Masataka Katagiri

Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer

It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.

Magnetic resonance imaging findings of nodular fasciitis in the mental region.

Nodular fasciitis (NF) is a benign reactive lesion of the soft tissues related to the fascia and characterized by fibroblastic proliferation. The most common site is the upper extremities (46%), followed by the head and neck region (20%). In the orofacial region, the lesion typically develops within the subcutaneous structures overlying the angle and inferior border of the mandible and the zygoma. Magnetic resonance imaging (MRI) findings of NF in the orofacial region are almost unreported in the literature. In the present case report, we describe MRI findings of mental NF in a 19-year-old woman. MRI revealed a well-defined, round soft-tissue mass lying on the mentum. On T1-weighted MRI, the lesion was isointense to skeletal muscle; it was hyperintense to skeletal muscle on T2-weighted MRI, and was enhanced by Gd-diethylenetriamine pentaacetic acid (DTPA). Histologic examination revealed abundant myxoid degeneration dispersed in the lesion. The T2-weighted higher heterogeneous signal intensity was likely due to abundant myxoid degeneration or the cellular component of the lesion. A strong bright signal intensity belt appeared in the periphery of the lesion on Gd-DTPA enhancement. This rim enhancement appearred to represent small arterioles and venules that were visible in the peripheral area on histologic examination.

Immunohistochemical localization of parathyroid hormone-related protein (PTHrP) and serum PTHrP in normocalcemic patients with oral squamous cell carcinoma.

Cancer cells produce parathyroid hormone-related protein (PTHrP) in the early phase of malignancy development, before hypercalcemia occurs. The relationship between PTHrP and the clinicopathologic features of oral squamous cell carcinoma is poorly understood. We studied 60 patients (43 men, 17 women; mean age, 64.8 ± 11.2 years) with primary oral squamous cell carcinoma, from whom pretreatment biopsy specimens were obtained. We examined the relationship among immunohistochemical PTHrP expression, serum PTHrP levels, clinical characteristics of the tumor, and histopathologic aspects of the tumor. The mean calcium concentration for the 60 patients was 9.1 ± 0.4 mg/dl. No patients had laboratory evidence of hypercalcemia before treatment. Six patients had serum levels of C-terminal (C)-PTHrP higher than the normal level of 55.3 pmol/l. There were no significant differences in serum C-PTHrP levels according to TNM stages. Abundant positive immunoreactivity for anti-PTHrP (1-34) antibody was recognized diffusely in the whole cytoplasm of many tumor cells. Anti-PTHrP (38-64) antibody staining tended to localize as small granules in the cytoplasm, especially close to the nuclear periphery. There was no correlation between the serum C-PTHrP concentration and the intensity of either immunostain. The intensity of PTHrP was proportionally related to the degree of differentiation or extent of keratinization (P < 0.05) and the histologic malignancy grade of the tumor (P < 0.05), when using antibody against PTHrP (1-34), but not when using antibody against PTHrP (38-64). Serum C-PTHrP levels did not correlate with the intensity of cellular PTHrP expression and characteristics of the tumor at the initial patient visit. The fragment that includes PTHrP (1-34) may be involved in the differentiation of oral squamous cell carcinoma. The differences between immunoreactivities may have been due to differing tissue malignancies and the use of different antibodies. The results suggest the need for caution when interpreting immunoreactivities of PTHrP in malignancies.

Autoradiographic evaluation of 99mTc-methylene diphosphonate accumulation in oral cancer invading the mandible

PURPOSE Skeletal scintigraphy, a sensitive diagnostic tool used to detect changes in bone, is helpful for evaluating bone invasion by oral cancer. However, the exact sites of accumulation of 99mTc-phosphate compounds in the mandible have not yet been fully elucidated. The aim of this study was to determine the localization of 99mTc-methylene diphosphonate (MDP) in the areas of mandible that have been invaded by cancer. PATIENTS AND METHODS Seven patients with oral cancer (lower gingiva, 4; tongue, 2; floor of the mouth, 1) who underwent surgical treatment with mandibular bone resection were included in the study. Autoradiography and contact macroradiography were used for evaluation of 99mTc-MDP accumulation. RESULTS Radioactivity reflecting accumulation of 99mTc-MDP was documented encircling the portion of the mandible with cancerous invasion, suggesting that 99mTc-MDP accumulated in immature bone. High uptake also was found in the periosteal reactive bone around the cortical bone. CONCLUSIONS The amount of increased 99mTc-MDP circumscribing carcinoma invasion varies among cases. Additionally, uptake may not correspond directly with the amount of the carcinoma invasion; that seen in periosteal bone could be attributed mistakenly to bone invasion in planar scintigraphy.

Cervical Lymph Node Metastasis and Histopathological Malignancy Grading of Primary Oral Squamous Cell Carcinoma

Objectives: Malignant lesions of patients with primary oral squamous cell carcinoma were examined and graded histologically. The rate of p53 positive findings and the density of microvessels in these lesions were assessed as possible predictors of cervical lymph node metastasis. Patients and Methods: Forty six patients with primary oral squamous cell carcinoma who underwent neck dissection to excise the primary tumour were included in the study. Malignant lesions were histologically graded and biopsy samples from the primary tumours were immunostained for p53 and CD31. Result: There were significant differences between the pathological lymph node—positive and pathological lymph node—negative groups for degree of keratinisation, pattern of invasion, and total score. The p53-positive rate showed no statistical significance for any parameter. The density of microvessels was lower in the high malignancy group than in the low malignancy group, but none of the parameters differed significantly. Based on the histological grading of these lesions, the 10-year survival rate was 85.7% for the low malignancy group and 52.0% for the high malignancy group (p < 0.05). No significant difference was found between the p53-positive and p53-negative groups. Conclusions: Histological grading of malignant primary tumours may predict cervical lymph node metastasis. However, positive findings are influenced by multiple factors, ranging from p53 positivity to the density of microvessels. Further detailed study of the association between these factors is warranted.

A case of peripheral cementifying fibroma of the mandible

Peripheral cementifying fibroma is a rare tumor. It is classified as an osteogenic neoplasm by the WHO classification (1992). We encountered a 67 years old man who developed it on the buccal gingiva in the left lower posterior molar region of the mandible. The lesion was diagnosed clinically as epulis osteoplastica. The lesion was surgically excised under local anesthesia with first and second molar extractions. Histopathological examination indicated the lesion to be a peripheral cementifying fibroma. The post operative course was good.

Clinical and histopathological study of simus lift procedure

Sixteen sinuses of 11 patients performed by sinus lift procedure were retrospectively discussed clinically and histopathological investigations from grafted materials. Grafted materials were 10 autogenous bones harvested from 1 iliac crest and 9 chin bones, 1 non-resorbable hydroxyapatite plus mandibular alveolar ridge bone, and 1 mixed of resorbable hydroxyapatite plus human freezed dry bone. Histopathological investigation on several small speciemens taken from grafts of these different materials was performed. New bone formation, small amount of bone resorption and fibrous encapsuling tissue were observed for autogenous bone graft, but new bone formation was delayed around non-resorbable hydroxyapatite particles, and most of all grafted specimens of human freezed dry bone was replaced and encapsulated by fibrous tissues. These results showed that autogenous bone is highly recommended as graft material for sinus lift procedure. Endosseous implants were placed for 8 patients in the first group after an average period of 9.2 months of elevation, and for 2 patients in the second group at the time of elevation. One patient in the third group received a second sinus elevation to prevent maxillary sinusitis by perforating through maxillary sinus membrane following the installation. The survival rate of dental implants with sinus lift procedure was 94.1% after fabrication of prosthesis without any complication.