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  • Author or Editor: Jun Hatazawa x
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Toshiaki Hayashi, Akifumi Suzuki, Jun Hatazawa, Iwao Kanno, Reizo Shirane, Takashi Yoshimoto and Nobuyuki Yasui

Object. The mechanism of reduction of cerebral circulation and metabolism in patients in the acute stage of aneurysmal subarachnoid hemorrhage (SAH) has not yet been fully clarified. The goal of this study was to elucidate this mechanism further.

Methods. The authors estimated cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), O2 extraction fraction (OEF), and cerebral blood volume (CBV) preoperatively in eight patients with aneurysmal SAH (one man and seven women, mean age 63.5 years) within 40 hours of onset by using positron emission tomography (PET). The patients' CBF, CMRO2, and CBF/CBV were significantly lower than those in normal control volunteers. However, OEF and CBV did not differ significantly from those in control volunteers. The significant decrease in CBF/CBV, which indicates reduced cerebral perfusion pressure, was believed to be caused by impaired cerebral circulation due to elevated intracranial pressure (ICP) after rupture of the aneurysm. In two of the eight patients, uncoupling between CBF and CMRO2 was shown, strongly suggesting the presence of cerebral ischemia.

Conclusions. The initial reduction in CBF due to elevated ICP, followed by reduction in CMRO2 at the time of aneurysm rupture may play a role in the disturbance of CBF and cerebral metabolism in the acute stage of aneurysmal SAH.

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Youichi Saitoh, Yasuhiro Osaki, Hiroshi Nishimura, Shun-ichiro Hirano, Amami Kato, Kazuo Hashikawa, Jun Hatazawa and Toshiki Yoshimine

✓ The mechanisms underlying poststroke pain have not been clearly identified. Although motor cortex stimulation (MCS) sometimes reduces poststroke pain successfully, the exact mechanism is not yet known. For further investigation of the neural pathways involved in the processing of poststroke pain and in pain reduction by MCS, the authors used positron emission tomography (PET) scanning to determine significant changes in regional cerebral blood flow (rCBF).

This 58-year-old right-handed man suffered from right-sided poststroke pain for which he underwent implantation of a stimulation electrode in the right motor cortex. After 30 minutes of stimulation, his pain was remarkably reduced (Visual Analog Scale scores decreased 8 to 1) and he felt warmth in his left arm. The rCBF was studied using PET scanning with 15O-labeled water when the patient was in the following states: before MCS (painful condition, no stimulation) and after successful MCS (painless condition, no stimulation). The images were analyzed using statistical parametric mapping software. State-dependent differences in global blood flow were covaried using analysis of covariance. Comparisons of the patient's rCBF in the painful condition with that in the painless condition revealed significant rCBF increases in the left rectus gyrus (BA11), left superior frontal lobe (BA9), left anterior cingulate gyrus (BA32), and the left thalamus (p < 0.05, corrected). On the other hand, there were significant decreases in rCBF in the right superior temporal gyrus (BA22, p < 0.01, corrected) and the left middle occipital gyrus (BA19, p < 0.05, corrected).

The efficacy of MCS was mainly related to increased synaptic activity in the thalamus, whereas the activations in the rectus gyrus, anterior cingulate gyrus, and superior frontal cortex as well as the inactivation of the superior temporal lobe may be related to emotional processes. This is the first report in which the contralateral thalamus was significantly activated and pain relief was achieved using MCS.

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Haruhiko Kishima, Youichi Saitoh, Yasuhiro Osaki, Hiroshi Nishimura, Amami Kato, Jun Hatazawa and Toshiki Yoshimine

Object

The mechanisms underlying deafferentation pain are not well understood. Motor cortex stimulation (MCS) is useful in the treatment of this kind of chronic pain, but the detailed mechanisms underlying its effects are unknown.

Methods

Six patients with intractable deafferentation pain in the left hand were included in this study. All were right-handed and had a subdural electrode placed over the right precentral gyrus. The pain was associated with brainstem injury in one patient, cervical spine injury in one patient, thalamic hemorrhage in one patient, and brachial plexus avulsion in three patients. Treatment with MCS reduced pain; visual analog scale (VAS) values for pain were 82 ± 20 before MCS and 39 ± 20 after MCS (mean ± standard error). Regional cerebral blood flow (rCBF) was measured by positron emission tomography with H2 15O before and after MCS. The obtained images were analyzed with statistical parametric mapping software (SPM99).

Results

Significant rCBF increases were identified after MCS in the left posterior thalamus and left insula. In the early post-MCS phase, the left posterior insula and right orbitofrontal cortex showed significant rCBF increases, and the right precentral gyrus showed an rCBF decrease. In the late post-MCS phase, a significant rCBF increase was detected in the left caudal part of the anterior cingulate cortex (ACC).

Conclusions

These results suggest that MCS modulates the pathways from the posterior insula and orbitofrontal cortex to the posterior thalamus to upregulate the pain threshold and pathways from the posterior insula to the caudal ACC to control emotional perception. This modulation results in decreased VAS scores for deafferentation pain.

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Manabu Kinoshita, Hideyuki Arita, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima, Naoya Hashimoto, Hisashi Tanaka, Yoshiyuki Watanabe, Eku Shimosegawa, Jun Hatazawa, Yasunori Fujimoto and Toshiki Yoshimine

OBJECTIVE

Diffusion MRI is attracting increasing interest for tissue characterization of gliomas, especially after the introduction of antiangiogenic therapy to treat malignant gliomas. The goal of the current study is to elucidate the actual magnitude of the correlation between diffusion MRI and cell density within the tissue. The obtained results were further extended and compared with metabolic imaging with 11C-methionine (MET) PET.

METHODS

Ninety-eight tissue samples from 37 patients were stereotactically obtained via an intraoperative neuronavigation system. Diffusion tensor imaging (DTI) and MET PET were performed as routine presurgical imaging studies for these patients. DTI was converted into fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps, and MET PET images were registered to Gd-administered T1-weighted images that were used for navigation. Metrics of FA, ADC, and tumor-to-normal tissue ratio of MET PET along with relative values of FA (rFA) and ADC (rADC) compared with normal-appearing white matter were correlated with cell density of the stereotactically obtained tissues.

RESULTS

rADC was significantly lower in lesions obtained from Gd-enhancing lesions than from nonenhancing lesions. Although rADC showed a moderate but statistically significant negative correlation with cell density (p = 0.010), MET PET showed a superb positive correlation with cell density (p < 0.0001). On the other hand, rFA showed little correlation with cell density.

CONCLUSIONS

The presented data validated the use of rADC for estimating the treatment response of gliomas but also caution against overestimating its limited accuracy compared with MET PET.

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Yasuyoshi Chiba, Manabu Kinoshita, Yoshiko Okita, Akihiro Tsuboi, Kayako Isohashi, Naoki Kagawa, Yasunori Fujimoto, Yusuke Oji, Yoshihiro Oka, Eku Shimosegawa, Satoshi Morita, Jun Hatazawa, Haruo Sugiyama, Naoya Hashimoto and Toshiki Yoshimine

Object

Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd-enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of 11C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OSWT1).

Methods

Fourteen patients with recurrent malignant glioma were included in the study, and OSWT1 was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of 11C-methionine; and 3) a more detailed voxel-wise PRM analysis of MET-PET pre- and post-WT1 immunotherapy.

Results

The PRM analysis was able to identify the following 3 areas within the tumor core: 1) area with no change in 11C-methionine uptake pre- and posttreatment; 2) area with increased 11C-methionine uptake posttreatment (PRM+MET); and 3) area with decreased 11C-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OSWT1 (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM+MET area showed excellent correlation (p = 0.008) with OSWT1.

Conclusions

This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel-wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas. Clinical trial registration no.: UMIN000002001.

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Takero Hirata, Manabu Kinoshita, Keisuke Tamari, Yuji Seo, Osamu Suzuki, Nobuhide Wakai, Takamune Achiha, Toru Umehara, Hideyuki Arita, Naoki Kagawa, Yonehiro Kanemura, Eku Shimosegawa, Naoya Hashimoto, Jun Hatazawa, Haruhiko Kishima, Teruki Teshima and Kazuhiko Ogawa

OBJECTIVE

It is important to correctly and precisely define the target volume for radiotherapy (RT) of malignant glioma. 11C-methionine (MET) positron emission tomography (PET) holds promise for detecting areas of glioma cell infiltration: the authors’ previous research showed that the magnitude of disruption of MET and 18F-fluorodeoxyglucose (FDG) uptake correlation (decoupling score [DS]) precisely reflects glioma cell invasion. The purpose of the present study was to analyze volumetric and geometrical properties of RT target delineation based on DS and compare them with those based on MRI.

METHODS

Twenty-five patients with a diagnosis of malignant glioma were included in this study. Three target volumes were compared: 1) contrast-enhancing core lesions identified by contrast-enhanced T1-weighted images (T1Gd), 2) high-intensity lesions on T2-weighted images, and 3) lesions showing high DS (DS ≥ 3; hDS). The geometrical differences of these target volumes were assessed by calculating the probabilities of overlap and one encompassing the other. The correlation of geometrical features of RT planning and recurrence patterns was further analyzed.

RESULTS

The analysis revealed that T1Gd with a 2.0-cm margin was able to cover the entire high DS area only in 6 (24%) patients, which indicates that microscopic invasion of glioma cells often extended more than 2.0 cm beyond a Gd-enhanced core lesion. Insufficient coverage of high DS regions with RT target volumes was suggested to be a risk for out-of-field recurrence. Higher coverage of hDS by T1Gd with a 2-cm margin (i.e., higher values of “[T1Gd + 2 cm]/hDS”) had a trend to positively impact overall and progression-free survival. Cox regression analysis demonstrated that low coverage of hDS by T1Gd with a 2-cm margin was predictive of disease recurrence outside the Gd-enhanced core lesion, indicative of out-of-field reoccurrence.

CONCLUSIONS

The findings of this study indicate that MRI is inadequate for target delineation for RT in malignant glioma treatment. Expanding the treated margins substantially beyond the MRI-based target volume may reduce the risk of undertreatment, but it may also result in unnecessary irradiation of uninvolved regions. As MET/FDG PET-DS seems to provide more accurate information for target delineation than MRI in malignant glioma treatment, this method should be further evaluated on a larger scale.

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Shuichi Izumoto, Akihiro Tsuboi, Yoshihiro Oka, Tsuyoshi Suzuki, Tetsuo Hashiba, Naoki Kagawa, Naoya Hashimoto, Motohiko Maruno, Olga A. Elisseeva, Toshiaki Shirakata, Manabu Kawakami, Yusuke Oji, Sumiyuki Nishida, Satoshi Ohno, Ichiro Kawase, Jun Hatazawa, Shin-ichi Nakatsuka, Katsuyuki Aozasa, Satoshi Morita, Junichi Sakamoto, Haruo Sugiyama and Toshiki Yoshimine

Object

The object of this study was to investigate the safety and clinical responses of immunotherapy targeting the WT1 (Wilms tumor 1) gene product in patients with recurrent glioblastoma multiforme (GBM).

Methods

Twenty-one patients with WT1/HLA-A*2402–positive recurrent GBM were included in a Phase II clinical study of WT1 vaccine therapy. In all patients, the tumors were resistant to standard therapy. Patients received intra-dermal injections of an HLA-A*2402–restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was obtained by measuring the contrast-enhanced area on magnetic resonance images, was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST) 12 weeks after the initial vaccination. Patients who achieved an effective response continued to be vaccinated until tumor progression occurred. Progression-free survival and overall survival after initial WT1 treatment were estimated.

Results

The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: partial response in 2 patients, stable disease in 10 patients, and progressive disease in 9 patients. No patient had a complete response. The overall response rate (cases with complete or partial response) was 9.5%, and the disease control rate (cases with complete or partial response as well as those in which disease was stable) was 57.1%. The median progression-free survival (PFS) period was 20.0 weeks, and the 6-month (26-week) PFS rate was 33.3%.

Conclusions

Although a small uncontrolled nonrandomized trial, this study showed that WT1 vaccine therapy for patients with WT1/HLA-A*2402–positive recurrent GBM was safe and produced a clinical response. Based on these results, further clinical studies of WT1 vaccine therapy in patients with malignant glioma are warranted.