論文 - 戸田　正博

A case of moyamoya disease symptomatized early after nivolumab initiation – Possible association between immune checkpoint inhibitors and moyamoya disease

Takahashi S., Matsui Y., Kubo H., Toda M.

Clinical Neurology and Neurosurgery （Clinical Neurology and Neurosurgery）  200 2021年01月

ISSN  03038467

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Orthostatic Enlargement of a Supracerebellar Arachnoid Cyst With Cerebellar Descent Visualized by Upright Computed Tomography

Yoshida K., Toda M., Yamada Y., Yamada M., Yokoyama Y., Fujiwara H., Kosugi K., Sasaki H., Jinzaki M.

World Neurosurgery （World Neurosurgery）  145   256 - 259 2021年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  18788750

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Background: Posterior fossa arachnoid cysts are often asymptomatic, but can rarely cause postural headache, the mechanism of which remains unknown. Case Description: We present a 40-year-old woman with an asymptomatic supracerebellar arachnoid cyst. Upright computed tomography (CT) showed enlargement of the arachnoid cyst and caudal descent of the cerebellum compared with supine CT with narrowing of the craniocervical junction cerebrospinal fluid space. Conclusions: This finding aids in understanding the association of posterior fossa arachnoid cysts with orthostatic headache. Clinicians should be aware of possible posture-related changes in intracranial structures.

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Pterygovaginal artery as a target of embolization before endoscopic skull base surgery

Yoshida K., Akiyama T., Raz E., Kamamoto D., Ozawa H., Toda M.

Neuroradiology Journal （Neuroradiology Journal）  2021年

ISSN  19714009

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Background: The pterygovaginal artery (PtVA), a recurrent branch of the internal maxillary artery (IMA), can be a feeder of skull base tumors. Preoperative embolization can help endoscopic resection of hypervascular lesions, which is performed under a narrow surgical space with restricted instrumental maneuverability. Methods: We performed preoperative embolization in five cases with hypervascular skull base lesions supplied by the PtVA, four of which were resected via endoscopic endonasal approach. In two cases, selective PtVA embolization through the distal IMA was successfully conducted. Results: In all the cases, intraoperative bleeding during endoscopic resection was easily controlled. The medial and lateral origins of the PtVA from the IMA were demonstrated by cone-beam CT images reconstructed from three-dimensional rotational angiography, and anastomoses around the eustachian tube and soft palate were visualized by superselective angiography. Conclusions: The PtVA embolization can be an effective strategy before endoscopic skull base tumor resection. When embolizing through the PtVA, clinicians should be aware of its anatomical variations and dangerous anastomoses. Understanding the surrounding angioarchitecture by angiographic techniques helps ensure safe embolization.

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うつ病への脳深部刺激（DBS）療法　脳外科医と精神科医の視点から

高宮彰紘、福村麻里子、小杉健三、戸田正博、三村　將

精神医学 63 （ 12 ） 1825 - 1832 2021年

研究論文（学術雑誌）, 共著, 最終著者,  ISSN  04881281

Quiescent and Activated Fibroblasts in Lateral Ventricular Meningioma With a Dura-like Membrane

Sato M., Tamura R., Morimoto Y., Oishi Y., Yoshida K., Toda M.

World Neurosurgery （World Neurosurgery）  S1878-8750(20)32591-2 （ 20 ） 32591 - 32592 2020年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  18788750

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Background: Lateral ventricular meningioma (LVM) is a rare entity, accounting for 0.5%–5% of all intracranial meningiomas. This type of meningioma arises from meningothelial inclusion bodies in the tela choroidea and/or mesenchymal stroma of the choroid plexus. Although not yet fully characterized, a membranous structure is frequently observed around LVMs. This study analyzed quiescent and activated fibroblast phenotypes in LVMs with focus on the relationship between tumor growth and development of the membranous structure. Methods: This retrospective study analyzed 9 LVM cases for which gross total removal was achieved. Expression of the ependymal cell marker (Forkhead Box J1 [FoxJ1]) was histopathologically evaluated. The distribution of quiescent and activated fibroblasts was also analyzed using anti-fibroblast-specific protein-1 (FSP1)/S100A4 antibody and anti-α-smooth muscle actin (αSMA) antibody, respectively. The control group was 5 cases with primary convexity meningioma for which Simpson grade I removal was achieved. Results: Small LVMs (≤30 mm) were covered by a FoxJ1-positive(+) ependymal cell monolayer; no αSMA(+) cells were detected in the tumor; and a thick membrane capsule was not observed. None of the convexity meningiomas showed FoxJ1(+) cells. Large LVMs (>30 mm) had thick membrane capsules without an ependymal cell monolayer, which resembled dura mater. The FSP1/S100A4(+) and αSM(+) cells were clearly concentrated in the peripheral area just below the thick dura mater-like membrane capsules. Conclusions: This study found an association between activated fibroblasts and dura mater–like membrane capsules in LVMs. The characteristics of membranous structure in LVMs may differ depending on tumor size.

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Endoscopic Endonasal Management of Pterygopalatine Fossa Tumors

Ozawa H, Sekimizu M, Saito S, Shintaro Nakamura S, Mikoshiba T, Toda M and Ogawa K

The Journal of Craniofacial Surgery Epub ahe 2020年11月

研究論文（学術雑誌）, 共著, 査読有り

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Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Patients With Meningiomas

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

Frontiers in Oncology （Frontiers in Oncology）  Epub ahe 2020年11月

研究論文（学術雑誌）, 共著, 査読有り

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Background: Meningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies. Materials and Methods: This retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS). Results: Forty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P < 0.001, < 0.001, 0.002, < 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014). Conclusions: NLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.

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Historic overview of genetic engineering technologies for human gene therapy

Tamura R., Toda M.

Neurologia Medico-Chirurgica （Neurologia Medico-Chirurgica）  60 （ 10 ） 483 - 491 2020年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  04708105

　概要を見る

The concepts of gene therapy were initially introduced during the 1960s. Since the early 1990s, more than 1900 clinical trials have been conducted for the treatment of genetic diseases and cancers mainly using viral vectors. Although a variety of methods have also been performed for the treatment of malignant gliomas, it has been difficult to target invasive glioma cells. To overcome this problem, immortalized neural stem cell (NSC) and a nonlytic, amphotropic retroviral replicating vector (RRV) have attracted attention for gene delivery to invasive glioma. Recently, genome editing technology targeting insertions at site-specific locations has advanced; in particular, the clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/ Cas9) has been developed. Since 2015, more than 30 clinical trials have been conducted using genome editing technologies, and the results have shown the potential to achieve positive patient outcomes. Gene therapy using CRISPR technologies for the treatment of a wide range of diseases is expected to continuously advance well into the future.

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Targeted Embolisation for Coexisting Conus Medullaris Arteriovenous Malfomation and Cauda Equina Arteriovenous Fistulas with a Varix on a Shared Drainer

Yoshida K, Niimi Y, Kamamoto D, Fukumura M, Imai R, Nagoshi N, Akiyama T

British Journal of Neurosurgery 2020年10月

研究論文（学術雑誌）, 共著, 査読有り

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Posture-induced changes in the vessels of the head and neck: evaluation using conventional supine CT and upright CT

Kosugi K., Yamada Y., Yamada M., Yokoyama Y., Fujiwara H., Yoshida K., Yoshida K., Toda M., Jinzaki M.

Scientific Reports （Scientific Reports）  10 （ 1 ）  2020年10月

研究論文（学術雑誌）, 共著, 査読有り

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Since the venous system is affected by gravity, upright computed tomography (CT) in addition to conventional supine CT has great potential for evaluating postural changes in the venous system. We evaluated the morphological differences in the head and neck vessels by performing a contrast CT study in both the supine and the sitting positions. In this study, the 20 included participants (10 men and 10 women) were healthy adults aged 30 to 55 years. The cross-sectional area of the cervical vessels, craniocervical junction veins, and intracranial vessels were obtained quantitatively. Venous sinuses and venous plexuses that were difficult to measure were evaluated qualitatively. The average change in areas from a supine to an upright posture was − 77.87 ± 15.99% (P < 0.0001) in the right internal jugular vein (IJV), − 69.42 ± 23.15% (P < 0.0001) in the left IJV, − 61.52 ± 12.81% (P < 0.0001) in the right external jugular vein (EJV), and − 58.91 ± 17.37% (P < 0.0001) in the left EJV. In contrast, the change in the anterior condylar vein (ACV) from a supine to an upright posture was approximately + 144% (P < 0.005) on the right side and + 110% (P < 0.05) on the left side. In addition, according to the qualitative analysis, the posterior venous structures including the anterior condylar confluence (ACC) of the craniocervical junction became more prominent in an upright posture. Despite these changes, the intracranial vessels showed almost no change between postures. From a supine to an upright position, the IJVs and EJVs above the heart collapsed, and venous channels including the ACCs and ACVs opened, switching the main cerebral venous drainage from the IJVs to the vertebral venous system. Upright head CT angiography can be useful for investigating physiological and pathophysiological hemodynamics of the venous system accompanying postural changes.

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Pros and Cons of the Exoscope for Otologic Surgery

Kanzaki S., Takahashi S., Toda M., Yoshida K., Ogawa K.

Surgical Innovation （Surgical Innovation）  2020年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15533506

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Introduction. There are a few discussions regarding usefulness of an exoscope in otologic surgery compared to a traditional microscope. Objective. The pros and cons of using a newly developed exoscope (ORBEYE™) during microotologic surgery were evaluated. Methods. The usefulness of the ORBEYE™ exoscope was retrospectively assessed in 6 otologic surgeries by 8 surgeons postoperatively. A questionnaire comprising 20 questions was designed and used for evaluation. Results. All the otologic surgeons agreed that the exoscope is useful as an educational tool; the exoscope had the highest score in the questionnaire (average: 4.75). The question “Will the ORBEYE exoscope replace the conventional tympanoplasty or stapes surgery?” had the lowest score (average: 3.13). Conclusions. The quality of the images and movies in the exoscope was considered to be high and improved; therefore, the exoscope was considered as a useful educational tool in otologic surgery. Similar to otologic endoscopic surgery, all the members such as the operator and assistants could head up and share 1 image. TM

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Endoscopic endonasal transinfraturbinate approach with nasoseptal window for removal of the pterygopalatine fossa tumor

Yamada H, Toda M, Abiko T, Ozawa H, Ogawa K, Yoshida K

J Craniofac Surg 2020年09月

研究論文（学術雑誌）, 共著, 査読有り

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A pilot study of the adverse events caused by the combined use of bevacizumab and vascular endothelial growth factor receptor-targeted vaccination for patients with a malignant glioma

Tamura R., Morimoto Y., Sato M., Hikichi T., Yoshida K., Toda M.

Vaccines （Vaccines）  8 （ 3 ） 1 - 10 2020年09月

　概要を見る

Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.

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Current understanding of lymphatic vessels in the central nervous system

Tamura R., Yoshida K., Toda M.

Neurosurgical Review （Neurosurgical Review）  43 （ 4 ） 1055 - 1064 2020年08月

ISSN  03445607

　概要を見る

Lymphangiogenesis is associated with some pathological conditions such as inflammation, tissue repair, and tumor growth. Recently, a paradigm shift occurred following the discovery of meningeal lymphatic structures in the human central nervous system (CNS); these structures may be a key drainage route for cerebrospinal fluid (CSF) into the peripheral blood and may also contribute to inflammatory reaction and immune surveillance of the CNS. Lymphatic vessels located along the dural sinuses absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system, which is composed of aquaporin-4 water channels expressed on perivascular astrocytic end-feet membranes. Magnetic resonance imaging (MRI) clearly visualized these lymphatic vessels in the human dura mater. The conception of some neurological disorders, such as multiple sclerosis and Alzheimer’s disease, has been changed by this paradigm shift. Meningeal lymphatic vessels could be a promising therapeutic target for the prevention of neurological disorders. However, the involvement of meningeal lymphatic vessels in the pathophysiology has not been fully elucidated and is the subject of future investigations. In this article, to understand the involvement of meningeal lymphatic vessels in neurological disorders, we review the differences between lymphangiogenesis in the CNS and in other tissues during both developmental and adulthood stages, and pathological conditions that may be associated with meningeal lymphatic vessels in the CNS.

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Sinking skin flap syndrome visualized by upright computed tomography

Yoshida K., Toda M., Yamada Y., Yamada M., Yokoyama Y., Fujiwara H., Kosugi K., Fukumura M., Koike K., Takahashi S., Yoshida K., Jinzaki M.

Acta Neurochirurgica （Acta Neurochirurgica）  162 （ 8 ） 1825 - 1828 2020年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00016268

　概要を見る

Sinking skin flap syndrome is a craniectomy complication characterized by new neurological dysfunction that typically worsens in the upright position and improves after cranioplasty. We present a 33-year-old man who experienced hemiparesis in the upright position after craniectomy. Upright computed tomography (CT) before cranioplasty showed a remarkable shift of the brain compared to supine CT. After cranioplasty, both symptoms and brain shift on CT resolved. Upright CT enables detection and objective evaluation of paradoxical herniation and midline shift that is not obvious on supine imaging modalities. Clinicians need to be aware of positional brain shift in postcraniectomy patients.

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Endoscopic endonasal removal of a pediatric paranasal ossifying fibroma using preoperative embolization

Saito S., Ozawa H., Ikari Y., Nakahara N., Ito F., Sekimizu M., Kameyama K., Akiyama T., Toda M., Ogawa K.

Otolaryngology Case Reports （Otolaryngology Case Reports）  14 2020年03月

　概要を見る

Background: Ossifying fibroma arising in the sinonasal tract is rare. Its treatment includes complete resection; however, this can be challenging to perform due to the well-vascularized nature of the fibroma. Some surgical techniques can control intraoperative hemorrhage; however, to date, no reports have assessed the use of preoperative embolization. Methods: We report a case of a child with ossifying fibroma arising from the ethmoid sinus, which was resected by endoscopic surgery using preoperative transarterial embolization. Conclusions: Embolization was effective in decreasing intraoperative hemorrhage. No complications related to the procedure or operation were encountered. Preoperative embolization should be considered for better control of the bleeding that occurs in ossifying fibromas, similar to that in other well-vascularized tumors.

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A case of moyamoya disease symptomatized early after nivolumab initiation - Possible association between immune checkpoint inhibitors and moyamoya disease

Ozawa H, Sekimizu M, Saito S, Nakamura S, Mikoshiba T, Toda M, Ogawa K

Clin Neurol Neurourg 2020年01月

研究論文（学術雑誌）, 共著, 査読有り

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Cerebrospinal fluid leakage due to nasoseptal flap partial necrosis: a pitfall for skull base reconstruction of endoscopic endonasal surgery

Yamada H, Toda M, Fukumura M, Ozawa H, Ogawa K, Yoshida K

Surg Neurol Int （Surgical Neurology International）  11 （ 121 ）  2020年

研究論文（学術雑誌）, 共著

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Background: Vascularized nasoseptal flaps allow for the reconstruction of large dural defects and have remarkably reduced the incidence of postoperative complications during endoscopic endonasal skull base surgery. Nevertheless, some complications related to nasoseptal flap have been reported. Flap necrosis is a rare, but serious issue is associated with meningitis and cerebrospinal fluid (CSF) leak. Case Description: We performed endoscopic endonasal removal of the tuberculum sella meningioma in a 39-year-old woman with a history of Turner syndrome using abdominal fat, fascia, and a vascularized nasoseptal flap for dural and skull base defect reconstruction. After surgery, she developed CSF leak, and reoperation revealed partial necrosis of the septal flap that caused leakage. At this time, with a concern that removal of the necrotic part may lead to the insufficient size of the flap, we filled the gap tightly with fat pieces. However, the CSF leak recurred, and thus, we performed debridement of the necrotic region and reformed the multilayered reconstruction, following which she no longer experienced CSF leakage. Conclusion: Our case suggested that partial rather than total flap necrosis could occur, possibly due to variances of vascular anatomy, leading to focal ischemia. Debridement of the necrotic region may be an important solution for recurrent cerebrospinal leakage secondary to partial necrosis of a nasoseptal flap.

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Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas.

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

J Neurooncol （Journal of Neuro-Oncology）  146 （ 2 ） 265 - 273 2020年

研究論文（学術雑誌）, 共著,  ISSN  0167594X

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Background: Neurofibromatosis type 2 (NF2) patients uniformly develop multiple schwannomas. The tumor-microenvironment (TME) is associated with hypoxia and consists of immunosuppressive cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). The hypoxic TME of NF2 schwannomas remains unclear. In addition, no comparative study has investigated immunosuppressive cells in NF2 and sporadic schwannomas. Methods: In 22 NF2 and 21 sporadic schwannomas, we analyzed the immunohistochemistry for Ki-67, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, platelet derived growth factor receptor-beta (PDGFR-β), programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1), Foxp3, CD163, CD3, and CD8 to assess the immunosuppressive TME. Results: Most vessels in sporadic schwannomas exhibited slight or negative VEGFR1 and 2 expressions with pericytes coverage. In contrast, large vessels in NF2 schwannomas exhibited strong VEGFR1 and 2 expressions without pericytes. The number of CD3 , CD8 , and CD163 cells was significantly higher in NF2 schwannomas than in sporadic ones. The expression of PD-L1 and nestin positive cell ratio was higher in NF2 schwannomas than that in sporadic ones. The number of CD163 cells, nestin positive cell ratio, and HIF-1α expression were significantly associated with shorter progression-free survival in NF2 schwannomas. Conclusions: This study presents the clinicopathological features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between NF2 and sporadic schwannomas. Hypoxic TME was first detected in NF2-schwannomas, which was associated with the tumor progression. + + + +

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Prediction of postoperative recurrence of chronic subdural hematoma using quantitative volumetric analysis in conjunction with computed tomography texture analysis.

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

J Clin Neurosci （Journal of Clinical Neuroscience）  72   270 - 276 2020年

研究論文（学術雑誌）, 共著,  ISSN  09675868

　概要を見る

Chronic subdural hematoma (CSDH) is a common disease in older individuals with a substantial rate of recurrence. The mechanism of CSDH recurrence remains unclear. This study aimed to detect imaging parameters that could indicate the risk for CSDH recurrence by using quantitative volumetric analysis and computed tomography (CT) texture analysis (CTTA). Clinical and imaging parameters were retrospectively investigated in 147 newly diagnosed CSDH lesions in 114 patients surgically treated at the Keio University Hospital during a 6-year period. For CT images, quantitative volumetric and texture analyses were performed. Hematoma volume, postoperative air volume, hematoma density, and texture parameters including kurtosis, skewness, and entropy were evaluated and compared with CSDH recurrence rate. Data were statistically evaluated, and a difference of p < 0.05 was considered significant. Reoperation for CSDH recurrence was required in 27 sides (18.4%) of 26 patients. Multivariate analysis showed that postoperative hematoma volume and postoperative hematoma density were independent risk factors for symptomatic CSDH recurrence that required reoperation. Postoperative hematoma volume, postoperative significant residual air, and postoperative hematoma density were also identified as independent risk factors for potential CSDH recurrence. Preoperative hematoma entropy was prone to be associated with both symptomatic and potential CSDH recurrence in univariate analysis, but not in multivariate analysis because of confounding factors. Quantitative volumetric analysis and CTTA could aid in distinguishing individuals at risk for CSDH recurrence.

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