Daisuke Takeda

Risk Factors Associated with Distant Metastasis in Patients with Oral Squamous Cell Carcinoma

Objective 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). Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods 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. Results 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. Conclusion 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.

Risk factors associated with postoperative delirium after surgery for oral cancer

OBJECTIVE The purpose of this study was to retrospectively investigate the multivariate relationships among the various risk factors for postoperative delirium in patients undergoing oral cancer surgery. MATERIAL AND METHODS The medical records of all patients with oral cancer who underwent curative head and neck surgery between April 2011 and March 2013 at our institution were retrospectively reviewed. There was a total of 188 patients, including 110 males and 78 females. RESULTS We found that older age, extensive surgical procedure, longer operation, excessive hemorrhage, blood transfusion, longer postoperative management in the intensive care unit, longer postoperative hospital stay, lower albumin level in the preoperative blood test, and lower total protein, albumi, n and hemoglobin levels and a higher C-reactive protein (CRP) level in the postoperative blood tests were significant variables in the univariate analysis (p < 0.05). We also determined that an older age (odds ratio [OR] = 6.83), intraoperative lower hemoglobin levels (OR = 6.82), and excessive hemorrhage (OR = 3.62) during surgery were significant variables in the multivariate analysis. CONCLUSION Clinicians should pay special attention to preventing delirium during the postoperative management of older patients with these risk factors. Furthermore, increasing the hemoglobin levels during surgery may be able to prevent postoperative delirium.

Transcutaneous Carbon Dioxide Induces Mitochondrial Apoptosis and Suppresses Metastasis of Oral Squamous Cell Carcinoma In Vivo

Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

Low-intensity pulsed ultrasound enhances bone morphogenetic protein expression of human mandibular fracture haematoma-derived cells.

We previously demonstrated that human mandibular fracture haematoma-derived cells (MHCs) play an important role in mandibular fracture healing and that low-intensity pulsed ultrasound (LIPUS) accelerates this effect by stimulating various osteogenic cytokines. In the present study, we investigated how LIPUS affects the expression of bone morphogenetic proteins (BMPs), which are also known to have the ability to induce bone formation. MHCs were isolated from human mandibular fracture haematomas and the cells were divided into two groups: a LIPUS (+) group and a LIPUS (-) group, both of which were cultured in osteogenic medium. LIPUS was applied to the LIPUS (+) group 20 min a day for 4, 8, 14, and 20 days (1.5 MHz, 30 mW/cm(2)). Real-time PCR and immunofluorescence studies were carried out to determine the expression of BMP-2, 4, and 7. Compared to the LIPUS (-) group, gene expression levels were significantly increased in the LIPUS (+) group for BMP-2 on day 20 (67.38 ± 26.59 vs. 11.52 ± 3.42, P < 0.001), for BMP-4 on days 14 (45.12 ± 11.06 vs. 9.20 ± 2.88, P = 0.045) and 20 (40.96 ± 24.81 vs. 3.22 ± 1.53, P = 0.035), and for BMP-7 on day 8 (48.11 ± 35.36 vs. 7.03 ± 3.96, P = 0.034). These findings suggest that BMP-2, 4, and 7 may be mediated by LIPUS therapy during the bone repair process.

The osteogenic activity of human mandibular fracture haematoma-derived cells is stimulated by low-intensity pulsed ultrasound in vitro

Low intensity pulsed ultrasound (LIPUS) stimulation is a clinically established treatment method used to accelerate long bone fracture healing; however, this method is currently not applied to mandibular fractures. In this study, we investigated the effects of LIPUS on human mandibular fracture haematoma-derived cells (MHCs) in order to explore the possibility of applying LIPUS treatment to mandibular fractures. MHCs were isolated from five patients. The cells were divided into two groups: (1) LIPUS (+) group: MHCs cultured in osteogenic medium with LIPUS treatment; and (2) LIPUS (-) group: MHCs cultured in osteogenic medium without LIPUS treatment. The osteogenic differentiation potential and proliferation of the MHCs were compared between the two groups. The waveform used was equal to the wave conditions of a clinical fracture healing system. The gene expression levels of ALP, OC, Runx2, OSX, OPN, and PTH-R1 and mineralization were increased in the LIPUS (+) group compared to the LIPUS (-) group. There were no significant differences in cell proliferation between the two groups. These findings demonstrate the significant effects of LIPUS on the osteogenic differentiation of MHCs. This study provides significant evidence for the potential usefulness of the clinical application of LIPUS to accelerate mandibular fracture healing.

Survival of Brånemark System Mk III implants and analysis of risk factors associated with implant failure

The purpose of this study was to retrospectively investigate the outcomes of Brånemark System Mk III TiUnite/Groovy implants placed in patients at Kobe University Hospital. Various risk factors for implant failure, including mechanical coupling, were investigated by univariate and multivariate analysis. The predictive variables investigated included age, sex, smoking habit, general health, history of radiation therapy, application of a dentomaxillary prosthesis, type of prosthesis, use of alveolar bone augmentation, site of implant insertion, mechanical coupling between implants, and the length and diameter of the implants. Of the 907 implants investigated, only 23 were unsuccessful; the overall survival rate was 96.7%. Increased age, radiation therapy, application of a removable prosthesis or dentomaxillary prosthesis, lack of mechanical coupling between implants, and shorter implants (≤8.5mm) were significant risk factors for implant failure according to univariate analysis (P<0.05). Multivariate analysis identified a significant association (P<0.05) between dental implant failure and a lack of mechanical coupling between implants (odds ratio 6.88) and shorter implants (≤8.5mm) (odds ratio 3.43). The findings of this study demonstrated multivariate relationships between various risk factors and dental implant failure.

Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma

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.

Effect of local application of transcutaneous carbon dioxide on survival of random-pattern skin flaps

INTRODUCTION Skin flap procedures are widely used to reconstruct skin and soft tissue defects. Skin flap necrosis is a serious postoperative complication. Many researchers have introduced pharmacological agents to improve flap ischemia in experimental studies. However, outcomes of these studies remain controversial. We previously demonstrated that transcutaneous CO2 application improves hypoxia in fracture repair. In this study, we hypothesized that improving hypoxia by transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis. We investigated whether transcutaneous CO2 application can increase the survival of random-pattern skin flaps. MATERIALS AND METHODS Six-week-old male Sprague-Dawley rats were divided into two equal groups: the control group (n = 6) and CO2 group (n = 6). A random-pattern skin flap was constructed in these rats. Topical CO2 was applied using a hydrogel every day for 5 days in the CO2 group. The flap survival area was measured on postoperative days 1, 3, and 5. The vessel density and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hypoxia-inducible factor-1α (HIF-1α) were evaluated on postoperative day 5. RESULTS A statistically significant difference was found in the percentage of the flap survival area between the two groups on postoperative days 3 and 5 (p < 0.05). Furthermore, the expression of VEGF and bFGF was significantly higher and that of HIF-1α was significantly lower in the CO2 than in the control group (p < 0.05). CONCLUSIONS Transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis, thus increasing the survival of random-pattern skin flaps.

Decreased mitochondrial copy numbers in oral squamous cell carcinoma.

Mitochondrial dysfunction and altered respiration have long been suspected to affect the development and progression of cancer. Although quantitative changes in mitochondrial DNA (mtDNA) have been reported in head and neck squamous cell carcinoma (SCC), differences in mtDNA copy numbers between normal and cancerous tissues from same patients have not been assessed.

Differences between osteoradionecrosis and medication-related osteonecrosis of the jaw

PurposeThe appearance of osteoradionecrosis (ORN) and medication-related osteonecrosis of the jaw (MRONJ) is similar, but clinically important differences between ORN and MRONJ exist. The aim of this study was to compare the clinical data between ORN and MRONJ and to reveal the critical differences between these diseases.MethodsWe retrospectively reviewed the epidemiological data, clinical findings, and treatment in 27 ORN and 61 MRONJ patients. Radiographic signs before the initiation of treatment were also assessed.ResultsThe median age (P = 0.0474) and the ratio of female to male patients (P < 0.0001) were significantly higher in MRONJ patients. There were significantly more MRONJ patients who reported a history of pain when compared with ORN patients (P = 0.0263). As an aetiological factor, tooth extraction was significantly more relevant to MRONJ than ORN (P = 0.0352). When assessing the radiographic signs on computed tomographic images, periosteal reaction was found only in MRONJ patients (P = 0.0158). Minimal debridement was performed significantly more frequently for MRONJ (P = 0.0093), and by contrast, surgical resection was performed more frequently for ORN (P = 0.0002).ConclusionsUnderstanding the clinical and underlying pathological differences between ORN and MRONJ probably contributes to the selection of appropriate treatment for each patient.