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Toru Iwama, Yoshinori Akiyama, Masafumi Morimoto, Akio Kojima and Kohei Hayashida

The purpose of this study was to elucidate the difference in cerebral hemodynamics and metabolic status between patients with bleeding- and ischemic-type moyamoya disease. Regional cerebral blood flow (rCBF), regional cerebral metabolic rate of oxygen (rCMRO2), regional oxygen extraction fraction (rOEF), and regional cerebral blood volume (rCBV) in the cortex of the middle cerebral artery (MCA) territories and rCBV in the striatum were measured using positron emission tomography (PET) in 17 patients with moyamoya disease. Patients were divided into three subgroups according to type of disease manifestation and age: adult bleeding type (five cases), adult ischemic type (10 cases), and childhood ischemic type (two cases). When compared with adult controls, statistically significant reductions in rCBF and rCMRO2, elevation in rOEF in the MCA territories, and elevation of rCBV in the striatum were observed in PET studies for all three subgroups. Between the adult bleeding type and ischemic type, rCBF, rCMRO2, and rOEF in the MCA territories were not different, but rCBV in the striatum was higher in patients with ischemic-type moyamoya disease than in those with the bleeding type. In adult patients with bleeding and ischemic types, rOEF and rCBV in the MCA territories and rCBV in the striatum were significantly lower than in patients with childhood ischemic-type moyamoya disease. In adult patients with bleeding-type moyamoya disease, cerebral hemodynamics were impaired and similar to those in adult ischemic type.

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Toru Iwama, Nobuo Hashimoto, Tatemi Todaka, Yoshikado Sasako, Syuji Inamori and Masakazu Kuro

✓ The key to successful surgical resection of cerebral arteriovenous malformations (AVMs) is control of bleeding and cerebral swelling. Induced hypotension is one of the most valuable means of achieving this control. The authors introduced induced hypotension with mild hypothermia by using a percutaneous cardiopulmonary support system (PCPS) to resect a large, high-flow AVM. The efficacy and technical points of this method are discussed.

The PCPS, whose entire intraluminal surface was coated with heparin, was established through a transfemoral route. During resection of the AVM, a mean arterial blood pressure of 60 mm Hg and a mean body temperature of 30°C were easily maintained by regulating the flow rate of the PCPS and by blood cooling. The activated coagulation time was maintained at approximately 250 seconds with a minimum systemic administration of heparin.

The authors report the case of a 30-year-old woman who presented with intraventricular hemorrhage and was diagnosed as having a large, high-flow AVM located in the left sylvian fissure. The AVM was fed by the left middle, posterior, and anterior cerebral arteries and drained by the many cortical ascending veins and the basal vein. The patient underwent surgery after hypotension and hypothermia had been induced via the PCPS method. Induced hypotension decreased the tension of the nidus and made its dissection easier. The AVM was totally resected and no hemostatic difficulties were encountered.

On the basis of the authors' experience, they suggest that hypotension and hypothermia induced by using the PCPS is a powerful tool for the successful resection of large, high-flow AVMs.

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Toru Iwama, Nobuo Hashimoto, Yasushi Takagi, Michihiro Tanaka, Satoshi Yamamoto, Shogo Nishi and Kohei Hayashida

✓ In patients with intracranial dural arteriovenous fistulas (AVFs), clinical symptoms and angiographic findings vary. The relevance of disturbed venous drainage to clinical symptoms and prognosis has been recognized. However, the roles of cerebral hemodynamics and metabolism, which are impaired by shunt flow or disturbed venous drainage, have not been fully evaluated. The authors studied the cerebral hemodynamic and metabolic status in 10 patients with intracranial dural AVFs using positron emission tomography (PET) scanning. Ten patients with dural AVFs underwent a PET study before treatment. The regional cerebral blood flow (rCBF), regional oxygen extraction fraction (rOEF), regional cerebral metabolic rate of oxygen (rCMRO2), and regional cerebral blood volume (rCBV) were measured using the 15O-labeled gas inhalation steady-state method. The PET parameters that were obtained were analyzed and compared with the patients' neurological and angiographic findings. In six of the 10 patients, a PET study was also performed after treatment. Before treatments, all four patients with cerebral symptoms showed a severe reduction in rCBF and a mild elevation in the rOEF. The areas showing reduced rCBF corresponded with areas in which retrograde venous drainage into the cortical veins and delayed parenchymal circulation were seen on angiograms. In another two patients with occlusion of the affected sinus and/or retrograde drainage into the cortical veins, mild abnormalities were demonstrated in rCBF mapping. In the remaining four patients, all PET parameters except rCBV were within normal limits and venous flow was not impaired on the angiograms. In four patients who underwent surgical excision or transvenous embolization of the affected sinus, the cerebral hemodynamics and metabolism were improved, as were the clinical symptoms. In two patients who underwent transarterial embolization of the feeding vessels only or craniotomy, no hemodynamic improvement was achieved. Our results indicate that hemodynamic insufficiency detected by the PET study corresponded well with cerebral symptoms and angiographic findings of retrograde venous drainage into the cortical veins and delayed parenchymal circulation, but not with sinus occlusion or arterial blood supply. Eradication or prevention of retrograde venous drainage from the affected sinus into the cortical veins should be a treatment goal in patients with dural AVFs.

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Toru Iwama, Kohei Hayashida, Jun C. Takahashi, Izumi Nagata and Nobuo Hashimoto

Object. The purpose of this study was to evaluate cerebral hemodynamic and metabolic features in patients with arteriovenous malformations (AVMs) by using positron emission tomography (PET) scanning.

Methods. Twenty-four patients with supratentorial cerebral AVMs participated in PET studies in which 15O inhalation steady-state methods were used. The authors recorded the values of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), the regional oxygen extraction fraction (rOEF), and the regional cerebral metabolic rate of O2 (rCMRO2) at three designated regions of interest (ROIs) in each patient. These ROIs included perilesional (ROI-p), ipsilateral remote (ROI-i), and contralateral symmetrical (ROI-c) brain regions. To identify the factors that exert a direct effect on the hemodynamics of brains affected by AVM, we also separated the lesions according to their size and flow type shown on angiograms, and grouped the patients according to the presence or absence of progressive neurological deficits. We then compared the PET parameters at different ROIs in individual patients and evaluated the mean values obtained for all 24 patients according to AVM flow type and size, and the presence or absence of progressive neurological deficits.

Conclusions. Overall, mean rCBV and rOEF values were significantly higher in ROI-p than in ROI-c (p = 0.00046 and p = 0.015, respectively). No significant differences were seen between the ROI-i and ROI-c with respect to rCBF, rCBV, and rOEF. Mean rCMRO2 values were similar in the three ROIs; however, the mean rCBF was significantly lower in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.019), large AVMs (p = 0.017), and progressive neurological deficits (p = 0.021). Furthermore, the mean rOEF values were significantly higher in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.005), large AVMs (p = 0.019), and progressive neurological deficits (p = 0.017). The PET studies revealed hemodynamic impairment characterized by decreased rCBF and increased rOEF and rCBV values in the ROI-p of patients with large, high-flow AVMs regardless of whether they exhibited progressive neurological deficits.

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Jun Shinoda, Hirohito Yano, Shin-Ichi Yoshimura, Ayumi Okumura, Yasuhiko Kaku, Toru Iwama and Noboru Sakai

✓ The authors have recently performed a fluorescence-guided tumor resection procedure by using high-dose fluorescein sodium without any special surgical microscopes for the intraoperative visualization of glioblastoma multiforme (GBM), and they report on the actual procedure and clinicopathological findings.

Thirty-two patients with GBMs underwent tumor resection during which this fluorescence-guided procedure was used. Fluorescein sodium (20 mg/kg) was intravenously injected after dural opening at the craniotomy site. The tumor was stained almost homogeneously yellow and the color was intense enough to be readily perceived for resection. The center of the solid lesion was stained a deep yellow and surrounded by a transition zone that was faintly stained. The colored lesion was clearly distinguishable from the unstained zone outside the GBM, particularly in the white matter. Both the deeply and faintly stained regions included endothelial proliferation and dense tumor cells. In the unstained region, less dense tumor cells were consistently revealed; however, no endothelial proliferation could be seen. Grosstotal resection (GTR) was successful in 84.4% of the patients who received an injection of fluorescein sodium, which accounted for 100% of those in whom all the visible yellow color (both the deeply and faintly stained regions) was judged to have been resected during operation. Gross-total resection was performed in 100% of the patients who underwent the fluorescence-guided procedure and assigned to Stage I, a GBM stage in which, as a therapeutic policy, the tumor should be resected as radically as possible. The GTR rates in patients who received fluorescein sodium were significantly higher than those in patients who did not (73 patients with GBMs who underwent tumor resection without the fluorescence-guided procedure). Although the extent of surgery was revealed to be one of the significant and independent prognostic factors for GBM, the fluorescein sodium—guided resection procedure was not a significant or independent prognostic factor in this series.

This surgical procedure does not require any special surgical microscopic equipment and is simple, safe, useful, readily accomplished, and universally available for resection of GBMs. Its efficacy simplifies the surgical procedure of navigating the stained lesion from the unstained area to achieve GTR of GBMs, which can be demonstrated on magnetic resonance images.

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Yusuke Egashira, Shinichi Yoshimura, Yukiko Enomoto, Mitsunori Ishiguro, Takahiko Asano and Toru Iwama


Hematoma growth unrelated to aneurysmal rebleeding is recognized as a somewhat common complication following endovascular embolization of ruptured aneurysms, but it is scarcely studied. The aim of this study is to elucidate the possible risk factors for this phenomenon.


Included in this study were 101 consecutive patients with subarachnoid hemorrhage (SAH) who underwent endovascular embolization for saccular aneurysms at the authors' institution within 72 hours of symptom onset. All endovascular procedures were conducted under intraprocedural systemic anticoagulation. Age, sex, hypertension, type 2 diabetes, preoperative antiplatelet or anticoagulation use, neurological grade, Fisher grade, location and size of the aneurysm, grade of aneurysm occlusion, and timing of the endovascular procedure were retrospectively analyzed to determine the risk factors for hematoma growth unrelated to aneurysmal rebleeding. To determine the clinical significance of this complication, the authors also investigated the risk factors for poor clinical outcome (modified Rankin Scale Scores 3–6 at 30 days after onset).


This series included 32 men (31.7%) and 69 women (68.3%) with a mean age ± SD of 65.5 ± 14.0 years. The mean time from onset to endovascular procedure was 12.1 ± 14.0 hours. After the procedure, hematoma growth unrelated to aneurysmal rebleeding occurred in 14 patients (13.9%), 10 of whom required surgical removal of the hematoma and/or ventriculostomy to control intracranial pressure. All 14 patients had an anterior circulation aneurysm and had Fisher Grade 3 or 4 SAH. Ultra-early embolization (conducted within 6 hours after onset), female sex, history of hypertension, and poor neurological grade (World Federation of Neurosurgical Societies Grades IV and V) were significant risk factors for hematoma growth (p < 0.05 for all, univariate logistic analysis). In multivariate analysis, ultra-early embolization (OR 18.0 [95% CI 3.26–338], p < 0.001) and female sex (OR 9.83 [95% CI 1.73–187], p = 0.007) were independent risk factors for this phenomenon. Anterior circulation aneurysms and Fisher Grade 3 or 4 SAH were also revealed to be significant risk factors (p = 0.02 for each, chi-square test). Furthermore, hematoma growth without aneurysmal rebleeding was determined as an independent risk factor for poor clinical outcome by multivariate logistic analysis (OR 11.8 [95% CI 2.31–87.1], p = 0.002).


Ultra-early endovascular embolization for ruptured cerebral aneurysms under systemic anticoagulation increases the risk of growth of hematomas unrelated to aneurysmal rebleeding. It is important to recognize the risk of this complication and to either reduce the amount of heparin or to refer the patient for direct clipping if appropriate.

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Hiromichi Ando, Masanao Saio, Noriyuki Tamakawa, Naoyuki Ohe, Takashi Nakayama, Hai Yu, Yasuhiko Kaku, Toru Iwama, Jun Shinoda, Noboru Sakai and Tsuyoshi Takami

Object. It is well known that the central nervous system (CNS) is an immunologically privileged site. To characterize CD8+ tumor-infiltrating lymphocytes (TILs) recovered from the CNS, the authors compared these cells with TILs recovered from subcutaneous tissue by using a B7.1 gene—modified tumor implantation model.

Methods. The authors established a B7.1 gene—modified EL4 murine lymphoma cell line (EL4-B7.1) and implanted the cells into the CNS to observe the duration of tumor-free survival. Although EL4-B7.1 cells were completely rejected in a subcutaneous implantation model, 40% of animals died after the CNS implantation (all animals in which the parent tumor was implanted died within 16 days). Therefore, the authors isolated TILs from each implantation site and analyzed the expressions of activation antigens CD25 and CD69 by performing the anti-CD8 magnetic beads separation method and flow cytometric analysis. After implantation of the parent tumor, there was no difference in the number of TILs from each site (CD25 1.7–3.2%, CD69 21.9–34.3%). After implantation of the B7.1-modified tumor, the CD25-expressing TIL population from the subcutaneous site was 4.68 times higher than that from the CNS site (17.8% compared with 3.8%). Based on these findings, the authors used a mitomycin C—treated EL4-B7.1 subcutaneous vaccination with various protocols. Vaccination before tumor challenge was sufficient to prevent the development of the tumor. For animals with established tumor, the vaccination protocol was able to prolong host survival (p = 0.0053).

Conclusions. The data clearly demonstrate that the CNS environment fails to activate CD8+ TILs fully. These are the first data indicating in detail a difference between CD8+ TILs from the CNS and those from other sites based on a B7.1-modified tumor model.

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Motoshi Sawada, Yasuhiko Kaku, Shinichi Yoshimura, Masahiro Kawaguchi, Takashi Matsuhisa, Toshifumi Hirata and Toru Iwama

✓ Occlusion of the parent artery is a traditional method of treatment of unclippable cerebral aneurysms. Surgical or endovascular occlusion of the parent artery proximal to the aneurysm has been recommended for the treatment of dissecting aneurysms located in the vertebrobasilar circulation. Nevertheless, occlusion of the parent artery may not result in permanent exclusion of the aneurysm from the systemic circulation because, occasionally, postoperative rebleeding occurs after proximal occlusion. Alternatively, endovascular occlusion of the affected site, including the aneurysmal dilation, and parent artery, is a safe and reliable treatment for dissecting aneurysms.

The authors present two rare cases of ruptured vertebral artery (VA) dissecting aneurysms that were treated by endovascular occlusion of the affected site including the aneurysm and parent artery by using Guglielmi detachable coils. In both cases the VA recanalized in an antegrade fashion during the follow-up period. Based on these unique cases, the authors suggest that a careful angiographic follow up of dissecting aneurysms is required, even in patients successfully treated with endovascular occlusion of the affected artery and aneurysm.

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Hiroaki Takei, Jun Shinoda, Soko Ikuta, Takashi Maruyama, Yoshihiro Muragaki, Tomohiro Kawasaki, Yuka Ikegame, Makoto Okada, Takeshi Ito, Yoshitaka Asano, Kazutoshi Yokoyama, Noriyuki Nakayama, Hirohito Yano and Toru Iwama


Positron emission tomography (PET) is important in the noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 WHO classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification). Here, the authors investigated the relationship between uptake of 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) on PET imaging and isocitrate dehydrogenase (IDH) status (wild-type [IDH-wt] or mutant [IDH-mut]) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification.


In total, 105 patients with newly diagnosed cerebral gliomas (6 diffuse astrocytomas [DAs] with IDH-wt, 6 DAs with IDH-mut, 7 anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, 5 GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake value (SUV) of the tumor/mean SUV of normal cortex (T/N) ratios for MET, CHO, and FDG were calculated, and the mean T/N ratios of DA, AA, and GBM with IDH-wt and IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the 3 PET tracers.


There were significant differences in the mean T/N ratios for all 3 PET tracers between the IDH-wt and IDH-mut groups of all histological classifications (p < 0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all 3 PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all 3 PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p < 0.01). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that in the IDH-mut group for both MET (p = 0.034) and CHO (p = 0.01). However, there was no significant difference in the ratio for FDG.


PET imaging using MET, CHO, and FDG was suggested to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.