Publications by authors named "Yasuo Iwadate"

95 Publications

The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.

Cancer Sci 2021 Mar 16. Epub 2021 Mar 16.

Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared to controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as potent therapeutic strategies against GBM.
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http://dx.doi.org/10.1111/cas.14885DOI Listing
March 2021

Predicting Potential of Rapid Tumor Growth in Small to Medium Vestibular Schwannomas on the Basis of Sway Assessed Using Posturography.

World Neurosurg 2021 Apr 11;148:e406-e414. Epub 2021 Jan 11.

Departments of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Objective: The relationship between quantitative posturography results and growth of vestibular schwannomas (VSs) during conservative management has not been studied. We aimed to clarify the relationship between the presence of disequilibrium based on posturographic measurement and VS growth.

Methods: This retrospective, single-center study included 53 patients with VSs (Koos stage I or II) managed conservatively after initial diagnosis. Radiographic progression was considered present if 20% volumetric growth was observed over the imaging interval. Posturography was performed at initial diagnosis, and sway velocity (SV) and sway area were calculated. Tumor growth-free survival was estimated using the Kaplan-Meier method.

Results: Mean follow-up period was 2.87 ± 2.58 years, up to tumor growth detection or last follow-up magnetic resonance imaging. Tumor growth incidence was 40.8% and 61.2% at 2 and 5 years, respectively. Cerebellopontine angle extension and SV with eyes open were related to tumor growth. Tumor growth-free survival of patients with cerebellopontine angle extension and patients with intracanalicular tumor at 2 years was 37.3% and 76.4%, respectively. Tumor growth-free survival of patients with SV >2.06 cm/second and patients with SV ≤2.06 cm/second at 2 years was 30.8% and 68.9%, respectively. The Cox hazard model demonstrated a significant risk for future tumor growth with SV >2.06 cm/second (relative risk, 2.475; 95% confidence interval, 1.11-5.37, P = 0.027).

Conclusions: We demonstrated a positive correlation between SV with eyes open and future tumor growth. Posturographic data are objective and quantitative; thus, SV may be a potential predictor of future growth of VSs.
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http://dx.doi.org/10.1016/j.wneu.2020.12.175DOI Listing
April 2021

Predicting Neurocognitive Change after Bilateral Deep Brain Stimulation of Subthalamic Nucleus for Parkinson's Disease.

World Neurosurg 2021 Mar 5;147:e428-e436. Epub 2021 Jan 5.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Objective: Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) is a standard surgical treatment option in patients with advanced Parkinson's disease. Adverse effects on cognitive function have been reported, impacting the quality of life of patients and caregivers. We aimed to investigate a quantitative predictive preexisting cognitive factor for predicting postoperative cognitive changes.

Methods: Thirty-five patients underwent STN-DBS. A battery of neuropsychological tests were used to examine executive function, processing speed, and visuospatial function both preoperatively and 1 year postoperatively. A multiple logistic regression analysis was performed to investigate the relationships between preoperative factors and cognitive outcomes. The predictive value of the preoperative factors for global cognitive decline during long-term follow-up were evaluated.

Results: The patients exhibited significant changes in processing speed and visuospatial function after surgery. Using reliable change index values, lower preoperative scores on the Similarities and Object Assembly subtests of the Wechsler Adult Intelligence Scale III were associated with decreases in visuospatial function at 1 year after DBS. The odds ratios were 10.2 for Similarities and 9.53 for Object Assembly. The proportion of Mini Mental State Examination-maintained patients with low scores on the Similarities subtest was significantly lower than that of patients with high scores at 3 and 5 years. No factors were found to be related to decreases in processing speed.

Conclusions: Preoperative evaluation of the Similarities and Object Assembly subtests may be useful to identify patients who are at a greater risk of experiencing decreases in visuospatial functioning after STN-DBS. Furthermore, a low score on the Similarities subtest may predict future global cognitive deterioration.
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http://dx.doi.org/10.1016/j.wneu.2020.12.081DOI Listing
March 2021

CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy.

Cancer Immunol Immunother 2020 Oct 31. Epub 2020 Oct 31.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.
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http://dx.doi.org/10.1007/s00262-020-02742-1DOI Listing
October 2020

Two cases of symptomatic secondary hypophysitis due to Rathke's cleft cysts treated with glucocorticoids: long-term follow-up.

Endocr J 2021 Mar 21;68(3):269-279. Epub 2020 Oct 21.

Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.
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http://dx.doi.org/10.1507/endocrj.EJ20-0361DOI Listing
March 2021

Association between serum anti‑ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension.

Int J Mol Med 2020 Oct 29;46(4):1274-1288. Epub 2020 Jul 29.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan.

The aim of the present study was to identify novel antibody markers for the early diagnosis of atherosclerosis in order to improve the prognosis of patients at risk for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). A first screening involved the serological identification of antigens by recombinant cDNA expression cloning and identified additional sex combs‑like 2 (ASXL2) as a target antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. Antigens, including the recombinant glutathione S‑transferase‑fused ASXL2 protein and its synthetic peptide were then prepared to examine serum antibody levels. Amplified luminescence proximity homogeneous assay‑linked immunosorbent assay, which incorporates glutathione‑donor beads and anti‑human‑IgG‑acceptor beads, revealed significantly higher serum antibody levels against the ASXL2 protein and its peptide in the patients with AIS, diabetes mellitus, AMI, chronic kidney disease, esophageal squamous cell carcinoma, or colorectal carcinoma compared with those in healthy donors. The ASXL2 antibody levels were well associated with hypertension complication, but not with sex, body mass index, habitual smoking, or alcohol intake. These results suggest that the serum ASXL2 antibody marker can discriminate between hypertension‑induced atherosclerotic AIS and AMI, as well as a number of digestive organ cancers.
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http://dx.doi.org/10.3892/ijmm.2020.4690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447314PMC
October 2020

Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases.

Cancer Sci 2020 Dec 4;111(12):4453-4464. Epub 2020 Oct 4.

Department of Gastroenterological Surgery and Clinical Oncology, Toho University Graduate School of Medicine, Tokyo, Japan.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti-human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S-transferase-fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis-related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well-known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.
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http://dx.doi.org/10.1111/cas.14652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734161PMC
December 2020

Elevated levels of autoantibodies against DNAJC2 in sera of patients with atherosclerotic diseases.

Heliyon 2020 Aug 19;6(8):e04661. Epub 2020 Aug 19.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Background: Serum antibody markers have been increasingly identified not only for cancer and autoimmune diseases but also for atherosclerosis-related diseases such as acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD). Biomarkers for transient ischemic attack (TIA) and non-ST segment elevation acute coronary syndrome (NSTEACS) are potentially useful for detection of early phase of atherosclerotic changes against AIS and AMI, respectively.

Methods: We utilized serological identification of antigens by recombinant cDNA expression cloning (SEREX) using a human aortic endothelial cell cDNA phage library and sera from patients with TIA or NSTEACS. Serum antibody levels were measured by amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using purified recombinant antigens.

Results: Screening of sera from patients with TIA identified DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2) as a candidate antigen, which was also isolated by SEREX screening using sera of patients with NSTEACS. The validation cohort revealed significantly higher DNAJC2 antibody (DNAJC2-Ab) levels in the sera of patients with TIA or AIS than those in healthy donors (HDs). Multivariate logistic regression analysis indicated that the predictive odds ratios (OR) of DNAJC2-Ab levels for TIA and AIS were 2.54 (95% confidence interval [CI]: 1.36-4.74, = 0.0034) and 2.14 (95% CI: 1.39-3.30, = 0.0005), respectively. Serum DNAJC2-Ab levels were also higher in patients with AMI, DM, and CKD than those in HDs.

Conclusion: Serum DNAJC2-Ab level may be useful for early detection of atherosclerotic lesions, which lead to AIS and AMI.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452465PMC
August 2020

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

Breast Cancer Res Treat 2020 Nov 1;184(1):149-159. Epub 2020 Aug 1.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Introduction: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy.

Methods: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis.

Results: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03).

Conclusions: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.
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http://dx.doi.org/10.1007/s10549-020-05835-8DOI Listing
November 2020

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL.

Sci Rep 2020 05 21;10(1):8435. Epub 2020 May 21.

Osaka Iseikai Clinic for Cancer Therapy, Iseikai Holonics Group, Osaka, Japan.

Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin's B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. These results suggest that the GSEA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances.
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http://dx.doi.org/10.1038/s41598-020-65463-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242340PMC
May 2020

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

J Neurooncol 2020 May 4;148(1):17-27. Epub 2020 May 4.

Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone.

Experimental: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations.

Results: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found.

Conclusion: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.
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http://dx.doi.org/10.1007/s11060-020-03505-9DOI Listing
May 2020

miR-101, miR-548b, miR-554, and miR-1202 are reliable prognosis predictors of the miRNAs associated with cancer immunity in primary central nervous system lymphoma.

PLoS One 2020 26;15(2):e0229577. Epub 2020 Feb 26.

Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043771PMC
June 2020

Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers.

J Neurooncol 2020 Mar 5;147(1):237-246. Epub 2020 Feb 5.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Purpose: Stereotactic radiosurgery (SRS) is typically considered for patients who cannot undergo surgical resection for large (> 10 cm) brain metastases (BMs). Staged SRS requires adaptive planning during each stage of the irradiation period for improved tumor control and reduced radiation damage. However, there has been no study on the tumor reduction rates of this method. We evaluated the outcomes of two-stage SRS across multiple primary cancer types.

Methods: We analyzed 178 patients with 182 large BMs initially treated with two-stage SRS. The primary cancers included breast (BC), non-small cell lung (NSCLC), and gastrointestinal tract cancers (GIC). We analyzed the overall survival (OS), neurological death, systemic death (SD), tumor progression (TP), tumor recurrence (TR), radiation necrosis (RN), and the tumor reduction rate during both stages.

Results: The median survival time after the first Gamma Knife surgery (GKS) procedure was 6.6 months. Compared with patients with BC and NSCLC, patients with GIC had shorter OS and a higher incidence of SD. Compared with patients with NSCLC and GIC, patients with BC had significantly higher tumor reduction rates in both sessions. TP rates were similar among primary cancer types. There was no association of the tumor reduction rate with tumor control. The overall cumulative incidence of RN was 4.2%; further, the RN rates were similar among primary cancer types.

Conclusions: Two-stage SRS should be considered for BC and NSCLC if surgical resection is not indicated. For BMs from GIC, staged SRS should be carefully considered and adapted to each unique case given its lower tumor reduction rate and shorter OS.
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http://dx.doi.org/10.1007/s11060-020-03421-yDOI Listing
March 2020

Circulating Anti-Sorting Nexins 16 Antibodies as an Emerging Biomarker of Coronary Artery Disease in Patients with Obstructive Sleep Apnea.

Diagnostics (Basel) 2020 Jan 27;10(2). Epub 2020 Jan 27.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Chiba, Japan.

Biomarkers are not available for monitoring the onset and progression of coronary artery disease (CAD) in patients with obstructive sleep apnea (OSA), a major risk factor for arteriosclerotic cardiovascular diseases. This study aimed to test for correlation between circulating anti-Sorting Nexins 16 antibody (SNX16-Ab) levels, CAD history and clinical parameters of patients with OSA. Sixty-four healthy donors, 82 adults with OSA, and 96 with acute coronary syndrome (ACS) were studied. Serum samples were collected at diagnostic polysomnography in the OSA group or at the disease onset in the ACS group. Serum SNX16-Ab levels were measured by amplified luminescence proximity homogeneous assay (AlphaLISA), and correlation between SNX16-Ab levels and clinical parameters was analyzed. SNX16-Ab levels and apnea-hypopnea index (AHI) were weakly correlated. Additionally, logistic regression analyses of OSA group identified that elevated SNX16-Ab level associated with the history of CAD. Circulating SNX16-Ab could increase during CAD pathogenesis in patients with OSA. Further prospective studies are required to prove the predictive potential of SNX16-Ab level in CAD onset of patients with OSA.
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http://dx.doi.org/10.3390/diagnostics10020071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168932PMC
January 2020

White matter dissection and structural connectivity of the human vertical occipital fasciculus to link vision-associated brain cortex.

Sci Rep 2020 01 21;10(1):820. Epub 2020 Jan 21.

Department of Functional Anatomy, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

The vertical occipital fasciculus (VOF) is an association fiber tract coursing vertically at the posterolateral corner of the brain. It is re-evaluated as a major fiber tract to link the dorsal and ventral visual stream. Although previous tractography studies showed the VOF's cortical projections fall in the dorsal and ventral visual areas, the post-mortem dissection study for the validation remains limited. First, to validate the previous tractography data, we here performed the white matter dissection in post-mortem brains and demonstrated the VOF's fiber bundles coursing between the V3A/B areas and the posterior fusiform gyrus. Secondly, we analyzed the VOF's structural connectivity with diffusion tractography to link vision-associated cortical areas of the HCP MMP1.0 atlas, an updated map of the human cerebral cortex. Based on the criteria the VOF courses laterally to the inferior longitudinal fasciculus (ILF) and craniocaudally at the posterolateral corner of the brain, we reconstructed the VOF's fiber tracts and found the widespread projections to the visual cortex. These findings could suggest a crucial role of VOF in integrating visual information to link the broad visual cortex as well as in connecting the dual visual stream.
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http://dx.doi.org/10.1038/s41598-020-57837-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972933PMC
January 2020

Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL.

Sci Rep 2019 07 10;9(1):10004. Epub 2019 Jul 10.

Laboratory of Molecular Target Therapy for Cancer, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

In current molecular medicine, next-generation sequencing (NGS) for transcript variant detection and multivariable analyses are valid methods for evaluating gene expression, cancer mechanisms, and prognoses of patients. We conducted RNA-sequencing on samples from patients with primary central nervous system lymphoma (PCNSL) using NGS and performed multivariable analysis on gene expression data and correlations focused on Th-1/Th-2 helper T cell balance and immune checkpoint to identify diagnosis/prognosis markers and cancer immune pathways in PCNSL. We selected 84 transcript variants to limit the analysis range for Th-1/Th-2 balance and stimulatory and inhibitory checkpoints in 31 PCNSLs. Of these, 21 highly-expressed transcript variants were composed of the formulas for prognoses based on Th-1/Th-2 status and checkpoint activities. Using formulas, Th-1, Th-2, and stimulatory checkpoint resulted in poor prognoses. Further, Th-1Th-2 was associated with good prognoses. On the other hand, CD40-001 and CD70-001 as stimulatory genes, and LAG3-001, PDCD1 (PD-1)-001/002/003, and PDCD1LG2 (PD-L2)-201 as inhibitory genes were associated with poor prognoses. Interestingly, Th-1Th-2 and Th-1Th-2 were correlated with stimulatory checkpoint as CD70-001 and inhibitory checkpoint as HAVCR2 (TIM-3)-001 and PDCD1LG2-001/201, respectively. Focused on the inhibitory checkpoint, specific variants of CD274 (PD-L1)-001 and PDCD1-002 served severe hazard ratios. In particular, PDCD1-002 by a cut off score was associated with poor prognoses, in addition to PDCD1-001/003, PDCD1LG2-201, and LAG3-001. These results mainly suggest that expression of transcript variants of PDCD1 and PDCD1LG2 on the Th-1/Th-2 balance enable prognostic prediction in PCNSL. This study provides insights for development of molecular target therapies and identification of diagnosis/prognosis markers in PCNSL.
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http://dx.doi.org/10.1038/s41598-019-46473-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620277PMC
July 2019

Unilateral Occipital Transtentorial Approach with Multimodal Assistance for Resection of Large Supracerebellar Hemangioblastomas: Preliminary Experience of 2 Cases.

World Neurosurg 2019 Sep 13;129:e733-e740. Epub 2019 Jun 13.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: The surgical resection of large supracerebellar hemangioblastomas (SHBs) is exceptionally challenging due to their vascularity and deep anatomic location and is associated with a high risk of postoperative complications and mortality. Access to the posterior incisural space can be achieved by either an infratentorial supracerebellar approach or occipital transtentorial approach (OTA). However, the optimal surgical strategy has not yet been established. Here, we report 2 cases of large SHBs that were successfully and safely resected via a unilateral OTA with multimodal assistance.

Case Description: Two patients presented to our hospital with ataxia due to large, solid SHBs. After preoperative embolization, gross total resection of the SHBs was achieved via an OTA. Furthermore, endoscopic assistance was used to resect the remnant portion of the tumor in the second patient. Both patients experienced transient ataxia but were discharged from the hospital without serious complications.

Conclusions: The combination of an OTA with preoperative embolization and endoscopic assistance may reduce the intraoperative risk and contribute to improved outcome in patients with such clinically challenging tumors.
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http://dx.doi.org/10.1016/j.wneu.2019.06.001DOI Listing
September 2019

Postoperative Cerebellar Cyst with Pseudomeningocele After Tumor Removal at the Craniovertebral Junction.

World Neurosurg 2019 Oct 4;130:71-76. Epub 2019 Jul 4.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Cerebellar cyst formation after surgery is uncommon, and few cases of this condition have been previously reported. These cases had an intraparenchymal cyst in the cerebellar hemisphere that required surgical fenestration of the cyst. We herein present a rare case of a postoperative cerebellar cyst with pseudomeningocele and magnetic resonance images indicating a fistula between the cyst and pseudomeningocele.

Case Description: A patient presented with an intraparenchymal cyst and surrounding edema in the cerebellar hemisphere that developed after a C1 laminectomy and a small suboccipital craniectomy for the removal of an accessory nerve neurinoma at the craniovertebral junction. Fast imaging employing steady-state acquisition images identified the fistula connecting the cyst and extradural cerebrospinal fluid retention. Conservative management with administration of dexamethasone induced spontaneous regression of the cyst, and no recurrence had occurred by the 1-year follow-up.

Conclusions: Watertight dural closure is important for the prevention of this rare complication after posterior fossa surgery. However, an arachnoid tear on the cerebellar fissure and adjacent dural defect are necessary antecedents for this rare condition. High-resolution fast imaging employing steady-state acquisition images could provide additional information for the etiology of postoperative cerebellar cyst.
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http://dx.doi.org/10.1016/j.wneu.2019.06.197DOI Listing
October 2019

Predictive potential of preoperative electroencephalogram for neuropsychological change following subthalamic nucleus deep brain stimulation in Parkinson's disease.

Acta Neurochir (Wien) 2019 10 5;161(10):2049-2058. Epub 2019 Jul 5.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.

Background: Deep brain stimulation of the bilateral subthalamic nucleus (STN-DBS) improves motor fluctuation and severe dyskinesia in advanced Parkinson's disease (PD). Effects on non-motor symptoms, such as neurocognitive side effects, can also influence the quality of life of both patients with PD and caregivers. Predictive quantitative factors associated with postoperative neurocognitive deterioration therefore warrant further attention. Here, we evaluated preoperative electroencephalogram (EEG) as a predictive marker for changes in neurocognitive functions after surgery.

Methods: Scalp EEG was recorded preoperatively from 17 patients with PD who underwent bilateral STN-DBS. Global relative power in the theta, alpha, and beta bands was calculated. Cognitive function was assessed with neuropsychological batteries preoperatively and 1 year after STN-DBS.

Results: Performance on the Symbol Search subtest of the WAIS III declined 1 year after DBS. The theta band was chosen for analysis with a 40% cutoff point for increased (≥ 40%) and decreased (< 40%) power. No significant differences between the two groups in baseline performance on most neuropsychological batteries were found, except for the Digit Symbol Coding subtest of the WAIS III. Changes in visual spatial functions were significantly different between groups. The increased theta band power group demonstrated a significant deterioration in performance on the WAIS III Matrix Reasoning subtest and the copy and immediate recall tasks of the Rey-Osterrieth complex figure test.

Conclusions: These findings suggest that preoperative increases in theta power are related to postoperative deterioration of visuospatial function, which indicates the predictive potential of preoperative quantitative EEG for neurocognitive changes after STN-DBS.
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http://dx.doi.org/10.1007/s00701-019-03991-5DOI Listing
October 2019

Function-Preserving Multimodal Treatment for Jugular Foramen Meningiomas.

J Neurol Surg B Skull Base 2019 Jun 21;80(3):239-243. Epub 2018 Aug 21.

Department of Neurosurgery, Seikei-kai Chiba Medical Center, Chiba, Japan.

 Despite being pathologically benign, jugular foramen meningioma (JFM) may be locally aggressive and spread in three compartments. Because of the complex anatomical location, radical removal of JFM usually causes serious morbidity through lower cranial nerve (LCN) deficits. To accomplish long-standing tumor control with good functional outcomes, we report function-preserving multimodal treatment (FMT) for JFM, comprising the combination of intradural tumor removal with the preservation of LCN function and stereotactic radiosurgery (RS) for the residual tumor.  This study investigated six JFM patients (five women, one man). Preoperatively, five patients showed no LCN sign.  All patients underwent function-preserving retrosigmoid intradural tumor removal, and no patient developed new LCN deficit. Three patients underwent RS for the residual tumor at 8 to 12 months after surgery. After RS, all three tumors were controlled. No patients showed tumor recurrence or new LCN deficits in the follow-up period (2 months to 8 years).  FMT for JFMs can accomplish long-standing tumor control with excellent functional outcomes.
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http://dx.doi.org/10.1055/s-0038-1668137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534742PMC
June 2019

Mechanism of Corpus Callosum Infarction Associated with Acute Hydrocephalus: Clinical, Surgical, and Radiological Evaluations for Pathophysiology.

World Neurosurg 2019 Jul 4;127:e873-e880. Epub 2019 Apr 4.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba-City, Japan.

Background: Corpus callosum (CC) infarction has been reported to be rare because of the rich blood supply in the CC. The pathophysiology of CC infarction associated with acute hydrocephalus is unknown. The aim of the present study was to clarify the characteristics and mechanism of CC infarction associated with acute noncommunicating hydrocephalus (ANCH).

Methods: We reviewed clinical the data from all patients who had undergone surgical intervention for ANCH at Chiba University Hospital from January 2008 to March 2018. Patients with vascular lesions, a history of hydrocephalus, and lacking magnetic resonance imaging studies were excluded. The clinical, surgical, and radiological parameters were obtained retrospectively for pathophysiological analysis.

Results: A total of 23 patients with ANCH who had undergone surgical intervention and had met the inclusion criteria were included in the present study. Of the 23 patients, 6 (23%) had developed CC infarction. All CC infarctions were located in the splenium. Although no clinical or surgical features were associated with splenial infarction, the radiological parameters of lateral ventricle enlargement and a narrower callosal angle at the posterior commissure and the foramen of Monro were significantly associated with splenial infarction.

Conclusion: The present study has presented evidence that increased intraventricular pressure by ANCH applied transversely in the splenium will directly induce compression of the superior branch of the posterior callosal artery and pericallosal pial plexus, resulting in splenium-specific infarction in patients with ANCH.
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http://dx.doi.org/10.1016/j.wneu.2019.03.288DOI Listing
July 2019

Photo-immune therapy with liposomally formulated phospholipid-conjugated indocyanine green induces specific antitumor responses with heat shock protein-70 expression in a glioblastoma model.

Oncotarget 2019 Jan 4;10(2):175-183. Epub 2019 Jan 4.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Glioblastoma (GBM) is the most common malignant brain tumor, and infiltrates into the surrounding normal brain tissue. Induction of a tumor-specific immune response is one of the best methods to obtain tumor-specific cytotoxicity. Photodynamic therapy (PDT) is known to effectively induce an antitumor immune response. We have developed a clinically translatable nanoparticle, liposomally formulated phospholipid-conjugated indocyanine green (LP-iDOPE), applicable for PDT. This nanoparticle accumulates in tumor tissues by the enhanced permeability and retention effect, and releases heat and singlet oxygen to injure cancer cells when activated by near infrared (NIR) light. We assessed the effectiveness of the LP-iDOPE system in brain using the rat 9L glioblastoma model. Treatment with LP-iDOPE and NIR irradiation resulted in significant tumor growth suppression and prolongation of survival. Histopathological examination showed induction of both apoptosis and necrosis and accumulation of CD8+ T-cells and macrophages/microglia accompanied by marked expressions of heat shock protein-70 (HSP70), which was not induced by mild hyperthermia alone at 45° C or an interleukin-2-mediated immune reaction. Notably, the efficacy was lost in immunocompromised nude rats. These results collectively show that the novel nanoparticle LP-iDOPE in combination with NIR irradiation can efficiently induce a tumor-specific immune reaction for malignant gliomas possibly by inducing HSP70 expression which is known to activate antigen-presenting cells through toll-like receptor signaling.
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http://dx.doi.org/10.18632/oncotarget.26544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349435PMC
January 2019

MicroRNA signature constituted of miR-30d, miR-93, and miR-181b is a promising prognostic marker in primary central nervous system lymphoma.

PLoS One 2019 7;14(1):e0210400. Epub 2019 Jan 7.

Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

MicroRNAs (miRNAs) are small RNA molecules that inhibit gene function by suppressing translation of target genes. However, in primary central nervous system lymphoma (PCNSL), the biological significance of miRNAs is largely unknown, although some miRNAs are known to be prognosis markers. Here, we analyzed 847 miRNAs expressed in 27 PCNSL specimens using microarray profiling and surveyed miRNA signature for prognostic prediction. Of these, 16 miRNAs were expressed in 27 PCNSL specimens at a frequency of 48%. Their variable importance measured by Random forest model revealed miR-192, miR-486, miR-28, miR-52, miR-181b, miR-194, miR-197, miR-93, miR-708, and let-7g as having positive effects; miR-29b-2*, miR-126, and miR-182 as having negative effects; and miR-18a*, miR-425, and miR-30d as neutral. After principal component analysis, the prediction formula for prognosis, consisting of the expression values of the above-mentioned miRNAs, clearly divided Kaplan-Meier survival curves by the calculated Z-score (HR = 6.4566, P = 0.0067). The 16 miRNAs were enriched by gene ontology terms including angiogenesis, cell migration and proliferation, and apoptosis, in addition to signaling pathways including TGF-β/SMAD, Notch, TNF, and MAPKinase. Their target genes included BCL2-related genes, HMGA2 oncogene, and LIN28B cancer stem cell marker. Furthermore, three miRNAs including miR-181b, miR-30d, and miR-93, selected from the 16 miRNAs, also showed comparable results for survival (HR = 8.9342, P = 0.0007), suggestive of a miRNA signature for prognostic prediction in PCNSL. These results indicate that this miRNA signature is useful for prognostic prediction in PCNSL and would help us understand target pathways for therapies in PCNSL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322780PMC
October 2019

Eighty percent survival rate at 15 years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

J Neurooncol 2019 Jan 18;141(1):205-211. Epub 2018 Dec 18.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Chiba, Japan.

Introduction: Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20 years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine.

Methods: This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included.

Results: The median follow-up period was 13 years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146 months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life.

Conclusions: The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.
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http://dx.doi.org/10.1007/s11060-018-03027-5DOI Listing
January 2019

The Tethered Effect of Vestibular Schwannoma Tumor Shrinkage Following Stereotactic Radiosurgery in Secondary Trigeminal Neuralgia.

World Neurosurg 2019 Mar 12;123:136-141. Epub 2018 Dec 12.

Department of Neurosurgery, Seikei-kai Chiba Medical Center, Chiba, Japan.

Background: Compression of the trigeminal nerve by vessels and tumors causes trigeminal neuralgia. However, a tethering effect, provoking an abnormal root-stretching force, has been previously reported to play a role in trigeminal nerve hyperexcitability. We report 2 patients with vestibular schwannomas treated by stereotactic radiosurgery (SRS) who presented with typical manifestations of trigeminal neuralgia after tumor shrinkage. Furthermore, we discuss the mechanisms of trigeminal neuralgia.

Case Description: Two patients without a history of trigeminal dysfunction, including trigeminal neuralgia, underwent SRS for vestibular schwannomas. Both patients demonstrated tumor shrinkage after transient tumor expansion following SRS. Neither patient presented with facial pain or dysesthesia at the time of peak tumor volume. However, trigeminal neuralgia occurred after tumor shrinkage. One patient underwent surgery, as the neuralgia was refractory to medical treatment; although the trigeminal nerve was adhered and tethered to the tumor, no neurovascular conflict was identified between the tumor and the nerve. We removed the tumor partially, dissecting between the nerve and the tumor, and relieved the tethered effect. Trigeminal neuralgia was relieved without medication after surgery.

Conclusions: The present cases demonstrate a tethered effect of tumor shrinkage after SRS, which was considered to play a role in trigeminal neuralgia. Surgical dissection surrounding the nerve root is effective for medically resistant neuralgia, even if the tumor shrinks. Partial tumor removal is adequate in such cases, as the tumor has been controlled by radiosurgery.
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http://dx.doi.org/10.1016/j.wneu.2018.12.002DOI Listing
March 2019

Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury.

J Vis Exp 2018 11 9(141). Epub 2018 Nov 9.

Division of Neurosurgery, Rehabilitation Center for Traumatic Apallics Chiba, National Agency for Automotive Safety and Victims' Aid.

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances. As a consequence of an insufficient ability to communicate, objective evaluations are needed from family members, medical staff, and caregivers. One such evaluation is the assessment of functioning brain areas. Recently, multimodal brain imaging has been used to explore the function of damaged brain areas. [F]-fluorodeoxyglucose positron emission tomography-computed tomography ([F]FDG-PET/CT) is a successful tool for examining brain function. However, the assessment of brain glucose metabolism based on [F]FDG-PET/CT is not standardized and depends on several varying parameters, as well as the patient's condition. Here, we describe a series of semiquantitative assessment protocols for a region-of-interest (ROI) image analysis using self-produced [F]FDG tracers in patients with sTBI. The protocol focuses on screening the participants, preparing the [F]FDG tracer in the hot lab, scheduling the acquisition of [F]FDG-PET/CT brain images, and measuring glucose metabolism using the ROI analysis from a targeted brain area.
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http://dx.doi.org/10.3791/58641DOI Listing
November 2018

Long-term use of a neural prosthesis in progressive paralysis.

Sci Rep 2018 11 14;8(1):16787. Epub 2018 Nov 14.

Systems Neuroscience Section, Department of Rehabilitation for Brain Functions, Research Institute of National Rehabilitation for Persons with Disabilities, Saitama, Japan.

Brain-computer interfaces (BCIs) enable communication with others and allow machines or computers to be controlled in the absence of motor activity. Clinical studies evaluating neural prostheses in amyotrophic lateral sclerosis (ALS) patients have been performed; however, to date, no study has reported that ALS patients who progressed from locked-in syndrome (LIS), which has very limited voluntary movement, to a completely locked-in state (CLIS), characterized by complete loss of voluntary movements, were able to continue controlling neural prostheses. To clarify this, we used a BCI system to evaluate three late-stage ALS patients over 27 months. We employed steady-state visual evoked brain potentials elicited by flickering green and blue light-emitting diodes to control the BCI system. All participants reliably controlled the system throughout the entire period (median accuracy: 83.3%). One patient who progressed to CLIS was able to continue operating the system with high accuracy. Furthermore, this patient successfully used the system to respond to yes/no questions. Thus, this CLIS patient was able to operate a neuroprosthetic device, suggesting that the BCI system confers advantages for patients with severe paralysis, including those exhibiting complete loss of muscle movement.
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http://dx.doi.org/10.1038/s41598-018-35211-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235856PMC
November 2018

Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio.

J Infect Chemother 2019 Feb 10;25(2):124-128. Epub 2018 Nov 10.

Division of Pharmacy, Chiba University Hospital, Chiba, Japan.

Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 μg/mL and 3.31 ± 3.14 μg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis.
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http://dx.doi.org/10.1016/j.jiac.2018.10.013DOI Listing
February 2019

Real-time methylation-specific PCR for the evaluation of methylation status of MGMT gene in glioblastoma.

Oncotarget 2018 Jun 12;9(45):27728-27735. Epub 2018 Jun 12.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is a strong predictor for the efficacy of temozolomide chemotherapy and survival periods. However, the correlation between the extent of methylation and the difference in survival times has not been fully clarified. Simple and quantitative evaluations of the methylation status in the promotor region of the MGMT gene are expected to be worldwide standardized diagnostics. We applied real-time semi-quantitative methylation-specific polymerase chain reaction (SQ-MSP) of the MGMT gene promoter region to 84 glioblastoma patients. The SQ-MSP result showed that the ΔCt value, which represents the difference between uCt and mCt (uCt value - mCt value), is inversely correlated with overall survival. With adequate cutoff setting, this assay showed that those patients suffering from a tumor with low ΔCt (methylated) survived significantly longer than those having tumors with high ΔCt (un-methylated). The most significant difference was observed when the cutoff was set at a ΔCt of 2. Using this cutoff point, the result of MGMT immunohistochemical analysis was also significantly correlated with the methylation status examined with real-time SQ-MSP. These results collectively show that MGMT promoter methylation status actually affects patients' survival and protein expression depending on its methylation level, and the extent of methylated CpGs would be better assessed with real-time SQ-MSP than with the standard gel-based MSP. This method is cost- and labor-saving compared with pyrosequencing, and significantly contributes to the accurate and objective prediction of patient survival.
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http://dx.doi.org/10.18632/oncotarget.25543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021237PMC
June 2018