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Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA. Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that contacts the subventricular zone (SVZ) have decreased survival. A putative source of GBM cells is the SVZ, the largest area of neurogenesis in the adult human brain. GBM stem cells in the SVZ that are positive for the neural stem cell surface antigen CD133 are highly tumorigenic and enriched in recurrent GBM. LPA1 expression appears to be increased in these cells. Here, the author reviews research on the ATX/LPAR axis, focusing on GBM and an ATX/LPAR-targeted approach. © 2015 Tabuchi.


Tabuchi S.,Tottori Prefectural Central Hospital
Behavioural Neurology | Year: 2015

Aneurysmal subarachnoid hemorrhage (SAH) is one of the most severe forms of stroke, which results from the rupture of a cerebral aneurysm. SAH is the only type of stroke with a female predominance, suggesting that reproductive factors may play a significant role in the etiology. Estrogen has important effects on vascular physiology and pathophysiology of cerebral aneurysm and SAH and, thus, potential therapeutic implications. There have been growing bodies of epidemiological and experimental studies which support the hypothesis of a significant relationship between estrogen deficiency and cerebral aneurysm formation with subsequent SAH. This hypothesis is the focus of this review as well as possible pathology-based therapeutics with regard to aspects of molecular pathophysiology, especially related to women's health. © 2015 Sadaharu Tabuchi.


Purpose: Locally advanced carcinomas arising in the hypopharynx have been traditionally treated by resection of the hypopharynx, larynx, and cervical esophagus. However, the prognosis of these patients is still low. In the present study, we retrospectively analyzed the long-term survival of patients with locally advanced hypopharyngeal squamous cell carcinoma (HSCC) reconstructed by jejunal graft. Methods: Between 2004 and 2014, 68 patients with HSCC were treated at Tottori University Hospital. Nine patients with synchronous esophageal cancer were excluded. We analyzed the overall survival of 59 patients with clinical stage III and IV HSCC who underwent pharyngo-laryngo-cervical esophagectomy with definitive tracheostomy followed by free jejunal graft reconstruction. Additionally, prognostic significances of preoperative patients’ Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), and prognostic nutritional index were analyzed. Results: Postoperative complications occurred in 18.6 % of 59 patients. There were no cases of graft loss, and no patient died from complications. Preoperative poor performance status of patients was a risk factor for postoperative complications. The 5-year overall survival rate of the 59 patients was 46.1 %, and the median survival time was 28 months. In univariate and multivariate survival analyses, high GPS (1 or 2), and high NLR (≥5) were recognized as independent poor prognostic markers for patients with HSCCs. Conclusions: Pharyngo-laryngo-cervical esophagectomy followed by free jejunal reconstruction was performed safely. Additional treatment, such as chemoradiotherapy, should be introduced for patients with high preoperative GPS or NLR after curative operation. © 2016 Springer-Verlag Berlin Heidelberg


Souri M.,Yamagata University | Biswas A.,University of Bonn | Misawa M.,Ako Central Hospital | Omura H.,Tottori Prefectural Central Hospital | Ichinose A.,Yamagata University
Haemophilia | Year: 2014

Factor XIII (FXIII) consists of the A and B subunits (FXIII-A and FXIII-B) and stabilizes fibrin clots. Defects in either the FXIII-A or FXIII-B gene lead to congenital FXIII deficiency, which manifests a life-long haemorrhagic tendency. Thus, prophylactic FXIII replacement therapy is recommended. To establish a management plan for a 30-year-old male patient with 'indefinite' FXIII deficiency (<40% of the normal FXIII), he was characterized by state-of-the-art techniques as guided by the FXIII/Fibrinogen subcommittee of ISTH/SSC. FXIII activity turned out to be virtually undetectable by three functional assays. Four immunological assays detected essentially no FXIII protein, FXIII-A antigen, and A2B2 antigen, but normal FXIII-B antigen. Accordingly, he was diagnosed as a 'severe' FXIII-A deficiency case. He had no anti-FXIII antibodies, because a 1:1 cross-mixing test (ammonia release assay) and a five-step mixing test (amine incorporation assay) between his plasma and normal plasma demonstrated deficiency patterns. Furthermore, a dosing test using plasma-derived FXIII concentrates revealed its normal recovery. DNA sequencing analysis identified two novel mutations, W187X & G273V, in the F13A gene. Genetic analyses confirmed that he was a compound heterozygote and his mother and sister were heterozygotes of either one of these mutations, indicating the hereditary nature of this disorder. Molecular modelling predicted that the G273V mutation would cause clashes with the surrounding residues in the core domain of FXIII-A, and ultimately would result in the instability of the mutant molecule. Detailed characterization of 'indefinite' FXIII deficiency made it possible to make its definite diagnosis and best management plan. © 2013 John Wiley & Sons Ltd.


Tsukamoto K.,Tottori University | Matsusue E.,Tottori Prefectural Central Hospital | Kanasaki Y.,Tottori University | Kakite S.,Tottori University | And 3 more authors.
Neuroradiology | Year: 2012

Introduction The clinical differentiation of Parkinson's disease (PD) from multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) may be challenging, especially in their early stages. The aim of this study was to evaluate the utility of apparent diffusion coefficient (ADC) measurement to distinguish among these degenerative disorders. Methods Twenty-five MSA, 20 PSP, and 17 PD patients and 18 healthy controls were retrospectively studied. Axial diffusion-weighted and T2-weighted images were obtained using a 3-T MR system. Regions of interest (ROIs) were precisely placed in the midbrain, pons, putamen, globus pallidus, caudate nucleus, thalamus, superior cerebellar peduncle, middle cerebellar peduncle, cerebellar white matter, and cerebellar dentate nucleus, and the regional ADC (rADC) value was calculated in each ROI. Results In MSA, rADC values in the pons, middle cerebellar peduncle, cerebellar white matter, and cerebellar dentate nucleus were significantly higher than in PSP, PD, and controls. Furthermore, rADC values in the posterior putamen were significantly higher inMSA than in PSP and controls. In PSP, rADC values were significantly higher in the globus pallidus and midbrain than in MSA, PD, and controls. Furthermore, rADC values in the caudate nucleus and superior cerebellar peduncle were significantly higher in PSP than in MSA and controls. In PD, there were no significant differences in the rADC values compared to in MSA, PSP, and controls in all regions. Conclusion Evaluation of rADC values in characteristic lesions in MSA, PSP, and PD by placing ROIs using 3-T systems can provide useful additional information for differentiating these disorders. © 2012 Springer-Verlag.

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