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Obturator hernia is a rare condition. Preoperative diagnosis is difficult to achieve because the hernia swelling is rarely palpable. Diagnosis is often delayed, and the hernia can become fatal if intestinal strangulation occurs, especially in older patients. Hesitation in the intervention will result in perforation, peritonitis, sepsis, and death. We herein report a case involving a Japanese woman in her 90s who visited our emergency room with nausea and right inner thigh pain. Computed tomography (CT) at onset revealed intestinal incarceration between the piriformis and external obturator muscles; therefore, a right-sided obturator hernia was diagnosed. Manual release of the incarceration, combined with echo probe manipulation and lower extremity movement, was successfully performed. The patient's pain was dramatically reduced, and emergency surgery was avoided. A prompt hernia release after reaching the correct diagnosis is very important for obturator hernia patients. Scheduled minimally invasive surgery (transabdominal pre-peritoneal repair, TAPP) was subsequently performed. Intraoperatively, a coexistence of ipsilateral femoral hernia was detected by laparoscope. Therefore, we tried to cover not only the obturator canal but also the subclinical coexistence of ipsilateral groin hernias. All four hernia orifices (obturator hernia orifice, internal inguinal hernia orifice, external inguinal hernia orifice, and femoral hernia orifice) were covered at the same time with a single large mesh of 15 × 10 cm. Reports detailing such approaches (total and simultaneous coverage of the obturator canal and myopectineal orifice with one rectangular mesh) are relatively rare in the literature., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Urade et al.)

Background: Medical institutions are required to report suspected cases of child abuse to administrative agencies, such as child guidance centers in Japan. It is left to the discretion of the medical institutions whether to notify the family of the child or the center. However, it is unclear what kinds of measures are being taken to ensure a robust policy of notification versus non-notification and how notifying the family will affect the child., Methods: An unregistered questionnaire survey on reporting suspected child abuse cases to child consultation centers and notifying families was conducted by mail across 518 pediatric specialist training facility hospitals designated by the Japanese Pediatric Society., Results: Responses were received from 323 facilities (62.4% response rate), of which 5 facilities were excluded because of incomplete responses. Therefore, in all, 318 facilities were included in the analysis. The results showed that 59.8% of the facilities had a policy of notifying the family, 33.7% said the decision varies from case to case, and 6.6% did not have a policy of notifying the family. The facilities that had a policy of either notifying or not notifying the family were less likely to experience problems than those with a policy of deciding on a case-by-case basis. The proportion of cases in which some problems occurred was higher in the cases where families were notified than in the cases where they were not, with 51.4% of the children experiencing worsening of relationships with family members. In the cases where the families were not notified, the children were twice as likely to experience further abuse than in cases where the families were notified., Conclusion: Problems arise in the case of both notification and non-notification. It is necessary to examine background factors and specific methods of notification in the cases where problems arise.

Endoscopic stenting is useful for amelioration of gastrointestinal stenosis. This procedure benefits severely compromised patients who cannot afford surgery. Although the self-expandable metallic stent (SEMS) is safe, it is also associated with several complications such as perforation, migration, and fracture. Migration of a SEMS is not particularly rare; however, fracture of a SEMS is relatively rare. An 88-year-old man underwent stenting for dysphagia at another hospital. He was being treated for gastric cancer at the esophagogastric junction. After appropriate stenting, he regained his ability to eat and was discharged the hospital. Only 2 months later, however, he again lost his ability to eat and visited our hospital. Abdominal X-ray and computed tomography revealed a stent fracture. The proximal fragment was in the esophagus, and the distal fragment was in the stomach. An emergency operation involving gastrotomy and gastrostomy was performed. Open gastrotomy was performed to remove the fractured distal stent, and percutaneous tube gastrostomy was placed through the same gastric incision for nutrition support. The surgery was successful, and he was again able to eat. In this report, we discuss the occurrence of SEMS fracture within a short time periods after insertion., (© 2022. Japanese Society of Gastroenterology.)

Simple liver cysts are usually asymptomatic, and complications are uncommon. However, infection of cysts can very occasionally occur, and this troublesome complication requires treatment. An 87-year-old woman admitted for dyspnea, abdominal discomfort, fever, and mild icterus underwent ultrasonographic (US) and computed tomography (CT) examinations, and a huge cystic lesion was identified in the right hepatic lobe. The diagnosis of an infected gigantic liver cyst was made by abdominal CT and percutaneous transhepatic drainage under ultrasonographic guidance. The pus viscosity was so high that pus drainage was ineffective. Bacterial culture was positive for Klebsiella pneumoniae. The cyst diameter was approximately 21 cm, and the total pus discharge was 3.8 l. Emergency operation to fenestrate the cyst wall relieved the patient's critical condition. This report is clinically significant because 3.8 l of pus may be one of the largest reported quantity of drained pus from an infected cyst. We found no reports of > 3.8 l of drained pus in an English literature search. It is also very rare that imaging identified postoperative liver regeneration filling the huge empty space previously occupied by the cyst. Large liver cysts in older people should be carefully followed, preparing for the rare possibility of infection.

We report on the findings of the first antimicrobial susceptibility surveillance study in Japan of isolates recovered from odontogenic infections. Of the 38 facilities where patients representing the 4 groups of odontogenic infections were seen, 102 samples were collected from cases of periodontitis (group 1), 6 samples from pericoronitis (group 2), 84 samples from jaw inflammation (group 3) and 54 samples from phlegmon of the jaw bone area (group 4) for a total of 246 samples. The positivity rates of bacterial growth on culture were 85.3%, 100%, 84% and 88.9%, respectively, for groups 1, 2, 3 and 4. Streptococcus spp. isolation rates according to odontogenic infection group were 22% (group 1), 17.7% (group 3) and 20.7% (group 4). Anaerobic isolation rates were 66.9% (group 1), 71.8% (group 3) and 68.2% (group 4). Drug susceptibility tests were performed on 726 strains excluding 121 strains that were undergrown. The breakdown of the strains subjected to testing was 186 Streptococcus spp., 179 anaerobic gram-positive cocci, 246 Prevotella spp., 27 Porphyromonas spp., and 88 Fusobacterium spp. The isolates were tested against 30 antimicrobial agents. Sensitivities to penicillins and cephems were good except for Prevotella spp. The low sensitivities of Prevotella spp is due to β-lactamase production. Prevotella strains resistant to macrolides, quinolones, and clindamycin were found. No strains resistant to carbapenems or penems were found among all strains tested. No anaerobic bacterial strain was resistant to metronidazole. Antimicrobial susceptibility testing performed on the S. anginosus group and anaerobic bacteria, which are the major pathogens associated with odontogenic infections, showed low MIC 90 values to the penicillins which are the first-line antimicrobial agents for odontogenic infections; however, for Prevotella spp., penicillins combined with β-lactamase inhibitor showed low MIC 90 values., Competing Interests: Declaration of competing interest Tetsuya Matsumoto received speaker honoraria from MSD K.K., and Pfizer Japan Inc., Hiroshi Kiyota received scholarship donations from Taisho Toyama Pharmaceutical Co., Ltd., Fujifilm Toyama Chemical Co., Ltd., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Taiho Pharmaceutical Co., Ltd., and Sanofi K.K., Kazuhiro Tateda received speaker honoraria from Pfizer Japan Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., and Taisho Toyama Pharmaceutical Co., Ltd., and grant support from Hitachi, Ltd., Nissui Pharmaceutical Co., Ltd., BD Japan Co., Ltd., Denka Co., Ltd., Kaneka Co., and Shimadzu Co., received scholarship donations from Fujifilm Toyama Chemical Co., Ltd., Meiji Seika Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Shionogi & Co., Ltd., and Asahi Kasei Pharma Co., Hiromitsu Kishimoto received speaker honoraria from Daiichi Sankyo Co., Ltd., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Ectopic pancreas is a congenital developmental anomaly that may be caused by embryologic errors. The pathogenetic details of ectopic pancreas remain unclear, but it has gradually been determined to originate at the gene level. DNA errors during embryological development cause ectopic pancreas. Ectopic pancreas is generally asymptomatic and harmless throughout the patient's entire life; in very rare cases, however, it can be symptomatic and harmful, causing pain, fever, bleeding, and other adverse effects. We herein report an unusual case involving a 52-year-old Japanese woman who presented with nausea and vomiting due to inflammation of an ectopic pancreas in the gastric antrum. Ectopic pancreatitis caused severe pyloric stenosis, and she was unable to ingest food or water even after admission to the internal medicine ward. Ectopic pancreatitis is a very rare clinical condition, but clinicians should be cautious of this uncommon disease in patients who develop gastric outlet obstruction without cancer or ulcers. The present case report is clinically significant because surgical treatment (distal partial gastrectomy) relieved the patient's serious distress rapidly and successfully after unsuccessful conservative treatments for acute ectopic pancreatitis. Antrectomy (distal partial gastrectomy) might be useful for ectopic pancreas, especially in case of gastric outlet obstruction due to the ectopic pancreatitis.

Background: The effectiveness of an oral hygiene program for children living in a children's home has been reported. However, to the best of our knowledge, no studies have evaluated the possible effects of self-checking of oral health among children residing in a children's home. The objective of this study was to examine if self-checking using plaque disclosing solution improves oral hygiene in schoolchildren living in a children's home., Methods: We enrolled nine schoolchildren (six girls) without untreated decayed teeth living in a children's home in Japan. This preliminary study was designed as a 5-month program comprising group and individual instructions and self-checking using plaque disclosing solution. Paired t-test and Wilcoxon signed-rank test were used for statistical analysis to evaluate the change of Plaque Control Record (PCR) and Patient Hygiene Performance (PHP)., Results: The mean PCR significantly decreased to 38.7% after 3 months of self-checking using disclosing solution compared with that before self-checking (i.e., at 1 month) (60.7%) ( P  < 0.01). PHP score significantly decreased to 1.4 at 4 months compared with that at baseline (2.8) and at 1 month (2.7) ( P  = 0.012 and P  = 0.018). Improvement of oral hygiene status was evaluated according to the ratio of PCR at 4 months to that at 1 month. The average improvement ratio was 0.4 ± 0.35 (range: 0.0-1.0). Significant correlation was not found between improvement rate and school grade ( r  = 0.63, P  = 0.070)., Conclusions: Our results suggest that self-checking with disclosing solution may be effective in improving oral hygiene among schoolchildren at a children's home., Competing Interests: The study design was approved by the Ethical Committee of Hiroshima University (No. 1814) and informed consent was obtained from all participants and individuals in parental authority.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an intractable, though rare, complication in cancer patients with bone metastases and patients with osteoporosis who are treated with antiresorptive agents, including bisphosphonates and denosumab. Despite the more than 10 years that have passed since the first cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) were reported, our understanding of the epidemiology and pathophysiology of ARONJ remains limited, and data supported by evidence-based medicine are still sparse. However, the diagnosis and staging of ARONJ, identification of risk factors, and development of preventive and therapeutic approaches have advanced significantly over the past decade. The Position Paper 2017 is an updated version of the Position Paper 2010 of the Japanese Allied Committee on Osteonecrosis of the Jaw, which now comprises six Japanese academic societies. The Position Paper 2017 describes a new diagnostic definition for ARONJ, as proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS), summarizes our current understanding of the pathophysiology of ARONJ based on a literature search, and suggests methods for physicians and dentists/oral surgeons to manage the disease. In addition, the appropriateness of discontinuing antiresorptive medications (drug holiday) before, during, and after invasive dental treatments is discussed extensively. More importantly, the manuscript also proposes, for the first time, the importance of interactive communication and cooperation between physicians and dentists/oral surgeons for the successful treatment of ARONJ. The Position Paper 2017 is intended to serve as a guide for improving the management of ARONJ patients in Japan.

Following the publication of this article, an interested reader drew to our attention an anomaly associated with the presentation of Figs. 2 and 3. Essentially, there was a direct duplication of certain of the western blotting data between Fig. 2 (the E-cadherin and Actin data) and Fig. 3C (the Zyxin and Actin data). After having re-examined our original data, we realize that we inadvertently duplicated the data from Fig. 2 in Fig. 3C (the Zyxin and Actin data). A corrected version of Fig. 3C (containing the true Zyxin and Actin data), and, by natural process, also of Fig. 6, are presented below, in which the Zyxin data in Figs. 3C and 6 are now correctly shown. Since the Zyxin data was a control for the siZyxin knockout of HOC313, this error did not affect the results of the Rho family analysis in this study. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience this mistake has caused. [the original article was published in the International Journal of Oncology 42: 873-880, 2013; DOI: 10.3892/ijo.2013.1761].

Background: We evaluated the side effects of bisphosphonate (BP) on tooth extraction socket healing in spontaneously diabetic Torii (SDT) rats, an established model of non-obese type 2 diabetes mellitus, to develop an animal model of BP-related osteonecrosis of the jaws (BRONJ)., Materials and Methods: Male Sprague-Dawley (SD) rats and SDT rats were randomly assigned to the zoledronic acid (ZOL)-treated groups (SD/ZOL or SDT/ZOL) or to the control groups (SD/control or SDT/control). Rats in the SD/ZOL or SDT/ZOL groups received an intravenous bolus injection of ZOL (35 μg/kg) every 2 weeks. Each group consisted of 6 rats each. Twenty-one weeks after ZOL treatment began, the left maxillary molars were extracted. The rats were euthanized at 2, 4, or 8 weeks after tooth extraction, and the total maxillae were harvested for histological and histochemical studies., Results: In the oral cavity, bone exposure persisted at the tooth extraction site in all rats of the SDT/ZOL group until 8 weeks after tooth extraction. In contrast, there was no bone exposure in SD/control or SDT/control groups, and only 1 of 6 rats in the SD/ZOL group showed bone exposure. Histologically, necrotic bone areas with empty lacunae, microbial colonies, and less invasion by inflammatory cells were observed. The number of tartrate-resistant acid phosphatase-positive osteoclasts was lower in the SDT/ZOL group than in the SD/control group. The mineral apposition rate was significantly lower in the SDT/ZOL group compared with the SD/control group., Conclusions: This study demonstrated the development of BRONJ-like lesions in rats and suggested that low bone turnover with less inflammatory cell infiltration plays an important role in the development of BRONJ.

Dental implants play an important role in postoperative rehabilitation after surgical treatment of oral cancer through the provision of prosthetic tooth replacement. Two major implant prosthesis designs are available: fixed implant-supported prostheses and implant-supported overdentures. We herein report a case of a 16-year-old female patient who underwent alveolar ridge resection for treatment of mandibular gingival carcinoma. Following surgery, oral rehabilitation was attempted using an implant-supported overdenture on a gold bar retainer splinting four implants. However, the patient was not satisfied with this prosthesis because of mucosal pain and discomfort, and she gradually ceased its use. Consequently, contact with the opposing teeth caused wear of the prosthetic screws. We elected to replace the implant-supported overdenture with an implant-fixed prosthesis approximately 16 years after insertion of the overdenture to prevent further wear of the prosthetic screws. The patient was highly satisfied with the improved stability of the implant-fixed prosthesis. This case report indicates that the clinician must occasionally re-evaluate and sometimes alter the direction of treatment, even after definitive therapy has been completed.

Neuronal excitability in the trigeminal sensory nuclei (TSN) changes after nerve transection. We examined the effects of chronic transection of the trigeminal nerve on the c-Fos-immunoreactivity in the TSN induced 2 h after 10 min of electrical stimulation of the trigeminal ganglion (TG) at C-fiber activating condition (1.0 mA, 5 ms, 5 Hz) in urethane-anesthetized rats. In the non-transected control rats, stimulation of the TG induced c-Fos-immunoreactive cells (c-Fos-IR cells) mostly in superficial layers (VcI/II) of the nucleus caudalis (Vc) in its full extent along the dorsomedial-ventrolateral axis, but modestly in the rostral TSN above the obex, the principal, oral, and interpolar nuclei. Three days, 1, 2, or 3 weeks after transection of the inferior alveolar (IAN), infraorbital, or masseteric nerves, the stimulation of the TG induced c-Fos-IR cells in the central terminal fields of the transected nerve in the rostral TSN and magnocellular zone of the Vc. However, the number of c-Fos-IR cells in the VcI/II decreased inside the central terminal fields of the transected nerve and increased outside the fields. These results indicate that transection of the trigeminal nerve increases the excitability of TSN neurons that receive inputs from injured mechanoreceptors and uninjured nociceptors, but decreases it from injured nociceptors. The altered c-Fos responses may imply mechanisms of neuropathic pain seen after nerve injury.

Study Objectives: Sleep bruxism (SB) is reported to vary in frequency over time. The aim of this study was to assess the first night effect on SB., Methods: A retrospective polysomnographic (PSG) analysis was performed of data from a sample of SB patients (12 females, 4 males; age range: 17-39 years) recorded in a sleep laboratory over 2 consecutive nights. Sleep parameters and jaw muscle activity variables (i.e., rhythmic masticatory muscle activity [RMMA]) for SB were quantified and compared between the 2 nights. Subjects were classified into groups according to severity of RMMA frequency, such as low frequency (2-4 episodes/h and/or < 25 bursts/h) and moderate-high frequency (≥ 4 episodes/h and ≥ 25 bursts/h)., Results: Overall, no first night effects were found for most sleep variables. However, total sleep time, sleep efficiency, and stage transitions showed significant time and group interactions (repeated measures ANOVAs, p ≤ 0.05). The RMMA episode index did not differ between the 2 nights, whereas the second night showed significantly higher burst index, bruxism time index, and mean burst duration (repeated measure ANOVAs, p ≤ 0.05). Five patients of 8 in the low frequency group were classified into the moderate-high frequency group on the second night, whereas only one patient in the moderate-high frequency group moved to the low frequency group., Conclusions: The results showed no overall first night effect on severity of RMMA frequency in young and healthy patients with SB. In clinical practice, one-night sleep recording may be sufficient for moderate-high frequency SB patients. However, low RMMA frequency in the first night could be confirmed by a second night based on the patient's medical and dental history.

Nitric oxide (NO) is related to angiogenesis and tumor progression and chemokine receptor-4 (CXCR4) plays a central role in cell migration in metastasis and dissemination of cancer. The present study evaluated the effectiveness of a NOS inhibitor and a CXCR4 antagonist, given as single agents or in combination, in a xenotransplanted mouse model of adenoid cystic carcinoma (ACC) of the oral floor. A metastatic tumor (ACCIM) derived from a cervical metastatic lesion of human ACC that was transplantable in nude mice was used. ACCIM showed a high frequency of spontaneous metastasis to the lung when transplanted subcutaneously in nude mice. Mice with subcutaneous transplants of ACCIM were subdivided into six groups and intraperitoneally received one of the following treatments daily for 5 weeks: a) PBS (control), b) AMD3100 (CXCR4 antagonist), c) L-NAME (NOS inhibitor), d) 1400W (iNOS inhibitor), e) both AMD3100 and L-NAME (AMD3100+L-NAME) and f) both AMD3100 and 1400W (AMD3100+1400W). Tumor growth was evaluated during treatment and metastasis was assessed at 28 weeks. Single-agent treatment with AMD3100, L-NAME or 1400W inhibited tumor growth by 20.8, 26.5 and 54.5%, respectively. Combined treatment with AMD3100+L-NAME and AMD3100+1400W inhibited tumor growth remarkably by 48.0 and 50.2%, respectively. Immunohistochemical analysis revealed lower expression of CXCR4, iNOS and eNOS in tumor cells treated with AMD3100+L-NAME or AMD3100+1400W compared to control tumor cells and increased numbers of apoptotic tumor cells were demonstrated using the TUNEL method. CXCR4 expression decreased in 1400W-treated tumors using western blot analysis. When the effect of each agent on tumor-induced angiogenesis in tumor stroma was examined histologically, microvessel density was significantly lower in the groups treated with 1400W, AMD3100+L-NAME or AMD3100+1400W compared to the control, AMD3100 and L-NAME groups. Moreover, treatment with AMD3100 or 1400W markedly inhibited lung metastasis. Our results indicated that single-agent treatment with 1400W and combined treatment with AMD3100+L-NAME or AMD3100+1400W induced apoptosis and significantly inhibited tumor-induced angiogenesis and proliferation of ACCIM in vivo. Blockade of CXCR4 and iNOS was suggested to inhibit lung metastases from ACCIM. CXCR4 and iNOS may, thus, be important prognostic factors for long-term survival in ACC.

Objective: We compared joint pain (JP) in patients diagnosed with and without articular disc displacement without reduction (ADD) based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and identified the characteristics of each JP., Study Design: Fifty-eight patients with restricted mouth opening and pain in temporomandibular joint (TMJ) and with a magnetic resonance imaging diagnosis of ADD were selected. Diagnosis of ADD + JP and nonADD + JP was made with the use of the RDC/TMD., Results: A multiple regression analysis of the data disclosed a positive correlation between range of motion on maximum assisted mouth opening and visual analog scale (VAS) (severity of JP) in the ADD + JP group, and between chronic pain grade (CPG) and VAS in the nonADD + JP group. A significant difference was observed between ADD + JP and nonADD + JP groups in CPG; CPG was higher in the nonADD + JP than in the ADD + JP group., Conclusions: It is suggested that JP related and unrelated to ADD can indicate different types of disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Flavor perception, the integration of taste and odor, is a critical factor in eating behavior. It remains unclear how such sensory signals influence the human brain systems that execute the eating behavior., Methods: WE TESTED CEREBRAL BLOOD FLOW (CBF) IN THE FRONTAL LOBES BILATERALLY WHILE SUBJECTS CHEWED THREE TYPES OF GUM WITH DIFFERENT COMBINATIONS OF TASTE AND ODOR: no taste/no odor gum (C-gum), sweet taste/no odor gum (T-gum), and sweet taste/lemon odor gum (TO-gum). Simultaneous recordings of transcranial Doppler ultrasound (TCD) and near infrared spectrometer (NIRS) were used to measure CBF during gum chewing in 25 healthy volunteers. Bilateral masseter muscle activity was also monitored., Results: We found that subjects could discriminate the type of gum without prior information. Subjects rated the TO-gum as the most flavorful gum and the C-gum as the least flavorful. Analysis of masseter muscle activity indicated that masticatory motor output during gum chewing was not affected by taste and odor. The TCD/NIRS measurements revealed significantly higher hemodynamic signals when subjects chewed the TO-gum compared to when they chewed the C-gum and T-gum., Conclusions: These data suggest that taste and odor can influence brain activation during chewing in sensory, cognitive, and motivational processes rather than in motor control.

Zyxin is an evolutionarily conserved protein that has been implicated in the regulation of actin assembly and is mainly located at focal adhesions. However, the biological roles of Zyxin in cancer cells are incompletely understood. We analyzed the functions of Zyxin in cell migration and the invasive potential of OSCC. Zyxin expression was examined using eight OSCC cell lines with two different cell morphologies (6 epithelial type and 2 fibroblastic type). To knockdown Zyxin expression, OSCC cells were transfected with Zyxin siRNA and control siRNA. The cell lines were studied by western blot analysis, immunocytochemical analysis and cell migration and invasion assay. Epithelial type OSCC cells showed a high level of E-cadherin expression and a low level of Zyxin expression. N-cadherin as well as Zyxin were strongly expressed in fibroblastic type OSCC cells. Expression levels of LPP and TRIP6, members of the human Zyxin family, did not differ between epithelial type and fibroblastic type. Knockdown of Zyxin expression by siRNA in fibroblastic type OSCC cells was associated with cell morphological changes from spindle (fibroblastic) to polygonal (epithelial) shape and significantly inhibited cell growth as well as cell migration and invasion. Expression levels of Rac1 and Cdc42 were weaker in Zyxin siRNA-treated fibroblastic type OSCC cells than in control siRNA-treated cells, but the expression of RhoA did not differ significantly. Treatment of fibroblastic type OSCC cells with Rac1 inhibitor decreased the expression of Zyxin mRNA and protein. Zyxin is suggested to promote growth, migration and invasiveness of fibroblastic type OSCC cells by upregulating Rac1 and Cdc42.

Because barium sulfate (BaSO(4)) is not harmful to the mucosa, it is widely used for gastrointestinal imaging. Barium appendicitis is a very rare complication of barium meals and barium enema. We report a case of acute appendicitis associated with retained appendiceal barium. A 47-year-old man presented with right lower abdominal pain after upper gastrointestinal imaging was performed using barium 1 month earlier. The abdominal plain roentgenogram showed an area of retained barium in the right lower quadrant. Multiplanar reconstruction of computed tomography scans showed barium retention in the appendix. Emergency appendectomy was performed. A cross section of the specimen revealed the barium mass. Barium-associated appendicitis is a very rare clinical entity but we should be cautious of this uncommon disease when we encounter barium deposits in the appendix after barium examination. This report is significant because barium was identified both macroscopically and microscopically.

Diffuse sclerosing osteomyelitis of the mandible (DSOM) is an uncommon chronic inflammatory disease of bone that is refractory to conventional treatments, such as antibiotics, nonsteroidal anti-inflammatory drugs, and decortication. We report a case of chronic DSOM of 15 years' duration in a 61-year-old woman that was successfully treated with a single infusion of pamidronate. Persistent, intractable pain resolved 3 days after infusion. Intense accumulation on (99m)Tc scintigraphy decreased 2 months after infusion, and almost disappeared after 3 years. Panoramic radiography demonstrated a clear decrease in pathologic changes, close to that of normal bone architecture, which has not been reported in DSOM treated with bisphosphonates., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: This retrospective cohort study was conducted to investigate the influence of wearing dentures in the initial occurrence site of bisphosphonate-related osteonecrosis of the jaws (BRONJ)., Study Design: A questionnaire regarding the prevalence, therapy, and outcome of jawbone lesions during 2006-08 was mailed to 248 medical institutions with an oral and maxillofacial surgery department in Japan., Results: Ninety-nine patients wearing dentures had significantly shorter duration until occurrence than 151 patients not wearing dentures. In addition, remission of BRONJ affecting the mandibular canine and premolar region in denture-wearing patients was significantly more difficult. Poor oral hygiene status was found to affect significantly the prognosis of BRONJ in denture-wearing patients. Alcohol habit also delayed remission, but high body mass index promoted remission., Conclusion: Wearing a denture in the initial occurrence site of BRONJ was shown to influence the prognosis of BRONJ, especially in mandibular denture-wearing patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Interleukin (IL)-22 acts on non-immune cells to induce anti-microbial responses, protection from tissue damage, and enhance cell regeneration. However, little is known about the involvement of IL-22 in periodontal biology. This study investigated the biological effects of IL-22 on periodontal ligament (PDL) cells as part of studies to assess the involvement of IL-22 in periodontal disease., Materials and Methods: Gene expression levels of IL-22 and its receptors in PDL cells and gingival tissue samples were evaluated by real-time PCR. Proliferative responses and mineralized-matrix forming activities of PDL cells were examined in the presence and absence of IL-22., Results: In contrast to the expression of IL-22 receptors detected in PDL tissues and their cell lines, gingival tissues showed modest or no gene expressions of IL-22. The production of several cytokines including IL-11, IL-8 and CCL2 was upregulated by IL-22 treatment of PDL cells in a dose-dependent manner. IL-22 treatment had no effect on the proliferative response in PDL cells. Meanwhile, IL-22 precipitated mineralized nodule formation and induced gene expressions of RUNX2, MSX2 and osteocalcin in PDL cells, suggesting that IL-22 enhances the mineralized matrix-forming activities of PDL cells., Conclusion: IL-22 has the potential to promote mineralizing activity in PDL cells and to develop appropriate regenerative therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Mechanism(s) of cisplatin-induced acute renal failure, as manifested by increases in blood urea nitrogen and creatinine, was evaluated in relation to production and activation of endogenous mediator(s) in mice. In interleukin (IL)-18-deficient (IL-18KO) mice, cisplatin failed to induce acute renal failure. Administration of recombinant IL-18 prior to cisplatin restored acute renal failure in IL-18KO mice. Accumulation of cisplatin in the kidney was not different in IL-18KO and wild-type (WT) mice, but, clearance of cisplatin was more rapid in IL-18KO mice than in WT mice. Cisplatin increased serum levels of aldosterone and angiotensin II in WT mice, but only angiotensin II levels in IL-18 KO mice. Administration of IL-18 augmented plasma levels of aldosterone and angiotensin II in WT mice. Eplerenone, an aldosterone receptor blocker, TY-51469, a chymase inhibitor and PD123319, a selective angiotensin II type 2 (AT2) receptor antagonist, but not benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, a selective angiotensin II type 1 (AT1) receptor antagonist improved acute renal failure caused by cisplatin, confirming involvement of IL-18, aldosterone and angiotensin II in cisplatin-induced, chymase-dependent acute renal failure in mice. These results show that IL-18, aldosterone and angiotensin II synergistically act to prolong the accumulation of cisplatin in the kidney, leading to acute renal failure. Combined therapy with inhibitors for chymase and aldosterone receptors or AT2 receptors might reduce acute renal failure induced by cisplatin., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin2, LCN2) is a secreted glycoprotein with increased expression in solid tumors. The expression and functions of NGAL in oral cancer, however, remain unclear. We investigated the expression of NGAL in oral cancer tissues and oral cancer cell lines. By immunohistochemical examinations, NGAL expression was strongly up-regulated in well-differentiated OSCC tissues and moderately to weakly up-regulated in moderately to poorly differentiated OSCC tissues. In contrast, NGAL expression was weak or very weak in normal mucosa and leukoplakia. By western blot analysis, NGAL expression levels positively correlated with cell morphology patterns and loss of E-cadherin. In addition, the enzymatic activity of the NGAL/MMP-9 complex significantly correlated with the results obtained by zymographic analysis. In conclusion, NGAL expression is high in well-differentiated cancer, suggesting that NGAL may be a useful diagnostic marker of tumor-cell differentiation.

Purpose: A nationwide retrospective cohort study was conducted by the Japanese Society of Oral and Maxillofacial Surgeons to assess the occurrence of bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) during 2006 to 2008 and to elucidate the outcome and factors associated with remission of BRONJ., Materials and Methods: A written questionnaire, including the clinical characteristics, management, and outcome of patients with BRONJ, was sent to 248 institutions certified as training facilities by the Japanese Society of Oral and Maxillofacial Surgeons in 2008., Results: A total of 568 patients with BRONJ, including suspicious cases, were registered. Of these 568 patients, 263, including the maxilla in 81, the mandible in 160, and both in 22, met the working definition of BRONJ proposed by the American Association of Oral and Maxillofacial Surgeons. The patients included 219 women (83.3%) and 44 men (16.7%). Of these patients, 152 (57.8%) had received intravenous BPs, 104 (39.5%) had received oral BPs, and 7 (2.7%) had received both. The mean duration of administration until onset of BRONJ was 23.6 months for intravenous BPs and 33.2 months for oral BPs. BRONJ was stage 1 in 42 patients (16.0%), stage 2 in 187 (71.1%), stage 3 in 32 (12.2%), and unknown in 2. Of these patients, 34.2% had remission of BRONJ, 46.0% had persistent or progressive disease, and 19.7% died of malignancy or were lost to follow-up. Statistical analysis revealed that surgical treatment, including tooth extraction, sequestrectomy, and segmental mandibulectomy, contributed to the remission of BRONJ. In contrast, conservative treatment, concurrent anticancer drugs, poor oral hygiene, and the use of intravenous BPs did not., Conclusions: The relative ratio of BRONJ related to the use of oral BPs was greater in Japan than in the United States and European Union. Surgical treatment contributed to remission of BRONJ, and conservative treatment, concurrent anticancer drugs, poor oral hygiene, and intravenous BPs did not., (Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The present study was undertaken to elucidate the factors responsible for the failure of arthrocentesis to cure persistent joint pain in patients with nonreducing articular disc displacement in the temporomandibular joint (TMJ)., Patients and Methods: Thirty-six patients with internal derangement of the TMJ were selected. Magnetic resonance imaging was used to examine the configuration and position of the articular discs, cortical changes, and bone marrow abnormalities in the condyle and the presence of joint effusion. Arthrocentesis was then performed, and the patients were followed for 6 weeks. The results were then classified as poor or improved., Results: The effects of arthrocentesis did not depend on the configuration of the disc, disc position and motion, or bone marrow abnormalities. Joints with no or minimal amounts of joint effusion achieved a good response to arthrocentesis. Joints with erosive cortical changes of the condyle were less responsive to arthrocentesis., Conclusion: Persistent joint pain after arthrocentesis is generally associated with extensive amounts of joint effusion or erosive cortical changes of the condyle., (Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant mode, and is characterized by a combination of developmental abnormalities and predisposition to form a variety of tumors. The hedgehog receptor Patched1 (PTCH1) has been identified as the gene mutated in NBCCS. We analyzed PTCH1 in two familial and three sporadic Japanese NBCCS cases, and identified five germline mutations in PTCH1. Two cases have a nonsense mutation (c.3058C>T and c.2760C>A), one a splice site mutation (c.584+2T>G), one a 1 bp insertion (c.2712&#95;2713insA) and one a 1 bp deletion (c.980Gdel). All mutations induce truncation of the PTCH1 protein or could induce nonsense-mediated mRNA decay. The 11-year-old male patient with splice-site mutation (c.584+2T>G) had medulloblastoma (MB) at the age of 1 year. This is the first NBCCS patient with molecularly defined MB in Japan.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) develops as a side effect of long-term administration of bisphosphonates (BP) , especially intravenous preparations. The lesion is a new disease entity which was first reported in 2003 in the United States. Since then, the number of patients with BRONJ is increasing year by year. In Japan, the first case was reported in 2006, and at that time 30 cases of BRONJ were registered in the nationwide survey by the Japanese Society of Oral and Maxillofacial Surgeons. However, the patients with BRONJ increased rapidly in the second survey after 2 years, and more than 250 cases of BRONJ which met the criteria of clinical diagnosis were determined. Approximately 95% of the BRONJ patients received intravenous BPs and less than 5% received oral BPs in the United States and European Union, whereas 58% of the patients received intravenous BPs and 40% received oral BPs in Japan. The relative ratio of BRONJ associated with the use of oral BPs was higher in Japan than in the United States and European Union. BRONJ is refractory to treatment, and an efficient and useful therapy is not yet established.

A 61-year-old man was hospitalized for treatment of portal and superior mesenteric venous thrombosis (PSMVT). We selected interventional radiology (IVR) because there were no signs of intestinal necrosis. The thrombosis was significantly reduced and the patient made progress after we performed thrombectomy via catheter aspiration, and thrombolytic therapy via both the superior mesenteric artery and vein. Even if there are no signs of intestinal necrosis, treatment which prevents intestinal necrosis is vital. In the present case, single-stage IVR therapy via both the superior mesenteric artery and vein improved the therapeutic outcome of PSMVT.

Oral squamous cell carcinomas (OSCCs) are considered to arise from human oral keratinocytes. DNAs of human papillomaviruses (HPVs), predominantly types 16 and 18, etiological agents of cervical cancer, have been detected in approximately 25% of OSCCs. In accordance with the established role of E6 and E7 in inactivating p53 and pRB, respectively, mutations of p53 and inactivation of p16(INK4a) are frequently observed in HPV-negative OSCCs. In addition, other alterations such as overexpression of epidermal growth factor receptor (EGFR) are often observed in both HPV-positive and -negative OSCCs. However, causal-relationships between accumulation of these abnormalities and multi-step carcinogenesis are not fully understood. To elucidate underlying processes, we transduced either HPV16 E6/E7 or mutant CDK4 (CDK4(R24C)), cyclin D1 and human telomerase reverse transcriptase (TERT) into primary human tongue keratinocytes (HTK), and obtained immortal cell populations, HTK-16E6E7 and HTK-K4DT. Additional transduction of oncogenic HRAS or EGFR together with MYC into the HTK-16E6E7 and dominant-negative p53 expressing HTK-K4DT resulted in anchorage-independent growth and subcutaneous tumor formation in nude mice. These results indicate that either HRAS mutation or activation of EGFR in cooperation with MYC overexpression play critical roles in transformation of HTKs on a background of inactivation of the pRB and p53 pathways and telomerase activation. This in vitro model system recapitulating the development of OSCCs should facilitate further studies of mechanisms of carcinogenesis in the oral cavity.

Carcinosarcoma is a rare malignant tumour composed of a mixture of carcinomatous and sarcomatous elements. Carcinosarcoma metastatic to the tongue is extremely rare. An 84-year-old woman presented with a rapidly growing mass on the tongue. She had a history of surgery for carcinosarcoma of the occipital skin 9 months before. An excisional biopsy of the tongue mass was performed, and the lesion was histopathologically diagnosed as carcinosarcoma. PET after diagnosis showed multiple hot uptakes in the whole body. The patient died of the disease 2 months after diagnosis. Therapies for patients with metastatic malignant tumours to the oral cavity are difficult, especially in aggressive case such as this. To the authors' knowledge, this is the first case of metastatic carcinosarcoma to the tongue., (Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

To understand the role of cyclooxygenase (COX)-2 in metastatic potential of oral cancer, COX-2 overexpressing KB/COX-2 cells were inoculated orthotopically into the masseter muscle or injected into the left cardiac ventricle of nude mice. KB/COX-2 showed about 4-fold increase of COX-2 protein expression as compared to KB/Neo which was a mock transfected control. In orthotopic inoculation, metastasis to the regional lymph nodes occurred in 2 out of 15 mice, and metastasis to the lung in 3 out of 15 mice. On the other hand, in intra-cardiac injection, hematogenous metastasis to the lung and bone occurred in 8 out of 10 mice in KB/COX-2, but no metastasis occurred except for only one metastasis to the femur bone out of 10 mice in KB/Neo. Treatment of KB/COX-2 with COX-2 small interfering RNA (siRNA) inhibited the colony formation but not cell growth in vitro, and suppressed tumorigenicity and hematogenous metastasis in nude mice. When expression of adhesion molecules such as E-cadherin, alpha-catenin, beta-catenin and CD44 was examined, there was no difference in alpha- and beta-catenin between the cells. However, expression of E-cadherin was detected in KB/Neo, but not in KB/COX-2. In contrast, expression of CD44 was markedly increased in KB/COX-2 as compared to KB/Neo. Treatment with COX-2 siRNA resulted in suppression of CD44 expression and detectable expression of E-cadherin in KB/COX-2. These findings suggested that overexpression of COX-2 increased hematogenous metastasis, at least in KB cells, via down-regulating E-cadherin and up-regulating CD44 expression.

Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are major inflammatory mediators. Nitric oxide (NO) produced by iNOS has been shown to have an important role in carcinogenesis. Recent studies have suggested that COX-2 expression also contributes to carcinogenesis, as well as tumor growth, invasion, and metastasis. COX-2 inhibitors such as celecoxib are widely recognized to have antitumor activity, but can cause adverse effects. We investigated possible relations between COX-2 and NO with the use of a human epidermoid carcinoma cell line, designated KB, in which overexpression of COX-2 protein was induced by gene transfer. We also assessed the possibility of using NOS inhibitor as an antitumor drug. We isolated a COX-2 transfected clone (KB/COX-2) and used a neomycin-transfected clone (KB/neo) as control. NG-nitro-L-arginine-methyl ester (L-NAME) was used as a NOS inhibitor, dihydrochloride (1400W) as an iNOS inhibitor, and celecoxib as a selective COX-2 inhibitor. All agents inhibited the cell growth of both clones to similar extents in a dose-dependent manner. Prostaglandin E2 (PGE2) production and COX-2 expression in KB/COX-2 were inhibited not only by celecoxib, but also by L-NAME and 1400W. The decreases in PGE2 production and COX-2 expression were most prominent with celecoxib and L-NAME. In vivo, L-NAME and celecoxib significantly inhibited the proliferation of KB/COX-2-xenografted tumors. Tumor weight was reduced by L-NAME (60.6% decrease), 1400W (38.0% decrease), and celecoxib (74.5% decrease) as compared with the control after 21 days of treatment. Immunohistochemically, xenografted tumors expressed COX-2, iNOS, and eNOS. Such expression was suppressed by treatment with L-NAME and celecoxib. These results suggest that L-NAME and celecoxib significantly inhibit the proliferation of murine squamous cell carcinoma in vivo. L-NAME as well as celecoxib might thus be useful for the design and development of new antitumor drugs.

Bisphosphonates (BPs) have been widely, efficiently, and safely used for the treatment of osteoporosis, malignant hypercalcemia, bone metastasis of solid cancers, and multiple myeloma bone diseases. Accumulating recent reports describe that surgical dental treatments in patients with cancer or osteoporosis who have been receiving intravenous or oral BPs are associated with osteonecrosis of the jaw (bisphosphonate-related osteonecrosis of the jaw, BRONJ). The accurate incidence, clinical backgrounds, and pathogenesis of BRONJ have been unclear and appropriate approaches for prevention and treatment have not been established to date. To address the current situation of BRONJ in Japan, the "Allied Task Force Committee of Bisphosphonate-Related Osteonecrosis of the Jaw," consisting of physicians specializing in bone biology, orthopedic surgery, rheumatology, obstetrics/gynecology, and medical oncology and dentists specializing in oral surgery, periodontology, dental radiology, and oral pathology, was organized. The committee attempted to propose a standard position paper for the treatment of BRONJ. The committee expects that this proposal will provide objective and correct scientific information on BRONJ and will serve as a reference for conducting dental procedures for patients receiving BPs and in designing prevention and treatment of BRONJ. However, because this position paper is not based on direct clinical evidence, it should be used as a reference, and a decision on treatment in each case should be made after an extensive discussion among physicians, dentists/oral surgeons, and the patients.

We report a case of foreign bodies, staples, accidentally put in the oral cavity. One of the staples had migrated from the oral floor through the submandibular space and penetrated the submandibular gland. The staple was removed successfully using CT scan and fluoroscope imaging.

In this study, we performed tests to determine whether tooth pulp stimulation (TPS) increases hippocampal blood flow (HBF), and if so, to investigate whether the increase in HBF is mediated via the activation of adenosine receptors. We measured HBF in urethane-anesthetized rats using laser Doppler flowmetry (LDF) and examined the effect of theophylline, a nonselective adenosine receptor antagonist, on TPS-induced HBF responses. TPS increased HBF, and its response was significantly attenuated by the intraperitoneal administration of theophylline (20 mg/kg). These results suggest that the HBF response induced by TPS may be, at least in part, produced through adenosine receptors.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a newly emerging condition in a long-term administration of mainly intravenous bisphosphonates for the treatment of hypercalcemia associated with malignancy, multiple myeloma, and metastatic breast and prostate cancers. The incidence of BRONJ is not so high, but it is very refractory to ordinary dental treatments, and the bone exposure, a typical symptom, continues for several months. Although many cases of BRONJ have been reported worldwide, the precise pathogenesis remains obscure. Diabetes mellitus (DM) is one of the systemic risk factors contributing in the development of BRONJ. DM is generally associated with microvascular ischemia of the bone, endothelial cell dysfunction, decreased bone turnover and remodeling, resulting in a delayed wound healing and easy to infection. In this issue, the relation of DM as a systemic risk factor with development of BRONJ as well as the incidence, clinical manifestations and prevention and treatment of BRONJ are described.

Basal cell carcinoma (BCC) is the most common skin cancer. Its occurrence in the oral mucosa is extremely rare. We report the clinical course of BCC arising in the inferior surface of the tongue. We performed a super selective intra-arterial chemotherapy combined with radiotherapy for this case. Local tumor response showed CR, and no recurrence was seen after the treatment.

In order to investigate the involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and chemoprevention for it, we examined the COX-2 expression during dimethylbenzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis and the inhibitory effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on the carcinogenesis and its derived squamous carcinoma cell line HCPC-1. From the beginning of DMBA application, basal diet or diets containing sulindac 200 or 400 ppm were given to hamsters, and observation of tumor development and measurement of body weight were performed. Immunohistochemical analysis revealed that COX-2 expression was increased toward carcinogenesis from epithelial dysplasia to squamous cell carcinoma (SCC). All hamsters developed SCC, but the onset of carcinoma formation was significantly delayed up to 14.8 and 11.8 weeks in the 200 ppm, and 400 ppm sulindac group, respectively, as compared to 8.7 weeks in the control group. In addition, tumor growth was retarded in the group of sulindac treatment, and mean survival time was 23.7 weeks in the control group and 36.3 and 33.8 weeks in the 200 and 400 ppm sulindac group, respectively. Body weight loss was not observed during the experimental period. Histologically, administration of sulindac inhibited angiogenesis in the tumor stroma. Treatment with sulindac sulfide, an active metabolite of sulindac, caused inhibition of cell growth, PGE2 production and VEGF production in HCPC-1 cells in vitro. Expression of COX-2 protein in HCPC-1 cells was also decreased 2-fold by treatment with sulindac sulfide. It was thus indicated that inhibitory effects were partly due to inhibition of tumor angiogenesis by sulindac. These findings suggested the involvement of COX-2 in DMBA-induced hamster cheek pouch carcinogenesis and the chemopreventive potential of sulindac.

Bisphosphonates (BP) have clinically been used as a highly effective drug in the treatment of hypercalcemia of malignancy, multiple myeloma, skeletal events associated with metastatic breast cancer and prostate cancer, and osteoporosis. Despite these benefits, however, the emergence of BP-related osteonecrosis of the jaws (BRONJ) becomes a growing and significant problem in a subset of patients receiving these drugs, especially intravenous preparations. It has also been reported in the patients receiving oral BP, although the incidence is extremely low. Most of BRONJ cases occur after dental treatments such as tooth extraction, periodontal surgery, and dental implants, and are refractory to conventional treatment modalities such as debridement, antibiotics and hyperbaric oxygen therapy. As compared to EU and USA, the number of BRONJ case is still small in Japan, but it is exactly increasing year by year. The ratio of the number of BRONJ in patients receiving oral BP to that in patients receiving intravenous BP is higher in Japan than in EU and USA, speculating due to the difference of time of approval. In this communication, the practical guidelines for prevention, diagnosis and treatment of BRONJ recently released from USA and Canada were introduced. Although no effective therapy for BRONJ is established yet, the importance of oral hygiene, patient education and treatments suitable for clinical stage is emphasized. In addition, it is considered that the survey of incidence of BRONJ in Japan and the preparation of Japanese guideline are urgent need.

Adenoid cystic carcinoma (ACC) may acquire a chemokine-mediated mechanism during the process of metastasis. To investigate the involvement of chemokines in metastasis from ACC, expression of CXCR4 in surgical specimens of ACC and two tumor lines transplantable to nude mice was examined immunohistochemically. In addition, the expression levels of CXCR4 protein and mRNA were examined by Western blotting and reverse-transcription polymerase chain reaction. Our results showed that patients whose tumors expressed high levels of CXCR4 had metastases to the regional lymph nodes and the lung, resulting in poor outcomes. ACCs showing a solid or cribriform pattern with distant metastasis were strongly positive for CXCR4, while those showing a tubular or cribriform pattern without metastasis were weakly positive for CXCR4. In the in vivo model, ACCY tumor showed increasing expression levels of CXCR4 with tumor growth, and the histological pattern changed from cribriform to solid. The histological pattern of ACCI, associated with spontaneous metastasis to the neck, changed from cribriform to undifferentiated carcinoma and was highly metastatic to the lung. This tumor showed high levels of CXCR4 protein and mRNA. These results suggest that CXCR4 expression, histological patterns, and metastatic potential are closely related in ACC.

Objectives: The relationship of bony changes in the condylar surfaces in articular disc displacement without reduction in temporomandibular joint (TMJ) was investigated using diagnostic imaging. The study also evaluated whether the bony changes in the condylar surfaces limit disc and condyle motion, and produce pathological joint sounds., Materials and Methods: Thirty-seven joints in 28 patients diagnosed with degenerative bony changes in the condylar surfaces radiographically and anterior disc displacement without reduction using magnetic resonance imaging (MRI) were studied. The bony changes were assessed by radiographic examination and classified into two types: pathological bone changes (PBCs) including erosion, osteophyte formation and deformity, and adaptive bone changes (ABCs) including flattening and concavity. MRI was performed on the TMJ to examine the configuration and position of the discs. Joint sounds in the TMJ were determined using electrovibratograghy with a joint vibration analysis., Results: The articular disc motion to the condyle in the PBC group was smaller than in the ABC group irrespective of the configuration of the disc, even though there were no significant differences between the two types of bony changes in the disc position during jaw closing. The joint vibration analysis of the TMJ showed that joint sounds with a higher frequency were observed in the PBC group than in the ABC group. High energy levels needed to produce the higher frequencies (over 300 Hz) were observed only in the PBC group.

Malignant fibrous histiocytoma (MFH) is one of the highest-grade sarcomas arising in bone and soft tissue. Its prognosis is poor because of chemoresistance and high metastatic potential to various organs. Few cases arising of MFH of the mandible or oral cavity have been documented. We established a tumor line in nude mice (MFH-N), which was derived from human MFH of the mandible and examined the characteristics of this tumor line. Histologically, MFH-N was identical to the original tumor and showed a storiform-pleomorphic pattern, but had low metastatic potential. Immunohistochemically, both the original and xenografted tumors expressed vimentin, S-100, alpha-SMA, and histiocytic marker CD68. Lysozyme was expressed by the original tumor, but only sporadically by the xenografted tumor. RT-PCR analysis demonstrated human beta-actin in this tumor line, indicating the human origin. In a parallel experiment, we established a new MFH cell line (MFH-NC) from MFH-N. Tumor cells inoculated into the flanks and submandibular region of nude mice developed into tumors histologically similar to MFH-N and the original tumor; multiple lung metastases were detected approximately 5 months after inoculation. The expression levels of various metastasis-related molecules differed between MFH-N and MFH-NC on Western blotting. In MFH-NC, the expressions of MMP7, MMP9, MT1-MMP, CXCR4, COX-2 and integrin alpha4 were up-regulated, while those of MMP2 and TIMP1 were down-regulated. Expression of TIMP2, integrinalphaL and sialyl lewis X were not detected in either line. Our findings suggest that the MFH-N tumor line transplantable in nude mice is a useful model for studying the biological behavior of MFH.

In order to investigate the malignant phenotype of cyclooxygenase (COX)-2 overexpressing cancer cells, a human epidermoid KB carcinoma cell line minimally expressing COX-2 protein was transfected with human COX-2 cDNA. In this study, we used a COX-2 transfected clone KB/COX-2 and a neomycin-transfected clone KB/neo as the control. When we examined the susceptibility to anticancer agents, there was no difference between these two clones in vincristine, bleomycin and 5-fluorouracil, although KB/COX-2 showed a 2.5-fold resistance to cisplatin (CDDP) as compared with KB/neo. The IC50 for CDDP was 4.3 microM in KB/COX-2 and 1.7 microM in KB/neo. Treatment with small interfering RNA (siRNA) mediated the inhibition of COX-2 significantly increasing the level of susceptibility to CDDP in COX-2 siRNA as compared to that of the control siRNA. The expression of MRP1 and MRP2 was stronger in KB/COX-2 than in KB/neo by Western blot analysis. In addition, apoptosis induction by CDDP was at a lower level in KB/COX-2 (31%) than in KB/neo (38%). These results suggested that the overexpression of COX-2 increases the intracellular production of MRP1 and MRP2 and causes drug resistance to CDDP.

The involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and outcome of the patients is not fully understood. To determine whether COX-2 expression could serve as an indicator for them, we examined the expression of COX-2 and DNA topoisomerase (DNA-Topo) II alpha as an index of cell proliferating activity in precancerous and cancerous lesions of the oral mucosa. A 164 samples composed of 60 intraepithelial dysplasias (IEDs), 12 carcinomas in situ (CISs), 72 squamous cell carcinomas (SCCs) including 12 early invasive SCCs, 10 undifferentiated carcinomas (UCs), and 10 epithelial hyperplasias (EHPs) in the oral mucosa were examined immunohistochemically for COX-2 and DNA-Topo II alpha. Normal squamous epithelium as the control showed no COX-2 expression, whereas 41% of IEDs, 67% of CISs, 74% of SCCs, and 86% of UCs demonstrated increased COX-2 expression with elevated DNA-Topo II alpha labeling index (LI). High COX-2 expression was also observed in 61% of EHPs, but DNA-Topo II alpha LI was very low. Increased expression of COX-2 protein correlated with elevated DNA-Topo II alpha LI, indicating that COX-2 may contribute to malignant transformation and tumor growth. These two enzyme activities were increased as T, N, and M categories and stages proceeded. The patients with high expression of both COX-2 and DNA-Topo II alpha showed poor prognosis. Our results suggested that COX-2 expression become a possible indicator in oral carcinogenesis and may reflect the outcome of the patients.