研究者詳細 - 戸田　正博

論文 - 戸田　正博

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Efficacy of a topical gelatin-thrombin hemostatic matrix, FLOSEAL®, in intracranial tumor resection.

Kamamoto D, Kanazawa T, Ishihara E, Yanagisawa K, Tomita H, Ueda R, Jinzaki M, Yoshida K, Toda M

Surgical Neurology International （Surgical Neurology International） 72 （ 16 ） 270 - 276 2020年

研究論文（学術雑誌）, 共著

Background: Hemostasis plays an important role in safe brain tumor resection and also reduces the risk for surgical complications. This study aimed to evaluate the efficacy of FLOSEAL®, a topical hemostatic agent that contains thrombin and gelatin granules, in brain tumor resections. Methods: We evaluated the hemostatic effect of FLOSEAL by scoring the intensity of bleeding from 1 (mild) to 4 (life threatening). We assessed the rate of success of hemostasis with 100 patients who underwent intracranial tumor resection. We also investigated the duration of the operation, the amount of intra- and postoperative bleeding, the number of hospital stays, and adverse events in patients who used FLOSEAL compared with those who did not use FLOSEAL. Results: FLOSEAL was applied to a total of 109 bleeding areas in 100 patients. A total of 95 bleeding areas had a score of 1 and 91 (96%) showed successful hemostasis. Thirteen bleeding areas scored 2 and 8 (62%) showed hemostasis with the first application of FLOSEAL. The second application was attempted with five bleeding areas and four showed hemostasis. About 94% (103/109 areas) of bleeding points successfully achieved hemostasis by FLOSEAL. Moreover, FLOSEAL significantly decreased the amount of intraoperative bleeding and postoperative bleeding as assessed with computed tomography on 1 day postoperatively compared with no use of FLOSEAL. There were no adverse events related to FLOSEAL use. Conclusion: Our results indicate that FLOSEAL is a reliable, convenient, and safe topical hemostatic agent for intracranial tumor resection.

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Surgical outcomes of anterior cerebellopontine angle meningiomas using the anterior transpetrosal approach compared with the lateral suboccipital approach.

Hassaan SA, Tamura R, Morimoto Y, Kosugi K, Mahmoud M, Abokerasha A, Moussa A, Toda M, Yoshida K

Acta Neurochir (Wien) （Acta Neurochirurgica） 162 （ 6 ） 1243 - 1248 2020年

研究論文（学術雑誌）, 共著, ISSN 00016268

Background: Anterior transpetrosal approach (ATPA) and lateral suboccipital approach (LSO) are the major surgical approaches for cerebellopontine angle (CPA) meningiomas. Particularly, anterior CPA meningiomas are challenging lesions to be treated surgically. To date, only a few studies have directly compared the outcomes of both approaches focusing on the anterior CPA meningiomas. Methods: For the comparative analysis, anterior CPA meningiomas that were eligible for both APTA and LSO were collected in our hospital from April 2005 to March 2017. Anterior CPA meningiomas targeted for this study were defined as follows: (1) without cavernous sinus, clivus, and middle cranial fossa extension, (2) the posterior edge is 1 cm behind the posterior wall of the internal auditory canal, and (3) the inferior edge is above the jugular tuberculum. Based on these criteria, the operative outcomes of 17 patients and 13 patients who were operated via ATPA and LSO were evaluated. Results: The complication rate of the LSO group was significantly higher than that of the ATPA group (30.7% vs. 0%, p = 0.033). The removal rate did not differ between the ATPA and LSO groups (97.35% vs. 99.23%, p = 0.12). The operative time was significantly shorter in the LSO group than in the ATPA group (304.3 min vs. 405.8 min, p = 0.036). Conclusions: Although the LSO is more widely used for CPA meningiomas, ATPA is also considered for these anterior CPA meningiomas.

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Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors.

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

Exp Mol Pathol （Experimental and Molecular Pathology） 114 2020年

研究論文（学術雑誌）, 共著, ISSN 00144800

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-β and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

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Gene Therapy Using Neural Stem/Progenitor Cells Derived from Human Induced Pluripotent Stem Cells: Visualization of Migration and Bystander Killing Effect.

Tamura R, Miyoshi H, Morimoto Y, Oishi Y, Sampetrean O, Iwasawa C, Mine Y, Saya H, Yoshida K, Okano H, Toda M

Hum Gene Ther （Human Gene Therapy） 31 （ 5-6 ） 352 - 366 2020年

研究論文（学術雑誌）, 共著, ISSN 10430342

Glioblastoma is the most aggressive brain tumor characterized by diffuse infiltration into the normal brain parenchyma. Neural stem cells are known to possess the tumor-tropic migratory capacity and thus can be used as cellular vehicles for targeted delivery of therapeutic agents. In the present study, we evaluated the efficacy of herpes simplex virus thymidine kinase (HSV-TK) suicide gene therapy for glioblastoma using neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs). Although transduction of hiPSCs is preferable for a safe and stable supply in the clinical setting, high-level and/or constitutive HSV-TK expression was highly cytotoxic to hiPSCs. To overcome this problem, we used the tetracycline-inducible system to control the expression of HSV-TK. hiPSC-derived NS/PCs expressing HSV-TK were transplanted in an orthotopic xenograft mouse model of human glioblastoma. Glioblastoma cell growth in mice was dramatically inhibited following ganciclovir (GCV) administration. Survival of the mice was significantly prolonged with administration of GCV compared with control groups. Time-lapse imaging of organotypic brain slice cultures first demonstrated the directional migration of NS/PCs toward glioblastoma cells and the bystander killing effect upon GCV treatment. hiPSC-derived NS/PCs with HSV-TK/GCV suicide gene system may have considerable therapeutic potential for the treatment of glioblastoma. Color images are available online.

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Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series.

Tamura R, Morimoto Y, Kosugi K, Sato M, Oishi Y, Ueda R, Kikuchi R, Nagashima H, Hikichi T, Noji S, Kawakami Y, Sasaki H, Yoshida K, Toda M

BMC Cancer （BMC Cancer） 20 （ 1 ） 196 2020年

研究論文（学術雑誌）, 共著

Background: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. Methods: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ) -based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre- and post- vaccination specimens. Results: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre- and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. Conclusions: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. Trial registration: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs031180170 on 1 March, 2019.

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Analysis of the superficial middle cerebral vein in sphenoid ridge meningioma using contrast-enhanced dynamic computed tomography angiography.

Murase M, Mizutani K, Kawata K, Fujiwara H, Jinzaki M, Toda M, Yoshida K

Clin Neurol Neurosurg （Clinical Neurology and Neurosurgery） 191 （ 105683 ） 2020年

研究論文（学術雑誌）, 共著, ISSN 03038467

Objective: The superficial middle cerebral vein (SMCV) is of clinical importance because of its contribution to the venous drainage of the superficial part of the cerebrum. Sphenoid ridge meningioma (SRM) grows adjacent to the SMCV and its drainage routes, and is thought to occasionally influence the hemodynamics of the SMCV, although this has seldom been suggested in the literature. We investigated the effect of SRM on the SMCV via blood flow analysis using multi-detector computed tomography. Patients and Methods: Overall, 22 patients with SRM who preoperatively underwent contrast-enhanced dynamic computed tomography at our institution were included in this study. We serially measured the Hounsfield units at each point of the SMCV and its adjacent veins on the side on which the tumor was located. We then obtained a time-density curve for each point via gamma distribution fitting. We determined the time-to-peak at each point by calculating the derivative of the time-density curve function and deduced the direction of blood passing through each vein by comparing the time-to-peak values between several points. Results: In total, 26 SMCVs were measured in 19 out of 22 cases. Of the 26 SMCVs, 16 were patent in the medial portion and contributed to normal venous drainage: 4 of them emptied into the cavernous sinus (CS), and 12 of them into the para-cavernous sinus (ParaCS). Out of the 10 that had their medial portions occluded because of the effects of the tumor, 6 SMCVs mainly drained into the vein of Labbé and/or the vein of Trolard retrogradely. However, in 2 of these, the small medial portions of the SMCVs near the occluded portion were maintained anterogradely by the collateral venous structures. In 4 SMCVs, the blood flow through the collateral veins remained anterograde; this was considered to contribute to normal venous drainage. Conclusion: The SRM is likely to cause occlusion or stenosis in the SMCV and influence its hemodynamics. In cases in which the connection between the SMCV and the CS or the ParaCS has been lost, the SMCV may still be involved in normal venous drainage via the collateral veins in some of those cases. Thus, the contribution of these veins to normal venous drainage in the brain should be analyzed preoperatively in careful detail.

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A Comparative Study Between Traditional Microscopic Surgeries and Endoscopic Endonasal Surgery for Skull Base Chordomas

Oishi Y, Tamura R, Takahashi S, Morimoto Y, Sato M, Horikoshi T, Hassaan S, Yoshida K, Toda M

World Neurosurg （World Neurosurgery） 134 e1099 - e1107 2020年

研究論文（学術雑誌）, 共著, ISSN 18788750

Background: Skull base chordomas (SBCs) are rare clinically aggressive neoplasms, developing local recurrences after surgical resection. Although SBCs have traditionally been resected by craniotomy or microscopic transsphenoidal surgery (TSS), the recent development of the endoscopic endonasal approach (EEA) has revolutionized treatment strategies through minimally invasive techniques. This study aimed to evaluate clinical outcomes after traditional microsurgeries or EEAs for SBCs. Methods: The present retrospective study investigated 66 patients with primary SBCs who underwent surgery between 1977 and 2019. Resection was performed via EEA in 17 cases, craniotomy in 23, transoral approach in 8, TSS in 12, staged surgery in 4, and others in 2. The median follow-up period for progression-free survival (PFS) was 19.5 months. Results: There were no significant differences in preoperative tumor volume or resection rate among these approaches. The incidence of postoperative cranial nerve palsy was significantly lower in EEA than that in craniotomy (P < 0.05). Although total resection was observed in 4 cases of EEA expanding into the superior and inferior part of the clivus, no cases of transoral approach or TSS achieved total resection for both parts. No significant difference in PFS was found among these approaches. Multivariate analysis showed that being female and the absence of radiotherapy were significantly associated with shorter PFS (P < 0.05 and P < 0.001, respectively). The resection rate was not associated with PFS. Conclusions: EEA is a less invasive surgical approach for SBCs. The development of surgical instruments and postoperative radiotherapy will further improve patients' outcomes.

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A Novel Flow Dynamics Study of the Intracranial Veins Using Whole Brain Four-Dimensional Computed Tomography Angiography

Mizutani K., Arai N., Toda M., Akiyama T., Fujiwara H., Jinzaki M., Yoshida K.

World Neurosurgery （World Neurosurgery） 131 e176 - e185 2019年11月

ISSN 18788750

Background: The flow dynamics of the intracranial venous channels are fundamentally important for understanding intracranial physiology and pathophysiology. However, the method clinically applicable to the evaluation of the flow dynamics of the intracranial venous system has not been well described in the reported data. We have developed a new method to evaluate intracranial venous flow direction and velocity using 4-dimensional (4D) computed tomography angiography (CTA). The aim of the present study was to verify the accuracy and validity of 4D-CTA in a clinical setting. Methods: We retrospectively analyzed 97 veins from 26 patients (16 cases of arteriovenous shunt disease, 9 intracranial tumor cases, and 1 cerebral aneurysm case) who had undergone both 4D-CTA and conventional digital subtraction angiography (DSA). Using 4D-CTA, we analyzed the time-density curve with gamma distribution extrapolation and obtained the direction of the flow and flow velocity of each vein. The direction of the flow in 4D-CTA was also collated with that obtained using conventional DSA to verify the experimental method. Results: The direction of the flow determined by 4D-CTA was consistent with that of conventional DSA in 94.8% of cases. The average venous flow velocity was 64.3 mm/second and 81.8 mm/second, respectively, in the antegrade and retrograde channels affected by arteriovenous shunts. Conclusions: The present flow analysis using 4D-CTA enabled us to evaluate the direction and velocity of intracranial venous flow. Other than some limitations, the presented method is reliable and its potential for application in clinical settings is promising.

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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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戸田 正博

論文 - 戸田 正博

戸田　正博

論文 - 戸田　正博