Impact of beta-tricalcium phosphate on preventing tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaw in rats.

Antiresorptive or antiangiogenic drugs can cause medication-related osteonecrosis of the jaw that is refractory. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be caused by procedures such as tooth extraction damage the alveolar bone, release bisphosphonates (BPs) and impede healing. This study investigated strategies for BRONJ prevention and molecular mechanisms of its onset. We assessed the effectiveness of filling extraction sockets with beta-tricalcium phosphate (ß-TCP). Rats were administered zoledronic acid (ZA) 1.2 mg/kg once per week for 2 weeks, and a molar was extracted. They were randomly assigned to the ß-TCP group (bone defects filled with 0.01 g of ß-TCP) or control group. Tissue content measurements indicated 2.2 ng of ZA per socket in the ß-TCP group and 4.9 ng in the control group, confirming BP distribution and BP adsorption by ß-TCP in vivo. At 4 weeks after extraction, the ß-TCP group had normal mucosal coverage without inflammation. Moreover, at 8 weeks after extraction, enhanced bone healing, socket coverage, and new bone formation were observed in the ß-TCP group. Connective tissue in the extraction sockets suggested that local increases in BP concentrations may suppress the local autophagy mechanisms involved in BRONJ. Filling extraction sockets with ß-TCP may prevent BRONJ.

Cepharanthine and Oral Lichen Planus Efficacy (COLE) study: protocol for a multicentre randomised controlled study assessing the efficacy and safety of cepharanthine with topical corticosteroids in oral lichen planus.

INTRODUCTION: Oral lichen planus (OLP) is a chronic, inflammatory oral condition leading to a range of symptoms from mild discomfort to severe pain, affecting patients' quality of life. Standard therapy involves the use of topical corticosteroids, although some patients respond insufficiently or develop resistance to therapy. We aim to explore if adding cepharanthine, an herbal extract from Stephania cepharantha Hayata, can enhance the efficacy of corticosteroid therapy in symptomatic OLP. METHODS AND ANALYSIS: This open-label, parallel-group, multi-centre, randomised controlled study will be conducted at three Japanese hospitals. It will compare safety and efficacy of integrated oral cepharanthine and corticosteroid therapy versus standard corticosteroid therapy. 50 symptomatic OLP patients will be randomised 1:1 to receive cepharanthine (30 mg/day) plus topical dexamethasone, or topical dexamethasone alone for 8 weeks. The primary outcome will be changed in pain intensity while drinking room-temperature water, measured on a visual analogue scale. The primary outcome is the change in pain intensity from baseline when drinking room-temperature water, evaluated using a visual analogue scale. Secondary outcomes are changes in the longest diameter of the target lesion from baseline to weeks 4 and 8, improvement and deterioration rates according to appearance and severity criteria at weeks 4 and 8, change in pain intensity when drinking room-temperature water from baseline to week 4, changes in pain intensity at rest from baseline to weeks 4 and 8, and the rates of adverse events. ETHICS AND DISSEMINATION: This protocol was approved by the Certified Review Board of Nara Medical University (CRB5200002). Participants will provide informed consent. Results will be disseminated in peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCTs051220130).

Volume-based 18F-fluorodeoxyglucose positron emission tomography/computed tomography parameters correlate with delayed neck metastasis in clinical early-stage oral squamous cell carcinoma.

OBJECTIVE: There is no known preoperative marker that can effectively predict the risk of delayed neck metastasis (DNM), which is an important factor that determines the prognosis of early-stage oral cancer. In this study, we examined whether 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/computed tomography (CT) uptake parameters of primary cancer can predict the risk of DNM in early-stage oral squamous cell carcinoma (OSCC). METHODS: Data from patients with stage I-II OSCC who underwent surgical resection of the primary tumor without elective neck dissection between January 2009 and December 2016 were retrospectively reviewed. Patient characteristics, histopathological factors, and PET/CT parameters (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were evaluated for their association with DNM. DNM rates were calculated, and the parameters that were statistically significant in the univariate analysis were used as explanatory variables. Independent factors associated with DNM were identified using multivariate analysis. For all statistical analyses, p-values < 0.05 were considered statistically significant. RESULTS: Data from 71 patients were analyzed in the study. The overall DNM rate among all patients was 21.8%. The univariate analysis showed that the T classification, depth of invasion, pattern of invasion, lymphovascular invasion, SUVmax, MTV, and TLG were significant predictors of DNM. However, the multivariate analysis revealed that only the depth of invasion, MTV, and TLG were independent predictors of DNM. CONCLUSION: This study suggests that, in addition to conventional predictors, volume-based PET parameters are useful predictors of DNM in those with early-stage OSCC.

Peri-operative hemostatic management of tooth extraction in patients with hemophilia A, with and without inhibitors, receiving emicizumab prophylaxis.

INTRODUCTION: Emicizumab treatment may allow patients with hemophilia A without (PwHA) and with inhibitors (PwHA-I) to undergo some minor surgeries, such as tooth extraction, without peri-operative factor infusions. However, criteria for determining the necessity of factor infusions before minor surgeries are unknown. AIM: We report the peri-operative hemostatic management and outcomes of emicizumab-treated PwHA and PwHA-I cases who underwent tooth extractions using our institutional protocol. METHODS: We retrospectively evaluated PwHA and PwHA-I who underwent tooth extraction with emicizumab prophylaxis at our institution. Local bleeding risk was assessed based on the method, number, and site of tooth extraction. Hemostasis was monitored peri-operatively by rotational thromboelastometry (ROTEM). Hemostatic agents and a mouth splint were used. RESULTS: Twenty-nine extractions (17 interventions) were performed in eight PwHA and two PwHA-I. Based on ROTEM, pre-operative factor infusions were used in ten PwHA and four PwHA-I interventions. Among nine low local bleeding risk interventions, three (33.3%) each received no infusions, one dose of factor infusion pre-operatively, and pre- and post-operative factor infusions. All eight high local bleeding risk interventions involved planned factor infusions. Absorbable hemostats were used in all extractions. A mouth splint was used in 21/25 (84.0%) PwHA and in 4/4 (100%) PwHA-I extractions. No post-extraction bleeding or thrombotic events occurred. CONCLUSIONS: Use of a systemic hemostatic treatment plan according to the local bleeding risk, peri-operative coagulation status assessment using ROTEM, filling the extraction socket with hemostats, and use of a mouth splint can achieve effective and safe hemostatic management in emicizumab-treated PwHA and PwHA-I.

Examination of Suprahyoid Muscle Resection and Other Factors Affecting Swallowing Function in Patients With Advanced Oral Cancer After Surgical Resection and Reconstruction.

Dysphagia is one of the most common adverse effects associated with oral cancer therapy and could greatly impair postoperative quality of life. The objective of this study was to analyze postoperative swallowing outcomes and factors influencing postoperative swallowing function in patients with advanced oral cancer who underwent primary reconstruction after surgical resection to identify patients at risk of experiencing severe dysphagia after immediate reconstruction of surgical defects, and to determine an ideal approach to provide appropriate perioperative interventions. The swallowing status was evaluated at 4 week postoperatively using the Functional Oral Intake Scale. We also analyzed the effects of patient, tumor, surgical, and other factors on postoperative swallowing function. The study included 67 patients. At 4 weeks postoperatively, 11 patients showed reduced swallowing function, whereas 56 patients showed good swallowing function. The number of resected suprahyoid muscles (odds ratio, 1.55; 95% confidence interval, 1.03-2.32; P=0.035) was an independent factor influencing postoperative swallowing function. Thus, among patients who underwent radical resection of oral cancer with primary reconstruction, those with extensive resection of the suprahyoid muscles were at higher risk of developing postoperative dysphagia. These findings are expected to facilitate increased vigilance for dysphagia, better counseling, and appropriate rehabilitation interventions.

Salivary gland polymorphous adenocarcinoma: Clinicopathological features and gene alterations in 36 Japanese patients.

BACKGROUND: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma. METHODS: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival. CONCLUSION: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.

Effect of smoking status and programmed death-ligand 1 expression on the microenvironment and malignant transformation of oral leukoplakia: A retrospective cohort study.

Tobacco smoking is associated with an increased risk of oral leukoplakia and head and neck cancer. Although it has recently been reported that the establishment of an immunosuppressive microenvironment in oral potentially malignant disorders may lead to malignant transformation, it is unclear whether the microenvironments of oral potentially malignant disorders differ according to smoking status. We examined differences in programmed death-ligand 1 (PD-L1) expression and subepithelial CD163+ TAM and CD8+ cell/lymphocyte counts in the microenvironment of oral leukoplakia of smoking and non-smoking patients and investigated their associations with malignant transformation. Pathology reports and original biopsy request forms from 1995-2015 were retrospectively reviewed. Lesions clinically characterized as white plaques/lesions of the oral mucosa and pathologically diagnosed as oral epithelial dysplasia were included. Immunohistochemistry was performed to evaluate PD-L1 expression and subepithelial CD163+/CD8+ cell counts. The significance of prognostic factors in predicting malignant transformation was determined using Cox regression analysis. Statistical significance was defined as P<0.05. In total, 200 patients with oral leukoplakia were selected. The mean age at diagnosis was higher in non-smoking patients (n = 141; 66.9 years) than in smoking patients (n = 59; 60.5 years). The 5-year cumulative malignant transformation rate was higher in non-smoking patients than in smoking patients (9.3% vs. 3.0%, respectively). Oral leukoplakia was associated with significantly higher PD-L1 expression and increased numbers of subepithelial CD163+ cells in the non-smoking group compared with the smoking group. Non-smoking-related oral leukoplakia with positive PD-L1 expression was associated with a 6.97-fold (95% confidence interval: 2.14-22.7) increased risk of malignant transformation. The microenvironment of oral leukoplakia differed according to smoking status. A combination of smoking status and PD-L1 expression may predict malignant transformation in oral leukoplakia patients. This study highlights the importance of understanding the interaction between smoking and the microenvironment in oral leukoplakia.

Risk factors for post-extraction bleeding in patients with haemophilia: a retrospective cohort study.

Many guidelines and studies describe haemostatic management protocols for patients with haemophilia, but few have evaluated the risk factors for post-extraction bleeding. This retrospective cohort study was performed to investigate these risks among this group of patients. We used medical records to identify patients with haemophilia who underwent tooth extraction(s) between April 2006 and April 2019 in the Department of Oral and Maxillofacial Surgery at Nara Medical University Hospital, Nara, Japan, and conducted logistic regression analyses to identify risk or protective factors for post-extraction bleeding in procedures involving factor replacement therapy. Post-extraction bleeding was defined as bleeding that could not be stopped by biting down on gauze, and that required medical treatment between 30min and 14 days after the extraction. A total of 151 extractions (84 interventions) in 55 patients fulfilled the inclusion criteria (130 extractions (72 interventions) in 48 patients with haemophilia A, and 21 extractions (12 interventions) in seven patients with haemophilia B). Post-extraction bleeding was observed in nine patients (16.3%), 10 interventions (11.9%), and 12 extractions (7.9%). On average, it occurred six days after the intervention, and on the fifth postoperative day after extractions. Use of mouth splints significantly reduced the risk (odds ratio: 0.13; p=0.01) in patients on factor replacement therapy. We will conduct a prospective study to investigate the optimal type of splint and optimal splint-wearing period.

Relationship Between EGFR Expression in Oral Cancer Cell Lines and Cetuximab Antibody-dependent Cell-mediated Cytotoxicity.

BACKGROUND/AIM: Cetuximab treatment targets the epidermal growth factor receptor (EGFR) overexpressed in oral cancer. This study aimed to investigate the anti-tumour activity of cetuximab against oral cancer cell lines with respect to antibody-dependent cell-mediated cytotoxicity (ADCC), and determine the correlation between ADCC and EGFR expression. MATERIALS AND METHODS: EGFR expression in oral cancer cells was measured by quantitative flow cytometric analysis and immunohistochemistry. ADCC activity was measured by 4-h calcein release assays. RESULTS: Cetuximab-mediated ADCC against oral cancer cells was detectable at a concentration of 0.1 µg/ml. A high correlation was observed between the number of EGFR molecules on the surface of oral cancer cells and ADCC (correlation coefficient: 0.847; p=0.032). CONCLUSION: ADCC is an important mechanism underlying the therapeutic effect of cetuximab, and EGFR expression in tumour cells might serve as a predictive marker to evaluate the effect of cetuximab treatment.

Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats.

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 µg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.

Risks of postextraction bleeding after receiving direct oral anticoagulants or warfarin: a retrospective cohort study.

OBJECTIVE: The effect of direct oral anticoagulants (DOACs) on the risk of bleeding after tooth extraction remains unclear. This study aimed to evaluate the incidence of postextraction bleeding among patients who received DOAC and vitamin K antagonists (VKAs), such as warfarin. DESIGN: This study was a retrospective cohort analysis. Incidence rates and propensity score-matched regression models were used to compare the risks of bleeding after tooth extractions involving DOACs and VKAs. SETTING: The study took place in a single university hospital in Japan. PARTICIPANTS: Between April 2013 and April 2015, 543 patients underwent a total of 1196 simple tooth extractions. PRIMARY OUTCOME MEASURE: The primary outcome measure was the occurrence of postextraction bleeding, which was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 min and 7 days after the extraction. RESULTS: A total of 1196 tooth extractions (634 procedures) in 541 patients fulfilled the study criteria, with 72 extractions (41 procedures) involving DOACs, 100 extractions (50 procedures) involving VKAs and 1024 extractions (543 procedures) involving no anticoagulants. The incidences of postextraction bleeding per tooth for the DOAC, VKA and no anticoagulant extractions were 10.4%, 12.0% and 0.9%, respectively. The incidences of postextraction bleeding per procedure for DOACs, VKAs and no anticoagulants were 9.7%, 10.0% and 1.1%, respectively. In comparison to the VKA extractions, the DOAC extractions did not significantly increase the risk of postextraction bleeding (OR 0.69, 95% CIs 0.24 to 1.97; p=0.49). CONCLUSIONS: The risk of postextraction bleeding was similar for DOAC and VKA extractions.

Programmed death ligand 1 (PD-L1) expression and tumor microenvironment: Implications for patients with oral precancerous lesions.

OBJECTIVES: Cancer immunoediting represents a relatively novel concept attempting to explain the process of tumor escape from the host immune system response. Here, we attempted to elucidate the role of programmed death ligand 1 (PD-L1), the tumor microenvironment, and tumor escape mechanisms that allow malignant transformation of oral precancerous lesions. MATERIALS AND METHODS: Patients with oral precancerous lesions managed at the Nara Medical University Hospital, Japan, (n=120) were enrolled in this study. Epithelial dysplasias were graded by experienced pathologists, and subepithelial PD-L1-, CD163-, and CD8-positive cells were counted in the superficial lamina propria of oral mucosa. Epithelial PD-L1 expression was evaluated according to the staining intensity. The association of clinicopathological factors with epithelial dysplasia, malignant-free survival time, and significance of risk factors for malignant transformation were determined. RESULTS: Multivariate analysis showed that the subepithelial CD163-positive cell count was the only significant risk factor for high-grade epithelial dysplasia (P<0.001), while subepithelial CD163- and PD-L1-positive cell counts, and epithelial PD-L1 positivity were significantly associated with malignant-free survival (P=0.004, 0.04, and <0.001, respectively). Subepithelial PD-L1-positive cell count and epithelial PD-L1 positivity were significantly associated with malignant transformation (P=0.01 and 0.04, respectively). CONCLUSION: Our results indicate that PD-L1-expressing dysplastic epithelial and recruited subepithelial cells in oral precancerous legions may evade the host immune system, and that the inhibition of PD-1/PD-L1 pathway may potentially prevent malignant transformation of oral precancerous legions as well as can treat advanced cancers.

A Foreign Body Granuloma of the Buccal Mucosa Induced by Honeybee Sting.

A foreign body granuloma of the buccal mucosa induced by honeybee sting was reported. The patient was an 82-year-old female who presented with a submucous mass at the right buccal mucosa. The mass was 20 mm in diameter, elastically firm, partly mobile without pain or tenderness, and covered with almost normal mucosa. MR image did not delineate the lesion clearly. Under clinical diagnosis of a benign tumor, the lesion was excised under local anesthesia. The excised lesion was 14 × 11 × 9 mm in size and solid and yellowish in cut surface. Histologically, the lesion consisted of granulomatous tissue with a few narrow, curved, eosinophilic structures compatible with decomposed fragments of a honeybee sting and was diagnosed as a foreign body granuloma, although the patient did not recall being stung.

Maxillofacial bone regeneration with osteogenic matrix cell sheets: An experimental study in rats.

OBJECTIVE: Regeneration of maxillofacial bone defects, characterized by relatively small but complicated shapes, poses a significant clinical challenge. Osteogenic matrix cell sheets (OMCSs) have osteogenic ability and good shaping properties and may be ideal graft materials. Here, we assessed whether implantation of OMCSs could be used to repair maxillofacial bone defects. DESIGN: We adopted a rat mandibular symphysis model. The rat mandible is formed by a paired bone and the central portion consisting of fibrous tissue. There is no bone tissue at the site; accordingly, this site was interpreted as a physiological bone gap and was used for evaluation. Rat bone marrow cells were cultured in medium containing dexamethasone and ascorbic acid phosphate to create OMCSs. The OMCSs were implanted into the rat mandibular symphysis without a scaffold. Microcomputed tomography and histological analyses were conducted after 2, 4, and 8 weeks. RESULTS: Two weeks after implantation, microcomputed tomography images and histological sections showed some sparse granular calcification tissue within the bone gap at the mandibular symphysis. At 4 weeks, the calcification tissue spread, and the gap of the mandibles were continued. At 8 weeks, this continuous new bone tissue was matured. The experimental group showed abundant new bone tissue in the group with OMCS implantation, but not in the group with sham implantation. CONCLUSIONS: Our present results indicated that use of OMCSs may be an optimal approach towards achieving maxillofacial regeneration.

Multivariate analyses of Ki-67, cytokeratin 13 and cytokeratin 17 in diagnosis and prognosis of oral precancerous lesions.

BACKGROUND: Ki-67, cytokeratin 13, and/or cytokeratin 17 detection by immunohistochemistry has been reported to be useful for the diagnosis of oral precancerous lesions. However, the use of these markers remains controversial because of the lack of appropriately designed statistical studies. We assessed the hypothesis that Ki-67, cytokeratin 13, or cytokeratin 17 immunohistochemistry could facilitate the diagnosis of oral precancerous lesions and/or predict prognosis. METHODS: Epithelial dysplasia was classified as low grade (none or mild dysplasia) or high grade (moderate dysplasia, severe dysplasia, or carcinoma in situ). This study included 58 low-grade and 36 high-grade dysplasia cases. We used logistic regression to assess the diagnostic values of Ki-67, cytokeratin 13, and cytokeratin 17 for high-grade dysplasia. Correlations between these markers and the prognosis of oral atypical epithelium were assessed using the Cox proportional hazards model. RESULTS: Ki-67 overexpression and cytokeratin 13 loss were independent diagnostic markers for high-grade dysplasia (odds ratios, 1.92 and 2.53; 95% confidence intervals, 1.03-3.58, and 1.19-5.38, respectively). The area under the curve of Ki-67 was 0.73 and that of cytokeratin 13 was 0.72. However, the combination of Ki-67 and cytokeratin 13 yielded the area under the curve of 0.78. Ki-67 overexpression was significantly associated with recurrence and/or malignant transformation of oral atypical epithelium (hazard ratio, 7.25; 95% confidence interval, 1.07-48.92). CONCLUSIONS: Ki-67 overexpression and cytokeratin 13 loss may be useful for distinguishing oral precancerous lesions from reactive atypical epithelium. Moreover, Ki-67 overexpression may be a risk factor for recurrence and/or malignant transformation of oral atypical epithelium.

Unique and reliable rat model for the assessment of cell therapy: bone union in the rat mandibular symphysis using bone marrow stromal cells.

Many kinds of bone graft materials have been developed and reported to repair various bone defects. The defects are usually created by surgical resection of pre-existing bone tissue. However, spontaneous healing of bone defects without implantation of materials could be seen, because bone tissue possesses inherent repairing property. The central portion of the lower jaw bone in many animals consists of fibrous tissue and is called the mandibular symphysis. It persists even in old animals and thus can be interpreted as a physiological bone gap or a non-healing bone defect. We implanted calcium phosphate porous ceramics alone or composites of the ceramics and bone marrow stromal cells (BMSCs) into the bone defect (mandibular symphysis) to examine whether it could be filled with new bone tissue, resulting in bone union. Eight weeks after implantation, micro-computed tomography (micro-CT) and histological and biomechanical analyses demonstrated that bone union of the mandibles occurred in all rats with composites but in none of those with ceramics alone. These results showed that the rat mandibular symphysis is a unique bone defect site for the evaluation of bone graft materials. These analyses demonstrated that ceramics alone could not contribute to bone healing in the defect; however, supplementation with BMSCs drastically changed the properties of the ceramics (turning them into osteogenic ceramics), which completely healed the defect. As BMSCs can be culture-expanded using small amounts of bone marrow, the use of the composites might have clinical significance for the reconstruction of various bone tissues, including facial bone.

Osteogenic potential of mesenchymal stem cells on expanded polytetrafluoroethylene coated with both a poly-amino-Acid urethane copolymer and collagen.

We have developed an expanded polytetrafluoroethylene polymer (e-P) coated with both poly-amino-acid urethane copolymer and collagen (e-PPC) to be used for cell culture substrata. Rat mesenchymal stem cells (MSC) were cultured on the e-P and e-PPC polymers in the presence of dexamethasone. After 24 h, the MSC contacted well with the e-PPC surface and after 14 days, the MSC showed high levels of alkaline phosphatase activity, and calcium and bone-specific osteocalcin protein deposition. The MSC cultured on these polymers for 1 week were then implanted at rat subcutaneous sites and harvested after 4 weeks. Microcomputed tomography as well as histological analyses showed that any hard tissue could not be seen in implants of the MSC/e-P composites, whereas new bone formation could be detected in the MSC/e-PPC composites. These in vitro as well as in vivo results confirmed the importance of polymer surface to support the osteogenic differentiation, which resulted in new bone formation. The surface modification using poly-amino-acid urethane copolymer and collagen together with tissue engineering technology might facilitate bone anchoring to the polymers for dental and orthopedic applications.

Lymphomatoid gastropathy: a distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation.

Diagnostic errors in distinguishing between malignant and reactive processes can cause serious clinical consequences. We report 10 cases of unrecognized self-limited natural killer-cell proliferation in the stomach, designated as lymphomatoid gastropathy (LyGa). This study included 5 men and 5 women (age, 46-75 years) without any gastric symptoms. Gastroscopy showed elevated lesion(s) (diameter, ∼ 1 cm). Histologically, medium-sized to large atypical cells diffusely infiltrated the lamina propria and, occasionally, the glandular epithelium. The cells were CD2(+/-), sCD3(-), cCD3(+), CD4(-), CD5(-), CD7(+), CD8(-), CD16(-), CD20(-), CD45(+), CD56(+), CD117(-), CD158a(-), CD161(-), T cell-restricted intracellular antigen-1(+), granzyme B(+), perforin(+), Epstein-Barr early RNA(-), T-cell receptor αß(-), and T-cell receptor γδ(-). Analysis of the 16 specimens biopsied from 10 patients led to a diagnosis of lymphoma or suspected lymphoma in 11 specimens, gastritis for 1 specimen, adenocarcinoma for 1 specimen, and LyGa or suspected LyGa for 3 specimens. Most lesions underwent self-regression. Three cases relapsed, but none of the patients died. According to conventional histopathologic criteria, LyGa is probably diagnosed as lymphoma, especially as extranodal natural killer/T-cell lymphoma, nasal type. However, LyGa is recognized as a pseudomalignant process because of its clinical characteristics. The concept of LyGa should be well recognized.

Hard tissue-forming potential of stem/progenitor cells in human dental follicle and dental papilla.

OBJECTIVE: The existence of stem/progenitor cells in dental tissue has been suggested but their characterization in the human tooth germ remains elusive. The purpose of this study was to investigate these cells in human dental follicles and dental papillae at the crown-forming stage and compare their potential for hard tissue formation. DESIGN: We used dental follicle cells (DFCs) and dental papilla cells (DPCs) derived from dental follicles and dental papillae at the crown-forming stage and compared their proliferative capacity, cell surface antigens and ability to form hard tissue in vitro and in vivo. RESULTS: Both DFCs and DPCs had extensive proliferation ability, expressed similar cell surface antigens and were capable of forming hard tissue in vivo as well as in vitro. However, there were two differences between DFCs and DPCs. First, DPCs had a significantly higher calcium accumulation than that in DFCs. Second, DFCs expressed a cementoblast marker, whereas DPCs expressed an odontoblast marker. CONCLUSIONS: We propose that dental follicles and dental papillae at the crown-forming stage contain different types of stem/progenitor cells and may have hard tissue-forming ability in a possibly origin-specific lineage direction.

Recurrence of keratocystic odontogenic tumor: clinicopathological features and immunohistochemical study of the Hedgehog signaling pathway.

AIMS: Critical factors responsible for the recurrence of keratocystic odontogenic tumor (KCOT) were examined. METHODS: The clinicopathological features were retrospectively studied in 74 patients with 75 sporadic KCOTs. From the 75 KCOTs, 23 were examined for the expression of Sonic Hedgehog (SHH), Patched and Smoothened (SMO) by immunohistochemistry. RESULTS: Recurrence in multilocular lesions was more frequent than in unilocular lesions. Nine (64%) of 14 multilocular lesions recurred, in contrast to 2 (7%) of 27 unilocular lesions (p = 0.0350). The average length of recurrent lesions (62.8 +/- 6.5 mm) was larger than that of nonrecurrent lesions (43.0 +/- 4.0 mm; p = 0.0363). The immunoreactivity of proliferation-related SMO in KCOTs with recurrence was higher than that of those without recurrence (p = 0.0475), whereas the expressions of a ligand, SHH, and an inhibitory receptor, Patched, were not associated with KCOT recurrence. The expressions of SHH and SMO showed inverse correlation in whole KCOT (p = 0.0318). CONCLUSION: These findings suggest that recurrence of KCOT is associated with multilocular large lesions and high SMO expression.