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The submandibular gland (SMG) is one of the major salivary glands that play important roles for variety of physiological functions, such as digestion of foods, prevention of infection, and lubrication of the mouth. Dysfunction of the SMG, often associated with a salivary inflammation, adversely influences a person's quality of life. However, the mechanism underlying inflammation-driven dysfunction of the SMG is largely unknown. Here, we used a mouse model in which the main excretory duct of the SMG is ligated unilaterally to induce inflammation of the gland and examined the expression of Wnt5a, Ror1 and Ror2 genes, encoding Wnt5a ligand and its cognate receptors, which have been implicated in tissue damage or inflammatory responses in variety of tissues. We show that expression levels of Ror1, Ror2, and Wnt5a are increased in the ligated SMG undergoing interstitial fibrosis, which is accompanied by robust expression of fibrosis-associated genes, such as TGF-β1, TNF-α, IL-1β, and MMP-2. Increased immunostaining signal of Ror2 was detected in the fibrotic tissues with abundant accumulation of fibroblasts and collagen fibers in the ligated SMG, suggesting that Ror2-mediated signaling might be activated in response to tissue damage and associated with progression of fibrosis in the SMG.Key words: submandibular gland, Ror2, Wnt5a, fibrosis, inflammation.

Objective: This retrospective study aimed to report the incidence of neurosensory complications after third molar extraction and also to identify current problems and discuss appropriate management of these complications. Method: Patients who underwent extraction of deeply impacted mandibular third molars under general anesthesia were included. The following epidemiological data were retrospectively gathered from medical charts: type of neurosensory complication, treatment for complication, and outcome. Results: A total 369 mandibular third molars were extracted in 210 patients under general anesthesia during this study period. Thirty-one of the 369 teeth (8.4%) in 31 patients had neurosensory complications during the first postoperative week resulting from inferior alveolar nerve damage. Neurosensory complications lasting from 1 to 3 months postoperatively included 17 cases of hypoesthesia and 8 of dysesthesia in 19 patients. Five cases of hypoesthesia and 4 of dysesthesia in 5 patients persisted over 1 year postoperatively. Sixteen of 369 teeth (4.3%) in 16 patients had persistent neurosensory complications after third molar extraction under general anesthesia. Stellate ganglion block was performed in 4 patients. Early initiation of stellate ganglion block (within 2 weeks postoperatively) produced better outcomes than late stellate ganglion block (over 6 months postoperatively). Conclusion: Refractory neurosensory complications after third molar extraction often combine both hypoesthesia and dysesthesia. Current problems in diagnosis and treatment included delayed detection of dysesthesia and the lack of uniform timing of stellate ganglion block. In the future, routinely inquiring about dysesthesia and promptly providing affected patients with information about stellate ganglion block might produce better outcomes.

Objective Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. Methods HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC + G). Gabapentin was maintained at 900 mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. Results Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC + G (n = 11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC + G arm (47 in SPC vs. 74 in SPC + G, p = 0.517; 215 mg vs. 745.3 mg, p = 0.880; and 1260 mg vs. 1537.5 mg, p = 0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC + G arm for weight gain (p = 0.005). Adverse events related to gabapentin were manageable. Conclusions This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted.

We report on the findings of the first antimicrobial susceptibility surveillance study in Japan of isolates recovered from odontogenic infections. Of the 38 facilities where patients representing the 4 groups of odontogenic infections were seen, 102 samples were collected from cases of periodontitis (group 1), 6 samples from pericoronitis (group 2), 84 samples from jaw inflammation (group 3) and 54 samples from phlegmon of the jaw bone area (group 4) for a total of 246 samples. The positivity rates of bacterial growth on culture were 85.3%, 100%, 84% and 88.9%, respectively, for groups 1, 2, 3 and 4. Streptococcus spp. isolation rates according to odontogenic infection group were 22% (group 1), 17.7% (group 3) and 20.7% (group 4). Anaerobic isolation rates were 66.9% (group 1), 71.8% (group 3) and 68.2% (group 4). Drug susceptibility tests were performed on 726 strains excluding 121 strains that were undergrown. The breakdown of the strains subjected to testing was 186 Streptococcus spp., 179 anaerobic gram-positive cocci, 246 Prevotella spp., 27 Porphyromonas spp., and 88 Fusobacterium spp. The isolates were tested against 30 antimicrobial agents. Sensitivities to penicillins and cephems were good except for Prevotella spp. The low sensitivities of Prevotella spp is due to β-lactamase production. Prevotella strains resistant to macrolides, quinolones, and clindamycin were found. No strains resistant to carbapenems or penems were found among all strains tested. No anaerobic bacterial strain was resistant to metronidazole. Antimicrobial susceptibility testing performed on the S. anginosus group and anaerobic bacteria, which are the major pathogens associated with odontogenic infections, showed low MIC90 values to the penicillins which are the first-line antimicrobial agents for odontogenic infections; however, for Prevotella spp., penicillins combined with β-lactamase inhibitor showed low MIC90 values.

The present retrospective multicenter study intended to investigate the factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas. A total of 326 patients who underwent radiotherapy for oral and oropharyngeal cancers were enrolled in the study. The patients’ age, sex, body mass index, primary site, diabetes, serum albumin, creatinine, hemoglobin, leukocyte and lymphocyte, concurrent cisplatin or cetuximab, method of radiation, total radiation dose, feeding route, use of spacers, pilocarpine hydrochloride, and corticosteroid ointment were examined, and the associations of each variable with oral mucositis and candidiasis were analyzed by multivariate Cox regression analysis. Grade 3 oral mucositis occurred in 136 (41.7%) patients. Male sex, oropharyngeal cancer, low hemoglobin levels, low leukocytes or lymphocytes, concurrent cisplatin or cetuximab, and oral feeding were found to be significantly associated with a higher incidence of severe oral mucositis. Oral candidiasis occurred in 101 (31.0%) patients. Oropharyngeal cancer, low leukocyte count, and oral mucositis of grade 2 or higher were found to be significantly associated with a higher incidence of oral candidiasis. The use of a topical steroid ointment was not found to be a risk factor for oral candidiasis. The present retrospective study demonstrated that certain factors may predispose patients with oral and oropharyngeal cancers receiving radiotherapy to develop severe oral mucositis and oral candidiasis. A preventive strategy for severe oral mucositis needs to be established in the future for high-risk cases.

Treatment strategies of medication-related osteonecrosis of the jaw (MRONJ) are controversial. Recently, surgical treatment has been reported as superior to nonsurgical treatment, but the contribution discontinued antiresorptive agent use during MRONJ treatment remains unclear. This study aimed to evaluate the efficacy of drug holidays and treatment strategies in MRONJ cases. Four-hundred and twenty-seven patients with MRONJ treated at nine hospitals from 2009 to 2017 were included in this multicenter retrospective study. Multivariate Cox regression analysis showed that the primary disease (osteoporosis or malignant tumor), diabetes, serum albumin, and treatment method (surgical or nonsurgical) were significantly correlated with the cure rate. The cumulative 1-year cure rates in the surgical and nonsurgical treatment groups were 64.7% and 18.2%, respectively. However, discontinuing antiresorptive agents did not influence the treatment outcome in the cohort overall, or in 230 patients after performing propensity score matching among the discontinuation and continuation groups. When stratifying by treatment method, antiresorptive agent discontinuation significantly increased the cure rate in patients with osteoporosis who underwent nonsurgical treatment. In patients with malignant tumors undergoing nonsurgical therapy, discontinuing the antiresorptive agent was associated with a better treatment outcome, but not with statistical significance. In contrast, drug holidays showed no effect on improving outcomes in patients with both osteoporosis and malignant tumors who underwent surgical therapy. Thus, regardless of the primary disease, discontinuing antiresorptive agents during treatment for MRONJ may not be necessary and may be helpful in some cases. Future prospective trials should examine this question further.

Background/aim We recently investigated the contribution of the iPS-related genes SOX2, OCT4, and Nanog to de-differentiation by assaying for their mRNA levels. Given that mRNA expression does not always correlate with the protein levels, the aim of this study was to retrospectively determine the expression of these four iPS-related factors in human OSCC specimens by immunohistochemistry and examine their association with patient prognosis. Materials and methods iPS cell-related gene expression in 89 OSCC patients by tissue microarray, and its correlation with clinicopathological factors, differentiation, metastasis, and poor prognoses were investigated. Results No evidence of statistically significant relationships was found between the expression of iPS cell-related genes and clinicopathological parameters. However, our data indicated that KLF4 expression was associated with survival, and poor tumor differentiation. In addition, high expression of KLF4 was an independent poor prognostic factor (p=0.004) for OSCC patients. Conclusion In preoperative biopsies, higher KLF4 and poor differentiation may be clinically effective predictors for the prognosis of oral cancer.

OBJECTIVE The authors investigated the clinical and histopathologic significance of medial pectoral nerve preservation/reinnervation of pectoralis major musculocutaneous flap for oromandibular reconstruction. MATERIALS AND METHODS The authors compared 13 patients treated with pectoralis major musculocutaneous flap reconstruction and 6 control patients treated by rectus abdominis musculocutaneous flap reconstruction without motor nerve restoration. Subjective awareness was scored to evaluate changes in the facial contour due to muscle atrophy, and objective evaluation was performed in few patients. In addition, the authors performed histopathologic analysis of both muscle atrophy and nerve regeneration in 20 patients from whom samples were available. RESULTS Subjective awareness of changes in the facial contour induced by muscle atrophy was low among patients with nerve preservation/reinnervation, but there were objective changes at 3 months after surgery among patients who underwent nerve resection. In the patients who had medial pectoral nerve preservation or nerve restoration by nerve suture, favorable facial symmetry was retained at 5 years after surgery. Even though the motor nerve was preserved or restored, fatty degeneration and fibrosis were noted in approximately 30% of the total surface area of the muscle, and type I fibers had decreased to 36% that of control at 7 years after surgery. However, regressive changes were inhibited for 1 year after surgery; in contrast, changes corresponding to those noted at 7 years after surgery were observed by 3 months in the patients with nerve resection. CONCLUSION Thus, the authors showed that preservation or restoration of nerves can delay muscle and have highlighted the potential benefits of this approach.

A multi‐institutional study was undertaken to determine whether mandibular canal (MC) invasion and mandibular medullary bone invasion are independent factors in lower gingival squamous cell carcinoma (SCC). A total of 345 patients with lower gingival SCC were retrospectively reviewed. Mandibular bone invasion was categorized into three types; no bone invasion; invasion through cortical bone (medullary); and MC invasion. The overall survival rate and factors affecting local, regional, and distant failures were assessed by Cox proportional hazards regression analysis and Kaplan–Meier estimates. Bone invasion was present in 201 (58%) patients, of whom 107 (31%) had medullary invasion and 94 (27%) had MC invasion. Using the International Union Against Cancer (UICC) staging system and American Joint Committee on Cancer (AJCC) system, 171 (50%) patients were classified as T4a. When the bone invasion criteria were excluded from the UICC/AJCC system definition, 152 T4a tumors were downstaged and reclassified to T1 in 12 (3%), to T2 in 98 (28%), and to T3 in 42 (12%). In Cox multivariate analysis, MC invasion was an independent predictor of overall survival but medullary bone invasion was not. Medullary bone invasion was an independent variable for distant control. The current T staging system has restricted prognostic utility. The authors recommend a modified T staging system, whereby tumors with MC invasion instead of medullary bone invasion are classified as T4a, and tumors are first classified as T1 to T3 based on size and then upstaged by one T classification in the presence of medullary invasion.

Objective In this study, we investigated the degree of concordance in the histopathological diagnosis among lesions clinically diagnosed with oral lichen planus (OLP) to understand the importance of the histopathological examination. Methods In total, 169 patients clinically diagnosed with OLP on their initial visit to our hospital between 2001 and 2012 were experienced. Of them, histopathological examinations were carried out for 77 patients (83 lesions), and they were selected as the subjects of this study. The age, gender, location of the lesion, clinical type of OLP determined via visual inspection, and histopathological findings were investigated. Results Of the 77 patients, 12 were male and 65 were female, with a mean age of 63.9 years. Histopathological examinations were performed in 83 lesions, of which 54 were diagnosed as OLP. Among the diagnostically discordant 29 lesions, most were histopathologically diagnosed as leukoplakia (15 lesions, 51.7%), whereas one was diagnosed as squamous cell carcinoma (3.4%). The most frequent location of discordant lesions was the tongue (discordant rate: 77.8%), and the most clinical type was plaque (discordant rate: 90.0%); all of which were atypical types of OLP. Conclusions The rate of discordance between the clinical and histopathological diagnoses was 34.9%. These results indicate that histopathological examinations are essential for obtaining the differential diagnosis to distinguish the lesion from other diseases with a clinical presentation similar to that of OLP.

Purpose The purpose of this study was to analyze jaw movement during mastication in patients who underwent mandibular reconstruction following segmental mandibulectomy, including mouth opening and mastication time, based on four-dimensional computed tomography (4D CT) images. Material and methods This study included six surgical patients, who underwent segmental mandibulectomy and simultaneous reconstruction with a free fibula osteocutaneous flap, and four controls. 4D CT was performed during mastication of a cookie to evaluate the movement of the jaw during natural function. The maximum mouth opening, mastication time, and movement of the mandibular angle during mastication were evaluated from the 4D CT images. Results 4D CT images enabled visualization of jaw movement during mastication. When compared with the controls, the maximum mouth opening during mastication and excursion of the mandibular angle, especially on the diseased side, tended to decrease in surgical patients; however, this did not occur with mastication time. The numerical differences between the diseased and nondiseased side in surgical patients tended to be higher than the crosswise differences in controls. Conclusion 4D CT images revealed differences in jaw function between patients who underwent mandibular reconstruction and controls. 4D CT could be used to evaluate postoperative outcomes following mandibular reconstruction.

Oral squamous cell carcinoma (OSCC) is the most common form of oral cancers. Recent studies have shown that the malignant transformation of various carcinomas, including OSCC, is associated with epithelial-mesenchymal transition (EMT), and that expression of the EMT factors are significantly associated with tumor invasion, tumor metastasis, and survival rates in OSCC patients. Hence, there is a possibility that EMT suppression may improve the prognosis of OSCC patients. Hypoxia inducible factor-1α (HIF-1α) is a crucial microenvironmental factor in tumor progression, which induces the expression of EMT factors. We previously reported that transcutaneous CO2 suppresses both human OSCC tumor growth and metastasis to the regional lymph nodes by improving hypoxia in treated tissue. According to this background, we hypothesized that increased EMT with HIF-1α expression may increase the progression and the metastatic potential of OSCC, and that decreased hypoxia by transcutaneous CO2 could suppress EMT. In the present study, in vitro studies showed that hypoxic conditions increased the expression of HIF-1α and EMT factors in OSCC cells. In addition, in vivo studies revealed that transcutaneous CO2 increased E-cadherin expression with the decreased expression of HIF-1α, Snail, Slug, N-cadherin, and Vimentin in tumor treatment. These results suggest that transcutaneous CO2 could suppress EMT by improving hypoxia, resulting in the reduction of metastatic potential of OSCC. The findings indicate that transcutaneous CO2 may be able to improve the prognosis of OSCC patients through the suppression of EMT.

Objective This study aimed to compare postoperative outcomes between free-flap reconstruction and prosthesis after secondary healing for moderate-sized maxillectomy defects. Methods We enrolled patients who underwent tumor ablation extending to the alveolus, antral walls, masticatory space, and surrounding soft tissue but not the orbital floor with either radial forearm free-flap reconstruction (RFFF) or no reconstruction (NR) and compared the extent of cheek concavity on the resected side, evaluated using axial computed tomography images, and time to prosthesis insertion between the RFFF and NR groups. Results There was a significant difference between the RFFF and NR groups in operative duration (P = 0.010) but not blood loss. The postoperative cheek concavity was significantly smaller in the RFFF group (P = 0.037). Although the between group difference in time to prosthesis insertion was not significant, prostheses tended to be inserted earlier in the RFFF group; median time to prosthesis insertion was 49 days in the RFFF group and 67 days in the NR group. Conclusions Reconstruction of a moderate-sized maxillectomy defect with radial forearm free-flap transfer can improve postoperative outcome.

Only a few reports on the level of progression of extracapsular spread (ECS) have been published. The aim of this study was to evaluate the efficacy of the level of progression of ECS in identifying those patients with oral squamous cell carcinoma (OSCC) at a high risk of recurrence who would benefit most from the intensification of adjuvant therapy. The level of progression of ECS for cervical lymph node metastasis in OSCC was divided into three types (A-C), and their relationships with patient prognosis were examined. ECS was observed in 87 of 441 patients with OSCC. The recurrence rate in patients with type C, which was defined as macroscopic tumour invasion into perinodal fat or muscle tissue, was high (69.8%), with 13 cases of death due to distant metastasis. The 3-year disease-specific survival rate for patients with type C was 49.0% and these patients also had a significantly poorer prognosis (P

Purpose Patients with oral cancer who undergo resection with simultaneous reconstruction are presumed to be at high risk for developing venous thromboembolism (VTE) according to current criteria. The primary purpose of this retrospective study was to report the incidence of VTE after oral cancer surgery requiring primary reconstruction and to identify the potential risk factors for VTE in this population. Materials and Methods This retrospective study evaluated 133 consecutive patients who had undergone oral cancer resection with simultaneous reconstruction from April 2007 through December 2014. Bilateral lower-extremity venous duplex ultrasonography (VDUS) was routinely performed 2 days after surgery. Pulmonary embolism was confirmed with computed tomography. The Caprini risk score (CRS) was obtained for each patient. Patients with and without VTE were compared using the χ 2 test and Student t test with some variables. Univariate predictors associated with VTE were entered into a multivariate logistic regression analysis. A P value less than .05 was regarded as indicating statistical significance. Results The incidence of VTE after oral oncologic surgery with simultaneous reconstruction was 26.3% (35 of 133 patients): deep vein thrombosis (DVT) and pulmonary embolism occurred in 2.3% (3 of 133) and DVT alone was found in 24.0% (32 of 133). Multivariate logistic regression analysis showed that only a high CRS was statistically relevant to VTE occurrence. Conclusions Because a high incidence of VTE was found after major oral and maxillofacial surgery, lower-extremity VDUS should be undertaken in patients who undergo oral cancer surgery with simultaneous reconstruction, especially those with a high CRS.

Objective This purpose of this study was to investigate whether CT is useful for diagnosing BRONJ by comparing CT findings in BRONJ patients. Methods CT images of the mandible were obtained from a total of 14 patients with BRONJ, 14 patients treated with BPs and 14 control patients. In each patient, 15 transaxial CT images were selected and 30 configured regions of interest (ROI) were identified. We measured the CT values in the interdentium mandibular region between the bilateral second molars. On the axial CT images, CT measurements were obtained in the mesiodistal direction in order to assess the widest diameter of osteolysis/sequestrum. Results Regarding the total area, the CT values in the BRONJ group were higher than those observed in the bisphosphonate treatment group ( P = 0.011), which were higher than those observed in the control group ( P = 0.014). There were no significant differences between the sites with and without BRONJ development in the incisal areas ( P = 0.13); however, there was a significant difference in the molar areas ( P = 0.001). Conclusions Assessing the molar area is more useful than assessing the incisal area for evaluating BRONJ. Measuring of CT values may be useful for diagnosis and early detection of BRONJ.

Supplemental Digital Content is available in the text, Patients develop a number of oral complications during cancer treatments. Oral bacteria are associated with the onset of dental focal infections and the progression of oral mucositis. Dental focal infections are frequently associated with the systemic onset of bacteremia, sepsis, and pneumonia. The degeneration of oral function with these complications may become an obstacle to cancer treatments. Although comprehensive oral management, including oral care, the removal of dental focal infections, and improvements in oral function with dentures, is conducted for cancer patients in Japan, few studies have assessed its efficacy. The aim of the present study was to investigate the incidence of dental/oral complications in cancer patients with perioperative oral managements (POMs) based on a large number of case series with a multicenter retrospective analysis. The medical records of cancer patients with POMs were retrospectively reviewed and the incidence of oral complications and efficacy of oral management were investigated. A total of 2744 cancer patients with POMs (1684 males and 1080 females, mean age 65.9 ± 13.0 years) were included and investigated in the present study. Among these patients, 2097 (76.4%) started POM before the initiation of cancer treatments, with 2130 (77.6%) receiving oral care only and 391 (14.2%) being subjected to invasive treatments, such as tooth extraction. The incidence of dental focal infections during the period of cancer treatments was 8.2%. The most frequent infection was acute periodontitis, including alveolar abscesses (112 patients, 4.1%). The incidence of grade 2 and 3 oral mucositis was 2.8%. Prolonged fever was observed in 113 patients (4.1%), with 7 having dental focal infections (6.2%). These incidence rates were lower than those reported previously. Based on analyses of a large number of patients, the present results support the efficacy of oral management in cancer patients. However, further studies are needed to establish adequate oral management guidelines for cancer patients.

This study aimed to explore novel metabolite biomarker candidates for screening oral squamous cell carcinoma (OSCC).We collected plasma samples from 48 patients with OSCC and 29 with an oral disease and conducted a plasma metabolomics analysis of patients with OSCC using gas chromatography mass spectrometry. Then, we used the cross-validation procedure to ensure the accuracy of biomarker candidates.We selected four biomarker candidates against OSCC. Their sensitivity was more than 90%, and the AUC was over 0.9 according to the receiver operating characteristic curve analysis.The findings of this study suggest four potential metabolites as biomarkers for OSCC screening.

Objective Musculocutaneous flap reconstruction surgery is one of the standard procedures following head and neck cancer resection. However, no previous studies have classified flaps in terms of muscle and fat or examined them after long-term follow-up. The purpose of this study was to estimate the fat and muscle volume changes in musculocutaneous flaps during long-term follow-up. Methods We conducted a retrospective analysis of 35 patients after musculocutaneous flap reconstruction. The total, fat, and muscle volumes of the musculocutaneous flaps were measured using 3-dimensional images. Changes in flap volumes over time (1 month, 1 year [POY1], and 5 years [POY5] postoperatively) were assessed. Flap persistence was calculated using flap volumes at 1 month after reconstruction for reference. Results Flap persistence at POY5 was 42.0% in total, 64.1% in fat, and 25.4% in muscle. Muscle persistence was significantly decreased (p Conclusion Reconstruction flaps are well-preserved with high fat-to-muscle ratios. Recommendations for weight maintenance are necessary for patients less than 2 years after surgery due to the influence of BMI on fat persistence. Radiation therapy is necessary for some patients based on their disease state. Intensity-modulated radiation therapy can be offered to reduce scattering irradiation to normal tissues.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure–related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Purpose Few studies exist that focus on the details of perioperative antibiotic administration for surgery to treat medication-related osteonecrosis of the jaw (MRONJ). The regime and duration of perioperative antibiotics applied in published studies were reviewed to clarify appropriate perioperative antibiotic use in MRONJ surgery. Methods A literature search was conducted using the MEDLINE database via PubMed. Results The search resulted in 453 hits on PubMed. After reading the downloaded full-text articles, 17 articles met the inclusion and exclusion criteria. The most common perioperative antibiotic used for MRONJ surgery was a combination of penicillin-based antibiotics and β-lactamase inhibitor (52.9%), and the second most common regime was penicillin-based antibiotics with metronidazole (17.6%). The duration of administration was 2 weeks postoperatively in nine studies, whereas four studies applied long-term administration (2-6 weeks postoperatively). Conclusions Oral and maxillofacial surgeons mostly prefer penicillin-based antibiotics plus β-lactamase inhibitor or metronidazole for MRONJ surgery. The duration of administration of these medications may be based on empirical experience.

The aim of this case series was to reveal the difficulties in diagnosing fibro-osseous lesions with radiological and histopathological examinations and quantify the potential risk of infection to fibro-osseous legions. To analyze the concordance between radiological and histopathological diagnoses, this retrospective case series included patients who were clinically diagnosed with fibro-osseous lesions via radiological findings and excluded the patients who did not undergo histopathological examinations. This study also included the patients in whom histopathological results confirmed fibro-osseous legions when preoperative radiological diagnosis did not include fibro-osseous legions. Eleven patients (three men, eight women; median age 24.5 years, range 15–57 years) were enrolled. Although radiological diagnoses of fibrous dysplasia (FD) corresponded with histopathological diagnoses in seven patients, mismatches between radiological findings and histopathological results were found in three patients. In one patient, suspected diagnosis with radiological examinations was malignant lymphoma or FD. In two patients, the histopathological differentiation between FD and ossifying fibroma (OF) was difficult. One patient had lesion recurrence which was suspected to be OF with surgical findings and postoperative course after the initial surgery. In three patients, infections of FD were found. Preoperative diagnosis of OF with radiographic feature of unilocular radiolucency is difficult. In cases in which histopathological differentiation between FD and OF is difficult, operative findings should be used because OF is often found to be well-encapsulated and easily enucleated. Bone in FD showing mixed radiolucent-radiopaque may be vulnerable to infection.

BACKGROUND Dental rehabilitation with osseointegrated implants in reconstructed mandibles remains one of the most challenging procedures for oral and maxillofacial surgeons. Satisfactory outcome requires appropriate assessment of graft morphology. There are few analyses of the morphology of fibulae in reconstructed mandibles, although cadaver studies on fibular shape have been performed. MATERIALS AND METHODS In this study, we used postoperative computed tomography to retrospectively evaluate the shape, height, and orientation of fibulae transferred after mandibulectomy in 19 patients. RESULTS The average height of transferred fibulae was 14.3 mm (range, 10.8-20.5 mm). The cross-sectional morphology of transferred fibulae could be classified into 2 types: apex and nonapex. The former type included knife-edged and triangular shapes; the latter included square and circular shapes. CONCLUSION When implant insertion is planned in a reconstructed mandible, the orientation of the apex of transferred fibula should be evaluated preoperatively to allow for adjustments in implant procedure because the ridge at the apex of the fibula is narrow.

Objective: The criteria for T4 staging of carcinoma of the mandibular gingiva are controversial. Oral cancer staged as T4 implies "invasion to an adjacent organ" such as the skin, extrinsic muscles of the tongue, masticator space, or mandibular bone. In this study, we compared different T classifications and retrospectively investigated the correlation between each classification and the prognosis of patients with carcinoma of the mandibular gingiva. Methods: We investigated 81 patients with squamous cell carcinoma of the mandibular gingiva treated at two institutions. Results: There was a significant correlation between soft tissue classification and local recurrence ( P< 0.05) and that the correlation with prognosis is borderline significant ( P= 0.05). Conclusions: Soft tissue classification, which does not consider bone invasion, was the most useful for diagnosis, selecting the appropriate surgical procedure, and assessing the correlation to prognosis. We recommended using this classification to define T4. Because this classification is not new but is based on International Union Against Cancer classification, it could be easily adopted. However, the current study is a retrospective analysis of a small number of patients. A multi-institutional, prospective study is necessary to determine the appropriate criteria for the TNM staging of carcinoma of the mandibular gingiva., Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 27(5), pp.631-636; 2015

The purpose of this study was to examine the efficacy of ultrasonography (US) and unenhanced magnetic resonance imaging (MRI) to determine the location of the internal maxillary artery (IMA) before orthognathic surgery. The study subjects were 19 patients (seven males and twelve females) with mandibular prognathism seen at the authors' institution between March 2012 and April 2013. The distance from the skin to the IMA (S-IMA) and the distance from the mandibular notch to the IMA (MN-IMA) were measured. Using the US and coronal MRI images, S-IMA(cl) and MN-IMA(cl) in the closed position and S-IMA(op) and MN-IMA(op) in the open position were measured at a total of four points in each cross-section. There were significant correlations between the distances measured on coronal MRI and US for all groups (P0.05). A total of 35 (92%) IMAs were classified as clear and three (8%) as unclear based on the US findings. Regarding the location of the IMA, 37 of the 38 sides studied (97%) were of the lateral type, while only one (3%) was of the medial type. The results of this study indicate that US can be used effectively to determine the location of the IMA.

Objective Previous studies have described the clinical statistics and treatment outcomes of leukoplakia of the oral cavity. However, because leukoplakia is often clinically diagnosed without any histopathological examination, current opinion regarding treatment methods and preoperative pathological diagnosis is inconsistent and no standard site-specific treatment guidelines exist for oral leukoplakia. The purpose of this study is to clinically evaluate carbon dioxide (CO 2 ) laser treatment for leukoplakia of the tongue. Methods We examined 38 lesions in 35 patients of lingual leukoplakia who underwent CO 2 laser treatment with using Lugol staining at our department over a 10-year period, i.e., from 2001 to 2010. We investigated gender-related differences, age distribution, left and right differences, clinical classification, histopathological diagnosis (presence or absence of epithelial dysplasia), treatment technique (excision or evaporation), recurrence rate, residual rate, and malignant transformation among these cases. Results Of the 38 lesions that fulfilled the inclusion requirements, 35 were excised and 3 were evaporated. After CO 2 laser treatment, the recurrence and residual rates for lingual leukoplakia were 10.5% and 7.9%, respectively. The recurrence rate of cases examined in this study was lower than that reported by our hospital previously (2004) and many other hospitals. None of the lesions exhibited malignant transformation. Conclusions Our results suggest that the CO 2 laser excision method with using Lugol staining, as performed at our hospital, is useful for the treatment of lingual leukoplakia.

The purpose of this study was to retrospectively evaluate the incidence of distant metastasis (DM) after curative surgical treatment and assess the multivariate relationships among various risk factors for DM in patients with oral squamous cell carcinoma (OSCC).Case series with chart review.Tertiary referral center.The medical records of all patients with OSCC without DM who underwent curative surgery with or without postoperative adjuvant chemoradiation between January 2001 and February 2014 at our institution were retrospectively reviewed. There were a total of 451 patients, including 271 men and 180 women, with a mean age of 65.9 ± 13.5 years.Of these patients, 30 (6.7%) developed DM. During the follow-up period, the 5-year overall survival rate was 76.2%. Sites of DM comprised the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). We found the T classification and N classification as well as the histologic grade to be significant risk factors associated with the development of DM in the univariate analysis only (P = .003), whereas locoregional failure (odds ratio [OR], 4.03), multiple lymph node metastases (more than 4 positive nodes; OR, 3.32) and positive extracapsular spread (OR, 3.06) were identified to be significant risk factors associated with the development of DM in the multivariate analysis.We demonstrated multivariate relationships among various risk factors for DM in OSCC patients. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors.

Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment.

Various chemotherapeutic agents used in patients with hematopoietic malignancy cause serious side effects, including myelosuppression and immunosuppression. Immunosuppression makes patients more susceptible to infection, resulting in an increased risk of infectious complications, including the development of severe septicemia that may be life-threatening. It is necessary for dental staff to be familiar with an appropriate protocol in such cases and to share information about the chemotherapy with a hematologist. To verify the effectiveness of our dental intervention protocol, we conducted a prospective study on the incidence of complications for each myelosuppressive grade of chemotherapy in patients with hematopoietic malignancy. We compared the incidence of complications between treatment P (patients who finished all the dental treatments according to the protocol) and treatment Q (patients who did not) per grade (A, B, C, D) and incidence of systemic or oral findings. We also compared the incidence of oral complication related to the residual teeth between first chemo (patients who were undergoing chemotherapy for the first time) and prior chemo (not the first time). There were significant differences in inflammatory complications between treatment P and treatment Q. We found that both systemic and oral inflammatory complications increased with higher-grade myelosuppressive chemotherapy. Additionally, there was a significant difference between the incidence of oral complications related to the residual teeth between first chemo and prior chemo. Complete implementation of the dental intervention protocol was associated with fewer oral and systemic infectious and inflammatory complications in patients with hematopoietic malignancies undergoing chemotherapy. The incidence of oral and systemic complications also increased with grade of chemotherapy. These results support the validity of our dental intervention protocol. We should pay close attention to the oral state of de novo hematopoietic malignancy patients.

Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis.

Background: This study aimed to evaluate posttreatment soft-tissue changes in patients with oral cancer with computed tomography (CT). To accomplish that purpose, a scoring system was established, referring to the criteria of lower leg lymphedema (LE). Methods and Results: One hundred and six necks in 95 patients who underwent oral oncologic surgery with neck dissection (ND) were analyzed retrospectively using routine follow-up CT images. A two-point scoring system to evaluate soft-tissue changes (so-called “LE score”) was established as follows: Necks with a “honeycombing” appearance were assigned 1 point. Necks with “taller than wide” fat lobules were assigned 1 point. Necks with neither appearance were assigned 0 points. Comparisons between patients with LE score ≥1 and LE score = 0 at 6 months postoperatively were performed using the Fisher exact test for discrete variables and the Mann–Whitney U test for continuous variables. Univariate predictors associated with posttreatment changes (i.e., LE score ≥1 at 6 months postoperatively) were entered into a multivariate logistic regression analysis. Values of p

Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1α in parallel with increased expression of the cleaved forms of caspase-3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC.

Mandibular cortical bone measurement with x-ray imaging is known to be a potentially useful tool in the detection of dimensional changes caused by bisphosphonate. The primary purpose of this study was to assess the meaning and limitation of cortical bone measurement with computed tomography (CT) in patients with medication-related osteonecrosis of the jaw (MRONJ). The investigators obtained DentaScan images of the mandible from 15 patients with MRONJ, 15 patients with a history of antiresorptive agent administration without symptoms of MRONJ (non-MRONJ), and 15 control subjects. The cortical bone width measured on DentaScan images was compared between the three groups (ANOVA and Tukey’s test). Interobserver reliability between two observers was also assessed. The values of interclass correlation coefficient were 0.48 in the MRONJ group, 0.29 in the Non-MRONJ group, and 0.34 in control group. The cortical bone widths calculated both by observer 1 and observer 2 were thicker in patients with MRONJ than in the non-MRONJ group and controls. There were significant differences in cortical bone width among the MRONJ, non-MRONJ, and control groups in observer 1 (P < 0.001) and observer 2 (P < 0.001), specifically comparing the MRONJ group with the non-MRONJ group and the control group. Cortical bone width measurement is useful for the distinction between medication-related osteonecrosis of the jaw and normal bone, in spite of the low interobserver reliability.

The purpose of this study was to retrospectively investigate the multivariate relationships between specific risk factors and postoperative hemorrhage after tooth extraction in patients who were prescribed oral antithrombotic therapy. Risk factors for postoperative hemorrhage after tooth extraction were evaluated using univariate and multivariate analyses. Patient characteristics such as age and gender; the presence or absence of known comorbidities such as diabetes mellitus, hypertension, cerebral infarction, and alcohol consumption; and perioperative diarrhea were assessed. The drug used for antithrombotic therapy, preoperative blood test results, the presence or absence of preoperative antibiotics or nonsteroidal anti-inflammatory drug (NSAID) administration, the total number of extracted teeth, and the type of surgical procedures were also evaluated. We found that the preoperative administration of antibiotics (odds ratio (OR) = 2.52), an increased prothrombin time international normalized ratio (PT-INR) value (OR = 1.94), and the extraction of multiple teeth (OR = 2.10) were significantly associated with postoperative hemorrhage. There was no significant association between postoperative hemorrhage and any other demographic factors or comorbidities, including concomitant alcohol use. We demonstrated the multivariate relationship between the risk factors and postoperative hemorrhage after tooth extraction in patients receiving oral antithrombotic therapy. Surgeons should be aware of these risks and monitor the PT-INR of anticoagulated patients.