Faculty Profiles - SAITO Ryuta

Rapid detection of mutation in isocitrate dehydrogenase 1 and 2 genes using mass spectrometry. Reviewed

Masayuki Kanamori, Masamitsu Maekawa, Ichiyo Shibahara, Ryuta Saito, Masashi Chonan, Miki Shimada, Yukihiko Sonoda, Toshihiro Kumabe, Mika Watanabe, Nariyasu Mano, Teiji Tominaga

Brain tumor pathology Vol. 35 ( 2 ) page： 90 - 96 2018.4

Language：English Publishing type：Research paper (scientific journal)

The 2016 World Health Organization classification of tumors of the central nervous system was recently revised. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and chromosome 1p/19q codeletion are especially important for both the integrated diagnosis and the determination of surgical strategy. To establish a method for intraoperative molecular diagnosis, a simple, rapid method was developed for the measurement of 2-hydroxyglutarate (2-HG), a specific oncometabolite formed in the presence of IDH gene mutation, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). This method requires only 10 min to measure the level of 2-HG from tissue preparation to completion of examination. Using this method, the level of 2-HG was analyzed in 105 patients with diffuse infiltrating glioma, and showed that IDH mutated glioma had significantly higher level of 2-HG compared to IDH wild-type glioma. Receiver operating characteristic curve analysis showed the area under the curve, sensitivity, and specificity were 0.9815, 97.5, and 100%, respectively. In contrast, tumor grade and presence of chromosome 1p/19q codeletion in the IDH mutated glioma could not be predicted from the level of 2-HG. Measurement of 2-HG level using LC/ESI-MS/MS can provide rapid and accurate information of mutation status in the IDH gene.

DOI： 10.1007/s10014-018-0317-0

Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model. Reviewed International journal

Shinya Haryu, Ryuta Saito, Wenting Jia, Takuhiro Shoji, Yui Mano, Aya Sato, Masayuki Kanamori, Yukihiko Sonoda, Oltea Sampetrean, Hideyuki Saya, Teiji Tominaga

Journal of neuro-oncology Vol. 136 ( 1 ) page： 23 - 31 2018.1

Language：English Publishing type：Research paper (scientific journal)

Expression of CD44 in glioma cells was previously correlated with tumor grade and is considered a stem cell marker. CD44 stabilizes the cystine-glutamate transporter (xCT) and inhibits apoptosis in cancer stem cells (CSCs). Recently it was found that Sulfasalazine (SSZ), an anti-inflammatory drug, acts as an inhibitor of xCT and therefore has potential as a targeted therapy for CSCs. In this study, we tested an efficacy of SSZ against glioma stem cell model developed in rats. As poor penetration of blood-brain barrier resulted in insufficient efficacy of systemic SSZ treatment, SSZ was delivered locally with convection-enhanced delivery (CED). In vitro, expression of CD44 in glioma cells and efficacy of SSZ against glioma cells and glioma stem cells were confirmed. SSZ demonstrated anti-proliferative activity in a dose dependent manner against these cells. This activity was partially reversible with the addition of antioxidant, N-acetyl-L-cysteine, to the medium. In vivo, CED successfully delivered SSZ into the rat brain parenchyma. When delivered at 5 mM concentration, which was the highest possible concentration when SSZ was dissolved in water, CED of SSZ resulted in almost no tissue damage. Against highly malignant bRiTs-G3 brain tumor xenografted rat model; the glioma stem cell model, CED of SSZ at 5 mM concentration induced apoptosis and prolonged survival. Consequently, CED of SSZ induced glioma stem cell death without evidence of tissue damage to normal brain parenchyma. This strategy may be a promising targeted treatment against glioma stem cells.

DOI： 10.1007/s11060-017-2621-7

Fingolimod-associated PML with mild IRIS in MS: A clinicopathologic study. Reviewed International journal Open Access

Shuhei Nishiyama, Tatsuro Misu, Yukiko Shishido-Hara, Kazuo Nakamichi, Masayuki Saijo, Yoshiki Takai, Kentarou Takei, Naoki Yamamoto, Hiroshi Kuroda, Ryuta Saito, Mika Watanabe, Teiji Tominaga, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

Neurology(R) neuroimmunology & neuroinflammation Vol. 5 ( 1 ) page： e415 2018.1

Language：English Publishing type：Research paper (scientific journal)

Objective: To clarify the clinical, neuropathologic, and virologic characteristics of progressive multifocal leukoencephalopathy (PML) and its immune reconstitution inflammatory syndrome (IRIS) in a patient with fingolimod-treated MS. Methods: A case study. Results: A 34-year-old patient with MS using fingolimod for 4 years had a gradual progression of right hemiparesis and aphasia with a new subcortical white matter lesion in the precentral gyrus by initial MRI. Blood tests were normal, except for lymphopenia (160 cells/μL). One month after the cessation of fingolimod, brain MRI depicted a diffusely exacerbated hyperintensity on fluid-attenuated inversion recovery and diffusion-weighed imaging in the white matter with punctate gadolinium enhancement, suggesting PML-IRIS. A very low level of JC virus (JCV)-DNA (15 copies/mL) was detected in the CSF as judged by quantitative PCR. Brain tissues were biopsied from the left frontal lesion, which showed some small demyelinated foci with predominant loss of myelin-associated glycoprotein with infiltrations of lymphocytes and macrophages, but clear viral inclusion was not observed with hematoxylin-eosin staining. JCV-DNA was uniquely detectable in an active inflammatory demyelinating lesion by in situ hybridization, possibly suggesting an early phase of PML. DNA extracted from the brain sample was positive for JCV-DNA (151 copies/cell). It took 3 months to normalize the blood lymphocyte count. The patient was treated with 1 g of IV methylprednisolone for 3 days and a weekly oral dose (375 mg) of mefloquine, and her symptoms gradually improved. Conclusion: Low CSF JCV-DNA and unfound viral inclusions initially made her diagnosis difficult. The clinical course of fingolimod-associated PML may be associated with mild immune reconstitution.

DOI： 10.1212/NXI.0000000000000415

Open Access

Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations. Reviewed

Ichiyo Shibahara, Yukihiko Sonoda, Hiroyoshi Suzuki, Akifumi Mayama, Masayuki Kanamori, Ryuta Saito, Yasuhiro Suzuki, Shoji Mashiyama, Hiroshi Uenohara, Mika Watanabe, Toshihiro Kumabe, Teiji Tominaga

Brain tumor pathology Vol. 35 ( 1 ) page： 10 - 18 2018.1

Language：English Publishing type：Research paper (scientific journal)

Pilocytic astrocytomas and low-grade gliomas are more common compared with glioblastomas in patients with neurofibromatosis 1 (NF1). A recent genome-wide analysis has shown frequent NF1 gene alterations in the mesenchymal subtype of a glioblastoma; however, little is known about clinicopathological features of glioblastomas in NF1 patients (NF1 glioblastomas). We analyzed four NF1 glioblastomas. Radiographical and intraoperative findings showed well-circumscribed tumors from surrounding brain. Pathological analysis presented a paucity of processes with an eosinophilic cytoplasm, bizarre nuclei, xanthomatous-like appearance, multinucleated giant cells, and histiocytoid appearance. During the follow-up period, one patient died at 49 months and others remained alive for 60, 87, and 106 months; thus, patients with NF1 glioblastoma presented a relatively favorable survival. None of the NF1 glioblastomas harbored isocitrate dehydrogenase 1 (IDH1) gene mutation, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation, and telomerase reverse transcriptase (TERT) gene promoter mutation. We identified that NF1 glioblastoma is a unique subset of glioblastoma.

DOI： 10.1007/s10014-017-0302-z

Opening the ventricle during surgery diminishes survival among patients with newly diagnosed glioblastoma treated with carmustine wafers: a multi-center retrospective study Reviewed International journal

Yukihiko Sonoda, Ichiyo Shibahara, Ken-ichiro Matsuda, Ryuta Saito, Tomoyuki Kawataki, Masaya Oda, Yuichi Sato, Hirokazu Sadahiro, Sadahiro Nomura, Toshio Sasajima, Takaaki Beppu, Masayuki Kanamori, Kaori Sakurada, Toshihiro Kumabe, Teiji Tominaga, Hiroyuki Kinouchi, Hiroaki Shimizu, Kuniaki Ogasawara, Michiyasu Suzuki

JOURNAL OF NEURO-ONCOLOGY Vol. 134 ( 1 ) page： 83 - 88 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efficacy. Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not significantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.

DOI： 10.1007/s11060-017-2488-7

Distant recurrences limit the survival of patients with thalamic high-grade gliomas after successful resection Reviewed International journal

Ryuta Saito, Toshihiro Kumabe, Masayuki Kanamori, Yukihiko Sonoda, Teiji Tominaga

NEUROSURGICAL REVIEW Vol. 40 ( 3 ) page： 469 - 477 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The indications of surgery for thalamic high-grade gliomas are not well established. The present study investigated the outcome of 21 patients treated by surgery and reports the high incidence of distant recurrences including disseminations after successful removal. Twenty-one patients with thalamic high-grade gliomas not invading the pyramidal tract or midbrain underwent cytoreductive surgery at our institute from June 1997 to August 2015. Surgery was performed with the aid of a neuronavigation system, electrophysiological monitoring, and fluorescence navigation. Tumor histology included 12 cases of the World Health Organization grade III and nine cases of grade IV. Gross total resection was achieved in six cases, subtotal in 13, and partial in two. Motor weakness accompanied by sensory disturbance deteriorated immediately after surgery in 13 patients. However, five patients were determined to show deterioration at 2 months after surgery. Postoperative radiation and chemotherapy were given to every patient, and median progression-free survival of patients with grade III and IV tumors was 12.1 and 7.0 months, respectively. Median overall survival of patients with grade III and IV tumors was 25.6 and 12.6 months, respectively. High incidence of distant recurrences was found, with distant lesions at recurrence in 13 of 19 patients with recurrence, suggesting the life-restricting factor in these patients. Thalamic high-grade glioma without invasion into the pyramidal tract and brainstem can be considered as a candidate for surgical resection. Distant lesion limits the survival of patients after successful resection.

DOI： 10.1007/s10143-016-0804-x

Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models Reviewed International journal

Shogo Ogita, Toshiki Endo, Shinichiro Sugiyama, Ryuta Saito, Tomoo Inoue, Akira Sumiyoshi, Hiroi Nonaka, Ryuta Kawashima, Yukihiko Sonoda, Teiji Tominaga

ACTA NEUROCHIRURGICA Vol. 159 ( 5 ) page： 939 - 946 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER WIEN

Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier.
To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model.
Toxicity studies were performed in 42 rats following the administration of 4 mu l of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically.
The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test).
ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.

DOI： 10.1007/s00701-017-3123-2

Intraoperative Visualization of Subependymal Arteries at the Atrium Supplying the Descending Motor Pathway Reviewed International journal

Mitsuto Hanihara, Sumito Sato, Ichiyo Shibahara, Ryuta Saito, Masayuki Kanamori, Yukihiko Sonoda, Hiroyuki Kinouchi, Teiji Tominaga, Toshihiro Kumabe

WORLD NEUROSURGERY Vol. 101 page： 296 - 303 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

OBJECTIVE: We previously disclosed that damage to the subependymal arteries (SEAs) caused by coagulation of the choroid plexus at the atrium can result in infarction within the lateral posterior choroidal artery territory, followed by hemiparesis. The present study describes the intra-operative anatomical findings of the SEAs and choroid plexus at the atrium, which were verified only by a few cadaveric studies.
METHODS: Locations of the SEA and descending motor pathway were determined with the neuronavigation system and subcortical electrical stimulation in 8 cases of periatrial brain tumor. Indocyanine green videoangiography was performed to verify the blood flowin the choroid plexus and SEAs.
RESULTS: Intraoperative visualization of the SEAs was performed successfully in all patients. The neuronavigation system and subcortical electrical stimulation mapping demonstrated that these SEAs penetrated into the descending motor pathway. Indocyanine green depicted the blood flow of the SEAs entering the wall of the lateral ventricle and adjacent brain parenchyma. The blood flow directions between the SEAs and choroid plexus were not uniform, because the SEAs were filled ahead of the choroid plexus in 3 cases, whereas the choroid plexus was filled first in the other 2 cases.
CONCLUSIONS: Manipulations to the inner side of the choroid plexus at the transition from the atrium to the body of lateral ventricle can damage the SEAs. Not only coagulation of the SEAs themselves, but also coagulation of choroid plexus itself may reduce the blood flow in the SEAs, resulting in ischemic complications at descending motor pathway.

DOI： 10.1016/j.wneu.2017.02.022