論文 - 戸田　正博

Predictive markers for MGMT promoter methylation in glioblastomas.

Kanazawa T, Minami Y, Jinzaki M, Toda M, Yoshida K, Sasaki H

Neurosurg Rev （Neurosurgical Review）  42 （ 4 ） 867 - 876 2019年

研究論文（学術雑誌）, 共著,  ISSN  03445607

　概要を見る

The promoter methylation status of the O -methylguanine-DNA methyltransferase (MGMT) gene has been described as the most important predictor of chemotherapeutic response and patients’ survival in glioblastomas (GBs). Therefore, prediction of the MGMT promoter methylation status by imaging would help to preoperatively decide the overall treatment strategy as well as surgical strategy. This study aimed to detect imaging parameters to predict MGMT promoter methylation in GBs by using a commercially available software. We investigated three imaging features (ring enhancement, tumor location, and laterality) and apparent diffusion coefficient (ADC) parameters in 48 newly diagnosed GBs treated at Keio University Hospital in 2006 or later. For ADC, texture analyses were performed. Regions of interest (ROIs) were drawn manually with reference to contrast-enhanced areas, excluding necrotic and cystic regions. Mean ADC value and ADC histogram parameters, including kurtosis, skewness, and entropy, were compared with MGMT promoter methylation. Each parameter was evaluated to determine correlation with MGMT promoter methylation, and the parameters with significant associations with the methylation status were correlated with the MGMT-positive cell ratio determined by immunohistochemistry (IHC) analysis. The mean ADC value and ADC entropy were significantly associated with MGMT promoter methylation. The combination of mean ADC value and ADC entropy predicted MGMT promoter methylation, with a PPV of 81.2% and specificity of 88.9%. The mean ADC value and ADC entropy were negatively correlated with the MGMT-positive cell ratio in the IHC analysis. This study demonstrated that texture analyses of ADC histograms in GBs were predictive of MGMT promoter methylation. 6

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Visualization of spatiotemporal dynamics of human glioma stem cell invasion.

Tamura R, Miyoshi H, Sampetrean O, Shinozaki M, Morimoto Y, Iwasawa C, Fukaya R, Mine Y, Masuda H, Maruyama T, Narita M, Saya H, Yoshida K, Okano H, Toda M

Molecular Brain 12 （ 45 ）  2019年

研究論文（学術雑誌）, 共著

In Reply to the Letter to the Editor Regarding “Treatment Strategy for Tuberculum Sellae Meningiomas Based on Preoperative Radiologic Assessment”

Kuga D, Toda M, Yoshida K.

World neurosurg 125 （ 1 ）  2019年

研究論文（学術雑誌）

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Magnetic resonance imaging texture analyses in lower-grade gliomas with a commercially available software: correlation of apparent diffusion coefficient and T2 skewness with 1p/19q codeletion

Kanazawa T, Minami Y, Takahashi H, Fujiwara H, Toda M, Jinzaki M, Yoshida K, Sasaki H

Neurosurg Rev （Neurosurgical Review）  43 （ 4 ） 1211 - 1219 2019年

研究論文（学術雑誌）, 共著,  ISSN  03445607

　概要を見る

Preoperative prediction of molecular information of lower-grade gliomas (LrGGs) helps to determine the overall treatment strategy as well as the initial surgical strategy. This study aimed to detect magnetic resonance imaging (MRI) texture parameters to predict the molecular signature of LrGGs using a commercially available software and routine MR images. Forty-three patients treated at Keio University Hospital who had World Health Organization grade II or III gliomas were included. All patients having preoperative T1- and T2-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted (DW) images were also included. Texture analyses of T2, FLAIR, and apparent diffusion coefficient (ADC) histograms were performed using a commercially available software. Texture parameters including kurtosis, skewness, and entropy were investigated to determine any correlation with the presence or absence of isocitrate dehydrogenase (IDH) mutations, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. ADC skewness and T2 skewness were significantly associated with 1p/19q codeletion status. ADC skewness of ≥ 0.25 predicted 1p/19q codeletion with a sensitivity and specificity of 80% and 65.2%, respectively (AUC = 0.728). T2 skewness of ≥ − 0.11 predicted 1p/19q codeletion with a sensitivity and specificity of 80% and 91.3%, respectively, (AUC = 0.866). None of the texture parameters were associated with IDH mutation and MGMT promoter methylation. MRI texture analysis using a commercially available software demonstrated that T2 skewness could predict 1p/19q codeletion with high sensitivity and specificity, suggesting a clinical utility.

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Analysis of temporobasal vein with short subdural segment for anterior transpetrosal approach

Tamura R, Toda M, Morimoto Y, Sato M, Akiyama T, Yoshida K

World Neurosurg （World Neurosurgery）  132   e554 - e562 2019年

研究論文（学術雑誌）, 共著,  ISSN  18788750

　概要を見る

Background: The anterior transpetrosal approach (ATPA) is applied to petroclival and brainstem lesions. Although neurosurgeons need to minimize the risk of neurologic complications, brain retraction is necessary for procedures of ATPA. Bridging veins (BVs) limit mobility of the temporal lobe. In the present study, BVs around the petrous bone were analyzed, focusing on the dural entrance and termination points. Methods: The relationship between subdural and meningeal segments of temporobasal veins (TBVs) was analyzed by preoperative computed tomography venography in 102 patients who underwent ATPA. TBVs were classified by the dural entrance and termination points. Results: TBVs mainly entered the transverse sinus and rarely entered transverse-sigmoid sinus (T-S) junction and superior petrosal sinus (SPS). TBVs entered a dural sinus either directly or indirectly through a meningeal vein. The changes in vascular diameter of the lumen, shape, and course were identified between the subdural and meningeal segments. Generally, BVs with long subdural segment do not limit mobility of the temporal lobe. TBVs draining into the T-S junction and SPS tended to be shorter than those draining into the transverse sinus. Furthermore, a few TBVs indirectly entered the dural sinuses through the meningeal vein (early dural entrance). The subdural segment of these TBVs was much shorter. Conclusions: TBVs entering the T-S junction or SPS with short subdural segment may limit the mobility of the temporal lobe. Changes in vascular diameter, shape, and course were detected by computed tomography venography, which was helpful to detect the subdural-meningeal transition.

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Identification of KLRC2 as a candidate marker for brain tumor-initiating cells

Ishihara E, Takahashi S, Fukaya R, Ohta S, Yoshida K, Toda M

Neurol Res （Neurological Research）  41 （ 11 ） 1043 - 1049 2019年

研究論文（学術雑誌）, 共著,  ISSN  01616412

　概要を見る

Objective: Brain tumor-initiating cells are characterized by their features of self-renewal, multi-lineage differentiation, and tumorigenicity. We analyzed the gene expression of brain tumor-initiating cells to identify their novel cellular markers. Methods: We performed cDNA microarray, in silico expressed sequence tags (ESTs), RT-PCR, and q-PCR analyses. Results: We identified 10 genes that were more highly expressed in brain tumor-initiating cells than in neural stem cells. In addition, we identified 10 other genes that were more highly expressed in brain tumor-initiating cells than in glioma cell line cells from the cDNA microarray analysis. Using the EST database, we looked to see if the 20 genes were expressed more highly in gliomas, compared with normal adult brains. Among the 20 genes, five (KLRC2, HOXB2, KCNJ2, KLRC1, and COL20A1) were expressed more than twice in glioma samples, compared with normal adult brains, and, therefore, were referred for further evaluation. RT-PCR was conducted using cDNA samples obtained from neural stem cells, normal brain tissue, fetal brain tissue, glioma cell lines, and glioma tumor-initiating cell lines. KLRC2, a transmembrane activating receptor in natural killer cells, was expressed more highly in glioma-initiating cells than in neural stem cell lines or normal adult brain tissue. The q-PCR analysis revealed that expression of KLRC2 was significantly higher in brain tumor-initiating cells compared to normal brain controls. Conclusion: KLRC2 could be a novel cellular marker for brain tumor-initiating cells.

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Early prediction of clinical outcomes in patients with aneurysmal subarachnoid hemorrhage using computed tomography texture analysis

Kanazawa T, Takahashi S, Minami Y, Jinzaki M, Toda M, Yoshida K

J Clin Neurosci （Journal of Clinical Neuroscience）  71   144 - 149 2019年

研究論文（学術雑誌）, 共著,  ISSN  09675868

　概要を見る

Radiological evaluation of subarachnoid hemorrhage (SAH) is often subject to interobserver variability. The aim of this study was to retrospectively detect computed tomography (CT) texture parameters in the early postictal state to predict cerebral vasospasm, delayed cerebral ischemia (DCI), and functional outcome in aneurysmal SAH using quantitative CT texture analysis (CTTA) via a commercially available software program and routine CT images. 40 patients with aneurysmal SAH surgically treated at the Keio University Hospital during a four-year period were analyzed. CT texture analyses were performed using a commercially available software program (Synapse Vincent). The following texture parameters of blood clots in the subarachnoid space and cerebral edema were assessed: mean CT value, entropy, skewness, and kurtosis. The mean CT value of blood clots in the subarachnoid space was significantly associated with cerebral vasospasm, DCI, and functional outcome. The mean CT value ≥ 49.64 Hounsfield units (HU) predicted cerebral vasospasm with a sensitivity and specificity of 85.7% and 61.5%, respectively (area under the curve [AUC] = 0.758). The mean CT value ≥ 49.95 HU predicted DCI with a sensitivity and specificity of 100% and 60.6%, respectively (AUC = 0.810). The mean CT value ≥ 53.00 HU predicted poor functional outcome with a sensitivity and specificity of 56.3% and 91.7%, respectively (AUC = 0.747). CTTA using a commercially available software program demonstrated that the mean CT value of clots in the subarachnoid space in the early postictal state could predict vasospasm, DCI, and clinical outcome with a high sensitivity and specificity.

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A VEGF receptor vaccine demonstrates preliminary efficacy in Neurofibromatosis type 2.

Tamura R, Fujioka M, Morimoto Y, Ohara K, Kosugi K, Oishi Y, Sato M, Ueda R, Fujiwara H, Hikichi T, Noji S, Oishi N, Ogawa K, Kawakami Y, Ohira T, Yoshida K, Toda M

Nature Commun （Nature Communications）  10 （ 1 ） 5758 2019年

研究論文（学術雑誌）, 共著

　概要を見る

The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.

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Relationship between pneumatization of lateral recess in the sphenoid sinus and removal of cavernous sinus invasion in pituitary adenomas by endoscopic endonasal surgery.

Kosugi K, Tamura R, Mase T, Tamura H, Jinzaki M, Yoshida K, Toda M

Surg Neurol Int 10   222 2019年

研究論文（学術雑誌）, 共著

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Long-Term Clinical Outcome of First Recurrence Skull Base Meningiomas.

Kuranari Y, Tamura R, Tsuda N, Kosugi K, Morimoto Y, Yoshida K, Toda M

J Clin Med 9 （ 1 ） e106 2019年

研究論文（学術雑誌）, 共著

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Endoscopic endonasal approach combined with a simultaneous transcranial approach for giant pituitary tumors.

Kuga D, Toda M, Ozawa H, Ogawa K, Yoshida K

World Neurosurg 121   173 - 179 2019年

研究論文（学術雑誌）, 共著, 査読有り

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In Reply to the Letter to the Editor Regarding “Treatment Strategy for Tuberculum Sellae Meningiomas Based on Preoperative Radiologic Assessment”

114 Kuga D, Toda M, Yoshida K.

World neurosurg  125 （ 1 ）  2019年

研究論文（学術雑誌）, 共著

Surgical management of trigeminal schwannomas: Preservation of the trigeminal nerve

Toda M., Tamura R., Yoshida K.

Japanese Journal of Neurosurgery （Japanese Journal of Neurosurgery）  28 （ 7 ） 407 - 413 2019年

ISSN  0917950X

　概要を見る

Trigeminal schwannomas can develop anywhere along the course of the trigeminal root, ganglion, and nerve branches. The most frequent tumor site is Meckel’s cave. The tumor, is dumbbell in shape, often extends to the posterior cranial fossa. A series of surgical approaches, which primarily include skull base extradural approaches, used for the management of trigeminal schwannomas has been discussed based on tumor site. More recently, an endoscopic endonasal approach has been used for lesions in Meckel’s cave, pterygoid palatine fossa, and infratemporal fossa. This article describes anatomy‒based surgical approaches for the management of trigeminal schwannoma and surgical approaches aimed at functional preservation.

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Difference in Immunosuppressive Cells Between Peritumoral Area and Tumor Core in Glioblastoma

Tamura R., Ohara K., Sasaki H., Morimoto Y., Kosugi K., Yoshida K., Toda M.

World Neurosurgery （World Neurosurgery）  120   e601 - e610 2018年12月

ISSN  18788750

　概要を見る

Background: Vascular endothelial growth factor (VEGF)-A and VEGF receptor expression in the peritumoral brain zone (PBZ) differs from that in the tumor core (TC) of glioblastoma. To date, no comparative study has investigated the expression of immunosuppressive cells in the PBZ and TC of glioblastoma. Methods: In 10 patients with newly diagnosed glioblastoma, we used immunohistochemistry to analyze the expression of VEGF-A, hypoxia-inducible factor-1α, programmed cell death-1 (PD-1), Foxp3, CD163, CD4, and CD8 to assess the immunosuppressive microenvironment. Results: The number of Foxp3 and CD163 cells was significantly greater in the TC than in the PBZ and correlated with greater expression of hypoxia-inducible factor-1α and VEGF-A in the TC than in the PBZ. The number of CD8 T cells was lower in the TC than in the PBZ, and the TC had more PD-1 CD8 T cells compared with the PBZ. These results suggest that the hypoxic condition could be associated with PD-1 expression on lymphocytes, the distribution of Foxp3 regulatory T cells and CD163 tumor-associated macrophages. Conclusions: The present study reports the first clinicopathologic features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between the TC and PBZ of glioblastoma. + + + + + + +

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Pros and cons of using ORBEYE™ for microneurosurgery

Takahashi S., Toda M., Nishimoto M., Ishihara E., Miwa T., Akiyama T., Horiguchi T., Sasaki H., Yoshida K.

Clinical Neurology and Neurosurgery （Clinical Neurology and Neurosurgery）  174   57 - 62 2018年11月

ISSN  03038467

　概要を見る

© 2018 Elsevier B.V. Objective: To evaluate the pros and cons of using a newly developed microscope, ORBEYE™, during microneurosurgery. Patients and methods: ORBEYE™ use in 14 microneurosurgical procedures was retrospectively assessed by nine neurosurgeons after the procedure. A questionnaire comprising 20 questions was designed and used for evaluation. Results: Compared with the current gold standard, the binocular microscope, ease of setting up the equipment was scored the highest, whereas ease of conducting surgery in a position of an assistant was scored the lowest. Among characteristics of ORBEYE™ itself, the space-saving feature was scored the highest and was followed by the ability to perform procedures in a comfortable position. The only characteristic that was rated below average was ease of operation in a position of an assistant. Neurosurgeons with greater experience (more than five procedures using ORBEYE™) provided significantly higher scores (p = 0.0196) for characteristics of ORBEYE™ itself compared with neurosurgeon with fewer ORBEYE™ experience. Conclusions: The main benefits of the ORBEYETM are its compact size and freedom from focusing through the eye lens of a conventional binocular microscope. However, it appears to be disadvantageous for operating in a position of an assistant because the surgical field has a rotated view on the monitor from a position of an assistant. Nonetheless, because of certain advantages, we believe the ORBEYE™ could be of additional help to use of conventional binocular microscope at the moment and will facilitate microneurosurgery in the future.

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Intraosseous venous structures adjacent to the jugular tubercle associated with an anterior condylar dural arteriovenous fistula

Mizutani K., Akiyama T., Minami Y., Toda M., Fujiwara H., Jinzaki M., Yoshida K.

Neuroradiology （Neuroradiology）  60 （ 5 ） 487 - 496 2018年05月

ISSN  00283940

　概要を見る

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Although involvement of the osseous component with an anterior condylar dural arteriovenous fistula (AC-DAVF) has been frequently described, osseous venous structures in which AC-DAVFs develop have not been fully elucidated. We investigated osseous venous structures adjacent to the hypoglossal canal in normal controls and patients with AC-DAVFs. Methods: The study included 50 individuals with unruptured aneurysms as normal controls and seven patients with AC-DAVFs. Osseous venous structures adjacent to the hypoglossal canal in normal controls were analyzed using computed tomography (CT) digital subtraction venography. In patients with AC-DAVFs, the fistulous pouches, draining veins, and surrounding venous structures were examined using cone beam CT. Results: In 46.0% of laterals in normal controls, osseous venous structures were visualized within the jugular tubercle superomedially to the hypoglossal canal. We named these structures the jugular tubercle venous complex (JTVC). The JTVC was always continuous with the anterior condylar vein and was sometimes connected to surrounding venous channels. We detected nine fistulous pouches in the seven patients with AC-DAVFs. The fistulous pouches were in the JTVC (33.3%), anterior condylar vein (33.3%), and other venous channels within the exoccipital region (33.3%). Conclusion: Although the JTVC is a venous structure frequently found in normal people, it had not been investigated until now. The venous channel between the anterior condylar vein and JTVC is a common origin site for AC-DAVFs, and it was associated with 66.6% of the AC-DAVF cases in the current study.

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A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma

Shibao S., Ueda R., Saito K., Kikuchi R., Nagashima H., Kojima A., Kagami H., Pareira E., Sasaki H., Noji S., Kawakami Y., Yoshida K., Toda M.

Oncotarget （Oncotarget）  9 （ 30 ） 21569 - 21579 2018年04月

　概要を見る

© Shibao et al. Object: Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. Methods: Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T-lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. Results: This treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. Conclusion: These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.

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The analysis of the cerebral venous blood volume in cavernous sinus using 320 row multi-detector CT

Mizutani K., Toda M., Yajima Y., Akiyama T., Fujiwara H., Yoshida K., Jinzaki M.

Clinical Neurology and Neurosurgery （Clinical Neurology and Neurosurgery）  167   11 - 16 2018年04月

ISSN  03038467

　概要を見る

© 2018 Elsevier B.V. Objectives: : Functional venous anatomy in the brain has been mostly understood from the morphological and embryological points of view and no published study has directly evaluated the blood flow volume of cerebral small veins. We developed a method to directly evaluate the relative blood volume in small venous channels using multi-detector computed tomography (CT) and applied it to evaluate the blood volume in each tributary of the cavernous sinus, which plays an important role in cerebral venous drainage. Patients and Methods: : Ten patients with small brain tumors who had normal venous anatomy were included in the present study. All of them underwent preoperative 320-row multi-detector CT. After injecting the contrast bolus, we measured the Hounsfield units (HUs) at 10 time point over 60 s in each tributary of the cavernous sinus. The gamma distribution fitting to each HU enabled us to obtain a time-density curve and determine the relative venous volume in each venous channel. Results: : In terms of blood volume, the superficial middle cerebral vein and inferior petrosal sinus were the largest inflow and outflow channels of the cavernous sinus and accounted for 36.1% and 24.7% of its inflow and outflow on average, respectively. The superior orbital vein did not contribute to the blood volume passing through the cavernous sinus in the current study. Conclusions: : The present study allowed us to determine the relative blood volume in each tributary of the cavernous sinus, which was very useful to understand the physiological actual venous drainage pattern concerning the cavernous sinus in normal anatomy.

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An Analysis of Various Tracts of Mastoid Air Cells Related to Cerebrospinal Fluid Leak after the Anterior Transpetrosal Approach.

Tamura R,　Tomio　R,　Mohammad　F,　Toda　M, Yoshida　K

Journal of Neurosurgery 16   1 - 8 2018年03月

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Histopathological vascular investigation of the peritumoral brain zone of glioblastomas

Tamura R., Ohara K., Sasaki H., Morimoto Y., Yoshida K., Toda M.

Journal of Neuro-Oncology （Journal of Neuro-Oncology）  136 （ 2 ） 233 - 241 2018年01月

ISSN  0167594X

　概要を見る

© 2017, Springer Science+Business Media, LLC. To date, no histopathological vascular investigation focusing on peritumoral brain zone (PBZ) has been reported for glioblastoma. We analyzed 10 newly diagnosed cases of glioblastomas. For these PBZs, histopathological investigation was performed by hematoxylin–eosin (H&E) staining and immunohistochemistry was analyzed for CD31, CD34, Factor VIII, VEGF, VEGFR-1/2, Ki67, p53 and nestin. Although it was difficult to identify PBZ by H&E, Ki67 and p53 staining, there were apparent differences in nestin staining among PBZ, tumor core (TC), and normal zone (NZ). Therefore, in this study, we divided PBZ from TC and NZ by nestin staining. Differences in histological features, microvessel density, expression of VEGF and its receptors were assessed for PBZ, TC and NZ. The microvessel density, as determined by counting CD31, CD34 and VEGF receptors, and VEGF-A expression were lower in PBZ than TC. The expression patterns for CD31, CD34 and VEGF receptors in vessels show dissociation in PBZ. In addition, the vascular characteristics of the PBZ may correlate with findings of radiographic imaging. We provide the first clinicopathological evidence that PBZ exhibits unique angiogenic characteristics. These in situ observations will help to elucidate the mechanisms of tumor recurrence.

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