Daichi Chikazu

A simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed tomography

OBJECTIVES The aim of this study was to establish a simple method for the early detection of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using computed tomography (CT). MATERIALS AND METHODS CT images of the mandible were obtained from a total of 20 patients with BRONJ and 20 control subjects. BRONJ was classified into 2 groups, with bone exposure (Stage 1-3 BRONJ) or without (Stage 0 BRONJ). In each patient, 15 transaxial CT images were selected and 30 configured regions of interest (ROI) were identified. The ANOVA test was applied to test the relationship between the severity of systemic risk factors. RESULTS Regarding the local status of the mandible, significant differences were observed among the Stage 0 BRONJ, Stage 1-3 BRONJ, non-BRONJ and control groups in the cancellous bone CT radiodensity values, but there were no significant differences between the Stage 0 and Stage 1-3 BRONJ groups. In the cortical bone widths, significant differences were observed only between BRONJ and the controls. CONCLUSIONS Measuring cancellous bone CT radiodensity value has the potential to be a simple and quantitative method to detect the early stages of BRONJ.

Cyclo-Oxygenase–2 Expression Is Associated With Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis in Oral Squamous Cell Carcinoma

PURPOSE Cervical lymph node metastasis in oral squamous cell carcinoma (OSCC) is recognized as a poor prognostic factor, although its mechanism remains unclear. Recently, cyclo-oxygenase-2 (COX-2) level has been found to correlate highly with vascular endothelial growth factor C (VEGF-C) and lymph node metastasis, as in other solid tumors. However, there has been no report of this correlation in OSCC. Therefore, the aim of this study was to investigate whether COX-2 immunohistochemical expression in OSCC was associated with VEGF-C expression, histopathologic parameters, and lymph node metastasis. MATERIALS AND METHODS Lymphatic vessel density, VEGF-C, and COX-2 immunohistochemical expression were examined pathologically in 60 specimens of invasive OSCC. Relations of histopathologic parameters to lymph node metastasis were analyzed. RESULTS Expression levels of VEGF-C and COX-2 and lymphatic vessel density in the lymph node metastatic group were significantly higher than in the nonmetastatic group (P < .01). A significant correlation was found between the expression levels of VEGF-C and COX-2 (r = 0.512; P < .001). COX-2 expression was significantly related to lymph node metastasis (P = .004) and VEGF-C expression (P = .005). Univariate analysis showed that survival time was impaired by higher COX-2 and VEGF-C expression levels. Multivariate survival analysis showed that COX-2 expression was an independent prognostic factor. CONCLUSION This study showed that VEGF-C expression was upregulated by COX-2 in OSCC. High VEGF-C expression appears to promote peritumoral lymphangiogenesis. These data indicated that lymph node metastasis is promoted by COX-2 and VEGF-C in OSCC.

Preventive effect of rebamipide gargle on chemoradiotherpy-induced oral mucositis in patients with oral cancer: a pilot study.

ABSTRACT Objectives To assess the efficacy and safety of rebamipide in preventing chemoradiotherapy-induced oral mucositis in patients with oral cancer. Material and Methods Patients with oral cancer treated with chemoradiotherapy (daily radiotherapy plus docetaxel hydrate once a week) were enrolled for this study. They were assigned in a double-blind fashion to receive either rebamipide gargle or placebo on the days of chemoradiotherapy. Oral mucositis was assessed using the WHO grading system. The primary endpoint of this study was the incidence of grade 3 - 4 mucositis after exposure to 40 Gy radiation (4 weeks). The secondary endpoint was the effect of rebamipide gargle on tumour response to chemoradiotherapy. Results Twenty-four patients were randomly assigned to receive rebamipide gargle (n = 12) or placebo-gargle (n = 12) during chemoradiotherapy. The number of patients with severe mucositis (WHO ≥ 3) was higher in the placebo group than in the rebamipide group (83.3% vs. 33.3%, P = 0.036). In addition, no effect of rebamipide gargle on tumour response to chemoradiotherapy was recognized compared with the placebo group. Conclusions For patients with oral cancer undergoing chemoradiotherapy, rebamipide gargle may contribute to decrease the severity of oral mucositis.

Extracellular matrix loss in chondrocytes after exposure to interleukin-1β in NADPH oxidase-dependent manner

Osteoarthritis is a degenerative joint disease caused by excessive death of chondrocytes and loss of the extracellular matrix (ECM) in articular cartilage. We previously reported that reactive oxygen species (ROS) generated by the NADPH oxidase (NOX) isoform NOX-2 are involved in chondrocyte death induced by interleukin-1β (IL-1β). In this study, we investigate the role of NOX-2 in the production and degradation of ECM by chondrocytes. Although IL-1β lowered the mRNA expression of type II collagen (Col2a1) and aggrecan (Acan) in mouse chondrocyte-like ATDC5 cells, RNA silencing of Nox2 did not change the mRNA expression of these major components of the ECM of cartilage. Hence, NOX-2 is not involved in the IL-1β-induced suppression of ECM production. On the other hand, the NOX inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), the ROS scavenger N-acetylcysteine and an antisense oligodeoxynucleotide for Nox2 prevented the loss of proteoglycan induced by IL-1β in highly differentiated ATDC5 cells. Furthermore, AEBSF did not affect the expression of hyaluronidase-1 and −2, whereas it suppressed hyaluronidase activity in culture medium. IL-1β-induced intra- and extracellular acidification was also suppressed by AEBSF, as was the antisense oligodeoxynucleotide for Nox2. Since hyaluronidase activity is known to be higher under acidic conditions, NOX-2 probably contributes to ECM loss by the activation of hyaluronidase through acidification.

Expression of nephronectin is enhanced by 1α,25‐dihydroxyvitamin D3

The extracellular matrix protein nephronectin (Npnt), also called POEM, is considered to play critical roles as an adhesion molecule in development and functions of various tissues, such as the kidneys, liver, and bone. In the present study, we examined the molecular mechanism of Npnt gene expression and found that vitamin D3 (1α,25‐dihydroxyvitamin D3,VD3) strongly enhanced Npnt mRNA expression in MC3T3‐E1 cells from a mouse osteoblastic cell line. The VD3‐induced increase in Npnt expression is both time‐ and dose‐dependent and is mediated by the vitamin D receptor (VDR).

Characteristics of the early stages of intravenous bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer

Abstract Objective. The clinical features of the early stages of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients with breast cancer remain unclear. A retrospective cohort study was conducted of patients with breast cancer who received intravenous bisphosphonate (BP) treatment in a single center in order to clarify the status of the early stages of BRONJ. Materials and methods. A BRONJ oral monitoring program was established in 247 breast cancer patients given intravenous BP treatment at the institution. The differences in age, BP treatment period, number of remaining teeth, oral hygiene status, presence of regular oral monitoring and the existence of suspected BRONJ (stage 0) among eight BRONJ and 36 non-BRONJ subjects who completed oral examinations were then compared. Results. BRONJ was observed in 0.4% of subjects on the first visit to the oral surgery clinic and in 3.2% of subjects during the follow-up period. Logistic regression analysis revealed that the odds ratio for identifying patients with BRONJ during follow-up by the presence of stage 0 at first visit was 24.0 (95% confidence interval [CI] = 3.6–161.7). The area under the receiver operating characteristic curve for identifying subjects with BRONJ by the presence of stage 0 was 0.82 (95% CI = 0.63–1.00). Conclusion. The results suggest that patients with stage 0 BRONJ on the first visit may progress to advanced BRONJ during the follow-up period. The oral monitoring program may contribute to the early detection of BRONJ.

Application of custom-made bioresorbable raw particulate hydroxyapatite/poly-l-lactide mesh tray with particulate cellular bone and marrow and platelet-rich plasma for a mandibular defect: Evaluation of tray fit and bone quality in a dog model

The purpose of this study was to evaluate tray fit and bone quality of particulate cancellous bone and marrow (PCBM) mandibular reconstruction using custom-made bioresorbable forged composites of a raw particulate hydroxyapatite/poly-L-lactide (HA/PLLA) tray in a dog model. Mesh sheets of HA/PLLA were formed in a tray shape according to the mandible stereolithographs of 14 beagle dogs. Platelet-rich plasma (PRP) was obtained from venous blood, and PCBM was harvested from the iliac crest. Bone defects were made bilaterally on the lower borders of the mandible. The PCBM and PRP were mixed and compressed into the defects and a custom-made HA/PLLA or a manually adopted titanium tray was fixed by screws. Tray fit and bone qualities were evaluated using computed tomography, microfocus computed tomography and confocal laser scanning microscopy. In buccal side, there is no significant difference with tray fit between the HA/PLLA and the titanium type, but in lingual side, it was better in the HA/PLLA type than that of the Ti type. Bone volume fraction (BV/TV) had markedly increased on the HA/PLLA side at 12 months. In conclusion, the custom-made HA/PLLA tray was easily and accurately adapted to the mandible, and had achieved sufficient bone quality by 12 months.

Indications of Potassium Titanyl Phosphate Laser Therapy for Slow-Flow Vascular Malformations in Oral Region.

Background: Indications for laser therapy for slow-flow vascular malformations in the oral and maxillofacial regions have not been clearly documented. The authors aimed to estimate the frequency of resolution of slow-flow vascular malformations and to identify risk and prognostic factors associated with resolution in potassium titanyl phosphate (KTP) laser treatment. Methods: This study was designed as a prospective cohort study. Patients who had diagnosed slow-flow vascular malformations were continuously assigned to receive KTP laser therapy. All patients had intralesional laser photocoagulation performed under local anesthesia. Administered power of the KTP laser was fixed at 2 watts throughout the procedure in all patients. The primary endpoint was to understand the frequency of resolution of slow-flow vascular malformations in KTP laser treatment. Secondary endpoints were: treatment outcomes based on lesion size; treatment outcomes based on location; treatment outcomes based on total energy in joules; types of complications. Treatment outcomes were judged by a clinical assessment as well as reduction in lesion size on magnetic resonance imaging. Results: Data were obtained from 26 patients (9 men, 17 women) with 38 lesions. The average lesion size was 13.5 ± 7.7 mm. Treatment outcomes based on lesion size showed that cure and regression were obtained in lesions less than 30 mm in size. However, lesions larger than 30 mm showed no response. Lesions in the tongue and lips showed higher cure rates than in other areas. Treatment outcomes based on administered total energy in joules showed that 68% of lesions were treated and responded well at less than 400 joules. Complication rate was relatively high in the buccal mucosal lesions. Immediate postoperative complications such as necrosis were more common in high-energy administration than in low-energy administration. Conclusion: Our results indicated that KTP laser therapy was effective for slow-flow vascular malformations less than 30 mm in size without significant side effects.BACKGROUND Indications for laser therapy for slow-flow vascular malformations in the oral and maxillofacial regions have not been clearly documented. The authors aimed to estimate the frequency of resolution of slow-flow vascular malformations and to identify risk and prognostic factors associated with resolution in potassium titanyl phosphate (KTP) laser treatment. METHODS This study was designed as a prospective cohort study. Patients who had diagnosed slow-flow vascular malformations were continuously assigned to receive KTP laser therapy. All patients had intralesional laser photocoagulation performed under local anesthesia. Administered power of the KTP laser was fixed at 2 watts throughout the procedure in all patients. The primary endpoint was to understand the frequency of resolution of slow-flow vascular malformations in KTP laser treatment. Secondary endpoints were: treatment outcomes based on lesion size; treatment outcomes based on location; treatment outcomes based on total energy in joules; types of complications. Treatment outcomes were judged by a clinical assessment as well as reduction in lesion size on magnetic resonance imaging. RESULTS Data were obtained from 26 patients (9 men, 17 women) with 38 lesions. The average lesion size was 13.5 ± 7.7 mm. Treatment outcomes based on lesion size showed that cure and regression were obtained in lesions less than 30 mm in size. However, lesions larger than 30 mm showed no response. Lesions in the tongue and lips showed higher cure rates than in other areas. Treatment outcomes based on administered total energy in joules showed that 68% of lesions were treated and responded well at less than 400 joules. Complication rate was relatively high in the buccal mucosal lesions. Immediate postoperative complications such as necrosis were more common in high-energy administration than in low-energy administration. CONCLUSION Our results indicated that KTP laser therapy was effective for slow-flow vascular malformations less than 30 mm in size without significant side effects.

8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage

Abstract In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C‐type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8‐nitro‐cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8‐nitro‐cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8‐nitro‐cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8‐Nitro‐cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8‐bromo‐cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8‐nitro‐cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO. Graphical abstract Figure. No caption available. Highlights8‐Nitro‐cGMP is produced by chondrocytes in growth plate cartilage.8‐Nitro‐cGMP promotes the growth of bones cultured ex vivo.8‐Nitro‐cGMP enhances chondrocyte proliferation in growth plate cartilage.

Wnt/β-catenin signaling activates nephronectin expression in osteoblasts

Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles as an adhesion molecule in the development and functions of various organs and tissues, such as the kidneys and bone. In the present study, we found that Wnt3a strongly enhanced Npnt mRNA expression in osteoblast-like MC3T3-E1 cells, while it also induced an increase in Npnt gene expression in both time- and dose-dependent manners via the Wnt/β-catenin signaling pathway. These results suggest novel mechanisms for Wnt3a-induced osteoblast proliferation and cell survival via Npnt gene expression.