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Prognostic Significance of VEGF Receptors Expression on the Tumor Cells in Skull Base Chordoma

Morimoto Y, Tamura R, Ohara K, Kosugi K, Oishi Y, Kuranari Y, Yoshida K, Toda M.

Journal of Neuro-Oncology （Journal of Neuro-Oncology） 144 （ 1 ） 65 - 77 2019年06月

研究論文（学術雑誌）, 共著, ISSN 0167594X

Background: Chordoma is a rare refractory neoplasm that arises from the embryological remnants of the notochord, which is incurable using any multimodality therapy. Vascular endothelial growth factor (VEGF) is a potent activator of angiogenesis that is strongly associated with the tumor-immune microenvironment. These factors have not been elucidated for chordomas. Methods: To evaluate the characteristics of vascular and tumor cells in chordoma, we first analyzed the expression of VEGF receptor (VEGFR) 1, VEGFR2, CD34, and Brachyury in a cell line and 54 tumor tissues. Patients with primary skull base chordomas were divided into the following two groups as per the tumor growth rate: patients with slow progression (SP: < 3 mm/year) and those with rapid progression (RP: ≥ 3 mm/year). Thus, the expressions of VEGF-A, VEGFR 1, and VEGFR2 on tumor cells; tumor infiltrative immune cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs); and immune-checkpoint molecules (PD-1/PD-L1) were analyzed with the clinical courses, especially in a comparison between the two groups. Results: In chordomas, both VEGFR1 and VEGFR2 were strongly expressed not only on vascular endothelial cells, but also on tumor cells. The recurrent cases showed significantly higher VEGFR1 expressions on tumor cells than the primary cases. The expression of VEGF-A was significantly higher in RP than that in SP group. The numbers of CD163+ TAMs and Foxp3+ Tregs were higher in RP than that in SP group. Conclusions: Expression of VEGFR1 and VEGFR2 on tumor cells and immunosuppressive tumor-microenvironment were related to tumor growth in patients with chordomas.

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Immunological and vascular characteristics in cavernous sinus meningioma.

Kosugi K, Tamura R, Ohara K, Morimoto Y, Kuranari Y, Oishi Y, Yoshida K, Toda M

Journal of Clinical Neuroscience （Journal of Clinical Neuroscience） 67 198 - 203 2019年06月

研究論文（学術雑誌）, 共著, ISSN 09675868

Objectives: It is difficult to treat cavernous sinus (CS) meningiomas because of their complex vascular and neurological structures. Recently, immunotherapy has become an attractive therapeutic modality, but the role of tumor immune microenvironment is yet to be investigated for CS meningiomas. In the current study, these molecular and histopathological characteristics were examined in CS meningiomas. Methods: The present study used twenty-eight meningioma tissues arising in two different locations (8 CS and 20 convexity meningiomas). Immunohistochemical analyses were performed with CD3, CD4, CD8, Foxp3, CD163, PDGFR-β, VEGF receptors 1 & 2 (VEGFR-1, VEGFR-2), VEGF-A and HIF-1α. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression of Foxp3, VEGF-A, CD163, VEGFRs-1 & 2 and HIF-1α. Results: The numbers of different tumor-infiltrating immune cells, such as immunosuppressive cells, were significantly lower in CS meningiomas compared with convexity meningiomas. Analysis of the vascular characteristics showed the vessels in the CS meningiomas were covered with PDGFR-β-positive pericytes and were negative or had only very low amounts of VEGFR-1 and VEGFR-2. However, most vessels in convexity meningiomas showed high VEGFRs expression and were not covered with pericytes. Immunohistochemical and qPCR analyses revealed that the expression of HIF-1α, VEGF-A and VEGFRs-1 & 2 was lower in CS meningiomas. Conclusion: Fewer immunocompetent cells were observed in CS meningiomas compared with convexity meningiomas. Lower expression of VEGF-A, VEGFRs-1 and 2, and the vascular structure may contribute to this specific immune microenvironment.

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Characteristics intracranial epidermoid cyst between two hospital from developed vs developing institution and literature review

Sutiono A.B., Sidbutar R, Pareira E.S., Toda M, Yoshida K

Interdisciplinary Neurosurgery （Interdisciplinary Neurosurgery: Advanced Techniques and Case Management） 18 2019年06月

共著

Introduction: Intracranial epidermoid tumors are slow-growing lesions, which may recur after incomplete resection (surgery), but may do so over many years. These slow growing benign tumors encase and surround nerves and arteries rather than displacing them and the treatment of choice is radical surgery. Therefore the clinical symptoms are varies. The incidence of intracranial epidermoids is between 0.3% and 1.8% of all brain tumors. Whether the characteristics of tumor are related with culture of clinical neurologic in different developed and developing institution has not been discussed yet. Methods: Between 2015 until 2017, we collected data from two institutions, Keio University hospital Tokyo Japan and Hasan Sadikin Hospital Padjadjaran University Bandung Indonesia. We collect 16 patients from Keio University hospital (KUH) and 10 patients from Hasan Sadikin hospital (HSH). Results: In which the 11 cases is located in infratentorial and 5 cases were in supratentorial region at KUH. Meanwhile in HSH, we found that 10 patients were in infratentorial. The characteristic of cranial nerve palsy and/or neurological deficits are mainly similar in infratentorial region whether from KUH or HSH, including supratentorial epidermoid are also similar. At KUH, the location of epidermoid is located in the CPA (cerebellopontine angle) in 8 patients, 3 in suprasellar region, 1 in Meckel's cave, 1 in 4th ventricle, 1 in medulla, 1 in petroclival and 1 in occipital lobe. In HSH, the lesions are located in infratentorial in which 5 patient in CPA, 4 in petroclival region and 1 case in Meckel's cave. In infratentorial lesion the CNs (cranial nerves) palsy were found in CN IV, V, VI, VII, VIII, and none in IX, X, XI, XII. In supratentorial lesion the chief complaint was mainly headache. Conclusion: The epidermoid of the brain are mostly located in the infratentorial region rather than in supratentorial. The CNs deficit are commonly arose in infratentorial lesion meanwhile the supratentorial region symptom is headache. It is reasonable if the patient came with infratentorial multiple CNs palsy to be suspicious for epidermoid benign tumor in the intracranial. Those characteristics are found in both developed and developing hospitals.

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Bridging vein and tentorial sinus in the subtemporal corridor during the anterior transpetrosal approach

Shibao S., Toda M., Fujiwara H., Jinzaki M., Yoshida K.

Acta Neurochirurgica （Acta Neurochirurgica） 161 （ 4 ） 821 - 829 2019年04月

ISSN 00016268

© 2019, Springer-Verlag GmbH Austria, part of Springer Nature. Background: The bridging vein (BV) and the tentorial sinus (TenS) are important venous structures in neurological surgery. These venous structures during the anterior transpetrosal approach (ATPA) have not been reported. The objective of this study is to examine the BV and the TenS in the subtemporal corridor during the ATPA and propose a technique to identify the BV preoperatively. Methods: This study included 126 patients treated via the ATPA. The BV and the TenS located in the operative fields were analyzed. Furthermore, in the preoperative evaluation, the cross-sectional shapes of the intradural vein and the interdural sinus were analyzed by curved planar reconstruction (CPR), and the flattening rate was calculated. Flattening rate = (a-b)/a = 1-b/a (a: long radius, b: short radius). Results: Seventeen BVs and 18 TenS were identified. The bridging site was divided into two groups: tentorial and middle fossa. The middle fossa group was divided into three subgroups: cavernous sinus, middle fossa dural sinus, and middle fossa dural adherence. Five isolated TenS were sacrificed and no venous complications were observed. The mean flattening rate was 0.13 in the intradural vein and 0.51 in the interdural sinus, respectively (P = 0.0003). Conclusions: We showed classification of the BV, and preservation of the BV and TenS during the ATPA. Furthermore, we found that the interdural sinus was significantly flatter than the intradural veins. Measuring the flattening rate by CPR may be useful to identify BVs preoperatively.

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Analysis of tumor angiogenesis and immune microenvironment in non-functional pituitary endocrine tumors.

Sato M, Tamura R, Tamura H, Mase T, Kosugi K, Morimoto Y, Yoshida K, Toda M

J.Clin.Med 8 （ 5 ） 2019年03月

研究論文（学術雑誌）, 共著

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Endoscopic Endonasal Removal of Large Calcified Pituitary Adenoma: Case Report and Review of the Literature

Murase M., Toda M., Ohara K., Ishihara E., Yoshida K.

World Neurosurgery （World Neurosurgery） 123 239 - 243 2019年03月

ISSN 18788750

© 2018 Elsevier Inc. Background: Large calcified intrasellar masses, called pituitary stones, have been reported as calcified pituitary adenomas in the literature. Although relatively rare, calcified pituitary adenomas appear in various formations. Thus, whether the lesion is removable—and, if so, which approach is appropriate—mainly depends on its formation and quality. Case Description: A 46-year-old woman presented with visual loss and amenorrhea. Although computed tomography showed a uniformly calcified sellar tumor, magnetic resonance imaging displayed heterogenous intensity on T2-weighted images and mild gadolinium enhancement, suggesting that the lesion was a mixture of pituitary adenoma and fine calcification. Thus, we undertook tumor resection via an endoscopic endonasal approach, which resulted in total removal. The pathological diagnosis was a pituitary adenoma with rich calcification. Conclusions: We report a rare case of a large pituitary stone that was successfully removed via an endoscopic endonasal approach. This could therefore be a feasible, effective technique for the removal of pituitary stones, although careful analysis of preoperative magnetic resonance imaging is required.

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PITX2 Expression in Non-functional Pituitary Neuroendocrine Tumor with Cavernous Sinus Invasion.

Tamura R, Ohara K, Morimoto Y, Kosugi K, Oishi Y, Sato M, Yoshida K, Toda M

Endocr Pathol. （Endocrine Pathology） 30 （ 2 ） 81 - 89 2019年03月

研究論文（学術雑誌）, 共著, ISSN 10463976

Although most pituitary neuroendocrine tumors (PitNETs) show benign behavior, a significant number of PitNETs exhibit an aggressive course including cavernous sinus (CS) invasion. To date, the cause of CS invasion has not been fully elucidated. In this study, we analyzed the relationship between CS invasion in PitNETs and the expression of PITX2 and SNAIL1, which are the transcription factors associated with the morphogenesis of pituitary gland. Sixty cases with non-functional PitNETs were classified into four types: type 1a, none of CS invasion and suprasellar expansion; type 1b, suprasellar expansion without CS invasion; type 2a, CS invasion without suprasellar expansion; and type 2b, CS invasion with suprasellar expansion. We analyzed the expression of PITX2 and SNAIL1 employing quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. Other parameters such as mitotic count, Ki-67 index, and p53 expression were also analyzed, which were previously reported as potential tumor proliferative markers in PitNETs. PITX2 expression was significantly higher in PitNETs with CS invasion than PitNETs without CS invasion (P = 0.019). Expression of SNAIL1 was significantly elevated in PitNETs with suprasellar expansion compared with PitNETs without suprasellar expansion (P = 0.02). There was no apparent relationship between CS invasion and mitotic count, Ki-67 index, and p53 expression (mitotic count, P = 0.11; Ki-67 index, P = 0.61; p53, P = 0.66). High PITX2 expression was observed in non-functional PitNETs with CS invasion, suggesting that PITX2 may be involved in CS invasion of PitNETs.

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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

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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

© 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.

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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

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.

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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

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.

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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 2019年

研究論文（学術雑誌）, 共著

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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

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

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

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

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

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

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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