Details of a Researcher - Tamura, Ryota

Papers - Tamura, Ryota

Division display >> ／ All the affair displays 1 - 67 of about 67

Suboccipital trans-horizontal fissure approach for cerebellar hemorrhage with rupture into the upper 4th and 3rd ventricles: the first clinical experience

Tamura R, Katayama M, Kuranari Y, Horiguchi T. Suboccipital trans-horizontal fissure approach for cerebellar hemorrhage with rupture into the upper 4th and 3rd ventricles: the first clinical experience

J Neurosurg; Case Lessons 3 CASE21647 2022

Research paper (scientific journal), Accepted

Schwannoma:Update on Molecular Profiling and Therapeutic Advances

Tamura R, Toda M

No Shinkei Geka 50 162 - 170 2022

Thesis (other), Accepted

Bilaterally Asymmetric Helical Myofibrils in Ascidian Tadpole Larvae

Matsuo K., Tamura R., Hotta K., Okada M., Takeuchi A., Wu Y., Hashimoto K., Takano H., Momose A., Nishino A.

Frontiers in Cell and Developmental Biology (Frontiers in Cell and Developmental Biology) 9 2021.12

The locomotor system is highly bilateral at the macroscopic level. Homochirality of biological molecules is fully compatible with the bilateral body. However, whether and how single-handed cells contribute to the bilateral locomotor system is obscure. Here, exploiting the small number of cells in the swimming tadpole larva of the ascidian Ciona, we analyzed morphology of the tail at cellular and subcellular scales. Quantitative phase-contrast X-ray tomographic microscopy revealed a high-density midline structure ventral to the notochord in the tail. Muscle cell nuclei on each side of the notochord were roughly bilaterally aligned. However, fluorescence microscopy detected left-right asymmetry of myofibril inclination relative to the longitudinal axis of the tail. Zernike phase-contrast X-ray tomographic microscopy revealed the presence of left-handed helices of myofibrils in muscle cells on both sides. Therefore, the locomotor system of ascidian larvae harbors symmetry-breaking left-handed helical cells, while maintaining bilaterally symmetrical cell alignment. These results suggest that bilateral animals can override cellular homochirality to generate the bilateral locomotor systems at the supracellular scale.

Access to Document (DOI)

Histopathological investigation of dura-like membrane in vestibular schwannomas

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

Brain Sciences (Brain Sciences) 11 ( 12 ) 2021.12

The dura-like membrane (DLM) is an outermost membranous structure arising from the dura mater adjacent to the internal auditory meatus (IAM) that envelops some vestibular schwannomas (VSs). Its recognition is important for the preservation of the facial and cochlear nerves during tumor resection. This study analyzes the histopathological characteristics of the DLM. The expression of CD34 and αSMA was histopathologically analyzed in tumor and DLM tissue of 10 primary VSs with and without a DLM. Tumor volume, resection volume percentage, microvessel density (MVD), and vessel diameter were analyzed. Volumetric analysis revealed that the presence of a DLM was significantly associated with lower tumor resection volume (p < 0.05). Intratumoral vessel diameter was significantly larger in the DLM group than the non-DLM group (p < 0.01). Larger VSs showed a higher intratumoral MVD in the DLM group (p < 0.05). Multilayered αSMA-positive vessels were identified in the DLM, tumor, and border; there tended to be more of these vessels within the tumor in the DLM group compared to the non-DLM group (p = 0.08). These arteriogenic characteristics suggest that the DLM is formed as the tumor induces feeding vessels from the dura mater around the IAM.

Access to Document (DOI)

History and current progress of chronic subdural hematoma

Tamura R., Sato M., Yoshida K., Toda M.

Journal of the Neurological Sciences (Journal of the Neurological Sciences) 429 2021.10

ISSN 0022510X

Chronic subdural hematoma (CSDH) is characterized by an encapsulated collection of old blood. Although CSDH has become the most frequent pathologic entity in daily neurosurgical practice, there are some unresolved research questions. In particular, the causes and recurrent risk factors of CSDH remain as an object of debate. The split of the dural border layer forms a few tiers of dural border cells over the arachnoid layer. Tissue plasminogen activator plays an important role as a key factor of defective coagulation. Historically, CSDH has often been treated via burr hole craniostomy using a closed drainage system. Several different operative strategies and peri-operative strategies such as the addition of burr holes, addition of cavity irrigation, position of drain, or postural position, have been described previously. Although the direction of the drainage tube, residual air, low intensity of T1-weighted images on MRI, and niveau formation have been reported as risk factors for recurrence, antiplatelet or anticoagulant drug use has not yet been verified as a risk factor. Recently, pharmaceutical strategies, including atorvastatin, significantly improved the neurological function in CSDH patients. Many case series, without randomization, have been reported; and given its promising result, several randomized clinical trials using pharmaceutical as well as operative and perioperative strategies were initiated to obtain sufficient data. In contrast, relatively fewer basic studies have achieved clinical applications in CSDH, although it is one of the most common clinical entities. Further scientific basic research may be essential for achieving a novel treatment strategy for CSDH.

Access to Document (DOI)

Current understanding of neurofibromatosis type 1, 2, and schwannomatosis

Tamura R.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 22 ( 11 ) 2021.06

ISSN 16616596

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

Access to Document (DOI)

Novel histopathological classification of meningiomas based on dural invasion

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

Journal of Clinical Pathology (Journal of Clinical Pathology) 74 ( 4 ) 238 - 243 2021.04

ISSN 00219746

Aims Histological invasion into the adjacent brain parenchyma is frequently investigated in meningioma because it is an important morphological criterion for grade II meningioma according to the 2016 WHO classification. However, few studies have focused on dural invasion of meningiomas. Herein, we propose a novel histopathological classification based on dural invasion of meningiomas. Methods Forty-nine cases with WHO grade I meningiomas who underwent Simpson grade I removal were collected. After the meningeal layer (ML) and periosteal layer (PL) of dura mater were visualised by Masson's trichrome stain, we evaluated the depth (to the ML and PL) and the patterns (1, expanding; 2, infiltrating) of dural invasion of meningiomas using serial paraffin sections. Invasion-associated markers, including Ki-67, matrix metalloproteinase (MMP)-1, MMP-9 and MMP-13, aquaporin 1 and Na-K-2Cl cotransporter, were quantitatively analysed by immunohistochemistry. Results Thirty-five cases (71.4%) showed the dural invasion. In 27 of these 35 cases (77.1%), dural invasion was localised in ML. Type 1 (expanding type) and type 2 (infiltrating type) invasions were observed in 23 and 12 cases, respectively. The recurrence rate in cases with type 2 invasion was significantly higher than that in cases with type 1 invasion. The percentage of MMP-1-positive tumour cells was also significantly higher in cases with dural invasion than those without, suggesting involvement of MMP-1 in dural invasion. Conclusions We quantitatively evaluated the depth and patterns of dural invasion in meningiomas. The patterns of dural invasion were associated with meningioma recurrence.

Access to Document (DOI)

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) 147 e215 - e224 2021.03

ISSN 18788750

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.

Access to Document (DOI)

Recent progress in the research of suicide gene therapy for malignant glioma

Tamura R., Miyoshi H., Yoshida K., Okano H., Toda M.

Neurosurgical Review (Neurosurgical Review) 44 ( 1 ) 29 - 49 2021.02

ISSN 03445607

Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.

Access to Document (DOI)

Suboccipital Trans-horizontal Fissure Approach for Posterior Cranial Fossa Lesions: A Cadaveric Study and First Clinical Experience. Oper Neurosurg (Hagerstown)

Tamura R, Katayama M, Yamamoto K, Horiguchi T

Oper Neurosurg (Hagerstown) 21 E479 - E487 2021

Research paper (scientific journal), Accepted

A Multilayered Dural Repair Technique Using Duragen For Early Cranioplasty Following Decompressive Craniotomy

Tamura R, Kuranari Y, Mishima M, Katayama M

Surgeries 2 371 - 377 2021

Research paper (scientific journal), Accepted

Anterior transpetrosal approach: experiences in 274 cases over 33 years. Technical variations, operated patients, and approach-related complications

Tomio R, Horiguchi T, Borghei-Razavi H, Tamura R, Yoshida K, Kawase T

J Neurosurg 13 1 - 9 2021

Research paper (scientific journal), Accepted

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) 10 2020.11

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.

Access to Document (DOI)

Historic overview of genetic engineering technologies for human gene therapy

Tamura R., Toda M.

Neurologia Medico-Chirurgica (Neurologia Medico-Chirurgica) 60 ( 10 ) 483 - 491 2020.10

ISSN 04708105

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.

Access to Document (DOI)

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 2020.09

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.

Access to Document (DOI)

Current understanding of lymphatic vessels in the central nervous system

Tamura R., Yoshida K., Toda M.

Neurosurgical Review (Neurosurgical Review) 43 ( 4 ) 1055 - 1064 2020.08

ISSN 03445607

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.

Access to Document (DOI)

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

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

Acta Neurochirurgica (Acta Neurochirurgica) 162 ( 6 ) 1243 - 1248 2020.06

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.

Access to Document (DOI)

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.

Experimental and Molecular Pathology (Experimental and Molecular Pathology) 114 2020.06

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.

Access to Document (DOI)

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., Noji S., Kawakami Y., Sasaki H., Yoshida K., Toda M.

BMC Cancer (BMC Cancer) 20 ( 1 ) 2020.03

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.

Access to Document (DOI)

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.

Human Gene Therapy (Human Gene Therapy) 31 ( 5-6 ) 352 - 366 2020.03

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.

Access to Document (DOI)

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

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

World Neurosurgery (World Neurosurgery) 134 e1099 - e1107 2020.02

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.

Access to Document (DOI)

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.

Journal of Neuro-Oncology (Journal of Neuro-Oncology) 146 ( 2 ) 265 - 273 2020.01

ISSN 0167594X

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.

Access to Document (DOI)

Tumor immune microenvironment is associated with the growth of intracranial germinomas

Nishimoto M., Ohara K., Kamamoto D., Tamura R., Miwa T., Yoshida K., Sasaki H.

Journal of Neuro-Oncology (Journal of Neuro-Oncology) 146 ( 1 ) 139 - 146 2020.01

ISSN 0167594X

Introduction: The role of immune checkpoint molecules and the tumor immune microenvironment in the development of intracranial germ cell tumors remains unclear. Methods: We investigated the expression of programed cell death-1 (PD-1), programed cell death ligand-1 (PD-L1), and tumor-infiltrating lymphocytes (TILs) in 8 patients who had intracranial germinomas with sufficient tumor tissue by immunohistochemistry, to analyze the associations between their clinical courses and radiological features. The 8 patients were categorized based on the duration between symptom onset and pathological diagnosis into the long-term onset (LTO) group (> 1 year of symptoms) and the short-term onset (STO) group (< 1 year of symptoms). Results: Three patients belonged to the LTO group and 5 patients to the STO group. Compared with STO tumors, LTO tumors were significantly associated with a lower ratio of PD-L1–positive tumor cells (p = 0.012), higher number of infiltrating CD3- and CD8-positive lymphocytes (p = 0.016, 0.003, respectively), and lower ratio of PD-1–positive cells per CD8-positive lymphocytes (p = 0.047). LTO germinomas were significantly smaller in size than STO tumors, not associated with hydrocephalus, and tended to be present in patients with older age at diagnosis and atypical tumor location. Conclusions: Our data suggest that the tumor immune microenvironment, including PD-1/PD-L1 signaling, is associated with the growth of intracranial germinomas.

Access to Document (DOI)

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

Tamura R., Tanaka T., Akasaki Y., Murayama Y., Yoshida K., Sasaki H.

Medical Oncology (Medical Oncology) 37 ( 1 ) 2020.01

ISSN 13570560

The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological “cold tumors” into the “hot tumors”. Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

Access to Document (DOI)

Long-term clinical outcome of first recurrence skull base meningiomas

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

Journal of Clinical Medicine (Journal of Clinical Medicine) 9 ( 1 ) 2020.01

Skull base meningiomas (SBMs) are considered to be less aggressive and have a slower growth rate than non-SBMs. However, SBMs often develop local recurrences after surgical resection. Gross total removal is difficult because SBMs are deep-seated tumors and involve critical neurovascular structures. The treatment strategy for recurrent SBMs remains controversial. The present study aimed to evaluate the long-term clinical course and prognostic factors associated with shorter progression-free survival (PFS) of recurrent SBMs. This retrospective study included 85 recurrent SBMs from 65 patients who underwent surgery from January 2005 to September 2018. Overall survival (OS) and PFS were evaluated, and the associations among shorter PFS and age, sex, tumor size, lesions, World Health Organization (WHO) grading, removal rate, and time since prior surgery were analyzed. The median follow-up period for PFS was 68 months. The 2-, 5-, and 10-year PFS rates were 68.0%, 52.8%, and 22.7%, respectively. WHO grade II or III, multiple lesions, and tumor size were significantly associated with shorter PFS (p < 0.0001, p = 0.030, and p = 0.173, respectively). Although, radiotherapy did not improve PFS and OS for overall patients, PFS of the patients with subtotal and partial removal for WHO grade II SBMs was significantly improved by the radiotherapy. Multivariate analysis identified WHO grade II or III and multiple lesions as independent prognostic factors for shorter PFS (p < 0.0001 and p = 0.040, respectively). It is essential to estimate the risks associated with shorter PFS for patients with recurrent SBMs to aid in the development of appropriate postoperative strategies.

Access to Document (DOI)

Recent progress in stem cell research of the pituitary gland and pituitary adenoma

Toda M, Tamura R, Toda M

Endocrines 1 49 - 57 2020

Research paper (scientific journal), Accepted

Alterations of the tumor microenvironment in glioblastoma following radiation and temozolomide with or without bevacizumab

Tamura R, Tanaka T, Morimoto Y, Kuranari Y, Yamamoto Y, Takei J, Murayama Y, Yoshida K and Sasaki H

Annal Transl Med 8 297 2020

Research paper (scientific journal), Accepted

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., Noji S., Oishi N., Ogawa K., Kawakami Y., Ohira T., Yoshida K., Toda M.

Nature Communications (Nature Communications) 10 ( 1 ) 2019.12

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

Access to Document (DOI)

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 Neurosurgery (World Neurosurgery) 132 e554 - e562 2019.12

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.

Access to Document (DOI)

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 2019.09

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.

Access to Document (DOI)

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 2019.08

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.

Access to Document (DOI)

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.

Endocrine Pathology (Endocrine Pathology) 30 ( 2 ) 81 - 89 2019.06

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.

Access to Document (DOI)

Visualization of spatiotemporal dynamics of human glioma stem cell invasion

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

Molecular Brain (Molecular Brain) 12 ( 1 ) 2019.05

Glioblastoma exhibits phenotypic and genetic heterogeneity, aggressive invasiveness, therapeutic resistance, and tumor recurrence, which can be explained by the existence of glioma stem cells (GSCs). In this study, we visualized the spatiotemporal dynamics of invasion of human GSCs in an orthotopic xenograft mouse model using time-lapse imaging of organotypic brain slice cultures and three-dimensional imaging of optically cleared whole brains. GSCs implanted in the striatum exhibited directional migration toward axon bundles, perivascular area, and the subventricular zone around the inferior horn of the lateral ventricle. GSCs migrated in a helical pattern around axon bundles in the striatum and invaded broadly in both the rostral and caudal directions. GSCs in the corpus callosum migrated more rapidly and unidirectionally toward the contralateral side with pseudopod extension. These characteristics of GSC invasion shared histological features observed in glioblastoma patients. Spatiotemporal visualization techniques can contribute to the elucidation of the mechanisms underlying GSC invasion that may lead to the development of effective therapy for glioblastoma.

Access to Document (DOI)

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.

Journal of Clinical Medicine (Journal of Clinical Medicine) 8 ( 5 ) 2019.05

Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been examined for PitNETs. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is strongly associated with the tumor immune microenvironment. In the present study, these molecular and histopathological characteristics were examined in invasive non-functional PitNETs (NF-PitNETs). Twenty-seven patients with newly diagnosed NF-PitNETs (with CS invasion: 17, without CS invasion: 10) were analyzed by immunohistochemistry for VEGF-A/VEGFR1 and 2, hypoxia-inducible Factor (HIF), tumor-infiltrating lymphocytes, immunosuppressive cells including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and immune checkpoint molecules. Previously validated tumor proliferation markers including mitotic count, Ki-67 index, and p53 were also analyzed for their expressions in NF-PitNETs. VEGF-A and VEGFR1 were expressed on not only vascular endothelial cells, but also on tumor cells. The expressions of VEGF-A and VEGFR1 were significantly higher in NF-PitNETs with CS invasion. The number of TAMs and the expression of PD-L1 were also significantly higher in NF-PitNETs with CS invasion than in NF-PitNETs without CS invasion. The high expression of VEGF-A and VEGFR1 and associated immunosuppressive microenvironment were observed in NF-PitNETs with CS invasion, suggesting that a novel targeted therapy can be applied.

Access to Document (DOI)

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

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

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 20 ( 4 ) 2019.02

ISSN 16616596

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

Access to Document (DOI)

A pilot study of vaccine therapy withmultiple 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.

Journal of Clinical Medicine (Journal of Clinical Medicine) 8 ( 2 ) 2019.02

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.

Access to Document (DOI)

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

Tamura R., Tanaka T., Ohara K., Miyake K., Morimoto Y., Yamamoto Y., Kanai R., Akasaki Y., Murayama Y., Tamiya T., Yoshida K., Sasaki H.

Cancer Science (Cancer Science) 110 ( 2 ) 499 - 508 2019.02

ISSN 13479032

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P <.01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P <.01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P <.01; CD8, P =.06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P <.01 for each; CD163, P <.01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.

Access to Document (DOI)

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

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

Journal of Neurosurgery (Journal of Neurosurgery) 130 ( 2 ) 360 - 367 2019.02

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.

Access to Document (DOI)

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

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

Surgical Neurology International (Surgical Neurology International) 10 2019

Background: Endoscopic endonasal transsphenoidal surgery (EES) is the gold standard for pituitary adenoma (PA) resection. The sphenoid sinus (SS), a highly variable anatomic structure, is located in the center of the cranial base. It has previously been reported that poor pneumatization of the lateral recess of the SS (LRSS) increases the difficulty level of the surgery and the risk of neural and vascular injury. However, to date no studies have evaluated the association between LRSS volume and PAs removal rate by EES. Methods: The present study analyzed 23 consecutive patients with new-onset PAs categorized as Knosp Grades 3 and 4 who underwent EES. A retrospective radiographic analysis was conducted on patients undergoing magnetic resonance imaging and high-resolution computed tomography scans. Results: Among PA cases categorized as Knosp 3 and 4, no significant association was found between the whole tumor's resection rate and LRSS volume (R = 0.08, P = 0.70). However, a significant association was found between cavernous sinus (CS) tumors' removal rate and LRSS volume (R = 0.52, P = 0.011). The same results were achieved in PAs with a Knosp Grade 4, with a stronger correlation (R = 0.60, P = 0.014). Conclusion: The development of LRSS pneumatization affects the removal rate of CS tumors in PAs. Preoperative analysis of LRSS development should be considered when planning EES against PA with CS invasion.

Access to Document (DOI)

Surgical management of trigeminal schwannomas: Preservation of the trigeminal nerve

Toda M., Tamura R., Yoshida K.

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

ISSN 0917950X

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

Access to Document (DOI)

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

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

World Neurosurgery (World Neurosurgery) 120 e601 - e610 2018.12

ISSN 18788750

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

Access to Document (DOI)

Dual role of macrophage in tumor immunity

Tamura R., Tanaka T., Yamamoto Y., Akasaki Y., Sasaki H.

Immunotherapy (Immunotherapy) 10 ( 10 ) 899 - 909 2018.08

ISSN 1750743X

Macrophages are significant in immune responses, assuming a defensive role. In contrast, macrophages often cause undesirable changes. These reactions are processes by which macrophages express different functional programs in response to microenvironmental signals, defined as M1/M2 polarization. Tumor immunity has been acknowledged for contributing to the elucidation of the mechanism and clinical application in cancer therapy. One of the mechanisms for the refractoriness to cancer immunotherapy is the production of inhibitory cytokines by tumor cells or macrophages. Therefore, therapeutic strategy targeting macrophage or macrophage-derived cytokines may be effective and attractive. This review aims to investigate macrophage-associated pathophysiology and biological behavior in cancers, especially related to microenvironment, such as hypoxia, and current topics regarding some therapies involving macrophages.

Access to Document (DOI)

Histopathological vascular investigation of the peritumoral brain zone of glioblastomas

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

Journal of Neuro-Oncology (Journal of Neuro-Oncology) 136 ( 2 ) 233 - 241 2018.01

ISSN 0167594X

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

Access to Document (DOI)

Severe headache in a patient with meningioma showing extensive dural tail correlates with IgG4-positive plasma cells and eosinophils: A case report and review of literature

Kuranari Y., Tamura R., Mikami S., Ohara K., Toda M., Yoshida K.

Surgical Neurology International (Surgical Neurology International) 9 ( 1 ) 2018

Background: Meningiomas originate from meningothelial cells of the arachnoid membrane. Few cases of meningioma with infiltration of inflammatory cells, such as lymphocytes and plasma cells, have been reported, and the mechanisms underlying meningioma-induced inflammatory reactions have not been fully elucidated. Case Description: In this study, we report an extremely rare case of meningioma with infiltration of both IgG4-positive plasma cells and eosinophils showing extensive dural tail and reactive inflammation of the surrounding arachnoid tissue. The main clinical manifestation was a severe headache, which was improved by surgical excision of the tumor. Conclusion: Only 8 cases of meningioma with IgG4-positive plasma cells have been reported, and only one case exhibited eosinophil infiltration. IgG4-related inflammatory response might mediate inflammation in surrounding tissue, resulting in thickening of the dura adjacent to a meningioma and severe headache. The mechanisms underlying inflammation by meningiomas require further investigation.

Access to Document (DOI)

Stem cell-based therapies for neurological disorders

Tamura R, Toda M

AIMS Cell and Tissue Engineering 2 24 - 47 2018

Research paper (scientific journal), Accepted

Crowned Dens Syndrome Occurred in a Patient after Simple Drainage for Chronic Subdural Hematoma: A Case Report.

Tamura R, Takahashi S, Kamamoto D, Horikoshi T, and Yoshida K

NMC Case Rep J 4 15 - 17 2017

Research paper (scientific journal), Accepted

Paradoxical findings of tumor vascularity and oxygenation in recurrent glioblastomas refractory to bevacizumab

Yamamoto Y. Tamura R. Tanaka T. Ohara K. Tokuda Y. Miyake K. Takei J. Akasaki Y. Yoshida K. Murayama Y. Sasaki H

Oncotarget 8 103890 - 103899 2017

Research paper (scientific journal), Accepted

A case of acute subdural hematoma due to bleeding from metastatic chondrosarcoma of the skull

Kosugi K, Takahashi S, Sasaki H, Tamura R, Ohara K, Yoshida K

Surg Neurol Int 8 23 2017

Research paper (scientific journal), Accepted

nusual Magnetic Resonance Imaging Findings of a Glioblastoma Arising During Treatment with Lenvatinib for Thyroid Cancer

Arai N, Sasaki H, Tamura R, Ohara K, Yoshida K

World Neurosurg 107 1047.e9 - 1047.e15 2017

Research paper (scientific journal), Accepted

Diagnosis and Treatment for Pure Aqueductal Tumor

Tamura R, Miwa T, Ohira T, Yoshida K

J Clin Neurosci 44 260 - 263 2017

Research paper (scientific journal), Accepted

Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response

Tamura R, Tanaka T, Miyake K, Yoshida K, Sasaki H

Brain Tumor Pathol 34 62 - 77 2017

Research paper (scientific journal), Accepted

A case of glioblastoma resected immediately after administering bevacizumab: consideration on histopathological findings and safety of surgery.

Tokuda Y, Tamura R, Ohara K, Yoshida K, Sasaki H

Brain Tumor Pathol 34 98 - 102 2017

Research paper (scientific journal), Accepted

Leukoencephalopathy, cerebral calcifications, and cysts: a clinical case involving a long-term follow-up and literature review.

Tamura R, Ohira T, Emoto K, Fujiwara H, Horikoshi T, Yoshida K

J Neurol Sci 373 60 - 65 2017

Research paper (scientific journal), Accepted

Improvement of long‑term blindness caused by compression from inner‑third sphenoid wing meningioma after optic canal decompression: An extremely rare case report

Tamura R, Takahashi S, Horikoshi T, Yoshida K

Surg Neurol Int 7 67 2016

Research paper (scientific journal), Accepted

Endonasal endoscopic approach for a giant cavernous sinus meningioma that extended to the middle cranial fossa with preoperative embolization

Tamura R, Toda M, Kohno M, Ozawa H, Tomita T, Akiyama T, Ogawa K, Yoshida K

Interdiscip Neurosurg 6 20 - 22 2016

Research paper (scientific journal), Accepted

Simultaneous decompression of the orbital lateral wall and optic canal for fibrous dysplasia in early adolescence

Tamura R, Miwa T, Sakamoto Y, Kohno M, Kishi K, Yoshida K

Splingerplus 5 719 2016

Research paper (scientific journal), Accepted

Histopathological investigation of glioblastomas resected under bevacizumab treatment.

Tamura R, Tanaka T, Miyake K, Tabei Y, Ohara K, Sampetrean O, Kono M, Mizutani K, Yamamoto Y, Murayama Y, Tamiya T, Yoshida K, Sasaki H.

Oncotarget 7 52423 - 52435 2016

Research paper (scientific journal), Accepted

Neuro-endoscopic removal of acute subdural hematoma with contusion: advantages for elderly patients.

Tamura R, Nakamura Y, Kuroshima Y

Case Rep Neurol Med 2016 2056190 2016

Research paper (scientific journal), Accepted

Vascularized middle turbinate flap for the endoscopic endonasal reconstruction of the anterior olfactory groove.

Tamura R, Toda M, Kohno M, Watanabe Y, Ozawa H, Tomita T, Ogawa K, Yoshida K.

Neurosurg Rev 39 297 - 302 2016

Research paper (scientific journal), Accepted

Giant Cell Tumor of the Skull: Review of the Literature.

Tamura R, Miwa T, Shimizu K, Mizutani K, Tomita H, Yamane N, Tominaga T, Sasaki S.

J Neurol Surg A Cent Eur Neurosurg 77 239 - 246 2016

Research paper (scientific journal), Accepted

A case of arthrorheumatism with methotrexate-associated lymphoproliferative disorder in the brain.

Tamura R, Nakamura Y, Kuroshima Y.

J Neurosurg Sci 60 400 - 401 2016

Research paper (scientific journal), Accepted

Intraosseous Schwannoma of the Petrous Apex.

Tamura R, Takahashi S, Kohno M, Kameyama K, Fujiwara H, Yoshida K

J Neurol Surg Rep 76 135 - 139 2015

Research paper (scientific journal), Accepted

GH-Producing Pituitary Adenoma and Concomitant Rathke's Cleft Cyst: A Case Report and Short Review.

Tamura R, Takahashi S, Emoto K, Nagashima H, Toda M, Yoshida K.

Case Rep Neurol Med 2015 948025 2015

Research paper (scientific journal), Accepted

The new way to predict recurrence of chronic subdural hematoma.

Tamura R, Nakamura Y, Kuroshima Y

Geriatric Neurosurgery 27 107 - 111 2014

Research paper (scientific journal), Accepted

Primary neuroendocrine tumor in brain.

Tamura R, Kuroshima Y, Nakamura Y.

Case Rep Neurol Med 2014 295253 2014

Research paper (scientific journal), Accepted

The importance of amyloid β protein in cerebrospinal fluid when you recognize convexal subarachnoid hemorrhage.

Tamura R, Tomita H, Mizutani K, Miwa T.

Eur Neurol 71 283 - 287 2014

Research paper (scientific journal), Accepted

Low-grade meningioma showing nearly equal density with spinal fluid on radiographic images.

Tamura R, Tomita H, Shimizu K, Sugiyama K.

BMJ Case Rep 2013 bcr2013009554 2013

Research paper (scientific journal), Accepted

　 Previous page - Next page 　