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| 1.
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Misaki, Koichi ; Uchiyama, Naoyuki ; Inaki, Anri ; Kinuya, Seigo ; Nambu, Iku ; Kamide, Tomoya ; Mohri, Masanao ; Hayashi, Yasuhiko ; Nakada, Mitsutoshi ; 見崎, 孝一 ; 内山, 尚之 ; 稲木, 杏吏 ; 絹谷, 清剛 ; 林, 康彦 ; 中田, 光俊
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金沢大学附属病院脳神経外科<br />Background and purpose: Hemodynamic impairments are considered risk factors of cerebral hyperperfusio
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n after carotid artery stenting (CAS); measurement by Single-photon emission computed tomography (SPECT) using a subjective region of interest (ROI) method lacks consistency and reproducibility. Materials and methods: The present study compared objective perfusion analysis (stereotactic extraction estimation [SEE] method) with the ROI method for preoperative SPECT to predict the hyperperfusion phenomenon (HPP) after CAS. Preoperative resting asymmetry index (cerebral blood flow [CBF] ratio from the affected to unaffected hemisphere) and cerebrovascular reactivity (CVR) to acetazolamide were measured by N-isopropyl-p-[123I]-iodoamphetamine SPECT using the SEE and ROI method in 84 patients. CBF was also measured the day after CAS. Perfusion data with the highest area under the curve (AUC) by receiver-operating characteristic (ROC) analysis was considered a perfusion risk factor of HPP. Multivariate analyses for clinical characteristics and perfusion risk factors were performed to determine predictors of HPP. Results: The HPP was observed in 10 patients (11.9%). Female sex, contralateral stenosis, and degree of stenosis were significantly associated with HPP development on univariate analysis, and symptomatic stenosis was not found to be a significant factor. On SPECT analysis, CVR in the MCA area by SEE method had the highest AUC (0.981). Multivariate analysis showed that CVR in the MCA area was a significant predictor of HPP (P = 0.041). To predict hyperperfusion, the ROC curve of the CVR showed a cutoff value of –0.60%, sensitivity of 94.6%, and specificity of 100% (P < 0.001). Conclusions: Objective SEE method had better a predictive capability than ROI method to identify risk of hyperperfusion after CAS. © 2018 Elsevier Masson SAS<br />Embargo Period 12 months
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2. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
Yamamoto, Yasuhiko ; Liang, Mingkun ; Munesue, Seiichi ; Deguchi, Kisaburo ; Harashima, Ai ; Furuhara, Kazumi ; Yuhi, Teruko ; Zhong, Jing ; Akther, Shirin ; Goto, Hisanori ; Eguchi, Yuya ; Kitao, Yasuko ; Hori, Osamu ; Shiraishi, Yoshitake ; Ozaki, Noriyuki ; Shimizu, Yu ; Kamide, Tomoya ; Yoshikawa, Akifumi ; Hayashi, Yasuhiko ; Nakada, Mitsutoshi ; Lopatina, Olga ; Gerasimenko, Maria ; Komleva, Yulia ; Malinovskaya, Natalia ; Salmina, Alla B. ; Asano, Masahide ; Nishimori, Katsuhiko ; Shoelson, Steven E. ; Yamamoto, Hiroshi ; Higashida, Haruhiro ; 山本, 靖彦 ; 棟居, 聖一 ; 古原, 和美 ; 堀, 修 ; 白石, 昌武 ; 尾﨑, 紀之 ; 吉川, 陽文 ; 中田, 光俊 ; 東田, 陽博
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金沢大学医薬保健研究域医学系<br />Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bo
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nding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.<br />30820471
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中嶋, 理帆 ; 中田, 光俊 ; Nakajima, Riho ; Nakada, Mitsutoshi
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従来，右前頭葉は損傷されたとしても，ヒトが生きる上での致命的な障害を残す可能性が低いことから，脳損傷後に生じる右前頭葉機能の障害にはあまり注意が払われてこなかった。しかし，実際には右前頭葉の損傷後，麻痺や言語障害がないとしても上手く社会復
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帰できない患者が少なからず存在したことも事実である。近年，脳画像解析の技術が進歩し，脳機能およびそのネットワークに関する理解は飛躍的に進歩した。これらの進歩と共に，右前頭葉はヒトが社会生活を営む上で欠かすことができない種々の機能を司っていることが明らかになってきた。本項では，種々の右前頭葉機能のうち，作業記憶，視空間認知，メンタライジング，注意に焦点を絞ってその症状と関連するネットワークについて最新の知見をまとめた。さらに，近年注目されている脳腫瘍の手術法，覚醒下手術における右前頭葉機能の温存についても言及した。<br />Disorders of right frontal lobe function have attracted relatively little attention as theygenerally do not have major adverse effects on activities of daily living. However, somepatients have difficulty in returning to their professional lives after right frontal lobedamage, even though they do not have language or motor deficits. Recent developmentsin neuroimaging methodologies have increased our understanding of neuropsychologicalfunctions and networks, and have shown that the right frontal lobe plays critical roles insocial life, including working memory, visuospatial cognition, mentalizing, and attention.This review presents a summary of recent findings regarding right frontal lobe functionsand their neural networks focusing on the above four functions.
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Hayashi, Yasuhiko ; Sasagawa, Yasuo ; Kita, Daisuke ; Fukui, Issei ; Oishi, Masahiro ; Tachibana, Osamu ; Ueda, Fumiaki ; Nakada, Mitsutoshi
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Purpose: Although hemorrhage within pituitary adenomas frequently exacerbates the symptoms, there are many grades of sev
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erity. Moreover, the contributing factors for symptom severity are still controversial. Methods: This retrospective study included 82 patients who underwent transsphenoidal surgery for pituitary adenomas with intratumoral hemorrhage. The grades of preoperative symptoms were classified into group A, asymptomatic or minor symptoms; group B, moderate symptoms sufficient for complain; and group C, severe symptoms disturbing daily life. Results: The hemorrhage volume within an adenoma was significantly higher in group C (92.6%) than in groups A (48.6%) and B (58.7%). Both headache and diplopia were dominant in group C, occurring in 72.2% and 27.8% of the patients, respectively. In group C, there was no significant difference in frequency between adenoma extensions into the sphenoid sinus (0%) and involvement of the cavernous sinus of Knosp grade 4 (0%), and extensions into the suprasellar region were not common (38.9%). The most distinctive feature was that “no extrasellar extension” was found only in group C (41.2%), and “multidirectional extension” was not detected in this group (0%). Multiple regression analysis revealed that the most powerful determining factors were the high frequencies of intratumoral hemorrhage and lack of extrasellar and multidirectional extensions. Conclusion: Rapid volume expansion of a hematoma and lack of extension or unidirectional extension might lead to significant compression of the sellar and surrounding structures. Of note, the integrity of the sellar dura might contribute to the acute onset of symptom manifestations caused by hemorrhage in pituitary adenomas. © 2017 Springer Science+Business Media, LLC<br />Embargo Period 12 months
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Chinbe, Hiroyuki ; Yoneyama, Takeshi ; Watanabe, Tetsuyou ; Miyashita, Katsuyoshi ; Nakada, Mitsutoshi
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Purpose: Development and evaluation of an effective attachment device for a bilateral brain tumor resection robotic surg
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ery system based on the sensory performance of the human index finger in order to precisely detect gripping- and pulling-force feedback. Methods: First, a basic test was conducted to investigate the performance of the human index finger in the gripping- and pulling-force feedback system. Based on the test result, a new finger-attachment device was designed and constructed. Then, discrimination tests were conducted to assess the pulling force and the feedback on the hardness of the gripped material. Results: The results of the basic test show the application of pulling force on the side surface of the finger has an advantage to distinguish the pulling force when the gripping force is applied on the finger-touching surface. Based on this result, a finger-attachment device that applies a gripping force on the finger surface and pulling force on the side surface of the finger was developed. By conducting a discrimination test to assess the hardness of the gripped material, an operator can distinguish whether the gripped material is harder or softer than a normal brain tissue. This will help in confirming whether the gripped material is a tumor. By conducting a discrimination test to assess the pulling force, an operator can distinguish the pulling-force resistance when attempting to pull off the soft material. Pulling-force feedback may help avoid the breaking of blood pipes when they are trapped in the gripper or attached to the gripped tissue. Conclusion: The finger-attachment device that was developed for detecting gripping- and pulling-force feedback may play an important role in the development of future neurosurgery robotic systems for precise and safe resection of brain tumors. © 2017 CARS<br />Embargo Period 12 months
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Yoneyama, Takeshi ; Watanabe, Tetsuyou ; Kagawa, Hiroyuki ; Hamada, Jun-ichiro ; Hayashi, Yutaka ; Nakada, Mitsutoshi
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Purpose For the application of less invasive robotic neurosurgery to the resection of deep-seated tumors, a prototype sy
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stem of a force-detecting gripper with a flexible micromanipulator and force feedback to the operating unit will be developed. Methods Gripping force applied on the gripper is detected by strain gauges attached to the gripper clip. The signal is transmitted to the amplifier by wires running through the inner tube of the manipulator. Proportional force is applied on the finger lever of the operating unit by the surgeon using a bilateral control program. A pulling force experienced by the gripper is also detected at the gripper clip. The signal for the pulling force is transmitted in a manner identical to that mentioned previously, and the proportional torque is applied on the touching roller of the finger lever of the operating unit. The surgeon can feel the gripping force as the resistance of the operating force of the finger and can feel the pulling force as the friction at the finger surface. Results A basic operation test showed that both the gripping force and pulling force were clearly detected in the gripping of soft material and that the operator could feel the gripping force and pulling force at the finger lever of the operating unit. Conclusions A prototype of the force feedback in the microgripping manipulator system has been developed. The system will be useful for removing deep-seated brain tumors in future master-slave-type robotic neurosurgery. © 2013 CARS.
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Misaki, Kouichi ; Nakada, Mitsutoshi ; Mohri, Masanao ; Hayashi, Yutaka ; Hamada, Jun-ichiro
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Choroid plexus carcinoma (CPC) is a malignant tumor with a strong tendency to spread along the cerebrospinal fluid pathw
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ay. There is no standardized chemotherapy protocol for this rare tumor. We report a 38-year-old man with CPC in the lateral ventricle with obstructive hydrocephalus. Because of the poor demarcation between thalamus and fornix, subtotal tumor resection was performed. Postoperative spine magnetic resonance (MR) image revealed whole spinal axis dissemination. After diagnosis of CPC, the patient was treated with whole ventricular and spine radiation concomitant with temozolomide chemotherapy, although the O 6-methylguanine-DNA methyltransferase (MGMT) promoter was found to be unmethylated. Although MR images revealed transient stable disease during adjuvant therapy, tumor progression was depicted after four cycles of temozolomide therapy. We discuss the ineffectiveness of adjuvant temozolomide therapy for CPC in connection with O 6-methylguanine-DNA methyltransferase promoter methylation. © 2011 The Japan Society of Brain Tumor Pathology.
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Yoneyama, Takeshi ; Watanabe, Tetsuyo ; Kagawa, Hiroyuki ; Hamada, Jun-ichiro ; Hayashi, Yasuhiko ; Nakada, Mitsutoshi
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In order to realize a less invasive robotic neurosurgery for the deeply seated tumor, a force detecting gripper with a f
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lexible micro manipulator has been developed. Gripping force applied on the gripper is detected by strain gages fit on the gripper clip. Signal is conducted to the amplifier by the cables through the inner pipe of the manipulator. In order to approach to the deeply seated tumor through a narrow hole, a micro manipulator which can flex at the end part to face the gripper for the target and can rotate the closing direction of the gripper at the end of the manipulator has been developed. Some operation test showed that the developed manipulator can approach flexibly to the target, and the taking out force of a target on the soft material was detected clearly. © 2011 IEEE.
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Yoneyama, Takeshi ; Watanabe, Tetsuyou ; Kagawa, Hiroyuki ; Hamada, Jun-ichiro ; Hayashi, Yutaka ; Nakada, Mitsutoshi
概要:
In order to realize a less invasive robotic neurosurgery for the deeply seated tumor, a force detecting gripper with a flexible micro manipulator has been developed. Gripping force applied on the gripper is detected by strain gages fit
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on the gripper clip. Signal is conducted to the amplifier by the cables through the inner pipe of the manipulator. In order to approach to the deeply seated tumor through a narrow hole, a micro manipulator which can flex at the end part to face the gripper for the target and can rotate the closing direction of the gripper at the end of the manipulator has been developed. Some operation test showed that the developed manipulator can approach flexibly to the target, and the taking out force of a target on the soft material was detected clearly.
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Chinbe, Hiroyuki ; Yoneyama, Takeshi ; Watanabe, Tetsuyou ; Nakada, Mitsutoshi
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The human fingertip has very high density of the receptor to accept sense of touch stimulation. The corresponding somati
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c sensory area in a brain is very large, and considered to be a specialized part for palpation. A lot of haptic display system then have been developed with the investigation of human haptic perception. However, the researches about the human perception for pulling force at grasping, namely static frictional force are limited. This paper investigated it, aiming at a future development of pulling and grasping force feedback system for neurosurgical robotic systems. For the purpose, this paper explored the possibility of displaying pulling force to an index finger during grasping. The absolute and difference thresholds for pulling sense were the targets. The results showed that grasping disturbs the pulling sense, and the sides of index fingertip can be used to display pulling sense, relatively large force, namely scaled force feedback is required for the perception. The results provide an important insight at a hardware and controller design of force feedback systems. © 2016 IEEE.<br />42nd Conference of the Industrial Electronics Society, IECON 2016; Palazzo dei CongressiFlorence; Italy; 24 October 2016 through 27 October 2016; Category numberCFP16IEC-ART; Code 125546
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Yoneyama, Takeshi ; Watanabe, Tetsuyo ; Kagawa, Hiroyuki ; Hayashi, Yutaka ; Nakada, Mitsutoshi
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Background In photodynamic diagnosis using 5-aminolevulinic acid (5-ALA), discrimination between the tumor and normal ti
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ssue is very important for a precise resection. However, it is difficult to distinguish between infiltrating tumor and normal regions in the boundary area. In this study, fluorescent intensity and bright spot analyses using a confocal microscope is proposed for the precise discrimination between infiltrating tumor and normal regions. Methods From the 5-ALA-resected brain tumor tissue, the red fluorescent and marginal regions were sliced for observation under a confocal microscope. Hematoxylin and eosin (H&E) staining were performed on serial slices of the same tissue. According to the pathological inspection of the H&E slides, the tumor and infiltrating and normal regions on confocal microscopy images were investigated. From the fluorescent intensity of the image pixels, a histogram of pixel number with the same fluorescent intensity was obtained. The fluorescent bright spot sizes and total number were compared between the marginal and normal regions. Results The fluorescence intensity distribution and average intensity in the tumor were different from those in the normal region. The probability of a difference from the dark enhanced the difference between the tumor and the normal region. The bright spot size and number in the infiltrating tumor were different from those in the normal region. Conclusions Fluorescence intensity analysis is useful to distinguish a tumor region, and a bright spot analysis is useful to distinguish between infiltrating tumor and normal regions. These methods will be important for the precise resection or photodynamic therapy of brain tumors. © 2016 Elsevier B.V.<br />Embargo Period 12 months
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Chinbe, Hiroyuki ; Yoneyama, Takeshi ; Watanabe, Tetsuyou ; Nakada, Mitsutoshi
概要:
The human fingertip has very high density of the receptor to accept sense of touch stimulation. The corresponding somati
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c sensory area in a brain is very large, and considered to be a specialized part for palpation. A lot of haptic display system then have been developed with the investigation of human haptic perception. However, the researches about the human perception for pulling force at grasping, namely static frictional force are limited. This paper investigated it, aiming at a future development of pulling and grasping force feedback system for neurosurgical robotic systems. For the purpose, this paper explored the possibility of displaying pulling force to an index finger during grasping. The absolute and difference thresholds for pulling sense were the targets. The results showed that grasping disturbs the pulling sense, and the sides of index fingertip can be used to display pulling sense, relatively large force, namely scaled force feedback is required for the perception. The results provide an important insight at a hardware and controller design of force feedback systems. © 2016 IEEE.<br />42nd Conference of the Industrial Electronics Society, IECON 2016; Palazzo dei CongressiFlorence; Italy; 24 October 2016 through 27 October 2016; Category numberCFP16IEC-ART; Code 125546
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13. Silicone retractor with embedded force-sensing function for attachment to surgical suction pipes
Koyama, Toshio ; Iwai, Takanobu ; Yoneyama, Takeshi ; Kagawa, Hiroyuki ; Hayashi, Yutaka ; Nakada, Mitsutoshi ; Watanabe, Tetsuyou
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A silicone retractor that can be attached to suction pipes was developed in order to enhance the usability [1]. The meas
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urement of the retracting force is desired in order to avoid damage to brain tissue due to an unexpected large force. This paper presents a force-sensing embedded silicone retractor that can be attached to suction pipes. The developed silicone retractor can provide three functions at the same time: suction, retracting, and retracting force measurement. The force-sensing system is based on a visualization mechanism that displays the force as a colored pole motion. The surgeon can then roughly estimate the retracting force. With a fiberscope, the retracting force can be measured with a resolution of 0.05-0.3 N. The retractor is made of silicone and has the advantages of disposability, low cost, and easy sterilization/disinfection. The system was validated through finite element method analysis and experiments. © 2015 IEEE.<br />IEEE/ASME International Conference on Advanced Intelligent Mechatronics, AIM 2015; BEXCOBusan; South Korea; 7 July 2015 through 11 July 2015; Category numberCFP15775-ART; Code 117136
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Koyama, Toshio ; Yoneyama, Takeshi ; Nakada, Mitsutoshi ; Watanabe, Tetsuyou
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This paper presents a silicone retractor, which is a continuation and extension of a previously developed system that ha
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d the same three functions as the old version: 1) retracting, 2) suction, and 3) force sensing. These features make the retractor a safe choice for use in neurosurgery. Suction is achieved by attaching the retractor to a suction pipe. The retractor has a deformation area filled with an incompressible liquid that is displaced in proportion to the extent of deformation; fiberscopes or human eyes detecting the displacement get a visual representation of the force. The new design improves on the old one in three ways—miniaturization, made possible by the incompressible-liquid-based mechanism, and measurement of force distribution by distribution of the areas deformed by force. The system was validated by conducting experiments.
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Kamide, Tomoya ; Nakada, Mitsutoshi ; Hayashi, Yutaka ; Hayashi, Yasuhiko ; Uchiyama, Naoyuki ; Hamada, Jun-ichiro
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金沢大学医薬保健研究域医学系<br />We report a 57-year-old man with intraparenchymal pneumocephalus caused by ethmoid sinus osteoma. He
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had a history of severe allergic rhinitis, which caused him to frequently blow his nose, and he was referred to our hospital with headache and mild left hemiparesis. CT scans revealed a large volume of intraparenchymal air entrapped in the right frontal lobe related to an osteoma in the ethmoid sinus. The osteoma eroded the upper wall of the sinus and extended into the anterior cranial fossa. At operation, we observed that the osteoma had protruded intracranially through the skull base, disrupted the dura and extended into the frontal lobe. To our knowledge, this is the first report of a patient with intraparenchymal pneumocephalus caused by an ethmoid sinus osteoma. © 2009 Elsevier Ltd. All rights reserved.
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Hayashi, Yasuhiko ; Shima, Hiroshi ; Kinoshita, Masashi ; Nakada, Mitsutoshi ; Miyashita, Katsuyoshi ; Hamada, Jun-ichiro
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金沢大学附属病院脳神経外科<br />A 30-year-old man presented with a history of several convulsive episodes. A CT scan showed a calcifi
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ed focus in the right temporal lobe. Cerebral angiography yielded no abnormal findings. At craniotomy, the M3 portion of the middle cerebral artery was found to terminate with a blind end at the junction with the calcified mass. A pathological diagnosis of an ossified cerebral aneurysm was made. Calcified cerebral aneurysms are not rare; they are thought to be the result of intra-aneurysmal thrombosis or degenerative changes in the aneurysmal wall. However, complete mural ossification of a cerebral aneurysm is seldom seen, and ossified peripheral middle cerebral artery aneurysms are extremely rare in young individuals. The ossified aneurysm that we report developed over a prolonged period and may have arisen during childhood. © 2008 Elsevier Ltd. All rights reserved..
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Kinoshita, Masashi ; Nakada, Mitsutoshi ; Tanaka, Shingo ; Ozaki, Noriyuki ; Hamada, Jun-ichiro ; Hayashi, Yutaka
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金沢大学医薬保健研究域医学系<br />Background: The retrochiasmatic region is one of the most challenging areas to surgically expose. Th
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e authors evaluated the transcrusal approach, which involves removal of the superior and posterior semicircular canal from the ampulla to the common crus, to expose the retrochiasmatic region and compared it with the retrolabyrinthine approach, both of which are a variation of the posterior petrosal approach with hearing preservation, with a special emphasis on the influence of temporal lobe retraction. Methods: Six sides of silicone-injected cadaveric heads were dissected using two approaches: the transcrusal approach and the retrolabyrinthine approach. For each craniotomy, 3 exposure parameters in the retrochiasmatic region were measured: (1) horizontal distance, (2) vertical distance, and (3) triangular area of exposure, at three different levels of temporal lobe retractions: 0, 5, and 10 mm of retraction from the level of the tentorial incisura. Results: Without temporal lobe retraction, only the transcrusal and not the retrolabyrinthine approach provided a direct exposure of the retrochiasmatic region, especially in the horizontal distance (p < 0.001). At all levels of temporal lobe retraction, the transcrusal approach provided greater exposure in the horizontal and vertical distances and in the area of exposure. Nonetheless, in the horizontal distance, the difference between the transcrusal and retrolabyrinthine approaches decreased along with increased temporal lobe retraction, and almost no difference was obtained at 10 mm of retraction. Conclusions: Posterior petrosal approaches can provide an excellent exposure of the retrochiasmatic region. Of these two approaches, namely, transcrusal and retrolabyrinthine with hearing preservation, the transcrusal approach offers greater exposure than the retrolabyrinthine approach. The beneficial effect of partial labyrinthectomy of the transcrusal approach to the retrochiasmatic region is accentuated in the exposure of the horizontal distance with less temporal lobe retraction. © 2010 Springer-Verlag.
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Kitajima, Shinji ; Sakai, Norihiko ; Furuichi, Kengo ; Tomokage, Miki ; Hara, Akinori ; Kitagawa, Kiyoki ; Sawada-Kitamura, Seiko ; Zen, Yoh ; Nakada, Mitsutoshi ; Kaneko, Shuichi ; Wada, Takashi
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金沢大学医薬保健研究域医学系<br />We described a case of neurosarcoidosis with necrotizing sarcoid granulomatosis in a 22-year-old man
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. Contrast-enhanced brain computed tomography scan and magnetic resonance imaging showed intracerebral multiple nodular lesions. Noncaseating and partial necrotizing granulomas were detected in the specimen resected by neurosurgery. In addition, immunohistochemical examination revealed the expression of angiotensin-converting enzyme in necrotizing granuloma. Thus, these findings were consistent with neurosarcoidosis. Clinical and pathological presentation, immunological features, and treatment modalities of neurosarcoidosis are discussed. © 2010 Japan College of Rheumatology.<br />This is the pre-peer reviewed version of the following article: [Full cite], which has been published in final form at [link to final article].
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Kawahara, Yosuke ; Nakada, Mitsutoshi ; Hayashi, Yutaka ; Watanabe, Takuya ; Tamase, Akira ; Hayashi, Yasuhiko ; Uchiyama, Naoyuki ; Nitta, Hisashi ; Hamada, Jun-ichiro
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A 62-year-old woman presented with an uncommon case of anaplastic meningioma manifesting as recent memory disturbance. Magnetic resonance imaging revealed a mass located in the right temporal lobe. She became unconscious because of uncal
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herniation and underwent urgent surgery. The tumor was completely resected, except for a lesion tightly attached to arteries. Histological examination indicated the presence of anaplastic meningioma with an extremely high MIB-1 labeling index (70%). After 43 days, the patient developed local recurrence and dissemination in the left temporal lobe. The exceptionally high MIB-1 labeling index corresponded with a short tumor doubling time (8.2 days). Whole-brain irradiation and linear accelerator surgery for disseminated lesions were performed, and the tumor growth halted. Although meningiomas rarely show malignant behavior, corresponding to World Health Organization grade III, it is necessary to consider malignant behavior when treating meningiomas.
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Hayashi, Yutaka ; Nakada, Mitsutoshi ; Konoshita, Masashi ; Hamada, Jun-ichiro
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Nonenhancing intrinsic brain tumors have been empirically treated with a strategy that has been adopted for World Health Organization (WHO) grade II gliomas (low-grade gliomas: LGGs), even though small parts of the tumors might
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have been diagnosed as WHO grade III gliomas after surgery. However, the best surgical strategy for nonenhancing gliomas, including LGGs, is still debatable. LGGs have the following features: slow growth, high possibility of histologically malignant transformation, and no clear border between the tumor and adjacent normal brain. We retrospectively examined 26 consecutive patients with nonenhancing gliomas who were surgically treated at Kanazawa University Hospital between January 2006 and May 2012, with special reference to functional reorganization, extent of resection (EOR), and functional mapping during awake surgery. These categories are closely related with the features of LGG, i.e. functional reorganization due to slow-growing nature, EOR with related malignant transformation, and functional mapping for delineating the unclear tumor border. Finally, we discuss surgical strategies for slow-growing gliomas that are represented by LGGs and nonenhancing gliomas. In conclusion, slow-growing gliomas tend to undergo functional reorganization, and the functional reorganization affects the presurgical evaluation for resectability based on tumor location related to eloquence. In the clinical setting, to definitely identify the reorganized functional regions, awake surgery is recommended. Therefore, awake surgery could increase the extent of the resection of the tumor without deficits, resulting in the delay of malignant transformation and increase in overall survival.
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Shimizu, Yu ; Watanabe, Takuya ; Nakada, Mitsutoshi ; Hayashi, Yutaka ; Hamaguchi, Yasuhito ; Sugimori, Naomi ; Hamada, Jun-ichiro
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Takino, Takahisa ; Yoshimoto, Taisuke ; Nakada, Mitsutoshi ; Li, Zichen ; Domoto, Takahiro ; Kawashiri, Shuici ; Sato, Hiroshi
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Fibronectin matrix formation requires the increased cytoskeletal tension generated by cadherin adhesions, and is suppres
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sed by membrane-type 1 matrix metalloproteinase (MT1-MMP). In a co-culture of Rat1 fibroblasts and MT1-MMP-silenced HT1080 cells, fibronectin fibrils extended from Rat1 to cell-matrix adhesions in HT1080 cells, and N-cadherin adhesions were formed between Rat1 and HT1080 cells. In control HT1080 cells contacting with Rat1 fibroblasts, cell-matrix adhesions were formed in the side away from Rat1 fibroblasts, and fibronectin assembly and N-cadherin adhesions were not formed. The role of N-cadherin adhesions in fibronectin matrix formation was studied using MT1-MMP-silenced HT1080 cells. MT1-MMP knockdown promoted fibronectin matrix assembly and N-cadherin adhesions in HT1080 cells, which was abrogated by double knockdown with either integrin β1 or fibronectin. Conversely, inhibition of N-cadherin adhesions by its knockdown or treatment with its neutralizing antibody suppressed fibronectin matrix formation in MT1-MMP-silenced cells. These results demonstrate that fibronectin assembly initiated by MT1-MMP knockdown results in increase of N-cadherin adhesions, which are prerequisite for further fibronectin matrix formation. © 2014 Elsevier Inc. All rights reserved.
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| 23.
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Hayashi, Yasuhiko ; Oishi, Masahiro ; Fukui, Issei ; Sasagawa, Yasuo ; Harada, Ken-ichi ; Nakada, Mitsutoshi
概要:
Background: In Rathke cleft cysts (RCCs), inflammation by the cyst contents infrequently spreads to the surrounding stru
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ctures. Calcification, which is regarded as a result of chronic inflammation of the cyst wall, can rarely be found in RCCs. Moreover, ossification is extremely rare. Case Description: A 60-year-old woman experienced headaches, fatigue, and weight loss owing to pan-hypopituitarism. Magnetic resonance imaging revealed a mass lesion in the sellar region, which was composed of two different parts, with hypointensity anteriorly and hyperintensity posteriorly on T1-weighted image, and the rim with significant hypointensity entirely on T2-weighted image. During the transsphenoidal surgery, the cyst wall was so rigid that it was difficult to cut and remove it. The cyst contained mucinous fluid with both old and new hemorrhages, and a yellowish, elastic hard, solid nodule. Postoperative histologic diagnosis was RCC with unusual lymphocyte infiltration, massive granulation, and mature bone formation. Six months later, the fluid in the cyst reaccumulated, and the patient complained of headaches. Removal of the entire cyst wall and the aspiration of the cyst content were performed to collapse the cyst cavity and, consequently, to prevent further recurrence. Postoperatively, panhypopituitarism was unchanged and the symptoms were treated with hormonal replacement. The cyst has not recurred for 2 years after the second surgery. Conclusions: Persistent, long-term inflammation induced by the RCC content, mucin-containing fluid, and several phases of hemorrhage presumably promoted the formation of mature bone on the cyst wall and of the elastically solid nodule within the cyst. © 2016 Elsevier Inc.<br />Embargo Period 12 months
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| 24.
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Misaki, Kouichi ; Uchiyama, Naoyuki ; Mohri, Masanao ; Aida, Yasuhiro ; Uno, Takehiro ; Nakada, Mitsutoshi
概要:
Background: Dural arteriovenous fistulas (DAVFs) presenting with ocular symptoms, such as exophthalmos and chemosis, are
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commonly situated in the cavernous sinus (CS). DAVFs at the sphenoid wing with a drainage route into the superior orbital vein (SOV) should be considered as one of the differential diagnoses of ocular symptoms. Case Description: A 41-year-old woman presented with progressive left-sided chemosis and proptosis after left pulsating tinnitus that disappeared spontaneously. Cerebral angiography showed that the fistula was situated along the inferior edge of the superior orbital fissure on the greater sphenoid wing and drained solely into the SOV without flowing into the CS that caused ocular symptoms. Transvenous selective catheterization was performed via the facial vein and SOV. The fistula was then embolized using detachable coils. Conclusions: After embolization, the ocular symptoms resolved, and the patient was discharged without neurologic deficit. Herein, we discuss the developmental mechanism of the unique drainage pattern, including the clinical symptoms and anatomic features of greater sphenoid wing DAVFs. © 2016 Elsevier Inc.<br />Embargo Period 12 months
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| 25.
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Hayashi, Yasuhiko ; Kita, Daisuke ; Fukui, Issei ; Sasagawa, Yasuo ; Oishi, Masahiro ; Tachibana, Osamu ; Ueda, Fumiaki ; Nakada, Mitsutoshi
概要:
Introduction Endoscopic endonasal transsphenoidal surgery (EETS) is increasingly applied to treat tuberculum sellae meni
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ngiomas. However, if the tumor adheres firmly to the optic nerve, dissection of the interface between both structures should be prudent to preserve visual function. The purpose of this study was to investigate whether tumor adhesion to the optic nerve can be predicted preoperatively by fast imaging with steady-state acquisition (FIESTA). Methods Twenty-two patients with tuberculum sellae meningioma treated with EETS were retrospectively identified. Clinical characteristics, radiologic studies, intraoperative findings, and outcomes were reviewed from their clinical charts. Results Patients' symptoms included visual function impairment in 18 patients and headaches in 4 patients. Symptoms were resolved in 19 patients after operation. Preoperative radiologic evaluation was performed in 44 sides (22 patients) of the interface between tumors and the optic nerves and showed absence of peritumoral hyperintensity on FIESTA in 7 sides in 7 patients. In 5 of the 7 sides, tumor dissection was complicated by firm adhesion to the optic nerves. Among these cases, visual functions were unchanged in 1 patient after complete removal of the adhesion but substantially improved in 3 patients after partial resection. In the remaining 37 sides with preoperative peritumoral hyperintensity, no adhesion was found between both structures intraoperatively. Conclusions Absence of peritumoral hyperintensity between tuberculum sellae meningioma and the optic nerve on FIESTA may indicate firm adhesion at the interface, severely complicating complete removal. Preoperative recognition of this adhesion is important for safe tumor removal and preservation of visual functions. © 2017 Elsevier Inc.<br />Embargo Period 12 months
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| 26.
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Fukui, Issei ; Hayashi, Yasuhiko ; Kita, Daisuke ; Sasagawa, Yasuo ; Oishi, Masahiro ; Tachibana, Osamu ; Nakada, Mitsutoshi
概要:
Purpose Rathke cleft cysts (RCC) usually are asymptomatic and can be observed via the use of conservative methods. Some
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patients with RCCs, however, have severe headaches even if they are small enough to be confined to the sella, and these small RCCs seldom have been discussed. This study presents an investigation into clinical characteristics of small RCCs associated with severe headaches, demonstrating efficacy and safety of endoscopic transsphenoidal surgery (ETSS) to relieve headaches. Methods In this study, 13 patients with small RCCs (maximum diameter <10 mm) who presented with headaches and were treated by ETSS at our institute from 2009 to 2014 were recruited. These RCCs were treated Headache Impact Test-6 (HIT-6) score was calculated both pre- and postoperatively to evaluate headache severity. Results All patients complained of severe headaches, which disturbed their daily life. Most headaches were nonpulsating and localized in the frontal area. Characteristically, 6 patients (46%) experienced severe headaches with sudden onset that continued chronically. HIT-6 score was 64 on average, meaning headaches affected daily life severely. After surgical decompression of the cyst, headache in all of the patients improved dramatically and HIT-6 score decreased significantly to 37, suggesting that headaches were diminished. No newly developed deficiencies of the anterior pituitary lobe function were detected. Postoperative occurrence of diabetes insipidus was found in 2 patients, both of which were transient. No recurring cysts were found. Conclusions Severe headaches can develop from small RCCs. In the present study, ETSS was performed on such patients effectively and safely to relieve their headaches. © 2017 Elsevier Inc.<br />Embargo Period 12 months
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| 27.
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Kamide, Tomoya ; Nomura, Motohiro ; Tamase, Akira ; Mori, Kentaro ; Seki, Shunsuke ; Kitamura, Yoshihisa ; Nakada, Mitsutoshi
概要:
Background: The internal carotid artery (ICA) usually runs posterolaterally to the external carotid artery (ECA), but oc
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casionally we encounter the twisted carotid bifurcation, a variant in which the ICA courses medially to the ECA during carotid endarterectomy (CEA). Prediction of this anomaly in the preoperative evaluation is mandatory, although descriptions in the literature are limited. We reviewed the clinical features of patients who underwent CEA and analyzed preoperative cerebral angiography, especially the anteroposterior (AP) view to determine whether it could be a predictive modality. Methods: In 58 consecutive CEA cases, we simply classified them into three groups; type 1 (the ICA runs laterally and the ECA runs medially), type 2 (the ICA and ECA run to overlap each other), and type 3 (the ICA runs medially and the ECA runs laterally), based on the findings of AP view of cerebral angiography. We compared the clinical features and intraoperative findings of these groups. Results: Of 58 cases, types 1–3 were 24, 30, and four cases, respectively. Twisted carotid bifurcations were recognized in seven cases (12.4 %), including three cases in type 2 and four in type 3, and all twisted cases were found on the right side. Twisted carotids and right-sided lesion were significantly frequent in type 3, but no statistical differences of coexisting diseases were recognized among the three groups. CEAs of twisted carotid bifurcations were performed successfully with correction of the carotid position in three and as it was in four cases. Conclusions: Twisted carotid bifurcations were observed during operation in 10 % in type 2 and 100 % in type 3. CEA of twisted carotid bifurcations can be performed safely with or without correction of the carotid position. AP view of cerebral angiography could be useful for preoperative evaluation. © 2016 Springer-Verlag Wien<br />Embargo Period 12 months
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| 28.
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Furuta, Takuya ; Nakada, Mitsutoshi ; Watanabe, Takuya ; Hayashi, Yutaka ; Hamada, Jun-ichiro
概要:
Background: Because extra-axial cavernous malformations (CMs) are rare, the common clinical course remains unclear. We r
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eport the case of a patient with progressive CM originating from the cerebellar tentorium. Case Description: A 64-year-old woman was admitted to our hospital with the complaint of diplopia. Magnetic resonance (MR) imaging revealed a lesion attached to the left cerebellar tentorium, close to the cerebral peduncle. This well-demarcated lesion rapidly enlarged for 3 months and eroded into the midbrain. Cerebral angiography showed a branch of the middle meningeal artery supplying the lesion and pooling of the contrast medium in the venous phase. A dark reddish and mulberry-like mass of the tentorium was observed intraoperatively, allowing the diagnosis of a tentorial CM. The feeding artery was identified in the tentorium and was coagulated. Postoperative MR imaging showed remarkable mass reduction and central necrosis of the lesion. However, the lesion recurred in 3 months; consequently, gamma knife radiosurgery was performed. After an additional 2 months, the lesion shrank in response to the radiosurgery. Conclusions: We report an extremely rare case of tentorial CM which showed rapid growth in a short period. Coagulation of the feeding artery was not sufficient to control the lesion. Gamma knife radiosurgery may prove highly effective for recurrent lesions. Copyright: © 2012 Furuta T.
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| 29.
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Hayashi, Yasuhiko ; Kita, Daisuke ; Iwato, Masayuki ; Fukui, Issei ; Oishi, Masahiro ; Tsutsui, Taishi ; Tachibana, Osamu ; Nakada, Mitsutoshi
概要:
Object: Headache is the most common symptom of both primary and metastatic brain tumor, and is generally considered the
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primary symptom in patients with large pituitary adenomas. However, patients with small pituitary adenomas rarely complain of intractable headache, and neurosurgeons are unsure whether such small adenomas actually contribute to headache. If conventional medical treatments for headache prove ineffective, surgical removal of the adenoma can be considered as an alternative management strategy. Methods: We conducted a retrospective review of 180 patients who underwent transsphenoidal surgery (TSS) for pituitary adenomas at Kanazawa University Hospital between 2006 and 2014. Patients with acute phase intratumoral hemorrhage were excluded. We identified nine patients with intractable headache as the chief complaint associated with small pituitary adenoma (diameters 15.8 ± 2.6 mm, 11–20 mm), non-functioning in eight, and prolactin-secreting in one. The preoperative neuroradiological studies and headache characteristics were assessed retrospectively, and the intrasellar pressure evaluation was performed during TSS in the last seven patients. Results: All nine patients had complete or substantial resolution of their formerly intractable headache after TSS. Headaches consisted of ocular pain ipsilateral to the adenoma localization within the sella in four cases and bifrontal headache in five. Magnetic resonance imaging of these patients revealed small diaphragmatic foramen, which were so narrow that only the pituitary stalk could pass. Computed tomography scans showed ossification beneath the sellar floor in the sphenoid sinus, presellar type in six cases, and choncal type in three. The adenomas included cysts in seven cases. There was no cavernous sinus invasion. Intrasellar pressure measurements averaged 41.5 ± 8.5 mmHg, range 34–59, significantly higher than in control patients without headache (n = 12), namely 22.2 ± 10.6 mmHg (16–30). Conclusion: In this study, the authors demonstrated the validity of TSS in the treatment of intractable headache associated with pituitary adenoma. The presence of ocular pain, especially ipsilateral to the adenoma, integrity of the diaphragm sella, and ossification in the sphenoid sinus, cyst or hemorrhage and the absence of cavernous sinus invasion were the indications for TSS for patients complaining of intractable headache and having pituitary adenomas. © 2015 Springer Science+Business Media New York<br />Embargo Period 12 months
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| 30.
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Misaki, Kouichi ; Uchiyama, Naoyuki ; Mohri, Masanao ; Hayashi, Yutaka ; Ueda, Fumiaki ; Nakada, Mitsutoshi
概要:
Background and purpose To assess the relationship between plaque volume evaluated by multidetector computed tomographic
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angiography (MDCT) and in-stent restenosis (ISR) after carotid artery stenting (CAS). Materials and methods From a retrospectively maintained database, data were collected for 52 patients with carotid artery stenosis treated with CAS between 2007 and 2012. We defined ISR of ≥ 50% as a peak systolic velocity ≥ 200 cm/s on echo-duplex scan. Carotid plaques were subdivided into four components according to radiodensity in Hounsfield units (HU) as follows: < 0, 0–60, 60–130, and > 600 HU. Risk factors that influenced ISR were compared using univariate and multivariate Cox regression analyses. Results During a median follow-up period of 36 months, ISR of ≥ 50% was detected in five patients (9.6%). In the univariate Cox proportional hazard regression analysis, renal insufficiency, coronary artery disease, total plaque volume, and plaque volumes with radiodensities < 0 and ≥ 600 HU increased the risk for ISR (P < 0.10). When the significant risk factors determined from the univariate analysis were subjected to a multivariate analysis, only the volumes of the plaque components with radiodensities < 0 HU independently predicted the development of ISR (hazard ratio: 1.041; 95% confidence interval: 1.006–1.078; P = 0.021). Conclusion Our data suggest that the high volume of the plaque components with radiodensities < 0 HU was independently associated with the increased risk of ISR after CAS. Quantitative and qualitative tissue characterizations of carotid plaques using MDCT might be a useful predictive tool of the development of ISR.<br />Embargo Period 12 months
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| 31.
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Misaki, Kouichi ; Uchiyama, Naoyuki ; Nambu, Iku ; Aida, Yasuhiro ; Kamide, Tomoya ; Mohri, Masanao ; Ueda, Fumiaki ; Nakada, Mitsutoshi
概要:
Background: During endovascular treatment of an aneurysm, the importance of the initial coil volume for facilitating tig
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ht packing is unclear. We retrospectively studied the relationships between initial packing density (PD; initial coil volume divided by aneurysm volume), final PD (volume of all coils divided by aneurysm volume). Methods: We reviewed 105 aneurysms in 98 patients who underwent endovascular coiling between April 2011 and March 2014. The initial coil was defined as the first coil in the single-catheter method and the first 2 coils in the double-catheter method. The patient data were divided into groups with or without a final PD ≥20%, and the significant predictors of a final PD ≥20% were determined using multivariable logistic regression. The optimal cutoff value for the initial PD was determined using a receiver operating characteristic curve. Results: Of 105 aneurysms, 56 and 49 were treated with single- and double-catheter methods, respectively. Statistically significant differences in rupture status, neck size, dome/neck ratio, and initial PD were observed between aneurysms with and without a final PD ≥20% (all P < 0.05). Multivariate analysis showed that initial PD (P = 0.025; odds ratio, 1.22) and rupture status (P = 0.002; odds ratio, 0.19) were significantly associated with a final PD ≥20%. Using receiver operating characteristic curve analysis, the cutoff points of initial PD to achieve a final PD ≥20% were 8.0% and 10.0% in single- and double-catheter groups, respectively. Conclusions: Initial PD appears to be a critical factor for achieving tight packing. © 2016 Elsevier Inc. All rights reserved.<br />Embargo Period 12 months
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| 32.
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Sasagawa, Yasuo ; Tachibana, Osamu ; Doai, Mariko ; Hayashi, Yasuhiko ; Tonami, Hisao ; Iizuka, Hideaki ; Nakada, Mitsutoshi
概要:
Purpose: To analyze the clinical characteristics of acromegalic patients with empty sella (ES, herniation of the subarac
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hnoid space within the sella turcica) and the impact of ES on transsphenoidal surgery in such patients. Methods: Seventy-eight patients, newly diagnosed with acromegaly who underwent transsphenoidal surgery were included. ES was defined as the pituitary gland and adenoma occupying less than 50% of the sella turcica on midsagittal magnetic resonance (MR) imaging. Results: Twelve patients (15.4%), predominantly female (10 women, p = .047), had ES in preoperative MR imaging. ES patients had smaller mean tumor diameter (6.3 mm) than non-ES patients (11.2 mm, p = .001). In preoperative MR imaging, occult adenoma was found in three (25%) ES and three (4.5%) non-ES patients (p = .044). Intraoperative cerebrospinal fluid (CSF) leakage was more frequent in the ES patients than in the non-ES patients (58.3 vs. 25.8%, p = .024). This led to an increased rate of sellar floor reconstruction using abdominal fat and/or postoperative lumber drainage in the ES patients (ES: 41.7 vs. non-ES: 16.7%, p = .063). Endocrinological remission after surgery was more frequent in the non-ES patients (72.7%) than in the ES patients (58.3%) (p = .248). Conclusions: Co-existence of acromegaly with ES is not rare, and is associated with occult adenoma, intra/postoperative CSF leakage, and a worse endocrinological outcome after transsphenoidal surgery; although, the underlying mechanism remains unclear. © 2017 Springer Science+Business Media New York<br />Embargo Period 12 months
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| 33.
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Samuraki, Miharu ; Sakai, Kenji ; Odake, Yasuko ; Yoshita, Mitsuhiro ; Misaki, Kouichi ; Nakada, Mitsutoshi ; Yamada, Masahito
概要:
An 80-year-old man developed dysarthria, quadriplegia, sensory disturbance and ataxia in all limbs. Brain and spinal mag
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netic resonance imaging (MRI) revealed multiple enhanced lesions. Cerebrospinal fluid (CSF) levels of adenosine deaminase (ADA) remarkably elevated. Tuberculosis DNA was not detected, and tuberculosis was not cultured either in the CSF. Brain biopsy revealed the inflammatory demyelinating lesions. With the diagnosis of multiple sclerosis, corticosteroid therapy resulted in rapid improvement of his symptoms and MRI abnormalities. CSF levels of ADA also decreased. Multiple sclerosis should be included in differential diagnosis of disorders with ADA elevation in the CSF. © 2017 Elsevier B.V.<br />Embargo Period 12 months
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| 34.
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Hayashi, Yasuhiko ; Kita, Daisuke ; Fukui, Issei ; Sasagawa, Yasuo ; Oishi, Masahiro ; Okajima, Michiko ; Tachibana, Osamu ; Nakada, Mitsutoshi
概要:
Introduction: Symptomatic Rathke cleft cysts (RCCs) are rarely detected in neuroradiological screening and are less comm
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only found in children than in adults. However, when RCCs are observed in children, it is important to carefully distinguish a RCC from a cystic craniopharyngioma (CP) even if surgically treated or conservatively followed up. Methods: We conducted a retrospective review of clinical data from 11 patients with symptomatic RCCs whose ages were under 18 years and compared the data with data from 15 age- and sex-matched patients with cystic CP who were treated at our institute. Results: The mean age of the patients with RCCs was 12.2 years (range, 6–18). There were six males and five females. As initial symptoms, nine patients presented with headache, while two each had impaired visual function, diabetes insipidus, and activity loss. The 14 patients with CP suffered from impaired visual function. Magnetic resonance imaging (MRI) mainly showed hyperintensity on T1-weighted images (WIs) and hypointensity on T2-WI in patients with RCC. However, patients with CP had characteristic hyperintensity on T2-WI. The average maximum diameter of the RCCs was 19.0 mm on average (range, 8–33 mm). The RCCs were thus significantly smaller than CPs (34.9 mm; range, 21–54 mm). The RCCs were usually oval or dumbbell-shaped and regular in appearance, while the larger CPs were lobular and irregular. A preoperative endocrinological evaluation revealed insufficiencies in four axes in five patients with RCC. Postoperative endocrinological status improved in three patients, remained unchanged in three, and worsened in one. The gonadotropin axis was damaged in a majority (nine) of the patients with CP preoperatively. Postoperative evaluation revealed deficits in five axes in 14 patients with CP, which is a significantly different trend than observed in patients with RCC. Eight patients underwent surgical procedures (transsphenoidal surgery (TSS) in four, craniotomy in four). Two of these patients experienced a recurrence of the cysts. One of these patients subsequently underwent two craniotomies followed by radiation and other underwent TSS. Among the three conservatively treated patients, two experienced a transient worsening of their symptoms along with cyst enlargement. However, none of the three conservatively treated patients required an operation. Conclusions: When RCCs become symptomatic in children, the most common symptom they lead to is headache. The cysts are commonly small, regular, and oval in shape. Hypointensity of cyst contents on MRI is a characteristic of RCCs, which distinguishes them from CPs. Surgical intervention can be effective and lead to the relief of symptoms without a high rate of complications. However, there seems to be a relatively high recurrence rate following surgery. Thus, if the patient’s symptoms remain minor, the surgical treatment option should be used only when prudent, as the patient’s symptoms may improve over time. © 2016 Springer-Verlag Berlin Heidelberg<br />In Press / Embargo Period 12 months
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| 35.
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Hayashi, Yasuhiko ; Kita, Daisuke ; Iwato, Masayuki ; Fukui, Issei ; Sasagawa, Yasuo ; Oishi, Masahiro ; Tachibana, Osamu ; Nakada, Mitsutoshi
概要:
Objectives It is important to identify and maintain a midline orientation during endoscopic transsphenoidal surgery (ETS
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S) for sellar lesions to prevent critical injury to the internal carotid artery. Therefore, the preoperative neuroradiological assessment of the bony structures in the sphenoid sinus, including the septum attachment to the sellar floor and its surrounding structures, is essential. It has been reported that the midline filum of the sellar dura can function as a useful intraoperative orientation guide during ETSS. However, the relationship between the midline dural filum and the intrasinus bony structures, such as the sellar floor, the intrasinus septation and the ossification, remains unclear and the mechanisms underlying development of the midline dural filum have also not yet been explored. Methods This retrospective study included 160 patients undergoing ETSS to assess both the midline dural filum and the intrasinus bony structures, using video recording reviews. The intrasinus septum and the ossification in the sphenoid sinus were evaluated on the computed tomography images of the bone window. Results A midline dural filum was identified in 66 (41.3%) of 160 patients. Attachment of the septum to the sellar midline was found in 61 (39.4%) of 155 patients, after excluding 5 patients with the conchal type of sphenoid sinus, 55 (90.2%) of 61 patients with a septum on the midline and only 6 (6.4%) of the remaining 94 patients without a septum on the midline had a midline dural filum. The relationship between a midline dural filum and a septum on midline was statistically significant (p < 0.001), regardless of the number of intrasphenoidal septa. In terms of the types of sphenoid sinus, the midline dural filum was predominantly detected in patients where ossification extended over the midline filum. In patients with the sellar type of sphenoid sinus, 49 (36.0%) of 136 had a midline dural filum, meanwhile, 16 (84.2%) of 19 patients with the pre-sellar type (p = 0.039) and all 5 patients (100%) with the choncal type harbored a midline dural filum (p < 0.001). Conclusion This study clearly verified the importance of the midline dural filum in a large series and evaluated the obvious relationship between the midline dural filum and the bony structures on the sellar floor. Our results strongly suggest that, during developing of the midline dural filum, the sellar dura becomes tethered to the bony elements attached to the sellar surface, such as the septum on the midline and the ossification in both the pre-sellar and the conchal type of sphenoid sinus. © 2016 Elsevier B.V. All rights reserved.<br />Embargo Period 12 months
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| 36.
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Misaki, Kouichi ; Uchiyama, Naoyuki ; Mohri, Masanao ; Kamide, Tomoya ; Tsutsui, Taishi ; Kanamori, Naomi ; Kurokawa, Keisuke ; Nakada, Mitsutoshi
概要:
This is the first report on the mechanism of pseudoaneurysm formation after withdrawal of a stent retriever. A 79-year-o
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ld woman developed cardiogenic embolization of the distal middle cerebral artery (M2). The deployed stent retriever bent because of vessel tortuosity. After withdrawal of the stent with strong resistance, complete revascularization was achieved, but an extravasation was detected at the site. Eight hours after disappearance of the extravasation, re-bleeding occurred with aneurysm-like pooling of contrast media. Direct surgical observation confirmed a pseudoaneurysm formation. The pseudoaneurysm was likely formed by avulsion of a fine vessel during withdrawal of the stent retriever at a tortuous vessel. © 2016 Springer-Verlag Wien<br />In Press / Embargo Period 12 months
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Kita, Daisuke ; Hayashi, Yasuhiko ; Watanabe, Takuya ; Korshunov, Andrey ; von Deimling, Andreas ; Nakada, Mitsutoshi ; Kasahara, Yoshihito ; Zen, Yoh ; Hamada, Jun-ichiro ; Hayashi, Yutaka
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| 38.
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Hayashi, Yasuhiko ; Shima, Hiroshi ; Kinoshita, Masashi ; Nakada, Mitsutoshi ; Miyashita, Katsuyoshi ; Hamada, Jun-ichiro
概要:
金沢大学附属病院脳神経外科<br />A 30-year-old man presented with a history of several convulsive episodes. A CT scan showed a calcifi
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ed focus in the right temporal lobe. Cerebral angiography yielded no abnormal findings. At craniotomy, the M3 portion of the middle cerebral artery was found to terminate with a blind end at the junction with the calcified mass. A pathological diagnosis of an ossified cerebral aneurysm was made. Calcified cerebral aneurysms are not rare; they are thought to be the result of intra-aneurysmal thrombosis or degenerative changes in the aneurysmal wall. However, complete mural ossification of a cerebral aneurysm is seldom seen, and ossified peripheral middle cerebral artery aneurysms are extremely rare in young individuals. The ossified aneurysm that we report developed over a prolonged period and may have arisen during childhood. © 2008 Elsevier Ltd. All rights reserved.
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| 39.
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Hayashi, Yasuhiko ; Shima, Hiroshi ; Miyashita, Katsuyoshi ; Kinoshita, Masashi ; Nakada, Mitsutoshi ; Kida, Shinya ; Hamada, Jun-ichiro
概要:
金沢大学医薬保健研究域医学系<br />金沢大学附属病院脳神経外科<br />A 48-year-old man presented with a pseudoaneurysm at the cervical portion of the
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left internal carotid artery (ICA) secondary to infection in the deep neck space. Magnetic resonance (MR) imaging demonstrated enhancement of the wall of the ICA and a pseudoaneurysm, considered to be sequelae of infection spread. ICA occlusion occurred on the next day resulting in sudden onset of right hemiparesis and motor aphasia. The ICA pseudoaneurysm shrank gradually and his neurological deficits improved with conservative therapy. One month later, he presented with aneurysm regrowth. The common carotid artery was occluded with Guglielmi detachable coils to block arterial flow into the pseudoaneurysm. There were no neurological complications. Marked enhancement of the ICA wall on computed tomography and MR imaging may indicate the possibility of vascular complications such as rupture, pseudoaneurysm development, or ICA occlusion, and consequent neurological deficits. ICA occlusion caused by spread of infection in the deep neck space may cause accelerated coagulopathy due to ICA wall inflammation.
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| 40.
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Miyashita, Katsuyoshi ; Nakada, Mitsutoshi ; Shakoori, Abbas ; Ishigaki, Yasuhito ; Shimasaki, Takeo ; Motoo, Yoshiharu ; Kawakami, Kazuyuki ; Minamoto, Toshinari
概要:
金沢大学がん研究所分子標的がん医療研究開発センター<br />Improvement in the outcome of cancer patients who are refractory to currently available t
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reatments relies on the development of target-directed therapies. One group of molecular targets with potential clinical relevance is a set of protein tyrosine kinases encoded mostly by proto-oncogenes and that are frequently deregulated in cancer. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target for common chronic diseases including type 2 diabetes mellitus, neurodegenerative disorders, inflammation and osteoporosis. This is based on its currently known functions and primary pathologic causalities. GSK3β has well characterized roles in the regulation of gene transcription and in oncogenic signaling. We have shown that deregulated GSK3β promotes gastrointestinal, pancreatic and liver cancers and glioblastomas. Furthermore, we have demonstrated that inhibition of GSK3β attenuates cancer cells survival and proliferation, induces cell senescence and apoptosis and sensitizes tumor cells to chemotherapeutic agents and ionizing radiation. This has led us to propose GSK3β as a potential therapeutic target in cancer. The anti-tumor effects of GSK3β inhibition are mediated by changes in the expression and phosphorylation of molecules critical to the regulation of cell cycling, proliferation and apoptosis and underlie the pathological role for GSK3β in cancer. Investigation of the mechanisms responsible for deregulation of GSK3β and the consequent downstream pathologic effects in cancer cells has shed light on the molecular pathways leading to tumorigenesis. This will allow exploration of novel therapeutic strategies for cancer that target aberrant GSK3β. © 2009 Bentham Science Publishers Ltd.
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| 41.
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Kitano, Ayako ; Shimasaki, Takeo ; Chikano, Yuri ; Nakada, Mitsutoshi ; Hirose, Mayumi ; Higashi, Tomomi ; Ishigaki, Yasuhito ; Endo, Yoshio ; Takino, Takahisa ; Sato, Hiroshi ; Sai, Yoshimichi ; Miyamoto, Ken-ichi ; Motoo, Yoshiharu ; Kawakami, Kazuyuki ; Minamoto, Toshinari
概要:
Background and Purpose: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resis
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tance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer. Methods: Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined. Results: Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts. Conclusion: The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer. © 2013 Kitano et al.
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| 42.
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Domoto, Takahiro ; Pyko, Ilya V. ; Furuta, Takuya ; Miyashita, Katsuyoshi ; Uehara, Masahiro ; Shimasaki, Takeo ; Nakada, Mitsutoshi ; Minamoto, Toshinari
概要:
Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefo
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re, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. © 2016 Japanese Cancer Association.<br />(Please refer to a different file for the Supporting information of this article.)
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| 43.
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Takino, Takahisa ; Yoshimoto, Taisuke ; Nakada, Mitsutoshi ; Li, Zichen ; Domoto, Takahiro ; Kawashiri, Shuichi ; Sato, Hiroshi
概要:
Fibronectin matrix formation requires the increased cytoskeletal tension generated by cadherin adhesions, and is suppres
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sed by membrane-type 1 matrix metalloproteinase (MT1-MMP). In a co-culture of Rat1 fibroblasts and MT1-MMP-silenced HT1080 cells, fibronectin fibrils extended from Rat1 to cell-matrix adhesions in HT1080 cells, and N-cadherin adhesions were formed between Rat1 and HT1080 cells. In control HT1080 cells contacting with Rat1 fibroblasts, cell-matrix adhesions were formed in the side away from Rat1 fibroblasts, and fibronectin assembly and N-cadherin adhesions were not formed. The role of N-cadherin adhesions in fibronectin matrix formation was studied using MT1-MMP-silenced HT1080 cells. MT1-MMP knockdown promoted fibronectin matrix assembly and N-cadherin adhesions in HT1080 cells, which was abrogated by double knockdown with either integrin β1 or fibronectin. Conversely, inhibition of N-cadherin adhesions by its knockdown or treatment with its neutralizing antibody suppressed fibronectin matrix formation in MT1-MMP-silenced cells. These results demonstrate that fibronectin assembly initiated by MT1-MMP knockdown results in increase of N-cadherin adhesions, which are prerequisite for further fibronectin matrix formation. © 2014 Elsevier Inc. All rights reserved.
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| 44.
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Nanjo, Shigeki ; Nakagawa, Takayuki ; Takeuchi, Shinji ; Kita, Kenji ; Fukuda, Koji ; Nakada, Mitsutoshi ; Uehara, Hisanori ; Nishihara, Hiroshi ; Hara, Eiji ; Uramoto, Hidetaka ; Tanaka, Fumihiro ; Yano, Seiji
概要:
がん進展制御研究所<br />EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate
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the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments. © 2015 The Authors.
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| 45.
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Takino, Takahisa ; Nakada, Mitsutoshi ; Li, Zichen ; Yoshimoto, Taisuke ; Domoto, Takahiro ; Sato, Hiroshi
概要:
A histone acetyltransferase Tat-interacting protein 60 kDa (Tip60) regulates the DNA damage response by acetylating hist
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one and remodeling chromatin. In addition to histone acetyltransferase activity, Tip60 is known to regulate a variety of cellular functions, including gene expression, DNA damage response, cell migration and apoptosis. Lower expression of Tip60 is observed in lymphomas, melanomas, breast, colon, and lung cancer. It is widely accepted that Tip60 functions as a tumor suppressor. However, a role of Tip60 in gliomas still remains unclear. In this study, we investigated the role of Tip60 in the malignant behavior of human gliomas. By quantitative RT-PCR analysis using fresh human brain tumor tissues from 55 patients, we found that lower Tip60 expression and higher membrane-type 1 matrix metalloproteinase (MT1-MMP) expression are associated with advanced tumor grade in glioma tissues. Knockdown of Tip60 in glioblastoma cells promoted cell adhesion, spreading and MT1-MMP transcription and thereby invasion, which was suppressed by inhibition of MT1-MMP and nuclear factor-kappa B (NF-κB) activity. We demonstrate for the first time that tumor suppressor Tip60 down-regulates cell adhesion and MT1-MMP expression and thereby invasion of glioblastoma cells by suppressing NF-κB pathway. © 2015, Springer Science+Business Media Dordrecht.<br />Embargo Period 12 months
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| 46.
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Nanjo, Shigeki ; Ebi, Hiromichi ; Arai, Sachiko ; Takeuchi, Shinji ; Yamada, Tadaaki ; Mochizuki, Satsuki ; Okada, Yasunori ; Nakada, Mitsutoshi ; Murakami, Takashi ; Yano, Seiji
概要:
Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor
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(TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.
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| 47.
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Takino, Takahisa ; Nakada, Mitsutoshi ; Li, Zichen ; Yoshimoto, Taisuke ; Domoto, Takahiro ; Sato, Hiroshi
概要:
A histone acetyltransferase Tat-interacting protein 60 kDa (Tip60) regulates the DNA damage response by acetylating hist
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one and remodeling chromatin. In addition to histone acetyltransferase activity, Tip60 is known to regulate a variety of cellular functions, including gene expression, DNA damage response, cell migration and apoptosis. Lower expression of Tip60 is observed in lymphomas, melanomas, breast, colon, and lung cancer. It is widely accepted that Tip60 functions as a tumor suppressor. However, a role of Tip60 in gliomas still remains unclear. In this study, we investigated the role of Tip60 in the malignant behavior of human gliomas. By quantitative RT-PCR analysis using fresh human brain tumor tissues from 55 patients, we found that lower Tip60 expression and higher membrane-type 1 matrix metalloproteinase (MT1-MMP) expression are associated with advanced tumor grade in glioma tissues. Knockdown of Tip60 in glioblastoma cells promoted cell adhesion, spreading and MT1-MMP transcription and thereby invasion, which was suppressed by inhibition of MT1-MMP and nuclear factor-kappa B (NF-κB) activity. We demonstrate for the first time that tumor suppressor Tip60 down-regulates cell adhesion and MT1-MMP expression and thereby invasion of glioblastoma cells by suppressing NF-κB pathway. © 2015 Springer Science+Business Media Dordrecht<br />Embargo Period 12 months
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| 48.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学医薬保健研究域医学系<br />難治疾患である悪性脳腫瘍に対してバイオマーカーは同定されていない。本研究は、原発性脳腫瘍の中で最も高頻度かつ高悪性度の膠芽腫の診断を迅速・簡便・確実に可能とする血液バイオマーカーの開発を目的とした。革
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新型プロテオミクス法による膠芽腫および健常血漿内タンパクの比較定量を行った。962種類のタンパクを同定し、両者間で有意差を認め新規性の高い5種類の分子を抽出した。膠芽腫において高値を示したα-1-antichymotripsinとcompliment component C9、低値を示したgelsolin、Ig α-1 chain C region、apolipoprotein A-IVである。<br />Reliable blood biomarkers could be helpful for the management of glioblastoma (GBM) patients. Mass spectrometry (MS)-based proteomic analysis of human clinical blood is a powerful tool to investigate cancer biomarkers. To identify the biomarkers for GBM, we applied the highly accurate and reproducible SWATH (Sequential Windowed Acquisition of all Theoretical fragment ions)-MS technique. Quantitative comparisons of the plasma proteomes of GBM, IDH-wildtype patients (n = 14) and healthy controls (n = 15) were performed. Data dependent analysis mode of LC-MS/MS (Liquid chromatography tandem-MS) detected total 962 species of proteins in the samples used. Through the SWATH analysis, we identified five biomarker candidates for GBM: up-regulated proteins; α-1-antichymotrypsin (SERPINA3), and complement component C9 (C9), down-regulated proteins; gelsolin (GSN), Ig α-1 chain C region (IGHA1), and apolipoprotein A-IV (APOA4).<br />研究課題/領域番号:16K15645, 研究期間(年度):2016-04-01 - 2018-03-31
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| 49.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学医薬保健研究域医学系<br />本研究ではタンパク質の絶対定量値を取得できる独自のプロテオミクス技術を用いた新規の膠芽腫サブタイプ分類の樹立を試みた。相互排他的な発現パターンを示すEGFR, ERBB2, PDGFRαに着目し、初発
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膠芽腫をEGFR群25例、PDGFRα群11例、ERBB2群7例に分類した。PFS中央値はそれぞれ8.3, 12.8, 37ヶ月で、OS中央値はそれぞれ16.1, 17.9, 25.7ヶ月であり、ERBB2群でPFS, OSが延長する傾向があった。以上の結果から、絶対定量プロテオミクスによるチロシンキナーゼの絶対発現量に基づいた膠芽腫のサブタイプ分類が可能であると考えられた。<br />The purpose of this study is to attempt to classify GBM subtypes based on the molecular profile determined by absolute quantitative proteomics and to investigate its clinical significance. GBMs in our study harbored mutually exclusive dominant expression of three RTKs; EGFR, PDGFRα and ERBB2. Therefore, we propose a subclassification of GBM with respect to the dominant expression of these proteins; EGFR (n=25), PDGFRα (n=11) and ERBB2 (n=7). PFS and OS tended to be longer in ERBB2 group in comparison with EGFR and PDGFRα group. Molecular subclassification of GBM based on the absolute quantitative proteomics reflects the clinical behavior and might have clinical significance.<br />研究課題/領域番号:26670638, 研究期間(年度):2014-04-01 - 2016-03-31
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| 50.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学医薬保健研究域医学系<br />本研究では悪性グリオーマ発生の根幹をなすグリオーマ幹細胞に対して抗腫瘍効果を有する薬剤を1,300種類の既存医薬品の中から探索した。グリオーマ幹細胞に対する増殖抑制効果をスクリーニングした後に既報告薬
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剤および臨床試験済薬剤を除外した。絞られた候補薬剤の中で、分子量が小さく抗精神病薬として使用されているfluspirileneに着目した。Fluspirileneはグリオーマ幹細胞形質を濃度依存性に阻害し、グリオーマ細胞株の増殖、浸潤を濃度依存性に抑制した。さらにマウスモデルにおいて腫瘍の形成、増殖、浸潤を抑制した。以上よりfluspirileneは有用な抗グリオーマ薬と考えられた。<br />Glioma stem cell (GSC)-targeted therapy is a promising approach to treat patients with glioblastoma (GBM). Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs with the purpose of drug repositioning. We initially screened drug libraries for small-molecule compounds showing a greater efficacy in inhibiting the proliferation and survival of different GSC lines. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Among the candidate drugs, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.<br />研究課題/領域番号:26293322, 研究期間(年度):2014-04-01 - 2017-03-31
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| 51.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
本研究では膠芽腫に対するAkt阻害剤、Notch阻害剤の併用療法の有用性とGSK3β阻害によるテモゾロミド（TMZ）薬剤感受性亢進メカニズムを検討した。Akt阻害剤、Notch阻害剤両者の併用により細胞浸潤抑制効果は増強されたが、増殖抑制効
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果はAkt単独添加と同程度にとどまった。併用療法は増殖抑制には効果が少ないが浸潤抑制には効果的であることが示唆された。TMZとGSK3β阻害試薬の併用は相加的、相乗的な細胞増殖抑制効果を示した。GSK3β阻害によるTMZに対する膠芽腫細胞の感受性増強作用は、c-Mycを介してMGMT promoterのメチル化が促進されることを明らかにした。<br />We assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors. Additionally, we investigated the molecular mechanisms of sensitization of glioblastoma (GBM) cells to temozolomide (TMZ) by GSK3beta inhibition. Notch and Akt inhibitors significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. However, the effect of combination treatment did not exceed that of Akt inhibitor monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy. Therefore, combination therapy may be effective for inhibiting invasion but not proliferation. GSK3beta inhibition enhanced TMZ effect. c-Myc binds to the MGMT promoter with consequent recruitment of DNMT3A, regulating the levels of MGMT promoter methylation. Therefore, GSK3beta inhibition enhances TMZ effect by silencing MGMT expression via c-Myc-mediated promoter methylation.<br />研究課題/領域番号:23592117, 研究期間(年度):2011-2013
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| 52.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
本研究では、幹細胞様グリオーマ細胞の高い浸潤能を規定する分子を探索した。グリオーマ組織中のCD133陽性細胞において普遍的にintegrin α3が高発現していることを見出した。ヒト膠芽腫組織において、浸潤グリオーマ細胞にintegrin
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α3の局在を認めた。Integrin α3の発現とグリオーマ細胞の浸潤能は正の相関を示し、その下流のシグナルとしてextracellular signal-regulated kinase(ERK)1/2が示された。integrin α3はERK1/2の活性を介して幹細胞様グリオーマ細胞の遊走・浸潤能を亢進させることが示唆された。<br />Glioma stem-like cells are shown to be invasive but its mechanism remains to be elucidated. In this study we demonstrate the function of integrin in glioma stem-like cell invasion. The expression profile of integrin family in CD133+ and - cells was determined. Integrin α3 was overexpressed in CD133+ cells compared with CD133- cells. Immunohistochemistry demonstrated the localization of integrin alpha3 in invading glioblastoma cells. The activity of glioma cell invasion was associated with the expression level of integrin α3. The migration activity of glioma cell lines was linked to the phosphorylation level of ERK (extracellular signal-regulated kinase) 1/2. Our results suggest that endogenous integrin alpha3 contributes the invasive nature of glioma stem-like cells, which renders integrin alpha3 as a prime candidate for anti-invasion therapy for glioblastoma.<br />研究課題/領域番号:21689038, 研究期間(年度):2009-2010
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| 53.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
我々はEph /ephrinチロシンキナーゼファミリーに着目し神経膠芽腫浸潤における働きとその臨床像に与える影響を検討した。その結果、EphB2/ephrin-B2シグナルが神経膠芽腫の浸潤能を亢進させ悪性化に寄与していることが明らかになっ
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た。さらに、Ephrin-A2がEphAシグナルを介して神経膠芽腫浸潤に抑制的に働き、臨床上有用な予後規定因子になりうることを示した。これらのことからEphA/ephrin-AとEphB/ephrin-Bは神経膠芽腫の浸潤において逆の作用を有し両者のシグナルバランスで浸潤が制御されている可能性が示された。<br />研究課題/領域番号:19790992, 研究期間(年度):2007-2008<br />出典：「Eph/ephrinバイオロジーと神経膠腫浸潤」研究成果報告書 課題番号19790992（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-19790992/19790992seika/)を加工して作成
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| 54.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学医薬保健研究域医学系<br />ヒト右前頭葉が担う高次脳機能である、視空間認知機能・作業記憶・社会的認知機能の機能局在を明らかにした。このことから高次脳機能温存の観点から右前頭葉病変に対する外科的治療の明確な摘出限界を科学的に定めた
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。これらの局在を覚醒下手術中の電気刺激により同定することで高次機能を温存する近未来の脳神経外科手術法を提案した。<br />The functional localizations of spatial cognition, working memory, and social cognition, which are higher brain functions of the human right frontal lobe, were clarified. Accordingly, a clear limitation of surgical removal for right frontal lobe lesion was scientifically determined from the viewpoint of preserving higher brain function. We proposed a future neurosurgery that preserves higher cognitive functions by identifying these localizations by electrical stimulation during awake surgery.<br />研究課題/領域番号:18K19606, 研究期間(年度):2018-04-01 - 2020-03-31<br />出典：「高次脳機能局在に基づく右前頭葉腫瘍に対する摘出限界策定の試み」研究成果報告書 課題番号18K19606（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18K19606/18K19606seika/)を加工して作成
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| 55.
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学医薬保健研究域医学系<br />膠芽腫は脳腫瘍の中で最も悪性度が高く、非常に難治性である。膠芽腫に対する新たな治療を開発するためには、腫瘍の増大や進展の分子機構を解明する必要がある。近年、細胞が分泌するエクソソームという細胞外小胞の
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作用が様々な悪性腫瘍で注目されている。今回われわれは膠芽腫細胞が分泌するエクソソームについて研究した結果、WT1タンパクを含有したエクソソームが膠芽腫細胞から分泌され、それが周囲のマイクログリアに伝播し、血管新生抑制タンパクであるThrombospondin 1がマイクログリア内で低下することで腫瘍形成を促進することを明らかにした。<br />Glioblastoma is the most malignant brain tumor. In order to develop new treatments for glioblastoma, it is necessary to elucidate the mechanism of tumor growth and progression. Recently, extracellular vesicles called exosomes, which are secreted by cells, have been attracting attention in various malignant tumors. In this study, we studied the exosomes secreted by glioblastoma cells. We found that the exosomes containing WT1 protein are secreted by glioblastoma cells, then expression of thrombospondin-1, a negative regulator of angiogenesis, was downregulated in surrounding microglia. This intercellular regulatory pathway promotes glioblastoma progression. Our findings establish a novel model of tumor progression via exosome-mediated WT1-Thbs1, which may be a future diagnostic or therapeutic target.<br />研究課題/領域番号:18H02910, 研究期間(年度):2018-04-01 - 2021-03-31<br />出典：「悪性神経膠腫由来のエクソソームを介したミクログリアによる微小環境整備の解明」研究成果報告書 課題番号18H02910（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18H02910/18H02910seika/）を加工して作成
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| 56.
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Hayashi, Yasuhiko ; Aida, Yasuhiro ; Sasagawa, Yasuo ; Oishi, Masahiro ; Kita, Daisuke ; Tachibana, Osamu ; Ueda, Fumiaki ; Nakada, Mitsutoshi ; 林, 康彦 ; 笹川, 泰生 ; 大石, 正博 ; 中田, 光俊
概要:
金沢大学医薬保健研究域医学系<br />Background: Diabetes insipidus (DI) is a major complication of transsphenoidal surgery (TSS). DI usu
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ally occurs within a couple of days after TSS. Delayed occurrence of postoperative DI is rarely observed and its developing mechanisms remain unknown. Methods: Six patients were identified as having postoperative delayed DI, which was defined as DI that first occurred 2 or more weeks after TSS. They consisted of 1 male and 5 females, and their mean age was 38.3 years (range, 10–76 years). Five patients were histologically diagnosed with Rathke cleft cyst (RCC), and one had RCC coexisting with prolactin-secreting adenoma. Sequential T1-weighted magnetic resonance imaging was evaluated for hyperintensity (HI) in the pituitary stalk and the posterior lobe, indicating the location of antidiuretic hormone. Results: No patients had any DI before TSS. Delayed DI occurred 2 weeks to 3 months after TSS and persisted for 2 weeks to 5 months. T1-weighted magnetic resonance imaging showed that the HI in the posterior lobe became faint but did not disappear after DI occurrence, and their intensities increased with recovery from DI. In contrast, the HI in the pituitary stalk was found faintly preoperatively and turned clear postoperatively and decreased with recovery from DI. The morphologic patterns were dependent on DI duration. Conclusions: In the delayed occurrence of DI, it was suggested that preoperative antidiuretic hormone transport was mildly congested yet not completely blocked when DI manifested postoperatively. Gradual spreading of inflammation to the infundibulum after RCC removal was considered as 1 possible mechanism of this delayed DI development. © 2017 Elsevier Inc.<br />Embargo Period 12 months
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中田, 光俊 ; Nakada, Mitsutoshi
概要:
金沢大学附属病院<br />【目的】我々は近年,gliomaの浸潤に関与する細胞外マトリックス分解酵素MT1-MMP (membrane type 1-matrix metalloproteinase)に対する抑制分子を脳細胞外マトリックス
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Testican family(TF)内に見出した(Cancer Res 61:8896-902,2001)。本研究ではTF間の相互作用およびヒトglioma組織におけるTFの発現および局在を検討した。【方法】MT1-MMP, MMP-2とともにTFの発現ベクターおよびdeletion mutantを293T細胞に遺伝子導入し,Zymographyと免疫沈降を行った。またWound assayによりglioma細胞株に対する浸潤抑制効果を検討した。Glioma 51例につき,ABI PRISM 7700を用いmRNA発現量を計測した。またin situ hybridizationを行った。【結果】MT1-MMP阻害効果を有しないT-2は同効果を有するT-1,T-3,N-Tesと結合することによりその働きを阻害することが分かった。その結合サイトはT-1,T-3,N-Tesのextracellular calcium binding (EC) domainとT-2のunique domainであった。N-TesのEC domainを欠失した変異体(Δ122)はMT1-MMPを抑制し,かつT-2との結合を逃れた。Wound assayの結果もこれと矛盾しない所見であった。またTFの発現量はいずれもglioblastomaで有意に低く,その局在はneuronで強く,腫瘍細胞では弱かった。発現量はTFのうちT-2で最も高かった。【結論】脳組織内に比較的多量に存在するT-2はT-1,T-3,N-TesのMT1-MMP阻害能を解除することによって浸潤を促進させる。Δ122は抗浸潤治療の候補分子になり得ることが示唆された。<br />研究課題/領域番号:14770707, 研究期間(年度):2002-2003<br />出典：「新規細胞外マトリックス分解酵素阻害分子による神経膠芽腫浸潤抑制の試み」研究成果報告書 課題番号14770707（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14770707/)を加工して作成
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