論文 - 戸田　正博

A pilot study of vaccine therapy with multiple glioma oncoantigen/glioma angiogenesis-associated antigen peptides for patients with recurrent/progressive high-grade glioma.

Kikuchi R, Ueda R, Saito K, Shibao S, Nagashima H, Tamura R, Morimoto Y, Sasaki H, Noji S, Kawakami Y, Yoshida K, Toda M

J.Clin.Med.  8 （ 2 ）  2019年02月

• Access to Document (DOI)

Increased cytotoxicity of herpes simplex virus thymidine kinase expression in human induced pluripotent stem cells

Iwasawa C., Tamura R., Sugiura Y., Suzuki S., Kuzumaki N., Narita M., Suematsu M., Nakamura M., Yoshida K., Toda M., Okano H., Miyoshi H.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  20 （ 4 ）  2019年02月

ISSN  16616596

　概要を見る

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Human induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine. The major safety concern is the tumorigenicity of transplanted cells derived from iPSCs. A potential solution would be to introduce a suicide gene into iPSCs as a safety switch. The herpes simplex virus type 1 thymidine kinase (HSV-TK) gene, in combination with ganciclovir, is the most widely used enzyme/prodrug suicide system from basic research to clinical applications. In the present study, we attempted to establish human iPSCs that stably expressed HSV-TK with either lentiviral vectors or CRISPR/Cas9-mediated genome editing. However, this task was difficult to achieve, because high-level and/or constitutive expression of HSV-TK resulted in the induction of cell death or silencing of HSV-TK expression. A nucleotide metabolism analysis suggested that excessive accumulation of thymidine triphosphate, caused by HSV-TK expression, resulted in an imbalance in the dNTP pools. This unbalanced state led to DNA synthesis inhibition and cell death in a process similar to a “thymidine block”, but more severe. We also demonstrated that the Tet-inducible system was a feasible solution for overcoming the cytotoxicity of HSV-TK expression. Our results provided a warning against using the HSV-TK gene in human iPSCs, particularly in clinical applications.

• Access to Document (DOI)

Analysis of various tracts of mastoid air cells related to CSF leak after the anterior transpetrosal approach

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

Journal of Neurosurgery （Journal of Neurosurgery）  130 （ 2 ） 360 - 367 2019年02月

ISSN  00223085

　概要を見る

OBJECTIVE The anterior transpetrosal approach (ATPA) was established in 1984 and has been particularly effective for petroclival tumors. Although some complications associated with this approach, such as venous hemorrhage in the temporal lobe and nervous disturbances, have been resolved over the years, the incidence rate of CSF leaks has not greatly improved. In this study, some varieties of air cell tracts that are strongly related to CSF leaks are demonstrated. In addition, other pre- and postoperative risk factors for CSF leakage after ATPA are discussed. METHODS Preoperative and postoperative target imaging of the temporal bone was performed in a total of 117 patients who underwent ATPA, and various surgery-related parameters were analyzed. RESULTS The existence of air cells at the petrous apex, as well as fluid collection in the mastoid antrum detected by a postoperative CT scan, were possible risk factors for CSF leakage. Tracts that directly connected to the antrum from the squamous part of the temporal bone and petrous apex, rather than through numerous air cells, were significantly related to CSF leak and were defined as “direct tract.” All patients with a refractory CSF leak possessed “unusual tracts” that connected to the attic, tympanic cavity, or eustachian tube, rather than through the mastoid antrum. CONCLUSIONS Preoperative assessment of petrous pneumatization types is necessary to prevent CSF leaks. Direct and unusual tracts are particularly strong risk factors for CSF leaks.

• Access to Document (DOI)

Endonasal Chiasmapexy Using Autologous Cartilage/Bone for Empty Sella Syndrome After Cabergoline Therapy for Prolactinoma

Ishihara E., Toda M., Sasao R., Ozawa H., Saito S., Ogawa K., Yoshida K.

World Neurosurgery （World Neurosurgery）  121   145 - 148 2019年01月

ISSN  18788750

　概要を見る

Background: Visual field deterioration caused by secondary empty sella after cabergoline therapy for prolactinoma is a rare event. Chiasmapexy is performed to treat empty sella syndrome. Although various materials have been used for the elevation of the optic chasm, the most appropriate material remains to be established. Here, we describe the efficiency of chiasmapexy for empty sella syndrome following dopamine agonist treatment and the utility of septal cartilage and sphenoidal sinus bone as materials for chiasmapexy. Case Description: A 35-year-old male with a history of cabergoline therapy for prolactinoma presented with visual deterioration. His magnetic resonance imaging revealed optic chiasm herniation into the empty sella. Endoscopic endonasal transsphenoidal chiasmapexy was performed using septal cartilage and sphenoidal sinus bone as materials for elevating the chiasm. Visual function improved immediately after operation. Conclusions: Chiasmapexy is an effective surgical method for treating visual deterioration caused by empty sella after cabergoline treatment. Endoscopic endonasal chiasmapexy with septal cartilage and sphenoidal sinus bone is a considerable option because it is minimally invasive and involves decreased risk of infection.

• Access to Document (DOI)

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 2019年

研究論文（学術雑誌）, 共著

• Access to Document (DOI)

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

• Access to Document (DOI)

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）

• Access to Document (DOI)

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.

• Access to Document (DOI)

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.

• Access to Document (DOI)

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.

• Access to Document (DOI)

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.

• Access to Document (DOI)

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.

• Access to Document (DOI)

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

• Access to Document (DOI)

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

• Access to Document (DOI)

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

• Access to Document (DOI)

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.

• Access to Document (DOI)

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. + + + + + + +

• Access to Document (DOI)

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.

• Access to Document (DOI)