for ORN after C-ion RT remain unclear. Therefore, the present study aimed to investigate the effects of the dose-volume relationship on and risk factors for ORN development after C-ion RT. We, however, focused on the maxillary bone because most tumors treated with C-ion RT were primarily located in the sinonasal cavity. METHODS: The patients enrolled in this study received more than 10% of the prescribed total dose of 57.6 Gy equivalent (GyE) in 16 fractions to their maxilla. All patients were followed up for more than 2 years after C-ion RT. Those with tumor invasion to the maxilla before C-ion RT or local recurrence after the treatment were excluded from the study to accurately evaluate the effects of irradiation on the bone. Sixty-three patients were finally selected. The severity of ORN was assessed according to the Common Terminology Criteria for Adverse Events version 4.0. The correlation between clinical and dosimetric parameters and ORN incidence was retrospectively analyzed. RESULTS: The median follow-up period was 79 months. Of the 63 enrolled patients, 26 developed ORN of grade ≥1. Multivariate analysis revealed that the maxilla volume receiving more than 50 GyE (V50) and the presence of teeth within the planning target volume were significant risk factors for ORN. Dose-volume histogram analysis revealed that V10 to V50 parameters were significantly higher in patients with ORN than in those without ORN. CONCLUSIONS: V50 and the presence of teeth within the planning target volume were independent risk factors for the development of ORN after C-ion RT using a 16-fraction protocol.

Profiling of extracellular matrix and cadherin family gene expression in mouse feeder layer cells: type VI collagen is a candidate molecule inducing the colony formation of epithelial cells.

Mouse 3T3 feeder layer has been utilized for epidermal and corneal epithelial cell culture to promote tissue-like cell stratification. However, the molecular mechanism underlying epithelial-feeder layer interactions remains poorly understood. Here, the feeder layer activity of six different mouse cell lines was examined in terms of the colony-forming efficiency (CFE) of primary limbal epithelial cells, including corneal epithelial stem/progenitor cells. When epithelial cells and feeder layers were separated by culture inserts, the CFE was significantly lower than that of epithelial cells, which were cultured with feeder cells on the same dish surfaces, implying that direct contacts between these cells and/or pericellular extracellular matrix (ECM) deposition by feeder layers have an important role in feeder layer activity. With TaqMan polymerase chain reaction assay, the gene expression of 29 ECM molecules and 32 cadherin family genes was profiled in two highest and two lowest cell lines in the CFE for limbal and oral mucosal epithelial cells. A significant difference in the expression correlated with the CFE was observed in six ECM molecules and four kinds of cadherin family genes. In these results, type VI collagen was confirmed to be able to promote the colony formation of epithelial cells in vitro effectively.

Periodontal regeneration with multi-layered periodontal ligament-derived cell sheets in a canine model.

Periodontal regeneration has been challenged with chemical reagents and/or biological approaches, however, there is still no sufficient technique that can regenerate complete periodontium, including alveolar bone, cementum, and well-oriented collagen fibers. The purpose of this study was to examine multi-layered sheets of periodontal ligament (PDL)-derived cells for periodontal regeneration. Canine PDL cells were isolated enzymatically and expanded in vitro. The cell population contained cells capable of making single cell-derived colonies at an approximately 20% frequency. Expression of mRNA of periodontal marker genes, S100 calcium binding protein A4 and periostin, was observed. Alkaline phosphatase activity and gene expression of both osteoblastic/cementoblastic and periodontal markers were upregulated by osteoinductive medium. Then, three-layered PDL cell sheets supported with woven polyglycolic acid were transplanted to dental root surfaces having three-wall periodontal defects in an autologous manner, and bone defects were filled with porous beta-tricalcium phosphate. Cell sheet transplantation regenerated both new bone and cementum connecting with well-oriented collagen fibers, while only limited bone regeneration was observed in control group where cell sheet transplantation was eliminated. These results suggest that PDL cells have multiple differentiation properties to regenerate periodontal tissues comprising hard and soft tissues. PDL cell sheet transplantation should prove useful for periodontal regeneration in clinical settings.