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Hitachi-Naka, Japan

Little information is available on staged Gamma Knife surgery (GKS) with an interval of 3 years or more when used to treat arteriovenous malformations (AVMs) with volumes larger than 10 cm(3). The goal of this study was to increase knowledge in this area by reporting the authors' experience. The authors describe an institutional review board-approved retrospective study in which they examined databases including information on 250 patients who consecutively underwent GKS for cerebral AVMs during a 16-year period (1988-2004). Among the 250 patients the authors identified 31 patients (12.4%, 15 female and 16 male patients with a mean age of 29 years [range 10-63 years]) in whom 2-stage GKS was intentionally planned at the time of initial treatment because the volume of the AVM nidus was larger than 10 cm(3). The most common presentation was bleeding (14 patients), followed by seizures (9 patients), incidental findings (7 patients), and headache with scintillation (1 patient). One patient underwent GKS for the treatment of 2 AVMs simultaneously, and thus 32 AVMs are included in this study. The mean nidus volume was 16.2 cm(3) (maximum 55.8 cm(3)). In all 31 patients, relatively low radiation doses (12-16 Gy directed at the periphery of the lesion) were intentionally used for the first GKS. The second GKS was scheduled for at least 36 months after the first. Complete nidus obliteration was obtained after the first GKS in 1 patient. To date, 26 patients have undergone a second procedure with a post-GKS mean interval of 41 months (range 24-83 months); 2 other patients refused to undergo the second GKS, and no further treatment was given because of severe morbidity in 1 case and death due to bleeding in the other case. Among the 26 patients who did undergo a second procedure, 3 patients refused follow-up digital subtraction (DS) angiography, another is scheduled for follow-up DS angiography, and 2 patients died, one of bleeding and the other of an unknown cause. The remaining 20 patients underwent follow-up DS angiography. Complete nidus obliteration was confirmed in 13 patients (65.0%) and remarkable nidus shrinkage in the other 7 patients (35.0%). In 2 of these 7 patients, a third GKS achieved complete nidus obliteration. Therefore, the cumulative complete obliteration rate in this series was 76.2% (16 of 21 eligible patients). Seven patients (22.6%) experienced bleeding. The bleeding rates were 9.7%, 16.1%, 16.1%, and 26.1%, respectively, at 1, 2, 5, and 10 years post-GKS. There were 2 deaths and 3 cases of morbidity (persistent coma, mild hemimotor weakness, and hemianopsia in 1 patient each). Hemorrhage did not produce neurological deficits in the other 2 patients. During the mean post-GKS follow-up period of 105 months (range 42-229 months) to date, mild symptomatic GKS-related complications occurred in 2 patients (6.5%); these were classified as Radiation Oncology Group Neurotoxicity Grade 1 in 1 patient and Grade 2 in the other. Among various pre-GKS clinical factors, univariate analysis showed only patient age to impact complications (hazard ratio 0.675, 95% CI 0.306-0.942, p = 0.0085). The rate of complications in the pediatric cases was 33.3%, whereas that in the adolescent and adult cases was 0% (p = 0.0323). Although a final conclusion awaits further studies and patient follow-up, these results suggest 2-stage GKS to be beneficial even for relatively large AVMs.

Tamura K.,Tokyo Medical and Dental University | Aoyagi M.,Tokyo Medical and Dental University | Ando N.,Tokyo Medical and Dental University | Ogishimao T.,Tokyo Medical and Dental University | And 3 more authors.
Journal of Neurosurgery | Year: 2013

Object: Recent evidence suggests that a glioma stem cell subpopulation may determine the biological behavior of tumors, including resistance to therapy. To investigate this hypothesis, the authors examined varying grades of gliomas for stem cell marker expressions and histopathological changes between primary and recurrent tumors. Methods: Tumor samples were collected during surgery from 70 patients with varying grades of gliomas (Grade II in 12 patients, Grade III in 16, and Grade IV in 42) prior to any adjuvant treatment. The samples were subjected to immunohistochemistry for MIB-1, factor VIII, GFAP, and stem cell markers (CD133 and nestin). Histopathological changes were compared between primary and recurrent tumors in 31 patients after radiation treatment and chemotherapy, including high-dose irradiation with additional stereotactic radiosurgery. Results: CD133 expression on glioma cells was confined to de novo glioblastomas but was not observed in lower-grade gliomas. In de novo glioblastomas, the mean percentage of CD133-positive glioma cells in sections obtained at recurrence was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). CD133 and Ki 67 dual-positive glioma cells were significantly increased in recurrent de novo glioblastomas as compared with those in primary tumors (14.5% ± 6.67% vs 2.16% ± 2.60%, respectively). In contrast, secondary glioblastomas rarely expressed CD133 antigen even after malignant progression following radiotherapy and chemotherapy. Conclusions: The authors' results indicate that CD133-positive glioma stem cells could survive, change to a proliferative cancer stem cell phenotype, and cause recurrence in cases with de novo glioblastomas after radiotherapy and chemotherapy. © AANS, 2013.

Osuka S.,University of Tsukuba | Matsushita A.,University of Tsukuba | Yamamoto T.,University of Tsukuba | Isobe T.,University of Tsukuba | And 5 more authors.
Journal of Neurosurgery | Year: 2010

Object. Ventriculomegaly is a common imaging finding in many types of conditions. It is difficult to determine whether it is related to true hydrocephalus or to an atrophic process by using only imaging procedures such as MR imaging after traumatic injury, stroke, or infectious disease. Diffusion tensor (DT) imaging can distinguish the compression characteristics of white matter, indicating that increased diffusion anisotropy may be related to white matter compression. In this preliminary study, the authors compared the DT imaging findings of ventriculomegaly with those of chronic hydrocephalus or atrophy to clarify the potential of diffusion anisotropy in the identification of hydrocephalus. Methods. Ten patients with chronic hydrocephalus, 8 patients with atrophy (defined by conventional devices and surgical outcome), and 14 healthy volunteers underwent DT imaging. Images were acquired before and after shunting or once in cases without shunting. The fractional anisotropy (FA) values at many points around the lateral ventricle were evaluated. Results. The FA patterns around the lateral ventricle in the chronic hydrocephalus and atrophy groups were different. Especially in the caudate nucleus, FA was increased in the chronic hydrocephalus group compared with the atrophy group. Furthermore, the FA values returned to normal levels after shunt placement. Conclusions. Assessment of the FA value of the caudate nucleus may be an important, less invasive method for distinguishing true hydrocephalus from ventriculomegaly. Further research in a large number of patients is needed to verify the diagnostic ability of this method.

Tamura K.,Tokyo Medical and Dental University | Aoyagi M.,Tokyo Medical and Dental University | Wakimoto H.,Tokyo Medical and Dental University | Ando N.,Tokyo Medical and Dental University | And 4 more authors.
Journal of Neurosurgery | Year: 2010

Object. Recent evidence suggests that a glioma stem cell subpopulation might contribute to radioresistance in malignant gliomas. To investigate this hypothesis, the authors examined recurrent malignant gliomas for histopathological changes after high-dose irradiation with Gamma Knife surgery (GKS) and external beam radiation therapy (EBRT). Methods. Thirty-two patients with malignant gliomas (Grade 3 in 8 patients, Grade 4 in 24) underwent GKS in combination with EBRT. Serial MR and L-[methyl-11C] methionine PET images were employed to assess remnant or recurrent tumors after GKS. Twelve patients underwent surgical removal after GKS and EBRT. Histological sections were subjected to immunohistochemistry for MIB-1, factor VIII, and stem cell markers, nestin and CD133. Results. The site of GKS treatment failure was local in 16 (76.2%) of 21 patients with glioblastomas showing progression; in 9 of these 16 patients, the recurrence clearly arose within the target lesion of GKS. Histopathological examination after GKS and EBRT showed variable mixtures of viable tumor tissues and necrosis. Viable tumor tissues exhibited high MIB-1 indices but reduced numbers of tumor blood vessels. There was marked accumulation of CD133-positive glioma cells, particularly in remnant tumors within the necrotic areas, in sections obtained after GKS plus EBRT, whereas CD133-positive cells appeared very infrequently in primary sections prior to adjuvant treatment. Conclusions. The results indicate that CD133-positive glioma stemlike cells can survive high-dose irradiation, leading to recurrence, despite prolonged damage to tumor blood vessels. This could be an essential factor limiting the effectiveness of GKS plus EBRT for malignant gliomas.

Kawabe T.,Katsuta Hospital Mito GammaHouse
Journal of neurosurgery | Year: 2012

Because brainstem metastases are not deemed resectable, stereotactic radiosurgery (SRS) is the only treatment modality expected to achieve a radical cure. The authors describe their treatment results, focusing particularly on how long patients can survive without neurological deterioration following SRS for brainstem metastases. This was an institutional review board-approved, retrospective cohort study in which the authors pulled from their database information on 2553 consecutive patients with brain metastases who underwent Gamma Knife surgery (GKS) at the Mito GammaHouse between July 1998 and July 2011. Among the 2553 patients, excluding cases in which there was meningeal dissemination, 200 cases of brainstem metastases (78 women and 122 men with a mean age of 64 years [range 36-86 years]) were identified and analyzed. The most common primary site was the lung (137 patients) followed by the gastrointestinal tract (24 patients), breast (17 patients), kidney (12 patients), and others (10 patients). Among the 200 patients, 15 patients (7.5%) harbored at least 2 tumors in the brainstem: 11 patients had 2 tumors, 2 patients had 3 tumors, and 1 patient each had 4 or 5 tumors. Therefore, a total of 222 tumors were irradiated. These 222 tumors were located in the pons (121 lesions), the midbrain (65 lesions), and the medulla oblongata (36 lesions). The mean and median tumor volumes were 1.3 and 0.2 cm(3) (range 0.005-10.7 cm(3)), and the median peripheral radiation dose was 18.0 Gy (range 12.0-25.0 Gy). The overall median survival time (MST) was 6.0 months. Distribution of MSTs across Recursive Partitioning Analysis (RPA) classes showed that the MSTs were 9.4 months in Class I (20 patients), 6.0 months in Class II (171 patients), and 1.9 months in Class III (9 patients). Better Karnofsky Performance Scale score, single metastasis, and well-controlled primary tumor were significant predictive factors for longer survival. The neurological and qualitative survival rates were 90.8% and 89.2%, respectively, at 24 months post-GKS. Better KPS score and smaller tumor volume tended to be associated with prolonged qualitative survival. Follow-up imaging studies were available for 129 patients (64.5%). The tumor control rate was 81.8% at 24 months post-GKS. Smaller tumor volume tended to contribute to tumor control. The present results indicate that GKS is effective in the treatment of brainstem metastases, particularly from the viewpoint of maintaining a good neurological condition in the patient.

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