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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.

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.

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 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。

Dopaminergic neurons are more vulnerable than other types of neurons in cases of Parkinson disease and ischemic brain disease. An increasing amount of evidence suggests that endogenous dopamine plays a role in the vulnerability of dopaminergic neurons. Although glutamate toxicity contributes to the pathogenesis of these disorders, the sensitivity of dopaminergic neurons to glutamate toxicity has not been clarified. In this study, we demonstrated that dopaminergic neurons were preferentially affected by glutamate toxicity in rat mesencephalic cultures. Glutamate toxicity in dopaminergic neurons was blocked by inhibiting extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase, and p38 MAPK. Furthermore, depletion of dopamine by alpha-methyl-dl-p-tyrosine methyl ester (alpha-MT), an inhibitor of tyrosine hydroxylase (TH), protected dopaminergic neurons from the neurotoxicity. Exposure to glutamate facilitated phosphoryration of TH at Ser31 by ERK, which contributes to the increased TH activity. Inhibition of ERK had no additive effect on the protection offered by alpha-MT, whereas alpha-MT and c-jun N-terminal kinase or p38 MAPK inhibitors had additive effects and yielded full protection. These data suggest that endogenous dopamine is responsible for the vulnerability to glutamate toxicity of dopaminergic neurons and one of the mechanisms may be an enhancement of dopamine synthesis mediated by ERK.

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.

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.

Recent studies on prostanoids showed that some of prostanoid receptors are expressed in rat dorsal root ganglion (DRG) neurons. These facts suggest that prostanoid receptors might be involved in the excitation mechanism of DRG neurons. In the present study, PCR experiments revealed that one of prostanoid receptor, prostacyclin receptor (IP receptor) was expressed in L6 and S1 rat DRG neurons and that the expression of IP receptor was not changed in DRG neurons obtained from the cyclophosphamide (CYP)-induced cystitis rat. We examined the functional role of IP receptor agonist and other prostanoids by measuring cyclic AMP (cAMP) accumulation and substance P (SP) release in primary cultured DRG neurons. The pretreatment of DRG neurons with prostanoid agonists such as iloprost (IP), butaprost (EP(2)), misoprostol (EP(2-4)), PGE(2) (EP(1-4)) or PGD(2) (DP and CRTH2) sensitized the DRG neurons and hence potentiated the lys-bradykinin-induced SP release. The increase of SP release by lys-BK plus prostanoid agonists was proportion to cAMP accumulation. Iloprost was the most potent agonist to induce cAMP accumulation and SP release among prostanoid agonists evaluated in this study and its effect is mediated by IP receptor. Moreover, capsaicin-, ATP- and KCl-induced SP release was also enhanced by iloprost although iloprost did not change intracellular Ca(2+) and membrane depolarization induced by these chemical stimuli. These results strongly indicate that IP receptor play an important role in the sensitization of rat sensory neuron.

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

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。

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.

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.

血液透析 (HD) 患者・CAPD患者および健常者の血圧と心拍数 (HR) を, 携帯型自動測定装置を用いて30分間隔で48時間連続モニター (ABPM) した. 得られた時系列成績の変動型と変動周期を, 高速フーリエ変換 (FFT) を用いた周期回帰分析法にて群別に比較検討した. 健常者およびCAPD患者においては, 収縮期血圧 (SBP)・拡張期血圧 (DBP) はともに夜間に下降する規則正しい変動型を示し, 24時間の概日リズムは保たれていた. しかしHD患者の場合は, SBP・DBPの周期回帰曲線はいずれも透析日の夜には下降するものの非透析日の夜には下降せず, 午後11時頃から翌朝6時頃にかけて逆に上昇する特徴的なパターン (midnight surge) を示した. フーリエ変換にて得られた周期寄与率を検討した結果, HD患者の血圧は24時間周期ではなく48時間周期で変動しているものと考えられた. さらに, 一日尿量の減少および透析による除水量の増加に比例して48時間周期成分に対する寄与率の増加とmidnight surgeの明瞭化を認めたことより, HD患者の血圧変動周期の48時間への移行の原因は体液貯留と透析による短時間の除水であると結論された. 一方, HRの変動周期に関してはHD患者も他の群と同様に24時間の規則正しい変動周期を示し, 体液因子の影響をあまり受けないものと考えられた. しかし変動型に関しては回帰曲線の振幅の減弱化と夜間の最低心拍数の高値化を認め, 軽度の自律神経障害が示唆された. 最後に, 糖尿病 (DM) を有するHD患者のみを選び周期解析したところ, SBP・DBP・HRすべてにおいて24時間や48時間の周期成分は有意には検出されず12時間周期のみが検出された. このことはDMを有する患者は体液因子のみではなく, 自律神経因子も高度に障害されているためと推定された.

慢性腎不全患者の血圧日内変動の詳細を明らかにする目的で, 腎不全患者をその病期によって複数の群 (保存期腎不全患者群, 血液透析患者の透析前日群, 血液透析患者の透析当日群, CAPD群) に分け, それぞれの血圧を携帯型自動測定装置を用いて, 30分間隔にて24時間連続モニターした. 得られた時系列データを, 昼夜変化率などの統計学的手法とコサイナー法による推計学的手法にて分析検討した. 慢性腎不全患者の血圧は健常者と比較してどの群でも上昇傾向にあり, 昼と夜の血圧較差は近接していた. しかし, 昼夜変化率のTukey検定にて夜間血圧の逆転上昇を有意に認めたのは血液透析前日群のみで, 保存期腎不全群・血液透析当日群・CAPD群では夜間血圧は下降していた. コサイナー法のパラメータを分析すると, 透析前日群のAcrophase (頂点位相) は健常者も含めた他の群よりも夜方向に180°ずれており, 夜間血圧の上昇はこの血圧変動パターンのずれによって起こると考えられた. さらに, 血液透析という行為が24時間周期の日内リズムを変化させていることも示唆された.

Purpose To evaluate the therapeutic results and histopathological effects of treatment with thermochemoradiation therapy using superselective intra-arterial infusion via the superficial temporal and occipital arteries for N3 cervical lymph node metastases of advanced oral cancer. Methods and Materials Between April 2005 and September 2010, 9 patients with N3 cervical lymph node metastases of oral squamous cell carcinoma underwent thermochemoradiation therapy using superselective intra-arterial infusion with docetaxel (DOC) and cisplatin (CDDP). Treatment consisted of hyperthermia (2-8 sessions), superselective intra-arterial infusions (DOC, total 40-60 mg/m 2 ; CDDP, total 100-150 mg/m 2 ) and daily concurrent radiation therapy (total, 40-60 Gy) for 4-6 weeks. Results Six of 9 patients underwent neck dissection 5-8 weeks after treatment. In four of these 6 patients, all metastatic lymph nodes, including those at N3, were grade 3 (non-viable tumor cells present) or grade 4 (no tumor cells present) tumors, as classified by the system by Shimosato et al (Shimosato et al Jpn J Clin Oncol 1971;1:19-35). In 2 of these 6 patients, the metastatic lymph nodes were grade 2b (destruction of tumor structures with a small amount of residual viable tumor cells). The other 3 patients did not undergo neck dissection due to distant metastasis after completion of thermochemoradiation therapy (n=2) and refusal (n=1). The patient who refused neck dissection underwent biopsy of the N3 lymph node and primary sites and showed grade 3 cancer. During follow-up, 5 patients were alive without disease, and 4 patients died due to pulmonary metastasis (n=3) and noncancer-related causes (n=1). Five-year survival and locoregional control rates were 51% and 88%, respectively. Conclusions Thermochemoradiation therapy using intra-arterial infusion provided good histopathologic effects and locoregional control rates in patients with N3 metastatic lymph nodes. However, patients with N3 metastatic lymph nodes experienced a high rate of distant metastases.

Background. The efficacy of concurrent intra-arterial infusion chemoradiotherapy for adenoid cystic carcinoma (ACC) has been described in only a few reports. Herein, we report on 2 patients with unresectable ACC of the maxillary sinus treated with this approach. Methods. Patients received concurrent chemoradiotherapy. External beam radiation was administered 5 times a week at 2 Gray (Gy) per fraction for a total of 60 Gy. Chemotherapy consisting of docetaxel and cisplatin was administered by superselective intra-arterial infusion via a superficial temporal artery. Results. After the completion of all treatments in both patients, biopsy specimens of the primary lesions showed complete disappearance of all viable and nonviable tumor cells and new bone formation at the bony walls of the maxillary sinus. Although complications such as mucositis, neutropenia, and anorexia were observed, they were well-tolerated and manageable. Conclusion. Concurrent chemoradiotherapy using superselective intra- arterial infusion is a potential option for patients with unresectable maxillary ACC. V C 2011 Wiley Periodicals, Inc. Head Neck 35: E89-E93, 2013

Aims The current study aimed to investigate the effects of repeated treatment with nicotine on nicotinic and muscarinic receptors in the rat bladder. Main methods Rats were administered nicotine (4.3 μmol/kg) subcutaneously (sc) twice a day for 10 days. The messenger RNA (mRNA) expression of nicotinic and muscarinic receptors in the bladder was examined by reverse transcription polymerase chain reaction (RT-PCR) and by a radioligand binding assay using [ N -methyl- 3 H]scopolamine methyl chloride ([ 3 H]NMS). The concentrations of nicotine and cotinine in plasma, tissues, and urine were estimated by ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS). Key findings mRNA of nicotinic receptor subunits (α1–α7, β1–β4, e) and muscarinic receptor subtypes (M 1 –M 5 ) was detected in the rat bladder. There was a significant increase in the mRNA expression of α3, β1, β2 and β4 in the nicotine-treated rats (4.3 μmol/kg, s.c., b.i.d.) compared to the saline-treated group. Repeated administration of nicotine significantly increased the mRNA expression of the M 2 and M 3 muscarinic receptor subtypes in the rat bladder with a significant enhancement of [ 3 H]NMS binding sites, compared to the saline-treated tissue. Nicotine was distributed at higher concentrations in the bladder than the heart and cerebral cortex. Furthermore, nicotine was excreted in rat urine at high concentrations. Significance The present study is the first to show that repeated treatment with nicotine affects pharmacologically-relevant nicotinic and muscarinic receptors in the bladder. Such changes may contribute to the etiology of lower urinary tract symptoms (LUTS) due to cigarette smoking.

The aims of this study were to explore the feasibility of a novel combination therapy comprising hyperthermia (HT) and dendritic cell (DC) application for squamous cell carcinoma (SCC), and to optimize the conditions of this therapy. In vitro, the correlation between maturation of DCs by co-culture with SCCVII cells and HT was investigated. DCs did not mature in simple HT (43 °C for 30 min) with SCCVII cells. On the other hand, DC maturation occurred in additional mild HT (mHT: 41 °C for 30 min) with simple HT. To assess whether additional mHT was effective, in vivo combined treatment was performed using tumor-bearing C3H/HeJ mice. A more suppressive effect of tumor growth was observed, and cytotoxic T cell infiltration was significantly increased by adding mHT compared to conventional only simple HT with DCs. These phenomena also occurred in non-treated contralateral tumors as well as treated ones. Our data suggest that the combination of 43 °C preheated simple HT SCCVII tumors and additional 41 °C heat mHT promotes DC maturation, resulting in suppression of tumor growth systemically and lifetime prolongation in mice. A three-step process of additional mHT after local HT and intratumoral immature DC (iDC) injection could be a more effective and novel method for the treatment of SCC.

筆者らは, 当院および関連病院にて10年以上の長期血液透析患者87例 (男女比50:37, 年齢51.9歳, 透析期間13.6年) を対象とし, 破壊性頸椎関節症群 (I群) 22例, 境界群 (II群) 22例, 正常群 (III群) 43例に分け, その背景 (生化学所見: 血清C-PTH, ALP, Al, β2-MG, 透析歴, 透析開始時年齢, 代謝性骨病変, CTSの有無) を検討した. また, 頸椎亜脱臼を呈した2例の組織所見を検討した. その結果, 透析歴および開始時年齢は各々I群とIII群, 14.7年と12.8年 (p