Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Influence of intracoronal bleaching agents on the ultimate strength and ultrastructure morphology of dentine.

OBJECTIVE: To evaluate the effects of intracoronal bleaching on ultimate tensile strength (UTS) of sound and etched dentine and its ultrastructure morphology. METHODOLOGY: Bovine dentine specimens with (e) or without previous etching with 37% phosphoric acid for 15 s were used for the intracoronal bleaching experiments. Teeth were randomly assigned to five treatments (n = 10): (C) control--no bleaching, (SP) sodium perborate, (CP) 35% carbamide peroxide, (25% HP) 25% hydrogen peroxide and (35% HP) 35% hydrogen peroxide. Bleaching was performed four times within a 72 h interval and afterwards, dentine pulp chamber blocks were obtained. The blocks were sectioned in 0.7 mm-thick slices and these were trimmed to reduce the inner dentine to a dumbbell shape with a cross-sectional area of 0.8 mm(2). Specimens were tested with the microtensile method (0.5 mm min(-1)) and data were analysed (two-way ANOVA-Tukey test, P < 0.05). Additional teeth were prepared for transmission electron microscopy (TEM) to evaluate dentine ultramorphology. RESULTS: The mean values of the UTS (SD) in MPa for sound dentine were: C = 48.3(8.5)a, SP = 34.6 (8.2)b, CP = 32.9 (8.9)b, 25% HP = 28.0(4.6)b, 35% HP = 26.4(6.6)b, and pre-etched dentine: Ce = 38.9(13.8)a, SPe = 31.3 (9.3)ab, CPe = 28.4 (6.2)ab, 25% HPe = 30.0 (7.9)ab, 35% HPe = 19.9(4.6)b. Significant differences between the means are indicated by the letters. TEM observations exhibited demineralization areas for all bleaching treatments. CONCLUSION: Bleaching decreased dentine UTS after treatment. Pre-etched not-bleached dentine (Ce) presented UTS similar to pre-etched bleached dentine, except for 35% HPe. The decrease of UTS of bleached dentine could be attributed to ultrastructural alterations such as loss of inorganic components.

Intraarterial infusion chemotherapy and conformal radiotherapy for cancer of the mouth: prediction of the histological response to therapy with magnetic resonance imaging.

BACKGROUND: Although intraarterial chemotherapy has been used to treat head and neck cancers, some cases have shown poor response. If we can predict the response to this therapy on MRI, individual treatment plans may be altered to the most appropriate form of treatment. PURPOSE: To evaluate whether MRI can predict the histological response to preoperative chemoirradiation in patients with cancer of the mouth. MATERIAL AND METHODS: This study comprised of 29 consecutive patients with 30 oral cancers. All patients underwent tumor resection after intraarterial infusion chemotherapy and conformal radiotherapy. We compared the margin of the tumor, the presence of bone invasion, tumor area, and volume on pre- and post-treatment MRI with histological responses. RESULTS: Eighteen lesions showed an excellent response, nine exhibited a good response, and three a poor response. Only the tumor area on pretreatment T1-weighted images and the tumor area and volume on pretreatment enhanced T1-weighted images were significantly correlated with the histological response (P = 0.039, 0.008, and 0.016, respectively); smaller cancers showed better responses. The other factors were not significantly correlated with the histological responses. CONCLUSION: MRI parameters, excluding initial tumor area and volume, were not predictive of the histological response of oral tumors to preoperative treatment.

Novel integrative methodology for engineering large liver tissue equivalents based on three-dimensional scaffold fabrication and cellular aggregate assembly.

A novel engineering methodology for organizing a large liver tissue equivalent was established by intergrating both 'top down' and 'bottom up' approaches. A three-dimensional (3D) scaffold was engineered comprising 43 culture chambers (volume: 11.63 cm(3)) assembled in a symmetrical pattern on 3 layers, a design which enables further scaling up of the device to a clinically significant size (volume: 500 cm(3)). In addition, an inter-connected flow channel network was designed and proved to homogenously deliver culture medium to each chamber with the same pressure drop. After fabrication using nylon-12 and a selective laser sintering process, co-cultured cellular aggregates of human hepatoma Hep G2 and TMNK-1 cells were loosely packed into the culture chambers with biodegradable poly-L-lactic acid fibre pieces for 9 days of perfusion culture. The device enabled increased hepatic function and well-maintained cell viability, demonstrating the importance of an independent medium flow supply for cell growth and function provided by the current 3D scaffold. This integrative methodology from the macro- to the micro-scale provides an efficient way of arranging engineered liver tissue with improved mass transfer, making it possible to further scale up to a construct with clinically relevant size while maintaining high per-volume-based physiological function in the near future.

A drug formulation using an alginate hydrogel matrix for efficient oral delivery of the manganese porphyrin-based superoxide dismutase mimic.

In order for patients to avail of the therapeutic benefits of antioxidant drugs efficiently and conveniently, a robust oral delivery system needs to be developed. However, a common problem in oral drug delivery is ensuring that the drug remains functionally intact even after it has passed through the acidic environment of the gastrointestinal (GI) tract. To protect drugs within the GI environment, we formulated a design based on encapsulating liposomal drugs by using an alginate matrix as a carrier. The liposomal drug was composed of manganese porphyrin (Mn-por), which has been developed as a mimic of superoxide dismutase (SOD), as the therapeutic agent based on the antioxidative effect, namely superoxide (O2˙(-)) inhibitory activity. A cytochrome c assay revealed that the O2˙(-) inhibitory activity of Mn-por could be maintained even after treatment with simulated gastric and intestinal fluids. We demonstrated that oral administration of the formulated drug significantly inhibited the growth of transplanted tumors in mice. The drug formulation presented in this study would be a good candidate for orally available systems, which can effectively deliver SOD mimics.

Effect of streptozotocin diabetes on gingivitis in plaque-susceptible rats.

The periodontal pocket probing depths of mandibular incisors of plaque-susceptible (Sus) rats, which spontaneously exhibit gingivitis with accumulation of plaque, were increased 20 days after injection of streptozotocin (70 mg/kg, i.v.). The accumulated plaque weights were also increased in Sus rats with streptozotocin diabetes, and a positive correlation was found between the plaque weights and the pocket depths. Histological findings showed that this inflammatory reaction in gingival tissue was higher and more extensive in diabetic Sus rats than in control Sus rats. These findings suggest that the accumulated plaque is the important factor for the severe breakdown of gingival tissue in this experimental model.

Experimental gingivitis in ODU plaque-susceptible rats. I. Changes of plaque formation and body weight.

New strains of ODU plaque-susceptible and resistant rats have been developed starting from litter mating at our laboratory, in 1972. Those strains were selected and mated for further generations. ODU plaque-susceptible and resistant rats are those that show the presence or absence of plaque formation in their gingiva of lower incisors after they are fed a commercially available powder diet. Experiments were started when rats weighing 75 to 85 gm were about 5 weeks old being fed with 20 gm of a powder diet a day. Almost every 4 days, plaque formation was observed in terms of 5 degrees from zero to 4 degrees and body weight. As a result, plaque formation in plaque-susceptible and resistant rats clearly showed their quality in their 3rd generation. Those qualities will be further emphasized as the generation advances. In the 3rd generation of plaque-susceptible rats, no difference was found in growth between those ingested with a powder diet and those with a solid diet of the same ingredients. But in the first 2 months, male plaque-resistant rats of the 3rd generation grew more quickly than susceptible rats.

Experimental gingivitis in ODU plaque-susceptible rats. II. Biochemical nature of the rat plaque.

The characterization of the dental plaque from ODU plaque-susceptible rats is reported. The comparison between the rat dental plaque and a human dental plaque indicates that content of extractable hexose and inorganic salts and amino acid composition are different from each other. Electron microscopic study indicates that bacterial flora of the rat dental plaque seems to be little different from a human dental plaque. In spite spite of obvious differences in biochemical nature between the rat dental plaque and the human dental plaque, there are enough similarities to warrant intensive investigation regarding the relationship between the dental plaque and gingivitis.

Experimental gingivitis in ODU plaque-susceptible rats. III. Toxic activity of the rat dental plaque.

The toxicity tests of the dental plaque from ODU plaque-susceptible rats showed strong lethal effect on mice, and abscess forming effect on guinea-pigs. Bacterial cells isolated from the rat dental plaque also showed strong toxicity on both animals and capillary permeable activity on rabbits. Among these bacterial cells, Corynebacterium showed the strongest toxic effects on these animals. These facts suggested an important role of the dental plaque on initiation and development of gingivitis and that especially Corynebacterium may play an important role on gingivitis in ODU plaque-susceptible rats.

Leucocyte function in rats with naturally occurring gingivitis.

The severity of gingivitis in relation to abnormal macrophage chemotaxis and superoxide (O2-) production was investigated in rats with naturally occurring gingivitis (plaque-susceptible rats). Macrophage chemotaxis was measured by the membrane filter method; zymosan-activated serum was used as a chemo-attractant. O2- production was measured by the reduction of cytochrome c method. Opsonized zymosan, phorbol myristate acetate and calcium ionophore A23187 were used as stimulants. The macrophage chemotaxis and O2- production in the plaque-susceptible rats with deep pockets were significantly lower than those in the susceptible rats with shallow pockets or the normal group. In addition, there was a negative correlation between the severity of gingivitis in plaque-susceptible rats and macrophage chemotaxis or O2- production. These findings suggest that impairement of the host defence mechanisms due to the reduction in macrophage chemotaxis and O2- production is related to the progression of periodontal disease in plaque-susceptible rats.

Humoral immune responses in experimental gingivitis in rats.

Serum IgG, IgM, and IgA antibody levels to extracts of rat dental plaque and five oral bacteria (Haemophilus actinomycetemcomitans Y-4, Bacteroides gingivalis 381, Bact. intermedius ATCC 25261, Capnocytophaga sp. M-12, Eikenella corrodens ODU) were determined by ELISA. In addition, the presence of rat dental plaque and oral bacterial components in the inflamed gingival tissue was studied using immunofluorescence techniques. Serum and gingival tissue samples were obtained from ODU plaque-susceptible and plaque-resistant rats. In several susceptible rats, IgG, IgM, and IgA antibodies against dental plaque and oral bacteria were detected. There was a correlation between the levels of IgG antibody to dental plaque and pocket probing depth, but not between pocket probing depth and the levels of IgM and IgA. Furthermore, components of rat dental plaque and oral bacteria were detected in the inflamed gingival tissue.

Induction of apoptosis in human gingival fibroblasts by a Porphyromonas gingivalis protease preparation.

Proteases produced by Porphyromonas gingivalis are believed to contribute to the pathogenesis of periodontal diseases. Here the cytotoxic effects of a purified preparation of a P. gingivalis protease with trypsin-like specificity were tested on human gingival fibroblasts in vitro. The active protease induced apoptotic cell death in the fibroblasts, as indicated by DNA fragmentation and the expression of 7A6 antigen. Thus, the production of proteases by periodontopathic bacteria could be an important factor in the induction of apoptosis of host cells in the aetiology of periodontal diseases.

Involvement of CD14 on human gingival fibroblasts in Porphyromonas gingivalis lipopolysaccharide-mediated interleukin-6 secretion.

The lipopolysaccharides (LPS) of Porphyromonas gingivalis are implicated in the initiation and development of periodontal diseases. However, the mechanisms underlying P. gingivalis LPS-mediated periodontal destruction are still unknown. Here, it was found that P. gingivalis LPS activates human gingival fibroblasts (HGF) to release interleukin 6 (IL-6) via CD14. Flow-cytometric analysis showed that HGFs bind to fluorescein-isothiocyanate (FITC)-labelled LPS, and express CD14 on their surfaces. The binding of FITC LPS was competitively suppressed by unlabelled synthetic lipid A as well as by LPS. LPS-induced IL-6 production was inhibited by anti-CD14 monoclonal antibody in a dose-dependent manner. The binding of FITC LPS to HGF was abrogated by anti-CD14 monoclonal antibody. Engagement of LPS initiated the protein tyrosine phosphorylation of several intracellular proteins including extracellular signal-regulated kinase (ERK) 1 and 2, and these events were suppressed by the anti-CD14 monoclonal. These results suggest that CD14 is a cell surface binding site for LPS and is involved in the LPS-mediated activation of HGF.

Numb chin syndrome as an initial symptom of acute lymphocytic leukemia: report of three cases.

This article describes three cases of acute lymphocytic leukemia that presented with mental neuropathy, or so-called "numb chin syndrome," as the initial symptom of the disease. This symptom heralded the initial progression of the disease in the first and second cases and the recurrence of the disease in the third case. In these cases tenderness in the mental foramen, percussion pain of the teeth, loosening and extrusion of the teeth, and radiographic abnormalities were also, if not always, observed in association with mental neuropathy. The radiographic abnormalities included a disappearance of the mandibular canals, an enlarged periodontal ligament space, a loss or thinning of the lamina dura, and a destruction of the alveolar crestal bone. This report indicates that oral manifestations can therefore occasionally play an extremely important role in the early recognition of acute lymphocytic leukemia. The unexplained oral abnormalities such as numbness of the chin and lower lip must thus be considered, potentially ominous indication of acute lymphocytic leukemia.

Morphologic analysis of odontogenic cysts with computed tomography.

PURPOSE: The purpose of this study was to analyze the effects of lesion site and epithelial keratinization on the morphologic characteristics of odontogenic cysts and clarify determinate factors for cyst morphology. MATERIAL AND METHODS: Computed tomographic images of 92 odontogenic cysts were analyzed: 31 primordial, 31 dentigerous and 30 radicular. Thirty-four cysts were located in the maxilla (6 primordial, 10 dentigerous, and 18 radicular) and 58 in the mandible (25 primordial, 21 dentigerous, and 12 radicular). Histologically, 31 cysts showed epithelial keratinization (18 primordial and 13 dentigerous). No keratinization was seen in radicular cysts. The morphologic features of cysts were assessed by measuring long length parallel to dental arch and short length vertical to it and calculating the long/short ratio. In addition, the computed tomography pattern of the cyst was classified into unilocular, lobulated, and multilocular patterns. Appearance of the sclerotic rim and surrounding cortex were classified into three and four patterns respectively to evaluate the developmental features of the cyst. RESULTS: As a whole, the long length of the primordial cysts was statistically larger than the other two cyst groups and resulted in a larger long/short ratio. Statistical differences of CT pattern were also seen among cyst groups. There was no preference in any cyst group for the appearance of the sclerotic rim and cortex. There were statistical differences between maxilla and mandible in short axis and long/short ratio. The maxillary cysts generally showed round shapes irrespective of their histologic characteristics. A multilocular pattern was more frequent in the keratinized group of mandibular primordial cysts. In dentigerous cysts, a multilocular pattern was seen only in the keratinized group and the long/short ratio was statistically larger; cyst shape was elliptical along the long axis. CONCLUSION: Our results demonstrated morphologic differences of odontogenic cysts caused by lesion site and keratinization. The dentigerous cyst with predominant keratinization should be included in the primordial cyst (odontogenic keratocyst) group.

Computed tomography appearance of marked keratinization of metastatic cervical lymph nodes: a case report.

A case of squamous cell carcinoma of the tongue is reported with emphasis on an atypical finding of cervical lymph node metastasis visible on computed tomography. Multiple cervical lymph nodes revealed a high computed tomographic value of about 330 HU, lower than that of calcification. The lymph nodes revealed well-defined elliptical hyperechoic masses with an echogenic line and posterior shadow on ultrasonography. The appearance of a high density mass on computed tomography with a computed tomographic value lower than that of calcification may be a reliable finding of metastasis because it demonstrates the presence of marked keratinization produced by squamous cell carcinoma.

Sonographic analysis of recurrent parotitis in children: a comparative study with sialographic findings.

OBJECTIVE: The sonographic features of recurrent parotitis in children were studied to clarify a relationship between sonographic and sialographic findings in this disease. STUDY DESIGN: Twenty-one glands (7 on follow-up) were examined by 7.5 MHz ultrasonography and sialography. Echo intensity level, distribution of the internal echoes, and size of hypoechoic areas were compared with the size of punctate shadows on the sialograms. Twenty other histopathologic specimens were analyzed to investigate the entity of hypoechoic areas. RESULTS: Sonography showed hypoechoic, heterogeneous internal echoes, the level of which increased as the punctate shadows enlarged. Hypoechoic areas, all of which were larger than the sialographic punctate shadows, were observed in 62% of the glands. Histopathologic analysis suggests that these hypoechoic areas represent dilated peripheral ducts with lymphocytic infiltration. Sonography was likely to detect changes over time more sensitively than sialography. CONCLUSIONS: Sonography should be performed as the test of first choice, both in the primary and follow-up stages, in cases of recurrent parotitis in children.

Mucoepidermoid carcinoma in the mandible: findings of panoramic radiography and computed tomography.

Six patients with mucoepidermoid carcinoma in the mandible were studied with both panoramic radiography and computed tomography. Lesion shape and margin were evaluated on panoramic radiography, and bony expansion and cortical plate destruction were evaluated on computed tomography. In addition, a possible correlation among radiographic findings, histologic findings, and prognosis was investigated. Lesions found on panoramic radiography were classified into three types; each type pertained to two of the six patients. The lesion types were as follows: cystic, characterized by a large, cystic radiolucent area; rarefying, characterized by rarefying changes of the trabeculae; and infiltrative, characterized by a central ill-defined area of bony destruction. The results show that computed tomography is useful in the identification of tumor extent, bony expansion, and cortical plate destruction resulting from tumors. None of the patients whose lesions were of the cystic or rarefying type showed evidence of disease after surgery. In contrast, both of the patients whose lesions were of the infiltrative type died of their tumors. Histologic findings of the cystic and rarefying types showed tumors that were well-differentiated or moderately well-differentiated, whereas findings of the infiltrative type showed poorly differentiated tumors. Radiographic findings correlated with histologic findings and prognosis of mucoepidermoid carcinoma in the mandible in this limited series.

An iatrogenic foreign body (dental bur) in the maxillary antrum: a report of two cases.

Two cases of foreign bodies of the antrum are reported. One was a turbine bur which presumably entered through an oro-antral fistula after a tooth extraction. The other was also a turbine bur where the mode of entry was not clear (lack of oro-antral fistula), but it presumably entered through the socket of the extracted tooth. The mucosa of the antrum appeared normal in spite of the lengthy presence of the foreign body.