Takaaki Beppu

Diffusion tensor imaging for preoperative evaluation of tumor grade in gliomas

The relationship between water diffusion parameters measured using diffusion tensor imaging (DTI) and histological malignancy of gliomas was investigated. DTI was performed using a 3.0T MR scanner in 41 consecutive patients with histologically proven gliomas. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated and compared with the WHO classification of the gliomas. The FA values of grade 1 gliomas (0.150 +/- 0.017) were significantly lower than those of grade 3 (0.23 +/- 0.033) or grade 4 gliomas (0.229 +/- 0.033) (P < 0.0001, respectively). The FA values of grade 2 gliomas (0.159 +/- 0.018) were significantly lower than those of grade 3 or grade 4 gliomas (P = 0.0002, P < 0.0001, respectively). The FA threshold between low grade and high grade gliomas was 0.188. The MD values of grade 1 gliomas (1619.1 +/- 157.4 x 10(-6) mm2/s) were significantly higher than those of grade 3 (1084.5 +/- 218.9 x 10(-6) mm2/s) (P = 0.0036) or grade 4 gliomas (1098.0 +/- 291.6 x 10(-6) mm2/s) (P = 0.0002). The MD values were not correlated with the other grades of glioma. FA values can distinguish between high grade and low grade gliomas. This is useful in deciding the surgical strategy or selecting the site of stereotactic biopsy.

Measurement of fractional anisotropy using diffusion tensor MRI in supratentorial astrocytic tumors.

In vivo, water diffusion displays directionality due to presence of complex microstructural barriers in tissue. The extent of directionality of water diffusion can be expressed as a fractional anisotropy (FA) value, using diffusion tensor MR imaging (DTI). The aim of this study was to determine whether FA values indicate microstructures in astrocytic tumors. We performed DTI in 31 patients with astrocytic tumor, and measured the FA values of tumor and normal brain regions prior to CT-guided stereotactic biopsy. After biopsy, FA values were compared to assess the cellularity and vascularity of tumor tissue. Although mean FA values trended to differ among histological types, all mean tumor FA values were lower than those of normal brain regions. Positive correlation was observed between FA values and both cellularity (r = 0.65, p < 0.05) and vascularity (r = 0.45, p < 0.05). We had hypothesized that the FA value of an astrocytic tumor would be determined by a balance between factors increasing the directionality of water diffusion, such as high cellularity and/or vascularity, and factors decreasing the directionality of water diffusion, such as fiber destruction. However, our results suggest that the FA values of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma and pilocytic astrocytoma are largely affected by cellularity and/or vascularity, whereas that of gliomatosis cerebri are largely affected by the preservation of nerve fibers. Measurement of FA value using DTI will allow prediction of histological characteristics such as cellularity, vascularity and/or fiber structure in astrocytic tumors.

Investigation of genetic alterations associated with the grade of astrocytic tumor by comparative genomic hybridization

Comparative genomic hybridization (CGH) is a technique that allows the detection of losses and gains in DNA copy number across the entire genome. We used CGH to study the genetic alterations that occur in primary astrocytomas, including 14 glioblastomas (GBM), 12 anaplastic astrocytomas (AA), and 7 low‐grade astrocytomas (LGA). The average numbers of total aberrations in GBM, AA, and LGA were 9.7, 5.4, and 4.0, respectively. The average number of DNA sequence losses in GBM was significantly higher than that in AA or LGA (P < 0.01). Frequently altered regions (> eight cases) observed in all grades of astrocytoma were 7p13‐p12 (gain), 7q31 (gain), 8q24.1‐q24.2 (gain), 9p21 (loss), 10p12‐p11 (loss), 10q22‐qter (loss), 13q21‐q22 (loss), and 20q13.1‐q13.2 (gain). Loss of 9p, 10p, or 10q, and the gain or amplification of 7p, were observed frequently in GBM (64%, 57%, 64%, and 50% of cases, respectively). Frequent alterations found in AA were losses of 9p, 10q, and 13q, and gains of 1q, chromosome 7, 11q, and Xq. Whereas 7p13‐p11 amplification occurred exclusively in cases with the loss of all or part of chromosome 10, this change never occurred in cases having an increase in copy number of 8q, which was the most frequent change observed in LGA (four of seven cases). These results may indicate that an increase in copy number of 8q is an important event in GBM, with a genetic pathway, which is distinct from that in GBM with 7p amplification. Genes Chromosomes Cancer 21:340–346, 1998.

Evaluation of the malignancy of glioma using 11C-methionine positron emission tomography and proliferating cell nuclear antigen staining.

Abstract 11C-methionine positron emission tomography (PET) and proliferating cell nuclear antigen (PCNA) staining were performed in 13 cases of glioma to investigate the relationship between the uptake of l-[methyl]-11C-methionine and the degree of malignancy and proliferative potential. The 11C-methionine uptake was significantly greater in high-grade gliomas compared to low-grade gliomas (P<0.05). The PCNA indexes were also significantly higher in the high-grade cases (P<0.05). Moreover, a strong positive correlation was found between the 11C-methionine values and the PCNA indexes (P<0.005), demonstrating that higher 11C-methionine uptake was associated with greater proliferative potential and greater malignancy. 11C-methionine PET is a potentially useful preoperative method to discriminate the malignacy of glioma.

Change of oxygen pressure in glioblastoma tissue under various conditions.

Measurement of oxygen pressure (pO2) in tumor tissue is important, because pO2 is a major factor for radiosensitivity in malignant glioma treatment. We attempted to elucidate the changes in pO2 level in glioblastoma tissue of patients under various conditions. Eighteen patients with newly diagnosed glioblastoma were recruited to this study. Disposable Clark-type electrodes were inserted using CT guided stereotactic surgery under local anesthesia and left in the intra- and peritumoral regions. pO2 was measured in patients under conditions of being awake and asleep, inhaling 100% O2, being administered osmotic diuretics and following hyperbaric oxygen exposure (HBO). Peritumoral tissue had a significantly higher pO2 value in both awake and sleeping patients. O2 inhalation could not significantly increase the pO2 level, whereas administration of osmotic diuretics induced an increase in pO2 levels in peritumoral tissue alone. The pO2 levels were significantly increased in both regions after HBO, and a high pO2 level was maintained until 15 min after HBO in both regions. It is possible that the pO2 level in peritumoral tissue is affected by intracranial pressure, whereas that in the intratumoral tissue is usually low. HBO was the optimal procedure for oxygenation, but its benefit was reduced over time.

Neoplastic cells and proliferating endothelial cells express connective tissue growth factor (CTGF) in glioblastoma

Abstract Connective tissue growth factor (CTGF) was recently described as a cysteine-rich mitogenic peptide that is the prototypic member of the CCN family of protein including CTGF/fisp12, cef/10/cyr61 and nov. Recently CTGF was reported to have a function of mediating endothelial cell adhesion and migration through integrin αvβ3, promoting endothelial cell survival, and inducing angiogenesis in vivo. To clarify involvement of CTGF in tumor angiogenesis, using brain tissues with glioblastoma, we examined CTGF expression and localization by immunohistochemical staining and reverse transcription-polymerase chain reaction. The result showed that both glioblastoma tumor cells and proliferating endothelial cells are positive for CTGF by immunohistochemical staining, and CTGF mRNA expression was evaluated by RT-PCR in the brain tissues of glioblastoma. These findings suggest that CTGF may have the potential to stimulate angiogenesis in glioblastoma and function as an angiogenic factor in the process of tumor growth.

Diffusion tensor imaging for differentiation of recurrent brain tumor and radiation necrosis after radiotherapy—Three case reports

Fractional anisotropy (FA) is influenced by histological data such as cellularity, vascularity and/or fiber structure in astrocytic tumors. We describe two patients with tumor recurrence and one patient with radiation necrosis who were diagnosed using assessment of FA value. The assessment of FA value in enhanced lesions after radiotherapy may be able to differentiate radiation necrosis from tumor recurrence.

A Phase II Study of Radiotherapy after Hyperbaric Oxygenation Combined with Interferon-beta and Nimustine Hydrochloride to Treat Supratentorial Malignant Gliomas

Hypoxic cells play a key role in the radioresistance of malignant glioma. Interferon-beta, ACNU as nimustine hydrochloride and radiotherapy (IAR) is a common therapy for malignant glioma in Japan. Since hyperbaric oxygenation (HBO) increases oxygen pressure in glioma tissue, we applied a modified IAR therapy, radiotherapy after HBO combined with interferon-beta and ACNU (HBO/IAR therapy), for supratentorial malignant gliomas. Daily radiation therapy was completed within 15min after HBO. We assessed HBO/IAR with respect to toxicity, response rates and the time of tumor progression (TTP). We also examined the incidence of responses by some prognostic factors before HBO/IAR, namely, age, Karnofsky performance scale (KPS), histological type, tumor size, tumor site and operation type. Of 39 patients who participated in this study, 35 underwent a complete schedule of HBO/IAR therapy in which toxicity was permissible. Thirty patients (76.9%) either maintained or increased KPS during HBO/IAR with a mean duration of 68±14 days. The response rates (CR+PR%) for glioblastoma, anaplastic astrocytoma and overall were 50%, 30% and 43%, respectively. The incidence of therapeutic responses among all prognostic factors before HBO/IAR did not significantly differ. Median TTP for patients with glioblastoma, patients with anaplastic astrocytoma, and overall were 38, 56 and 43 weeks, respectively. The present study suggested that HBO/IAR therapy could be applied to especially patients with poor prognostic factors, because of its short treatment period, its permissible toxicity and identical response to patients with good prognostic factors.

Association of stem cell marker CD133 expression with dissemination of glioblastomas

Dissemination of glioblastoma was once considered rare but is now increasingly encountered with longer survival of glioblastoma patients. Despite the potential negative impact of dissemination on clinical outcome, however, molecular markers useful for prediction of dissemination risk still remains ill defined. We tested in this study for an association between the expression of stem cell marker CD133 and the risk of dissemination in 26 cases of glioblastoma (16 with dissemination and 10 without dissemination). The protein expression of CD133 was examined by western blot analysis of tumor specimens, and the CD133 expression levels were quantified by densitometry and normalized to β-actin. The results indicated that CD133 expression levels are significantly higher in glioblastomas with dissemination (mean 10.3, range 0.20-27.8) than in those without (mean 1.18, range 0.07-3.58). The results suggest that CD133 could be a molecular predictor of glioblastoma dissemination, and also give rise to an intriguing idea that CD133-positive cancer stem cells may be implicated in the initiation of disseminated lesions.

A case of subcortical meningioma.

Summary¶ Subcortical meningioma, which has been reported as meningioma without dural attachment, a cerebral subcortical lesion, is extremely rare. Very few findings of radiological examination of subcortical meningioma have been described. Pre-operative differentiation of this lesion is generally difficult. We characterize the peritum oural oedema adjacent to the meningioma in this region, and we suggest that radiological findings of peritum oural oedema contribute to differential diagnosis of subcortical meningiomas.