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

The goal of surgery for patients with newly diagnosed glioblastoma (GBM) is maximum safe resection of the contrast-enhancing (CE) lesion on magnetic resonance imaging. However, there is no consensus on the efficacy of FLAIRectomy, which is defined as the possible resection of fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions surrounding the CE lesion. Although retrospective analyses suggested the potential benefits of FLAIRectomy, such outcomes have not been confirmed by prospective studies. Therefore, we planned a multicenter, open-label, randomized controlled phase III trial to evaluate the efficacy of FLAIRectomy compared with gross total resection of CE lesions in patients with newly diagnosed GBM. The primary endpoint is overall survival. In total, 130 patients will be enrolled from 47 institutions over 5 years. This trial has been registered at the Japan Registry of Clinical Trials (study number jRCT1031230245).

DOI： 10.1093/jjco/hyae130

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Language：English   Publisher：(一社)日本癌学会  

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

BACKGROUND: Complete resection of contrast-enhanced lesions [gross total resection (GTR)] without severe neurological deficits has been generally accepted as the goal of surgery. However, it remains unclear if additional resection of surrounding fluid-attenuated inversion recovery (FLAIR) hyper-intense lesions combined with GTR (FLAIRectomy) has survival advantage of primary glioblastoma patients. Multicenter, open-label, randomized phase III trial was commenced to confirm the superiority of FLAIRectomy to GTR alone followed by radiotherapy with concomitant and adjuvant temozolomide in terms of overall survival (OS) for primary glioblastoma IDH-wildtype patients. This trial investigates not only survival but also postoperative neurological and neurocognitive deficits in detail. METHODS: We assumed a 2-year OS of 50% in the GTR arm and expected a 15% improvement in the FLAIRectomy arm. A total of 130 patients is required with a one-sided alpha of 5%, power of 70%, and will be accrued from 49 Japanese institutions in 4 years and follow-up will last 2.5 years. Patients aged 18-75 years will be registered and randomly assigned to each arm with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, proportion of National Institutes of Health stroke scale preservation, proportion of mini-mental state examination preservation and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in May 2023. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in July 2023. RESULTS: If FLAIRectomy is superior to GTR alone, aggressive surgery will become a standard surgical treatment for glioblastoma with resectable contrast-enhanced lesion. CONCLUSIONS: Registry number: jRCT1031230245. Date of registration: 19/July/2023. Date of first participant enrollment: 28/July/2023.

DOI： 10.21037/cco-24-ab012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term “midline” areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4–78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9–11.9, 95% CI) and 16.6 ± 1.4 (13.9–19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

DOI： 10.1186/s40478-024-01808-w

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Other Link： https://link.springer.com/article/10.1186/s40478-024-01808-w/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Purpose

Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility.

Methods

In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan.

Results

The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 − 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population.

Conclusion

This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas.

DOI： 10.1007/s11060-024-04727-x

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Other Link： https://link.springer.com/article/10.1007/s11060-024-04727-x/fulltext.html

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

PURPOSE: The contents of Rathke's cleft cysts (RCCs) vary from clear and slightly viscous to purulent. Surgical treatment of symptomatic RCCs involves removing the cyst contents, whereas additional cyst-wall opening to prevent reaccumulation is at the surgeon's discretion. The macroscopic findings of the cyst content can reflect the nature of RCCs and would aid in surgical method selection. METHODS: We retrospectively reviewed the records of 42 patients with symptomatic RCCs who underwent transsphenoidal surgery at our institute between January 2010 and March 2022. According to the intraoperative findings, cyst contents were classified into type A (purulent), type B (turbid white with mixed semisolids), or type C (clear and slightly viscous). Clinical and imaging findings and early recurrence rate (within two years) were compared according to the cyst content type. RESULTS: There were 42 patients classified into three types. Patients with type C were the oldest (65.4 ± 10.4 years), and type A included more females (92.9%). For magnetic resonance imaging, type-A patients showed contrast-enhanced cyst wall (92.9%), type-B patients had intracystic nodules (57.1%), and all type-C patients showed low T1 and high T2 intensities with larger cyst volumes. Fewer asymptomatic patients had type C. Preoperative pituitary dysfunction was most common in type A (71.4%). Early recurrence was observed in types A and C, which were considered candidates for cyst-wall opening. CONCLUSION: The clinical characteristics and surgical prognosis of RCCs depend on the nature of their contents.

DOI： 10.1007/s11102-024-01395-y

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

The study aims to explore MRI phenotypes that predict glioblastoma’s (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images.

Methods

One hundred Ninety-three histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. Ninety-three patients from the Cancer Imaging Archive (TCIA) / Cancer Genome Atlas (TCGA) were used as validation cohorts. “Thickened structure” was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. “Methylated contrast phenotype” was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status.

Results

Fleiss’s Kappa coefficient for “Thickened structure” was 0.68 for the exploratory and 0.55 for the validation cohort, and for “Methylated contrast phenotype,” 0.30 and 0.39, respectively. The imaging feature, the presence of “Thickened structure” and absence of “Methylated contrast phenotype,” was significantly predictive of pMGMT unmethylation both for the exploratory (p = 0.015, odds ratio = 2.44) and for the validation cohort (p = 0.006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of “Thickened structure,” and the absence of “Methylated contrast phenotype” for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort.

Conclusion

The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM’s pMGMT methylation status.

DOI： 10.1093/noajnl/vdae016

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10072-024-07332-y

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Other Link： https://link.springer.com/article/10.1007/s10072-024-07332-y/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

The EF-14 clinical trial demonstrated the safety and efficacy of tumor-treating fields (TTFields) for newly diagnosed glioblastoma. This study aimed to clarify the current status, safety, and efficacy of TTFields in Japanese patients who meet the EF-14 inclusion criteria.

Methods

This was a multicenter retrospective cohort study. Background, treatment, and outcome data of patients who satisfied the inclusion criteria of the EF-14 trial were collected from 45 institutions across Japan. The rate, determinants, and current status of TTField use, including its safety and efficacy in terms of progression and survival, were retrospectively investigated. This study was conducted in accordance with the STROBE checklist.

Results

Among the 607 patients enrolled, 70 were excluded due to progressive disease during radiation and temozolomide therapy, age > 80 years old, and Karnofsky Performance Status score of <70. Among the remaining 537 patients, 210 (39%) underwent TTField treatment. Multivariate analysis revealed younger age and spouse as a caregiver as significant factors for TTField use. The compliance rate of TTField use exceeded 75% in 60% of patients, with a median TTField usage duration of 11 months. Skin disorders requiring medical treatment occurred in 56% of patients. Multivariate Cox proportional hazards analysis in the whole series and propensity score-matched analysis revealed that TTField use was not a prognostic factor for progression-free survival (PFS) or overall survival (OS).

Conclusions

TTField use did not have a substantial effect on either PFS or OS in Japanese patients with glioblastoma, despite compliance rates comparable to those observed in the EF-14.

DOI： 10.1093/noajnl/vdae176

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Other Link： https://academic.oup.com/noa/article-pdf/6/1/vdae176/60939346/vdae176.pdf

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Neuroendovascular Therapy  

DOI： 10.5797/jnet.oa.2024-0042

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Language：Japanese   Publisher：日本てんかん学会-北海道地方会  

てんかん外科の種類は「切除外科」「遮断外科」「緩和外科」に大別される。内側側頭葉てんかん(MTLE)に対する切除外科の種類には側頭葉前部切除術(ATL)と選択的扁桃体海馬切除術(SAH)がある。遮断外科の種類には脳梁離断術と軟膜下皮質多切術がある。当科では2014～2018年にMTLE 11例に対して外科切除を行い、うちATLが8例、SAHが3例であった。SAHを施行した症例は全て術後に発作抑制がみられた。ATLを施行した症例のうち、MRIで病変を認めていた4例中3例で術後に発作抑制がみられたのに対し、MRIで病変を認めていなかった4例中2例では発作抑制がみられなかった。また当科では2017～2018年に脳梁離断術を5例に行い、うち4例は転倒発作、1例は全身強直性の痙攣重積で、転倒発作は術後に4例とも消失した。

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

DOI： 10.1016/j.inat.2023.101939

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11060-023-04454-9

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Other Link： https://link.springer.com/article/10.1007/s11060-023-04454-9/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Neurosurgical Society  

DOI： 10.2176/jns-nmc.2023-0146

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurosurgery Publishing Group (JNSPG)  

OBJECTIVE

Antithrombotic medications pose a challenge for conducting surgical or invasive procedures, because their discontinuation is required to avoid postprocedural hemorrhagic complications but potentially increases the ischemic risk for the patient. This study aimed to estimate the increased risk of developing cerebral ischemic events during hospitalization requiring discontinuation of antithrombotic therapy.

METHODS

This investigation was a single-center retrospective observational study. Clinical data in patients scheduled for admission between January 1, 2021, and December 31, 2022, were collected. Patients requiring discontinuation of antithrombotic therapy were identified by referring to the admission database. Patients who developed cerebral ischemia were identified by referring to the institution’s stroke center database.

RESULTS

Seven hundred ninety-six patients scheduled for nonneurosurgical procedures and 39 scheduled for neurosurgical procedures underwent discontinuation of antithrombotic therapy. Anticoagulation therapy was prescribed in 40.0%, and antiplatelet therapy was prescribed in 69.1% of the patients. A total of 9.2% of the entire cohort of patients were receiving both anticoagulation and antiplatelet therapy. Bridging therapy was administered in 20.9% of nonneurosurgical patients. No ischemic event was observed in the patients undergoing neurosurgical procedures. Among the entire cohort, 3 patients encountered some kind of thrombotic event—2 of which were cerebral ischemia—accounting for an incidence of 0.24%, which was significantly higher than incidental in-hospital stroke unrelated to discontinuation of antithrombotic therapy (p = 0.04). Patients undergoing both anticoagulation and antiplatelet therapy harbored a significantly higher risk for cerebral ischemia related to discontinuation of antithrombotic therapy (p < 0.0001).

CONCLUSIONS

Discontinuing antithrombotic therapy during hospitalization for elective invasive procedures—including neurosurgical procedures—entailed a relatively small risk of developing cerebral ischemic events, but the risk was significantly higher compared to hospitalized patients without discontinuation of antithrombotic therapy.

DOI： 10.3171/2023.7.focus23341

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Other Link： https://thejns.org/downloadpdf/journals/neurosurg-focus/55/4/article-pE7.xml

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

Objective

The primary outcome measure used in mechanical thrombectomy (MT) trials is the modified Rankin Scale (mRS). However, the accuracy of mRS might be limited. On the other hand, the functional independence measure (FIM) is a widely used tool to quantify the extent to which patients require assistance during their activities of daily living. The current study aimed to reveal different clinical backgrounds that affect the efficacy of MT measured either by mRS or FIM.

Methods

Patients who underwent MT at our institution from January 2019 to July 2022 were included and divided into groups based on mRS scores of 0–2 and ≥ 3. Patients were also divided into two groups based on a cut-off value of FIM of ≥ 108, as patients with FIM ≥ 108 are capable of living an independent life.

Results

The mRS score was 0–2 in 33% of the patients, while the FIM score was ≥ 108 in only 15% of the patients. In the mRS groups, there were significant differences in terms of duration of hospitalization, National Institutes of Health Stroke Scale (NIHSS) scores, achievement of thrombolysis in cerebral infarction (TICI) reperfusion grade of 2b or 3, and postoperative bleeding. Multivariate logistic regression analysis revealed that NIHSS score and achievement of TICI 2b or 3 were significant factors related to mRS 0–2 at discharge. The FIM groups differed significantly in terms of age and, duration of hospitalization, NIHSS score, although multivariate logistic regression analysis revealed that only the NIHSS score was significantly associated with an FIM score of ≥ 108.

Conclusion

The study showed that the percentage of independent patients is significantly reduced when we evaluated the patients by the FIM. In addition, there are some differences in the clinical background that led to a good outcome between that evaluated by mRS and FIM.

DOI： 10.1177/15910199231185635

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/15910199231185635

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

Background:

Due to the presence of many perforating arteries and the deep location of basal ganglia tumors, dissection of the perforating arteries is critical during tumor resection. However, this is challenging as these arteries are deeply embedded in the cerebrum. Surgeons need to bend their heads for a long time using operative microscope and it is uncomfortable for the operating surgeon. A high-definition (4K-HD) 3D exoscope system can significantly improve the surgeon’s posture during resection and widen the operating view field considerably by adjusting the camera angle.

Methods:

We report two cases of glioblastoma (GBM) involving basal ganglia. We used a 4K-HD 3D exoscope system for resecting the tumor and analyzed the intraoperative visualization of the operative fields.

Results:

We could approach the deeply located feeding arteries before successfully resecting the tumor using a 4K-HD 3D exoscope system which would have been difficult with the sole use of an operative microscope. The postoperative recoveries were uneventful in both cases. However, postoperative magnetic resonance imaging showed infarction around the caudate head and corona radiata in one of the cases.

Conclusion:

This study has highlighted using a 4K-HD 3D exoscope system in dissecting GBM involving basal ganglia. Although postoperative infarction is a risk, we could successfully visualize and dissect the tumors with minimal neurological deficits.

DOI： 10.25259/sni_53_2023

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Other Link： http://surgicalneurologyint.com/surgicalint-articles/surgical-resection-of-glioblastoma-in-basal-ganglia-and-utility-of-exoscope-technical-case-reports/

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.

DOI： 10.1007/s11604-023-01434-x

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

DOI： 10.1016/j.mri.2023.03.001

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

BACKGROUND: New therapies for glioblastoma (GBM) are urgently needed because the disease prognosis is poor. Chimeric antigen receptor (CAR)-T cell therapy that targets GBM-specific cell surface antigens is a promising therapeutic strategy. However, extensive transcriptome analyses have uncovered few GBM-specific target antigens. METHODS: We established a library of monoclonal antibodies (mAbs) against a tumor cell line derived from a patient with GBM. We identified mAbs that reacted with tumor cell lines from patients with GBM but not with nonmalignant human brain cells. We then detected the antigens they recognized using expression cloning. CAR-T cells derived from a candidate mAb were generated and tested in vitro and in vivo. RESULTS: We detected 507 mAbs that bound to tumor cell lines from patients with GBM. Among them, E61 and A13 reacted with tumor cell lines from most patients with GBM, but not with nonmalignant human brain cells. We found that B7-H3 was the antigen recognized but E61. CAR-T cells were established using the antigen-recognition domain of E61-secreted cytokines and exerted cytotoxicity in co-culture with tumor cells from patients with GBM. CONCLUSIONS: Cancer-specific targets for CAR-T cells were identified using a mAb library raised against primary GBM tumor cells from a patient. We identified a GBM-specific mAb and its antigen. More mAbs against various GBM samples and novel target antigens are expected to be identified using this strategy.

DOI： 10.1093/noajnl/vdac177

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

The current study aimed to test whether the ratio of T1-weighted to T2-weighted signal intensity (T1W/T2W ratio: rT1/T2) derived from conventional MRI could act as a surrogate relaxation time predictive of IDH mutation status in histologically lower-grade gliomas. Strong exponential correlations were found between rT1/T2 and each of T1- and T2-relaxation times in eight subjects (rT1/T2 = 1.63exp^{−0.0005T1-relax} + 0.30 and rT1/T2 = 1.27exp^{−0.0081T2-relax} + 0.48; R² = 0.64 and 0.59, respectively). In a test cohort of 25 patients, mean rT1/T2 (mrT1/T2) was significantly higher in IDHwt tumors than in IDHmt tumors (p < 0.05) and the optimal cut-off of mrT1/T2 for discriminating IDHmt was 0.666–0.677, (AUC = 0.75, p < 0.05), which was validated in an external domestic cohort of 29 patients (AUC = 0.75, p = 0.02). However, this result was not validated in an external international cohort derived from TCIA/TCGA (AUC = 0.63, p = 0.08). The t-Distributed Stochastic Neighbor Embedding analysis revealed a greater diversity in image characteristics within the TCIA/TCGA cohort than in the two domestic cohorts. The failure of external validation in the TCIA/TCGA cohort could be attributed to its wider variety of original imaging characteristics.

DOI： 10.1038/s41598-022-23527-9

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Other Link： https://www.nature.com/articles/s41598-022-23527-9

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

BACKGROUND: The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. METHODS: An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ± 10 Gy boost (arm A) or WBRT ± boost with concomitant and maintenance TMZ for two years (arm B). The primary endpoint was overall survival (OS). RESULTS: Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, two-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. CONCLUSIONS: This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.

DOI： 10.1093/neuonc/noac246

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Authorship：Last author   Language：Japanese   Publisher：(株)メディカ出版  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：一般社団法人 日本内分泌学会  

DOI： 10.1507/endocrine.98.s.hpt_12

CiNii Research

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

当施設で2011〜2021年に診療した下垂体腺腫629例のうち、下垂体卒中の診断で急性期に入院となった37例を対象とし、初発症状別に、複視群(17例)、視力低下群(12例)、頭痛群(8例)に分け、「年齢」「性別」「内分泌機能」「診断までに要した期間」「急性期の治療内容」などについて調査し比較検討した。その結果、複視群の特徴として男性の比率が他の2群に比べて有意に高かった。視力低下群では発症から画像診断までに1週間以上要した症例の割合が他の2群に比べて有意に高かった。頭痛群では副腎不全合併例の割合が高かった。

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background: We aimed to evaluate the resected area of endonasal endoscopic approach (EEA) and transcranial approach (TCA) for skull base meningiomas (SBMs) using voxel-based-lesion mapping and visualized the appropriate tumor location in each approach. Methods: We retrospectively examined 182 patients with SBMs who underwent tumor resection in our hospital between 2014 and 2019. Pre- and post-operative SBMs were manually delineated on MRI to create the voxels-of-interest (VOIpre and VOIpost) and were registered onto the normalized brain (normalized VOIpre and normalized VOIpost). The resected map was created by subtracting normalized VOIpost from the normalized VOIpre divided by the number of cases. The resected maps of TCA and EEA were compared by subtracting them. Results: Twenty patients underwent EEA and 135 patients underwent TCA. The tumor resected map demonstrated that the resected area of EEA frequently accumulated on the central skull base, while that of TCA accumulated near the central skull base. The border of both approaches matched the circle that connects neural foramens at the skull base. Conclusions: The resected area of SBMs by EEA and TCA was well visualized by voxel-based-lesion mapping. The circle connecting the neural foramens was the border of EEA and TCA.

DOI： 10.3390/brainsci12070875

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

Background:

Neuroendocrine tumors (NETs) are uncommon neoplasms arising from neuroendocrine cells and are rarely associated with intracranial metastases.

Case Description:

We discuss the case of a 74-year-old woman with a right CPA tumor. She had a history of retroperitoneal NET, but was diagnosed with vestibular schwannoma due to a right-sided hearing loss and a right CPA tumor along the VII and VIII nerves. After a 3-year follow-up, she presented with repetitive vomiting, a 1-month history of gait instability, and a 3-month history of general fatigue. Brain imaging revealed tumor growth and edematous changes in the right cerebellum. She underwent retrosigmoid craniotomy and partial resection. Histopathological examination revealed metastatic NET. She underwent stereotactic radiosurgery for residual lesion and, at 11 months of follow-up, the lesion was confirmed to have shrunk on magnetic resonance imaging (MRI).

Conclusion:

This is the first case to report the natural course of cerebellopontine metastasis of a NET. The differential diagnosis of CPA tumors is diverse, and, in our case, we suspected a vestibular schwannoma because of the typical symptoms and imaging features. However, the tumor grew relatively faster than expected and showed intratumoral hemorrhage during the 3-year follow-up. Therefore, in patients with a history of a NET, a careful follow-up is advisable even for lesions highly suspected to be another benign tumor on MRI. Careful follow-up imaging and appropriate treatment strategies were useful to manage the brain metastasis. Although NETs metastasizing to the CPA are extremely rare, this possibility should be considered when patients with NETs have intracranial lesions.

DOI： 10.25259/sni_117_2022

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Other Link： http://surgicalneurologyint.com/surgicalint-articles/cerebellopontine-angle-metastasis-of-a-neuroendocrine-tumor-mimicking-vestibular-schwannoma-a-case-report/

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

A recurrent tumor is defined as a re-emerging subclone originating from an ancestorial clone of the primary neoplasm. Hence, it should be distinguished from de novo tumor emerging from other clones. Herein, we describe an exceptional case in which the locally re-emerging glioma did not share genetic alterations of the primary tumor. While the initial tumor harbored mutations in IDH1 and TERT genes as well as 1p/19q codeletion, the re-emerging tumor did not present any of these genetic abnormalities. Variant calling for tumor samples using whole-genome sequencing revealed that 1696 mutations within the primary tumor faded in the re-emerging tumor, and that 4591 mutations were newly detected in the re-emerging tumor. These results suggested that the initial and re-emerging tumors did not share same clonal origins, although the second tumor appeared adjacent to the old surgical cavity 5 years after the initial surgery. We finally speculated that the re-emerging tumor could be a "de novo glioma" or "radiation-induced glioblastoma following treatment of a diffuse glioma." This case highlights the importance of molecular re-evaluation of clinically diagnosed "recurrent" glioma lesions.

DOI： 10.1007/s10014-022-00438-1

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Other Link： https://link.springer.com/article/10.1007/s10014-022-00438-1/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurosurgery Publishing Group (JNSPG)  

OBJECTIVE

“Join,” an imaging technology–based telemedicine system, allows simultaneous radiological information sharing between physically remote institutions, virtually connecting advanced medical institutions and rural hospitals. This study aimed to elucidate the health economics effect of Join for neurological telemedicine in rural areas in Hokkaido, Japan.

METHODS

Information concerning 189 requests for patient transfer from Furano Kyokai Hospital, a regional rural hospital, to Asahikawa Medical University Hospital (AMUH), an advanced academic medical institution, was retrospectively collected. The Join system was established between Furano Kyokai Hospital and AMUH in February 2019. Data collected from patients between April 2017 and December 2018 were included in the non-Join group, and those collected between February 2019 and October 2020 were included in the Join group. Clinical variables, reasons for patient transfer requests, duration of hospital stay, and medical costs per patient were analyzed between these two groups. Furthermore, clinical characteristics were compared between patients who were transferred and not transferred based on Join.

RESULTS

More patients were discharged < 7 days after transfer to AMUH in the non-Join group compared with the Join group (p = 0.02). When focusing on the Join group, more patients who were not transferred were discharged < 1 week (p < 0.01). On the other hand, more patients required surgery (p = 0.01) when transferred. The ratio of patients whose medical cost was < USD5000 substantially decreased, from 33% for the non-Join group to 13% for the Join group.

CONCLUSIONS

An imaging technology–based telemedicine system, Join, contributed to reducing unnecessary neuro-emergency patient transfer in a remote rural area, and telemedicine with an integrated smartphone system allowed medical personnel to effectively triage at a distance neuro-emergency patients requiring advanced tertiary care.

DOI： 10.3171/2022.3.focus228

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Other Link： https://thejns.org/downloadpdf/journals/neurosurg-focus/52/6/article-pE2.xml

Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Japan Academy of Neurosonology  

DOI： 10.2301/neurosonology.35.1

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Scientific Scholar  

Background:

Eagle’s syndrome is famous for one of the causes of internal carotid artery dissection. The treatment strategy for the illness, however, is not well established. Here, we report a case of internal carotid dissection due to an elongated styloid process successfully treated by carotid artery stenting (CAS).

Case Description:

A 72-year-old male with temporary dysarthria and consciousness disorder was diagnosed to suffer from multiple cerebral infarctions due to Eagle’s syndrome. A cerebral blood flow (CBF) study revealed decreased blood flow and a CAS was performed 15 days after admission to preserve antegrade blood flow, resulting in full recovery of the affected CBF.

Conclusion:

We reported a case of vascular Eagle’s syndrome in which the patient showed fluctuated neurological deficits successfully treated by CAS. Our experience suggests that cases of vascular Eagle’s syndrome due to hemodynamic stress can be treated by CAS.

DOI： 10.25259/sni_47_2022

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Other Link： http://surgicalneurologyint.com/surgicalint-articles/carotid-artery-dissection-due-to-elongated-styloid-process-treated-by-acute-phase-carotid-artery-stenting-a-case-report/

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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

DOI： 10.1016/j.wneu.2022.02.084

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

One of the challenges in glioblastoma (GBM) imaging is to visualize non-enhancing tumor (NET) lesions. The ratio of T1- and T2-weighted images (rT1/T2) is reported as a helpful imaging surrogate of microstructures of the brain. This research study investigated the possibility of using rT1/T2 as a surrogate for the T1- and T2-relaxation time of GBM to visualize NET effectively. The data of thirty-four histologically confirmed GBM patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were collected for analysis. Two of them also underwent MR relaxometry with rT1/T2 reconstructed for all cases. Met-PET was used as ground truth with T2-FLAIR hyperintense lesion, with >1.5 in tumor-to-normal tissue ratio being NET. rT1/T2 values were compared with MR relaxometry and Met-PET. rT1/T2 values significantly correlated with both T1- and T2-relaxation times in a logarithmic manner (p < 0.05 for both cases). The distributions of rT1/T2 from Met-PET high and low T2-FLAIR hyperintense lesions were different and a novel metric named Likeliness of Methionine PET high (LMPH) deriving from rT1/T2 was statistically significant for detecting Met-PET high T2-FLAIR hyperintense lesions (mean AUC = 0.556 ± 0.117; p = 0.01). In conclusion, this research study supported the hypothesis that rT1/T2 could be a promising imaging marker for NET identification.

DOI： 10.3390/brainsci12010099

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Congress of Neurological Surgeons  

DOI： 10.7887/jcns.31.4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Background</title>
The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved.


</sec><sec>
<title>Methods</title>
This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m²/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m²/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71–75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020.


</sec><sec>
<title>Discussion</title>
If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.


</sec><sec>
<title>Trial registration</title>
Registry number: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://jrct.niph.go.jp/en-latest-detail/jRCTs031200099">jRCTs031200099</ext-link>.


Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.


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DOI： 10.1186/s12885-021-08834-0

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Other Link： https://link.springer.com/article/10.1186/s12885-021-08834-0/fulltext.html

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVE: The left atrial volume index (LAVI) is considered to be the most accurate index to estimate the size of the left atrium (LA). In this study, we investigated the relationship between LA size measured by LAVI and the occurrence of large-vessel occlusion (LVO) in patients with cardiogenic cerebral infarction (CCI). METHODS: This retrospective single-center cohort study involved 118 patients with CCI within the internal carotid artery (ICA) or middle cerebral artery regions seen between January 2015 and July 2020. In all patients, the type of CCI was determined according to the Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Scores (TOAST) subtype diagnosis criteria. LVO was defined as positive when magnetic resonance imaging and computed tomography angiography showed ICA, M1, or M2 occlusion, with all others defined as non-LVO. Clinical characteristics, including LAVI, were evaluated in the records of several patients to investigate if they were risk factors for developing LVO. RESULTS: Seventy patients (59%) were diagnosed as having LVO infarction (ICA occlusion, n = 19 [16%]; M1 occlusion, n = 26 [22%]; and M2 occlusion, n = 25 [21%]). Echocardiography showed no difference between LVO and non-LVO in terms of the ejection fraction (P = 0.64), LA dimension (P = 0.93), and LA volume (P = 0.06). However, LAVI significantly differed between the LVO and non-LVO groups (P = 0.02). Multivariate logistic regression analysis showed larger LAVI as a significant risk factor for LVO (P = 0.01). CONCLUSIONS: Our findings suggest that a larger LAVI is a predictor of developing LVO in patients with CCI.

DOI： 10.1016/j.wneu.2021.12.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

<bold>Purpose:</bold> Meningiomas are the most common primary intracranial neoplasms and clinical symptom appearance depends on their volume and location. This study aimed to identify factors that influence clinical symptoms and to determine a specific threshold tumor volume for the prediction of symptomatic progression in patients with convexity, parasagittal, and falx meningiomas.

<bold>Materials and Methods:</bold> We retrospectively studied patients with radiologically suspected convexity, parasagittal, or falx meningiomas at our institution.

<bold>Results:</bold> The data of three hundred thirty-three patients were analyzed. We further divided patients into two groups based on clinical symptoms: an asymptomatic group (250 cases) and a symptomatic group (83 cases). Univariate analysis revealed significant differences between the groups in terms of sex (<italic>p</italic> = 0.002), age at the time of volumetric analysis (<italic>p</italic> &amp;lt; 0.001), hyperintense lesions on T2-weighted images (<italic>p</italic> = 0.029), peritumoral edema (<italic>p</italic> &amp;lt; 0.001), maximum tumor diameter (<italic>p</italic> &amp;lt; 0.001), and tumor volume (<italic>p</italic> &amp;lt; 0.001). Further multivariate analysis revealed significant differences between the groups in terms of age at the time of volumetric analysis (<italic>p</italic> = 0.002), peritumoral edema (<italic>p</italic> &amp;lt; 0.001), and tumor volume (<italic>p</italic> &amp;lt; 0.001). The receiver operating characteristic curve revealed a threshold tumor volume of 21.1 ml for predicting whether a patient would develop symptoms (sensitivity 0.843, specificity 0.880, an area under the curve 0.919 [95% confidence interval: 0.887–0.951]).

<bold>Conclusion:</bold> We identified factors predictive of clinical symptoms in patients with convexity, parasagittal, and falx meningiomas and determined the first-ever threshold tumor volume for predicting symptomatic progression in such patients.

DOI： 10.3389/fneur.2021.769656

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Language：English   Publisher：(一社)日本癌治療学会  

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
Most atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system shows an inactivation of SMARCB1 (INI1) and is considered as the hallmark of this neoplasm. However, AT/RT could exceptionally rarely present retained SMARCB1 (INI1) but inactivated SMARCA4 (BRG1). Here, the authors report a rare case of a 2-year-old boy with a SMARCB1 (INI1) retained but SMARCA4 (BRG1) negative AT/RT arising at the bilateral cerebellopontine angles mimicking neurofibromatosis type 2. The tumor was highly aggressive and was refractory to all treatment modalities. This case highlights the challenges during differential diagnosis of atypical cerebellopontine angle tumors of childhood and the importance of thoroughly investigating SMARCB1 (INI1) and SMARCA4 (BRG1) when AT/RT is suspected.

DOI： 10.1093/jscr/rjab400

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

OBJECTIVE: Secondary adrenal insufficiency (sAI) is a severe endocrinologic complication associated with nonfunctioning pituitary adenoma (NFPA). However, its prevalence is not simply related to tumor size. In this study, we aimed to detect the clinical characteristics of NFPAs that cause sAI. METHODS: We retrospectively investigated the clinical data of 218 patients with newly diagnosed macro NFPA between April 2011 and March 2020. The patients for whom endocrinologists had prescribed hydrocortisone after comprehensive endocrinologic evaluation were defined as having sAI. The 7 clinical factors analyzed for association with sAI were age, sex, presence of neurologic symptoms, hospitalization for emergency management of pituitary apoplexy, degree of optic chiasm compression, and Knosp grades on both sides. RESULTS: Seventy-three patients (33%) were classified into the sAI group. Multinomial logistic regression showed the strongest correlation between sAI and Knosp grade on the less extending side (P = 0.0001), followed by sex (male) (P = 0.0013) and pituitary apoplexy (P = 0.098). Tumors that extended bilaterally and had Knosp grades of 1-3 were frequently observed in sAI and were common in males. CONCLUSIONS: The NFPAs that occupy the sella space and compress the walls on both sides of the cavernous sinus, but do not penetrate them, have a higher risk of developing sAI. This type is more common in males and is seen even in patients without visual field disturbances. This clinical finding will be beneficial in management of patients with NFPA.

DOI： 10.1016/j.wneu.2021.06.098

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

The purpose of the current study was to investigate the hypothesis that the spatial distribution of brain metastases could be affected by the biological subtypes of breast cancer. CT (n=1) or MRI (n=66) images of 67 patients with a total of 437 treatment-naive brain metastases from breast cancer were retrospectively reviewed. Patients were grouped according to the biological subtype of the tumor [luminal A, 28; luminal B, 9; human epidermal growth factor receptor 2 (HER2) positive, 14; triple-negative breast cancer (TNBC), 16]. All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. The distribution pattern of brain metastases after image standardization was analyzed. The cerebellum and the frontal lobe were more commonly affected by breast cancer brain metastases. Brain metastases from luminal A and B types of breast cancer arose more often in the cerebellum. Brain metastases from HER2-positive type breast cancer occurred more often in the putamen and the thalamus and less frequently in the cerebellum than other types (P=0.0057). The subtypes of breast cancer are related to differences in the spatial distributions of their brain metastases. These differences may be utilized to plan different cranial irradiation strategies according to the breast cancer subtypes.

DOI： 10.3892/mco.2021.2337

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

One of the most crucial yet challenging issues for glioma patient care is visualizing non-contrast-enhancing tumor regions. In this study, to test the hypothesis that quantitative magnetic resonance relaxometry reflects glioma tumor load within tissue and that it can be an imaging surrogate for visualizing non-contrast-enhancing tumors, we investigated the correlation between T1- and T2-weighted relaxation times, apparent diffusion coefficient (ADC) on magnetic resonance imaging, and 11C-methionine (MET) on positron emission tomography (PET). Moreover, we compared the T1- and T2-relaxation times and ADC with tumor cell density (TCD) findings obtained via stereotactic image-guided tissue sampling. Regions that presented a T1-relaxation time of &gt;1850 ms but &lt;3200 ms or a T2-relaxation time of &gt;115 ms but &lt;225 ms under 3 T indicated a high MET uptake. In addition, the stereotactic tissue sampling findings confirmed that the T1-relaxation time of 1850–3200 ms significantly indicated a higher TCD (p = 0.04). However, ADC was unable to show a significant correlation with MET uptake or with TCD. Finally, synthetically synthesized tumor load images from the T1- and T2-relaxation maps were able to visualize MET uptake presented on PET.

DOI： 10.3390/cancers13164067

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Language：English  

Only several cases of internal carotid artery (ICA) stenosis involving the persistent primitive hypoglossal artery (PPHA) have been treated with carotid endarterectomy (CEA) because of its extreme rarity. CEA was performed for an 87-year-old female with severe stenosis of the right ICA-PPHA bifurcation requiring shunting from CCA to both PPHA and ICA. We initially attempted to insert two intraluminal balloon shunts into the CCA, as previously reported. However, we found this procedure technically impossible to achieve. An improvised three-way junction tube was inserted distally into PPHA and ICA and proximally into CCA, securing blood flow during CEA. Unfortunately, the patient suffered post-operative ischemic brain lesions due to the prolonged ischemic time during our initial unsuccessful shunt attempt. A three-way junction shunting tube could be an effective shunt technique during an anatomically complicated CEA.

DOI： 10.1093/jscr/rjab362

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

Radiogenomics use non-invasively obtained imaging data, such as magnetic resonance imaging (MRI), to predict critical biomarkers of patients. Developing an accurate machine learning (ML) technique for MRI requires data from hundreds of patients, which cannot be gathered from any single local hospital. Hence, a model universally applicable to multiple cohorts/hospitals is required. We applied various ML and image pre-processing procedures on a glioma dataset from The Cancer Image Archive (TCIA, n = 159). The models that showed a high level of accuracy in predicting glioblastoma or WHO Grade II and III glioma using the TCIA dataset, were then tested for the data from the National Cancer Center Hospital, Japan (NCC, n = 166) whether they could maintain similar levels of high accuracy. Results: we confirmed that our ML procedure achieved a level of accuracy (AUROC = 0.904) comparable to that shown previously by the deep-learning methods using TCIA. However, when we directly applied the model to the NCC dataset, its AUROC dropped to 0.383. Introduction of standardization and dimension reduction procedures before classification without re-training improved the prediction accuracy obtained using NCC (0.804) without a loss in prediction accuracy for the TCIA dataset. Furthermore, we confirmed the same tendency in a model for IDH1/2 mutation prediction with standardization and application of dimension reduction that was also applicable to multiple hospitals. Our results demonstrated that overfitting may occur when an ML method providing the highest accuracy in a small training dataset is used for different heterogeneous data sets, and suggested a promising process for developing an ML method applicable to multiple cohorts.

DOI： 10.3390/cancers13143611

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Meningiomas are the most frequent primary brain tumors. The long-term natural history of asymptomatic meningiomas remains unclear and difficult to predict accurately, however. The purpose of this study was to determine the subsequent course of asymptomatic meningiomas preceded by 5 years of no treatment. METHODS: We retrospectively studied patients with radiologically suspected intracranial asymptomatic meningiomas preceded by 5 years of no treatment. We volumetrically measured the lesions' chronological changes during the initial 5 years to obtain the 5-year tumor doubling time (5y-TdT). RESULTS: A total of 201 cases met the inclusion criteria. They were further divided into 3 subgroups: those who remained asymptomatic (group A; 174 cases), those who developed neurological symptoms and underwent treatment (group B; 8 cases), and those who received intentional intervention for a preventative reason (group C; 19 cases). 5y-TdT of group B (median: 46.5 months) was significantly shorter than that of group A (median: 216.3 months) (P < 0.001). Progression-free survival (PFS) was significantly different between tumors that exhibited 5y-TdT ≥ 98.8 months and <98.8 months (P < 0.001). When we combined groups B and C and set the PFS endpoint as either disease progression or treatment, we found that more than 20% of patients would require treatment within 15 years. CONCLUSIONS: The present study revealed the subsequent course of asymptomatic meningiomas after 5 years of no treatment and demonstrated that 5y-TdT is useful to detect patients who may require treatment.

DOI： 10.1016/j.wneu.2021.05.023

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

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.

DOI： 10.1007/s00262-021-02954-z

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Language：English  

Isolated spontaneous common carotid artery (CCA) dissection is extremely rare. Moreover, only a few case reports for isolated spontaneous CCA dissection treated with carotid artery stenting (CAS) can be found so far. Here, the authors report a case where intravascular ultrasonography (IVUS) provided valuable information about lesion evaluation, stent selection and stent placement during CAS for isolated CCA dissection. A 69-year-old male was diagnosed with an isolated spontaneous left CCA dissection. CAS assisted with IVUS was performed to prevent further dissection and cerebral infarction recurrence. To the best of our knowledge, this is the first case report of an isolated spontaneous CCA dissection treated with CAS assisted by IVUS. CAS assisted by IVUS may be an effective treatment option to prevent intraoperative complications and further stroke recurrence for isolated spontaneous CCA dissection.

DOI： 10.1093/jscr/rjab232

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Authorship：Corresponding author   Language：Japanese   Publisher：日本脳神経外科コングレス  

Inferior fronto-occipital fasciculus(IFOF)は後頭皮質と前頭葉を結ぶ白質連合線維束として知られており、その機能は意味処理や統語処理に関連していると推測されている。言語優位半球の島回神経膠腫の切除において、IFOFの損傷は換語障害や意味性錯語の出現を引き起こす。島回神経膠腫に対する覚醒下手術を施行し、術中覚醒下において白質刺激により意味性錯語が認められ、IFOFを機能的に同定し得た症例を報告する。(著者抄録)

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Radiographic imaging enables minimally invasive observation of internal organs and is an indispensable medical technique for modern medicine. Just as histopathological findings reveal a lesion in the microscopic world, a radiographic image is an observation of the lesion from a macroscopic perspective. Since the discovery of X-rays, the progress of radiographic imaging technology has been remarkable. Radiographic images, which could only be expected to show structural images in the early days, are able to reveal brain functioning and are now anticipated to accomplish the qualitative diagnosis of lesions. However, clinicians will need to return to technical theory for critical evaluation from a neutral perspective. In this paper, we have summarized the "common knowledge," which is indispensable in radiographical diagnosis of glioma, emphasizing the theory of basic neuroradiography and predict the "near future" of radiological images of glioma imaging.

DOI： 10.11477/mf.1436204422

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Authorship：Last author,　Corresponding author   Language：English  

Tirabrutinib (ONO/GS-4059; Ono Pharmaceutical) is a newly developed drug that selectively and irreversibly inhibits Bruton's tyrosine kinase (BTK) and has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). However, its therapeutic effect is yet to be verified at the pathological level in human patients. A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646.

DOI： 10.1186/s40164-021-00222-5

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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

Machine learning models for automated magnetic resonance image segmentation may be useful in aiding glioma detection. However, the image differences among facilities cause performance degradation and impede detection. This study proposes a method to solve this issue. We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets. Three models for tumor segmentation are developed. In our methodology, the BraTS and JC models are trained on the BraTS and JC datasets, respectively, whereas the fine-tuning models are developed from the BraTS model and fine-tuned using the JC dataset. Our results show that the Dice coefficient score of the JC model for the test portion of the JC dataset was 0.779 ± 0.137, whereas that of the BraTS model was lower (0.717 ± 0.207). The mean Dice coefficient score of the fine-tuning model was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (p < 0.0001) and the BraTS and fine-tuning models (p = 0.002); however, no significant difference between the JC and fine-tuning models (p = 0.673). As our fine-tuning method requires fewer than 20 cases, this method is useful even in a facility where the number of glioma cases is small.

DOI： 10.3390/cancers13061415

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

BACKGROUND: In preoperative embolization for intracranial meningioma, endovascular intratumoral embolization is considered to be more effective for the reduction of tumorous vascularity than proximal feeder occlusion. In this study, we aimed to reveal different efficacies for reducing tumor blood flow in meningiomas by comparing endovascular intratumoral embolization and proximal feeder occlusion using dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI). METHODS: 28 consecutive patients were included. DSC-PWI was performed before and after embolization for intracranial meningiomas. Normalized tumor blood volume (nTBV) of voxels of interest of whole tumors were measured from the DSC-PWI data before and after embolization. ΔnTBV% was compared between the cases that received intratumoral embolization and proximal feeder occlusion. RESULTS: ΔnTBV% in the intratumoral embolization group (42.4±29.8%) was higher than that of the proximal feeder occlusion group (15.3±14.3%, p=0.0039). We used three types of embolic materials and ΔnTBV% did not differ between treatments with or without the use of each material: 42.8±42.4% vs 28.7±20.1% for microspheres (p=0.12), 36.1±20.6% vs 28.1±41.1% for n-butyl cyanoacrylate (p=0.33), and 32.3±37.3% vs 34.1±19.0% for bare platinum coils (p=0.77). CONCLUSIONS: The flow reduction effect of intratumoral embolization was superior to that of proximal feeder occlusion in preoperative embolization for intracranial meningioma in an assessment using DSC-PWI.

DOI： 10.1136/neurintsurg-2020-017116

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Background</title>
Wilms’ tumor gene 1 (WT1) peptide vaccine and anti-programmed cell death-1 (anti-PD-1) antibody are expected as immunotherapies to improve the clinical outcome of glioblastoma. The aims of this study were to clarify how each immunotherapy affects tumor-infiltrating immune cells (TIIs) and to determine whether the combination of these two therapies could synergistically work.


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<title>Methods</title>
Mice were transplanted with WT1 and programmed cell death-ligand 1 doubly expressing glioblastoma cells into brain followed by treatment with WT1 peptide vaccine, anti-PD-1 antibody, or the combination of the two, and survival of each therapy was compared. CD45+ cells were positively selected as TIIs from the brains with tumors, and TIIs were compared between WT1 peptide vaccine and anti-PD-1 antibody therapies.


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<sec>
<title>Results</title>
Most mice seemed to be cured by the combination therapy with WT1 peptide vaccine and anti-PD-1 antibody, which was much better survival than each monotherapy. A large number of CD4+ T cells, CD8+ T cells, and NK cells including WT1-specific CD8+ and CD4+ T cells infiltrated into the glioblastoma in WT1 peptide vaccine-treated mice. On the other hand, the number of TIIs did not increase, but instead PD-1 molecule expression was decreased on the majority of the tumor-infiltrating CD8+ T cells in the anti-PD-1 antibody-treated mice.


</sec>
<sec>
<title>Conclusion</title>
Our results clearly demonstrated that WT1 peptide vaccine and anti-PD-1 antibody therapies worked in the different steps of cancer-immunity cycle and that the combination of the two therapies could work synergistically against glioblastoma.


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DOI： 10.1093/noajnl/vdab091

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Other Link： http://academic.oup.com/noa/article-pdf/3/1/vdab091/39555523/vdab091.pdf

Language：Japanese   Publisher：日本脳神経外科コングレス  

機能性下垂体腺腫のうち、プロラクチノーマはドパミン作動薬による薬物治療が第一選択となるが、その診断にはいくつかの注意点がある。治療目標は患者の状況によって異なるが、長期間PRL値の制御が必要な若年女性のマクロ腺腫例には、総合的に外科治療の意義があると考える。先端巨大症とクッシング病に対しては外科治療が第一選択で、非寛解例に薬物治療が適用される。腫瘍を標的としたドパミン作動薬とソマトスタチン誘導体が治療の主軸で、GH受容体拮抗剤やコルチゾール合成阻害剤が補助的に使用される。それらの組み合わせで先端巨大症では内分泌学的に制御される例が増加したのに対し、クッシング病ではまだ薬物治療の効果は不十分である。さまざまな薬物が開発中であるが、機能性下垂体腺腫に対しては手術での摘出が理想的である。全摘出できない例でも最大限に腫瘍を摘出し、受容体や遺伝子の性状から有効な補助療法を選択するのが今後の方向性となるだろう。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J02632&link_issn=&doc_id=20210115280003&doc_link_id=10.7887%2Fjcns.30.19&url=https%3A%2F%2Fdoi.org%2F10.7887%2Fjcns.30.19&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background: Midline brain lesions, such as falx meningioma, arteriovenous malformations, and cavernous malformations, are usually approached from the ipsilateral interhemispheric fissure. To this end, patients are positioned laterally with the ipsilateral side up. However, some studies have reported the usefulness of gravity-assisted brain retraction surgery, in which patients are placed laterally with the ipsilateral side down or up, enabling surgeons to approach the lesions through the ipsilateral side or through a contralateral interhemispheric fissure, respectively. This surgery requires less brain retraction. However, when using an operative microscope, performing this surgery requires the surgeon to operate in an awkward position. A recently developed high-definition (4K-HD) 3-D exoscope system, ORBEYE, can improve the surgeon's posture while performing gravity-assisted brain retraction surgery. Methods: We report five cases with midline brain tumors managed by resectioning with gravity-assisted brain retraction surgery using ORBEYE. We also performed an ergonomic analysis of gravity-assisted brain retraction surgery with a craniotomy model and a neuronavigation system. Results: Gravity-assisted brain retraction surgery to the midline brain tumors was successfully performed for all five patients, using ORBEYE, without any postoperative neurological deficit. Conclusion: Gravity-assisted brain retraction surgery to the midline brain lesions using ORBEYE is feasible, and ORBEYE is ergonomically more favorable than a microscope. ORBEYE has the potential to generalize neurosurgical approaches considered difficult due to the surgeon's awkward position, such as gravity-assisted brain retraction surgery.

DOI： 10.25259/SNI_320_2021

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Radiological Technology  

DOI： 10.6009/jjrt.2021_jsrt_77.7.761

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Publishing type：Research paper (scientific journal)   Publisher：The Japanese Congress of Neurological Surgeons  

DOI： 10.7887/jcns.30.19

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Publishing type：Research paper (scientific journal)   Publisher：The Japanese Congress of Neurological Surgeons  

DOI： 10.7887/jcns.30.474

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

The surgical microscope has been the gold‒standard visual equipment for neurosurgical procedures since its introduction in the 1960s. Although it undoubtedly has made enormous contribution to the field, this medical device still offers room for improvement. In particular, physical size and weight restrict the relationship between surgeons and patient positions. The exoscope is a newly developed medical tool for microneurosurgery. The fundamental concept of this device is to provide excellent ergonomics during neu-rosurgical procedures while preserving the numerous advantages that surgical microscopes provide to surgeons. It is composed of a small stereo camera and a 4K three‒dimensional large display. Although its clinical impact remains debatable, this device may completely replace surgical microscopes in the coming years. The exoscope enables： 1．shallow‒angle surgical approaches without compromising the surgeon posture； 2．assistance in deep‒seated surgical fields； 3．the collection of three‒dimensional surgical field data with quantitative measurement of surgical maneuvers. This review article provides an overview of the advantages mentioned above using clinical cases oper-ated with exoscope assistance to help understand its clinical and technological impact on neurological sur-gery.

DOI： 10.7887/jcns.30.199

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Japan Neurosurgical Society  

DOI： 10.2176/nmc.ra.2021-0133

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Publishing type：Research paper (scientific journal)  

© 2020 The Authors Early diagnosis of primary central nervous system lymphoma (PCNSL) in the extra-axial region is difficult due to the corresponding atypical clinical symptoms and radiological findings. This case report documents the rare diagnosis and treatment of PCNSL of the bilateral Bochdalek's flower baskets (protrusions of the fourth ventricle choroid plexus into the cerebellopontine angles). The patient initially presented with subacute vertigo and left hearing loss. Radiological findings included symmetrical mass lesions in the bilateral cerebellopontine angles. An open biopsy enabled the pathological diagnosis of diffuse large B-cell lymphoma. The primary tumors were successfully removed through chemoradiation. However, the patient died six months after treatment completion due to cerebrospinal dissemination. PCNSL should be considered when diagnosing brain tumors with atypical symptoms and radiological findings.

DOI： 10.1016/j.inat.2020.100756

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AIM: To evaluate the association between 11C-methionine positron-emission tomography (11C-methionine PET) findings, isocitrate dehydrogenase (IDH) gene mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with grade II and III gliomas. MATERIALS AND METHODS: Data were collected from 40 patients with grade II and III gliomas who underwent both magnetic resonance imaging (MRI) and 11C-methionine PET as part of their pre-surgical examination. IDH mutation was examined via DNA sequencing, and MGMT promoter methylation via quantitative methylation-specific polymerase chain reaction (PCR). RESULTS: A threshold of MGMT promoter methylation of 1% was significantly associated with tumour/normal tissue (T/N) ratio. The T/N ratio in samples with MGMT promoter methylation ≥1% was higher than that in samples with MGMT promoter methylation <1%, and the difference was statistically significant (p=0.011). Reliable prediction of MGMT promoter methylation (<1% versus ≥1%) was possible using the T/N ratio under the receiver operator characteristic (ROC) curve with a sensitivity and specificity of 75% each (cut-off value=1.6: p=0.0226, area under the ROC curve [AUC]=0.76172). Conversely, the T/N ratio had no association with IDH mutation (p=0.6). The ROC curve revealed no reliable prediction of IDH mutation using the T/N ratio (p=0.606, AUC=0.60577). CONCLUSION: 11C-methionine PET parameters can predict MGMT promoter methylation but not IDH mutation status. 11C-methionine uptake may have limited potential to reflect DNA methylation processes in grade II and III gliomas.

DOI： 10.1016/j.crad.2020.03.033

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.wneu.2020.06.157

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

T2-fluid-attenuated inversion recovery images (FLAIR) mismatch sign is now known to be a specific yet insensitive image feature for IDH-mutant, 1p19q non-codeleted astrocytoma. The current study revealed that lesion presenting T2-FLAIR mismatch exhibited extremely long T1- and T2-relaxation time while T2-FLAIR matched lesions showed low to moderate values. On the other hand, IDH-wildtype tumors presented noticeably short T1- and T2-relaxation time. These different relaxation time characteristics seemed to render T2-FLAIR mismatch sign of becoming such a unique and specific image feature for IDH-mutant, 1p19q non-codeleted astrocytoma.

DOI： 10.2463/mrms.bc.2019-0196

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

Transient ischemia provides the tolerance against prolonged ischemia in the brain. In mouse experimental model, transient ischemia changes the composition ratio of circulating proteins, which associate with neuroprotection; however, the human evidence is lacking. Here we mimicked balloon test occlusion (BTO) of carotid artery as a transient ischemia and investigated the change of composition ratio of the circulating protein in the human plasma. We collected blood samples from nine patients (5 men and 4 women; mean age 64.2 years; range 45 to 77 years) before and 48 h after BTO and investigated the changes of circulating molecules level in the proteome using LC-MS/MS analysis. Leucine-rich alpha-2-glycoprotein and serum amyloid A-1 increased and protein AMBP decreased in the blood samples after BTO. Transient change of blood flow in the brain alters molecular expression in the plasma. Because the alteration of plasma protein composition is involved in ischemic tolerance in animal models, the proteins whose level was changed by BTO may be also involved in neuroprotection against ischemia in human.

DOI： 10.1016/j.jocn.2019.12.005

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Background</title>
Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC.


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<title>Methods</title>
This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured.


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<sec>
<title>Results</title>
Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, P &amp;lt; .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients.


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<sec>
<title>Conclusions</title>
Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.


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DOI： 10.1093/noajnl/vdaa064

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Other Link： http://academic.oup.com/noa/article-pdf/2/1/vdaa064/33373870/vdaa064.pdf

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The current research tested the hypothesis that inversion time (TI) shorter than 2,400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying IDHmt, non-CODEL astrocytomas. We prepared three different cohorts; 94 MRI from 76 IDHmt, non-CODEL Lower-grade gliomas (LrGGs), 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2,400 ms for 3T or 2,016 ms for 1.5T, and 112 MRI from 112 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the "T2-FLAIR mismatch sign" was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2,400 ms under 3T for FLAIR acquisition (p = 0.0009, Fisher's exact test). The T2-FLAIR mismatch sign was positive only for IDHmt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI (p = 0.0001, Fisher's exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify IDHmt, non-CODEL astrocytomas improved from 31, 90, 79, and 51% to 67, 94, 92, and 74%, respectively and the area under the curve of ROC improved from 0.63 to 0.87 when FLAIR was acquired with shorter TI. We revealed that TI for FLAIR impacts the T2-FLAIR mismatch sign's diagnostic accuracy and that FLAIR scanned with TI < 2,400 ms in 3T is necessary for LrGG imaging.

DOI： 10.3389/fonc.2020.596448

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Publishing type：Research paper (scientific journal)  

© 2020, The Japan Society of Brain Tumor Pathology. Aging is a known negative prognostic factor in glioblastomas (GBM). Whether particular genetic backgrounds are a factor in poor outcomes of elderly patients with GBM warrants investigation. We aim to elucidate any differences between older and younger adult patients with IDH-wildtype GBM regarding both molecular characteristics and clinical outcomes. We collected adult cases diagnosed with IDH-wildtype GBM from the Kansai Network. Clinical and pathological characteristics were analyzed retrospectively and compared between older (≥ 70 years) and younger (≤ 50 years) cases. Included were 92 older vs. 33 younger cases. The older group included more patients with preoperative Karnofsky performance status score < 70 and had a shorter survival time than the younger group. MGMT promoter was methylated more frequently in the older group. TERT promoter mutation was more common in the older group. There were significant differences in DNA copy-number alteration profiles between age groups in PTEN deletion and CDK4 amplification/gain. In the older group, no molecular markers were identified, but surgical resection was an independent prognostic factor. Age-specific survival difference was significant in the MGMT methylated and TERT wildtype subgroup. Elderly patients have several potential factors in poor prognosis of glioblastomas. Varying molecular profiles may explain differing rates of survival between generations.

DOI： 10.1007/s10014-020-00363-1

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

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.

DOI： 10.1371/journal.pone.0243272

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

Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.

DOI： 10.1038/s41598-019-56767-3

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

A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

DOI： 10.1093/jjco/hyz169

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

AIM: The most appropriate imaging protocol for three-dimensional rotational venography (3D RV) has not been established. The aim of this study was to optimise the protocol for 3D RV with low-dose contrast media using time-density curve analysis. METHODS: Twenty-five consecutive patients with brain tumours who received preoperative assessment with 3D RV were retrospectively collected and included in this study. To optimise the imaging delay time of 3D RV with low-dose contrast media, time-density curve analysis was performed on two-dimensional conventional angiography. The image quality for depicting cortical veins and venous sinuses was compared to that of magnetic resonance (MR) venography in five cases. RESULTS: A total of 27 3D RVs were performed in 25 patients. The time-density curves of cortical veins were different from those of cerebral arteries or sinuses. The mean time to peak of cortical veins was significantly longer than the time to peak of cerebral arteries (2.47 ± 0.35 seconds vs. 6.44 ± 1.14 seconds; p < 0.0001) and shorter than the time to peak of venous sinuses (6.44 ± 1.14 seconds vs. 8.18 ± 1.12 seconds; p < 0.0001). The optimal imaging delay time could be determined as the phases in which cortical arterial opacities disappeared and cortical veins started to appear. The mean dose of injected contrast media was 5.3 mL. The image quality of cortical veins in 3D RV was superior to that in MR venography in all cases. CONCLUSIONS: Three-dimensional RV with low-dose contrast media was useful for the preoperative assessment of cortical veins in patients with brain tumours.

DOI： 10.1177/1971400919873894

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
Visualization of non-contrast-enhancing tumor lesions in glioma is one of the most crucial yet challenging issues for patients with this pathology. This study examined the hypothesis that quantitative T1- and T2-relaxometry could reflect glioma tumor load within the brain and could further be used for visualizing non-enhancing heavily tumor-loaded areas. Participants comprised patients with low- or high-grade glioma. Correlation between T1- or T2-relaxation time and 11C-methionine uptake as measured by positron emission tomography (Cohort-1) was investigated followed by comparing T1- or T2-relaxation time with tumor cell density as measured by stereotactic image-guided tissue sampling in a different cohort (Cohort-2). T1-relaxometry was achieved by converting Magnetization Prepared Rapid Gradient Echo (MP2RAGE) images and T2-relaxometry by multi-echo T2-weighted images via Bayesian inference modeling. T1-relaxation time &gt;2000 ms but &lt; 3200 ms or T2-relaxation time &gt;115 ms but &lt; 265 ms were indicative of high 11C-methionine uptake. Stereotactic tissue sampling study confirmed that tissue cell densities obtained from locations with a T1-relaxation time of 2000–3200 ms or a T2-relaxation time of 125–225 ms were significantly higher than those obtained from other locations (p &lt; 0.001 and p = 0.03, respectively). Synthetic tumor load images were successfully reconstructed using T1- and T2-relaxation mapping. T1- and T2-relaxation times both correlated well with tumor cell density in glioma tissues. The ideal ranges for identifying high tumor load tissues were 2000–3200 ms for T1-relaxation time and 115–220 ms for T2-relaxation both measured at 3.0 T.

DOI： 10.1093/neuonc/noz175.691

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We attempted to establish a magnetic resonance imaging (MRI)-based radiomic model for stratifying prognostic subgroups of newly diagnosed glioblastoma (GBM) patients and predicting O (6)-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) status of the tumor. Preoperative MRI scans from 201 newly diagnosed GBM patients were included in this study. A total of 489 texture features including the first-order feature, second-order features from 162 datasets, and location data from 182 datasets were collected. Supervised principal component analysis was used for prognostication and predictive modeling for pMGMT-met status was performed based on least absolute shrinkage and selection operator regression. 22 radiomic features that were correlated with prognosis were used to successfully stratify patients into high-risk and low-risk groups (p = 0.004, Log-rank test). The radiomic high- and low-risk stratification and pMGMT status were independent prognostic factors. As a matter of fact, predictive accuracy of the pMGMT methylation status was 67% when modeled by two significant radiomic features. A significant survival difference was observed among the combined high-risk group, combined intermediate-risk group (this group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and combined low-risk group (p = 0.0003, Log-rank test). Radiomics can be used to build a prognostic score for stratifying high- and low-risk GBM, which was an independent prognostic factor from pMGMT methylation status. On the other hand, predictive accuracy of the pMGMT methylation status by radiomic analysis was insufficient for practical use.

DOI： 10.1038/s41598-019-50849-y

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Brain Tumor Image Analysis (BraTumIA) is a fully automated segmentation tool dedicated to detecting brain tumors imaged by magnetic resonance imaging (MRI). BraTumIA has recently been applied to several clinical investigations; however, the validity of this novel method has not yet been fully examined. The present study was conducted to validate the quality of tumor segmentation with BraTumIA in comparison with results from 11C-methionine positron emission tomography (MET-PET). A total of 45 consecutive newly diagnosed high-grade gliomas imaged by MRI and MET-PET were analyzed. Automatic tumor segmentation was conducted by BraTumIA and the resulting segmentation images were registered to MET-PET. Three-dimensional conformal association between these two modalities was calculated, considering MET-PET as the gold standard. High underestimation and overestimation errors were observed in tumor segmentation calculated by BraTumIA compared with MET-PET. Furthermore, when the tumor/normal ratio threshold was set at 1.3 from MET-PET, the BraTumIA false-positive fraction was ~0.4 and the false-negative fraction was 0.9. By tightening this threshold to 2.0, the BraTumIA false-positive fraction was 0.6 and the false-negative fraction was 0.6. Following comparison of segmentation performance with BraTumIA with regard to glioblastoma (GBM) and World Health Organization (WHO) grade III glioma, GBM exhibited better segmentation compared with WHO grade III glioma. Although BraTumIA may be able to detect enhanced tumors, non-enhancing tumors and necrosis, the spatial concordance rate with MET-PET was relatively low. Careful interpretation is therefore required when using this technique.

DOI： 10.3892/ol.2019.10734

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: It is important to correctly and precisely define the target volume for radiotherapy (RT) of malignant glioma. 11C-methionine (MET) positron emission tomography (PET) holds promise for detecting areas of glioma cell infiltration: the authors' previous research showed that the magnitude of disruption of MET and 18F-fluorodeoxyglucose (FDG) uptake correlation (decoupling score [DS]) precisely reflects glioma cell invasion. The purpose of the present study was to analyze volumetric and geometrical properties of RT target delineation based on DS and compare them with those based on MRI. METHODS: Twenty-five patients with a diagnosis of malignant glioma were included in this study. Three target volumes were compared: 1) contrast-enhancing core lesions identified by contrast-enhanced T1-weighted images (T1Gd), 2) high-intensity lesions on T2-weighted images, and 3) lesions showing high DS (DS ≥ 3; hDS). The geometrical differences of these target volumes were assessed by calculating the probabilities of overlap and one encompassing the other. The correlation of geometrical features of RT planning and recurrence patterns was further analyzed. RESULTS: The analysis revealed that T1Gd with a 2.0-cm margin was able to cover the entire high DS area only in 6 (24%) patients, which indicates that microscopic invasion of glioma cells often extended more than 2.0 cm beyond a Gd-enhanced core lesion. Insufficient coverage of high DS regions with RT target volumes was suggested to be a risk for out-of-field recurrence. Higher coverage of hDS by T1Gd with a 2-cm margin (i.e., higher values of "[T1Gd + 2 cm]/hDS") had a trend to positively impact overall and progression-free survival. Cox regression analysis demonstrated that low coverage of hDS by T1Gd with a 2-cm margin was predictive of disease recurrence outside the Gd-enhanced core lesion, indicative of out-of-field reoccurrence. CONCLUSIONS: The findings of this study indicate that MRI is inadequate for target delineation for RT in malignant glioma treatment. Expanding the treated margins substantially beyond the MRI-based target volume may reduce the risk of undertreatment, but it may also result in unnecessary irradiation of uninvolved regions. As MET/FDG PET-DS seems to provide more accurate information for target delineation than MRI in malignant glioma treatment, this method should be further evaluated on a larger scale.

DOI： 10.3171/2018.4.JNS1859

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Language：English   Publisher：(一社)日本癌学会  

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

PURPOSE: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. METHODS: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. RESULTS: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases). CONCLUSIONS: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.

DOI： 10.1007/s11060-019-03222-y

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The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies.

DOI： 10.1186/s40478-019-0749-8

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AIM: To evaluate the toxicity and efficacy of re-irradiation with salvage stereotactic radiotherapy (SRT) for recurrent glioma using CyberKnife. PATIENTS AND METHODS: This study retrospectively investigated 35 patients with 48 recurrent grade 2-4 gliomas who received SRT between 1998 and 2011. Six patients (17.1%) had grade 2 gliomas, nine (25.7%) had grade 3 gliomas, and 20 (57.1%) had glioblastomas; all initially underwent surgery and conventional radiotherapy. The median initial and subsequent radiotherapy doses were 60 and 26 Gy, respectively. RESULTS: After a median follow-up period of 9.0 months, the only toxicity of grade 2 or more was radiation-induced brain necrosis in four patients (11.4%). The median overall and progression-free survival periods following re-irradiation were 9.0 and 3.0 months, respectively. Univariate analysis revealed that performance status at salvage re-irradiation was a significant predictor of progression-free survival. CONCLUSION: Salvage re-irradiation using CyberKnife is feasible, with an acceptable toxicity profile, for patients with recurrent glioma.

DOI： 10.21873/anticanres.13423

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The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

DOI： 10.1007/s10014-019-00337-y

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BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment. METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed. RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level. CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.

DOI： 10.1007/s11060-019-03113-2

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DOI： 10.1371/journal.pone.0210709

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/neuonc/noy148.248

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INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.

DOI： 10.1007/s11060-018-2957-7

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Language：English   Publisher：日本癌学会  

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DOI： 10.1177/1591019918802924.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Molecular biological characterization of tumors has become a pivotal procedure for glioma patient care. The aim of this study is to build conventional MRI-based radiomics model to predict genetic alterations within grade II/III gliomas attempting to implement lesion location information in the model to improve diagnostic accuracy. One-hundred and ninety-nine grade II/III gliomas patients were enrolled. Three molecular subtypes were identified: IDH1/2-mutant, IDH1/2-mutant with TERT promoter mutation, and IDH-wild type. A total of 109 radiomics features from 169 MRI datasets and location information from 199 datasets were extracted. Prediction modeling for genetic alteration was trained via LASSO regression for 111 datasets and validated by the remaining 58 datasets. IDH mutation was detected with an accuracy of 0.82 for the training set and 0.83 for the validation set without lesion location information. Diagnostic accuracy improved to 0.85 for the training set and 0.87 for the validation set when lesion location information was implemented. Diagnostic accuracy for predicting 3 molecular subtypes of grade II/III gliomas was 0.74 for the training set and 0.56 for the validation set with lesion location information implemented. Conventional MRI-based radiomics is one of the most promising strategies that may lead to a non-invasive diagnostic technique for molecular characterization of grade II/III gliomas.

DOI： 10.1038/s41598-018-30273-4

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Gliomas are genetically and histopathologically heterogeneous. Intratumoral heterogeneity in the MGMT promoter methylation status is an important clinical biomarker of glioblastoma. A higher uptake of 11C-methionine in positron-emission tomography (PET) reportedly reflects increased MGMT promoter methylation; however, non-stereotactic comparison of MGMT methylation and 11C-methionine PET images may not be accurate. The present study examined the correlation between 11C-methionine uptake and MGMT promoter methylation in non-enhancing gliomas using stereotactic image-based histological analysis. Data were collected from 9 patients with newly diagnosed non-enhancing glioma who underwent magnetic resonance imaging and 11C-methionine PET during pre-surgical examination. Clinical data were also collected from 3 patients during repeat surgery. The correlation between 11C-methionine uptake and MGMT methylation or cell density was analyzed using histological specimens obtained by multiple stereotactic sampling and an exact local comparison of 11C-methionine PET images and histological specimens was made. A total of 31 stereotactic sample sites were identified. In newly diagnosed cases, the tumor to normal uptake (T/N) ratio revealed a significant positive correlation with MGMT methylation (R=0.54, P=0.009) and a marginal correlation with cell density (R=0.42, P=0.05). In recurrent cases, the T/N ratio demonstrated no correlation with MGMT methylation (R=0.01, P=0.97) or cell density (R=0.15, P=0.70). An increased uptake of 11C-methionine in PET may reflect increased MGMT promoter methylation according to stereotactic image-based histological analysis. 11C-methionine PET could therefore be a useful tool for detecting regional MGMT promoter methylation in non-enhancing primary glioma.

DOI： 10.3892/ol.2018.8866

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Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

DOI： 10.1200/JCO.2018.78.6186

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association of Neurological Surgeons  

OBJECTIVE In the present study the authors aimed to determine preferred locations of meningiomas by avoiding descriptive analysis and instead using voxel-based lesion mapping and 3D image-rendering techniques. METHODS Magnetic resonance images obtained in 248 treatment-naïve meningioma patients with 260 lesions were retrospectively and consecutively collected. All images were registered to a 1-mm isotropic, high-resolution, T1-weighted brain atlas provided by the Montreal Neurological Institute (the MNI152), and a lesion frequency map was created, followed by 3D volume rendering to visualize the preferred locations of meningiomas in 3D. RESULTS The 3D lesion frequency map clearly showed that skull base structures such as parasellar, sphenoid wing, and petroclival regions were commonly affected by the tumor. The middle one-third of the superior sagittal sinus was most commonly affected in parasagittal tumors. Substantial lesion accumulation was observed around the leptomeninges covering the central sulcus and the sylvian fissure, with very few lesions observed at the frontal, parietal, and occipital convexities. CONCLUSIONS Using an objective visualization method, meningiomas were shown to be located around the middle third of the superior sagittal sinus, the perisylvian convexity, and the skull base. These observations, which are in line with previous descriptive analyses, justify further use of voxel-based lesion mapping techniques to help understand the biological nature of this disease.

DOI： 10.3171/2017.3.JNS17169

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Authorship：Corresponding author   Language：English  

Papillary glioneuronal tumor (PGNT) is a rare brain tumor grouped under mixed glioneuronal tumors according to the World Health Organization Classification of the Central Nervous System. The natural history of this pathology is not yet well documented. We report a case of PGNT that increased in size after a follow-up period of 10 years. An enlarged cyst wall and nodule showed a low intensity signal on T2*-weighted, suggesting hemorrhage during the clinical course. Characteristic pathological findings along with absence of BRAFV600E mutation identified the tumor as PGNT. The tumor characteristics of PGNT are discussed based on the presented case, with reference to the existing literature.

DOI： 10.1093/jscr/rjy123

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

Background: Ruptured dissecting aneurysms located at the middle cerebral artery (MCA) are rare, and their standard treatment has not been defined. Furthermore, lenticulostriate artery involvement in the dissecting segment makes treatment extremely difficult, and no previous reports have described successful treatment for such conditions. Case Description: We herein report the case of a 74-year-old woman who presented with sudden severe headache from subarachnoid hemorrhage due to dissection in the proximal M1 segment of left MCA involving lenticulostriate arteries. Digital subtraction angiography on day 6 showed that the dissecting aneurysm had enlarged despite strict blood pressure control. On day 8, the patient was treated successfully with a self-expanding closed cell stent and coil embolization, preserving blood flow in the lenticulostriate arteries as well as the MCA. Conclusions: Follow-up digital subtraction angiography performed 5 weeks after endovascular therapy showed healing of the dissecting lesion, and the patient was discharged neurologically intact.

DOI： 10.1016/j.wneu.2018.02.117

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

A number of studies have revealed the usefulness of multimodal imaging in gliomas. Although the results have been heavily affected by the method used for region of interest (ROI) design, the most discriminatory method for setting the ROI remains unclear. The aim of the present study was to determine the most suitable ROI design for 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) positron emission tomography (PET), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) obtained by diffusion tensor imaging (DTI) from the viewpoint of grades of non-enhancing gliomas. A total of 31 consecutive patients with newly diagnosed, histologically confirmed magnetic resonance (MR) non-enhancing gliomas who underwent FDG-PET, MET-PET and DTI were retrospectively investigated. Quantitative measurements were performed using four different ROIs; hotspot/tumor center and whole tumor, constructed in either two-dimensional (2D) or three-dimensional (3D). Histopathological grading of the tumor was considered as empirical truth and the quantitative measurements obtained from each ROI was correlated with the grade of the tumor. The most discriminating ROI for non-enhancing glioma grading was different according to the different imaging modalities. 2D-hotspot/center ROI was most discriminating for FDG-PET (P=0.087), ADC map (P=0.0083), and FA map (P=0.25), whereas 3D-whole tumor ROI was best for MET-PET (P=0.0050). In the majority of scenarios, 2D-ROIs performed better than 3D-ROIs. Results from the image analysis using FDG-PET, MET-PET, ADC and FA may be affected by ROI design and the most discriminating ROI for non-enhancing glioma grading was different according to the imaging modality.

DOI： 10.3892/ol.2018.8319

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

BACKGROUND: Intra-axial brain tumors located at anatomically eloquent areas are challenging conditions. On one hand, it is often difficult to pursue maximum extent of resection of tumor in these locations. On the other hand, neuroplasticity occurs in some patients with low-grade glioma, and the primary neural functions are known to sometimes shift from conventional "eloquent cortices."
CASE DESCRIPTION: In a patient with a lower-grade glioma located at the precentral gyrus, shift of primary motor function from the precentral gyrus to the postcentral gyrus was detected on magnetoencephalography and functional magnetic resonance imaging. Aggressive removal of the pathologic precentral gyrus was accomplished via awake craniotomy without causing obvious motor function deficit.
CONCLUSIONS: This case highlights the importance of preoperative multimodal neurophysiologic imaging in patients with low-grade gliomas in eloquent areas.

DOI： 10.1016/j.wneu.2017.07.152

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：OXFORD UNIV PRESS INC  

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year-old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan.

DOI： 10.1177/1591019917710810

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND: Brain imaging in diffuse glioma is used for diagnosis, treatment planning, and follow-up.
PURPOSE: In this meta-analysis, we address the diagnostic accuracy of imaging to delineate diffuse glioma.
DATA SOURCES: We systematically searched studies of adults with diffuse gliomas and correlation of imaging with histopathology.
STUDY SELECTION: Study inclusion was based on quality criteria. Individual patient data were used, if available.
DATA ANALYSIS: A hierarchic summary receiver operating characteristic method was applied. Low- and high-grade gliomas were analyzed in subgroups.
DATA SYNTHESIS: Sixty-one studies described 3532 samples in 1309 patients. The mean Standard for Reporting of Diagnostic Accuracy score (13/25) indicated suboptimal reporting quality. For diffuse gliomas as a whole, the diagnostic accuracy was best with T2-weighted imaging, measured as area under the curve, false-positive rate, true-positive rate, and diagnostic odds ratio of 95.6%, 3.3%, 82%, and 152. For low-grade gliomas, the diagnostic accuracy of T2-weighted imaging as a reference was 89.0%, 0.4%, 44.7%, and 205; and for high-grade gliomas, with T1-weighted gadolinium-enhanced MR imaging as a reference, it was 80.7%, 16.8%, 73.3%, and 14.8. In high-grade gliomas, MR spectroscopy (85.7%, 35.0%, 85.7%, and 12.4) and C-11 methionine-PET (85.1%, 38.7%, 93.7%, and 26.6) performed better than the reference imaging.
LIMITATIONS: True-negative samples were underrepresented in these data, so false-positive rates are probably less reliable than true-positive rates. Multimodality imaging data were unavailable.
CONCLUSIONS: The diagnostic accuracy of commonly used imaging is better for delineation of low-grade gliomas than high-grade gliomas on the basis of limited evidence. Improvement is indicated from advanced techniques, such as MR spectroscopy and PET.

DOI： 10.3174/ajnr.A5368

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Background: Ischemic stroke is one form of cancer-associated thrombosis that can greatly worsen a patient's performance status. The present investigation aimed to elucidate the characteristic distribution pattern(s) of cryptogenic stroke lesions using a voxel-based lesion-mapping technique and examine the differences in clinical manifestations between cryptogenic and conventional strokes in patients with advanced cancer. Methods: Data from 43 patients with advanced cancer who developed acute ischemic stroke were retrospectively collected. Stroke etiology was grouped into either cryptogenic or conventional stroke etiology according to the ASCO stroke score. Clinical data were reviewed, and voxel-based lesion mapping using diffusion-weighted imaging (DWI) was performed to visualize the crosspatient spatial distribution of the lesions. Results: Of the 43 patients, 25 were classified as having cryptogenic stroke etiology and 18 were classified as having conventional stroke etiology. Median survival time of patients from stroke onset was 96 days for cryptogenic stroke etiology and 570 days for conventional stroke etiology (P = .01). D-dimer of patients was significantly higher in cryptogenic stoke etiology than in conventional stroke etiology (P = .006). Voxel-based lesion mapping showed that DWI hyperintense lesions accumulated at cortical and internal watershed areas of the cerebrum and at the vascular border zone of the superior cerebellar and posterior inferior cerebellar arteries at the cerebellum. Conclusions: Voxel-based lesion mapping for cryptogenic stroke in patients with advanced cancer showed that lesions accumulated at vascular border zones within the brain both at the cerebrum and at the cerebellum, but not at perforating arterial territories.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.02.038

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Brain metastasis is a common complication in patients with cancer, with lung cancer being the most frequent origin of brain metastases. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have begun to serve a pivotal role in lung cancer treatment and have been reported to demonstrate anticancer activity against brain metastases by penetrating the blood-brain barrier. The present study reports, to the best of our knowledge, the first case of EGFR-mutated non-small cell lung cancer (NSCLC) brain metastasis that was surgically resected while the lesion was responding to the EGFR-TKI erlotinib. The results of the present study demonstrated that EGFR-mutated NSCLC cells were able to evade the cytotoxic effect of EGFR-TKI by downregulating EGFR expression, without exhibiting the T790M EGFR mutation.

DOI： 10.3892/ol.2017.5677

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECTIVE Diffuse astrocytomas (DAs) have a high recurrence rate due to diffuse infiltration into the brain and spinal cord. Micro RNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been reported that miRNA-22 (miR-22) is involved in the invasion of some cancer cell lines. The aim of this study was to identify the biological effects of miR-22 in regard to the invasion of human DAs.
METHODS The authors evaluated whether the level of miR-22 is elevated in human spinal DAs by using miRNA chips. Next, the role of miR-22 in 1321N1 human astrocytoma cells was investigated. Finally, to elucidate whether miR-22 promotes invasion by astrocytoma cells in vivo, the authors transplanted miR-22 overexpressed astrocytoma cells into mouse thoracic spinal cord.
RESULTS The miR-22 significantly upregulated the invasion capacity of 1321N1 cells. Computational in silico.analysis predicted that tissue inhibitor of matrix metalloproteinase-2 (TIMP2) is a target gene of miR-22. This was confirmed by quantitative reverse transcription polymerase chain reaction and Western blotting, which showed that miR-22 inhibited TIMP2 mRNA and protein expression, respectively. Luciferase reporter assays demonstrated that miR-22 directly bound the 3'-untranslated regions of TIMP2. The authors further showed that miR-22 promoted invasiveness in 1321N1 astrocytoma cells when transplanted into mouse spinal cord.
CONCLUSIONS These data suggest that miR-22 acts to regulate invasion of 1321N1 astrocytoma cells by targeting TIMP2 expression. Additional studies with more cases and cell lines are required to elucidate the findings of this study for a novel treatment target for spinal DAs.

DOI： 10.3171/2016.8.SPINE16248

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Language：English   Publisher：SPRINGER  

DOI： 10.1007/s00401-016-1664-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background and Purpose
The analysis of the pulsation of unruptured intracranial aneurysms might improve the assessment of their stability and risk of rupture. Pulsations can easily be concealed due to the small movements of the aneurysm wall, making post-processing highly demanding. We hypothesized that the quantification of aneurysm pulsation is technically feasible and can be improved by computer-aided post-processing.
Materials and Methods
Images of 14 cerebral aneurysms were acquired with an ECG-triggered 4D CTA. Aneurysms were post-processed manually and computer-aided on a 3D model. Volume curves and random noise-curves were compared with the arterial pulse wave and volume curves were compared between both post-processing modalities.
Results
The aneurysm volume curves showed higher similarity with the pulse wave than the random curves (Hausdorff-distances 0.12 vs 0.25, p&lt;0.01). Both post-processing methods did not differ in intra-(r = 0.45 vs r = 0.54, p&gt;0.05) and inter-observer (r = 0.45 vs r = 0.54, p&gt;0.05) reliability. Time needed for segmentation was significantly reduced in the computer-aided group (3.9 +/- 1.8 min vs 20.8 +/- 7.8 min, p&lt;0.01).
Conclusion
Our results show pulsatile changes in a subset of the studied aneurysms with the final prove of underlying volume changes remaining unsettled. Semi-automatic post-processing significantly reduces post-processing time but cannot yet replace manual segmentation.

DOI： 10.1371/journal.pone.0166810

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECTIVE Diffusion MRI is attracting increasing interest for tissue characterization of gliomas, especially after the introduction of antiangiogenic therapy to treat malignant gliomas. The goal of the current study is to elucidate the actual magnitude of the correlation between diffusion MRI and cell density within the tissue. The obtained results were further extended and compared with metabolic imaging with C-11-methionine (MET) PET.
METHODS Ninety-eight tissue samples from 37 patients were stereotactically obtained via an intraoperative neuronavigation system. Diffusion tensor imaging (DTI) and MET PET were performed as routine presurgical imaging studies for these patients. DTI was converted into fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps, and MET PET images were registered to Gd-administered T1-weighted images that were used for navigation. Metrics of FA, ADC, and tumor-to-normal tissue ratio of MET PET along with relative values of FA (rFA) and ADC (rADC) compared with normal-appearing white matter were correlated with cell density of the stereotactically obtained tissues.
RESULTS rADC was significantly lower in lesions obtained from Gd-enhancing lesions than from nonenhancing lesions. Although rADC showed a moderate but statistically significant negative correlation with cell density (p = 0.010), MET PET showed a superb positive correlation with cell density (p &lt; 0.0001). On the other hand, rFA showed little correlation with cell density.
CONCLUSIONS The presented data validated the use of rADC for estimating the treatment response of gliomas but also caution against overestimating its limited accuracy compared with MET PET.

DOI： 10.3171/2015.11.JNS151848

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：OXFORD UNIV PRESS INC  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Reports have suggested that tumor textures presented on T2-weighted images correlate with the genetic status of glioma. Therefore, development of an image analyzing framework that is capable of objective and high throughput image texture analysis for large scale image data collection is needed. The current study aimed to address the development of such a framework by introducing two novel parameters for image textures on T2-weighted images, i.e., Shannon entropy and Prewitt filtering. Twenty-two WHO grade 2 and 28 grade 3 glioma patients were collected whose pre-surgical MRI and IDH1 mutation status were available. Heterogeneous lesions showed statistically higher Shannon entropy than homogenous lesions (p = 0.006) and ROC curve analysis proved that Shannon entropy on T2WI was a reliable indicator for discrimination of homogenous and heterogeneous lesions (p = 0.015, AUC = 0.73). Lesions with well-defined borders exhibited statistically higher Edge mean and Edge median values using Prewitt filtering than those with vague lesion borders (p = 0.0003 and p = 0.0005 respectively). ROC curve analysis also proved that both Edge mean and median values were promising indicators for discrimination of lesions with vague and well defined borders and both Edge mean and median values performed in a comparable manner (p = 0.0002, AUC = 0.81 and p &lt; 0.0001, AUC = 0.83, respectively). Finally, IDH1 wild type gliomas showed statistically lower Shannon entropy on T2WI than IDH1 mutated gliomas (p = 0.007) but no difference was observed between IDH1 wild type and mutated gliomas in Edge median values using Prewitt filtering. The current study introduced two image metrics that reflect lesion texture described on T2WI. These two metrics were validated by readings of a neuro-radiologist who was blinded to the results. This observation will facilitate further use of this technique in future large scale image analysis of glioma.

DOI： 10.1371/journal.pone.0164268

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Language：Japanese   Publisher：(公財)成長科学協会  

GH産生下垂体腺腫における上皮成長因子受容体(EGFR)の発現と臨床特性との関連性について検討した。免疫染色の工程を含め、病理組織学的に検討可能であったのは下垂体腺腫64例(男性28名、女性36名、平均43.6歳)であった。EGFR wt,pY1197陽性例は、非機能性腺腫と比較して機能性腺腫に有意に多かった。pY+3陽性症例は機能性腺腫に有意に多く、特にGHoma、ACTHomaで多かった。GH産生腺腫において、患者年齢が高齢であるほどEGFR wtおよびpY1197の陽性度が高かった。陽性強度がEGFR pY&gt;wtである6例は再発ACTHoma 2例を含み、MIB-1 LIは高かった。GHoma、PRLoma、ACTHoma、非機能性腺腫の4群間で、性差、年齢、MB-1 LIに有意差は認めなかった。手術時に摘出した組織のうち、余剰検体からmRNA発現量解析し得たのは28検体であった。EGHR mRNA発現量は、PRL産生腫瘍に有意に多かった。GH産生腫瘍13例では検体による差が大きく、mRNA定量では明らかな特徴は認めなかった。

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

The aim of this study was to evaluate whether advanced patient motion correction (APMC) can reduce the misregistration of pixels between the different X-ray tube positions in four-dimensional CT angiography (4D-CTA).
Eight patients with intracranial aneurysms were included in this retrospective study. We compared the CTA images with APMC reconstruction and half-scan reconstruction with regard to the following 3 items: (1) bone misalignment area; (2) image noise; and (3) aneurysm volume change.
The bone misalignment area and image noise were significantly reduced in the APMC images, as compared to that in the half-scan reconstruction images (bone misalignment area: 33.0 +/- A 18.1 cm(3) vs 152.0 +/- A 72.2 cm(3), respectively; p &lt; 0.001) (image noise at pons: 9.70 +/- A 2.58 vs 15.16 +/- A 5.02, respectively, p &lt; 0.001). The aneurysm volume and volume variance were significantly smaller in the APMC reconstruction than those in the half-scan reconstruction (volume: 1107.2 +/- A 1813.8 mm(3) vs 1135.1 +/- A 1853.8 mm(3); p &lt; 0.05; coefficient of variation: 0.0291 +/- A 0.014 vs 0.0463 +/- A 0.026, p &lt; 0.05, respectively).
Our results show that APMC reduces the reconstruction related misregistration between the cardiac phases compared to half-scan reconstruction.

DOI： 10.1007/s11604-016-0563-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P &lt; 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

DOI： 10.1186/s40478-016-0351-2

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

Background. The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases.
Methods. CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed.
Results. The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6-21.9) for exon 19 deleted EGFR, 11.5 mm (6.6-16.8) for L858R mutated, and 15.0 mm (10.0-20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P &lt; .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002).
Conclusion. This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer.

DOI： 10.1093/neuonc/nov266

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AimsPrimary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-B (NF-B) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-B pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.
MethodsWe conducted the systematic sequencing of 21 genes relevant to the NF-B signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.
ResultsThe results showed that 68 out of 71 PCNSLs had mutations in the NF-B gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.
ConclusionsThe prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

DOI： 10.1111/nan.12259

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AIMS: Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-κB (NF-κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL. METHODS: We conducted the systematic sequencing of 21 genes relevant to the NF-κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation. RESULTS: The results showed that 68 out of 71 PCNSLs had mutations in the NF-κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265. CONCLUSIONS: The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

DOI： 10.1111/nan.12259

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND AND PURPOSE: Noninvasive radiologic evaluation of glioma can facilitate correct diagnosis and detection of malignant transformation. Although positron-emission tomography is considered valuable in the care of patients with gliomas, F-18-fluorodeoxyglucose and C-11-methionine have reportedly shown ambiguous results in terms of grading and prognostication. The present study compared the diagnostic and prognostic capabilities of diffusion tensor imaging, FDG, and C-11-methionine PET in nonenhancing gliomas.
MATERIALS AND METHODS: Thirty-five consecutive newly diagnosed, histologically confirmed nonenhancing gliomas that underwent both FDG and C-11-methionine PET were retrospectively investigated (23 grade II and 12 grade III gliomas). Apparent diffusion coefficient, fractional anisotropy, and tumor-to-normal tissue ratios of both FDG and C-11-methionine PET were compared between grade II and III gliomas. Prognostic values of these parameters were also tested by using progression-free survival.
RESULTS: Grade III gliomas showed significantly higher average tumor-to-normal tissue and maximum tumor2-to-normal tissue than grade II gliomas in C-11-methionine (P = .013, P = .0017, respectively), but not in FDG-PET imaging. There was no significant difference in average ADC, minimum ADC, average fractional anisotropy, and maximum fractional anisotropy. C-11-methionine PET maximum tumor-to-normal tissue ratio of 2.0 was most suitable for detecting grade III gliomas among nonenhancing gliomas (sensitivity, 83.3%; specificity, 73.9%). Among patients not receiving any adjuvant therapy, median progression-free survival was 64.2 7.2 months in patients with maximum tumor-to-normal tissue ratio of &lt;2.0 for C-11-methionine PET and 18.6 +/- 6.9 months in patients with maximum tumor-to-normal tissue ratio of &gt;2.0 (P = .0044).
CONCLUSIONS: C-11-methionine PET holds promise for World Health Organization grading and could offer a prognostic imaging biomarker for nonenhancing gliomas.

DOI： 10.3174/ajnr.A4460

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

To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks from the first administration of maintenance temozolomide. All patients showed good tolerability during the observation period. Skin disorders, such as grade 1/2 injection-site reactions, were observed in all seven patients. Although grade 3 lymphocytopenia potentially due to concurrent radio/temozolomide therapy was observed in five patients (71.4 %), no other grade 3/4 hematological or neurological toxicities were observed. No autoimmune reactions were observed. All patients are still alive, and six are on Wilms tumor 1 peptide vaccination without progression, yielding a progression-free survival from histological diagnosis of 5.2-49.1 months. Wilms tumor 1 peptide vaccination was stopped in one patient after 12 injections by the patient's request. The safety profile of the combined Wilms tumor 1 peptide vaccination and temozolomide therapy approach for treating glioblastoma was confirmed.

DOI： 10.1007/s00262-015-1674-8

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

Neurosurgical patties are the most frequently used instruments during neurosurgical procedures, and their high performance is required to ensure safe operations. They must offer cushioning, water-absorbing, water-retaining, and non tissue adherent characteristics. Here, the authors describe a revised neurosurgical patty that is superior in all respects to the conventional patty available in Japan. Patty characteristics were critically and scientifically evaluated using various in vitro assays. Moreover, a novel ex vivo evaluation system focusing on the adherent characteristics of the neurosurgical patty was developed. The proposed assay could provide benchmark data for comparing different neurosurgical patties, offering neurosurgeons objective data on the performance of patties. The newly developed patty was also evaluated in real neurosurgical settings and showed superb performance during various neurosurgical procedures.

DOI： 10.3171/2014.9.JNS14347

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND AND PURPOSE: Although resection of a tumor by trans-sphenoidal surgery is considered the criterion standard for successful surgical treatment of functional pituitary microadenoma, MR imaging occasionally fails to visualize and identify the tumor and supplementary imaging modalities are necessary. We tested the possibility of dynamic contrast-enhanced multisection CT of the pituitary gland accompanying image reconstruction of contrast agent dynamics to identify the localizations of microadenomas and compared the diagnostic performance with conventional pituitary-targeted MR imaging.
MATERIALS AND METHODS: Twenty-eight patients with surgically confirmed functional pituitary microadenomas (including growth hormone, adrenocorticotropic hormone, and prolactin-secreting adenomas) who underwent pituitary-targeted dynamic contrast-enhanced multisection CT were retrospectively investigated. We undertook image reconstruction of the dynamics of the contrast agent around the pituitary gland in a voxelwise manner, visualizing any abnormality and enabling qualification of contrast dynamics within the tumor.
RESULTS: Fifteen cases were correctly diagnosed by MR imaging, while dynamic contrast-enhanced multisection CT correctly diagnosed 26 cases. The accuracy of localization was markedly better for adrenocorticotropic hormone secreting microadenomas, increasing from 32% on MR imaging to 85% by dynamic contrast-enhanced multisection CT. Compared with the normal pituitary gland, adrenocorticotropic hormone secreting adenoma showed the least difference in contrast enhancement of the different functional microadenomas. Images acquired at 45-60 seconds after contrast agent injection showed the largest difference in contrast enhancement between an adenoma and the normal pituitary gland.
CONCLUSIONS: Dynamic contrast-enhanced multisection CT combined with image reconstruction of the contrast-enhanced dynamic's holds promise in detecting MR imaging occult pituitary microadenomas.

DOI： 10.3174/ajnr.A4220

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND AND PURPOSE: Electrocardiogram-gated 4D-CTA is a promising technique allowing new insight into aneurysm pathophysiology and possibly improving risk prediction of cerebral aneurysms. Due to the extremely small pulsational excursions (&lt;0.1 mm in diameter), exact segmentation of the aneurysms is of critical importance. In vitro examinations have shown improvement of the accuracy of vessel delineation by iterative reconstruction methods. We hypothesized that this improvement shows a measurable effect on aneurysm pulsations in vivo.
MATERIALS AND METHODS: Ten patients with cerebral aneurysms underwent 4D-CTA. Images were reconstructed with filtered back-projection and iterative reconstruction. The following parameters were compared between both groups: image noise, absolute aneurysm volumes, pulsatility, and sharpness of aneurysm edges.
RESULTS: In iterative reconstruction images, noise was significantly reduced (mean, 9.8 +/- 4.0 Hounsfield units versus 8.0 +/- 2.5 Hounsfield units; P = .04), but the sharpness of aneurysm edges just missed statistical significance (mean, 3.50 +/- 0.49 mm versus 3.42 +/- 0.49 mm; P = .06). Absolute volumes (mean, 456.1 +/- 775.2 mm(3) versus 461.7 +/- 789.9 mm(3); P = .31) and pulsatility (mean, 1.099 +/- 0.088 mm(3) versus 1.095 +/- 0.082 mm(3); P = .62) did not show a significant difference between iterative reconstruction and filtered back-projection images.
CONCLUSIONS: CT images reconstructed with iterative reconstruction methods show a tendency toward shorter vessel edges but do not affect absolute aneurysm volumes or pulsatility measurements in vivo.

DOI： 10.3174/ajnr.A4000

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Cerebral malaria is a complication of Plasmodium falciparum infection characterized by sudden coma, death, or neurodisability. Studies using a mouse model of experimental cerebral malaria (ECM) have indicated that blood-brain barrier disruption and CD8 T cell recruitment contribute to disease, but the spatiotemporal mechanisms are poorly understood. We show by ultra-high-field MRI and multiphoton microscopy that the olfactory bulb is physically and functionally damaged (loss of smell) by Plasmodium parasites during ECM. The trabecular small capillaries comprising the olfactory bulb show parasite accumulation and cell occlusion followed by microbleeding, events associated with high fever and cytokine storm. Specifically, the olfactory upregulates chemokine CCL21, and loss or functional blockade of its receptors CCR7 and CXCR3 results in decreased CD8 T cell activation and recruitment, respectively, as well as prolonged survival. Thus, early detection of olfaction loss and blockade of pathological cell recruitment may offer potential therapeutic strategies for ECM.

DOI： 10.1016/j.chom.2014.04.008

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

MRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns.
MR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients.
A PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values .05 (random permutation analysis with voxel-wise Fisher exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.

DOI： 10.1093/neuonc/not319

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

ObjectiveWe recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH.
PatientsSixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status.
ResultsTwenty-six (388%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (731%). Among the paradoxical GH responders to TRH, 21 patients (429%) had a gsp mutation and 28 patients (571%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (808% and 683%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P=0045) and greater GH suppression by octreotide (887% vs 754% GH decrease, P=0003) than the gsp-negative group.
ConclusionParadoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

DOI： 10.1111/cen.12336

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

The prognosis for patients with glioblastoma is very poor, despite intensive treatment, including surgery and chemoradiotherapy. Wilms' tumor 1 (WT1) is expressed in most glioblastoma samples, and immunotherapy targeting WT1 has proven to be effective in recurrent glioblastoma. However, the functional roles of WT1 in glioblastoma are not clear. To examine the functional roles of WT1 in glioblastoma, glioblastoma cell lines with reduced WT1 expression were generated using short hairpin RNA(shRNA)-expressing lentivirus. Proliferation of WT1-knockdown glioblastoma cells was significantly slower than control cells with high WT1 expression. In addition, apoptosis was increased in WT1-knockdown glioblastoma cells. Furthermore, WT1-knockdown glioblastoma cells, and control glioblastoma cells were intracranially injected into immunodeficient mice. In vivo tumor growth of WT1-knockdown glioblastoma cells was significantly reduced compared to control glioblastoma cells. These results show that WT1 is involved in glioblastoma cell proliferation and apoptosis and that this protein has oncogenic roles in glioblastoma.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

The trigeminocardiac reflex (TCR) is defined as a reproducible hypotension and bradycardia coinciding with the manipulation around the trigeminal nerve. Here, we report a case of sudden bradycardia with falcine manipulation. As the falx cerebri is innervated by the nervus tentorii, which is a recurrent branch of the ophthalmic nerve, the observed asystole is highly possible to be caused by TCR. Anesthesiologists and neurosurgeons should be fully aware of the anatomical innervation of the falx cerebri and that the posterior third of the falx cerebri is one of the highest risk structures for TCR induction for safe operation around this region. © 2014 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.inat.2014.06.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Congress of Neurological Surgeons  

The authors describe the current status of immunotherapy targeting Wilms' tumor 1 (WTl) peptide for malignant gliomas, as well as other hematological and solid malignancies. WTl is expressed in various kinds of malignancies, having an oncogenic function. WTl antibodies at higher titers and WTl -specific cytotoxic T lymphocytes (CTLs) at higher frequencies were detected in cancer patients than in healthy donors, indicating that WTl protein has an immunogenic function. Those findings provided us with a rationale for cancer immunotherapy targeting WTl. Clinical trials of WTl peptide vaccination were started, and definite immunological and clinical responses were observed. Especially in recurrent glioblastomas, a disease control rate of 57.l% was achieved, with a median progression-free survival period of 20.0 weeks and a progression-free survival rate at 6 months of 33.3%. The trial showed that WTl vaccination for malignant gliomas, which are generally believed to be an intractable disease, was safe and had a clinical response. Further clinical studies with randomization to confirm the efficacy and immunological proof of concept in patients with malignant gliomas are warranted. An enhancement of efficacy of WTl vaccination can be expected by combined use of WTl-specific helper peptide or anticancer chemotherapeutic agents. WTl vaccination as one of the multiple modalities at initial treatment or in the setting of minimal residual disease may prolong survival time of patients with malignancies.

DOI： 10.7887/jcns.22.619

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

To retrospectively examine the outcomes of hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannomas.
Twenty-five patients with 26 vestibular schwannomas were treated with hypofractionated stereotactic radiation therapy using a CyberKnife. The vestibular schwannomas of 5 patients were associated with type II neurofibromatosis. The median follow-up time was 80 months (range: 6167); the median planning target volume was 2.6 cm(3) (0.315.4); and the median prescribed dose (D90) was 21 Gy in three fractions (1825 Gy in three to five fractions). Progression was defined as 2 mm 3-dimensional post-treatment tumor enlargement excluding transient expansion. Progression or any death was counted as an event in progression-free survival rates, whereas only progression was counted in progression-free rates.
The 7-year progression-free survival and progression-free rates were 78 and 95, respectively. Late adverse events (3 months) with grades based on Common Terminology Criteria for Adverse Events, v4.03 were observed in 6 patients: Grade 3 hydrocephalus in one patient, Grade 2 facial nerve disorders in two and Grade 12 tinnitus in three. In total, 12 out of 25 patients maintained pure tone averages 50 dB before hypofractionated stereotactic radiation therapy, and 6 of these 12 patients (50) maintained pure tone averages at this level at the final audiometric follow-up after hypofractionated stereotactic radiation therapy. However, gradient deterioration of pure tone average was observed in 11 of these 12 patients. The mean pure tone averages before hypofractionated stereotactic radiation therapy and at the final follow-up for the aforementioned 12 patients were 29.8 and 57.1 dB, respectively.
Treating vestibular schwannomas with hypofractionated stereotactic radiation therapy in three to five fractions may prevent tumor progression with tolerable toxicity. However, gradient deterioration of pure tone average was observed.

DOI： 10.1093/jjco/hyt082

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The prevalence of cerebral aneurysm was retrospectively investigated in 208 patients with acromegaly relative to the rate of cerebral aneurysm in a group of control subjects. Neuroradiological examinations of the cerebral vascular system were conducted in 208 acromegaly patients (101 men
mean age, 48.8 years). The prevalence of cerebral aneurysm in the acromegaly patients was compared to that in a control group consisting of 7,390 subjects who underwent "brain checkup" between 2006 and 2008 (mean age, 51.6 years). In the acromegaly group, cerebral aneurysm was detected in 4.3 % of patients. By sex, the prevalence was 6.9 % in males, a significantly proportion than that in the control group with an odds ratio of 4.40. The prevalence in females did not differ between the two groups. In the acromegaly group, the rate of hypertension was significantly higher in the patients with aneurysm compared to those without aneurysm. Multiple logistic regression identified acromegaly as a significant factor related to the prevalence of cerebral aneurysm in all male subjects
other factors, such as age, hypertension and smoking, were not found to be significant. A significantly higher prevalence of cerebral aneurysm was detected in male patients with acromegaly. This finding indicates that excess growth hormone or insulin-like growth factor 1 affects the cerebral vascular wall, resulting in aneurysm formation. In addition to known systematic complications in the cardiovascular, respiratory, metabolic, and other systems, the risk of cerebral aneurysm should be considered in the management of acromegaly. © 2012 Springer Science+Business Media, LLC.

DOI： 10.1007/s11102-012-0404-x

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Object. Existing training methods for neuroendoscopic surgery have mainly emphasized the acquisition of anatomical knowledge and procedures for operating an endoscope and instruments. For laparoscopic surgery, various training systems have been developed to teach handling of an endoscope as well as the manipulation of instruments for speedy and precise endoscopic performance using both hands. In endoscopic endonasal surgery (EES), especially using a binostril approach to the skull base and intradural lesions, the learning of more meticulous manipulation of instruments is mandatory, and it may be necessary to develop another type of training method for acquiring psychomotor skills for EES. Authors of the present study developed an inexpensive, portable personal trainer using a webcam and objectively evaluated its utility. Methods. Twenty-five neurosurgeons volunteered for this study and were divided into 2 groups, a novice group (19 neurosurgeons) and an experienced group (6 neurosurgeons). Before and after the exercises of set tasks with a webcam box trainer, the basic endoscopic skills of each participant were objectively assessed using the virtual reality simulator (LapSim) while executing 2 virtual tasks: grasping and instrument navigation. Scores for the following 11 performance variables were recorded: instrument time, instrument misses, instrument path length, and instrument angular path (all of which were measured in both hands), as well as tissue damage, max damage, and finally overall score. Instrument time was indicated as movement speed
instrument path length and instrument angular path as movement efficiency
and instrument misses, tissue damage, and max damage as movement precision. Results. In the novice group, movement speed and efficiency were significantly improved after the training. In the experienced group, significant improvement was not shown in the majority of virtual tasks. Before the training, significantly greater movement speed and efficiency were demonstrated in the experienced group, but no difference in movement precision was shown between the 2 groups. After the training, no significant differences were shown between the 2 groups in the majority of the virtual tasks. Analysis revealed that the webcam trainer improved the basic skills of the novices, increasing movement speed and efficiency without sacrificing movement precision. Conclusions. Novices using this unique webcam trainer showed improvement in psychomotor skills for EES. The authors believe that training in terms of basic endoscopic skills is meaningful and that the webcam training system can play a role in daily off-the-job training for EES. ©AANS, 2013.

DOI： 10.3171/2012.12.JNS12908

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Radiation-induced gliomas are uncommon and therapeutic options are limited due to prior exposure to radiotherapy. Meanwhile, the chemotherapeutic response of anaplastic ependymoma, another rare entity in adults, is often disappointing. We report on the first recorded case of radiation-induced anaplastic ependymoma, in which an excellent clinical response to temozolomide was demonstrated. © 2013 The Neurosurgical Foundation.

DOI： 10.3109/02688697.2012.741740

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

The linear correlation between C-11-methionine PET and tumor cell density is not well conserved at the tumor border in glioma. A novel imaging analysis method, voxelwise F-18-FDG-C-11-methionine PET decoupling analysis (decoupling score), was evaluated to determine whether it could be used to quantitatively assess glioma cell infiltration in MRI-nonenhancing T2 hyperintense lesions. Methods: Data collection was performed in a prospective fashion. Fifty-four MRI-nonenhancing T2 hyperintense specimens were stereotactically obtained from 23 glioma patients by intraoperative navigation guidance. The decoupling score and tumor-to-normal tissue (TIN) ratio of C-11-methionine PET were calculated at each location. Correlations between the tumor cell density at these lesions, decoupling score, and TIN ratio of C-11-methionine PET were then evaluated. Results: Both the decoupling score and the T/N ratio showed a linear correlation with tumor cell density at these specimens (R-2 = 0.52 and 0.53, respectively). Use of the decoupling score (cutoff = 3.0) allowed the detection of specimens with a tumor cell density of more than 1,000/mm(2), with a sensitivity and specificity of 93.5% and 87.5%, respectively, whereas conventional C-11-methionine PET (cutoff = 1.2 in T/N ratio) was able to detect with a sensitivity and specificity of 87.0% and 87.5%, respectively. Reconstructed images (decoupling map) using the decoupling score enabled the visualization of glioma lesions that were difficult to visualize by C-11-methionine PET alone. Conclusion: The decoupling score showed better performance in detecting glioma cell infiltration than C-11-methionine uptake alone, thus suggesting that F-18-FDG-C-11-methionine uptake decoupling analysis is a powerful imaging modality for assessing glionia invasion.

DOI： 10.2967/jnumed.112.104992

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Language：Japanese   Publisher：(NPO)日本小児血液・がん学会・(NPO)日本小児がん看護学会・(公財)がんの子供を守る会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

For improvement of prognosis for glioblastoma patients, which remains poor, identification and targeting of glioblastoma progenitor cells are crucial. In this study, we found that the Cluster of Differentiation (CD)166/activated leukocyte cell adhesion molecule (ALCAM) was highly expressed on CD133 glioblastoma progenitor cells. ALCAMCD133 cells were highly enriched with tumor sphere-initiating cells in vitro. Among gliomas with isocitrate dehydrogenase-1/R132H mutation, the frequencies of ALCAM cells were significantly higher for glioblastomas than for World Health Organization grade II or III gliomas. The function of ALCAM in glioblastoma was then investigated. An in vitro invasion assay showed that transfection of ALCAM small interfering RNA or small hairpin RNA into glioblastoma cells significantly increased cell invasion without affecting cell proliferation. A soluble isoform of ALCAM (sALCAM) was also expressed in all glioblastoma samples and at levels that correlated well with ALCAM expression levels. In vitro invasion of glioblastoma cells was significantly enhanced by administration of purified sALCAM. Furthermore, overexpression of sALCAM in U87MG glioblastoma cells promoted tumor progression in i.c. transplants into immune-deficient mice. In summary, we were able to show that ALCAM constitutes a novel glioblastoma progenitor cell marker. We could also demonstrate that ALCAM and its soluble isoform are involved in the regulation of glioblastoma invasion and progression.

DOI： 10.1093/neuonc/nor202

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

Objective: The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. This study aimed to clarify the relationship between TRH-induced GH responsiveness and other tumor characteristics.
Methods: Patients with acromegaly who underwent initial surgery between 2000 and 2012 were divided into TRH-responder and nonresponder groups. Clinical features were compared between the two groups with respect to tumor size, Knosp grade, endocrinological profiles, and histopathological findings revealed by cytokeratin staining. Tumor size was quantitatively evaluated with volumetry. Cytokeratin staining patterns were categorized into three groups: sparsely granulated type, densely granulated type, and intermediate type.
Results: Sixty-two patients were included in the study. TRH responders (n = 45) showed significantly smaller tumor size than nonresponders (n = 17) (2.78 +/- 4.71 vs. 7.56 +/- 9.00 ml, P &lt; 0.005). In addition, TRH responders showed significantly higher preoperative basal GH per volume ratio than nonresponders (10.1 +/- 8.4 vs. 7.72 +/- 11.85 ng/ml(2), P &lt; 0.05). Logarithmic regression modeling showed significant correlation between TRH responsiveness and tumor volume (r = -0.341; P &lt; 0.01). The difference between cytokeratin staining patterns was also significant: sparsely granulated-type adenomas were found in only 13% of TRH responders but in 64% of nonresponders (P &lt; 0.0005). TRH responders showed higher GH suppression rates in the octreotide test compared with nonresponders (86 vs. 68%, P &lt; 0.01).
Conclusion: The present data suggest that the responsiveness of serum GH level to TRH reflects significant tumor biological characteristics. (J Clin Endocrinol Metab 97: 2741-2747, 2012)

DOI： 10.1210/jc.2012-1125

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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

Hepatitis B virus (HBV) reactivation during anticancer chemotherapy or immunosuppressive therapy in chronic carriers can lead to fatal liver failure. We report a rare case of severe HBV reactivation during postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) for malignant glioma. A 49-year-old Japanese woman with a history of HBV carrier status with positive results for hepatitis B surface antigen presented with persistent headache due to a tumor in the left frontal lobe. The tumor was partially resected and anaplastic astrocytoma was diagnosed. Postoperative liver function was normal and radiotherapy plus concomitant and adjuvant TMZ was started. Impaired liver function became apparent just before administration of adjuvant TMZ, and acute liver failure developed. Antiviral therapy including entecavir, a nucleoside analog, led to a successful outcome and the patient survived. This case underlines the possibility of HBV reactivation due to TMZ and suggests the utility of HBV screening and antiviral prophylaxis before administration of TMZ to patients with malignant glioma.

DOI： 10.1007/s10147-011-0294-3

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publisher：日本脳腫瘍病理学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

Object. Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd-enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of C-11-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OSWT1).
Methods. Fourteen patients with recurrent malignant glioma were included in the study, and OSWT1 was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of C-11-methionine; and 3) a more detailed voxel-wise PRM analysis of MET-PET pre- and post-WT1 immunotherapy.
Results. The PRM analysis was able to identify the following 3 areas within the tumor core: I) area with no change in C-11-methionine uptake pre- and posttreatment; 2) area with increased C-11-methionine uptake posttreatment (PRM+MET); and 3) area with decreased C-11-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OSWT1 (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM+MET area showed excellent correlation (p = 0.008) with OSWT1.
Conclusions. This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel-wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas. Clinical trial registration no.: UMIN000002001. (http://thejns.org/doi/abs/10.3171/2011.12.JNS111255)

DOI： 10.3171/2011.12.JNS111255

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

The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including C-11-methionine and F-18-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on C-11-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and C-11-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, C-11-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of C-11-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of C-11-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of C-11-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P &lt; 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that C-11-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.

DOI： 10.1007/s11060-011-0759-2

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

BACKGROUND: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with 11C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and 11C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and 11C-methionine uptake have been limited. The present study aimed to clarify this issue. METHODS: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and 11 C-methionine uptake were analyzed by stereotactic sampling and image analysis. RESULTS: Uptake of 11 C-methionine correlated with cell density (R 2 0.322, P.0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 +/- 1080 vs 1450 +/- 1380/ mm 2, P.0132). Although both 11 C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in 11 C-methionine uptake was seen between fluorescence-positive and -negative areas (P.367). Multiple linear regression analysis revealed 11 C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density. CONCLUSIONS: These results indicate that 5-ALA fluorescence and 11 C-methionine PET image are separate index markers for cytoreduction surgery of gliomas. Cancer 2012; 118: 1619-27. VC 2011 American Cancer Society.

DOI： 10.1002/cncr.26445

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

Object. The precise natural history of incidentally discovered meningiomas (IDMs) remains unknown. It has been reported that for symptomatic meningiomas, tumor location can be used to predict growth. As to whether the same is true for IDMs has not been reported. This study aims to answer this question and provide biological evidence for this assumption by extending the study to involve symptomatic cases.
Methods. A total of 113 IDMs were analyzed by fine volumetry. A comparison of growth rates and patterns between skull base and non-skull base IDMs was made. Subsequently, materials obtained from 210 patients with symptomatic meningiomas who were treated in the authors' hospital during the same period were included for a biological comparison between skull base and non-skull base tumors using the MIB-1 index.
Results. The 110 patients with IDMs included 93 females and 17 males, with a mean follow-up period of 46.9 months. There were 38 skull base (34%) and 75 non-skull base (66%) meningiomas. Forty-two (37%) did not exhibit growth of more than 15% of the volume, whereas 71 (63%) showed growth. Only 15 (39.5%) of 38 skull base meningiomas showed growth, whereas 56 (74.7%) of 75 non-skull base meningiomas showed growth (p = 0.0004). In the 71 IDMs (15 skull base and 56 non-skull base), there was no statistical difference between the 2 groups in terms of mean age, sex, follow-up period, or initial tumor volume. However, the percentage of growth (p = 0.002) was significantly lower and the doubling time (p = 0.008) was significantly higher in the skull base than in the non-skull base tumor group. In subsequently analyzed materials from 94 skull base and 116 non-skull base symptomatic meningiomas, the mean MIB-1 index for skull base tumors was markedly low (2.09%), compared with that for non-skull base tumors (2.74%; p = 0.013).
Conclusions. Skull base IDMs tend not to grow, which is different from non-skull base tumors. Even when IDMs grow, the rate of growth is significantly lower than that of non-skull base tumors. The same conclusion with regard to biological behavior was confirmed in symptomatic cases based on MIB-1 index analyses. The authors' findings may impact the understanding of the natural history of IDMs, as well as strategies for management and treatment of IDMs and symptomatic meningiomas. (DOI: 10.3171/2011.11.JNS11999)

DOI： 10.3171/2011.11.JNS11999

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background and Purpose-The hemodynamic factors of aneurysms were recently evaluated using computational fluid dynamics in a static vessel model in an effort to understand the mechanisms of initiation and rupture of aneurysms. However, few reports have evaluated the dynamic wall motion of aneurysms due to the cardiac cycle. The objective of this study was to quantify cardiac cycle-related volume changes in aneurysms using 4-dimensional CT angiography.
Methods-Four-dimensional CT angiography was performed in 18 patients. Image data of 1 cardiac cycle were divided into 10 phases and the volume of the aneurysm was then quantified in each phase. These data were also compared with intracranial vessels of normal appearance.
Results-The observed cardiac cycle-related volume changes were in good agreement with the sizes of the aneurysms and normal vessels. The cardiac cycle-related volume changes of the intracranial aneurysms and intracranial normal arteries were 5.40%+/- 4.17% and 4.20 +/- 2.04%, respectively, but these did not differ statistically (P=0.12).
Conclusions-We successfully quantified the volume change in intracranial aneurysms and intracranial normal arteries in human subjects. The data may indicate that cardiac cycle-related volume changes do not differ between unruptured aneurysms and normal intracranial arteries, suggesting that the global integrity of an unruptured aneurysmal wall is not different from that of normal intracranial arteries. (Stroke. 2012;43:61-66.)

DOI： 10.1161/STROKEAHA.111.626846

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of F-18-fluorodeoxy glucose (FDG) and C-11-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and C-11-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and C-11-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher C-11-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/C-11-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up.

DOI： 10.1007/s11060-011-0688-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

This is the first report of success in numerically quantifying and visualizing cardiac cycle - related intracranial vessel motion and pulse waves in human subjects by using 320-detector CTA and a newly developed motion-detection algorithm to better understand the physiologies of intracranial arteries. This new technique promises to provide significant novel information for analyzing the elasticity of cerebral vessels and should be incorporated in the analysis of vessel fluid dynamics.

DOI： 10.3174/ajnr.A2354

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Language：English   Publisher：(一社)日本癌学会  

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

There have been few studies investigating neuro-oncologists&apos; attitudes toward the disclosure of the diagnosis. This study aimed to determine the current status of disclosure to glioma patients in Japan and to analyze the factors associated with disclosure.
A set of questionnaires about disclosure to patients with malignant glioma was distributed by e-mail to 191 physicians participating in the 27th Annual Meeting of the Japan Society for Neuro-Oncology.
The response rate was 73.8% (141/191). Of these, 44.3% disclosed the correct diagnosis to glioblastoma patients aged &lt; 60 years and 41.4% disclosed the correct diagnosis to those aged a parts per thousand yen70 years; for anaplastic astrocytoma patients, these proportions were 61.5 and 51.9%, respectively. Physicians working at facilities performing surgery on more than 50 cases of glioma per year, those in metropolitan areas, and those with other patient psychosocial support systems available disclosed the diagnosis and prognosis more frequently. The physicians&apos; gender and postgraduate period of practice did not influence disclosure. When the family opposed disclosing the diagnosis to the patient, more than half of the physicians respected the family&apos;s wishes.
This survey revealed that most of the physicians told at least the malignant nature of the disease to patients with malignant glioma, but they did not always tell the exact diagnosis. Physicians tended to modify their attitudes toward disclosing a diagnosis or prognosis of glioma depending on the histopathological grading, the hospital volume of cases, the location, the availability of patient psychological support systems, and the patient&apos;s family&apos;s wishes.

DOI： 10.1007/s10147-010-0152-8

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background: To investigate the treatment results of intracranial meningiomas treated with hypofractionated stereotactic radiation therapy in three to five fractions.
Methods: Thirty-one patients (32 lesions) with intracranial meningioma were treated with hypofractionated stereotactic radiation therapy in three to five fractions using CyberKnife. Fifteen lesions were diagnosed as Grade I (World Health Organization classification) by surgical resection and 17 lesions were diagnosed as meningioma based on radiological findings. The median follow-up time was 48 months. The median planning target volume was 6.3 cm(3) (range, 1.4-27.1), and the prescribed dose (D90 &lt;=) ranged from 21 to 36 Gy (median, 27.8) administrated in three to five fractions.
Results: Five-year overall and progression-free survival rate of all 31 patients with intracranial meningioma was 86 and 83%, respectively. Five-year progression-free rate of all 32 lesions was 87%. Six of the 31 patients (19%) developed marked peritumoral edema, three of whom were asymptomatic and three symptomatic, the latter with late adverse effects of more than or equal to Grade 3. The mean planning target volume of the six lesions with marked peritumoral edema was 15.6 cm(3), and for the remaining 26 lesions without marked peritumoral edema was 7.1 cm(3) (P = 0.004). The threshold diameter of 2.56 cm for meningioma was calculated from the planning target volume (11 cm(3)) and was used as marker of developing peritumoral edema (P = 0.003).
Conclusions: Tumor volume is a significant indicative factor for peritumoral edema in intracranial meningioma treated with hypofractionated stereotactic radiation therapy in three to five factions.

DOI： 10.1093/jjco/hyr022

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.

DOI： 10.2176/nmc.50.1079

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

We report the case of a 28-year-old man who presented with the sole complaint of lumbago. Spinal magnetic resonance imaging (MRI) revealed a solitary, well-defined intramedullary mass at the L1-L2 level typical of a primary spinal cord germinoma. However, cranial magnetic resonance imaging (MRI) showed a concomitant lesion in the suprasellar region. This article describes a rare case of simultaneously detected intracranial and intramedullary spinal cord germinoma and its possible etiopathology.

DOI： 10.1007/s10014-010-0269-5

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Primary central nervous system lymphoma (PCNSL) remains a devastating disease with poor prognosis, despite the improvement offered by methotrexate (MTX)-based chemotherapy. Several studies have attempted to identify biomarkers predictive of prognosis, which are expected to be both clinically useful and biologically important for understanding PCNSL. The present study attempts to classify human immunodeficiency virus (HIV)-unrelated PCNSL patients treated with radiation combined with rapid high-dose MTX chemotherapy according to B-cell differentiation status, and retrospectively examines the prognostic impact. Initial response to MTX was a strong predictor of favorable prognosis in terms of both progression-free survival (PFS) and overall survival (OS). Thirteen out of 29 cases were CD10(-)/BCL-6(+)/MUM-1(+), being more frequent compared with systemic peripheral nodal lymphoma. Although post-germinal-center B-cell-originating PCNSLs (CD10(-)/BCL-6(-)/MUM-1(+)) showed a trend towards better response to MTX and progression-free survival than did germinal-center-related B-cell-originating PCNSLs (CD10(+) OR CD10(-)/BCL-6(+)/MUM-1(+)), the difference was only marginal (P = 0.04 Gehan-Breslow-Wilcoxon, P = 0.17 log-rank). Our results imply that different B-cell stages in PCNSL have significant relevance in terms of biological behavior. However, clinical use as a prognostic marker requires further investigation.

DOI： 10.1007/s11060-010-0112-1

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Immunotherapy targeting the Wilms' tumour 1 gene product has been proven safe and effective for treating malignant glioma in a phase II clinical study. Currently, radiation/temozolomide therapy is the standard treatment with only modest benefit. Whether combining radiation/temozolomide therapy with WT1 immunotherapy will have a negating effect on immunotherapy is still controversial because of the significant lymphocytopaenia induced by the former therapy. To address this issue, we investigated the changes in frequency and number of WT1-specific T-cells in patients with malignant gliomas.
Twenty-two patients with newly diagnosed malignant glioma who received standard radiation/temozolomide therapy were recruited for the study. Blood samples were collected before treatment and on the sixth week of therapy. The frequencies and numbers of lymphocytes, CD8(+) T-cells, WT1-specific T-cells, regulatory T-cells, natural killer cells and natural killer T-cells were measured and analysed using T-tests.
Analysis of the frequency of T lymphocytes and its subpopulation showed an increase in regulatory T-cells, but no significant change was noted in the populations of T-cells, WT1-specific T-cells, NK cells and NKT cells. Reductions in the total numbers of T-cells, WT1-specific T-cells, NK cells and NKT cells were mainly a consequence of the decrease in the total lymphocyte count.
Radiation/temozolomide therapy did not significantly affect the frequency of WT1-specific T-cells, suggesting that the combination with WT1 immunotherapy may be possible, although further assessment in the clinical setting is warranted.

DOI： 10.1093/jjco/hyp196

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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We describe herein a surgically treated case of Lhermitte-Duclos disease in a 33-year-old man. The clinical presentation seemed typical in terms of symptoms, neurological signs, and neuroimaging. High and heterogenous fluorodeoxyglucose uptake in positron emission tomography study is presented and discussed. Furthermore, we performed volumetric analysis of the tumor with sequential magnetic resonance imaging over the course of 7 years before surgery, making this report the first with a long-term natural history, revealing that this rare disease entity may have a neoplastic nature.

DOI： 10.1007/s11060-009-0042-y

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

The use of Wilms&apos; tumor 1 (WT1) immunotherapy is considered to be an innovative approach for the treatment of malignant gliomas. Because of its novelty, tools that can accurately predict response to this therapy are still lacking. In this article, we investigated the role of WT1 protein expression level (score 1-4) and MIB-1 staining index in predicting survival outcome after therapy in patients with recurrent or progressive glioblastoma multiforme. Tumor samples from 37 patients enrolled in a phase II clinical trial on WT1 immunotherapy were immunohistochemically analyzed for WT1 levels and MIB-1 index. Results showed that median progression-free survival (PFS) was longer in the WT1 high expression group (score 3 and 4) compared with that of the low expression group (score 1 and 2) (20.0 weeks vs. 8.0 weeks; P = 0.022), and that the median overall survival (OS) was likewise longer in the former compared to the latter group (54.4 weeks vs. 28.4 weeks; P = 0.035). Furthermore, within the WT1 high expression group, tumors with intermediate staining intensity (WT1 score 3) have both the longest median PFS and OS, 24.4 weeks and 69.4 weeks, respectively. On the other hand, no significant correlation was noted between MIB-1 staining index and survival. In conclusion, our study has shown that WT1 protein expression level, not MIB-1 staining index, can be used as a prognostic marker to foretell outcome after immunotherapy, and that patients whose tumors have intermediate WT1 expression have the best survival outcome.

DOI： 10.1007/s10014-010-0265-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Diffusion tensor imaging (DTI) by magnetic resonance imaging (MRI) is now used not only for delineating white matter fiber tracts, but also for assessing the histological characteristics of pathological tissues. Among these uses, predicting the extent or existence of tumor cell invasion into white matter by DTI is under extensive investigation. The previously reported tumor infiltration index (TII) holds great potential for the discrimination of pure vasogenic edema from tumor-infiltrated edema. However, conflicting data are being reported questioning the clinical value of TII. The present investigation reevaluated the utility of TII in patients with meningioma or glioma. We found that TII was unable to discriminate vasogenic from tumor-infiltrated edema. Conversely, detailed voxel-by-voxel comparison of TII and C-11-methionie PET in the T2-hyperintense area of gliomas showed that TII and C-11-methionie PET has a positive correlation, suggesting that, although TII is unable to discriminate the cause of edema, the extent of tumor cell invasion into white matter is depicted in gliomas by TII. These data suggest that TII involves both vasogenic and tumor-infiltrated factors, rather than only a single factor. A more intensive investigation is required to reach a complete understanding of TII.

DOI： 10.1007/s11060-009-9979-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

C-11-methionine positron emission tomography (C-11-methionine PET) provides accurate detection of brain tumors. Several reports have analyzed the correlation between uptake of C-11-methionine and Ki-67 index or microvessel density non-stereotactically and Suggested that C-11-methionine uptake reflects both proliferation potential and angiogenic capability in gliomas. As gliomas possess heterogeneous histological architecture, non-stereotactic comparison of the histology and C-11-methionine PET image may not be accurate. in the present study, the correlation between C-11-methionine uptake and cell or microvessel density was analyzed using histological specimens obtained by stereotactic biopsy, and an exact local comparison of C-11-methionine PET image and histological specimens was conducted. The tumor/normal tissue (T/N) ratio of C-11-methionine positron emission tomography was found to correlate better with cell density (R = 0.747, p = 0.000042) and Ki-67 index (R = 0.675, p = 0.00041) than with microvessel density (R = 0.467. p = 0.025) in a histological comparison using a stereotactic image. Furthermore, multiple linear regression analysis revealed that cell density was the key determinant for predicting C-11-methionine level while microvessel density was not. These results suggest that cell density contributes more to C-11-methionine uptake than microvessel density in glioma tissues and that the previously reported correlation of C-11-methionine uptake and microvessel density in glioma patients requires reevaluation. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2009.11.024

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS LTD  

In vivo molecular imaging is a rapidly growing research area both for basic and clinical science. Non-invasive imaging of in vivo conditions at the molecular level increases understanding of the biological characteristics of normal and diseased tissues without the need for invasive surgical procedures. Among the various imaging modalities, magnetic resonance imaging (MRI) has garnered interest as a molecular imaging modality due to its high spatial resolution. Here, we have demonstrated that the combined use of HER-2 targeting affibody, a small 7 kDa molecule that behaves similarly to antibodies, and superparamagnetic iron oxide (SPIO) can non-invasively image HER-2 expressing cells or tissues both in vitro and in vivo by MRI. This preliminary study demonstrates that affibody-SPIO is a feasible, target-specific contrast agent for in vivo MR molecular imaging. Copyright (C) 2010 John Wiley & Sons, Ltd.

DOI： 10.1002/cmmi.363

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Language：Japanese   Publisher：(NPO)日本小児がん学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

A 23-year-old Japanese woman presented with a newly developed spinal extradural arteriovenous fistula (AVF) during pregnancy. She had been followed up for a suspected spinal cavernous angioma and became unable to walk during the 29th week of her pregnancy. Magnetic resonance (MR) imaging showed a spinal extradural AVF at the T3 to T4 levels compressing the spinal cord. After delivery by cesarean section, her neurological symptoms gradually began to resolve, and she was able to resume walking without assistance. MR imaging confirmed spontaneous regression of the AVF. This case suggests that exacerbated neurological symptoms and AVF growth triggered by pregnancy can improve after delivery without interventional treatment. Careful follow up of neurological findings is required to prevent unnecessary interventional procedures in pregnant women with spinal AVF.

DOI： 10.2176/nmc.49.313

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Multimodal imaging is one of the necessary steps in the treatment of malignant brain tumors, and use of magnetic resonance imaging (MRI) and positron emission tomography (PET) are the current gold standard technique for the morphological and biological assessment of malignant brain tumors. In addition, fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) and C-11-methionine PET are useful to determine the tumor border at the tumor and white matter interface. Although there is no question of their value, a universally accepted cut-off value to discriminate normal and abnormal tissue has not been established. In this study we attempted to calculate and determine the cut-off values in FA and C-11-methionine PET that will allow delineation of the tumor border at the tumor and white matter interface by combining these two modalities. We were able to determine individual cut-off values for 11 patients, and then found an average cut-off value in the T/N ratio of 11C-methionine PET of 1.27 and in FA of 0.26, values similar to those previously confirmed by histological study. Moreover, reconstructing images delineating the tumor border was possible combining these two imaging modalities. We propose that the combined analysis of DTI and C-11-methionine PET has the potential to improve tumor border imaging in glioma patients, providing important information for establishing neurosurgical strategies. (c) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2008.11.034

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Two distinct forms of malignant lymphomas can invade the central nervous system (CNS). Although primary CNS malignant lymphomas (PCNSMLs) invade the brain parenchyma, intravascular lymphomas (IVLs) form tumor cell aggregates in the vasculature and produce stroke-like symptoms and cognitive impairment. Although the tumor cells are mostly of B-cell origin in both types of lymphoma, their biological behavior is different, and the detailed mechanism(s) underlying this difference are not well understood. We studied the expression level of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and integrin-beta 1 in tumor tissue samples from patients with primary CNS lymphoma (n = 8) and intravascular lymphoma (n = 2) using immunohistochemical analysis. We also assessed the expression of the matrix metalloproteinases (MMP)-2 and MMP-9. ICAM-1 was positive in six and integrin-beta 1 was positive in seven patients among eight PCNSML patients. MMP-2 and MMP-9 were expressed in all PCNSML. In contrast, none of them was positive in both IVL cases. Our findings suggest that adhesion molecules and MMPs are essential for malignant lymphoma cell invasion from the vasculature into the brain parenchyma and that they may be the key determinants for malignant lymphoma cells to behave as PCNSML or IVL cells.

DOI： 10.1007/s10014-008-0232-x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

A noninvasive technique for assessing tumor tissue characteristics is required to assist preoperative surgical planning for malignant brain tumors. Preoperative information on tumor cell density within a tumor would help better define the target for tumor biopsy, resulting in more accurate diagnosis and grading of malignant brain tumors. One possible source of this information is diffusion tensor imaging (DTI), although to date studies have focused on its ability to delineate white matter fiber tracks by fiber-tracking and to detect tumor infiltration around the tumor and normal white matter interface.
However, the use of DTI for providing information on cell density has also been examined, although with the controversial results. In addition the exact relationships between cell density and the two key values that DTI provides, namely fractional anisotropy (FA) and mean diffusivity (MID), still need to be investigated. In the present study we performed a retrospective investigation of tumor cell density and FA and MD values in biopsy cases. We found that FA has a good positive correlation (R=0.75) and MD has a good negative correlation (R=0.70) with tumor cell density within the tumor core. Similar correlation was observed between the Ki-67 labeling index and FA (R=0.71) and MD (R=0.62).
Thus, measurement of both FA and MD within the tumor core has a potential to provide detailed information on tumor cell density within the tumor. Although data obtained from DTI should be interpreted carefully and comprehensively with other imaging modalities such as positron emission tomography, DTI seems to be informative for planning the best biopsy target containing the highest cell density. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2008.06.041

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Language：Japanese   Publisher：(一社)日本脳神経外科学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Ultrasound-induced intracellular drug delivery, sonoporation, is an appealing and promising technique for next generation drug delivery system. Many types of molecules, such as plasmid DNAs, siRNAs and peptides, have been demonstrated to be delivered into the cell by ultrasound with the aid of microbubbles both in vitro and in vivo. Although there are many reports on in vitro sonoporation, the efficiency of successful sonoporation and the viabilities of cells after the procedure documented in each report vary in a wide range, and the reasons for these differences are not fully understood. In this study, we have investigated how different experimental settings would affect sonoporation efficiency and cell viabilities after the procedure. Our results show that the fashion of cell culture (e.g. in suspension or in monolayer culture) and the presence of standing wave have a great impact on the overall results. These results indicate that in vitro sonoporation settings should be carefully evaluated in each experiment. The fact that standing wave is necessary to achieve high sonoporation efficiency may be a problematic issue for clinical application of sonoporation, as it may be difficult (although not impossible) to create standing wave in a human body. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.05.153

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The molecular mechanisms underlying ultrasound-induced apoptosis remain poorly understood. We have demonstrated that in Jurkat cells, the over-expression of the anti-apoptotic protein Bcl-2 inhibited ultrasound-induced apoptosis, but not necrosis. Inhibition of caspase activity also protected the cells from apoptosis, but not from necrosis, showing the involvement of different mechanisms in ultrasound-induced apoptosis and necrosis. Bak, a pro-apoptotic member of the Bcl-2 family proteins, was activated by ultrasound and its activation was completely inhibited by Bcl-2 over-expression, but not by caspase inhibition. Antioxidaut N-acetyl cysteine did not protect the cells from ultrasound-induced apoptosis or necrosis, nor did the inhibition of either c-Jun N-terminal kinase or p38, key factors in the radical oxygen species (ROS)-mediated cell stress response, suggesting that ROS do not play a crucial role in ultrasound-induced apoptosis. Our results confirm that ultrasound induces apoptosis via a pathway that involves Bak, Bcl-2, and caspases, but not ROS. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2006.12.055

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.

DOI： 10.1073/pnas.0604318103

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DOI： 10.1097/RMR.0b013e3180332e79

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：RADIATION RESEARCH SOC  

The biological effects of ultrasound have been investigated vigorously for various applications including the thermal coagulation of tissues, the opening of tight junctions, and localized gene or drug introduction. The synergistic cell killing effect of ultrasound and porphyrin derivatives, the so-called sonodynamic effect, holds promise for cancer treatment. Although several models to explain the sonodynamic effect have been proposed, its exact mechanism, especially in vivo, remains unknown. We examined the effect of a porphyrin derivative, protoporphyrin IX, on ultrasound-induced killing of HeLa cells. In some experiments, the intracellular protoporphyrin IX concentration was increased by 5-aminolevulinic acid treatment of the cells. Although extracellular protoporphyrin IX showed an enhanced cell killing effect by microbubble-enhanced ultrasound, intracellular protoporphyrin IX did not. On the other hand, intracellular protoporphyrin IX enhanced the cell killing effect of hyperthermia, which can be produced by ultrasound exposure, in a moderately acidic environment (pH 6.6). Because porphyrin derivatives are generally imported into the intracellular component in vivo, our results suggest that hyperthermia caused by ultrasound may play an important role in the sonodynamic effect induced by porphyrin derivatives. (C) 2006 by Radiation Research Society.

DOI： 10.1667/RR3510.1

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The blood-brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the marine CNS. Here, we demonstrate that Subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D-4 receptor-targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption. This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.12.112

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：AMER INST PHYSICS  

Bioactive substances such as peptides and nucleic acid based agents have attracted great attention for the next generation drug for various diseases. However, the greatest challenge for using these bioactive substances is the development of their delivery system, especially the method for delivering these substances through the cell membrane. With the advancement of ultrasound and ultrasound contrast agent technology, it has become possible to transiently change the permeability of the cell membrane. Moreover, using a focused ultrasound transducer, it is possible to narrow and focus the ultrasound energy within a small target, avoiding damage to the surrounding tissue. In this research we have searched the possibility of delivering the Bak BH3 peptide, the death domain of the Bcl-2 family of proteins, or the short interfering RNA (siRNA) targeting the enhanced green fluorescent protein (EGFP) using microbubble-enhanced focused ultrasound in an in vitro setting. Using a 1.696 MHz focused ultrasound and a microbubble ultrasound contrast agent OPTISON (R), we first tested the stability of BH3 peptide under microbubble-enhanced focused ultrasound exposure and proved that the peptide is stable under these circumstances. Next, we have tested the cell-killing effect of the intracellularly delivered Bak BH3 peptide in HeLa and BJAB cell line and observed a statistically enhanced cell death in BJAB cells but not in HeLa cells, leading to the conclusion that intracellularly delivered BH3 peptide by microbubble-enhanced ultrasound can exert its cell killing effect in some cells. We also investigated if we can silence the EGFP expression in the cell by delivering siRNA targeting the EGFP in both transient and stable EGFP expression cell line. Using a 1.653 MHz focused ultrasound and OPTISON (R), in both cases, intracellularly delivered siRNA by microbubble-enhanced ultrasound was able to knock down the EGFP expression, which demonstrates the feasibility of using this novel method for siRNA intracellular delivery. In conclusion, our investigation has proved the feasibility of using micro-bubble enhanced focused ultrasound as a method for intracellular delivery of peptides and siRNAs. Although further optimization of various parameters is necessary, we consider that this method could be a power tool for using these bioactive substances in the clinical field.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：IEEE  

Ultrasound induced intracellular drug delivery, sonoporation, is an appealing and promising technique for next generation drug delivery system. Many types of molecules, such as plasmid DNAs, siRNAs and peptides, have been demonstrated to be delivered into the cell by ultrasound with the aid of microbubbles both in vitro and in vivo. Although there are many repots on in vitro sonoporation, the efficiencies of successful sonoporation and the viabilities of cells after the procedure documented in each report varies in a wide range, and the reasons for these differences are not fully understood. In this study, we have investigated how different experimental settings would affect sonoporation efficiencies and cell viabilities after the procedure.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Short interfering RNA (siRNA) has attracted much attention for clinical use in various diseases. However, its delivery, especially through the cell membrane, continues to present a challenge. Advances in ultrasound- and ultrasound contrast-agent technologies have made it possible to change transiently the permeability of the cell membrane and, using a focused ultrasound transducer, to narrow and focus the ultrasound energy on a small target, thereby avoiding damage to surrounding tissue. In this in vitro study, we demonstrate that it is possible to deliver siRNA intracellularly via microbubble-enhanced focused ultrasound. Although further optimization is necessary, our novel method for siRNA transduction represents a powerful tool for using siRNA in vivo and possibly in the clinical setting. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.07.101

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

Background: Although craniopharyngiomas have a histologically benign nature, their treatment can be difficult. The correlation among clinical, proliferative, and immumohistologic features of female sex hormone receptors was determined in craniopharyngiomas to analyze whether they influence the growth of the tumor.
Methods: The study subjects were 43 patients with previously untreated craniopharyngioma who underwent surgery at our department over the past 15 years. Serial tissue sections were immunostained with the antibodies against estrogen receptor (ER), progesterone receptor (PR), and Ki-67.
Results: The Ki-67 labeling index was significantly higher in patients with regrowth (7.8%) than without regrowth (3.9%). ER and PR were detected in 9 of 30 (30%) craniopharyngiomas, and the incidence of postoperative tumor regrowth was significantly higher in patients negative for ER and PR (29%) than in those positive for both receptors (11%).
Conclusions: A high Ki-67 labeling index suggests a high possibility of tumor regrowth, and the presence of ER and PR is suggestive of a high tissue differentiating potential. ER and PR assay may be useful for determining the indication for additional radiation therapy in cramopharyngioma patients treated by incomplete resection. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.surneu.2004.08.094

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

Purpose To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound.
Methods HeLa and BJAB cells were exposed to 1.696-Mhz focused ultrasound with 2% microbubble contrast agents (OPTISON (R)). Cell- impermeable calcein was used as an indicator for successful sonoporation, and propidium iodide staining was used for cell viability assessment. Peptides were also exposed to ultrasound with OPTISON (R) and analyzed with mass spectrometry for evaluation of stability under ultrasound exposure. The effect of transduced Bak BH3 peptide was evaluated by the cell viability of successfully sonoporated cells.
Results Bak BH3 peptides did not undergo mechanical degradation with microbubble-enhanced ultrasound exposure. With the increase of acoustic energy exposure, the sonoporation efficiency saturated both in BJAB and HeLa cells, while direct cell death rate by ultrasound exposure tended to increase. When BJAB cells were treated with 100 mu M Bak BH3 peptides, and ultrasound exposure with ultrasound contrast agents (OPTISON (R)), an increased 35% cell death was confirmed. On the other hand, although HeLa cells had a similar trend, they failed to exhibit statistical significance.
Conclusions Our results suggest that microbubble-enhanced focused ultrasound peptide transduction is possible. Further optimization of ultrasound exposure conditions may be necessary.

DOI： 10.1007/s11095-005-2586-7

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

Background. Image-guided and temperature-controlled radiofrequency thermal ablation techniques were applied to reduce tumor volume and relieve the symptoms caused by extracranial extension of recurrent meningioma.Method. We treated two patients with recurrent meningioma, an 81-year-old woman presenting with bulging of the temple and a 68-year-old woman presenting with visual disturbance, facial disfigurement, and sensory disturbance. Neuroimaging in both patients, revealed a large tumor extending extracranially and involving the infratemporal fossa. To avoid injury to important anatomical structures either compressed or entrapped by the tumor, the spatial relation between the planned ablation volume and these structures was confirmed by 3-D reconstruction of the ablation target. During the ablation procedure, local temperatures over the tissue being cauterized were continuously monitored to limit the ablation area to that within the planned volume adjusting RF power.Finding. Radiofrequency ablation produced tumor necrosis as planned without adverse effects and resulted in swift relief of symptoms and signs with shrinkage of the tumor.Conclusion. This technique may be an effective alternative for recurrent meningiomas extending extracranially and for which radical surgical procedures are not indicated.

DOI： 10.1007/s00701-005-0509-3

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The fiber-tracking method enables in vivo visualization of the white matter tracts of the brain using a diffusion tensor MR imaging technique. While this method represents a promising tool in the field of neurosurgery, especially when confronted with brain tumors in eloquent areas, its reliability remains unknown. We present here our preliminary validation of tractography in human subjects harboring brain tumors by comparing the results produced by neuronavigation and electrical white matter stimulation in two patients with gliomas in the eloquent area. Although we were able to visualize the pyramidal tract with the fiber-tracking technique, the images failed to present the actual size of the fiber bundles. Here we discuss the advantages and limitations of fiber-tracking in the field of neurosurgery. (c) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2004.07.076

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

GM3, the simplest ganglioside, modulates cell adhesion, proliferation and differentiation in the central nervous system and exogenously added GM3 regulates cell-cell and cell-extracellular matrix adhesion and induces apoptosis. To assess the anti-tumor action of exogenous GM3, we examined its effect on the proliferation and invasion of glioma cells. Its inhibitory effect on cell proliferation was demonstrated in vitro by 3-(4,5-dimethyl-2-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and in vivo in rats with meningeal gliomatosis whose survival was significantly prolonged by the intrathecal injection of GM3. Terminal deoxynucleotidyl transferase- mediated dUTP-biotin nick end-labeling (TUNEL) assay revealed that GM3 induced glioma cell apoptosis in vitro and in vivo. In rat brain slice cultures, GM3 suppressed the invasion of glioma cells; this effect manifested earlier than the inhibition of cell proliferation and before apoptosis induction. Our results suggest exogenous GM3 as a potential therapeutic agent in patients with glioma requiring adjuvant therapy.

DOI： 10.1007/s11060-004-9602-3

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

An 11-year-old Japanese girl presented with a right frontal lobe anaplastic ependymoma. The tumor was removed surgically. However, she developed a secondary lesion and extracranial metastasis in the cervical lymph node. In total, she underwent eight intracranial tumor removal procedures, five stereotactic radiosurgeries with six targets, and five cervical lymph node removal surgeries during the course of 7 years. She is currently alive with a good quality of life, and has no major neurological deficits except right facial nerve palsy. The combination of surgery and radiosurgery can achieve local control of anaplastic ependymoma. Multiple surgery or radiosurgery procedures can result in good outcome, if the tumor does not involve crucial structures, even if extracranial metastasis occurs.

DOI： 10.2176/nmc.44.669

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

Object. Controlling hemorrhage is crucial in the safe and efficient removal of large meningiomas. Intravascular embolization is not always a satisfactory means of accomplishing this goal because of the procedure's hemostatic effect and risk of complications. The authors in this study used a volumetric thermal ablation technique incorporating radiofrequency energy, image guidance, and local temperature control to devascularize tumor tissue.Methods. Five patients with large meningiomas were treated. The target and orientation of the radiofrequency thermal ablation (RFTA) were simulated preoperatively to maximize devascularization of the lesion without thermal injury to adjacent critical structures. Image fusion, three-dimensional reconstruction, and image-guided methods provided for optimized trajectories and targets for insertion of the RFTA needle. During ablation, local temperatures of the tissue being cauterized were monitored continuously to limit the ablated lesion to within the target volume.The effects of devascularization and the softening of the tumor parenchyma facilitated lesion removal. The intracranial ablated meningioma changed into necrotic tissue and shrank within a few months. Histopathological examination of the ablated lesion revealed sharply demarcated coagulation necrosis.Conclusions. Volumetric thermal devascularization can be applied safely in the treatment of large meningiomas to facilitate surgical manipulation of the lesion as well as to reduce its size palliatively. The procedure's usefulness should be Studied further in a larger number of cases with different tumor characteristics.

DOI： 10.3171/jns.2004.101.5.0779

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Authorship：Lead author   Language：English   Publisher：ELSEVIER SCIENCE INC  

BACKGROUND Extra-axial primary CNS lymphoma, considered rare, mainly arise in the white matter of the brain. Though the tumor responds well to radiation and chemotherapy, the prognosis of primary CNS lymphoma remains poor. We report a case of primary lymphoma of Meckel's cave mimicking a trigeminal schwannoma radiographically, which achieved complete remission through use of rapid high-dose MTX therapy and radiation therapy.
CASE PRESENTATION The patient, a 55-year-old Japanese male, presented left trigeminal neuralgia. Magnetic resonance imaging (MRI) revealed a mass lesion in the left side of Meckel's cave, with extension into the cerebellopontine angle and the infratemporal fossa through the foramen ovale, suggesting trigeminal schwannoma. However, the patient suffered radiologically inexplicable progressive cranial nerve palsy, which suggested malignant disease. MRI and CSF disclosed malignant tumor dissemination; biopsy revealed malignant lymphoma. The treatment, composed of the rapid infusion of high-dose MTX and whole brain and spine radiation, resulted in complete remission.
CONCLUSION This case, which included atypical presentation of malignant lymphoma, illustrates the importance of including malignant lymphoma in the differential diagnosis of CP-angle and Meckel's cave tumor. The results also confirmed the usefulness of combined rapid high-dose MTX therapy and radiation. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0090-3019(03)01046-7

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Eight months after radical surgery for small-cell neuroendocrine carcinoma (SCNC) of the urinary bladder, a 69-year-old man was admitted with a brain tumor in the left frontal lobe. The tumor, about 5cm in diameter, was intensely but heterogeneously enhanced on computed tomography and magnetic resonance imaging. The tumor was subtotally removed, leaving only the portion adjacent to the anterior horn of the left lateral ventricle. Microscopically, the tumor was composed of diffuse sheets of small tumor cells with round to spindle-shaped nuclei, indistinct nucleoli, scant or absent cytoplasm, and indistinct cell margins. Immunohistochemically, the tumor cells were positive for synaptophysin, neuron-specific enolase, chromogranin A, and keratin. Ultrastructurally, the tumor cells showed classic neurosecretory granules and microvilli in the cytoplasm. The tumor was diagnosed as a brain metastasis from SCNC of the urinary bladder. After surgery, whole-brain radiation therapy of 40 Gy was performed, which succeeded in controlling the residual tumor. However, 4 months after surgery, the patient died of meningeal carcinomatosis. To our knowledge, this is the first report focusing on brain metastasis from SCNC of the urinary bladder. The clinicopathological features and pathological diagnosis of this tumor are discussed.

DOI： 10.1007/BF02478938

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Bcl-2 and Bcl-x(L) serve as critical inhibitors of apoptosis triggered by a broad range of stimuli, mainly acting on the mitochondria, We identified two members of the reticulon (RTN) family as Bcl-x(L) binding proteins, i.e,, NSP-C (RTNt-C) and a new family member, RTN-x(S), both of which did not belong to the Bcl-2 family and were predominantly localized on the endoplasmic reticulum (ER). RTN-x(S) interacted with both Bcl-x(L) and Bcl-2, increased the localization of Bcl-xL and Bcl-2 on the ER, and reduced the anti-apoptotic activity of Bcl-xL and Bcl-2. On the other hand, NSP-C interacted only with Bcl-x(L), affected the localization of Bcl-x(L), and reduced Bcl-xL activity, but had no effect on Bcl-2, These results suggest that RTN family proteins can modulate the anti-apoptotic activity of Bcl-x(L) and Bcl-2 by binding with them and can change their localization to the ER.

DOI： 10.1038/sj.onc.1203948

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS INC  

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Language：Japanese   Publisher：一般社団法人 日本内分泌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：近畿脳腫瘍病理検討会  

髄膜腫に対する術前塞栓術は、近年の血管内治療の進歩と塞栓物質の改良によってその安全性と有効性が向上している。一方で、手技による合併症が一定の確率で起こることや、内頸動脈系からの栄養血管の塞栓は危険性が高いことなどの問題がある。髄膜腫に対する術前塞栓術の方法、効果評価と有用性、合併症について述べた。また、塞栓術後髄膜腫の病理学的変化とそれに関わる異型性髄膜腫の定義の変遷について概説した。

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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