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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. [ABSTRACT FROM AUTHOR]

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]

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. [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]

Titanium dioxide (TiO2) is thought to be a photocatalytic agent excited by UV light. Our aim was to investigate the photocatalytic antitumor effect of water-dispersed TiO2 nanoparticles on C6 rat glioma cells and to evaluate the treatment responses by the spheroid models. Water-dispersed TiO2 nanoparticles were constructed by the adsorption of chemical modified polyethylene glycol (PEG) on the TiO2 surface (TiO2/PEG). Each monolayer and spheroid of C6 cells was coincubated with various concentrations of TiO2/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 TiO2/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 μg mL−1 TiO2/PEG. The irradiated spheroids in the presence of TiO2/PEG showed growth suppression compared with control groups. In TiO2/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 TiO2/PEG have antitumoral activity. Photodynamic therapy utilizing this material can be a clue to a novel therapeutic strategy for glioma. [ABSTRACT FROM AUTHOR]

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant,?EGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16INK4a/p19Arf or p53, respectively, with or without ectopic expression of?EGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of?EGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/?EGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/?EGFR(2-7) in glioblastoma patients.Oncogene (2004) 23, 6854-6863. doi:10.1038/sj.onc.1207872 Published online 26 July 2004 [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]

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. [ABSTRACT FROM AUTHOR]