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Satoshi Utsuki, Satoshi Tanaka, Hidehiro Oka, Kazuhisa Iwamoto, Takao Sagiuchi and Kiyotaka Fujii

✓ Extracranial bone metastasis from glioblastoma multiforme (GBM) has rarely been reported in the literature, and most metastatic GBMs are multiple bone metastases. The authors describe the first case of a GBM with metastasis only to the axis. This 42-year-old man presented with a 2-month history of headache, nausea, vomiting, and disorientation. Magnetic resonance imaging demonstrated a right temporal tumor, which was diagnosed as a GBM based on tumor resection. The patient was treated using radiation (6000 cGy) and the intravenous administration of nimustine hydrochloride. Eighteen months thereafter, he experienced the sudden onset of neck pain. Magnetic resonance studies revealed a tumor in the axis that was diagnosed as GBM based on biopsy procedure.

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Satoshi Tanaka, Tadashi Nagashima, Shinya Manaka, Tomokatsu Hori and Shigeru Yasumoto

✓ The effect of recombinant human interleukin-1 (rHuIL-1) derivatives on human glioma cell lines was examined in vitro. Five glioma cell lines, U-251 MG, U-373 MG, U-87 MG, A-172, and T98G, were incubated in medium containing 1% fetal calf serum and various concentrations of different types of rHuIL-1: OCT-43 (rHuIL-1β), OCT-7000 (rHuIL-1α), and OCT-8000 (rHuIL-1α). The high-affinity IL-1 receptors were expressed in the U-251 MG and U-373 MG cell lines, and rHuIL-1 was found to suppress cell growth and to induce morphological differentiation of these cell lines. Growth inhibition occurred in a dose-dependent manner in concentrations or rHuIL-1 ranging between 1 and 100 ng/ml. Interestingly, rHuIL-1 induced a transient growth of glioma cells shortly after administration, then suppressed cell growth with accompanying elongation of cytoplasmic processes. This unique process of transient growth stimulation followed by growth suppression was parallel to the efficacy of bromodeoxyuridine uptake in the rHuIL-1-treated cells. Concomitantly, accumulation of glial fibrillary acidic protein and cyclic adenosine monophosphate contents was observed in four glioma cell lines. Continuous rHuIL-1 treatment for longer than 30 days elicited irreversible astrocytic terminal differentiation. These results indicate that IL-1 is an effector on the growth regulation of glioma cells, resulting in astrocytic differentiation in vitro.

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Satoshi Utsuki, Hidehiro Oka, Sumito Sato, Sachio Suzuki, Satoru Shimizu, Satoshi Tanaka and Kiyotaka Fujii

✓The response of nonfluorescing infiltrating tumors that had been exposed to 5–aminolevulinic acid and irradiated using a laser at a wavelength of 405 nm was analyzed intraoperatively using spectroscopy. Histological analyses demonstrated that neoplastic cells were present in the tissue region that displayed a peak at 636 nm, whereas no neoplastic cells were present in the region that exhibited only the excitation light peak. The authors conclude that the intraoperative use of laser spectroscopy can allow the diagnosis of infiltrating tumor and the detection of boundaries of the infiltrate when standard fluorescence techniques fail.

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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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Takafumi Saito, Ryuichi Tanaka, Mituo Kouno, Kazuo Washiyama, Satoshi Abe and Toshiro Kumanishi

✓ Subpopulations of tumor-infiltrating lymphocytes (TIL's) and the major histocompatibility complex (MHC) antigens of neoplastic cells were examined in three intracranial germinomas by an immunohistochemical method using monoclonal antibodies. About 70% to 80% of TIL's were T lymphocytes which were either infiltrating diffusely or in clusters, whereas 20% to 30% of TIL's were B lymphocytes which tend to cluster in tumor tissues. Examination of T lymphocyte phenotypes revealed both the cytotoxic/suppressor and helper/inducer T lymphocytes, as in other tumors. However, the existence of a considerable number of B lymphocytes in the TIL population was uncommon and seemed to be a characteristic feature of the intracranial germinoma, which might suggest a difference of host immune response to this neoplasm as compared to other tumors.

On examination of the MHC antigens, no MHC class I or II antigens in the neoplastic cells were stained, while positive staining for both antigens was seen in the TIL and stroma tissues. From these findings, it was suggested that the degree of TIL infiltration might not be correlated with the expression of MHC antigens in neoplastic cells in cases of primary intracranial germinoma.

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Daina Kashiwazaki, Naoki Akioka, Naoya Kuwayama, Tomohide Hayashi, Kyo Noguchi, Kortaro Tanaka and Satoshi Kuroda

OBJECTIVE

The roles of endothelial progenitor cells (EPCs) in the development of carotid plaque are still obscure. This study aimed to clarify this by assessing the histological findings of specimens obtained from carotid endarterectomy.

METHODS

This study included 34 patients who underwent carotid endarterectomy. MR imaging was performed to semiquantitatively analyze the components of the carotid plaques in all patients. The surgical specimens were subjected to immunohistochemistry. The distributions of the CD34-, CD133-, VEGF-2R–positive cells in the carotid plaques were precisely analyzed, and their number was quantified. Simultaneously, the CD34-positive microvessels were localized.

RESULTS

The plaque component was judged as lipid-rich plaque in 19 patients, intraplaque hemorrhage (IPH) in 11 patients, and fibrous plaque in 4 patients. The CD34-positive microvessels were densely distributed in the plaque shoulder and interface-to-media regions. The CD34-, CD133-, and VEGF-2R–positive cells were mainly localized around the CD34-positive microvessels. The number of CD34-positive microvessels significantly correlated with the number of CD34-, CD133-, and VEGF-2R–positive cells (R = 0.308, p = 0.009; R = 0.324, p = 0.006; and R = 0.296, p = 0.013, respectively). Vulnerable plaques (lipid-rich and IPH) had significantly higher numbers of the CD34-positive microvessels (p = 0.007) and CD34-, CD133-, and VEGF-2R–positive cells than fibrous plaques (p = 0.031, p = 0.013, and p = 0.002).

CONCLUSIONS

These findings strongly suggest that neovascularization in the plaque shoulder and interface-to-media regions may play a key role in delivering EPCs from the peripheral blood to the carotid plaque, promoting the growth of carotid plaque. Furthermore, the invaded EPCs, especially the CD133-positive immature EPCs, may be related to plaque vulnerability.

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Satoshi Tanaka, Junko Takanashi, Kiyotaka Fujii, Hiroshi Ujiie and Tomokatsu Hori

✓Motor evoked potentials (MEPs) by direct brainstem stimulation were generated during 12 neurosurgical operations performed in five posterior fossa tumors, six vertebrobasilar aneurysms, and an arachnoid cyst. The anterior aspect of the brainstem was exposed using a subtemporal approach (in six cases), a presigmoid approach (one case), or a lateral suboccipital approach (five cases). A train of five monopolar 5 to 25 mA pulses was then applied, and MEPs were recorded from the extremities. Motor evoked potentials were recorded in all patients (four mappings and seven monitorings) except in a 12-year-old child who underwent surgery for a posterior cerebral artery aneurysm. Although he experienced postoperative motor palsy, the aneurysm ruptured before electrodes could be placed. Two patients with postoperative motor palsy, one with a clival meningioma and one with a basilar trunk aneurysm, had shown significant decreases in MEP amplitude and even complete disappearance of MEPs during intraoperative brainstem stimulation. Motor evoked potentials elicited by direct brainstem stimulation seem to be an accurate neurophysiological monitoring method during operations around the anterior and lateral aspects of the brainstem.

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Kazuyoshi Nakanishi, Nobuhiro Tanaka, Naosuke Kamei, Takeshi Hiramatsu, Satoshi Ujigo, Norihiko Sumiyoshi, Takanori Rikita, Atsushi Takazawa and Mitsuo Ochi

OBJECT

The occurrence of compressive cervical myelopathy (CCM) increases in adults over 50 years of age. In addition, diabetes mellitus (DM) is a frequent comorbidity for people of this age and may impact the severity of CCM. The authors assessed motor pathway function in diabetic patients with CCM to investigate the correlation between electrophysiological parameters and clinical symptoms.

METHODS

Motor evoked potentials (MEPs) were measured from the abductor digiti minimi muscle (ADM) and the abductor hallucis muscle (AH) following transcranial magnetic stimulation, as were M- and F-waves following electrical stimulation of the ulnar and tibial nerves, in 22 patients with CCM and diabetes mellitus (DM) who had not experienced symptomatic diabetic neuropathy (CCM-DM group), in 92 patients with CCM alone (CCM group), and in 24 healthy adults (control group). The peripheral conduction time (PCT; measured from the ADM and AH) was calculated as follows: (M-wave latency + F-wave latency −1)/2. The central motor conduction time (CMCT; measured from the ADM and AH) was calculated by subtracting the PCT from the onset latency of the MEPs. The Japanese Orthopaedic Association (JOA) score for cervical myelopathy was obtained before and 1 year after surgery as a clinical outcome measure.

RESULTS

MEP, PCT, and CMCT parameters in the CCM-DM and CCM groups were significantly longer than those in the control group (p = 0.000−0.007). The PCTs in the CCM-DM group were significantly longer than those in the CCM group (p = 0.001−0.003). No significant differences were detected in the MEP and CMCT parameters between the CCM-DM and CCM groups (p = 0.080–1.000). The JOA score before surgery in the CCM-DM group was 10.7 ± 2.0 points and was significantly lower than that in the CCM group (12.2 ± 2.5 points, p = 0.015). In the CCM-DM group, JOA scores before surgery correlated with MEP-AH (r = −0.610, p = 0.012) and PCT-AH (r = −0.676, p = 0.004) values, but not with CMCT values, while the JOA scores were related to both MEP and CMCT parameters in the CCM group. The JOA scores improved to 13.8 ± 2.2 points after surgery (p = 0.001) and correlated with MEP-AH (r = −0.667, p = 0.005) and PCT-AH (r = −0.611, p = 0.012) in the CCM-DM group.

CONCLUSIONS

The results suggest that MEP, PCT, and CMCT parameters each reveal abnormalities in the upper and lower motor neurons even in patients with DM. The results also show a prolonged PCT in CCM-DM patients, despite having no history of diabetic neuropathy. Corticospinal tract impairments are similar between CCM and CCM-DM patients, while the JOA score of the CCM-DM patients is lower than that in the CCM patients. The JOA score in CCM-DM patients may be influenced by additional impairments in peripheral nerves or other diabetic complications. These electrophysiological studies may be useful for screening motor pathway function for CCM in patients with DM.

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Kiyoharu Shimizu, Masaaki Takeda, Takafumi Mitsuhara, Shunichi Tanaka, Yushi Nagano, Hitoshi Yamahata, Kaoru Kurisu and Satoshi Yamaguchi

OBJECTIVE

Spinal dural arteriovenous fistulas (SDAVFs) commonly present with symptoms of myelopathy due to venous congestion in the spinal cord; asymptomatic SDAVFs are rarely encountered. To elucidate the clinical characteristics of asymptomatic SDAVFs, the authors present 5 new cases of asymptomatic SDAVF and report the results of their systematical review of the associated literature.

METHODS

Five databases were systematically searched for all relevant English-language articles on SDAVFs published from 1990 to 2018. The clinical features and imaging findings of asymptomatic SDAVFs were collected and compared with those of symptomatic SDAVFs.

RESULTS

Twenty cases, including the 5 cases from the authors’ experience, were found. Asymptomatic SDAVFs were more prevalent in the cervical region (35.0%); cervical lesions account for only 2% of all symptomatic SDAVFs. The affected perimedullary veins tended to drain more cranially (50.0%) than caudally (10.0%). Four cases of asymptomatic SDAVF became symptomatic, 1 case spontaneously disappeared, and the remaining 15 cases were unchanged or surgically treated.

CONCLUSIONS

The higher prevalence of asymptomatic SDAVFs in the cervical spine might be a distinct feature of asymptomatic SDAVFs. Given that venous congestion is the pathophysiology of a symptomatic SDAVF, abundant collateral venous pathways and unique flow dynamics of the CSF in the cervical spine might prevent asymptomatic cervical SDAVFs from becoming symptomatic. In cases in which venous congestion is avoidable, not all asymptomatic SDAVFs will become symptomatic.

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Satoshi Tanaka, Jiro Akimoto, Yoshitaka Narita, Hidehiro Oka and Takashi Tashiro

Object

Methylation of O6-methylguanine-DNA methyltransferase (MGMT) has been reported to be a good prognostic factor for patients with glioblastoma multiforme (GBM). To determine whether the absolute value of MGMT messenger RNA (mRNA) might be a prognostic factor and useful for predicting the therapeutic effectiveness of temozolomide, especially with regard to GBMs, the authors measured the absolute value of MGMT mRNA in gliomas by using real-time reverse-transcription polymerase chain reaction (RT-PCR).

Methods

MGMT mRNA was measured in 140 newly diagnosed gliomas by real-time RT-PCR using the Taq-Man probe. Among 73 GBMs, 45 had been initially treated with temozolomide and radiation.

Results

The mean MGMT mRNA value was significantly lower in oligodendroglial tumors than in other tumors. In the 73 GBMs, a significant prognostic factor for progression-free survival was fewer than 1000 copies/ μgRNA of MGMT mRNA (p = 0.0150). Of 45 patients with GBMs that had been treated with temozolomide and radiation, progression-free survival was significantly longer for those whose GMB had fewer than 1000 copies/μgRNA of MGMT mRNA than for those whose GBM had more than 1000 copies/μgRNA (p = 0.0090). In 32 patients with GBMs treated by temozolomide and radiation whose age was younger than 75 years and whose Karnofsky Performance Scale score was more than 70, progression-free and overall survival times were longer for those with GBMs of fewer than 5000 copies/μgRNA of MGMT mRNA than for those with GBMs of more than 5000 copies/μgRNA (p = 0.0365 and p = 0.0312).

Conclusions

MGMT mRNA might be useful as a prognostic factor and for predicting the results of therapy for GBMs treated by temozolomide. New individual adjuvant therapy based on the results of MGMT mRNA quantitation has been proposed.