Publications by authors named "Naoya Hashimoto"

116 Publications

Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model.

Cancer Gene Ther 2021 Jan 7. Epub 2021 Jan 7.

Department of Clinical Oncology, Kyoto Pharmaceutical University, Kyoto, Japan.

The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although the properties of Lgr5-positive GSCs remain unclear. Here, the Sleeping-Beauty transposon-induced glioblastoma model was used in Lgr5-GFP knock-in mice identify GFP-positive cells in neurosphere cultures from mouse glioblastoma tissues. Global gene expression analysis showed that Gli2 was highly expressed in GFP-positive GSCs. Gli2 knockdown using lentiviral-mediated shRNA downregulated Hedgehog-related and Wnt signaling pathway-related genes, including Lgr5; suppressed tumor cell proliferation and invasion capacity; and induced apoptosis. Pharmacological Gli inhibition with GANT61 suppressed tumor cell proliferation. Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.
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http://dx.doi.org/10.1038/s41417-020-00282-5DOI Listing
January 2021

FLAIR vascular hyperintensity with DWI for regional collateral flow and tissue fate in recanalized acute middle cerebral artery occlusion.

Eur J Radiol 2021 Feb 20;135:109490. Epub 2020 Dec 20.

Department of Neurosurgery, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Purpose: Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) extent or FVH-DWI mismatch as a primary influencing factor of clinical outcome in acute ischemic stroke is controversial. This study elucidated the regional pathophysiology and tissue fate in four types of cortical territories classified by the initial FVH and DWI findings in patients with acute proximal middle cerebral artery (M1) occlusion successfully recanalized using mechanical thrombectomy.

Methods: We retrospectively evaluated 35 patients successfully recanalized within 24 h of acute M1 occlusion onset between 2016 and 2019. Each Alberta stroke program early CT score area of M1-M6 were categorized as group A (DWI-, FVH-), B (DWI-, FVH+), C (DWI+, FVH+), or D (DWI+, FVH-). Territorial collateral status was graded on a 4-point scale by initial angiogram. Follow-up head computed tomography (CT) findings on days 2-9 were assessed for the territorial outcome.

Results: Overall, 210 cortical territories were identified; of these, 88 (41.9 %) were categorized into group A; 72 (34.3 %), group B; 37 (17.6 %), group C; and 13 (6.2 %), group D. The rate of territories with good collaterals (grade 2 or 3) significantly decreased in the order of groups as 78.3 %, 62.7 %, 27.6 %, and 0%, respectively (P <.001). Conversely, the rate of territories with any hypo- or hyper-density on follow-up CT significantly increased in the order of groups as 13.4 %, 23.1 %, 88.5 %, and 85.7 %, respectively (P <.001).

Conclusion: Categorization of cortical areas based on the FVH and DWI findings can stratify territorial collateral status and tissue fate.
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http://dx.doi.org/10.1016/j.ejrad.2020.109490DOI Listing
February 2021

Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report.

Invest New Drugs 2021 Feb 27;39(1):272-277. Epub 2020 Aug 27.

Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.

Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib. Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity. Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = - 0.80, P = 0.003 and r = - 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53-0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61-1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity. Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.
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http://dx.doi.org/10.1007/s10637-020-00994-3DOI Listing
February 2021

[A Case of Miliary Brain Metastases Molecularly Diagnosed as Silent Lung Adenocarcinoma Origin].

No Shinkei Geka 2020 Aug;48(8):701-706

Department of Neurosurgery, Kyoto Prefectural University Graduate School of Medical Science.

A 60-year-old woman was referred to our hospital because of possible miliary brain metastases of unknown primary origin. On admission, she was alert and had no apparent motor weakness. Neuroradiological examinations revealed more than 100 small enhancing lesions, some of which had undergone cystic changes, suggesting multiple metastases. However, plain chest and abdominal CT revealed no abnormalities, and fluorodeoxyglucose-positron emission tomography could not reveal the primary origin of the cancer. Blood examination revealed no apparent abnormalities, except for tumor markers, including pro-gastrin-releasing peptide and carcinoembryonic antigen. On day 22, the patient underwent a biopsy through right frontal craniotomy. Histopathological findings indicated metastases from cancer. Immunohistochemistry was positive for cytokeratin(CK)7 and thyroid transcription factor-1 while negative for CK20(-), CK5/6, and p40, resulting in the diagnosis of lung adenocarcinoma. Genetic testing showed negative for EGFR mutation and positive for ALK fusion gene. From the day 48, whole brain radiotherapy was started, and the ALK inhibitor was prescribed from day 64. Metastatic brain tumors of unknown primary are rare. Miliary brain metastases from an unknown primary origin are rare. To our knowledge, this is the first case of military brain metastases of an unknown primary origin, which was later determined to have originated from ALK fusion-positive lung cancer.
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http://dx.doi.org/10.11477/mf.1436204257DOI Listing
August 2020

Encouraging Clinical Evolution of a Pediatric Patient With Relapsed Diffuse Midline Glioma Who Underwent WT1-Targeting Immunotherapy: A Case Report and Literature Review.

Front Oncol 2020 24;10:1188. Epub 2020 Jul 24.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Japan.

Diffuse midline glioma (DMG) in children is a highly aggressive, malignant brain tumor that is fatal when relapsed. Wilms tumor 1 (WT1) is a high-priority antigen target for cancer immunotherapy. We hereby report on a pediatric patient who had DMG that regrew after chemoradiotherapy and underwent WT1 peptide vaccination. A 13-year-old Japanese boy presented with vertigo, diplopia, and right hemiplegia at the initial visit to another hospital, where he was diagnosed with DMG by magnetic resonance imaging (MRI); DMG was categorized to histological grade IV glioma. The patient underwent radiotherapy and chemotherapy with temozolomide. After three cycles of chemotherapy, MRI revealed tumor regrowth that translated into deteriorated clinical manifestations. Immunohistochemically, the H3.3K27M mutation in the biopsy specimen was confirmed and the specimen was positive for WT1 protein. The patient underwent WT1-targeting immunotherapy with the WT1-specific peptide vaccine because of having HLA-A24:02. Consequently, his quality of life drastically improved so much as to the extent that the patient became capable of conducting nearly normal daily activities at weeks 8 to 12 of vaccination. MRI at week 8 of vaccination revealed an obvious reduction in the signal intensity of the tumor. Furthermore, betamethasone dose could be reduced successively (4, 1, and 0.5 mg/day at weeks 4, 5, and 7, respectively) without deteriorating clinical manifestations. Best response among responses assessed according to the Response Assessment in Neuro-Oncology criteria was stable disease. Overall survival was 6.5 months after vaccination onset and was 8.3 months after relapse; the latter was markedly longer than the reported median OS of 3.2 months for pediatric patients with relapsed DMG in the literature. Modified WT1 tetramer staining revealed the WT1 peptide vaccine-induced production of WT1-specific cytotoxic T cells, and the interferon-γ (IFN-γ) ELISpot assay of peripheral blood mononuclear cells disclosed the production of IFN-γ. Delayed-type hypersensitivity test became positive. Any treatment-emergent adverse events did not occur except injection site erythema. Our pediatric patient exhibited an encouraging clinical evolution as manifested by stable disease, improved clinical manifestations, steroid dose reductions, a WT1-specific immune response, and a good safety profile. Therefore, WT1-targeting immunotherapy warrants further investigation in pediatric patients with relapsed DMG.
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http://dx.doi.org/10.3389/fonc.2020.01188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393264PMC
July 2020

Identification of two distinct populations of WT1-specific cytotoxic T lymphocytes in co-vaccination of WT1 killer and helper peptides.

Cancer Immunol Immunother 2021 Jan 22;70(1):253-263. Epub 2020 Jul 22.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Simultaneous induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) is required for an optimal anti-tumor immune response. WT1, a 16-mer WT1-derived helper peptide, induce HTLs in an HLA class II-restricted manner and enhance the induction of WT1-specific CTLs in vitro. However, in vivo immune reaction to WT1 vaccination in tumor-bearing patients remained unclear. Here, a striking difference in WT1-specific T cell responses was shown between WT1 CTL + WT1 helper peptide and WT1 CTL peptide vaccines in patients with recurrent glioma. WT1-specific CTLs were more strongly induced in the patients who were immunized with WT1 CTL + WT1 helper peptide vaccine, compared to those who were immunized with WT1 CTL vaccine alone. Importantly, a clear correlation was demonstrated between WT1-specific CTL and WT1-specific HTL responses. Interestingly, two novel distinct populations of WT1-tetramer WT1-TCR CD5 and WT1-tetramer WT1-TCR CD5 CTLs were dominantly detected in WT1 CTL + WT1 helper peptide vaccine. Although natural WT1 peptide-reactive CTLs in the latter population were evidently less than those in the former population, the latter population showed natural WT1 peptide-specific proliferation capacity comparable to the former population, suggesting that the latter population highly expressing CD5, a marker of resistance to activation-induced cell death, should strongly expand and persist for a long time in patients. These results demonstrated the advantage of WT1 helper peptide vaccine for the enhancement of WT1-specific CTL induction by WT1 CTL peptide vaccine.
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http://dx.doi.org/10.1007/s00262-020-02675-9DOI Listing
January 2021

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

Lumbar Subdural Hematoma Detected After Surgical Treatment of Chronic Intracranial Subdural Hematoma.

World Neurosurg 2020 Feb 19;134:472-476. Epub 2019 Nov 19.

Department of Neurosurgery, Kyoto Prefectural University Graduate School of Medical Science, Kyoto, Japan.

Background: Spinal subdural hematoma (SSDH), which can cause lower back pain, leg pain, and leg weakness, is rare and will usually be associated with a bleeding tendency, trauma, spinal vascular malformation, intraspinal tumor, or iatrogenic invasion. Only a few cases of SSDH after intracranial chronic subdural hematoma (CSDH) have been reported. We report a case of lumbar SSDH in the absence of predisposing factors after reoperation for recurrent intracranial CSDH, which improved with conservative treatment.

Case Description: Approximately 1 month after falling, a 63-year-old woman was experiencing left hemiparesis and impaired orientation that was diagnosed as right intracranial CSDH using computed tomography. Surgical treatment of the CSDH led to immediate improvement of her symptoms. On postoperative day 29, the right CSDH had recurred with left hemiparesis, and successful reoperation relieved the symptoms within a few hours postoperatively. However, 1 day after the second operation, very small acute subdural hematomas in regions along the left tentorium cerebelli and left falx cerebri were found on computed tomography. On day 31, she complained of sitting-induced bilateral radiating lower limb pain. Magnetic resonance imaging on day 34 showed an acute SSDH at the L4-L5 level and a sacral perineural cyst filled with hematoma, although her radiating pain was showing improvement. She was treated conservatively and was discharged without symptoms on day 44.

Conclusions: Although SSDH is rare, it is important for neurosurgeons and physicians to consider the possibility of a SSDH when lower limb pain or paresis occurs after procedures that will result in rapid intracranial pressure alterations such as drainage of an intracranial CSDH.
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http://dx.doi.org/10.1016/j.wneu.2019.11.053DOI Listing
February 2020

Aplastic or Twig-Like Middle Cerebral Artery Presenting with Intracerebral Hemorrhage During Pregnancy: Report of Two Cases.

World Neurosurg X 2019 Apr 5;2:100018. Epub 2019 Feb 5.

Department of Neurosurgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: An aplastic or twig-like middle cerebral artery (Ap/T-MCA) is a rare congenital anomaly that can present with both ischemic and hemorrhagic stroke. The etiology of this pathology has remained unclear. Here, we report 2 cases of intracerebral hemorrhage (ICH) owing to an Ap/T-MCA in pregnant patients.

Case Description: In both patients, cerebral angiography revealed a steno-occlusive lesion and an abnormal arterial network on the unilateral middle cerebral artery. One patient was treated conservatively for a putaminal hemorrhage, and a cesarean section was performed uneventfully 6 months after onset of the ICH. The other patient underwent a craniotomy for evacuation of the lobar hemorrhage. Subsequently, a cesarean section was performed uneventfully. Both patients gradually recovered without significant disabilities.

Conclusions: An Ap/T-MCA is a rare congenital anomaly and is a potential cause of ICH for pregnant patients. A cesarean section is a useful option for pregnant patients with this condition.
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http://dx.doi.org/10.1016/j.wnsx.2019.100018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580884PMC
April 2019

MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.

J Neurooncol 2019 Apr 30;142(2):241-251. Epub 2019 Jan 30.

Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

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.
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http://dx.doi.org/10.1007/s11060-019-03113-2DOI Listing
April 2019

A phase I clinical study of a cocktail vaccine of Wilms' tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma.

Cancer Immunol Immunother 2019 Feb 14;68(2):331-340. Epub 2018 Nov 14.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: The safety and clinical efficacy of WT1 human leukocyte antigen (HLA) class I peptide vaccine have been established, but the safety of a cocktail vaccine of WT1 HLA class I and II peptides has not. To verify its safety, we performed a phase I clinical trial for patients with recurrent malignant gliomas and assessed the immunological responses and survival data.

Patients And Methods: Fourteen HLA-A*24:02-positive patients with recurrent malignant glioma (2 with grade 3, 12 with grade 4) were enrolled. Every week, the patients received alternately a vaccine containing 3 mg of WT1 HLA-A*24:02-restricted (HLA class I) peptide and a cocktail vaccine of the HLA class I peptide and one of 0.75, 1.5 or 3 mg of the WT1 HLA class II peptide. For patients who showed no significant adverse effects within 6 weeks, the WT1 vaccine was continued at 2-4-week intervals.

Results: Eleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. All patients showed grade I level of skin disorders at the injection sites. No grade III/IV toxicity or dose-limiting toxicity was observed for any dose of WT1 HLA class II peptide. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively.

Conclusion: The safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma.
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http://dx.doi.org/10.1007/s00262-018-2274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394509PMC
February 2019

A Prospective Trial Evaluating the Safety of a Shortened Infusion of Ramucirumab in Patients with Gastrointestinal Cancer.

Oncologist 2019 02 10;24(2):159-e66. Epub 2018 Oct 10.

Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Lessons Learned: A shortened infusion of ramucirumab (from 60 to 20 minutes) was safe and feasible without infusion-related reactions.Twenty-minute infusions of ramucirumab can be an option for patients with no infusion-related reactions during the first 60-minute treatment.

Background: Ramucirumab is usually administered over 60 minutes, during which it is unlikely to cause infusion-related reactions (IRRs). This prospective study evaluated the safety of a shortened infusion of ramucirumab.

Methods: Patients who received their first dose of ramucirumab in a 60-minute infusion without developing IRRs were eligible and received their second ramucirumab dose for 20 minutes. The primary study endpoint was incidence of IRR during the first short-term infusion, and the secondary endpoints were incidence of IRR at any time and adverse events other than IRR.

Results: Of the 40 patients enrolled (median age, 68.5 years), 20 (55%) were male, 27 (67.5%) had stage IV gastric cancer, 25 (62.5%) received ramucirumab in combination with taxane-based chemotherapy, and 24 (60%) received only a single administration of ramucirumab prior to their enrollment. Notably, no IRR was observed during the first short-term infusion (IRR rate, 0%; 95% confidence interval [CI], 0%-0.72%). Among the 149 short-term infusions performed, there were no instances of IRRs or unexpected adverse events related to the treatment (Table 1).

Conclusion: For patients without development of IRRs upon the first ramucirumab administration, shortening infusion time (from 60 to 20 minutes) is safe and feasible.
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http://dx.doi.org/10.1634/theoncologist.2018-0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369950PMC
February 2019

11C-methionine-18F-FDG dual-PET-tracer-based target delineation of malignant glioma: evaluation of its geometrical and clinical features for planning radiation therapy.

J Neurosurg 2019 09;131(3):676-686

Departments of1Radiation Oncology.

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.
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http://dx.doi.org/10.3171/2018.4.JNS1859DOI Listing
September 2019

Unusual Presentations of Pediatric Skull Hemangiomas: Report of Two Cases.

World Neurosurg 2018 Nov 1;119:20-24. Epub 2018 Aug 1.

Department of Neurosurgery, Kyoto Prefectural University Graduate School of Medicine Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.

Background: Intraosseous hemangioma is a rare bone tumor, accounting for 0.7%-1.0% of all bone tumors. It can occur at any age, but only 9% of cases are younger than 10 years old. Although this tumor is usually slow-growing and clinically silent, we experienced 2 pediatric patients undergoing surgery for skull hemangioma who presented with uncommon clinical manifestations.

Case Decription: Case 1 was a 9-year-old boy who presented with sudden onset of headache and was referred to our hospital. Radiologic images revealed an osteolytic oval lesion in the right parietal bone and acute subdural hemorrhage in the right cerebral hemisphere. The right parietal lesion was removed surgically. The lesion was found to have grown into the dura and to be adherent to the pia matter. The removed lesion was histologically confirmed to be a hemangioma. Case 2 was an 8-year-old girl who was referred to our hospital with an elastic mass that had been slowly enlarging for 7 years. Radiologic images revealed an osteolytic oval lesion in the right parietal bone. Surgical removal was thus planned. The lesion was found to be attached to the dura, and we removed the lesion with the surrounding bone and attached dura. Histologic examination confirmed the lesion to be a hemangioma.

Conclusions: Although skull hemangiomas show clinical heterogeneity, surgical removal is usually diagnostic and leads to good patient outcomes. On occasion, however, this tumor causes secondary changes in the dura, such that dural incision and dural plasty should be planned in advance of lesion removal.
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http://dx.doi.org/10.1016/j.wneu.2018.07.201DOI Listing
November 2018

Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial.

J Clin Oncol 2018 Jun 20:JCO2018786186. Epub 2018 Jun 20.

Takamasa Kayama, Shinya Sato, Kaori Sakurada, Yukihiko Sonoda, Yamagata University Faculty of Medicine, Yamagata; Junki Mizusawa, Yoshitaka Narita, Yasuji Miyakita, Hiroshi Katayama, Haruhiko Fukuda, Soichiro Shibui, National Cancer Center Hospital; Minako Sumi, Cancer Institute Hospital; Akitake Mukasa, The University of Tokyo Graduate School of Medicine; Yoshihiro Muragaki, Motohiro Hayashi, Tokyo Women's Medical University; Takao Watanabe, Nihon University School of Medicine; Hikaru Sasaki, Keio University School of Medicine; Masao Tago, Teikyo University Mizonokuchi Hospital; Motoo Nagane, Kyorin University Faculty of Medicine, Tokyo; Ryo Nishikawa, Saitama Medical University International Medical Center, Saitama; Toshihiro Kumabe, Tohoku University Graduate School of Medicine; Eiji Shimizu, Tohoku University Hospital; Hidefumi Jokura, Furukawa Seiryo Hospital, Miyagi; Yoshiki Arakawa, Susumu Miyamoto, Takashi Mizowaki, Kyoto University Graduate School of Medicine, Kyoto; Takaaki Beppu, Iwate Medical University, Morioka; Kazuhiko Sugiyama, Hiroshima University Hospital, Hiroshima; Hirohiko Nakamura, Nakamura Memorial Hospital, Sapporo; Yoko Nakasu, Shizuoka Cancer Center, Shizuoka; Naoya Hashimoto, Osaka University Graduate School of Medicine; Manabu Kinoshita, Osaka International Cancer Institute; Akio Asai, Kansai Medical University; Koichi Iwasaki, Kitano Hospital; Tomokazu Aoki, Kitano Medical Research Institute and Hospital, Osaka; Mizuhiko Terasaki, Kurume University, Kurume; Akira Matsumura, Eiichi Ishikawa, University of Tsukuba, Tsukuba; Toshihiko Wakabayashi, Nagoya University, Nagoya; Yasuo Iwadate, Chiba University, Chiba; Shiro Ohue, Ehime University Graduate School of Medicine, Ehime; Hiroyuki Kobayashi, Hiroki Shirato, Hokkaido University Graduate School of Medicine, Hokkaido; Kenichiro Asano, Hirosaki University Graduate School of Medicine, Hirosaki City; Katsuyuki Tanaka, St Marianna University School of Medicine, Kanagawa; Hideo Nakamura, Kumamoto University, Kumamoto; Tatsuya Abe, Oita University Faculty of Medicine, Oita; Shuichi Izumoto, Hyogo College of Medicine, Hyogo; Masahiro Mizoguchi, Kyushu University, Fukuoka; Takayuki Matsuo, Nagasaki Graduate School of Biomedical Sciences, Nagasaki; and Hideo Takeshima, University of Miyazaki, Miyazaki, Japan.

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.
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http://dx.doi.org/10.1200/JCO.2018.78.6186DOI Listing
June 2018

Influence of region-of-interest designs on quantitative measurement of multimodal imaging of MR non-enhancing gliomas.

Oncol Lett 2018 May 22;15(5):7934-7940. Epub 2018 Mar 22.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

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 F-fluorodeoxyglucose (FDG) and C-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.
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http://dx.doi.org/10.3892/ol.2018.8319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920197PMC
May 2018

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma.

J Neurooncol 2018 Jul 20;138(3):627-636. Epub 2018 Mar 20.

Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: This study explored the superiority of temozolomide (TMZ) + interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design.

Experimental Design: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m, daily) followed by TMZ maintenance (100-200 mg/m/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNβ + RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8).

Results: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNβ + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNβ + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%.

Conclusions: TMZ + IFNβ + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.
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http://dx.doi.org/10.1007/s11060-018-2831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999164PMC
July 2018

Usefulness of 18F-fluorodeoxyglucose-Positron Emission Tomography in Comparison with Methionine-Positron Emission Tomography in Differentiating Solid Hemangioblastoma from Adult Cerebellar Tumors.

World Neurosurg 2018 Feb 21;110:e648-e652. Epub 2017 Nov 21.

Department of Neurosurgery, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

Background And Purpose: Among adults with posterior fossa tumors, an intraaxial location of the tumor is less common than an extraaxial location. Moreover, the differential diagnosis of a single cerebellar tumor in adults is sometimes difficult by conventional magnetic resonance imaging. We aimed to report the findings of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and methionine in adult patients with intraaxial and solitary metastatic brain tumors.

Materials And Methods: FDG-PET was performed on 12 patients with posterior fossa tumors: 4 had solid hemangioblastoma (HB), 3 had primary central nervous system lymphomas, 1 had a glioblastoma, and 4 had single metastatic brain tumors (METs). Methionine-PET was performed on 9 patients except for 1 patient with a MET. The maximum standardized uptake value (SUVmax) of the tumor was measured and compared with pathologic findings.

Results: The SUVmax of FDG in HB was lower compared with that of other tumors (P = 0.001). On the other hand, the SUVmax of methionine in the HB cases was almost the same as that in other tumors (P = 0.07).

Conclusion: FDG-PET was helpful in differentiating HBs from adult cerebellar tumors.
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http://dx.doi.org/10.1016/j.wneu.2017.11.054DOI Listing
February 2018

Voxel-based lesion mapping of meningioma: a comprehensive lesion location mapping of 260 lesions.

J Neurosurg 2018 06 1;128(6):1707-1712. Epub 2017 Sep 1.

1Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka; and.

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.
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http://dx.doi.org/10.3171/2017.3.JNS17169DOI Listing
June 2018

Diagnostic Performance and Safety of Positron Emission Tomography Using F-Fluciclovine in Patients with Clinically Suspected High- or Low-grade Gliomas: A Multicenter Phase IIb Trial.

Asia Ocean J Nucl Med Biol 2017 ;5(1):10-21

Clinical Development Department, Nihon Medi-Physics Co., Ltd., Tokyo, Japan.

Objectives: The study objective was to assess the diagnostic performance of positron emission tomography (PET) for gliomas using the novel tracer F-fluciclovine (anti-[F]FACBC) and to evaluate the safety of this tracer in patients with clinically suspected gliomas.

Methods: Anti-[F]FACBC was administered to 40 patients with clinically suspected high- or low-grade gliomas, followed by PET imaging. T1-weighted, contrast-enhanced T1-weighted, and fluid-attenuated inversion recovery (or T2-weighted) magnetic resonance imaging (MRI) scans were obtained to plan for the tissue collection. Tissues were collected from either "areas visualized using anti-[F]FACBC PET imaging but not using contrast-enhanced T1-weighted imaging" or "areas visualized using both anti-[F]FACBC-PET imaging and contrast-enhanced T1-weighted imaging" and were histopathologically examined to assess the diagnostic accuracy of anti-[F]FACBC-PET for gliomas.

Results: The positive predictive value of anti-[F]FACBC-PET imaging for glioma in areas visualized using anti-[F]FACBC-PET imaging, but not visualized using contrast-enhanced T1-weighted images, was 100.0% (26/26), and the value in areas visualized using both contrast-enhanced T1-weighted imaging and anti-[F]FACBC-PET imaging was 87.5% (7/8). Twelve adverse events occurred in 7 (17.5%) of the 40 patients who received anti-[F]FACBC. Five events in five patients were considered to be adverse drug reactions; however, none of the events were serious, and all except one resolved spontaneously without treatment.

Conclusion: This Phase IIb trial showed that anti-[F]FACBC-PET imaging was effective for the detection of gliomas in areas not visualized using contrast-enhanced T1-weighted MRI and the tracer was well tolerated.
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http://dx.doi.org/10.22038/aojnmb.2016.7869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221680PMC
January 2017

Monocyte chemoattractant protein 1 expression and proliferation in primary central nervous system lymphoma.

Oncol Lett 2017 Jul 4;14(1):264-270. Epub 2017 May 4.

Department of Neurosurgery, Hokuto Hospital, Obihiro, Hokkaido 080-0033, Japan.

Whether the poor prognosis of primary central nervous system lymphoma (PCNSL) compared with systemic diffuse large B cell lymphoma (DLBCL) is attributable to the immune privilege of the intracerebral location or to intrinsic differences in the biological characteristics of two types of lymphoma remains unclear. Monocyte chemoattractant protein 1 (MCP-1) is essential to support tumor cell survival and growth, and the present study aimed to compare MCP-1 expression in PCNSL and peripheral DLBCL. The present study included 19 patients with PCNSL and 16 patients with DLBCL, all of whom had tissue diagnosis and lymphoma tissue samples available for analysis. Histology included immunohistochemistry using antibodies against a panel of lymphoma markers, antibodies specific to MCP-1, and antibodies specific to tumor-associated macrophages. MCP-1 expression was quantified using immunostaining scoring. RNA extraction and reverse transcription-quantitative polymerase chain reaction were used to determine mRNA expression. In addition, a human brain-derived lymphoma cell line, HKBML, was stimulated with MCP-1 and cell proliferation was measured by 5-bromo-2'-deoxyuridine incorporation. The expression levels of mRNA and MCP-1 protein were significantly increased in PCNSL compared with peripheral DLBCL. MCP-1 induced tyrosine phosphorylation of mitogen-activated protein kinase in HKBML cells, as analyzed by western blotting. The results of the present study indicated that MCP-1 expression in PCNSL promoted cell proliferation in an autocrine manner.
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http://dx.doi.org/10.3892/ol.2017.6122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494900PMC
July 2017

Association between ABCG2 and SLCO1B1 polymorphisms and adverse drug reactions to regorafenib: a preliminary study
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Int J Clin Pharmacol Ther 2017 May;55(5):409-415

Objective: Due to the occurrence of severe adverse drug reactions to regorafenib, a drug used in cancer therapy, the identification of a predictive marker(s) is needed to increase the therapeutic applicability of this compound. We therefore investigated whether polymorphisms in the ABCG2 and SLCO1B genes are associated with adverse drug reactions to regorafenib.

Methods: For these analyses, 37 Japanese cancer patients were treated with regorafenib, genotyped for polymorphisms in ABCG2 and SLCO1B, and evaluated for drug-related adverse drug reactions.

Results: There was no association between the ABCG2 421C>A variant and adverse drug reactions to regorafenib. After treatment, the incidences of increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as increased total bilirubin (grade ≥ 2) were 8%, 4%, and 12%, and 42%, 25%, and 25% among SLCO1B1*1b carriers and non-carriers, respectively. There were no significant associations between elevated ALT and bilirubin and the SLCO1B1*1b allele. However, there were significantly lower incidences of increased AST (8% vs. 42%) and anemia (16% vs. 50%) in SLCO1B1*1b carriers than in non-carriers.

Conclusions: The absence of SLCO1B1*1b allele appears to be associated with the development of adverse drug reactions to regorafenib; however, further studies involving larger test groups and other populations are needed to confirm these findings.
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http://dx.doi.org/10.5414/CP202788DOI Listing
May 2017

Syndecan-4 as a biomarker to predict clinical outcome for glioblastoma multiforme treated with WT1 peptide vaccine.

Future Sci OA 2016 Dec 3;2(4):FSO96. Epub 2016 Oct 3.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita City, Osaka 565-0871, Japan; Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita City, Osaka 565-0871, Japan.

Aim: In cancer immunotherapy, biomarkers are important for identification of responsive patients. This study was aimed to find biomarkers that predict clinical outcome of WT1 peptide vaccination.

Materials & Methods: Candidate genes that were expressed differentially between long- and short-term survivors were identified by cDNA microarray analysis of peripheral blood mononuclear cells that were extracted from 30 glioblastoma patients (discovery set) prior to vaccination and validated by quantitative RT-PCR using discovery set and different 23 patients (validation set).

Results: mRNA expression levels distinguished between the long- and short-term survivors: 1-year survival rates were 64.0 and 18.5% in -low and -high patients, respectively.

Conclusion: is a novel predictive biomarker for the efficacy of WT1 peptide vaccine.
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http://dx.doi.org/10.4155/fsoa-2015-0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241910PMC
December 2016

Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401).

J Neurosurg 2016 12;125(Suppl 1):11-17

Department of Neurosurgery, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto.

OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death-free and deterioration-free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS. CONCLUSIONS The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.
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http://dx.doi.org/10.3171/2016.7.GKS161459DOI Listing
December 2016

Comparison of diffusion tensor imaging and C-methionine positron emission tomography for reliable prediction of tumor cell density in gliomas.

J Neurosurg 2016 11 26;125(5):1136-1142. Epub 2016 Feb 26.

Departments of 2 Neurosurgery.

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-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 < 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.
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http://dx.doi.org/10.3171/2015.11.JNS151848DOI Listing
November 2016

Introduction of High Throughput Magnetic Resonance T2-Weighted Image Texture Analysis for WHO Grade 2 and 3 Gliomas.

PLoS One 2016 7;11(10):e0164268. Epub 2016 Oct 7.

Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan.

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 < 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164268PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055327PMC
June 2017

[Vaccination therapy targeting Wilms' tumor 1 (WT1) gene products against malignant gliomas].

Authors:
Naoya Hashimoto

Nihon Rinsho 2016 09;74 Suppl 7:764-768

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September 2016

[Prognostic molecular-biological testing for brain tumors].

Authors:
Naoya Hashimoto

Nihon Rinsho 2016 09;74 Suppl 7:513-517

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September 2016