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A glandular odontogenic cyst (GOC), a rare type of cyst occurring in the jawbone, comprises about 0.2 % of all odontogenic cyst cases. Recurrence is likely, thus long-term follow-up examinations are necessary. The present patient was a 24-year-old Japanese female with a multilocular GOC that was extirpated following marsupialization. Two years after the initial extirpation, the GOC recurred and re-extirpation was performed, with no recurrence noted at two years after the second procedure. Although extirpation of a GOC after marsupialization can cause recurrence, it allows for preservation of teeth in the area of the lesion and maintenance of occlusion. The present case report includes a comparison of reports of GOC in Japan with those reported in other countries.

Background/Aim: Idiopathic condylar resorption (ICR) is a morphological change of the condylar head that occurs following orthodontic treatment or orthognathic surgery. This complication is serious, as it can cause relapse after mandible treatment. The aim of this experimental study was to evaluate the mechanism of influence of condylar resorption on compressive mechanical stress in temporomandibular joint following a change in occlusal position by mandible advancement. Materials and Methods: An osteotomy procedure at the midline of mandible was performed in 15 rabbits, with the left side moved forward by 3.5 mm. Advancement of the left side of the mandible resulted in compressive mechanical stress on condylar head on the left side. Samples were subjected to micro-computed tomography, histological staining and immunohistochemistry. Results: The area and depth of anterior condylar resorption at two weeks were significantly different as compared to those at one week (p

To characterize concentrated growth factors (CGFs) in vivo, we examined the degradation of implanted CGF in rabbits. Untreated CGF (U-CGF) and compressed CGF (C-CGF) were subcutaneously implanted into the dorsum. Histological analyses showed that the U-CGF and C-CGF induced very few inflammatory cells and that the U-CGF and C-CGF were subsequently degraded with dendritic invasion of granulation tissue. The C-CGF histopathologically remained for longer term than the U-CGF. Aggregated CD31+ and RAM11+ cells appeared in and around the implanted CGF. The number of macrophages and blood vessels in the CGF-implanted groups was greater than that in the sham group. There were more blood vessels in the U-CGF group than that in the C-CGF and sham group. We showed that CGF was degraded by macrophages in 4 weeks and enhanced angiogenesis with dendritically branching new capillaries. Therefore, the U-CGF and C-CGF can be clinically applied as a biomaterial inducing angiogenesis.

Cemento-ossifying fibroma (COF) is a clinicopatological variant of ossifying fibroma which is benign fibro-osseous neoplasm affecting jaw or cranial skeletons. It is also called central ossifying fibroma. COF is a slow-growing tumor and occurs exclusively in the tooth bearing areas of the jaws. This tumor particularly affects adult female and rarely occurs in children. Here we show a rare case of COF involving the anterior mandible in an 8-year-old girl. She was referred to our department with painless and hard swelling of the mandibular symphysis. Computed tomography (CT) showed that well circumscribed and mainly radiodense lesion with radiolucent areas expanded the inferior border of the mandible. The size of this lesion is 35 × 30 × 24 mm. Pathological diagnosis was COF. She had underwent two times of surgery for tumor enucleation through an intraoral approach, and after that, we removed bilateral central incisors with residual tumor around the roots. There has been no sign of recurrence 1 years after the last surgery. We have continued follow-up observation.

Spindle cell lipoma is a rare variety of lipoma that usually appears in subcutaneous tissue, for example, the posterior neck, shoulders, and back region, in middle-aged and older males. We reported a rare case of spindle cell lipoma of the floor of mouth. A 68-year-old man had a painless swelling of the floor of mouth. Clinical and image examination revealed that the mass was encapsulated, well-circumscribed, smooth-surfaced, and soft. Inside of the lesion was the same signal as adipose tissue, and the mass showed high signals at T1 and T2 weighted sequence in magnetic resonance imaging. However, the internal properties were non-uniform, and the vascular pattern was observed. Therefore, biopsy was performed before removal operation, and the mass was diagnosed as no malignancy. The encapsulated yellow mass was removed under general anesthesia. The histopathology showed that the well-demarcated mass was composed of mature adipocytes and spindle cells with bundles of collagen fibers. The size of mature adipocytes was uniform, and nuclear atypia was not observed. In immunohistochemical staining, the adipocytes were positive to S-100, and the spindle cells showed positive for CD34 and bcl-2 but S-100 negative. Based on the pathological features, the diagnosis was spindle cell lipoma. Differentiation of spindle cell lipoma includes solitary fibrous tumors, neurofibromas, subcutaneous fibrous malignancies, and well differentiated lipomas. S-100, CD34, and bcl-2 was able to differentiate these tumors and was very useful for the diagnosis of spindle cell lipoma. There were no signs of recurrence after 1-year follow up since the operation.

Regulatory T cells (Tregs) and tumour-associated macrophages (TAMs) contribute to the tumour microenvironment by inhibiting anti-tumour immune responses. This study was performed to investigate the roles of Tregs and TAMs in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPL). The expression of Treg markers CD25 and FoxP3 and TAM markers CD163 and CD204 was investigated in 82 OSCC and 45 OEPL specimens, and their associations with clinicopathological parameters were analyzed. Correlations were found among CD25, FoxP3, CD163, and CD204 levels (P 0.001), and these targets were up-regulated in OSCC compared to OEPL (P 0.001). In OSCC, infiltration of Tregs and/or M2 TAMs was associated with sex and clinicopathological features, such as tumour size, nodal metastasis, tissue differentiation, stromal reaction, invasive behaviour, and invasive depth. In OEPL, CD25, FoxP3, CD163, and CD204 immunoreactivities were significantly associated with sex, postoperative recurrence, and cancerization to OSCC. This study is novel in showing that the infiltration of Tregs and M2 TAMs is significantly associated with the progression of premalignant lesions to OSCC. This suggests that these cells represent prognostic biomarkers for premalignant lesion progression and that immunotherapeutic approaches to control Treg/M2 TAM numbers could protect against progression to malignancy.

Several growth factors and their receptors, such as epidermal growth factor receptor, have been studied as prognostic biomarkers for many epithelial malignancies. The signal transduction cascade of those receptors includes RAS/RAF/ERK, PI3K/Akt/mTOR, and STAT3 pathways. The aim of this study was to investigate the expression levels of several key proteins of those pathways in patients with oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), and to correlate the expressions of these proteins with clinicopathologic features and prognosis. Fifteen leukoplakia (LP), 15 low-grade epithelial dysplasia, 15 high-grade epithelial dysplasia (HD), and 132 OSCC specimens were immunohistochemically examined for KRAS, HRAS, NRAS, BRAF, pERK1/2, pAkt, pmTOR, and pSTAT3 expression. Immunoreactivity for these molecules predominantly occurred in regions OEPL basal to prickle layers and in most OSCC cells. KRAS and NRAS expression was significantly lower in OSCC than in OEPLs, while pAkt and pmTOR showed higher expression in OSCC than in OEPLs. pERK1/2 expression was significantly higher in HD than in LP. In OSCC, KRAS and NRAS immunoreactivity was significantly higher in advanced age and male gender. In addition, higher immunoreactivity was shown in pERK1/2 in female gender and advanced TNM stage, pAkt in advanced T classification and cases without postoperative metastasis, pmTOR in advanced mode of invasion, and pSTAT3 in invasion depth. Correlations between these markers and clinicopathological variables were also noted. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis.

This study was designed to examine osteoconductive effects of Mg in rats tibia. The animals were sacrificed after 1, 2, and 8 weeks. The elemental analysis was performed using SEM/EDX at week 1. Following X-ray micrography at weeks 2 and 8, samples were embedded in paraffin. The expression of osteocalcin was observed by immunohistochemical staining. The element concentrations of fibrous capsules around the specimens were also measured by ICP-MS. The concentrations of Ca and P on the surface of the Mg specimen increased in SEM/EDX. The tissue specimen showed new bone formation on the bone surface near the implanted area. The concentrations of Mg, Ca, and P were high in the fibrous capsules surrounding Mg. Implantation induced differentiation of osteoblasts, and this process was considered to be associated with new bone formation. Induction of cell differentiation may be influenced by corrosion products in addition to corroding magnesium.

Objectives To evaluate the ability of different imaging modalities to accurately detect bone invasion in oral squamous cell carcinomas. Patients and Methods Patients with oral squamous cell carcinoma, who were scheduled for mandibulectomy or maxillectomy, underwent clinical evaluation using five preoperative imaging diagnosis methods—contrast-enhanced MRI, CT, 99mTc scintigraphy (Tc scan), FDG-PET CT (PET/CT), and panoramic radiography. The sensitivity and specificity of each modality in detecting bone invasion were calculated by comparing the findings on the images with postoperative histopathological findings. In a subgroup of patients, we further assessed the ability of MRI and CT to detect the accurate extent of bone invasion, including the height, width, and depth in patients with pathological mandibular invasion. Results Overall, 50 patients were enrolled in this study, and nine patients with pathological mandibular invasion were included in our subgroup analysis. MRI was found to be the most useful method in detecting bone invasion, showing the highest sensitivity (88.9%) and negative predictive values (92.3%). CT (87.5% specificity and 77.8% sensitivity) was more specific than MRI, though less sensitive. Combined PET/CT was more sensitive (83.3%) and less specific (71.9%) than CT. Tc scan had high sensitivity (88.9%); however, the specificity was relatively low (71.9%). Conclusion MRI was the most useful method in detecting bone invasion. A negative MRI result definitively excludes bone marrow invasion. In patients with positive MRI findings, a negative CT may be useful in ruling out bone marrow invasion.

This study was conducted in order to investigate biological compatibility of a thin and flexible hydroxyapatite (HAP) paper which consists of ultralong hydroxyapatite nanowires. Circular-shaped cranial bone defects with a diameter of 8.8 mm were prepared to expose the dura maters in Wistar rats. The similar-sized, circular-shaped HAP paper was placed at the bottom of the bone defects. After 2, 4, and 8 weeks, the rats were sacrificed, and the experimental sections were examined by micro-CT scanning and histological observation. The HAP paper covered with fibrous tissues showed no inflammatory cell infiltration, and their thicknesses decreased over time. Tartrate-resistant acid phosphatase-positive osteoclast-like cells were induced around the edges of the HAP paper along with the exfoliation of the HAP paper. The newly-formed bones were observed in the bone-defected areas, either with a direct contact with the HAP paper or through thin fibrous tissues. The HAP paper-induced osteoblast differentiation was confirmed since the alkaline phosphatase activities were detected on the surfaces of the HAP paper. These results indicated that the HAP paper may induce osteogenesis without causing any harmful effects. The highly flexible HAP paper can contribute to further development of bone regenerative therapy.

Cyclin D1 is the most essential progressive regulator of the cell cycle, and its transcription is enhanced by CREPT (cell cycle-related and expression-elevated protein in tumour). These molecules regulate cell growth, and their aberrant expression can cause malignant transformation. In this study, the expression of these molecules was explored to investigate the molecular alterations in oral precancerous lesions and squamous cell carcinoma. Cyclin D1 and CREPT expression was examined immunohistochemically in tissue specimens from 55 patients with oral epithelial precursor lesions (OEPLs) and 84 patients with oral squamous cell carcinoma (OSCC). Associations between the results and clinicopathological variables were examined. Cyclin D1 and CREPT expression levels were higher in OSCC than in OEPLs. Furthermore, there were statistically significant differences in cyclin D1 expression among the different grades of OEPLs and OSCC lesions. In OSCC, there were statistically significant differences in CREPT expression according to sex, T stage, and degree of differentiation. In addition, the expression of both molecules was significantly correlated with postoperative metastasis and modes of invasion. The expression of cyclin D1 and CREPT was found to depend upon the state of development and progression of the oral epithelial lesions, and clinicopathological behaviours might be affected by these molecules in OSCC.

The present study was designed to investigate the biodegradation behavior of Mg alloy plates in the maxillofacial region. For in vitro analysis, the plates were immersed in saline solution and simulated body fluid. For in vivo, the plates were implanted into the tibia, head, back, abdominal cavity, and femur and assessed at 1, 2, and 4 weeks after implantation. After implantation, the plate volumes and the formed insoluble salt were measured via micro-computed tomography. SEM/EDX analysis of the insoluble salt and histological analysis of the surrounding tissues were performed. The volume loss of plates in the in vitro groups was higher than that in the in vivo groups. The volume loss was fastest in the abdomen, followed by the head, back, tibia, and femur. There were no statistically significant differences in the insoluble salt volume of the all implanted sites. The corrosion of the Mg alloy will be affected to the surrounding tissue responses. The material for the plate should be selected based on the characteristic that Mg alloys are decomposed relatively easily in the maxillofacial region.

An association of the programmed cell death-1 (PD-1) and its ligand PD-L1 with various types of malignant tumors has been established. This study aimed to investigate the role of the PD-L1/PD-1 pathway in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPL).We examined 106 OSCC and 79 OEPL specimens for PD-L1 and PD-1 expression by immunohistochemistry. The results were compared with clinicopathological features of OSCC patients.In OSCC and OEPL specimens, PD-L1 expression was detected predominantly in epithelial or carcinoma cells, whereas PD-1 expression was found mainly in infiltrating or stromal lymphocytes. Seventy-two OSCC (67.9%) and 21 OEPL (26.6%) specimens were positive for PD-L1, and 73 OSCC (68.9%) and 23 OEPL (29.2%) specimens were positive for PD-1. PD-L1 and PD-1 expression levels were significantly different between OEPL and OSCC specimens (P 0.001). There were significant positive correlations between PD-L1 and PD-1 expression in OEPL and OSCC specimens (P 0.001). PD-L1 and PD-1 immunoreactivity was significantly associated with tumor size (P 0.05). PD-L1 and PD-1 immunoreactivity in cases with advanced TNM staging was significantly higher than that in low staging cases (P 0.01). There were significant correlations between PD-L1 and PD-1 expression in OSCC specimens and pathological variables such as stromal lymphocytic reaction (P 0.05) and invasion depth (P 0.01).PD-L1 and PD-1 immunohistochemical status may be related to carcinogenesis, tumor progression, and prognosis in oral epithelial lesions. Agents targeting PD-1 and PD-L1 might be useful for OSCC treatment.

Objective We assessed the aetiology of idiopathic condylar resorption by examining the effects of oestrogen and compressive mechanical stress under a low systemic oestrogen condition in temporomandibular joints (TMJ) caused by an ovariectomy. Materials and methods Female rabbits were divided into non-ovariectomy (non-OVX) and ovariectomy (OVX) groups. A cortical osteotomy was performed with a custom device that was increased in length by 0.25 mm every 12 hr for 1 week after the operation, during which the TMJs in the rabbits received compressive mechanical stress. Samples from both groups were examined with micro-computed tomography and histological staining. Results Area and depth of bone resorption were both greater in the OVX group. Furthermore, a significantly earlier and greater prevalence of sub-condylar bone resorption was noted in that group, while cells positive for tartrate-resistant acid phosphatase were increased in the OVX group. Conclusions The present findings suggest that oestrogen induced a much greater amount of bone resorption on the anterior surface of the condylar head at an earlier stage in the TMJs of the present model rabbits. Thereafter, restoration of TMJ function appeared to occur in a normal manner.

Objective To investigate roles of hypoxia-related proteins in odontogenic tumors, we analyzed the immunohistochemical expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase IX (CA IX) and compared with angiogenesis. Methods 10 dental follicles and 67 ameloblastomas were immunohistochemically examined with antibodies against HIF-1α, CA IX, and CD34. Results Immunohistochemical reactivity for HIF-1α and CA IX was detected in odontogenic epithelial cells, as well as in several macrophages and fibroblasts, in dental follicles and ameloblastomas. HIF-1α was positive in 8 of 10 dental follicles, 45 of 48 primary ameloblastomas, and all 19 recurrent ameloblastomas. Increased HIF-1α reactivity was often found in keratinizing cells in acanthomatous ameloblastomas. Immunoreactivity for CA IX was detected in all samples of dental follicles and primary and recurrent ameloblastomas. CA IX reactivity was significantly higher in ameloblastomas than in dental follicles, in solid ameloblastomas than in unicystic ameloblastomas, and in follicular ameloblastomas than in plexiform ameloblastomas. Acanthomatous ameloblastomas showed increased CA IX reactivity around keratinizing areas, while granular cell ameloblastomas showed increased reactivity in peripheral non-granular cells. Microvessel density (MVD) of CD34-positive capillaries in solid ameloblastomas was significantly higher than in unicystic ameloblastomas. MVD tended to be greater in follicular ameloblastomas than in plexiform ameloblastomas, in granular cell ameloblastomas than in other subtypes of ameloblastomas, and in mural unicystic ameloblastomas than in other types of unicystic ameloblastomas. Conclusions Our data suggest that hypoxia-related molecules and angiogenesis play a role in tumorigenesis, tissue structuring, cell differentiation, and prognosis of ameloblastomas in the intraosseous microenvironment.

Actinomycosis, a rare chronic granulomatous bacterial infection induced by Actinomyces species, colonizes the mouth, colon, and vagina. Although Actinomyces spp. are well-known oral commensals, actinomycosis is a rare oral infection. It is difficult to detect Actinomyces in biopsies, using histopathologic methods, or through examination of bacterial cultures; therefore, providing an accurate diagnosis is problematic. Recently, oral brush scraping cytology has been performed for the diagnosis of premalignant and malignant lesions, but it is difficult to determine the efficacy of this method based on the published reports, and whether it is a suitable tool for detecting Actinomyces infections in the general public. Here, we report a rare case of actinomycosis of the buccal mucosa in an 8-year-old boy that was successfully diagnosed by scraping cytology. He exhibited pain and swelling in the left buccal, and was admitted to our hospital for emergency care. Clinical examination revealed pyrexia, tachycardia, trismus, ingestion disorder, lethargy, and ulcer as well as having an indurated mass in the left buccal mucosa accompanied by strong pain. Following a clinical diagnosis of acute phlegmon of the left buccal mucosa, antibiotic and fluid therapy was performed. Because of detection of Actinomyces colonies at the ulcer surface using scraping cytology, we continued to administer long-term antibiotic therapy with penicillin for 2 months. The patient’s general condition was improved, and this was confirmed by laboratory results, and the trismus and painful nodular mass were successfully cured. The patient has shown no subsequent evidence of recurrence for 7 months of following treatment.

Objective We experimentally compared the effects of compressive and tractional mechanical stress on the temporomandibular joint (TMJ) of rabbits to assess the etiology of progressive condylar resorption. Materials and methods We performed a cortical osteotomy using custom-made devices that were lengthened by 0.25 mm every 12 h for 1 week after surgery. During this time, the rabbit TMJ was under compressive or tractional mechanical stress. The samples in each group were examined using micro-computed tomography and histological staining. Results Scores for the area of bone resorption were higher in the compressive group than in the tractional group. Moreover, scores for the depth of bone resorption were higher in the compressive group than those in the tractional group. We observed a significantly higher prevalence of resorption in the subcondylar bone in the compressive group than in the tractional group. There were substantially more cells that were positive for tartrate-resistant acid phosphatase in the compressive group than in the control and tractional groups. Conclusions The outcomes here suggest that excessive mechanical stress, particularly compressive mechanical stress, may significantly affect morphological bone change findings in the TMJ.

A simple bone cyst (SBC) is an intrabone cavity without epithelial lining, which occasionally occur with fibrous-osseous lesions. The imaging finding of the scalloped border and conserving the lamina dura, periodontal ligament spaces, or follicular spaces are considered radiographically pathognomonic of SBC. SBC has been reported to occur with fibrous-osseous lesions, including cemento-osseous dysplasia (COD). Computed tomography (CT) imaging findings are sparse, and there are no reports of magnetic resonance imaging (MRI) findings, including apparent diffusion coefficient (ADC) value calculated by diffusion-weighted MRI for the florid COD-associated SBC. We report a case of a 39-year-old woman who was referred to our hospital because a panoramic radiograph of her right mandible showed asymptomatic radiolucency in the apical molar area. CT images showed a low-density lesion in the periapical areas of the right mandible, which accompanied a well-defined, high-density lesion, and a mixed low/high-density lesion with an unusual marked irregular border in the left mandible. The MRI showed cyst-like extremely hyperintense signals on fat-suppressed T2-weighted images at the right mandibular low-density and the left mandibular mixed low/high-density areas. ADC map showed high values (over 2.5×10−3 mm2/s) at the cystic areas in the bilateral mandible. We performed incisional biopsies of the bilateral mandibular lesions and resections of the bilateral maxillary lesions. Surgical and histopathological findings established a diagnosis of florid COD in the bilateral mandible and maxilla, simultaneously complicated by multiple SBCs in the bilateral mandible. The ADC value of cystic component is useful for the diagnosis, if the COD-associated SBC exhibits solitary, nonspecific, or rare imaging findings.

Background Carcinogenesis occurs when the cell cycle is compromised. Chromatin licensing and DNA replication factor 1, geminin, and γ-H2A histone family member X are expressed in cells in G1 phase, S/G2 /M phases, and apoptosis, respectively, and these three markers may be useful for histological evaluation of malignant lesions. Here, we aimed to identify cell cycle phases and apoptosis using immunohistochemistry in oral epithelial precursor lesions and oral squamous cell carcinoma. Methods Chromatin licensing and DNA replication factor 1, geminin, and γ-H2A histone family member X expression levels were immunohistochemically examined in tissue specimens from 55 patients with oral epithelial precursor lesions and 50 patients with oral squamous cell carcinoma. Associations of clinicopathological variables with marker expression were assessed. Results Chromatin licensing and DNA replication factor 1 was expressed in the prickle cell layer of oral epithelial precursor lesions and many carcinoma cells of oral squamous cell carcinoma. Geminin reactivity was widely distributed in high-grade dysplasia and oral squamous cell carcinoma rather than low-grade or no dysplastic cases. γ-H2A histone family member X was expressed in the superficial layer of oral epithelial precursor lesions and scattered carcinoma cells of oral squamous cell carcinoma. In oral squamous cell carcinoma, lower geminin expression was observed in recurrent cases. Geminin and γ-H2A histone family member X were associated with the degree of differentiation and mode of invasion. Conclusion Chromatin licensing and DNA replication factor 1, geminin, and γ-H2A histone family member X expression levels were correlated with oral carcinogenesis; these markers were associated with clinicopathological behaviors in oral squamous cell carcinoma.

The aim of this study was to investigate and compare the surface characteristics and initial bioactivity of ceria-stabilized zirconia/alumina nanocomposite (NANOZR) with those of yttria-stabilized zirconia (3Y-TZP) and pure titanium (CpTi) following the use of three surface modification methods; polishing, sandblasting/acid-etching (SB-E) and electrochemical deoxidation (ECD). Physical properties including surface morphology, chemical composition, X-ray diffraction, surface wettability, surface roughness, and hardness were measured. Osteoblast-like MC3T3-E1 cells were used to examine cell morphology and attachment to the surfaces of the materials. ECD treated NANOZR (NANOZR-E) showed a well-arranged, self-organized microporous surface structure with significantly low contact angles when compared with the other specimens (p

Objectives To study the role of epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma (OSCC), protein expression, gene amplification, and mutations were analyzed in OSCC as well as leukoplakia. Immunoreactivity of Ki-67 and K- Ras gene mutations were simultaneously evaluated. Material and methods Eighty-two OSCC and 10 leukoplakia specimens were immunohistochemically examined with antibodies against EGFR and Ki-67. Amplification of EGFR was evaluated by chromogenic in situ hybridization (CISH). In 14 OSCC samples, EGFR exons 19, 21 and K- Ras exon 2 were analyzed by direct DNA sequencing. Results Immunohistochemical reactivity for EGFR and Ki-67 was detected in epithelial cells of leukoplakia and in carcinoma cells of OSCC. EGFR and Ki-67 immunoreactivity was significantly higher in OSCC than in leukoplakia. Leukoplakia showed no EGFR amplification, whereas OSCC exhibited low-level amplification in 19 cases and high-level amplification in 3 cases, respectively. OSCC cases with EGFR amplification showed slightly higher EGFR and Ki-67 immunoreactivity than those without amplification. In OSCC, EGFR immunoreactivity significantly correlated with the mode of invasion, invasion depth, as well as EGFR amplification significantly correlated with the degree of differentiation, mode of invasion, recurrence, and postoperative metastasis. Direct DNA sequencing of EGFR and K- Ras did not show any gene alterations in OSCC. Conclusion EGFR aberrations might contribute to carcinogenesis, invasion, metastasis as well as poor outcomes in OSCC. EGFR-targeting therapy with anti-EGFR monoclonal antibody agents may be beneficial in OSCC patients.

To evaluate erythropoietin-producing hepatocellular carcinoma (Eph)/Eph receptor-interaction protein (ephrin) expression in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), EphA2, EphB4, and ephrinB2 were examined and compared with microvessel density (MVD) and lymphatic vessel density (LVD). Samples from 73 OSCC and 43 OEPLs patients were immunohistochemically analyzed with antibodies against EphA2, EphB4, ephrinB2, CD34, and D2-40. Results were compared with clinicopathological findings. Immunohistochemical reactivity for EphA2, EphB4, and ephrinB2 was detected in epithelial cells and some stromal vascular cells in OEPLs and OSCC, proportionately with the level of malignancy. The number of blood vessel endothelial cells stained with CD34 and lymphatic vessel endothelial cells stained with D2-40 was increased in OEPLs and OSCC. In OSCC, ephrinB2 and EphB4 exhibited significant correlation with recurrence and invasion depth, respectively. MVD was significantly lower in slight lymphocytic reaction than in prominent stromal reaction. Association was found between LVD and T classification, postoperative metastasis, survival, mode of invasion, and invasion depth. Expression of EphA2, EphB4, ephrinB2, MVD, and LVD might be associated with malignant potential of the oral epithelium. Angiogenesis and lymphangiogenesis appear to be related to progression of potentially malignant oral lesions.

The present study was designed to investigate the biodegradation behavior of Mg alloy plates in the maxillofacial region. For in vitro analysis, the plates were immersed in saline solution and simulated body fluid. For in vivo, the plates were implanted into the tibia, head, back, abdominal cavity, and femur and assessed at 1, 2, and 4 weeks after implantation. After implantation, the plate volumes and the formed insoluble salt were measured via micro-computed tomography. SEM/EDX analysis of the insoluble salt and histological analysis of the surrounding tissues were performed. The volume loss of plates in the in vitro groups was higher than that in the in vivo groups. The volume loss was fastest in the abdomen, followed by the head, back, tibia, and femur. There were no statistically significant differences in the insoluble salt volume of the all implanted sites. The corrosion of the Mg alloy will be affected to the surrounding tissue responses. The material for the plate should be selected based on the characteristic that Mg alloys are decomposed relatively easily in the maxillofacial region.

A clear cell variant of calcifying epithelial odontogenic tumor (CCEOT) affecting an extraosseous site is described. A 60-year-old male patient presented with gingival swelling on the lingual side of the anterior mandible. The results of biopsy suggested clear cell odontogenic carcinoma, and marginal resection of the mandible was performed. The resected specimen was composed of eosinophilic and clear cells with deposits of amyloid-like material. The clear cells exhibited granules that were positive for PAS. There was no calcification in the resected lesion. Based on these features, the conclusive diagnosis was peripheral CCEOT without calcification. No signs of recurrence were evident after 3 years of follow-up.

The number of people afflicted with oral carcinoma in Japan has increased in recent years. Although preoperative neoadjuvant therapy with cisplatin and 5-fluorouracil are performed, chemotherapeutic response varies widely among the patients. With the aim of establishing novel indices to predict the therapeutic response to chemotherapy, we investigated the relationship between morphological features of pre-treatment oral carcinoma nuclei and the chemotherapeutic response using quantifying morphology of cell nuclei in pathological specimen images. We measured 4 morphological features of the nucleus of oral squamous cell carcinoma cases classified by the response to chemotherapy: No Change (NC) group, Partial Response (PR) group and Complete Response (CR) group. Furthermore, we performed immunohistochemical staining for p53 and Ki67 and calculated their positive rates in cancer tissues. Compactness and symmetry of the nucleus were significantly higher and nuclear edge response was significantly lower in cancer cells with lower chemotherapeutic responses compared high chemotherapeutic responders. As for positive rates of p53 and Ki67, there were no significant differences between any of the response groups. Morphological features of cancer cell nuclei in pathological specimens are sensitive predictive factors for the chemotherapeutic response to oral squamous cell carcinoma.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. AhR signaling has also been proposed to mediate osteogenesis in experimental animals, but its details have remained unclear. Therefore, in this study, we examined the possible roles of AhR in human bone. Immunohistochemical analysis revealed that AhR was detected in both osteoblasts and osteoclasts. We then screened AhR-target genes using a microarray analysis in human osteoblastic hFOB cells. Results of microarray and subsequent PCR analysis did reveal that estrogen metabolizing and synthesizing enzymes, such as CYP1B1 and aromatase, were increased by 3-MC in hFOB and osteosarcoma cell line, MG-63. The subsequent antibody cytokine analysis also demonstrated that interleukin-1β and -6 expression was increased by 3-MC and β-NF in hFOB cells and these interleukins were well known to induce aromatase. We then examined the cell proliferation rate of hFOB and MG-63 cells co-treated with 3-MC and testosterone as an aromatase substrate. The status of cell proliferation in both hFOB and MG-63 cells was stimulated by 3-MC and testosterone treatment, which was also inhibited by an estrogen blocker, aromatase inhibitor, or AhR antagonist. These findings indicated that AhR could regulate estrogen synthesis and metabolism in bone tissues through cytokine/aromatase signaling.

Recent studies suggest that histamine-a regulator of the microcirculation-may play important roles in exercise. We have shown that the histamine-forming enzyme histidine decarboxylase (HDC) is induced in skeletal muscles by prolonged muscular work (PMW). However, histological analysis of such HDC induction is lacking due to appropriate anti-HDC antibodies being unavailable. We also showed that the inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α can induce HDC, and that PMW increases both IL-1α and IL-1β in skeletal muscles. Here, we examined the effects (a) of PMW on the histological evidence of HDC induction and (b) of IL-1β and TNF-α on HDC activity in skeletal muscles. By immunostaining using a recently introduced commercial polyclonal anti-HDC antibody, we found that cells in the endomysium and around blood vessels, and also some muscle fibers themselves, became HDC-positive after PMW. After PMW, TNF-α, but not IL-1α or IL-1β, was detected in the blood serum. The minimum intravenous dose of IL-1β that would induce HDC activity was about 1/10 that of TNF-α, while in combination they synergistically augmented HDC activity. These results suggest that PMW induces HDC in skeletal muscles, including cells in the endomysium and around blood vessels, and also some muscle fibers themselves, and that IL-1β and TNF-α may cooperatively mediate this induction.

Bisphosphonates (BPs), with a non-hydrolysable P-C-P structure, are cytotoxic analogues of pyrophosphate, bind strongly to bone, are taken into osteoclasts during bone-resorption and exhibit long-acting anti-bone-resorptive effects. Among the BPs, nitrogen-containing BPs (N-BPs) have far stronger anti-bone-resorptive effects than non-N-BPs. In addition to their pyrogenic and digestive-organ-injuring side effects, BP-related osteonecrosis of jaws (BRONJ), mostly caused by N-BPs, has been a serious concern since 2003. The mechanism underlying BRONJ has proved difficult to unravel, and there are no solid strategies for treating and/or preventing BRONJ. Our mouse experiments have yielded the following results. (a) N-BPs, but not non-N-BPs, exhibit direct inflammatory and/or necrotic effects on soft tissues. (b) These effects are augmented by lipopolysaccharide, a bacterial-cell-wall component. (c) N-BPs are transported into cells via phosphate transporters. (d) The non-N-BPs etidronate (Eti) and clodronate (Clo) competitively inhibit this transportation (potencies, Clo>Eti) and reduce and/or prevent the N-BP-induced inflammation and/or necrosis. (e) Eti, but not Clo, can expel N-BPs that have accumulated within bones. (f) Eti and Clo each have an analgesic effect (potencies, Clo>Eti) via inhibition of phosphate transporters involved in pain transmission. From these findings, we propose that phosphate-transporter-mediated and inflammation/infection-promoted mechanisms underlie BRONJ. To treat and/or prevent BRONJ, we propose (i) Eti as a substitution drug for N-BPs and (ii) Clo as a combination drug with N-BPs while retaining their anti-bone-resorptive effects. Our clinical trials support this role for Eti (we cannot perform such trials using Clo because Clo is not clinically approved in Japan).

Standard fractionated radiotherapy for the treatment of cancer consists of daily irradiation of 2-Gy X-rays, 5 days a week for 5–8 weeks. To understand the characteristics of radioresistant cancer cells and to develop more effective radiotherapy, we established a series of novel, clinically relevant radioresistant (CRR) cells that continue to proliferate with 2-Gy X-ray exposure every 24 h for more than 30 days in vitro. We studied three human and one murine cell line, and their CRR derivatives. Guanine nucleotide-binding protein 1 (GBP1) gene expression was higher in all CRR cells than their corresponding parental cells. GBP1 knockdown by siRNA cancelled radioresistance of CRR cells in vitro and in xenotransplanted tumor tissues in nude mice. The clinical relevance of GBP1 was immunohistochemically assessed in 45 cases of head and neck cancer tissues. Patients with GBP1-positive cancer tended to show poorer response to radiotherapy. We recently reported that low dose long-term fractionated radiation concentrates cancer stem cells (CSCs). Immunofluorescence staining of GBP1 was stronger in CRR cells than in corresponding parental cells. The frequency of Oct4-positive CSCs was higher in CRR cells than in parental cells, however, was not as common as GBP1-positive cells. GBP1-positive cells were radioresistant, but radioresistant cells were not necessarily CSCs. We concluded that GBP1 overexpression is necessary for the radioresistant phenotype in CRR cells, and that targeting GBP1-positive cancer cells is a more efficient method in conquering cancer than targeting CSCs.