Search

Objective: The authors aimed to investigate genetic alterations in low-grade gliomas (LGGs) in pediatric and young adult patients presenting with spontaneous hemorrhage., Methods: Patients younger than 30 years of age with a pathological diagnosis of World Health Organization (WHO) grade I or II glioma and who had undergone treatment at the authors' institution were retrospectively examined. BRAF V600E, FGFR1 N546/K656, IDH1 R132, IDH2 R172, and KIAA1549-BRAF (K-B) fusion genetic alterations were identified, and the presence of spontaneous tumoral hemorrhage was recorded., Results: Among 66 patients (39 with WHO grade I and 27 with grade II tumors), genetic analysis revealed K-B fusion in 18 (27.3%), BRAF V600E mutation in 14 (21.2%), IDH1/2 mutation in 8 (12.1%), and FGFR1 mutation in 4 (6.1%). Spontaneous hemorrhage was observed in 5 patients (7.6%); 4 of them had an FGFR1 mutation and 1 had K-B fusion. Univariate analysis revealed a statistically significant association of an FGFR1 mutation and a diencephalic location with spontaneous hemorrhage. Among 19 diencephalic cases including the optic pathway, hypothalamus, and thalamus, an FGFR1 mutation was significantly associated with spontaneous hemorrhage (p < 0.001). Four FGFR1 mutation cases illustrated the following results: 1) a 2-year-old female with pilomyxoid astrocytoma (PMA) harboring the FGFR1 K656E mutation presented with intraventricular hemorrhage (IVH); 2) a 6-year-old male with PMA harboring FGFR1 K656E and D652G mutations presented with intratumoral hemorrhage (ITH); 3) a 4-year-old female with diffuse astrocytoma harboring FGFR1 K656M and D652G mutations presented with IVH; and 4) a young adult patient with pilocytic astrocytoma with the FGFR1 N546K mutation presented with delayed ITH and IVH after 7 years of observation., Conclusions: Although the mechanism remains unclear, the FGFR1 mutation is associated with spontaneous hemorrhage in pediatric and young adult LGG.

Purpose: 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) appears to be a promising treatment for glioma. However, 5-ALA-mediated fluorescence cannot always be detected in grade II/III gliomas. We hypothesized that gene expression patterns in the Protoporphyrin IX (PpIX) synthesis pathway may be associated with intraoperative fluorescence status of grade II/III gliomas, and then attempted to identify the key molecule of 5-ALA-mediated fluorescence., Methods: Using 50 surgically obtained specimens, which were diagnosed as grade II and III gliomas, we analyzed gene expression within the PpIX synthesis pathway to identify candidate molecules according to intraoperative 5-ALA-mediated fluorescence status. The most likely candidate gene was selected and confirmed by protein expression analysis. To evaluate the biological function of the molecule in PpIX synthesis, functional analysis was performed using specific, small interference (si)RNA in the SW-1783 human grade III glioma cell line., Results: Among the genes involved in the porphyrin synthesis pathway, the mRNA expression of Peptide transporter 2 (PEPT2) in FGS fluorescence-positive gliomas was significantly higher than that in fluorescence-negative gliomas. Protein expression of PEPT2 was also significantly higher in the fluorescence-positive gliomas, which was confirmed by western blot analysis and immunofluorescence analysis. The siRNA-mediated downregulation of the mRNA and protein expression of PEPT2 led to decreased PpIX fluorescence intensity, as confirmed by fluorescence spectrum analysis., Conclusions: The results suggest PEPT2 is an important candidate molecule in 5-ALA-mediated FGS in grade II/III gliomas. As the overexpression of PEPT2 was associated with higher PpIX fluorescence intensity, PEPT2 may improve fluorescence-guided resection in grade II/III gliomas.

Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220-kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40°C) after treatment with 200 µg/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature ≤42°C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: This study noninvasively examined the electrical conductivity (σ) characteristics of diffuse gliomas using MRI and tested its validity., Methods: MRI including a 3D steady-state free precession (3D SSFP) sequence was performed on 30 glioma patients. The σ maps were reconstructed from the phase images of the 3D SSFP sequence. The σ histogram metrics were extracted and compared among the contrast-enhanced (CET) and noncontrast-enhanced tumour components (NCET) and normal brain parenchyma (NP). Difference in tumour σ histogram metrics among tumour grades and correlation of σ metrics with tumour grades were tested. Validity of σ measurement using this technique was tested by correlating the mean tumour σ values measured using MRI with those measured ex vivo using a dielectric probe., Results: Several σ histogram metrics of CET and NCET of diffuse gliomas were significantly higher than NP (Bonferroni-corrected p ≤ .045). The maximum σ of NCET showed a moderate positive correlation with tumour grade (r = .571, Bonferroni-corrected p = .018). The mean tumour σ measured using MRI showed a moderate positive correlation with the σ measured ex vivo (r = .518, p = .040)., Conclusions: Tissue σ can be evaluated using MRI, incorporation of which may better characterise diffuse gliomas., Key Points: • This study tested the validity of noninvasive electrical conductivity measurements by MRI. • This study also evaluated the electrical conductivity characteristics of diffuse glioma. • Gliomas have higher electrical conductivity values than the normal brain parenchyma. • Noninvasive electrical conductivity measurement can be helpful for better characterisation of glioma.

A 5-year-old boy underwent biopsy of an intra-axial calcified tumor in the hypothalamus, which was incidentally found. Based on the presence of ganglion-like cells combined with glial cell element, the pathological diagnosis was ganglioglioma. Because the tumor grew gradually in size over the next 2 years, he underwent chemotherapy with temozolomide. However, at 8 years of age, the boy developed hydrocephalus and the cystic lesion had re-grown. Endoscopic cyst fenestration and tumor biopsy was performed, and pathological diagnosis was tentatively oligodendroglioma based on the presence of tumor cells with a perinuclear halo. At 10 years of age, hydrocephalus recurred and the cystic lesion had re-grown. A second round of endoscopic cyst fenestration and tumor biopsy led to a pathological diagnosis of pilocytic astrocytoma due to a biphasic appearance with areas of dense tumor cells and microcystic areas, tumor cells with eosinophilic processes, and the presence of an eosinophilic granular body. Genetic analysis of the first biopsy successfully identified the BRAF V600E mutation. Because pathological diagnosis of diencephalic low-grade glioma harboring BRAF V600E would be sometimes difficult due to pathological variations, pathological diagnosis should be performed under the consideration of molecular diagnosis of BRAF V600E for optimal diagnosis and treatment.

Background: Bevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18F-Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage., Methods: We reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application., Results: After BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as "MRI-FMISO double responder". As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as "MRI-only responder". The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI ("non-responder"). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model., Conclusions: Recurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way., Competing Interests: The authors have declared that no competing interests exist.

Because it is highly infiltrative, malignant glioma is a cancer with a poor prognosis despite multidisciplinary treatment strategies, such as aggressive surgery and chemoradiotherapy, necessitating new therapeutic approaches to control migration of tumor cells. In our study, we investigated the efficacy of sonodynamic therapy of glioma cells in vitro using porphyrin derivatives, including 5-aminolevulinic acid, protoporphyrin IX and talaporfin sodium, as sonosensitizers. These substances have been known to accumulate in glioma cells and are expected to have cytotoxic effects on sonication. Our study found that the cytotoxicity of sonication of glioma cells is enhanced by each sonosensitizer and that the efficacy of sonodynamic therapy may depend on the degree of intracellular accumulation of sonosensitizer. Also, the study suggests that induction of apoptosis is a major mechanism underlying cell death. Though further investigations are necessary, our preliminary result indicates a potential for sonodynamic therapy with sonosensitizers in glioma treatment., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: (11)C-methionine (MET) PET is an established diagnostic tool for glioma. Studies have suggested that MET uptake intensity in the tumor is a useful index for predicting patient outcome. Because MET uptake is known to reflect tumor expansion more accurately than MRI, we aimed to elucidate the association between volume-based tumor measurements and patient prognosis., Methods: The study population comprised 52 patients with newly diagnosed glioma who underwent PET scanning 20 min after injection of 370 MBq MET. The tumor was contoured using a threshold of 1.3 times the activity of the contralateral normal cortex. Metabolic tumor volume (MTV) was defined as the total volume within the boundary. Total lesion methionine uptake (TLMU) was defined as MTV times the mean standardized uptake value (SUVmean) within the boundary. The tumor-to-normal ratio (TNR), calculated as the maximum standardized uptake value (SUVmax) divided by the contralateral reference value, was also recorded. All patients underwent surgery (biopsy or tumor resection) targeting the tissue with high MET uptake. The Kaplan-Meier method was used to estimate the predictive value of each measurement., Results: Grade II tumor was diagnosed in 12 patients (3 diffuse astrocytoma, 2 oligodendroglioma, and 7 oligoastrocytoma), grade III in 18 patients (8 anaplastic astrocytoma, 6 anaplastic oligodendroglioma, and 4 anaplastic oligoastrocytoma), and grade IV in 22 patients (all glioblastoma). TNR, MTV and TLMU were 3.1 ± 1.2, 51.6 ± 49.9 ml and 147.7 ± 153.3 ml, respectively. None of the three measurements was able to categorize the glioma patients in terms of survival when all patients were analyzed. However, when only patients with astrocytic tumor (N = 33) were analyzed (i.e., when those with oligodendroglial components were excluded), MTV and TLMU successfully predicted patient outcome with higher values associated with a poorer prognosis (P < 0.05 and P < 0.01, respectively), while the predictive ability of TNR did not reach statistical significance (P = NS)., Conclusion: MTV and TLMU may be useful for predicting outcome in patients with astrocytic tumor.

In the CNS, primary tumors with rhabdoid components are classified as atypical teratoid/rhabdoid tumor, rhabdoid meningioma or rhabdoid glioblastoma. The authors present a young adult patient with supratentorial rhabdoid tumor incidentally found after head trauma as a small pre-existing lesion in the parahippocampal gyrus. MRI demonstrated an area of hypointensity on T1-weighted images and hyperintensity on T2-weighted and fluid attenuated inversion recovery images. A serial MR scan revealed no change 3 months after the initial examination but drastic changes at 6 months. As the tumor and accompanying intratumoral hemorrhage enlarged rapidly, resection of the tumor was performed. Histopathology revealed that the main component of the tumor was typical rhabdoid cells with some necrotic areas. There were also pathological features consistent with oligoastrocytoma. The specimen had neither vascular proliferation usually seen in high-grade glioma nor the meningothelial pattern that suggests meningioma. Immunohistochemical findings revealed that cells were strongly positive for vimentin, epithelial membrane antigen and INI-1 antibody throughout the specimen. Further, monosomy 22 was detected by fluorescence in situ hybridization. The tumor was finally thought to be an unclassifiable primitive rhabdoid tumor with oligoastrocytoma that arose in the CNS. The patient died within 5 months of detection of the tumor, regardless of surgical resection, radiotherapy and chemotherapy., (© 2012 Japanese Society of Neuropathology.)

Glioma is one of the most common brain tumors in adults. Its diagnosis and management have been determined by histological classifications. It is difficult to establish new paradigms because the pathology has matured and a great deal of knowledge has accumulated. On the other hand, we understand that there are limitations to this gold-standard because of the heterogeneity of glioma. Thus, it is necessary to find new criteria independent of conventional morphological diagnosis. Molecular imaging such as positron emission tomography (PET) is one of the most promising approaches to this challenge. PET provides live information of metabolism through the behavior of single molecules. The advantage of PET is that its noninvasive analysis does not require tissue sample, therefore examination can be performed repeatedly. This is very useful for capturing changes in the biological nature of tumor without biopsy. In the present clinical practice for glioma, (18)F-fluorodeoxyglucose (FDG) PET is the most common tracer for predicting prognosis and differentiating other malignant brain tumors. Amino acid tracers such as (11)C-methionine (MET) are the most useful for detecting distribution of glioma, including low-grade. Tracers to image hypoxia are under investigation for potential clinical use, and recently, (18)F-fluoromisonidazole (FMISO) has been suggested as an effective tracer to distinguish glioblastoma multiforme from others.

Purpose: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that (18)F fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas., Methods: This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and (18)F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated., Results: Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p ≤ 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 ± 0.60, range 1.71-3.81) than in non-GBM patients (1.22 ± 0.06, range 1.09-1.29, p ≤ 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also higher in GBM patients (1.46 ± 0.75, range 0.91-3.79) than in non-GBM patients (1.07 ± 0.62, range 0.66-2.95, p ≤ 0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. The uptake volume of FMISO was larger in GBM (27.18 ± 10.46%, range 14.02-46.67%) than in non-GBM (6.07 ± 2.50%, range 2.12-9.22%, p ≤ 0.001)., Conclusion: These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas.

Objective: We reviewed the relationship between extent of resection and survival of patients with high-grade gliomas with special consideration of an oligodendroglial component., Methods: A retrospective review was performed on 160 adult patients with histological diagnosis of high-grade gliomas since 2000. All histological slides were categorized as high-grade astrocytomas or oligodendroglial tumors. Extent of resection was assessed by early post-operative magnetic resonance imaging and classified as complete resection, incomplete resection and biopsy. Measured outcomes were overall survival and progression-free survival. The independent association of extent of resection and survival was analyzed by the multivariate proportional hazard model adjusting for prognostic factors., Results: The lesions were classified as high-grade astrocytomas in 93 patients and high-grade oligodendroglial tumors in 67 patients. In high-grade astrocytomas, the median survival after complete resection (n = 36), incomplete resection (n = 36) and biopsy (n = 21) was 23.4, 15.3 and 12.6 months, respectively. Complete resection was independently associated with increased overall survival (P < 0.001) and progression-free survival (P = 0.002) compared with incomplete resection, while incomplete resection was not associated with survival benefit compared with biopsy by multivariate analysis. On the other hand, in high-grade oligodendroglial tumors, the majority of patients were still alive and there is no significant difference in the survival between complete resection (n = 24) and incomplete resection (n = 33), while even incomplete resection had a significantly longer overall survival (P < 0.001) and progression-free survival (P = 0.006) compared with biopsy (n = 10)., Conclusions: Maximal cytoreduction improves the survival of high-grade gliomas, although our data indicated that the impact of extent of resection in high-grade astrocytomas is different from that in high-grade oligodendroglial tumors.

Objective: Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is a new therapeutic modality for malignant glioma. This study is designed to evaluate acute morphological and histological changes of glioma cells after 5-ALA mediated PDT using fluorescence microscopy and three-dimensional spheroid models., Methods: Monolayer cultures and spheroids (small and large sizes) of C6 (rat glioma cell line) and U251MG (human glioma cell line) cells were co-incubated for 4 hours with 5-ALA (100 μg/ml) and irradiated using a diode laser (635±5 nm, 5-100 mW/cm(2), and total light dose 2.5-50 J/cm(2)). Growth kinetics of the spheroids were followed for 7 days after PDT and morphological changes were assessed by phase contrast microscopy. In addition to hematoxylin and eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick end-labeling, various fluorescent dyes including calcein AM, ethidium homodimer-1 (EthD-1), annexin V-FITC, propidium iodide and Hoechst 33342, were used to clarify the mechanism of cell death after PDT., Results: Although PDT spheroids of both cell lines showed growth inhibition during the first few days, resumption of spheroid growth on day 3 after irradiation was observed in most spheroids. Hematoxylin and eosin staining showed cells with condensed chromatin within the superficial layer of the PDT spheroids. In the PDT groups, monolayer cells in the irradiated area were negative for calcein AM and clearly positive for EthD-1. In C6 PDT spheroids, the outer layer of the spheroid was negative for calcein AM and positive for EthD-1. In monolayer cells, cells in the irradiation area in PDT groups were positive for propidium iodide and negative for Hoechst 33342., Conclusion: Light and fluorescence microscopic findings suggested necrotic cell death as an anti-tumor effect in the acute phase after PDT. These findings were observed in both C6 and U251MG monolayer culture cells and spheroids. Although various total light doses resulted in significant differences in the growth rate of spheroids after PDT, resumption of spheroid growth occurred in most spheroids.

Gliomas are regionally heterogeneous tumors. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) and (11)C-methionine (MET) evaluates the heterogeneity of histological malignancy within the tumor. We present two patients with oligodendrocytic tumors that showed discrepancies in the highest uptake areas with these two tracers. PET studies with MET and FDG were performed on the same day, 2 weeks before surgery. In both cases, biopsy specimens were separately obtained from the highest MET and FDG uptake areas guided by intraoperative neuronavigation. Histological examinations demonstrated that the specimens from the highest MET uptake area revealed low-grade oligoastrocytoma or oligodendroglioma, whereas histological anaplasias were contained in the specimens from the highest FDG uptake area. With gliomas with oligodendroglial components, the MET uptake ratio does not always correspond to histological anaplasia, which can be detected only by FDG PET. Sole application of MET PET for preoperative evaluation may lead to misunderstanding of histological heterogeneity in gliomas, especially those with oligodendroglial components. FDG and MET tracers play complementary roles in preoperative evaluation of gliomas.

Titanium dioxide (TiO(2)) is thought to be a photocatalytic agent excited by UV light. Our aim was to investigate the photocatalytic antitumor effect of water-dispersed TiO(2) nanoparticles on C6 rat glioma cells and to evaluate the treatment responses by the spheroid models. Water-dispersed TiO(2) nanoparticles were constructed by the adsorption of chemical modified polyethylene glycol (PEG) on the TiO(2) surface (TiO(2)/PEG). Each monolayer and spheroid of C6 cells was coincubated with various concentrations of TiO(2)/PEG and subsequently irradiated with UV light. Damage of the cells and spheroids was evaluated sequentially by staining with the fluorescent dyes. The cytotoxic effect was correlated with the concentration of TiO(2)/PEG and the energy dose of UV irradiation. More than 90% of cells were killed after 13.5 J cm(-2) of UV irradiation in the presence of 500 microg mL(-1) TiO(2)/PEG. The irradiated spheroids in the presence of TiO(2)/PEG showed growth suppression compared with control groups. In TiO(2)/PEG-treated spheroids, the number of Annexin V-FITC-stained cells gradually increased during the first 6 h, and subsequently propidium iodide-stained cells appeared. The results of this study suggest that newly developed photoexcited TiO(2)/PEG have antitumoral activity. Photodynamic therapy utilizing this material can be a clue to a novel therapeutic strategy for glioma.

Object: Intrinsic tumors arising in the dorsal midbrain cause obstructive hydrocephalus and have an indolent clinical course. Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (FDG) and l- [methyl-(11)C]methionine (MET) was used to evaluate the biological behaviors of dorsal midbrain tumors., Methods: The authors report on 4 patients (3 males and 1 female) with dorsal midbrain tumors who presented with obstructive hydrocephalus. A diagnosis was made with MR imaging in each patient. To manage the hydrocephalus, endoscopic third ventriculostomy was performed in all cases. The patients did not undergo any other surgical procedures except endoscopic biopsy procedure, chemotherapy, or radiation therapy. The patients in 3 cases underwent FDG- and MET-PET within 6 months of CSF-diverting procedures, and the patient in 1 case underwent PET 10 years after the procedure., Results: After the CSF-diverting procedure, clinical symptoms resolved or improved in all patients. Gliosis or glial proliferation was diagnosed in 1 patient, and possible low-grade glioma in 2 patients. Although all tumors appeared hyperintense on T2-weighted MR images, their appearance on T1-weighted images was variable (iso- and/or hypointense), and partial lesion enhancement was observed on images from 2 patients. On the other hand, the PET features of these lesions were almost identical, and the scans did not show a high uptake of FDG and MET compared with the cortical uptake in a normal brain. The mean tumor tissue/normal tissue ratio of FDG uptake was 0.65, and that of MET was 0.99., Conclusions: Positron emission tomography findings suggested that the indolent dorsal midbrain lesion had nontumorous characteristics, thus supporting a good prognosis. Positron emission tomography studies may be more informative and predictive of the biological behavior of dorsal midbrain tumors than a biopsy procedure.

Although C6 glioma spheroids have been widely utilized for assessment of new therapeutic modalities, they need to be generated for long-term use and special instruments. Therefore we generated a multicellular mass (spheroid) from C6 glioma cells on non-adhesive culture plates. Cells cultured in a spheroid plate (Sumiron Celltight Spheroid) spontaneously aggregated and formed a cell mass after 24 h in culture. After three days of culture, the cell mass became spherical with a diameter ranging from 300 to 650 microm. The size of the spheroid depended on the number of cells plated in each well. Histological examination indicated no spheroid had aggregations of cell death during the 8 days of culture. In the case where 1.0 x 10(3) cells were plated in each well, the size of the spheroid increased gradually and stagnated at approximately 850 microm. The present study demonstrated that a spheroid was easily generated from C6 glioma cells on a non-adhesive plate. This method could provide a new tool for analyzing therapeutic modalities for glioma.

Background: Bevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18F-Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage. Methods: We reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application. Results: After BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as “MRI-FMISO double responder”. As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as “MRI-only responder”. The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI (“non-responder”). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model. Conclusions: Recurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way. [ABSTRACT FROM AUTHOR]

Purpose: C-methionine (MET) PET is an established diagnostic tool for glioma. Studies have suggested that MET uptake intensity in the tumor is a useful index for predicting patient outcome. Because MET uptake is known to reflect tumor expansion more accurately than MRI, we aimed to elucidate the association between volume-based tumor measurements and patient prognosis. Methods: The study population comprised 52 patients with newly diagnosed glioma who underwent PET scanning 20 min after injection of 370 MBq MET. The tumor was contoured using a threshold of 1.3 times the activity of the contralateral normal cortex. Metabolic tumor volume (MTV) was defined as the total volume within the boundary. Total lesion methionine uptake (TLMU) was defined as MTV times the mean standardized uptake value (SUVmean) within the boundary. The tumor-to-normal ratio (TNR), calculated as the maximum standardized uptake value (SUVmax) divided by the contralateral reference value, was also recorded. All patients underwent surgery (biopsy or tumor resection) targeting the tissue with high MET uptake. The Kaplan-Meier method was used to estimate the predictive value of each measurement. Results: Grade II tumor was diagnosed in 12 patients (3 diffuse astrocytoma, 2 oligodendroglioma, and 7 oligoastrocytoma), grade III in 18 patients (8 anaplastic astrocytoma, 6 anaplastic oligodendroglioma, and 4 anaplastic oligoastrocytoma), and grade IV in 22 patients (all glioblastoma). TNR, MTV and TLMU were 3.1 ± 1.2, 51.6 ± 49.9 ml and 147.7 ± 153.3 ml, respectively. None of the three measurements was able to categorize the glioma patients in terms of survival when all patients were analyzed. However, when only patients with astrocytic tumor ( N = 33) were analyzed (i.e., when those with oligodendroglial components were excluded), MTV and TLMU successfully predicted patient outcome with higher values associated with a poorer prognosis ( P < 0.05 and P < 0.01, respectively), while the predictive ability of TNR did not reach statistical significance ( P = NS). Conclusion: MTV and TLMU may be useful for predicting outcome in patients with astrocytic tumor. [ABSTRACT FROM AUTHOR]

Gliomas are regionally heterogeneous tumors. Positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) and C-methionine (MET) evaluates the heterogeneity of histological malignancy within the tumor. We present two patients with oligodendrocytic tumors that showed discrepancies in the highest uptake areas with these two tracers. PET studies with MET and FDG were performed on the same day, 2 weeks before surgery. In both cases, biopsy specimens were separately obtained from the highest MET and FDG uptake areas guided by intraoperative neuronavigation. Histological examinations demonstrated that the specimens from the highest MET uptake area revealed low-grade oligoastrocytoma or oligodendroglioma, whereas histological anaplasias were contained in the specimens from the highest FDG uptake area. With gliomas with oligodendroglial components, the MET uptake ratio does not always correspond to histological anaplasia, which can be detected only by FDG PET. Sole application of MET PET for preoperative evaluation may lead to misunderstanding of histological heterogeneity in gliomas, especially those with oligodendroglial components. FDG and MET tracers play complementary roles in preoperative evaluation of gliomas. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography with 11C-methionine (MET) is well established in the diagnostic work-up of malignant brain tumors. Texture analysis is a novel technique for extracting information regarding relationships among surrounding voxels, in order to quantify their inhomogeneity. This study evaluated whether the texture analysis of MET uptake has prognostic value for patients with glioma. Methods: We retrospectively analyzed adults with glioma who had undergone preoperative metabolic imaging at a single center. Tumors were delineated using a threshold of 1.3-fold of the mean standardized uptake value for the contralateral cortex, and then processed to calculate the texture features in glioma. Results: The study included 42 patients (median age: 56 years). The World Health Organization classifications were grade II (7 patients), grade III (17 patients), and grade IV (18 patients). Sixteen (16.1%) all-cause deaths were recorded during the median follow-up of 18.8 months. The univariate analyses revealed that overall survival (OS) was associated with age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01–1.08, p = 0.0093), tumor grade (HR 3.64, 95% CI 1.63–9.63, p = 0.0010), genetic status (p < 0.0001), low gray-level run emphasis (LGRE, calculated from the gray-level run-length matrix) (HR 2.30 × 1011, 95% CI 737.11–4.23 × 1019, p = 0.0096), and correlation (calculated from the gray-level co-occurrence matrix) (HR 5.17, 95% CI 1.07–20.93, p = 0.041). The multivariate analyses revealed OS was independently associated with LGRE and correlation. The survival curves were also significantly different (both log-rank p < 0.05). Conclusion: Textural features obtained using preoperative MET positron emission tomography may compliment the semi-quantitative assessment for prognostication in glioma cases. [ABSTRACT FROM AUTHOR]

Abstract: Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO2) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO2 nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO2 nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO2 surface (TiO2/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100μg/ml of TiO2/PEG for 3h and subsequently irradiated by ultraviolet light (5.0mW/cm2) or 1.0MHz ultrasound (1.0W/cm2). Cell survival was estimated by MTT assay 24h after irradiation. In the presence of TiO2/PEG, the photodynamic cytotoxic effect was not observed after 20min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO2/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO2/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO2/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. [Copyright &y& Elsevier]