Reoxygenation of glioblastoma multiforme treated with fractionated radiotherapy concomitant with temozolomide: changes defined by 18F-fluoromisonidazole positron emission tomography: two case reports.

Two glioblastoma multiforme patients underwent (18)F-FMISO (fluoromisonidazole) positron emission tomography study to access the tumor oxygenation status before and immediately after fractionated radiotherapy concomitant with temozolomide chemotherapy. In both cases, a prominent (18)F-FMISO tumor accumulation observed in the first study was notably decreased in the second study, which was supposed to be a reoxygenation of the tumor. As far as we investigated, this is the first report of the changes of oxygenation status in glioblastoma multiforme treated through radiation therapy with temozolomide.

[Combined use of positron emission tomography with (18)F-fluorodeoxyglucose and (11)C-methionine for preoperative evaluation of gliomas].

OBJECT: The aim of this study was to evaluate the usefulness of combined use of positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) and (11)C-methionine (MET) for the preoperative evaluation of gliomas and to investigate the feasibility of PET in glioma surgery. METHODS: Preoperative FDG (n=25) and/or MET (n=22) PET studies were performed in 26 patients with primary and recurrent adult gliomas. We qualitatively (visual analysis) and quantitatively evaluated the uptake of both tracers in the tumor location. For quantitative analysis, data were analyzed by a region of interest method using the standard uptake value (SUV) and a calculated uptake ratio. We investigated the correlation among the tracer uptake ratios, histological tumor grading and tumor proliferation activity. RESULTS: On visual inspection, no patient (0/9) with high uptake of FDG had low grade gliomas and 94% (14/15) had high grade gliomas, while uptake of MET was present in all patients. On quantitative analysis, histological tumor grade was most reflected in FDG uptake ratio compared with contralateral white matter. The tumor/normal brain (T/N) uptake ratio of MET increased stepwise with increasing histological grade but was not significantly different from tumor grade. In comparison of FDG and MET uptake ratio with proliferation activity, a significant correlation was shown for FDG uptake ratio, but not for the T/N ratio of MET. CONCLUSIONS: MET is useful in detecting and delineating the extent of the tumor, but not in evaluating tumor grade and proliferative activity. The FDG uptake ratio correlates well with tumor grade and proliferative activity. Preoperative PET studies with FDG and MET play complementary roles in the planning of glioma surgery, and integrated information from both tracers helps us to plan the extent of tumor resection.

Occipitoparietal benign osteoblastoma: should entire lesion be resected when magnetic resonance images reveal wide abnormal signal intensity in surrounding bone marrow?

BACKGROUND: Benign osteoblastoma is an uncommon primary bone tumor that usually affects long bones and the vertebral column. Its occurrence in the calvarium is rare. Despite the characteristically benign nomenclature of osteoblastoma, it sometimes recurs with the possibility of transforming into a malignant form after an incomplete resection. Therefore, radical resection is recommended whenever possible. However, it has not been clarified whether the adjacent bones should also be completely resected when magnetic resonance (MR) images reveal abnormal signal intensity in the bone marrow. CASE DESCRIPTION: Presented in this case report is a 12-year-old boy with occipital tenderness associated with occipitoparietal bone tumor. Neuroradiological studies demonstrated a solid tumor located in the occipital bone extending over the right parietal bone. Magnetic resonance images further revealed abnormal signal intensity in the bone marrow of the entire occipital and bilateral parietal bones. Macroscopically, the calvarial bone adjacent to the solid tumor appeared to be reddish, but it was not covering the entire area, contradicting the abnormal intensity found on the preoperative MR images. The resected area was determined according to macroscopic findings, and bones with normal color tone were preserved. Because histological examination did not clearly indicate tumor invasion at the margin of the resection site, no additional therapy was given. Although MR images revealed abnormal intensity in the bone marrow of the surgical margin immediately after the operation, the intensity had been normalized by degrees and there was no evidence of recurrence during a follow-up period of 34 months. This may suggest that bone marrow lesion showing abnormal intensity was edema rather than tumor invasion. CONCLUSIONS: The authors conclude that total resection, including a bone marrow lesion, is not always necessary for benign osteoblastoma. Macroscopic findings that show an abnormal color tone of the cortex could be a good indicator in revealing tumor activity invading bone marrow.

Reduced blood flow and preserved vasoreactivity characterize oxygen hypometabolism due to incomplete infarction in occlusive carotid artery diseases.

UNLABELLED: Recent studies have clarified that hemodynamically compromised patients are at high risk for subsequent stroke. The acetazolamide test is widely used to detect the patients with hemodynamic compromise due to occlusive carotid artery disease. Previous studies have suggested that patients with impaired reactivity to acetazolamide had an increased oxygen extraction fraction (OEF) on PET. However, the underlying pathophysiology has not been defined in patients with reduced blood flow and preserved reactivity to acetazolamide due to carotid occlusive diseases regardless of a normal appearance on MRI. This study aimed to clarify hemodynamic and metabolic parameters in such patients, using (15)O gas and (11)C-flumazenil (FMZ) PET. METHODS: Our study included 15 patients who had reduced cerebral blood flow (CBF) and preserved cerebrovascular reactivity (CVR) to acetazolamide in the ipsilateral middle cerebral artery territory due to occlusive carotid diseases on N-isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP) SPECT. We determined the CBF, cerebral metabolic rate for oxygen (CMRO(2)), cerebral blood volume (CBV), and OEF using (15)O gas PET. The binding potential for (11)C-FMZ was also measured in 5 patients. All patients were medically treated and followed-up during a mean period of 2.7 y. RESULTS: (15)O gas PET scans revealed that the ipsilateral CBF and CMRO(2) were reduced to 80% +/- 11% (P < 0.0001) and 78% +/- 8% (P < 0.0001) of the contralateral side, respectively. However, there was no significant side-to-side difference in the CBV and OEF. The ipsilateral binding potential for (11)C-FMZ was also significantly reduced to 82% +/- 2% of the contralateral side (P < 0.05), being very similar to the asymmetry of the CBF and CMRO(2). No patients suffered further ischemic stroke in the ipsilateral hemisphere during the follow-up period. CONCLUSION: Our results strongly suggest that a reduced CBF and a normal CVR characterize oxygen hypometabolism probably due to ischemia-related neuronal loss-namely, incomplete infarction. Such an ischemic lesion is not hemodynamically compromised and is at very low risk for a subsequent ischemic stroke even if the patient is medically treated.

STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.

Prognostic implication of histological oligodendroglial tumor component: clinicopathological analysis of 111 cases of malignant gliomas.

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors.

Sonodynamic therapy using water-dispersed TiO2-polyethylene glycol compound on glioma cells: comparison of cytotoxic mechanism with photodynamic therapy.

Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO(2)) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO(2) nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO(2) nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO(2) surface (TiO(2)/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 µg/ml of TiO(2)/PEG for 3h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24h after irradiation. In the presence of TiO(2)/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO(2)/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 TiO(2)/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO(2)/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity.

Novel photodynamic therapy using water-dispersed TiO2-polyethylene glycol compound: evaluation of antitumor effect on glioma cells and spheroids in vitro.

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.

Identification of a novel small molecule HIF-1alpha translation inhibitor.

PURPOSE: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1alpha inhibitor was identified and its molecular mechanism was investigated. EXPERIMENTAL DESIGN: Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed. RESULTS: KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein synthesis. CONCLUSION: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study.