Search

Background: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM., Methods: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells., Results: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts., Conclusion: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells., (© 2024. The Author(s).)

Purpose: To identify qualitative MRI features of non-(contrast)-enhancing tumor (nCET) in glioblastoma's T2-FLAIR hyperintense lesion., Methods: Thirty-three histologically confirmed glioblastoma patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11 C-methionine positron emission tomography (Met-PET) were available were included in this study. Met-PET was utilized as a surrogate for tumor burden. Imaging features for identifying nCET were searched by qualitative examination of 156 targets. A new scoring system to identify nCET was established and validated by two independent observers., Results: Three imaging features were found helpful for identifying nCET; "Bulky gray matter involvement", "Around the rim of contrast-enhancement (Around-rim)," and "High-intensity on T1WI and low-intensity on T2WI (HighT1LowT2)" resulting in an nCET score = 2 × Bulky gray matter involvement - 2 × Around-rim + HighT1LowT2 + 2. The nCET score's classification performances of two independent observers measured by AUC were 0.78 and 0.80, with sensitivities and specificities using a threshold of four being 0.443 and 0.771, and 0.916 and 0.768, respectively. The weighted kappa coefficient for the nCET score was 0.946., Conclusion: The current investigation demonstrated that qualitative assessments of glioblastoma's MRI might help identify nCET in T2/FLAIR high-intensity lesions. The novel nCET score is expected to aid in expanding treatment targets within the T2/FLAIR high-intensity lesions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A recurrent tumor is defined as a re-emerging subclone originating from an ancestorial clone of the primary neoplasm. Hence, it should be distinguished from de novo tumor emerging from other clones. Herein, we describe an exceptional case in which the locally re-emerging glioma did not share genetic alterations of the primary tumor. While the initial tumor harbored mutations in IDH1 and TERT genes as well as 1p/19q codeletion, the re-emerging tumor did not present any of these genetic abnormalities. Variant calling for tumor samples using whole-genome sequencing revealed that 1696 mutations within the primary tumor faded in the re-emerging tumor, and that 4591 mutations were newly detected in the re-emerging tumor. These results suggested that the initial and re-emerging tumors did not share same clonal origins, although the second tumor appeared adjacent to the old surgical cavity 5 years after the initial surgery. We finally speculated that the re-emerging tumor could be a "de novo glioma" or "radiation-induced glioblastoma following treatment of a diffuse glioma." This case highlights the importance of molecular re-evaluation of clinically diagnosed "recurrent" glioma lesions., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4 + /CD8 + tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3 + or CD8 + T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4 + T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

INTELLANCE-J was a phase 1/2 study of a potent antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M), as a second- or first-line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second-line arms, patients with EGFR-amplified recurrent WHO grade III/IV glioma received Depatux-M plus chemotherapy (temozolomide) or Depatux-M alone regardless of EGFR status. In first-line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux-M plus chemoradiotherapy. The study was halted following lack of survival benefit with first-line Depatux-M in the global trial INTELLANCE-1. The primary endpoint was 6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy. Common nonocular treatment-emergent adverse events (TEAEs) with both second-line and first-line Depatux-M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second-line Depatux-M plus chemotherapy and all patients receiving second-line Depatux-M alone or first-line Depatux-M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6-month PFS estimate was 25.6% (95% confidence interval [CI] 11.4-42.6), and median PFS was 2.1 months (95% CI 1.9-3.9) with second-line Depatux-M plus chemotherapy in the EGFR-amplified subgroup. This study showed acceptable safety profile of Depatux-M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: Glioma is the most common type of central nervous system tumor reported worldwide. Current imaging technologies have limitations in the diagnosis and assessment of glioma. The present study aimed to confirm the diagnostic efficacy and safety of anti-1-amino-3-[ 18 F]fluorocyclobutane carboxylic acid ( 18 F-fluciclovine; anti-[ 18 F]FACBC) as a radiotracer for patients undergoing combined positron emission tomography and computed tomography (PET/CT) for suspected glioma., Methods: Combined data from two multicenter, open-label phase III clinical trials were evaluated for this study. The two trials enrolled patients with suspected high- or low-grade glioma on the basis of clinical symptoms, clinical course, and magnetic resonance imaging findings, and who were scheduled for tumor resection surgery. Patients fasted for ≥ 4 h and received 2 mL of 18 F-fluciclovine (radioactivity dose 78.3-297.0 MBq), followed by a 10-min PET scan 10-50 min after injection. The primary efficacy endpoint was the positive predictive value (PPV) of the gadolinium contrast-enhanced T1-weighted image negative [Gd (-)] and 18 F-fluciclovine PET-positive [PET ( +)] area of the scans, using the histopathological diagnosis of the tissue sampled from that area as the standard of truth. All adverse events reported during the study were recorded for safety analysis., Results: A total of 45 patients aged 23-89 years underwent 18 F-fluciclovine PET; 31/45 patients (68.9%) were male, and 30/45 patients (66.7%) were suspected to have high-grade glioma. The PPV of 18 F-fluciclovine PET in the Gd (-) PET ( +) area was 88.0% (22/25 areas, 95% confidence interval: 70.0-95.8). The extent of planned tumor resection was modified in 47.2% (17/36 cases) after 18 F-fluciclovine PET scan, with an extension of area in 30.6% (11/36 cases) and reduction in 16.7% (6/36 cases). Furthermore, tissue samples collected from PET ( +) areas tended to have a higher malignancy grade compared with those from PET (-) areas. Overall, 18 F-fluciclovine was well tolerated., Conclusion: 18 F-fluciclovine PET/CT is useful for determining the extent of tumor resection at surgical planning, and may serve as a safe and effective diagnostic tool for patients with suspected glioma., Trial Registration: These trials were registered in the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-152986, JapicCTI-152985)., (© 2021. The Japanese Society of Nuclear Medicine.)

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed., Methods: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan., Results: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them., Conclusion: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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

Aim: To evaluate the toxicity and efficacy of re-irradiation with salvage stereotactic radiotherapy (SRT) for recurrent glioma using CyberKnife., Patients and Methods: This study retrospectively investigated 35 patients with 48 recurrent grade 2-4 gliomas who received SRT between 1998 and 2011. Six patients (17.1%) had grade 2 gliomas, nine (25.7%) had grade 3 gliomas, and 20 (57.1%) had glioblastomas; all initially underwent surgery and conventional radiotherapy. The median initial and subsequent radiotherapy doses were 60 and 26 Gy, respectively., Results: After a median follow-up period of 9.0 months, the only toxicity of grade 2 or more was radiation-induced brain necrosis in four patients (11.4%). The median overall and progression-free survival periods following re-irradiation were 9.0 and 3.0 months, respectively. Univariate analysis revealed that performance status at salvage re-irradiation was a significant predictor of progression-free survival., Conclusion: Salvage re-irradiation using CyberKnife is feasible, with an acceptable toxicity profile, for patients with recurrent glioma., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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.

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.

: The structure and function of tumor blood vessels profoundly affects the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear. Here, we show that LPA4 activation promotes the formation of fine vascular structures in brain tumors. RhoA/ROCK signaling contributed to LPA-induced endothelial cell-cell adhesion, and RhoA/ROCK activity following LPA4 stimulation regulated expression of VCAM-1. This resulted in increased lymphocyte infiltration into the tumor. LPA improved delivery of exogenous IgG into brain tumors and enhanced the anticancer effect of anti-programmed cell death-1 antibody therapy. These results indicate the effects of LPA on vascular structure and function apply not only to chemotherapy but also to immunotherapy. SIGNIFICANCE: These findings demonstrate that lysophosphatidic acid, a lipid mediator, promotes development of a fine capillary network in brain tumors by inducing tightening of endothelial cell-to-cell adhesion, facilitating improved drug delivery, and lymphocyte penetration., (©2018 American Association for Cancer Research.)

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.

Enchondromatosis is a rare skeletal disorder characterized by the development of multiple enchondromas, which can also manifest non-cartilage tumors including gliomas. Here, we describe a genetic analysis of a low-grade glioma that developed in an enchondromatosis case. A 32-year-old man with a long history of enchondromatosis developed a left frontal tumor. The histopathological findings of his surgical specimen revealed characteristics of a low-grade glioma with an IDH1 c.395G>A (R132H) mutation and 1p/19q codeletion, which led to a definitive diagnosis of oligodendroglioma. A common point mutation in IDH1 (R132H) was detected in the patient's enchondroma and glioma-matched pair specimens. To the best of our knowledge, this is the first case of molecularly confirmed oligodendroglioma associated with enchondromatosis. Furthermore, identification of a common IDH1 mutation in enchondroma and oligodendroglioma-matched pair specimens supports the hypothesis that IDH1/2 mosaicism initiates tumorigenesis.

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 11 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.

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., Competing Interests: The authors have declared that no competing interests exist.

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

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner., Methods: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival., Findings: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084)., Interpretation: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection., Funding: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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

We investigated the clinical outcomes following treatment using stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for brain metastases from lung cancer. A total of 67 patients with 109 brain metastases from lung cancer treated using CyberKnife between 1998 and 2011 were retrospectively analyzed. SRS (median dose, 24 Gy) was used to treat 79 lesions, and 3-fraction SRT (median dose, 30 Gy) was used to treat 30 lesions. The median follow-up time was 9.4 months (range, 0.4-125 months). The 1-year local control rate was 83.3%, and the 1-year distant brain failure rate was 30.1%. The median survival time was 13.1 months, and the 1- and 3-year overall survival (OS) rates were 54.8% and 25.9%, respectively. On multivariate analysis, three factors were found to be statistically significant predictors of OS: (i) presence of uncontrolled primary disease [hazard ratio (HR) = 3.04; P = 0.002]; (ii) Brinkman index (BI) ≥ 1000 (HR = 2.75; P = 0.007); and (iii) pulmonary metastases (HR = 3.54; P = 0.009). Radionecrosis and worsening of neurocognitive function after radiosurgery were observed in 5 (7%) and 3 (4%) patients, respectively. Our results indicated that SRS/SRT for brain metastases from lung cancer was effective. Uncontrolled primary disease, high BI, and pulmonary metastases at treatment were significant risk factors for OS., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

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

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

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

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

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

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

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

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

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

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

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

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

Object: Due to advances in neuroimaging and the increasing use of imaging to screen for brain disease ("brain checkups"), meningiomas are now often detected as an incidental finding. The natural history of these asymptomatic meningiomas remains unclear, however. In this study, the authors investigated the natural history and growth pattern of incidentally detected meningiomas using serial volumetric assessment and regression analysis., Methods: In 70 patients with incidentally discovered meningiomas who underwent follow-up for longer than 1 year, tumor volumes were calculated volumetrically at each follow-up visit, and tumor growth was determined. In patients with tumor growth, regression analysis was performed to determine the pattern of growth., Results: Forty-four tumors exhibited growth and 26 did not. In a regression analysis, 16 of the tumors that grew followed an exponential growth pattern and 15 exhibited linear growth patterns. The presence of calcification was the only imaging characteristic that significantly distinguished the group with tumor growth from that without, although no radiological characteristics significantly distinguished the exponential growth group from the linear growth group. Two patients with obvious tumor growth underwent surgical removal and the pathological specimens extracted showed a high proliferative potential., Conclusions: The authors found that incidentally discovered meningiomas did not always follow an exponential growth pattern but often exhibited more complex patterns of growth. Serial monitoring of tumor volumes and regression analysis may reveal the growth pattern of incidental meningiomas and provide information useful for determining treatment strategy.

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

Two distinct forms of malignant lymphomas can invade the central nervous system (CNS). Although primary CNS malignant lymphomas (PCNSMLs) invade the brain parenchyma, intravascular lymphomas (IVLs) form tumor cell aggregates in the vasculature and produce stroke-like symptoms and cognitive impairment. Although the tumor cells are mostly of B-cell origin in both types of lymphoma, their biological behavior is different, and the detailed mechanism(s) underlying this difference are not well understood. We studied the expression level of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and integrin-beta1 in tumor tissue samples from patients with primary CNS lymphoma (n = 8) and intravascular lymphoma (n = 2) using immunohistochemical analysis. We also assessed the expression of the matrix metalloproteinases (MMP)-2 and MMP-9. ICAM-1 was positive in six and integrin-beta1 was positive in seven patients among eight PCNSML patients. MMP-2 and MMP-9 were expressed in all PCNSML. In contrast, none of them was positive in both IVL cases. Our findings suggest that adhesion molecules and MMPs are essential for malignant lymphoma cell invasion from the vasculature into the brain parenchyma and that they may be the key determinants for malignant lymphoma cells to behave as PCNSML or IVL cells.

The expression of Wilms' tumor gene WT1 protein was investigated immunohistochemically in 73 glial tumors, including 60 astrocytic tumors, eight oligodendroglial tumors, and five ependymal tumors. WT1 protein was detected in 70 of the 73 glial tumors (95.9%) examined. Almost all glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, and anaplastic oligodendrogliomas expressed high levels of WT1 protein. A significant (p < 0.001) correlation was found between WT1 protein expression and MIB-1 staining index. Histological examination found that WT1 protein was strongly expressed in the anaplastic portions and areas with perivascular proliferation and high cellularity, implying that WT1 gene might be important in glial tumor cell proliferation. WT1 gene is overexpressed in various types of solid tumors and WT1 protein is a target antigen for cancer immunotherapy. This study indicates that many malignant glial tumors are good candidates for cancer immunotherapy targeting WT1 protein and that WT1 protein expression could be used as a proliferation marker in glial tumors.

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

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

Genomic microarray systems can simultaneously provide substantial genetic and chromosomal information in a relatively short time. We have analyzed genomic DNA from frozen sections of 30 cases of primary glioblastomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Genes that were frequently amplified included RFC2/CYLN2 (63.3%), EGFR (53.3%), IL6 (53.3%), ABCB1 (MDR1) (36.7%), and PDGFRA (26.7%). Genes that were frequently deleted included (56.7%), FGFR2 (66.7%), MTAP (60.0%), DMBT1 CDKN2A (p16)/MTAP (50.0%), PIK3CA (43.3%), and EGR2 (43.3%), but deletion of RB1 or TP53 was rarely detected. Chromosomal gains were observed frequently for 7q (33.3%), 7p (20.0%), and 17q (13.3%). Loss of the 10q was frequently detected in 13 of 30 cases (46.7%). Loss of the entire chromosome 10 was seen in 9 of 30 cases (30.0%), and was often accompanied by EGFR amplification (7 cases, 77.8%). The GenoSensor Array 300 proved to be useful for identification of genome-wide molecular changes in glioblastomas. The obtained microarray profile can also yield valuable insight into the molecular events underlying carcinogenesis of brain tumors and may provide clues about clinical correlations, including response to treatment.