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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.

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.

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.

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.

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

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.

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.

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。

A patient with secondary hyperparathyroidism (2 degrees HPT) underwent a total parathyroidectomy (PTx) without autotransplantation and showed interesting changes in the morphology of his iliac bone before and after the surgery. A 70-year-old man had been on hemodialysis for chronic glomerulonephritis since 1987. He had been administered calcium carbonate 6.0 g daily to prevent reabsorption of phosphorus and alfacalcidol 1.0 microg three times weekly at the end of hemodialysis. In September 2000, his intact parathyroid hormone (iPTH; 1-84 PTH) was 610 pg/mL; therefore, from 2.5 microg to 10 microg 22-oxacalcitriol (maxacalcitol, a derivative of active vitamin D) was administered intravenously three times weekly at the end of hemodialysis. This compound is used in Japan for 2 degrees HPT. However, the iPTH progressed, and hypercalcemia and hyperphosphatemia were observed. Ultrasonography of the neck illustrated three enlarged parathyroid glands that were each over 1.0 cm in diameter. On 14 July 2004, a PTx without autotransplantation (PTx alone) and an iliac crest bone biopsy were performed. Bone specimens showed mild lesions of hyperparathyroidism, but did not meet the criteria for osteitis fibrosa. One year after the procedure, a second biopsy was obtained to investigate the bone turnover in response to a lack of parathyroid hormone. The bone specimen showed tetracycline labeling at the time of PTx alone, and new bone apposition on the surface without tetracycline labeling. This adynamic bone disease (ABD) suggested that new bone apposition in the absence of tetracycline labeling had occurred after the PTx alone, and it had likely occurred over the course of one year.

Recent reports have suggested that procedures using bone grafts from the tibia shorten operating time and reduce postoperative discomfort. Tibial grafts are thought to be less invasive than conventional iliac grafts, and we have obtained favourable results with tibial grafts. However, this report is of a 54-year-old woman who sustained a tibial fracture on the donor side in a fall after harvesting for the tibial graft. This suggests that although extraction of bone from the tibia is less invasive than extraction from the iliac crest, there is a need for a mandatory period of rest and reduced effort to allow bone regeneration at the donor site with the use of bone graft substitutes.

Background: We recently began using preoperative chemotherapy delivered by superselective intraarterialinfusion via the superficial temporal artery as a treatment for oral cancer. However, catheterization is difficultin some patients because of the presence of a common trunk and angiectopia and hemadostenosis of theexternal carotid artery and tumor nutrient arteries. The purpose of this study was to conduct a clinicoanatomicalinvestigation of the external carotid artery and tumor nutrient arteries by digital subtraction angiography.Method: We conducted an anatomical investigation of the external carotid artery and its branches in 58 patients (69 sites) by digital subtraction angiography.Results: There were many variations in the branch patterns of the external carotid artery. In 53.6% of thepatients, branches arose in the order of the superior thyroid, lingual, facial, occipital, and maxillary arteries fromthe proximal side. In 24.6 % of the patients, the lingual artery formed a common trunk with the facial artery. In1.4%, the lingual artery formed a common trunk with the superior thyroid artery. The length of the faciolingualtrunk in 76.5% of the patients was long and anticancer agents flowed into both the lingual and the facial arteries.Severe hemadostenosis of the main trunk of the external carotid artery was observed in 7.2% of the patients.Severe angiectopia of the main trunk of the external carotid artery interferred with catheterization in 5.8 % of thepatients.Conclusion: These results provide a clinicoanatomical basis for intraarterial infusion via the superficial temporalartery. The noteworthy points for catheterization were the presence and length of the common trunk of the tumornutrient arteries and the existence of angiectopia or hemadostenosis of the external carotid artery.

頭頸部癌に対する超選択的動注化学療法は，Seldinger法を用いた大腿動脈からの方法と浅側頭動脈よりの逆行性にカテーテルを挿入する方法（HFT法）とに大きくわけられる。HFT法はカテーテルの長期留置ができることから放射線との連日同時併用が可能であり，比較的安全性の高い治療方法である。今回われわれは進行口腔癌に対してdocetaxelとcisplatinを用い，超選択的動注化学療法と放射線療法との連日同時併用療法を行い，原発温存症例につき検討した。口腔癌T3，4の23例について検討した結果，19例（83%）については原発がコントロールされ，4例（17%）が再発した。4例中3例は手術を施行し，局所制御されている。23例中21例（87%）が生存し2例が死亡した。2例の内訳は1例が原発の再発で局所のコントロールができず，あとの1例は遠隔転移によるものであった。生存率は，1年生存率95.5%，3年生存率79.5%，5年生存率79.5%であった。超選択的動注化学療法では治療前に腫瘍の栄養動脈を同定し，確実に抗癌剤を投与することが重要である。HFT法を用いた連日同時放射線化学療法は生存率の向上，原発温存，さらには頸部郭清術の回避などの多くの利点を期待できる治療法である。

近年，細胞や細胞を支える生体吸収性の担体などを用いて，失われた組織を再生する再生医療が注目されている。移植のための組織を必要としないことから，患者への侵襲の少ない新たな治療として期待されている。現状では，再生可能な組織の大きさや種類は限られており，広範な腫瘍の再建手術に用いることは不可能である。しかしながら，将来的には現在行われている再建手術の一部が，再生医療により治療されることが望まれる。現在東京大学医科学研究所附属病院において，体性幹細胞である間葉系幹細胞と生体吸収性の担体であるβ-TCP顆粒を用いた骨再生の臨床研究が行われている。一方，再建に重要な役割を果たす組織として，骨以外も血管や末梢神経の再生研究が進められている。本稿では，これらの組織の再生研究についても紹介する。

Stem cells from human exfoliated deciduous teeth (SHEDs) can regenerate various tissues. We investigated the impact of SHED-conditioned medium (SHED-CM) on myocardial injury in a mouse model of ischemia-reperfusion (I/R). Wild-type (WT) mice were subjected to myocardial ischemia followed by reperfusion. SHED-CM was intravenously injected at 5 min after reperfusion. Administration of SHED-CM reduced myocardial infarct size as well as decreased apoptosis and inflammatory cytokine levels, such as TNF-α, IL-6 and IL-β, in the myocardium following I/R. In cultured cardiac myocytes, SHED-CM significantly suppressed apoptosis under hypoxia/serum-deprivation and reduced LPS-induced expression of pro-inflammatory genes. Furthermore, anti-apoptotic action of SHED-CM was stronger than bone marrow-derived stem cell (BMSC)-CM or adipose-derived stem cell (ADSC)-CM in cardiac myocytes. SHED-CM contains a higher concentration of hepatocyte growth factor (HGF) than BMSC-CM and ADSC-CM and neutralization of HGF attenuated the inhibitory actions of SHED-CM on apoptosis in cardiac myocytes. Finally, WT mice were intravenously treated with an HGF-depleted SHED-CM, followed by myocardial I/R. HGF depletion significantly attenuated the inhibitory actions of SHED-CM on myocardial infarct size and apoptosis after I/R. SHED-CM protects the heart from acute ischemic injury because it suppresses inflammation and apoptosis. SHED-CM could be a useful treatment option for acute myocardial infarction.

The objective of this study is to examine the effect of acarbose, an alpha-glucosidase inhibitor, on body weight in a real-life setting by pooling data from post-marketing surveillance.Data from 10 studies were pooled (n=67,682) and the effect of acarbose on body weight was analysed taking into account baseline body weight, glycemic parameters and other baseline characteristics.The mean relative reduction in body weight was 1.45 ± 3.24% at the 3-month visit (n=43,510; mean baseline 73.4 kg) and 1.40 ± 3.28% at the last visit (n=54,760; mean baseline 73.6 kg) (both p0.0001). These reductions were dependent on baseline body weight (overweight: -1.33 ± 2.98% [n=13,498; mean baseline 71.6 kg]; obese: -1.98 ± 3.40% [n=20,216; mean baseline 81.3 kg]). When analysed by baseline glycemic parameter quartiles, the reduction was independent of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA1c) and postprandial glucose excursion (PPGE). A bivariate analysis of covariance identified female sex, South East Asian and East Asian ethnicity, younger age, higher body mass index, short duration of diabetes, and no previous treatment as factors likely to impact positively on body weight reduction with acarbose.This post-hoc analysis showed that acarbose treatment reduces body weight independent of glycemic control status but dependent on baseline body weight.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti-inflammatory and reparative therapy for RA.

Background aims Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. Methods Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. Results A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow–derived macrophages into M2-like cells, which expressed high levels of Arginase1 , CD206 and Ym-1 . Discussion Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell–based ARDS therapies.

Aim: Vardenafil is a highly selective phosphodiesterase type-5 inhibitor for the treatment of erectile dysfunction (ED). Efficacy of vardenafil has been demonstrated in various ED populations, but that in Japanese patients with spinal cord injury (SCI) has not been assessed. Methods: This was an open-label, multicenter, flexible dose, 12-week study in patients with ED due to SCI. Following a 4-week observation period, patients received vardenafil 10 mg for 4 weeks, and based on efficacy, tolerability and patient preference, doses for the remaining 8 weeks were decided by investigators. The primary efficacy parameter was erectile function domain score of the International Index of Erectile Function. Results: Ten patients took 10 mg all through the study, while 22 patients took 20 mg after completing 4 weeks’ treatment with 10 mg. The erectile function domain score increased from 12.2 at baseline to 25.0 at Last Observation Carried Forward (LOCF) in the former group and from 10.3 to 22.5 in the latter group, respectively. Importantly, there was a 5.0 point increase in erectile function domain score after up-titration in the latter group. Drug-related adverse events were observed in 22% of patients including hot flushes (9%) and headache (6%), but these were transient and mild in intensity. Serious adverse events and adverse events leading to discontinuation of the study drug were not reported. Conclusions: Vardenafil 10 and 20 mg was well tolerated and improved erectile function in patients with SCI. Of interest, erectile function was further improved by 20 mg in patients who were not sufficiently treated with 10 mg.

BACKGROUND Traditional risk factors of cardiovascular disease do not fully explain the accelerated atherosclerosis present in patients with end-stage renal disease (ESRD). The goal of this study was to identify the association of clinical and laboratory factors including seropositivity for Chlamydia pneumoniae determined by a specific enzyme-linked immunosorbent assay (ELISA) with the presence of coronary artery disease identified by coronary angiography in ESRD patients. METHODS We prospectively enrolled 161 consecutive ESRD patients undergoing haemodialysis for >6 months (106 men, 55 women; mean age 63.1+/-10.2 years; mean dialysis duration 91.3+/-90.1 months). All patients underwent coronary angiography within 1 week after blood sampling. The associations of coronary artery disease with clinical parameters including C. pneumoniae IgA and IgG seropositivity were analysed using multiple logistic regression models. RESULTS Coronary stenosis >50% was found in 102 of 161 haemodialysis patients (63.4%). Of the 102 patients, 75.5% were asymptomatic. Seropositivity for C. pneumoniae IgA was found in patients with coronary stenosis (77 out of 102, 75.5%) more frequently (P

水処理装置 (以下RO装置) から個人用透析装置 (以下透析装置) までのRO水供給ライン (以下RO水ライン) は通常洗浄消毒されず, 一度汚染されると細菌繁殖が起こる可能性がある. われわれは, RO水ラインの洗浄消毒に適当と思われる残留性が低く強い酸化力のあるオゾン水に着目した. 今回, 新しく開発された高濃度オゾン水生成装置OZROCK-2 (ワールドメディカル社製) をRO装置後のRO水ライン上に設置し, オゾン水単独によるRO水ライン清浄化の保持と透析装置および周辺機器の洗浄消毒を行った. OZROCK-2は大気から分離した酸素ガスを用い電気分解にてオゾンガスを発生させ, RO水と混合することでオゾン水を生成する. OZROCK-2をRO装置直後のRO水ラインに設置し, オゾン水を流すことにより全てのRO水ラインおよび関連装置をオゾン水単独での洗浄・消毒が可能であった. 清浄化の指標であるET活性値は, 末端個人用透析装置入口において, オゾン水導入前後における15か月平均で, それぞれ導入前77.03±71.2EU/L, 後で3.83±7.2EU/Lと有意に低下した.オゾン水による透析装置への影響については, 使用6か月目に一部の透析装置にタンパク様物質の付着がみられたため, 塩素系薬剤との併用で解消した. また, 使用12か月目で一部メーカーの電磁弁弁シートに脱色が確認されたが, 部品の性能に問題はなかった.オゾン水によるRO水ラインおよび透析周辺機器の洗浄消毒は有効であり, 透析液の清浄化保持に有用と思われた.

口腔癌に対して浅側頭動脈よりの先端が屈曲しているカテーテルとPUカテーテルを用いた，新しい超選択的動注法を開発した。屈曲カテーテルは先端の形状により5種類あり，術前の血管造影撮影よりカテーテルを選択する。屈曲カテーテルの挿入方法は術中イメージ下で浅側頭動脈より逆行性にガイドワイヤーを用いて腫瘍の栄養血管に挿入する。屈曲カテーテルの挿入が不安定な場合はPUカテーテルを使う。挿入方法は屈曲カテーテルの中にガイドワイヤーを挿入し，ワイヤーを腫瘍の栄養血管まで挿入する。ガイドワイヤーをそのままにして屈曲カテーテルを抜去，ガイドワイヤーに添ってPUカテーテルを腫瘍栄養血管まで挿入する。

Alpha-glucosidase inhibitors are widely used especially in Asian countries as a treatment option for type 2 diabetes patients with high postprandial glycemia (PPG). The higher carbohydrate in the Indian diets lead to greater prandial glycemic excursion, increased glucosidase, and incretin activity in the gut and may need special therapeutic strategies to tackle these glucose peaks. This is the subgroup analysis of Indian subjects who participated in the GlucoVIP study that investigated the effectiveness and tolerability of acarbose as add-on or monotherapy in a range of patients with type 2 diabetes mellitus. A total of 1996 Indian patients were included in the effectiveness analysis. After 12.5 weeks (mean), the mean change in 2-hour PPG from baseline was −74.4 mg/dl, mean HbA1c decreased by -1.0%, and mean fasting blood glucose decreased by -37.9 mg/dl. The efficacy of acarbose was rated "very good" or "good" in 91.1% of patients, and tolerability as "very good" or "good" in 88.0% of patients. The results of this observational study suggest that acarbose was effective and well tolerated in the Indian patients with T2DM.

虚血性心疾患は血液透析患者の主要な死因の一つである. 冠動脈疾患の検出に心臓核医学検査は有用であるが運動・薬剤負荷を必要とし, 透析患者では, その実施・判定に困難を伴うことが多い. 正常心筋はエネルギー源の70%以上を効率のよい脂肪酸β酸化に依存しているが, 心筋虚血時には脂肪酸のβ酸化が抑制され, 代わってグルコースを利用した解糖系へ移行する. 透析患者の冠動脈病変検出における心筋脂肪酸代謝イメージング製剤である123I-BMIPPの安静時検査の有用性を検討した.慢性腎不全による維持血液透析患者130例 (平均透析期間88.5か月, 男性77例, 女性53例, 平均年齢63.8歳) に対し心筋血流製剤である塩化タリウム (201TI) ならびに123I-BMIPPのSPECT (single photon emission computed tomography) を施行し, その後60日以内に施行された冠動脈造影検査所見と対比した. 左室心筋を17分画し, TIおよびBMIPP SPECT所見を視覚的に判定, スコア化し (0: 正常-4: 欠損), その総計をTIならびにBMIPP summed scoreとした.冠動脈造影の結果, 対象患者の71.5%に75%以上の有意狭窄を認めた. BMIPP summed score 6以上を陽性とした場合, BMIPP-SPECTの冠動脈病変の総合正診率は90.0% (感度: 98.0%, 特異度: 65.6%) であった. 一方, TI-SPECTでは, TI summed score 1以上を陽性とした場合, 感度84.7%, 特異度46.9%, 総合正診率75.0%であった. ROC解析の結果, 冠動脈病変診断能を示すAUC (area under the curve) は, BMIPP SPECT 0.895, TI SPECT 0.727であった.BMIPP-SPECTはTI-SPECTに比して高い精度で冠動脈病変を検出できる. 慢性血液透析患者の冠動脈造影検査の適応判定ならびに冠動脈疾患合併の安全なスクリーニング検査として臨床的に有用である.

Background. The incidence of intracardiac thrombosis in haemodialysis patients has not been studied. Here we determined the incidence in end-stage renal disease patients on maintenance haemodialysis. Methods. Transoesophageal echocardiography was performed in 215 patients (125 males, 90 females; mean age 60 ± 9 years). Any potential candidate with current or past chronic or intermittent atrial fibrillation or with cardiovascular diseases was excluded from the study. Results. Thrombi were found in the left atrial appendages in 71 out of 215 subjects (33%). Based on multiple logistic regression analyses, the probability of finding a thrombus was found to be increased in patients on chronic antiplatelet therapy (odds ratio 4.268) and in those with diabetes mellitus and a low haematocrit (� 0.3; odds ratio 7.173). Other clinical parameters, including gender, age, duration of haemodialysis, blood pressure, left ventricular dimension, smoking habit or type of anticoagulation during dialysis, were not associated with the incidence of left atrial appendage thrombosis. Conclusions. Maintenance haemodialysis patients have a high incidence of left atrial appendage thrombosis. Either chronic use of antiplatelet drugs or the background conditions requiring antiplatelet therapy, and the concomitant presence of diabetes mellitus and a low haematocrit may be involved in left atrial appendage thrombosis.

1. Diabetes mellitus is significantly associated with the occurrence of congestive heart failure in end-stage renal disease patients undergoing maintenance haemodialysis. In the present study, we asked whether the left ventricular remodelling against sustained pressure and/or volume overload to the left ventricle may be different between diabetic and non-diabetic haemodialysis patients. 2. Left ventricular parameters, including left ventricular mass index (LVMI), interventricular septal wall thickness (IVST) and relative left ventricular wall thickness (rLVWT), were assessed in 486 patients receiving maintenance haemodialysis (145 diabetic and 341 non-diabetic patients) using transthoracic echocardiography. Plasma concentrations of B-type natriuretic peptide (BNP), measured with an immunoradiometric assay, were used as a humoral parameter indicating left ventricular wall stress. 3. In non-diabetic patients, the plasma BNP concentration correlated with LVMI (r = 0.245; P = 0.0001), IVST (r = 0.250; P = 0.0001) and rLVWT (r = 0.149; P = 0.006). Furthermore, LVMI was correlated with mean blood pressure and pulse pressure and IVST and rLVWT were correlated with pulse pressure. 4. In contrast, none of the measured factors was correlated with LVMI and IVST in diabetic patients. Plasma BNP concentrations were positively correlated with end-systolic and end-diastolic left intraventricular dimensions and were inversely correlated with rLVWT and left ventricular fractional shortening in diabetic patients, but not in non-diabetic patients. 5. In conclusion, a sustained increase in left ventricular wall stress is likely to elicit eccentric left ventricular remodelling in diabetic haemodialysis patients, whereas it causes concentric left ventricular remodelling in non-diabetic haemodialysis patients. This difference in left ventricular remodelling against left ventricular overload may be associated with the high incidence of congestive heart failure in diabetic haemodialysis patients.

目的: 慢性腎不全による維持血液透析例の左室肥大の成因について, 糖尿病 (DM) 罹患の有無の観点から臨床的に検討した. 対象と方法: 維持血液透析患者486例 (DM145例, 非DM341例) を対象に, 透析前に心臓超音波検査を施行し, 心機能とともに心室中隔径 (IVST), 相対的左室壁厚 (rLVWT), 左室重量係数 (LVMI) を計測した. 透析施行直前のヘマトクリット値, 血漿BNP濃度, 血漿アルドステロン濃度を測定し, 左室肥大との関係を検討した. 結果: 非DM例では, 左室壁ストレスの指標である血漿BNP濃度は, LVMI (r=0.245, p=0.0001), IVST (r=0.250, p=0.0001), rLVWT (r=0.149, p=0.006) と正相関を示した. LVWIは, 透析前後の平均血圧および脈圧, IVSTならびにrLVWTは, 透析前後の脈圧と正相関を示した. DM例では, LVMI, IVST, rLVWTのいずれも血漿BNP濃度, 透析前後の血圧・脈圧値との関連はなかった. 非DM・DM例ともに, ヘマトクリット値, 血漿アルドステロン濃度は左室肥大の指標との関連を認めなかった. 結論: 非DM性透析患者では持続的な容量・圧負荷による左室壁ストレス増加に対して左室心筋リモデリングによる代償性の左室肥大を生じる. DM性透析患者では, 左室肥大は圧・容量負荷とは関係なく生じ, 左室壁ストレスに対する心筋リモデリング・代償性左室肥大の機構に障害がある可能性がある.

Stage III, IVの38例の口腔癌患者に対して浅側頭動脈よりの超選択的動注法を用いた術前放射線化学療法を施行した。化学療法はCBDCA: 460mg/m2, 放射線治療は40Gyを連日併用で4週間行い, 後に根治手術を施行した。カテーテル挿入率は89.4%であり, 挿入が不可能であった症例は舌動脈と顔面動脈との長い共同幹などが原因であった。重篤な合併症はみられなかった。臨床効果はCRが9例 (26.5%), PRが25例 (73.5%) であった。原発巣の摘出物の病理効果は grade III, IVが10例 (29.4%), grade IIbが23例 (67.6%), grade IIaが2例 (5.8%) であった。経過観察期間は8ケ月から最高63ケ月であり, 平均35ケ月であった。予後は5年累積生存率は67.8%と高い値であった。浅側頭動脈からの超選択的動注療法は連日の放射線との併用療法が可能であり, また合併症も少なく, 有用性が期待できた。

Despite the human 5-HT5A receptor being cloned in 1994, the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. We recently reported that the selective 5-HT5A receptor antagonist ASP5736 ameliorated cognitive impairment in several animal models of schizophrenia. Given that areas of the brain with high levels of 5-HT5A receptor expression, such as the hippocampus and cerebral cortex, have important functions in cognition and memory, we evaluated the chemically diverse, potent and brain-penetrating 5-HT5A receptor antagonists ASP5736, AS2030680, and AS2674723 in rodent models of cognitive dysfunction associated with dementia. Each of these compounds exhibited a high affinity for recombinant 5-HT5A receptors that was comparable to that of the non-selective ligand of this receptor, lysergic acid diethylamide (LSD). Although each compound had a low affinity for other receptors, 5-HT5A was the only receptor for which all three compounds had a high affinity. Each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. Further, ASP5736 decreased the binding of LSD to 5-HT5A receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%–50% of brain 5-HT5A receptors at behaviorally effective doses. These results indicate that the 5-HT5A receptor is involved in learning and memory and that treatment with 5-HT5A receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia.

本実験では, ヒト頭頸部扁平上皮癌細胞に対する, アデノウイルス (Ad) ベクターを用いた自殺遺伝子治療の評価を行った。まず, 4種類の頭頸部扁平上皮癌細胞株において AdlacZ (lacZ 遺伝子を含んだAdベクター) によりMOI=1で約15%, MOI=10でほぼ100%の遺伝子導入効率を in vitro で認めた。さらに Adtk (HSVtk 遺伝子を含んだAdベクター) の感染とGCV 10μgの投与によりMOI=1で約70%, MOI=10でほぼ100%の殺細胞効果を認めた。つぎに, SAS細胞を移植したマウスの実験において, Adベクターによる遺伝子導入が可能であることを確認し, さらに自殺遺伝子治療による著明な抗腫瘍効果を認めた。しかし免疫染色においては, 自殺遺伝子治療がマウスの腫瘍免疫能を賦活化しているような結果は得られなかった。以上の結果より, Adベクターを用いた自殺遺伝子治療は, ヒト頭頸部扁平上皮癌に対し有効であることが示唆された。加えて, 自殺遺伝子治療の効果の増強を図る為にはバイスタンダー効果の機序の解明が重要であると思われた。

単副腎である慢性血液透析 (HD) 患者に合併した褐色細胞腫を経験した. 副腎皮質温存手術およびHD患者に発生した褐色細胞腫について文献的考察を加え, またHD患者の血漿バニルマンデル酸 (VMA) 値について検討した. 症例は, 56歳男子, 1978年1月より末期腎不全にて慢性血液透析中であった. 1995年2月, Aquired cystic disease of kidney (ACDK) に合併した腎細胞癌で根治的右腎摘除術 (右副腎合併切除を含む) および後腹膜リンパ節郭清術を受けている (RCC, papillary and common type, granular>clear cell subtype, G2, pT2, N3). 術後6か月のCTにて左副腎腫瘍を認めた. 腎摘除前のCTと比較したところ, 腫瘍径は約2cmで, 周囲との癒着を認めず, 明らかな増大は認めなかった. 10月選択的副腎動脈撮影を行った. 副腎腫瘍は血管陰影に乏しく右腎腫瘍の副腎転移とは診断し得なかった. また特別の症状もなく非機能性副腎腫瘍として経過観察とした. なお, 動脈撮影時明らかな血圧の上昇は認めなかった. その後約2か月, 透析終了時動悸を伴う高血圧発作を認め, 血漿CAおよびVMAの高値を認めた. I131MIBGシンチにて左副腎がhotに描出され, 左単副腎に発生した褐色細胞腫と診断した. 術前prazosinにて管理し, 副腎皮質温存を目的に褐色細胞腫核出術を行った. 術後cortisolの補充療法を行い28日後に離脱した. 術後血漿CAは正常化したが, VMAの高値が持続した. そこで, 慢性血液透析患者の血漿VMAについて検討した. その結果, 慢性血液透析患者の血漿VMAの基準値は432μg/ml (mean+2SD) 以下と推定され, HD患者の血漿VMA値の解釈には注意を要すると考えられた.

Alpha-glucosidase inhibitors (AGIs) are widely used especially in Asian countries as a treatment option for type 2 diabetes patients with high postprandial glycaemia. However, data from South Asia region is very limited. In order to examine the effect of AGI in real-life setting, 10 PMS/NIS from all over the world from the launch of acarbose to date were pooled in one database and exploratory analysis was performed for glycemic parameters and weight. In total 62,905 patients were pooled from 21 countries and regions. Mean follow up (± SD) was 12.2 ± 4.8 weeks (range 0.1-108.9). From South Asia region (India and Pakistan), 8,738 Asian patients were enrolled. Mean PPG decreased from 240.0 and 261.1 mg/dl at baseline by 70.26 ± 65.10 and 82.96 ± 56.59 mg/dl at the last visit in total and South Asian populations, respectively (n = 53,883; n = 7,991, P < 0.0001 for both). Mean FPG decreased from 171.6 and 176.5 mg/dl at baseline by 38.48 ± 47.83 and 49.59 ± 41.41 mg/dl at the last visit in total and South Asian populations, respectively (n = 56,672; n = 7,837, P < 0.0001 for both). Mean HbA1c decreased from 8.4 and 8.4% at baseline by 1.11 ± 1.31% and 0.91 ± 0.93% at the last visit in total and South Asian populations, respectively (n = 38,843; n = 2,343, P < 0.0001 for both). Mean relative reduction of body weight (BW) was 1.40 ± 3.28% and 1.10 ± 3.39% at the last visit for mean baseline BW 73.6 and 74.2 kg in total and South Asian populations, respectively (n = 54,760; n = 7,718, P < 0.0001 for both). Consistent with RCT meta-analyses, post-hoc analysis of real-life data showed acarbose treatment improved glycaemic control and reduced the BW. Acarbose treatment in real life setting showed significant reductions in all glycemic parameters and BW in Asian patients from South Asia region.

近年, 心拍のR-Rスペクトル解析の臨床応用が進むにつれて自律神経活動を交感神経系と副交感神経系に分離定量化し, さらに経時的にその活動状況を追跡することが可能になってきた. そこで今回我々は, 血液透析 (HD) 患者に48時間連続でホルター心電図計を装着し, 約20万beatの心拍変動をすべてフロッピーディスクに格納したのち最大エントロピー法 (MEM) にてスペクトル解析を施行した. さらに得られた高周波成分 (HF) や低周波成分 (LF) などの時系列成績をフーリエ変換 (FFT) を用いた周期回帰分析法にて曲線回帰し, 交感神経および副交感神経の日内変動パターンを変動周期と変動型に分けて分析検討した. 以上の結果, HD患者の自律神経活動は健常者とは異なり交感・副交感神経ともに48時間周期で変動しており, HD日には交感神経系の活動が亢進し, 逆に非HD日には副交感神経系の活動が亢進する特異な変動型を示すことが明らかになった. 一方, HD患者における心拍数の変動周期は, 約24時間の概日リズムを保持していた.