Masashi Yamashiro

Oral premalignant lesions: from a clinical perspective.

In this review article, the clinical and histopathological characteristics of oral premalignant lesions, and primarily oral leukoplakia, are noted and the risk factors for malignant transformation of oral leukoplakia are discussed. Malignant transformation rates of oral leukoplakia range from 0.13 to 17.5%. The risk factors of malignant transformation in the buccal mucosa and labial commissure are male gender with chewing tobacco or smoking in some countries such as India, or older age and/or being a non-smoking female in other countries. Some authors have reported that leukoplakia on the tongue or the floor of the mouth showed a high risk of malignant transformation, although others have found no oral subsites at high risk. In concurrence with some authors, the authors of this review view epithelial dysplasia as an important risk factor in malignant transformation; however, there are conflicting reports in the literature. Many authors believe that nonhomogeneous leukoplakia is a high risk factor without exception, although different terms have been used to describe those conditions. The large size of lesions and widespread leukoplakia are also reported risk factors. According to some studies, surgical treatment decreased the rate of malignant transformation; however, many review articles state that no definitive treatment including surgery can decrease the malignant transformation rate of oral leukoplakia because of the lack of randomized control trials of treatment. Tobacco chewing and smoking may be causative agents for cancerization of oral leukoplakia in some groups, and evidence for a role of human papilloma virus in the malignant transformation of oral leukoplakia is inconsistent. Further research to clarify its role in malignant transformation is warranted.

Silencing of Autocrine Motility Factor Induces Mesenchymal-to-Epithelial Transition and Suppression of Osteosarcoma Pulmonary Metastasis

Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while it acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF)-regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial-to-mesenchymal transition with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal-to-epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, HS-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which upregulation of E-cadherin and cytokeratins, as well as downregulation of vimentin, were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, MET completely suppressed the tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by upregulation of AMF/PGI, and waiver of malignancy might also be controlled by downregulation of AMF/PGI.

Oral Leukoplakia Related to Malignant Transformation

Abstract Oral leukoplakia and its malignant transformation are reviewed in this article. Oral leukoplakia is defined as a predominantly white lesion of the oral mucosa that can not be characterized as any other definable lesion; however, the lesion must be confirmed histopathologically by biopsy in order to discuss malignant transformation of oral leukoplakia. Malignant transformation rates of oral leukoplakia range from 0.13 to 17.5%, while the rates of five-year cumulative malignant transformation range from 1.2 to 14.5%. Some reports found a high incidence of malignant transformation in older patients. Chewing tobacco and smoking are distinct risk factors particularly among males in certain countries; however, other countries have noted that females or non-smokers may be at risk of malignant transformation. HPV has been detected in oral dysplasia lesions and cancer in non-smokers. Conflicting reports have been presented regarding the malignant transformation of oral leukoplakia with epithelial dysplasia; however, we and some authors believe that epithelial dysplasia is an important factor in the malignant transformation of oral leukoplakia. The majority of researchers showed non-homogenous leukoplakia as a risk factor, although different terms have been used to describe these lesions. There may be several routes to malignant transformation of oral leukoplakia, including transformations induced by carcinogenesis due to betel quid chewing or smoking, or by HPV infection. While no definite treatment modalities for oral leukoplakia have been established, we suggest surgical therapy with an adequate safety-margin and well-timed evaluation as an appropriate treatment in preventing malignant transformation.

Ultrasonography in the diagnosis of palatal tumors

OBJECTIVE The purpose of this study was to evaluate the usefulness of ultrasonography for the preoperative evaluation of palatal salivary gland tumors. STUDY DESIGN Eleven surgically treated patients with salivary gland tumors of the palate were examined retrospectively. Intraoral ultrasonic scanning examinations were performed with a 10-MHz transducer. RESULTS The ultrasonographically well-delimited tumors had a complete capsule histologically, whereas the poorly delimited tumors had no capsule or only an incomplete capsule. The tumors that had a reinforced posterior wall echo were associated with pressure bone absorption, and the tumors that had a reinforced posterior echo were associated with bone destruction. Echograms of the tumors were classified into 4 types on the basis of the internal echoes. CONCLUSIONS Intraoral ultrasonography of palatal tumors can be used to determine the localization and condition of the tumors by close analysis of the echogram. The internal echo pattern on the ultrasonogram of a palatal tumor was found to reflect the pathologic structure of the tumor. Ultrasonography can therefore be a quite useful technique for the preoperative evaluation of palatal salivary gland tumors.

CXCL2 synthesized by oral squamous cell carcinoma is involved in cancer-associated bone destruction

To explore the mechanism of bone destruction associated with oral cancer, we identified factors that stimulate osteoclastic bone resorption in oral squamous cell carcinoma. Two clonal cell lines, HSC3-C13 and HSC3-C17, were isolated from the maternal oral cancer cell line, HSC3. The conditioned medium from HSC3-C13 cells showed the highest induction of Rankl expression in the mouse stromal cell lines ST2 and UAMS-32 as compared to that in maternal HSC3 cells and HSC3-C17 cells, which showed similar activity. The conditioned medium from HSC3-C13 cells significantly increased the number of osteoclasts in a co-culture with mouse bone marrow cells and UAMS-32 cells. Xenograft tumors generated from these clonal cell lines into the periosteal region of the parietal bone in athymic mice showed that HSC3-C13 cells caused extensive bone destruction and a significant increase in osteoclast numbers as compared to HSC3-C17 cells. Gene expression was compared between HSC3-C13 and HSC3-C17 cells by using microarray analysis, which showed that CXCL2 gene was highly expressed in HSC3-C13 cells as compared to HSC3-C17 cells. Immunohistochemical staining revealed the localization of CXCL2 in human oral squamous cell carcinomas. The increase in osteoclast numbers induced by the HSC3-C13-conditioned medium was dose-dependently inhibited by addition of anti-human CXCL2-neutralizing antibody in a co-culture system. Recombinant CXCL2 increased the expression of Rankl in UAMS-32 cells. These results indicate that CXCL2 is involved in bone destruction induced by oral cancer. This is the first report showing the role of CXCL2 in cancer-associated bone destruction.

Colorimetric analysis of unstained lesions surrounding oral squamous cell carcinomas and oral potentially malignant disorders using iodine

To determine whether the measurement of staining with 3% Lugols solution provided efficient criteria for determining the area of resection for oral carcinomas and oral potentially malignant disorders, the authors analyzed the color of unstained lesions (USLs) in relation to histopathological findings. After vital iodine staining, USLs were seen in 48 of 54 patients (88.9%). A significant difference was seen in the value of lightness between stained lesions (SLs) and USLs for patients with moderate and severe epithelial dysplasia (P<0.001). The deviation between the macroscopically observable and the histopathological boundaries was -0.65+/-1.26 mm (range: -4.36 to 1.52). Color charts prepared on the basis of values for lightness and hue reproduced the macroscopic color differences in USLs, suggesting that it may become possible to diagnose USLs histologically on the basis of the measured color values and use of color charts to help determine the resection area in surgery.

Complications and Outcome of Free Flap Transfers for Oral and Maxillofacial Reconstruction: Analysis of 213 Cases

Abstract Microvascular free flap transfers have become a preferred reconstructive technique; however, rare complications may still prove devastating. This study reviewed 213 consecutive freetissue transfers in order to assess the incidence and causes of complications in patients undergoing microvascular free flap reconstruction in the oral and maxillofacial region. In most cases, reconstruction was undertaken after resection of a malignant tumor. The flap donor sites were the radial forearm (n=111), rectus abdominis (n=88), scapula (n=13), and latissimus dorsi (n=1). The superior thyroid artery and the external jugular vein were commonly used as recipient vessels for anastomosis. The overall flap success rate was 99%. There were 7 cases of postoperative vascular thrombosis (6 venous and 1 arterial), constituting 3.3% of the entire series. Five flaps were salvaged, representing a 71.4% successful salvage rate in cases of vascular complications. Most of the successful salvage attempts were made within 24 hours of the end of the initial operation, and the successful salvage rate for re-exploration was 100%. Finally, the total flap loss rate was 0.9% and the partial flap loss rate was 2.3%. We conclude that early re-exploration should be the first choice for management of vascular compromised flaps. Complications at the donor site occurred in 17 cases (8.0%), the most common complication of which was partial skin graft loss after harvesting a radial forearm flap (n=10; 9.0%). Recipient and donor site morbidity was limited and considered acceptable.

A structural modulator of tumor necrosis factor type 1 receptor promotes bone formation under lipopolysaccharide-induced inflammation in a murine tooth extraction model

Recently an increase in the serum levels of a bone formation marker after anti-tumor necrosis factor (TNF)-α therapy in rheumatoid arthritis patients has been reported. However, there remains no direct evidence that TNF-α antagonist could accelerate bone formation under inflammatory condition. Cavity-induced allosteric modification (CIAM) compound, F002, is a newly developed-TNF-α antagonist, which was designed by using the structure of TNF type 1 receptor, thus preventing TNF-α-induced signaling. In this study, we examined whether the CIAM compound can promote bone formation under inflammatory condition induced by lipopolysaccharide (LPS). Thirty-six 10-week-old male mice (C57BL/6J) were used. Half of the mice received 10 mg/kg LPS, while the other half received PBS. Thereafter, incisor extraction was performed at 4 days after either LPS or PBS injection. Intraperitoneal injections of 2 mg/kg/day, 4 mg/kg/day CIAM, or vehicle (10% DMSO) were performed once a day from day 0 to day 7 after incisor tooth extraction. The mice were sacrificed at 21 days after the extraction. The regenerated bone mineral density (BMD) in the tooth socket, and the mineral apposition rate and the bone formation rate, direct evidences of bone formation, were significantly decreased in the LPS-injected group compared to the PBS-injected group. CIAM compound dose-dependently prevented the decrease of BMD under the LPS-injected condition, and promoted both the mineral apposition rate and the bone formation rate significantly compared to the LPS-injected group. We did not observe any significant differences among the PBS-injected groups. Taken together, TNF-α antagonist CIAM compound, was found to accelerate bone formation under LPS-induced inflammatory condition.

Evaluation of plasma glutathione S-transferase-π (GST-π) as a tumor marker for oral squamous cell carcinoma

BackgroundThis study estimates the usefulness of plasma GST-π as a tumor marker for oral squamous cell carcinoma.MethodsIn a preliminary study, the plasma and serum GST-π levels were measured and compared. The positive rate for GST-π was 52.7% in plasma and 20.0% in serum. Thus the plasma GST-π was determined to be more sensitive and a useful tumor marker. Plasma GST-π levels were measured in untreated oral carcinoma cases, recurrent oral carcinoma cases, oral leukoplakia cases and healthy controls.ResultsThe positive rate was 57.1% in untreated carcinoma cases, 60.5% in recurrent carcinoma cases, 0.0% in leukoplakia cases. As for the untreated carcinoma cases, site, size, clinical stage, lymph node metastasis, and histopathological grading (WHO) were examined; but no relationship between plasma GST-π levels and each of these factors was found. The positive rates for plasma GST-π were compared with those for serum SCC antigen. The plasma GST-π showed a significantly higher positive rate and was considered more useful. Plasma GST-π levels tended to regress into a normal range after treatment. But in those patients with recurrence regression of plasma GST-π levels did not occur.ConclusionPlasma GST-π is considered clinically reliable and useful in the diagnosis of oral squamous cell carcinoma and early detection of recurrence or metastasis.

Clinical study on mandibular fracture after marginal resection of the mandible.

OBJECTIVES Postoperative mandibular fracture (PMF) after marginal resection (MR) of the mandible remains an unresolved issue, and it has been reported that at least 10 mm of postoperative mandibular body height (PMBH) is required to prevent PMF. This study evaluated the clinical, physical, and structural risk factors for PMF in MR patients and determined appropriate preventive measures for PMF. STUDY DESIGN This retrospective study included 44 patients with lower gingival carcinoma who underwent MR. PMF occurred in four of these patients. Thirteen associated factors identified from medical records and radiographs were statistically analyzed. RESULTS Mandibular body height (MBH) preservation ratio originally evaluated as less than 0.3, more than 20 remaining teeth after surgery, and inferior alveolar canal (IAC) exposure were significant risk factors for PMF. Prostheses and number of remaining teeth were also correlated with PMF. CONCLUSIONS The preserved mandibular bone should be reinforced in patients with an MBH preservation ratio of less than 0.3, more than 20 remaining teeth after surgery, and intraoperative IAC exposure. Patients with prostheses are at an increased risk of PMF compared with those without because of stable occlusion and a strong occlusal force. Our novel findings provide useful reference standards for PMF prevention in MR patients.