Fracture after radiation therapy for femoral metastasis: incidence, timing and clinical features.

We analyzed 428 femoral metastases initially treated with radiotherapy between 2002 and 2011 to clarify the clinical details of post-irradiation fractures of femoral metastasis. Patients included 161 men and 167 women, with a mean age of 62 years. Fracture incidence, fracture site, fracture risk based on X-ray images before radiotherapy, and interval from completion of radiotherapy to fracture occurrence were assessed. In addition, 24 pathological specimens obtained during 27 surgeries for these fractures were examined. Fractures occurred in 7.7% of 428 femoral metastases (total 33: 28 actual fractures and five virtual fractures with progressive pain and bone destruction). The fracture rate was 7.8% in the proximal femur and 1.5% in the shaft (P = 0.001). Fractures occurred a median of 4.4 months after radiotherapy, with 39.4% occurring within 3 months and 63.6% within 6 months. Among femurs with high fracture risk according to Harrington's criteria or Mirels' score, the fracture rate was 13.9% and 11.8%, respectively. Viable tumor cells were detected in all five patients with painful virtual fracture, in 85.7% of femurs with actual fractures that occurred within 3 months, and in only 25.0% of actual fractures occurring after 3 months. Post-irradiation fractures of femoral metastasis most frequently occurred within 3 months after radiotherapy, and were more common in the peritrochanteric area than in the shaft. Radiological evidence of impending fracture did not correlate with a high fracture rate. Actual fractures occurring after more than 3 months were likely caused by post-irradiation fragility of the femur, without viable tumor cells.

Asymmetrical vertebral collapse from spinal metastasis in lower thoracic and lumbar spine.

OBJECTIVE: The purpose of this study was to investigate the differences between spinal metastasis and osteoporotic compression fractures on plain X-ray images, focusing on asymmetrical vertebral collapse and fracture level. MATERIALS AND METHODS: This study included 180 patients with pathological collapse from spinal metastasis (188 vertebrae) who were treated at our institution and 70 patients (92 vertebrae) with osteoporotic compression fractures. Anteroposterior X-ray images of the lower thoracic and lumbar spine were evaluated for asymmetrical collapse deformity. RESULTS: Asymmetrical collapse was found in 134 vertebrae (71.3%) with metastasis, and in 20 osteoporotic vertebrae (21.7%); this difference was significant (p < 0.0001). The asymmetrical collapse angle in spinal metastasis patients ranged from 0 to 18°, with a mean of 7.0 and a standard deviation (SD) of 4.5. In contrast, the asymmetrical collapse angle in patients with osteoporotic fractures ranged from 0 to 13°, with a mean of 3.1 and a SD of 2.8. The difference in collapse angle between the two groups was statistically significant (p < 0.001). The cutoff value to suspect spinal metastasis was determined to be 5° or more (sensitivity 0.67, specificity 0.74). Fracture at Th10 or below L3 was found in 20.2% of spinal metastasis patients; only 3% of osteoporotic fractures occurred at these levels. CONCLUSION: Asymmetrical collapse with an angle of 5° or more and fractures at atypical levels on plain radiographs can be useful clues to spinal metastasis.

Quest for Cells Responsible for Age-related Increase of Salivary Glycine and Proline.

We have previously reported that salivary glycine and proline levels are increased to nearly butanoate level in elderly people. In order to identify the source of glycine and proline, we performed high-performance liquid chromatography analysis of amino acid production to a total of seven oral cells before and after stimulation with inflammation inducers. We found that production of amino acids (per a given number of cells) by normal oral mesenchymal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast) was approximately three-fold that of oral squamous cell carcinoma cell lines (HSC-2, HSC-3, HSC-4, Ca9-22), and that production of glycine and especially proline by all these seven cells was much lower than that of glutamine and glutamic acid. Treatment of three oral mesenchymal cells with interleukin (IL)-1ß or lipopoly-saccharide (LPS) reproducibly increased the production of glutamic acid and glutamine, but not that of glycine and proline. Glycine and proline only marginally stimulated the IL-8 production by IL-1ß-stimulated gingival fibroblast, whereas glycine dose-dependently inhibited the nitric oxide production by lipopolysaccharide-stimulated mouse macrophage-like RAW264.7 cells. These data demonstrated that normal oral mesenchymal cells are not the major source of glycine and proline that accumulates in the saliva of aged people, suggesting the involvement of the deregulation of collagen metabolism during aging.

Anti-inflammatory potential of Rikkosan based on IL-1ß network through macrophages to oral tissue cells.

Rikkosan is a traditional Kampo medicine using the control of oral pain caused by dental caries, pulpitis, periodontitis and stomatitis. In order to provide evidence for its clinical effects, we herein investigated whether Rikkosan inhibits the production of pro-inflammatory substances in human and mouse models of inflammation. Rikkosan alone did not induce prostaglandin E2 (PGE2) production, but inhibited interleukin-1ß (IL-1ß) (5 ng/ml)-stimulated PGE2 production in human gingival fibroblasts and human periodontal ligament fibroblasts, with a selectivity index higher than 4.0 and 4.3, respectively. Rikkosan alone dose-dependently stimulated tumor necrosis factor-α (TNF-α) production, reaching a peak level slightly lower than that attained by lipopolysaccharide (LPS) at 0.4 mg/ml in mouse macrophage-like RAW264.7 cells. At a higher concentration of Rikkosan (4 mg/ml), TNF-α production, however, declined significantly regardless of the presence or absence of LPS. Rikkosan dose-dependently inhibited IL-1ß production by LPS-stimulated RAW264.7 cells, with a selective index of 7.6. Five constituent extracts of Rikkosan, either alone or in combination, showed similar effects on TNF-α and IL-1ß productions in activated RAW264.7 cells, but to lower extents than that of Rikkosan. These results demonstrated that Rikkosan inhibited both IL-1ß production by LPS-activated macrophages and PGE2 production by IL-1ß-stimulated human gingival fibroblasts and human periodontal ligament fibroblasts, suggesting that anti-inflammatory effects of Rikkosan may partially be generated by the inhibition of these pro-inflammatory substances via the IL-1ß network through macrophages to oral tissue cells.

Anti-UV activity of Kampo medicines and constituent plant extracts: re-evaluation with skin keratinocyte system.

AIM: In order to search for new biological activity of Kampo medicines and their constituent plant extracts, we investigated their ability to protect the cells from UV irradiation (referred to as 'anti-UV activity') using the human immortalised skin keratinocyte cell line HaCaT. MATERIALS AND METHODS: Anti-UV activity was represented by the selectivity index (SI), defined as the ratio of the concentration that reduced the viable cell number by 50% to the concentration that increased the viability of UV-irradiated cells to 50%. RESULTS: HaCaT cells were highly resistant to UV irradiation, approximately 20% of cells survived even when the exposure time was prolonged to 480 min. Sodium ascorbate, a popular antioxidant, used as positive control, had excellent anti-UV activity (SI=200). Among 10 Kampo medicines, Shosaikoto (SI=34) had the highest anti-UV activity, followed by Hangesyashinto (SI>28), Unseiin (SI>23) and Ninjinyoeito (SI=23), Saireito (SI>19), whereas another four Kampo medicines were much less active (SI<9.6). Among 25 constituent plant extracts, Scutellaria root had the highest anti-UV activity (SI=38), followed by Polyporus sclerotium (SI>26), Gardenia fruit (SI>23), Japanese Gentian (SI>20) and Saposhnikovia root (SI>20). Glycyrrhizin also had potent anti-UV activity (SI=36). The SI values determined with the present HaCaT system were generally one order higher than those obtained with previously reported HSC-2 human oral squamous cell carcinoma system, although there was good correlation between these two systems (R(2)=0.9118). Conclusion. The present study highlights the improved sensitivity of anti-UV activity detection with the HaCaT system, and suggests the possible application of Kampo medicines as a component of sunscreening cosmetics.

Cortical bone remodeling in parosteal osteosarcoma mimicking medullary involvement: a case with the difficulty in pre-surgical staging.

Parosteal osteosarcoma (POS) is a low-grade well-differentiated variant of osteosarcoma that affects the metaphyseal surface of a long bone. Although Grade-1 POS sometimes involve the medullary canal, such patients are not at a greater risk of local recurrence or metastases. In this report, we describe a rare case of POS in the right distal femur with an intramedullary sclerotic lesion mimicking medullary involvement caused by secondary remodeling of the underlying cortex of the tumor. A 34-year-old woman complained of having a painful hard mass in her right knee for six months. Imaging studies revealed a broad-based sclerotic mass attached to the cortex of the distal and lateral aspect of the femur, along with an intramedullary lesion. Histopathological examination of a biopsy specimen revealed Grade-1 POS. We diagnosed a medullary involvement and we performed a wide resection, including the intramedullary lesion. Histopathological examination of the resected specimen revealed that the intramedullary lesion only exhibited remodeling of the underlying tumor cortex without tumor cell invasion. To the best of our knowledge, this is the first report of such imaging features and pathological findings in a patient with POS. Our experience with the present patient indicates that good local control and overall prognosis of patients with medullary involvement in Grade-1 POS may be due to the remodeling of the underlying cortex mimicking "medullary involvement." This feature will add to the range of diagnostic difficulty experienced during the preoperative staging of POS.

A novel open-tray impression technique for fabrication of a provisional prosthesis on immediate load implants in a completely edentulous arch.

PURPOSE: To evaluate the clinical outcome of a novel open-tray impression technique for fabrication of a provisional prosthesis supported by immediately loaded implants in a completely edentulous arch. MATERIALS AND METHODS: An open-tray impression technique was evaluated in this retrospective study that included patients treated between March 2006 and October 2009. Preoperatively, a diagnostic prosthesis was delivered, and a novel open tray was fabricated based on this prosthesis. After implant placement, the impression and interocclusal record were taken simultaneously using the novel open tray. Laboratory-fabricated, screw-retained, all-acrylic resin provisional restorations were delivered on the same day of surgery. The prosthesis was assessed from the day of surgery until replacement with a definitive prosthesis. RESULTS: The study included 21 patients (mean age, 64.5 years) and a total of 125 implants. Of these, 104 implants were immediately loaded. In all patients, well-fitting provisional restorations supported by a minimum of four implants were delivered. Fracture of the first molar cusp was observed in one case after 30 days. However, there was no extensive fracture in the framework or functional disorder of the prosthesis. No implant failed during the follow-up after implant surgery. CONCLUSION: This protocol enabled fabrication of a well-fitting acrylic resin provisional prosthesis supported by immediately loaded implants because the impression was taken while in centric occlusion and an occlusion identical to the diagnostic prosthesis could be reconstructed.

Anti-UV/HIV activity of Kampo medicines and constituent plant extracts.

AIM: In order to search for new biological activities of Kampo medicines and their constituent plant extracts, we investigated whether they protect the cells from the cytotoxicity induced by UV irradiation and human immunodeficiency virus (HIV) infection. MATERIALS AND METHODS: Anti-UV/HIV activity (SI value) was evaluated as the ratio of the CC(50) (concentration that reduced the viable cell number by 50%) to the EC(50) (the concentration that increased the viability of UV-irradiated or HIV-infected cells to 50%): SI=CC(50)/EC(50). The content of glycyrrhizin in each sample was determined by high performance liquid chromatography (HPLC). Caspase-3/-7 activity was assayed by cleavage of poly ADP ribose polymerase using western blot analysis. RESULTS: Among 25 plant extracts, Gardenia fruit had the highest anti-UV activity (SI≥8.0), followed by Glycyrrhiza (SI=4.3), Coptis rhizoma (SI=1.5), Cimicifuga rhizoma (SI>1.4), Saposhnikovia root (SI>1.3) and Japanese Gentian (SI>1.1). Among ten Kampo medicines, Unseiin and Hangesyashinto (SI>4.9) had the highest anti-UV activity, followed by Shosaikoto (SI>4.3), Saireito (SI>3.4), Rikkosan (SI>1.2) and Kikyoto (SI=1.1). Glycyrrhiza inhibited UV-induced caspase-3/-7 activation. Only Polyporus sclerotium (SI>4.4), Gardenia fruit (SI>2.7), Atractylodes lancea rhizoma (SI>1.9), Cnidium rhizoma (SI>1.5) and Japanese Angelica root (SI>1.1) exhibited some anti-HIV activity. There was no apparent correlation of their anti-UV/HIV activity and content of glycyrrhizin, a major component of Glycyrrhiza, which exhibited much higher anti-UV activity (SI=20.6) and some anti-HIV activity (SI>2.0). CONCLUSION: The present study suggests the involvement of substances other than glycyrrhizin in the anti-UV/HIV activity of Kampo medicines and their constituent plant extracts.

New bone formation in nongrafted sinus lifting with space-maintaining management: a novel technique using a titanium bone fixation device.

PURPOSE: Sinus lifting without graft materials allows new bone formation in the sinus, but the amount of bone formation varies. This study aimed to investigate whether nongrafted sinus lifting using a titanium bone fixation device can promote bone formation in the sinus. MATERIALS AND METHODS: Patients with atrophic posterior maxillae jeopardizing implant stability were included. After nongrafted sinus lifting in combination with implant placement, repositioning of the bone window and additional space-maintaining management were performed by use of the bone fixation device. The primary variables recorded retrospectively included implant survival and preoperative and postoperative alveolar crest height with and without Schneiderian membrane perforation. Independent variables included patient demographics, position and dimension of the implants, complications, and follow-up period. The t test was used for comparing differences in bone levels. The implant survival rate was estimated by uses of Kaplan-Meier statistics. RESULTS: The study included 11 patients (4 men and 7 women) and a total of 21 implants. Radiographically, new bone formation around the implant was generally observed in accordance with the implant apex. Postoperative alveolar crest height (mean, 10.9 ± 2.2 mm) was significantly higher compared with residual alveolar crest height (mean, 4.7 ± 1.4 mm), and no significant difference in bone formation was seen according to membrane perforation. The cumulative survival rate was 95.2%. CONCLUSIONS: This nongrafted sinus-lifting procedure using a bone fixation device could attain predictable bone formation. Additional space-maintaining management using a bone fixation device in a nongrafted sinus lift offers a useful technique for promoting bone formation in the sinus.

Development and growth of adenomatoid odontogenic tumor related to formation and eruption of teeth.

The number of published cases of adenomatoid odontogenic tumor (AOT) has steadily increased, and about half were reported in Asian populations. Although the clinicopathologic profile of AOT has been extensively reported, factual knowledge of its pathogenesis is rudimentary at best, and there is controversy as to precisely which odontogenic epithelium it arises from. AOT is a successional tooth-associated lesion which develops during the mixed dentition. The permanent successor differs from its deciduous predecessor in that it has an eruptive pathway from the dental follicle to the gingiva, the gubernaculum dentis. With this background in mind, the present review focuses mainly on the early development of AOT. We successfully demonstrated a close spatial relationship between AOT and the gubernaculum dentis in a typical case. From further observations of the same AOT in which an enclosed permanent canine showed enamel hypoplasia, it is possible to pinpoint areas around the crown of a developing successional tooth in continuity with the gubernaculum dentis as starting points. In addition, we discuss the unifying histogenetic concept of three clinical variants, namely, pericoronal (follicular), extracoronal (extrafollicular), (see Article note) and peripheral.

Effect of itraconazoles on the production of pro-inflammatory substances in mouse macrophage-like cells.

BACKGROUND, MATERIALS AND METHODS: Synthetic triazoles are widely used for the treatment of fungal infection. In order to understand their possible anti-inflammatory action, we investigated the effect of itraconazole and its hydroxylated derivative (hydroxyitraconazole) on the production of various pro-inflammatory substances by mouse macrophage-like RAW264.7 cells. RESULTS: These compounds did not apparently show any growth inhibitory or stimulatory effects over a wide range of concentrations (0.2-50 µg/ml). Itraconazoles dose-dependently increased the production of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) without affecting the production of interleukin-1ß (IL-1ß) and nitric oxide (NO). LPS treatment significantly enhanced the production of NO, PGE2, TNF-α and IL-1ß. The addition of itraconazoles to LPS-stimulated RAW264.7 cells significantly reduced the production of NO, but rather enhanced the production of PGE2, TNF-α and IL-1ß. ESR spectroscopy demonstrated that itraconazoles did not significantly scavenge NO and superoxide anion radicals, indicating that the inhibition of NO production by itraconazoles is not due to their radical-scavenging activity. Hydroxyitraconazole was slightly more cytostatic, and more efficiently inhibited NO production, but enhanced the production of other pro-inflammatory substances. CONCLUSION: These data suggest that itraconazoles regulate NO and other pro-inflammatory substances differently in activated macrophages.

Orthokeratinized odontogenic cyst of the mandible with heterotopic cartilage.

Cartilaginous metaplasia is a rare but well-documented phenomenon occurring in the wall of odontogenic keratocyst. The mural cartilage not associated with odontogenic keratocyst has been reported only once in a maxillary teratoid cyst of congenital origin to our knowledge. A case presented is a 38-year-old man with intraosseous keratinizing epidermoid cyst in the mandible, the wall of which contained a nodule of mature hyaline cartilage. The present lesion likely represents a previously undescribed, histologic hybrid consisting of orthokeratinized odontogenic cyst and cartilaginous heterotopia.

Bimodal effect of glycyrrhizin on macrophage nitric oxide and prostaglandin E2 production.

Glycyrrhizin is a major constituent of Kanzo, a popular herbal medicine used in food and cosmetics. Glycyrrhizin alone did not stimulate nitric oxide (NO) or prostaglandin E2 (PGE2) production by RAW 264.7 cells, but modified lipopolysaccharide (LPS)-stimulated NO and PGE2 production in a bimodal fashion: it was stimulatory at lower concentrations, whereas it was inhibitory at higher concentrations. Electron-spin resonance spectroscopy showed that glycyrrhizin slightly scavenged the superoxide anion generated by hypoxanthine-xanthine oxidase reaction, but did not scavenge the DPPH and NO radicals. The present study demonstrates the concentration-dependent action of glycyrrhizin on both PGE2 and NO production by activated macrophages.

COX-2 as possible target for the inhibition of PGE2 production by Rikko-san in activated macrophage.

We have previously reported that Rikko-san (RKS) inhibited the lipopolysaccharide (LPS)-stimulated prostaglandin (PG) E2 in mouse macrophage-like RAW264.7 cells without affecting the expression of cyclooxygenase (COX)-2. Here RKS inhibition of the enzyme activity of both COX-1 and COX-2 proteins was investigated. Western blot analysis showed that RKS did not significantly change the S-nitrosylated COX-2 protein level. On the other hand, RKS inhibited the PG production catalyzed by purified COX-2, more effectively than that catalyzed by purified COX-1. These results suggest that RKS inhibits the PGE2 production by selectively inhibiting the COX-2 activity in activated macrophages.

Concentration-dependent effect of Rikko-san on the prostaglandin E2 production by mouse macrophage-like cells.

Rikko-san (RKS) and its ingredients were investigated for their activity to stimulate prostaglandin E2 (PGE2) production by unstimulated and lipopolysaccharide (LPS)-stimulated mouse macrophage-like Raw 264.7 cells. LPS significantly stimulated the production and extracellular secretion of PGE2 by Raw 264.7 cells. RKS dose-dependently modified the LPS-stimulated PGE2 production. A lower concentration (0.04-0.4 mg/ml) of RKS stimulated PGE2 production without or with LPS, whereas a higher concentration (4 mg/ml) of RKS inhibited the LPS-stimulated PGE2 production, suggesting the presence of both stimulator(s) and inhibitor(s) for PGE2 production. The inhibitory effect of a higher concentration of RKS was slightly neutralized by supplementation of exogenous arachidonic acid. Among five RKS ingredients, Kanzo inhibited the LPS-stimulated PGE2 production to the greatest extent, whereas other ingredients (Shoma, Ryutan, Saishin, Bofu) stimulated PGE2 production. Western blot analysis demonstrated that RKS and all its ingredients enhanced the intracellular concentration of cyclooxygenase-2, whereas RKS did not significantly affect the phospholipase A2 protein level. The present study demonstrates that the concentration-dependent effect of RKS on the PGE2 production by macrophage cannot be explained only by the expression levels of cyclooxygenase-2 or phospholipase A2.

Oral injuries in children: comparison of those children who visit and do not visit the after-hours clinic after telephone consultation.

Pediatric patients who sustain oral and dental injuries during the evening or night require telephone consultation and/or examination at our regional medical center in the oral surgery clinic. Between April 1, 2001 and March 31, 2003, a total of 393 patients (1-15 years old) sought advice; 67.7% came for a visit and examination after telephone consultation (visited patients) and 32.3% received telephone advice, but did not need to come for a medical visit (non-visited patients). The busiest consulting time for both groups was the evening time band. Soft tissue injuries were the most frequent in both visited and non-visited patients, 66.9 and 85.0% respectively. Particularly in non-visited patients, the upper lip was the most significantly affected site (57.4%). The most common cause of injuries was falls (84.2% of visited and 77.2% of non-visited patients). Of non-visited patients, the most common reason not to visit was a minor injury that did not require examination (87.4%). We recommend that a personal telephone call from a dentist is important because telephone consultation can help triage patients and provide relief for the patient's guardians.

Inhibition by Rikko-san and its major ingredients of LPS-stimulated nitric oxide production by mouse macrophage-like cells.

Rikko-san and its ingredients were investigated for their activity to modify nitric oxide (NO) production by unstimulated and lipopolysaccharide (LPS)-stimulated mouse macrophage-like Raw 264.7 cells. LPS significantly stimulated the NO production by Raw 264.7 cells, and Rikko-san effectively inhibited the stimulation effect of LPS even at non-cytotoxic concentrations. Among 5 Rikko-san ingredients, Kanzo showed a similar magnitude of inhibition of NO production. Shoma was also slightly inhibitory. On the other hand, Ryutan, Saishin and Bofu did not show such a clear-cut stimulation effect, due to the co-existence of both inhibitory and stimulatory substance(s) for NO production. Thus NO stimulators were present in Rikko-san and its four ingredients except for Kanzo. Western blot analysis demonstrated that LPS induced the production of inducible NO synthase (iNOS), and that non-cytotoxic concentrations of Rikko-san and Kanzo significantly inhibited the LPS-stimulated iNOS expression. ESR spectroscopy showed that Rikko-san, Kanzo, Shoma and Saishin, but not Ryutan and Bofu, produced radical(s) under alkaline condition. All samples scavenged superoxide (produced by hypoxanthine-xanthine oxidase reaction) and NO (produced by 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7)), possibly by their general reducing activity. These data suggest that the inhibition of NO production by Chinese medicines investigated here may be the result of both the inhibition of iNOS expression and their radical scavenging activity.

Comparative ultrastructural and immunohistochemical study of perineurioma and neurofibroma of the oral mucosa.

In the course of assessing the cellular composition of intraoral neurofibroma (NF), we encountered a unique gingival tumor of putative perineurial (PN) origin. The lesion showed the ordinary light microscopic NF pattern, but the ultrastructural features of well-differentiated PN cells as well as an epithelial membrane antigen (EMA)-positive, S-100 protein-negative immunoprofile confirmed the diagnosis of soft tissue perineurioma (STP). In our small series of NF, there were three ultrastructural subtypes: Type I (common Schwann cell type), Type II (NF with a high content of PN cells) and Type III (predominantly fibroblastic NF), although inhomogeneous and overlapping assembly of cellular elements. A significant number of tumor cells in Type II showed the substantial reactivity for EMA, whereas many CD34-positive cells were noted in Type III. The present results confirm previous findings that PN lineage is an important constituent in the formation of NF and reinforce the value of electron microscopy in the diagnosis of peripheral nerve sheath tumors.