研究者詳細 - 齋藤　竜太

論文 - 齋藤　竜太

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脳腫瘍における基礎研究とトランスレーショナルリサーチの最新の知見マルチオミクス解析が明らかにする悪性神経膠腫の腫瘍間・腫瘍内多様性(Advances in basic and translational research in brain tumors Multi-omics analysis dissecting the intra- and inter-tumoral heterogeneity underlying glioblastoma pathogenesis)

中島拓真, 舟越勇介, 畝田篤仁, 南部翔平, 田中將太, 石田穣治, 齋藤竜太, 花谷亮典, 吉本幸司, 成田善孝, 鈴木啓道

日本癌学会総会記事 82回巻頁： 1691 - 1691 2023年9月

再生医療実現に向けたヒト多能性幹細胞由来下垂体細胞の皮下移植

佐々木博勇, 須賀英隆, 竹内和人, 永田雄一, 原田英幸, 近藤辰磨, 伊藤英治, 有馬寛, 齋藤竜太

日本内分泌学会雑誌 99 巻 ( S.HPT ) 頁： 4 - 6 2023年8月

特集覚醒下手術の最前線--臨床的意義と神経科学言語機能温存を目指したlower grade gliomaに対する覚醒下手術

本村和也, 齋藤竜太

医学のあゆみ 286 巻 ( 9 ) 頁： 707 - 713 2023年8月

TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation 査読有り国際誌 Open Access

Suzuki, MM; Iijima, K; Ogami, K; Shinjo, K; Murofushi, Y; Xie, JQ; Wang, XB; Kitano, Y; Mamiya, A; Kibe, Y; Nishimura, T; Ohka, F; Saito, R; Sato, S; Kobayashi, J; Yao, R; Miyata, K; Kataoka, K; Suzuki, HI; Kondo, Y

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 4521 - 4521 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

DOI： 10.1038/s41467-023-40243-8

Real-world data of clazosentan in combination therapy for aneurysmal subarachnoid hemorrhage: a multicenter retrospective cohort study 査読有り国際誌

Muraoka, S; Asai, T; Fukui, T; Ota, S; Shimato, S; Koketsu, N; Nishizawa, T; Araki, Y; Saito, R

NEUROSURGICAL REVIEW 46 巻 ( 1 ) 頁： 195 - 195 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neurosurgical Review

Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm, significantly associated with morbidity and mortality. In double-blind, placebo-controlled phase 3 studies, clazosentan reduces cerebral vasospasm-related morbidity and all-cause mortality in patients with aSAH. There are no reports about the clinical efficacy of clazosentan combination therapy with some other drugs. Initially, we explored the efficacy of clazosentan combination therapy with cilostazol, statin, and antiepileptic drugs. Subsequently, we assessed the add-on effect of fasudil to clazosentan combination therapy for aSAH patients. This multicenter, retrospective, observational cohort study included Japanese patients with aSAH between June 2022 and March 2023. The primary outcome was the ordinal score on the modified Rankin Scale (mRS; range, 0–6, with elevated scores indicating greater disability) at discharge. Among the 47 cases (women 74.5%; age 64.4 ± 15.0 years) undergoing clazosentan combination therapy, 29 (61.7%) resulted in favorable outcomes. Overall, vasospasm occurred in 16 cases (34.0%), with four cases (8.5%) developing vasospasm-related delayed cerebral ischemia (DCI). Both hypotension and vasospasm-related DCI were related to unfavorable outcome at discharge. Fasudil were added in 18 (38.3%) cases. Despite adding fasudil to clazosentan combination therapy, the incidence of aSAH-related vasospasm did not decrease. Added-on fasudil to combination therapy related to pulmonary edema, vasospasm, and vasospasm-related DCI, and unfavorable outcomes. Clazosentan combination therapy could potentially result in favorable outcomes for aSAH patients to prevent post-aSAH vasospasm-related DCI. The add-on effect of fasudil to combination therapy did not demonstrate a significant impact in reducing aSAH-related vasospasm or improving outcomes at discharge.

DOI： 10.1007/s10143-023-02104-2

Moyamoya disease-specific extracellular vesicle-derived microRNAs in the cerebrospinal fluid revealed by comprehensive expression analysis through microRNA sequencing 査読有り国際誌 Open Access

Ota, S; Yokoyama, K; Kanamori, F; Mamiya, T; Uda, K; Araki, Y; Wakabayashi, T; Yoshikawa, K; Saito, R

ACTA NEUROCHIRURGICA 165 巻 ( 8 ) 頁： 2045 - 2055 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Acta Neurochirurgica

Purpose: To examine the specific changes that occur in the expression levels of extracellular vesicle-derived microRNAs (miRNAs) in intracranial cerebrospinal fluid (CSF) in moyamoya disease. Methods: Patients with arteriosclerotic cerebral ischemia were used as controls to eliminate the effects of cerebral ischemia. Intracranial CSF was collected from moyamoya disease and control patients during bypass surgery. Extracellular vesicles (EVs) were extracted from the CSF. Comprehensive expression analysis of miRNAs extracted from EVs by next-generation sequencing (NGS) and validation by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed. Results: Experiments were conducted on eight cases of moyamoya disease and four control cases. In the comprehensive miRNA expression analysis, 153 miRNAs were upregulated, and 98 miRNAs were downregulated in moyamoya disease compared to the control cases (q-value < 0.05 and |log2 fold change|> 1). qRT-PCR performed on the four most variable miRNAs (hsa-miR-421, hsa-miR-361-5p, hsa-miR-320a, and hsa-miR-29b-3p) associated with vascular lesions among the differentially expressed miRNAs gave the same results as miRNA sequencing. On gene ontology (GO) analysis for the target genes, cytoplasmic stress granule was the most significant GO term. Conclusions: This study is the first comprehensive expression analysis of EV-derived miRNAs in the CSF of moyamoya disease patients using NGS. The miRNAs identified here may be related to the etiology and pathophysiology of moyamoya disease.

DOI： 10.1007/s00701-023-05579-6

Latest classification of ependymoma in the molecular era and advances in its treatment: a review 招待有り査読有り国際誌 Open Access

Yamaguchi, J; Ohka, F; Motomura, K; Saito, R

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 53 巻 ( 8 ) 頁： 653 - 663 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Clinical Oncology

Ependymoma is a rare central nervous system (CNS) tumour occurring in all age groups and is one of the most common paediatric malignant brain tumours. Unlike other malignant brain tumours, ependymomas have few identified point mutations and genetic and epigenetic features. With advances in molecular understanding, the latest 2021 World Health Organization (WHO) classification of CNS tumours divided ependymomas into 10 diagnostic categories based on the histology, molecular information and location; this accurately reflected the prognosis and biology of this tumour. Although maximal surgical resection followed by radiotherapy is considered the standard treatment method, and chemotherapy is considered ineffective, the validation of the role of these treatment modalities continues. Although the rarity and long-term clinical course of ependymoma make designing and conducting prospective clinical trials challenging, knowledge is steadily accumulating and progress is being made. Much of the clinical knowledge obtained from clinical trials to date was based on the previous histology-based WHO classifications, and the addition of new molecular information may lead to more complex treatment strategies. Therefore, this review presents the latest findings on the molecular classification of ependymomas and advances in its treatment.

DOI： 10.1093/jjco/hyad056

Surgical Outcomes of Common Peroneal Nerve Entrapment Neuropathy Associated with L5 Radiculopathy Open Access

Ishii, M; Nishimura, Y; Hara, M; Yamamoto, Y; Nagashima, Y; Tanei, T; Takayasu, M; Saito, R

NEUROLOGIA MEDICO-CHIRURGICA 63 巻 ( 8 ) 頁： 350 - 355 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neurologia Medico Chirurgica

Impingement of the common peroneal nerve, a branch of the L5 nerve root, causes common peroneal nerve entrapment neuropathy (CPNE). Although there are cases of CPNE associated with L5 radiculopathy, surgical intervention’s effectiveness remains to be elucidated. This retrospective case-control study aimed to evaluate the efficacy of surgery in patients with CPNE associated with L5 radiculopathy. Twenty-two patients (25 limbs) with surgically treated CPNE between 2015 and 2022 were retrospectively reviewed. The limbs were classified into two groups: group R (limbs of CPNE associated with L5 radiculopathy) and group O (limbs of CPNE without L5 radiculopathy). The durations from onset to surgery, the nerve conduction studies (NCSs), and postoperative improvement rates for motor weakness, pain, and dysesthesia were compared between the groups. Group R included 15 limbs (13 patients), and group O included 10 limbs (9 patients). There were no significant differences in the duration from onset to surgery or abnormal findings of NCS between the two groups. The postoperative improvement rates were 88% and 100% (p = 0.62) for muscle weakness, 87% and 80% (p = 0.53) for pain, and 71% and 56% (p = 0.37) for dysesthesia in group R and group O, respectively, without significant differences between groups. CPNE associated with L5 radiculopathy is common, and the results of the present study showed that the surgical outcomes in such cases were satisfactory and comparable to those in CPNE without L5 radiculopathy.

DOI： 10.2176/jns-nmc.2022-0313

【がんオルガノイド-創薬・個別化医療の革新的プレクリニカルモデルとして】脳腫瘍研究におけるオルガノイドモデルの現状と今後の可能性

山崎慎太郎, 大岡史治, 齋藤竜太

医学のあゆみ 286 巻 ( 7-8 ) 頁： 625 - 630 2023年8月

Direct Screw Osteosynthesis for an Elderly Osteoporotic Patient With C2 Complex Fracture 査読有り Open Access

Nagashima, Y; Nishimura, Y; Matsuo, M; Tanei, T; Saito, R

CUREUS JOURNAL OF MEDICAL SCIENCE 15 巻 ( 7 ) 頁： e42510 2023年7月

Brain metastasis and intracranial leptomeningeal metastasis from malignant peripheral nerve sheath tumors: illustrative cases 査読有り国際誌 Open Access

Ohno, M; Haimoto, S; Tsukushi, S; Hosoda, W; Ohka, F; Saito, R

JOURNAL OF NEUROSURGERY-CASE LESSONS 6 巻 ( 3 ) 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neurosurgery Case Lessons

OBSERVATIONS The authors report on a 73-year-old male whose MPNST metastasized to the brain and a 32-year-old male with leptomeningeal metastasis from MPNST and review 41 cases of MPNST that developed intracranial metastasis, as reported in the literature. LESSONS Brain metastasis and leptomeningeal metastasis of MPNSTs show different clinical courses and require pathology-specific treatment.

DOI： 10.3171/CASE23148

膠芽腫摘出における5-アミノレブリン酸による蛍光診断の意義

金森政之, 斎藤竜太, 下田由輝, 冨永悌二

日本レーザー医学会誌 44 巻 ( 2 ) 頁： 164 - 170 2023年7月

記述言語：日本語出版者・発行元：特定非営利活動法人日本レーザー医学会

<p>初発膠芽腫摘出における5-アミノレブリン酸（5-ALA）による蛍光診断所見と腫瘍制御の関係を明らかにすることを目的とした．当施設で5-ALAによる蛍光診断下に造影病変の可及的切除を施行した初発膠芽腫41例を対象とし，術中蛍光診断所見と術後造影の残存，再発部位について解析した．結果，蛍光病変全摘出はMRI上の造影病変全摘出と相関していた．さらに肉眼的全摘出・追加切除後の蛍光残存部分から再発する傾向が認められた．以上より，5-ALAによる蛍光診断所見から，術中の摘出度判断，および局所治療を強化すべき部位の推定につながる可能性が示唆された．</p>

DOI： 10.2530/jslsm.jslsm-44_0015

CiNii Research

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Surgical reconstruction for spheno-orbital meningioma extending into the sphenoid sinus with hyperostosis 査読有り国際誌 Open Access

Maki, T; Ito, E; Saito, K; Saito, R

CLINICAL CASE REPORTS 11 巻 ( 7 ) 頁： e7705 2023年7月

Two-Piece Craniotomy Is Associated With Improved Postoperative Outcomes of Combined Revascularization in Patients With Moyamoya Disease 査読有り Open Access

Kanamori, F; Takasu, S; Hatano, N; Araki, Y; Seki, Y; Saito, R

STROKE-VASCULAR AND INTERVENTIONAL NEUROLOGY 3 巻 ( 4 ) 頁： e000759 2023年7月

振戦優位型パーキンソン病(TD-PD)におけるMRガイド下集束超音波治療(MRgFUS)の適応判断と治療効果

中坪大輔, 津川隆彦, 加藤祥子, 前澤聡, 坪井崇, 鈴木将史, 鳥居潤, 武藤学, 伊藤芳記, 若林俊彦, 勝野雅央, 齋藤竜太

パーキンソン病・運動障害疾患コングレスプログラム・抄録集 17回巻頁： 101 - 101 2023年7月

Connectivity alteration in thalamic nuclei and default mode network-related area in memory processes in mesial temporal lobe epilepsy using magnetoencephalography 査読有り国際誌 Open Access

Ishizaki, T; Maesawa, S; Nakatsubo, D; Yamamoto, H; Torii, J; Mutoh, M; Natsume, J; Hoshiyama, M; Saito, R

SCIENTIFIC REPORTS 13 巻 ( 1 ) 頁： 10632 - 10632 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

This work aimed to investigate the involvement of the thalamic nuclei in mesial temporal lobe epilepsy (MTLE) and identify the influence of interictal epileptic discharges on the neural basis of memory processing by evaluating the functional connectivity (FC) between the thalamic nuclei and default mode network-related area (DMNRA) using magnetoencephalography. Preoperative datasets of nine patients with MTLE with seizure-free status after surgery and those of nine healthy controls were analyzed. The FC between the thalamic nuclei (anterior nucleus [ANT], mediodorsal nucleus [MD], intralaminar nuclei [IL]), hippocampus, and DMNRA was examined for each of the resting, pre-spike, spike, and post-spike periods in the delta to ripple bands using magnetoencephalography. The FC between the ANT, MD, hippocampus, and medial prefrontal cortex increased in the gamma to ripple bands, whereas the FC between the ANT, IL, and DMNRA decreased in the delta to beta bands, compared with that of the healthy controls at rest. Compared with the rest period, the pre-spike period had significantly decreased FC between the ANT, MD, and DMNRA in the ripple band. Different FC changes between the thalamic nuclei, hippocampus, and DMNRA of specific connections in a particular band may reflect impairment or compensation in the memory processes.

DOI： 10.1038/s41598-023-37834-2

Differential target multiplexed spinal cord stimulation using a paddle-type lead placed at the appropriate site for neuropathic pain after spinal cord injury in patients with past spinal surgical histories: study protocol for an exploratory clinical trial 査読有り国際誌 Open Access

Tanei, T; Maesawa, S; Nishimura, Y; Nagashima, Y; Ishizaki, T; Ando, M; Kuwatsuka, Y; Hashizume, A; Kurasawa, S; Saito, R

TRIALS 24 巻 ( 1 ) 頁： 395 - 395 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Trials

Background: Neuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation. Methods: A single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: (1) effectiveness of DTM and tonic stimulations during the SCS trial; (2) changes of assessment items from 1 to 24 months; (3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; (4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and (5) whether gait function improves from 1 to 24 months. Discussion: A paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories. Trial registration: Japan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07433-7

Rapid detection of the <i>MYD88</i> L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma 査読有り国際誌 Open Access

Yamaguchi, J; Ohka, F; Kitano, Y; Maeda, S; Motomura, K; Aoki, K; Takeuchi, K; Nagata, Y; Hattori, H; Tsujiuchi, T; Motomura, A; Nishikawa, T; Kibe, Y; Shinjo, K; Kondo, Y; Saito, R

CANCER SCIENCE 114 巻 ( 6 ) 頁： 2544 - 2551 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.

DOI： 10.1111/cas.15762

Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study 査読有り国際誌

Shiba, Y; Motomura, K; Taniguchi, R; Kurimoto, M; Mizutani, K; Ohka, F; Aoki, K; Ito, E; Nishikawa, T; Yamaguchi, J; Kibe, Y; Shimizu, H; Maeda, S; Nakashima, T; Suzuki, H; Muramatsu, H; Takahashi, Y; Saito, R

JOURNAL OF NEUROSURGERY-PEDIATRICS 31 巻 ( 6 ) 頁： 624 - 632 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neurosurgery Pediatrics

OBJECTIVE This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse. METHODS The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma. RESULTS The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics. CONCLUSIONS This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

DOI： 10.3171/2023.1.PEDS22345

当院における過去15年の小児・AYA世代上衣腫の治療成績

山口純矢, 芝良樹, 栗本路弘, 鈴木一秋, 清水大輝, 平松拓, 木部祐士, 大岡史治, 本村和也, 齋藤竜太

日本小児血液・がん学会雑誌 60 巻 ( 1 ) 頁： 78 - 78 2023年6月

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