Associations between Systemic Markers of Bone Turnover or Bone Mineral Density and Anti-Resorptive Agent-Related Osteonecrosis of the Jaw in Patients Treated with Anti-Resorptive Agents.

BACKGROUND: Some previous studies have examined anti-resorptive agent-related osteonecrosis of the jaw (ARONJ) prediction using systemic markers of bone turnover as risk factors. Radiographic imaging is also effective at detecting ARONJ. In this study, computed tomography (CT)-derived bone mineral density (BMD) values and the levels of systemic markers of bone turnover were evaluated, and then each parameter was compared between patients that developed ARONJ and those who did not after treatment with systemic anti-resorptive agents. The aim of this study was to determine whether systemic markers of bone turnover and/or BMD values can be used to predict the risk of ARONJ. METHODS: The subjects' serum levels of cross-linked N-terminal telopeptide of type I collagen (NTX) and bone alkaline phosphatase (BAP) (systemic markers of bone turnover) were measured. BMD was calibrated to CT values using a medical imaging phantom. Then, the subjects' BMD were assessed using quantitative computed tomography. Fifty-six patients who had received systemic anti-resorptive agents were included in this study. Thirty-two of the patients developed ARONJ after receiving the drugs whereas the remaining 24 did not. RESULTS: No correlation was observed between the serum levels of the systemic markers of bone turnover and the incidence of ARONJ. On the other hand, the ARONJ patients exhibited higher mandibular BMD values than the control group. BMD was not associated with healing or the clinical stage of ARONJ. CONCLUSION: These results suggest that increased mandibular BMD values are associated with ARONJ. Furthermore, mandibular BMD might serve as a novel marker for predicting the risk of ARONJ in patients that are taking anti-resorptive agents and are about to undergo tooth extraction. Accordingly, mandibular BMD could be a useful tool for aiding risk assessments and guiding treatment decisions.

[Successful outcome from treatment modality with low-dose S-1 for three oldest old patients with advanced oral cancer].

We herein present three oldest old patients with advanced oral cancer for whom low-dose S-1 treatment was effective and improved QOL. The first patient is a 90-year-old female with cancer of the maxilla(T4N0Mx). Because of her generally poor condition, her family did not desire radical therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. Because of a partial response without serious side effects, we increased the dose of S-1 to 50mg/m2. The tumor currently shows a tendency toward reduction. The second patient is a 96-year-old female with cancer of the mandible(T4N0Mx). Because of her old age, her family desired palliative therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. A complete response was obtained at the end of the second course. There has been no recurrence. The third patient is a 94-year-old female with cancer of the maxilla(T3N0M0). Her family selected palliative therapy. S-1(50mg/m2)was administered for 2 weeks followed by a 1-week interval. The tumor size decreased after administration of S-1, without serious side effects. However, the tumor increased after the end of the fifth course. Considering the patient's condition, S-1 administration was discontinued at the end of the eighth course. S-1 is considered to be an effective and safe treatment for the maintenance or improvement of the QOL of old and oldest old patients with advanced oral cancer.

High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas.

Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes and is important in cell cycle regulation. Overexpression of EZH2 protein has been associated with biological malignancy of prostate cancer and several other cancers. The aim of the present study was to evaluate the expression of EZH2 protein in human oral normal mucosa, dysplasia and oral squamous cell carcinoma (OSCC) with clinicopathological profiles. EZH2 expression was assessed by Western blotting and immunohistochemistry in 3 OSCC cell lines, 10 normal mucosae, 50 dysplasias and 102 OSCCs. The labeling indices (LIs) of EZH2, Ki-67, P53, and the apoptotic index (AI) were evaluated by immunohistochemistry and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Western blot analysis detected EZH2 protein as a single band at 91kDa in the 3 OSCC cell lines, but it was almost absent in non-tumoral oral mucosae. The LI of EZH2 was highest in the OSCCs, followed by the dysplasias (p<0.05) and normal mucosae (p<0.05) with significant difference. The LI of EZH2 correlated with the clinical stage, tumor size, lymph node metastasis and LIs of Ki-67 and P53, but not with the AI in OSCCs, and inversely correlated with the histological differentiation of OSCCs. The survival rate calculated by the Kaplan-Meier method revealed that OSCC patients with higher EZH2 expression showed poorer prognosis than those with a lower EZH2 expression (p<0.01). These results suggest that overexpression of EZH2 is correlated with malignant potential and poor prognosis in OSCCs. EZH2 might serve as a novel biomarker for predicting prognosis in patients with OSCCs.

High expression of enhancer of zeste homologue 2 indicates poor prognosis in patients with soft tissue sarcomas.

Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group of genes, is associated with malignancy in several human cancers. The purpose of this study was to examine the association between EZH2 expression and clinicopathological factors as compared to Ki-67 expression in human soft tissue sarcomas. Expression of EZH2 and Ki-67 was immunohistochemically determined in paraffin-embedded sections from 104 soft tissue sarcomas. High expression of both EZH2 and Ki-67 was significantly correlated with distant metastasis (P<0.01), histologic grade (P<0.01) and poor prognosis (P<0.01), but not with clinicopathological factors such as age, sex, and tumor location and size. Although EZH2 expression was significantly correlated with Ki-67 expression (rs=0.65, P<0.01), multivariate analysis showed that high expression of EZH2, but not of Ki-67, was an independent factor of poor prognosis (relative risk = 2.79; P=0.02). These data suggest that expression of EZH2 is a novel and reliable prognostic marker of human soft tissue sarcomas.

CYR61 downregulation correlates with tumor progression by promoting MMP-7 expression in human gastric carcinoma.

OBJECTIVE: CYR61 (cysteine-rich 61) belongs to the CCN (CYR61/CTGF/NOV) protein family and is involved in tumorigenesis. We have previously confirmed that the level of CYR61 protein is decreased in gastric carcinoma compared with nontumoral mucosa, by conducting proteome-based analyses. In this study, we examine the relationship between CYR61 expression and clinicopathological data of MMP-7 expression in human gastric mucosae and tumors. METHODS: Immunohistochemical and/or immunofluorescence analyses were performed to examine the histological expression of CYR61 in normal gastric mucosa, intestinal metaplasia, 33 adenomas, and 127 carcinomas. Seven gastric carcinoma cell lines were used to examine the expression of CYR61 and MMP-7 by Western blotting. RESULTS: The CYR61-expressing cells mostly coincided with the serotonin-containing cells, not only in nontumoral epithelia, but also among tumor cells. CYR61 expression was positive (labeling index: >2%) in 43 of 49 early gastric carcinomas (87.8%) and in 19 of 78 advanced gastric carcinomas (24.4%), the frequency being significantly lower in the latter (p < 0.001). All the normal mucosae, intestinal metaplasias and adenomas were in the positive group. The reduction in CYR61 expression correlated significantly with histological differentiation (p < 0.05), depth of invasion (p < 0.001), lymphatic invasion (p < 0.001), venous invasion (p < 0.001), lymph node metastasis (p < 0.001) and clinical stage (p < 0.001). Immunohistochemistry and Western blotting revealed the expression of CYR61 to be inversely correlated with that of MMP-7 (p < 0.001). CONCLUSIONS: CYR61 is expressed in serotonin-containing cells, and downregulation of the expression might contribute to the progression of cancer by promoting MMP-7 expression in human gastric carcinomas.