Yuzo Terakawa

Diagnostic Accuracy of 11C-Methionine PET for Differentiation of Recurrent Brain Tumors from Radiation Necrosis After Radiotherapy

We evaluated the diagnostic accuracy of PET with l-methyl-11C-methionine (11C-MET) for the differentiation of recurrent brain tumors from radiation necrosis. Methods: Seventy-seven patients who had been previously treated with radiotherapy after primary treatment for metastatic brain tumor (n = 51) or glioma (n = 26) were studied to clarify the diagnostic performance of 11C-MET PET in differentiating between recurrent brain tumors and radiation necrosis. A total of 88 PET scans with 11C-MET were obtained; sometimes more than one scan was obtained when there was an indication of recurrent brain tumor or radiation necrosis. A definitive diagnosis was made on the basis of pathologic examination for recurrent brain tumors and on the basis of pathologic examination or clinical course for radiation necrosis. Several indices characterizing the lesions were determined; these included mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) and the ratios of lesion uptake to contralateral normal frontal-lobe gray matter uptake corresponding to the SUVmean and the SUVmax (L/Nmean and L/Nmax, respectively). Receiver-operating-characteristic (ROC) curve analysis was used to determine the optimal index of 11C-MET PET and cutoff values for the differential diagnosis of tumor recurrence and radiation necrosis. Results: The values of each index of 11C-MET PET tended to be higher for tumor recurrence than for radiation necrosis. There were significant differences between tumor recurrence and radiation necrosis in all of the indices except for the L/Nmax for glioma. ROC analysis indicated that the L/Nmean was the most informative index for differentiating between tumor recurrence and radiation necrosis. An L/Nmean of greater than 1.41 provided the best sensitivity and specificity for metastatic brain tumor (79% and 75%, respectively), and an L/Nmean of greater than 1.58 provided the best sensitivity and specificity for glioma (75% and 75%, respectively). Conclusion: 11C-MET PET can provide quantitative values to aid in the differentiation of tumor recurrence from radiation necrosis, although these values do not appear to be absolute indicators. Quantitative analysis of 11C-MET PET data may be helpful in managing irradiated brain tumors.

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

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.

The role of drebrin in glioma migration and invasion

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172 GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility.

Surgical management of multicentric diffuse low-grade gliomas: functional and oncological outcomes

OBJECT Multicentric diffuse low-grade gliomas (DLGGs) are defined as widely separated lesions in different lobes or hemispheres where there is no anatomical continuity between lesions. This condition is rare and its clinicopathological characteristics have been scarcely described in the literature. Here, the authors report the first consecutive surgical series of multicentric DLGGs with functional and oncological outcomes. METHODS A retrospective review of patients surgically treated for histopathologically confirmed multicentric DLGGs between 2000 and 2012 was performed. Information regarding clinical features, surgical procedures, histopathological results, and clinical outcomes was collected and analyzed. RESULTS Five consecutive patients were included in this study. There were 3 men and 2 women, whose mean age was 27.4 years (range 23-35 years). The mean follow-up period after surgery was 46 months (range 11-138 months). Gross-total or subtotal resection was achieved in all cases, using a single surgery in 3 patients and a 2-stage surgery in 2 patients. There was no mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score ranged between 90 and 100 in all cases. Adjuvant chemotherapy was administered in 2 patients because of tumor regrowth with no malignant transformation. CONCLUSIONS Multicentric DLGGs can be removed safely without inducing severe permanent neurological deficits. Interestingly, a single-stage resection of multiple lesions within different lobes may be performed if tumors are located in the same hemisphere. Therefore, the authors suggest considering surgery as the first therapeutic option for multicentric DLGGs, as in solitary DLGGs.

Quantitative imaging of spontaneous neuromagnetic activity for assessing cerebral ischemia using sLORETA-qm.

To image cerebral neural activity in ischemic areas, we proposed a novel technique to analyze spontaneous neuromagnetic fields based on standardized low-resolution brain electromagnetic tomography modified for a quantifiable method (sLORETA-qm). Using a 160-channel whole-head-type magnetoencephalographic system, cerebral magnetic fields were obtained pre- and postoperatively from 5 patients with unilateral internal carotid artery occlusive disease and 16 age-matched healthy volunteers. For quantitative imaging, voxel-based time-averaged intensities of slow waves in 4 frequency bands (0.3-2 Hz, 2-4 Hz, 4-6 Hz and 6-8 Hz) were obtained by the proposed technique based on sLORETA-qm. Positron emission tomography with (15)O gas inhalation ((15)O-PET) was also performed in these patients to evaluate cerebral blood flow and metabolism. In all 5 patients, slow waves in every frequency band were distributed in the area of cerebrovascular insufficiency, as confirmed by (15)O-PET preoperatively. In 4 patients, slow-wave intensities in theta bands (4-6 Hz, 6-8 Hz) decreased postoperatively along with improvements in cerebral blood flow and metabolism, whereas delta bands (0.3-2 Hz, 2-4 Hz) showed no significant differences between pre- and postoperatively. One patient with deterioration of cerebral infarction after surgery showed marked increases in slow-wave intensities in delta bands (0.3-2 Hz, 2-4 Hz) postoperatively, with distribution close to the infarct region. The proposed quantitative imaging of spontaneous neuromagnetic fields enabled clear visualization and alternations of cerebral neural conditions in the ischemic area. This technique may offer a novel, non-invasive method for identifying cerebral ischemia, although further studies in a larger number of patients are warranted.

Activation of the serotonergic system by pedaling exercise changes anterior cingulate cortex activity and improves negative emotion

Pedaling exercise (PE) of moderate intensity has been shown to ease anxiety and discomfort; however, little is known of the changes that occur in brain activities and in the serotonergic (5-HT) system after PE. Therefore, this study was conducted for the following reasons: (1) to localize the changes in the brain activities induced by PE using a distributed source localization algorithm, (2) to examine the changes in frontal asymmetry, as used in the Davidson model, with electroencephalography (EEG) activity, and (3) to examine the effect of PE on the 5-HT system. A 32-channel EEG was used to record before and after PE. Profile of Mood States tests indicated that there was a significant decrease in tension-anxiety and a significant increase in vigor after PE. A standardized low-resolution brain electromagnetic tomography analysis showed a significant decrease in brain activities after PE in the alpha-2 band (10-12.5 Hz) in the anterior cingulate cortex (ACC). Moreover, a significant increase in frontal EEG asymmetry was observed after PE in the alpha-1 band (7.5-10 Hz). Urine 5-HT levels significantly increased after PE. Urine 5-HT levels positively correlated with the degree of frontal EEG asymmetry in the alpha-1 band and negatively correlated with brain activity in ACC. Our results suggested that PE activates the 5-HT system and consequently induces increases in frontal EEG asymmetry in the alpha-1 band and reductions of brain activity in the alpha-2 band in the ACC region.

Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma

The hepatocyte growth factor (HGF)/MET pathway plays a critical role in the development of the nervous system and has been implicated in medulloblastoma pathogenesis. Recent studies have shown a role for gene amplification of activators of this pathway, as well as silencing of its inhibitors in medulloblastoma pathogenesis. We analyzed exon array data from a cohort of 103 primary medulloblastomas to show that HGF/MET pathway elements are dysregulated in tumors compared to normal cerebellum. To determine if mutation of HGF/MET pathway genes is a mechanism for pathway dysregulation, we conducted a mutational analysis by exon resequencing of three key components of this pathway, including serine protease inhibitor Kunitz‐type 1 (SPINT1), serine protease inhibitor Kunitz‐type 2 (SPINT2), and MET, in 32 primary human medulloblastoma specimens. From this analysis, we identified multiple coding synonymous and nonsynonymous single nucleotide polymorphisms in these genes among the 32 tumor samples. Interestingly, we also discovered two unreported sequence variants in SPINT1 and SPINT2 in two tumors that resulted in Arginine to Histidine amino acid substitutions at codons 418 and 233, respectively. However, conservation assessment and functional assays of these two variants indicate that they involve nonconserved residues and that they do not affect the function of SPINT1 and SPINT2 as tumor suppressor genes. In conclusion, our data suggest that mutation alone plays a minor role in causing aberrancies of the HGF/MET pathway in medulloblastoma in comparison with other malignancies such as breast, hepatocellular, renal, and lung carcinomas.

Examination of 11C-Methionine Metabolism by the Standardized Uptake Value in the Normal Brain of Children

The aim of this study was to determine the uptake of L-[methyl-11C]-methionine (11C-MET) in the normal brain of patients younger than 20 y, to facilitate more accurate diagnoses in young patients. Methods: Eighty-two patients were categorized into 4 groups according to their age. They underwent 11C-MET PET, and a standardized uptake value (SUV) was determined for different brain regions including the frontal lobe, parietal lobe, cerebellum, and brain stem. Results: Compared with all other parts of the brain, the cerebellum had the highest SUV. A tendency for a positive relationship between SUV and age was found in all regions, and a significant relationship with SUV was found in the frontal lobe and cerebellum. Conclusion: The character of SUV in the normal brains of children is different from that of adults, and these normal SUV data will play an important role as a critical reference value.

Evaluation of the Accumulation of 11C-Methionine with Standardized Uptake Value in the Normal Brain

The aim of this study was to determine the normal l-[methyl-11C]-methionine (11C-methionine) uptake and the extent of variation using standardized uptake value (SUV). Methods: Five healthy volunteers and 58 adult patients with normal 11C-methionine uptake were included in the interindividual analysis and 22 patients in the intraindividual analysis. SUVs in different brain regions, age-associated changes, correlation between 2 correction methods (for body weight [w-SUV] or body surface area [s-SUV]), and intraindividual reproducibility were examined. Results: w-SUVs were statistically different between the brain regions. The frontal or parietal cortex showed lower coefficients of variation than did the cerebellum or brain stem. There was no significant age-associated change. w-SUVs showed lower coefficients of variation in interindividual analysis and lower symmetric percentage change in intraindividual reproducibility than did s-SUVs. Conclusion: SUVs in the normal brain show inter- and intraindividual variation, and our proposed normal w-SUVs represent an important reference value.

Quantitative analysis of MEG using modified sLORETA for clinical application

OBJECTIVE To determine whether standardised low-resolution brain electromagnetic tomography modified for a quantifiable method (sLORETA-qm) can be used for quantitative analysis in magnetoencephalography (MEG). METHODS Somatosensory evoked fields (SEFs) were obtained from 10 hemispheres of five healthy volunteers stimulated on the median nerve at 0.75, 1.0, 1.25, 1.5, 1.75 and 2.0 x threshold of thenar muscle twitch (TMT). N20 m intensity changes were analysed quantitatively using sLORETA-qm. Then, SEFs were measured with stimulation on the median nerve at 1.5 x TMT from 47 hemispheres in 24 subjects. sLORETA-qm intensity and the equivalent current dipole (ECD) moment of N20 m were calculated, and relationships between the values were evaluated. RESULTS sLORETA-qm intensity increased linearly with stimulus intensity between 0.75 and 1.5 x TMT, and tended to reach a plateau or decrease at higher stimulus intensities. The distribution of sLORETA-qm intensity after natural logarithmic transformation was normal and a close correlation was found between the ECD moment and sLORETA-qm intensity (r(s)=0.91, p<0.001). CONCLUSIONS The results of this study focusing on N20 m suggested that sLORETA-qm is reliable for quantitative analysis of MEG as well as ECD models. SIGNIFICANCE sLORETA-qm appears promising for quantitative analyses of MEG for which ECD models are inappropriate.