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A mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary gland. It frequently occurs in the parotid and minor salivary glands, but rarely originates from the sublingual gland. We report a case of a low-grade MEC arising from the sublingual gland with a MAML2 gene split on fluorescence in situ hybridization (FISH). In May 2017, a 57-year-old woman visited our hospital with left-sided tongue numbness and swelling of the floor of the mouth. We performed a biopsy, but the lesion was indistinguishable from malignant tumors such as MEC, or atypical epithelium associated with inflammation. Subsequently, an MEC was suspected based on computed tomography findings of invasion into the bone marrow and destruction of the outer margin of the mandibular cortex. In July 2017, tracheostomy, bilateral supraomohyoid neck dissection, combined resection of the floor of the mouth and reconstruction of the free peroneal composite flap with a vascular handle were performed under general anesthesia. Although perineural and mandibular invasion was observed, the tumor was considered a low-grade malignancy based on histopathological findings. Furthermore, a split signal in the MAML2 gene was detected on detailed molecular analysis using FISH. No recurrence was observed more than three years after definitive surgery. The presence of the MAML2 fusion gene is useful for the accurate diagnosis of an MEC. Overall, we report a rare case of an MEC in the sublingual gland with mandibular invasion where MAML2 fusion was confirmed.

COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.

Lingual artery (LA) aneurysms are particularly rare, and pseudoaneurysms are associated with trauma, infection, and surgical intervention. LA aneurysms can be fatal if not recognised or treated; however, only a few cases of idiopathic LA aneurysms have been reported in the literature, all of which have been described as pseudoaneurysms. To address this knowledge gap in reporting a true LA aneurysm, here, we describe a 55-year-old woman with an idiopathic aneurysm of the lingual artery. The lesion was detected by another department on a computed tomographic angiography of the neck, which was performed as a post-aneurysmectomy evaluation of the right internal carotid artery. The embolisation failed twice, after which we performed an aneurysmectomy of the left atrium. A histopathological examination of the excised aneurysms revealed fibromuscular dysplasia (FMD). Thus, we believe that FMD may be a cause of external LA aneurysms. Our findings will be relevant for oral surgeons and physicians who may consider FMD as a differential diagnosis when treating multiple LA aneurysms.

Ossifying fibroma is a fibro-osseous lesion of the jaw and usually occurs as a single lesion. Little is known about ossifying fibromas, which occur as a manifestation of hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant disorder. We experienced a patient with HPT-JT who had ossifying fibromas on both sides of the mandible. A 32-year-old female was referred to our department because of swelling on the right side of the mandible. She had a history of parathyroid adenomas and endometrial hyperplasia; however, there was no family history of parathyroid, mandibular, or renal lesions. She was diagnosed with recurrent parathyroid adenoma close to the time of her visit to our department. A biopsy revealed that the jaw lesion was an ossifying fibroma, and genetic testing revealed HPT-JT. She underwent surgery for the parathyroid and mandibular lesions and is currently undergoing follow-up. Accurate diagnosis of HPT-JT is important because it is an inherited condition and is associated with a high incidence of parathyroid carcinoma. This case indicates that cooperation among multiple medical care departments is essential for proper diagnosis and treatment of HPT-JT.

Objective Owing to variations in the exterior appearances of noncancerous diseases in the oral cavity, clinicians may have difficulty diagnosing oral squamous cell carcinoma (OSCC). Tissue biopsy is confirmatory, but invasive. Therefore, reliable tumor markers for OSCC are required. Here, exosomal Alix (exoAlix) levels were measured in serum/salivary samples from patients with OSCC and healthy controls (HCs). Methods Fifty-seven patients admitted to Nagoya University Hospital from 2017 through 2019 were enrolled, and serum samples (OSCC, n = 29; HC, n = 21) and/or saliva samples (OSCC, n = 23; HC, n = 20) were collected. Exosomal fractions were isolated using ultracentrifugation. ExoAlix levels were measured using enzyme-linked immunosorbent assay. Results Serum/salivary exoAlix levels were significantly higher in patients with OSCC than in HCs. Receiver operating characteristic analyses revealed that sensitivity, specificity, positive predictive value, and area under the curve were 0.345, 1.000, 1.000, and 0.685, respectively, for serum exoAlix and 0.348, 1.000, 1.000, and 0.712, respectively, for salivary exoAlix at optimal cut-off values (serum, 0.205; saliva, 0.193). All tested OSCC tissue sections (n = 21) were immuno-reactive for Alix. Conclusion Serum and salivary exoAlix were identified as potential diagnostic OSCC biomarkers. Serum exoAlix was suitable for prediction of therapeutic responses.

Post-transplant lymphoproliferative disorders (PTLDs) are lesions that proliferate lymphocytes or plasma cells and are caused by immunosuppression after organ transplantation or hepatopoietic stem cell transplantation. According to the 2016 WHO classification, PTLDs are classified into four types: early lesions, polymorphic PTLDs, monomorphic PTLDs, and classical Hodgkin lymphoma-type PTLDs. We report a case of PTLD that first occurred in the oral and maxillofacial area more than ten years after living renal transplantation. A sixty-one-year-old man visited our department in the middle of August 2013 because of right parotid gland swelling. We consulted with an otorhinolaryngologist and prescribed antibiotics to determine whether the swelling was parotitis or a tumor; however, the swelling did not improve. At the end of September 2013, a tumor was found in the right palatine tonsil; consequently, a biopsy was performed. After the biopsy, the lesion was diagnosed as monomorphic PTLD (diffuse large B-cell lymphoma), and the patient was admitted to the hematology and oncology ward. Immunosuppressants were interrupted or reduced. However, the tumor continued to swell, and R-CHOP treatment was started. The therapeutic value was PR, and the patient’s general condition was good; therefore, in mid-February, he discharged. However, at the end of April 2014, the patient experienced septic shock due to pneumonia and passed away the next day. As this case shows, it is important for oral and maxillofacial surgeons to consider the possibility of PTLD in the oral and maxillofacial area.

Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.

The 5-HT5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.

Maffucci syndrome, first described in 1881, is a rare, non-hereditary skeletal disorder characterized by multiple enchondromas in combination with soft tissue hemangiomas. Recent studies have implicated somatic mutations in IDH1/2 contributing to the pathogenesis of Maffucci syndrome. This study describes the first case of Maffucci syndrome harboring a mutation in IDH1, which was associated with a hemangioma in the oral mucosa. A 32-year-old man, who was diagnosed with Maffucci syndrome during childhood, was referred to our department in April 2020 due to a mass in the left buccal mucosa. The mass was soft, dome-shaped, had dark red protrusions and well-defined borders, and the dimensions were approximately 15 × 10 mm. Magnetic resonance imaging revealed a mass with a dimension of 13 × 10 mm, which appeared hyperintense on T2-weighted images. The vascular lesion was surgically resected under local anesthesia owing to hemangioma diagnosis. We then analyzed the IDH1/2 sequences using DNA extracted from the excised tumor tissue and peripheral blood. The analysis revealed the presence of a heterozygous mutation in IDH1 in the tumor tissue, corresponding to an R132C substitution. The mutation was not present in peripheral blood DNA. After over one year of resection, the patient is presently free from tumor recurrence and is under follow-up for the early detection of recurrent hemangioma.

Objective Members of the Notch family are frequently dysregulated in various types of cancers, and these alterations can lead to oncogenesis or tumor suppression depending on the context. The aim of this study was to elucidate the relationship between members of the Notch family and oral squamous cell carcinoma (OSCC) tumorigenesis, with a focus on epigenetic alteration, especially DNA methylation. Material and methods We analyzed the expression and DNA methylation of members of the Notch family in six OSCC cell lines. Additionally, we evaluated the DNA methylation level and the frequency of Notch3 methylation in clinical samples and compared the results between tumor and normal tissues using The Cancer Genome Atlas (TCGA) dataset. Further, we comprehensively evaluated DNA methylation and gene mutation of Notch3 in tumor tissues. Results Notch1, Notch2, and Notch4 were substantially expressed in all the OSCC cells, whereas Notch3 expression was not detected; moreover, Notch3 was highly methylated at the promoter region in one of the six cell lines. In the OSCC clinical samples, Notch3 methylation was significantly higher in tumor than in normal tissues (P = 0.04). Intriguingly, DNA methylation and loss of function mutation of Notch3 tended to be mutually exclusive. Conclusion Our data indicate that Notch3 is downregulated by multiple mechanisms during OSCC tumorigenesis, mainly due to DNA methylation.

Introduction: Direct oral anticoagulants are widely used in patients with nonvalvular atrial fibrillation (AF) to reduce the risk of stroke and systemic embolism, however, there is not enough real-world data of their effectiveness and safety in patients with worsening renal function (WRF). Xarelto post-authorization safety and effectiveness study in Japanese patients with atrial fibrillation (XAPASS) is a prospective observational post-marketing surveillance study mandated by the Japanese authority. It aims to examine safety and effectiveness of rivaroxaban in everyday clinical practice. This analysis investigated one year outcomes among patients with WRF and stable renal function (SRF) in XAPASS. Methods: One year follow-up data of 9578 patients enrolled in XAPASS were analyzed to evaluate baseline characteristics and safety/effectiveness profile among patients with WRF and SRF. WRF was defined as a decrease of more than 20% from enrollment creatinine clearance measurement at any time point during the study. SRF was defined as the absence of WRF at any time. Results: We identified 1229 patients (12.8%) with WRF and 6280 patients (65.6%) with SRF among 9578 patients. WRF patients were significantly older, and had significantly higher mean CHA 2 DS 2 -VASc score and modified HAS-BLED score compared to SRF patients. Prevalence of hypertension, congestive heart failure, ischemic stroke/transient ischemic attack, and myocardial infarction was higher in WRF patients. There was no difference in rates of major bleeding (hazard ratio (HR) 1.20; 95% confidence interval (CI) 0.75-1.90; p=0.45) or the composite endpoint of stroke, systemic embolism or myocardial infarction (HR 1.06; 95% CI 0.65-1.71; p=0.82) between patients with WRF and SRF. WRF patients experienced a higher incidence of transfusion of 2 units or more (0.46 versus 0.14 events per 100 patient-years; HR 3.19; 95% CI 1.04-9.74; p=0.03) versus SRF patients. Rates of other major bleeding subgroups defined according to ISTH criteria were similar between patients with WRF and SRF. Conclusions: WRF during rivaroxaban treatment did not significantly increase the rates of major bleeding or thromboembolic events, although it was associated with a higher incidence of transfusion of 2 units or more.

Exosomes are 50-100-nm-diameter membrane vesicles released from various types of cells. Exosomes retain proteins, mRNAs and miRNAs, which can be transported to surrounding cells. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, and is released from the cell surface to the culture medium in vitro. Recently, it was reported that secreted CD109 from the cell surface downregulates transforming growth factor-β signaling in human keratinocytes. In this study, we revealed that CD109 is a component of the exosome in conditioned medium. FLAG-tagged human CD109 (FLAG-CD109) in conditioned medium secreted from HEK293 cells expressing FLAG-CD109 (293/FLAG-CD109) was immunoprecipitated with anti-FLAG affinity gel, and the co-precipitated proteins were analyzed by mass spectrometry and western blotting. Exosomal proteins were associated with CD109. We revealed the presence of CD109 in exosome fractions from conditioned medium of 293/FLAG-CD109. Moreover, the localization of CD109 in the exosome was demonstrated using immuno-electron microscopy. When we used HEK293 cells expressing FLAG-tagged truncated CD109, which does not contain the C-terminal region, the association of truncated CD109 with exosomes was not detected in conditioned medium. These findings indicate that CD109 is an exosomal protein and that the C-terminal region of CD109 is required for its presence in the exosome.

Metal dental restoration materials cause dose enhancement upstream and dose disturbance downstream of the high‐density inhomogeneous regions in which these materials are used. In this study, we evaluated the impact of a dental metallic crown (DMC) on intensity‐modulated radiotherapy (IMRT) and volumetric‐modulated arc therapy (VMAT) for head and neck cancer. Additionally, the possibility of sparing the oral mucosa from dose enhancement using an individual intraoral mouthpiece was evaluated. An experimental oral phantom was designed to verify the dosimetric impact of a DMC. We evaluated the effect on single beam, parallel opposing beam, arc beam, IMRT, and VMAT treatment plans. To evaluate the utility of a 3‐mm‐thick intraoral mouthpiece, the doses across the mouthpiece were measured. For single beam irradiation, the measured doses at the entrance and exit planes of the DMC were 51% higher and 21% lower than the calculated dose by the treatment planning system, respectively. The maximum dose enhancements were 22% and 46% for parallel opposing beams and the 90° arc rotation beam, respectively. For IMRT and VMAT, the measured doses adjacent to the DMC were 12.2%±6.3% (mean±1.96 SD) and 12.7%±2.5% higher than the calculated doses, respectively. With regard to the performance of the intraoral mouthpiece for the IMRT and VMAT cases, the disagreement between measured and calculated doses at the outermost surface of the mouthpieces were −2.0%, and 2.0%, respectively. Dose enhancements caused by DMC‐mediated radiation scattering occurred during IMRT and VMAT. Because it is difficult to accurately estimate the dose perturbations, careful consideration is necessary when planning head and neck cancer treatments in patients with DMCs. To spare the oral mucosa from dose enhancement, the use of an individual intraoral mouthpiece should be considered. PACS numbers: 87.55.km, 87.55.N‐, 87.55.Qr

Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.

The 5-HT

Background Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. Methods Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. Results The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 ± 1.31% at the 3-month visit from 8.4% at baseline (p

Objectives The aims of the present study were to evaluate the correlation of Ki-67 and CD109 expression in tongue SCC (TSCC), and to confirm the utility of CD109 observation as a novel marker for cancer diagnosis. Material and methods The expression of Ki-67 and CD109 from 27 patients with pathologically diagnosed well or moderately differentiated TSCC, including carcinoma in situ (CIS), was analyzed by immunohistochemical staining with anti-Ki-67 and anti-CD109 antibody. Significant relations between Ki-67 and CD109 expression were statistically assessed. Each expression level was quantified as a labeling index (LI). Results Immunohistochemical staining revealed that the LI of CD109 was upregulated with that of Ki-67, and the highest LI of CD109 was frequently detected at 50–60% LI of Ki-67. Linear regression analysis showed a significant correlation between LI of Ki-67 and LI of CD109. In the group of low LI of Ki-67 less than 25%, CIS and some early invasive lesions indicated the high LI of CD109. Conclusions These findings suggest that a positive relation exists between Ki-67 and CD109 expression in well or moderately differentiated TSCC including CIS, and immunohistochemical assessment of both expressions may well contribute to its pathological diagnosis. Moreover, CD109 could be one of the useful diagnostic markers for the detection of early-stage TSCC.

PURPOSE Recently, it has been revealed that bone marrow-derived mesenchymal stem cells (MSCs) accelerate the healing of skin wounds. Although the proliferative capacity of MSCs decreases with age, MSCs secrete many growth factors. The present study examined the effect of mesenchymal stem cell-conditioned medium (MSC-CM) on wound healing. MATERIALS AND METHODS The wound-healing process was observed macroscopically and histologically using an excisional wound-splinting mouse model, and the expression level of hyaluronic acid related to the wound healing process was observed to evaluate the wound-healing effects of MSC, MSC-CM, and control (phosphate-buffered saline). RESULTS The MSC and MSC-CM treatments accelerated wound healing versus the control group. At 7 days after administration, epithelialization was accelerated, thick connective tissue had formed in the skin defect area, and the wound area was reduced in the MSC and MSC-CM groups versus the control group. At 14 days, infiltration of inflammatory cells was decreased versus 7 days, and the wounds were closed in the MSC and MSC-CM groups, while a portion of epithelium was observed in the control group. At 7 and 14 days, the MSC and MSC-CM groups expressed significantly higher levels of hyaluronic acid versus the control group (P < .05). The expression level of hyaluronic acid was lower at 14 days than at 7 days in all three groups. CONCLUSIONS Both the MSC and MSC-CM groups accelerated wound healing versus the control group to a similar degree. Accordingly, it is suggested that the MSC-CM contains growth factor derived from stem cells, is able to accelerate wound healing as well as stem cell transplantation, and may become a new therapeutic method for wound healing in the future.

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.

We aimed to estimate the scattered radiation from dental metallic crowns during head and neck radiotherapy by irradiating a jaw phantom with external photon beams. The phantom was composed of a dental metallic plate and hydroxyapatite embedded in polymethyl methacrylate. We used radiochromic film measurement and Monte Carlo simulation to calculate the radiation dose and dose distribution inside the phantom. To estimate dose variations in scattered radiation under different clinical situations, we altered the incident energy, field size, plate thickness, plate depth and plate material. The simulation results indicated that the dose at the incident side of the metallic dental plate was approximately 140% of that without the plate. The differences between dose distributions calculated with the radiation treatment-planning system (TPS) algorithms and the data simulation, except around the dental metallic plate, were 3% for a 4 MV photon beam. Therefore, we should carefully consider the dose distribution around dental metallic crowns determined by a TPS.

Tissue engineering is an effective approach for the treatment of bone defects. Statins have been demonstrated to promote osteoblastic differentiation of bone marrow-derived stromal cells (BMSCs). Electrospun biodegradable fibers have also shown applicability to drug delivery in the form of bone tissue engineered scaffolds with nano- to microscale topography and high porosity similar to the natural extracellular matrix (ECM). The aim of this study was to investigate the feasibility of a simvastatin-releasing, biodegradable, nano- to microscale fiber scaffold (SRBFS) for bone tissue engineering with BMSCs. Simvastatin was released from SRBFS slowly. BMSCs were observed to spread actively and rigidly adhere to SRBFS. BMSCs on SRBFS showed an increase in alkaline phosphatase activity 2 weeks after cell culture. Furthermore, osteoclastogenesis was suppressed by SRBFS in vitro. The new bone formation and mineralization in the SRBFS group were significantly better than in the biodegradable fiber scaffold (BFS) without simvastatin 12 weeks after implantation of the cell-scaffold construct into an ectopic site on the murine back. These results suggest that SRBFS promoted osteoblastic differentiation of BMSCs in vitro and in vivo, and demonstrate feasibility as a bone engineering scaffold.

Purpose To evaluate the therapeutic results and rate of organ preservation in patients with advanced head and neck cancer treated with superselective intra-arterial chemotherapy via a superficial temporal artery and daily concurrent radiotherapy. Methods and Materials Between April 2002 and March 2006, 30 patients with T3 or T4a squamous cell carcinoma of the head and neck underwent intra-arterial chemoradiotherapy. Treatment consisted of superselective intra-arterial infusions (docetaxel, total 60 mg/m 2 ; cisplatin, total 150 mg/m 2 ) and daily concurrent radiotherapy (total, 60 Gy) for 6 weeks. Results The median follow-up for all patients was 46.2 months (range, 10–90 months). The median follow-up for living patients was 49.7 months (range, 36–90 months). After intra-arterial chemoradiotherapy was administered, primary site complete response was achieved in 30 (100%) of 30 cases. Seven patients (23.3%) died. Using the Kaplan-Meier method, 1-year, 3-year, and 5-year survival rates were 96.7%, 83.1%, and 70.2%, respectively, while 1-year, 3-year, and 5-year local control rates were 83.3%, 79.7%, and 73.0%, respectively. Grade 3 or 4 mucositis occurred in 20 cases (66.7%). Grade 3 toxicities included dysphagia in 20 cases (66.7%), dermatitis in 6 cases (20%), nausea/vomiting in 2 cases (6.7%), and neutropenia and thrombocytopenia in 1 case (3.3%). No osteoradionecrosis of mandible and maxillary bones developed during follow-up. Conclusions Intra-arterial chemoradiotherapy using a superficial temporal artery provided good overall survival and local control rates. This combination chemoradiotherapy approach can preserve organs and minimize functional disturbance, thus contributing to patients' quality of life.

進行口腔癌に対する逆行性超選択的動注化学療法は放射線療法との連日同時併用が可能となることから高い抗腫瘍効果が得られる。今回われわれは進行口腔癌に対して根治的逆行性超選択的動注化学放射線療法を施行し，治療効果，累積生存率，局所制御率について検討したので報告する。2003年1月から2009年12月に受診した口腔・顎顔面悪性腫瘍688例中，根治的逆行性超選択的動注化学放射線療法を施行した175症例を対象とした。治療は逆行性超選択的動注化学放射線療法（docetaxel, total 60mg/m2, cisplatin, total 125-150mg/mm2, total 50-60Gy）を5～6週間行った。治療4週後に画像検索および原発の生検にて腫瘍残存の有無の確認を行ったところ，175例中160例（91.4%）がCR，腫瘍残存は15例（8.6%）に認めた。CRであった160例についてはその後の経過観察中に14例（8.0%）の再発を認めた。5年累積生存率および局所制御率はそれぞれ71.6%と82.2%であった。

The antipsychotic drug zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP; N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7- to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamine-induced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3beta,16beta,17alpha,18beta,20alpha)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.

CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-beta signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-beta signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-beta signaling nor affected TGF-beta-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-beta receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes.