Long-Term Results and Follow-Up Examinations after Endovascular Embolization for Unruptured Cerebral Aneurysms.

BACKGROUND AND PURPOSE: The appropriate period of follow-up examinations after endovascular embolization for cerebral aneurysms using time-of-flight MR angiography is not well-known. We retrospectively investigated long-term results after endovascular embolization for unruptured cerebral aneurysms and evaluated the periods from embolization to recanalization and retreatment. MATERIALS AND METHODS: Between April 2006 and March 2011, one hundred forty-eight unruptured aneurysms were treated with endovascular coil embolization. Among them, we investigated 116 unruptured aneurysms, which were followed up for >5 years. Time-of-flight MR angiography was performed at 1 day, 3-6 months, 1 year after the procedure, and every year thereafter. RESULTS: The mean follow-up period was 7.0 ± 1.4 years. Recanalization was observed in 19 (16.3%) aneurysms within 2 years. Among them, retreatment for recanalization was performed in 8 (6.8%) aneurysms. No recanalization was detected in any aneurysms that had been stable in the first 2 years after embolization. A larger maximum aneurysm size was significantly correlated with recanalization (P = .019). CONCLUSIONS: Aneurysms in which recanalization was not observed within 2 years after endovascular coil embolization were stable during a mean follow-up of 7 years. This result may be helpful in considering the appropriate span or frequency of follow-up imaging for embolized cerebral aneurysms.

Diagnostic and Prognostic Value of 11C-Methionine PET for Nonenhancing Gliomas.

BACKGROUND AND PURPOSE: Noninvasive radiologic evaluation of glioma can facilitate correct diagnosis and detection of malignant transformation. Although positron-emission tomography is considered valuable in the care of patients with gliomas, (18)F-fluorodeoxyglucose and (11)C-methionine have reportedly shown ambiguous results in terms of grading and prognostication. The present study compared the diagnostic and prognostic capabilities of diffusion tensor imaging, FDG, and (11)C-methionine PET in nonenhancing gliomas. MATERIALS AND METHODS: Thirty-five consecutive newly diagnosed, histologically confirmed nonenhancing gliomas that underwent both FDG and (11)C-methionine PET were retrospectively investigated (23 grade II and 12 grade III gliomas). Apparent diffusion coefficient, fractional anisotropy, and tumor-to-normal tissue ratios of both FDG and (11)C-methionine PET were compared between grade II and III gliomas. Prognostic values of these parameters were also tested by using progression-free survival. RESULTS: Grade III gliomas showed significantly higher average tumor-to-normal tissue and maximum tumor2-to-normal tissue than grade II gliomas in (11)C-methionine (P = .013, P = .0017, respectively), but not in FDG-PET imaging. There was no significant difference in average ADC, minimum ADC, average fractional anisotropy, and maximum fractional anisotropy. (11)C-methionine PET maximum tumor-to-normal tissue ratio of 2.0 was most suitable for detecting grade III gliomas among nonenhancing gliomas (sensitivity, 83.3%; specificity, 73.9%). Among patients not receiving any adjuvant therapy, median progression-free survival was 64.2 ± 7.2 months in patients with maximum tumor-to-normal tissue ratio of <2.0 for (11)C-methionine PET and 18.6 ± 6.9 months in patients with maximum tumor-to-normal tissue ratio of >2.0 (P = .0044). CONCLUSIONS: (11)C-methionine PET holds promise for World Health Organization grading and could offer a prognostic imaging biomarker for nonenhancing gliomas.

Feasibility of 2nd generation STS retinal prosthesis in dogs.

We developed a 2(nd) generation suprachoroidal transretinal stimulation (STS) system with a 49 channel electrode array and implanted in 2 dogs. One month after surgery, all electrodes were functioning and the ocular fundus was normal in both dogs. The results indicate the 2(nd) generation STS retinal prosthesis is feasible and can be considered for clinical use.

Radiation-induced anaplastic ependymoma with a remarkable clinical response to temozolomide: a case report.

Radiation-induced gliomas are uncommon and therapeutic options are limited due to prior exposure to radiotherapy. Meanwhile, the chemotherapeutic response of anaplastic ependymoma, another rare entity in adults, is often disappointing. We report on the first recorded case of radiation-induced anaplastic ependymoma, in which an excellent clinical response to temozolomide was demonstrated.

Stimulation of primary motor cortex for intractable deafferentation pain.

To treat intractable deafferentation pains, we prefer stimulation of the primary motor cortex (M1). The methods of stimulation we utilize are electrical stimulation and repetitive transcranial magnetic stimulation (rTMS). In our department, we first attempt rTMS, and if this rTMS is effective, we recommend the patient to undergo procedures for motor cortex stimulation (MCS). A 90% intensity of resting motor threshold setting is used for rTMS treatment. In this study ten trains of 5 Hz rTMS for 10 seconds (50 seconds resting interval) were applied to the M1, S1, pre-motor and supplementary motor areas. Only M1 stimulation was effective for pain reduction in 10 of 20 patients (50%). Twenty-nine MCS procedures were performed by subdural implantation of electrodes, and in the case of hand or face pain, electrodes were implanted within the central sulcus (11 cases), because the main part of M1 is located in the central sulcus in humans. The success rate of MCS was around 63%, and seemed to be higher in cases of pain with spinal cord and peripheral origins, while it was lower in cases of post-stroke pain.

Open radiofrequency ablation for the management of intractable epilepsy associated with sessile hypothalamic hamartoma.

Sessile hypothalamic hamartoma (HH) often causes intractable epilepsy, which is difficult to control even by microsurgical resection and gamma knife surgery (GKS), especially when the hamartoma is intrahypothalamic, large, or irregularly shaped. We successfully applied radiofrequency ablation (RFA) to reduce its epileptogenicity and to disconnect seizure propagation. The patient was a 26-year-old man who presented with refractory epilepsy and severe mental retardation from age 6 months. He had undergone three surgeries yielding partial resection and conventional irradiation treatments. The residual HH was thin and shaped like a bent plate, attached widely to the floor of the third ventricle. He underwent open RFA via the transcallosal sub-choroidal approach under strict image guidance, which resulted in immediate and remarkable seizure remission without complications. This suggests that open RFA is a minimally invasive technique for an irregularly shaped HH that is difficult to treat by other modalities.

Cerebral motor control in patients with gliomas around the central sulcus studied with spatially filtered magnetoencephalography.

OBJECTIVE: Application of spatially filtered magnetoencephalography (MEG) to investigate changes in the mechanism of cerebral motor control in patients with tumours around the central sulcus. METHODS: MEG records were made during a repetitive hand grasping task in six patients with gliomas around the central sulcus and in four control subjects. Power decreases in the alpha (8-13 Hz), beta (13-30 Hz), and low gamma bands (30-50 Hz) during the motor tasks (event related desynchronisation, ERD) were analysed statistically with synthetic aperture magnetometry. The tomography of ERD was superimposed on the individual's magnetic resonance image. RESULTS: beta ERD was consistently localised to the contralateral primary sensorimotor cortex (MI/SI) in control subjects, whereas the alpha and low gamma ERD showed considerable intersubject variability. beta ERD in patients during non-affected side hand movement was also localised to the contralateral MI/SI, but exclusively to the ipsilateral hemisphere during affected side hand movement. CONCLUSIONS: The altered pattern of ERD in the patient group during affected side hand movement suggests recruitment of diverse motor areas, especially the ipsilateral MI/SI, which may be required for the effective movement of the affected hand.

Stereotactic radiofrequency ablation for sessile hypothalamic hamartoma with an image fusion technique.

BACKGROUND: Radiosurgery has been advocated as a primary treatment for hypothalamic hamartoma (HH), but it has a risk of damaging the surrounding structures and does not have an immediate effect for refractory epilepsy, endocrinological and mental disorders. METHOD: We report on a 13-year-old boy with a large and sessile HH who presented with intractable seizures, precocious puberty and aggressiveness. Stereotactic radiofrequency ablation (SRA) combined with an image fusion technique was performed to make a maximum ablative lesion within the HH via multiple trajectories. FINDINGS: After surgery, we observed rapid cessation of the gelastic seizures and aggressiveness. The ophthalmological function did not get worse, and the hypothalamopituitary function improved. INTERPRETATION: SRA in combination with an image fusion technique is a viable alternative treatment for HH, because it provides precise preoperative simulation and immediate improvement of symptoms can be obtained.

Radiosensitive giant cell tumour of the sphenoid bone.

Giant cell tumours rarely occur in the cranial region. We encountered a radiosensitive giant cell tumour of the sphenoid in a 12-year-old girl. After a two-stage operation, the residual tumour regrew rapidly. The adjuvant radiotherapy subsequent to additional surgery has suppressed the growth of the residual tumour for 5 years.

Motor cortex stimulation for deafferentation pain.

OBJECT: The authors tested a modified motor cortex stimulation (MCS) protocol for the treatment of deafferentation pain in 15 patients: eight patients with poststroke pain, four with brachial plexus injury, two with phantom limb pain, and one with spinal cord injury. METHODS: Preoperative pharmacological tests were performed with phentolamine, lidocaine, ketamine, thiopental, morphine, and a placebo. In 12 patients we placed a 20- or 40-grid electrode in the subdural space to determine the best stimulation point for pain relief over a few weeks and therefore the optimum position for a permanent internal device. In four patients, the MCS devices were implanted in the interhemispheric fissure to reduce lower-extremity pain. In one patient, the MCS device was placed within the central sulcus, and a 20-grid electrode was placed on the brain surface. In two patients with pain extending from the upper extremity to the hyperbody, dual-electrode devices were implanted to drive two electrodes. In 10 of the 15 patients MCS-induced pain reduction was achieved (four with excellent, two with good, and four with fair alleviation of pain). The result of pharmacological testing indicated that patients with ketamine sensitivity seem to be good candidates for MCS. CONCLUSIONS: Test stimulation with a subdural multigrid electrode was helpful in locating the best stimulation point for pain relief.

Anticonvulsant-induced suppression of IFN-gamma production by lymphocytes obtained from cervical lymph nodes in glioma-bearing mice.

It is well known that phenytoin can cause impairment of cellular immunity. The authors investigated the potential role of other anticonvulsant drugs in the development of antitumor immunity in murine malignant glioma models. The survival rate was determined in murine glioma models using syngeneic 203 glioma cells following treatment with four anticonvulsants, which are most commonly administered to glioma patients, i.e., phenytoin, phenobarbital, valproate and zonisamide. In a second set of experiments, we further examined the effect of these drugs on interferon-gamma (IFN-gamma) secretion by lymphocytes prepared from cervical lymph nodes (CLN) in the same models. The IFN-gamma production of CLN lymphocytes as measured by ELISA method was markedly impaired in the early stage of tumor-bearing mice treated with phenytoin or zonisamide, and the median survival time (MST) of controls and of mice treated with either phenytoin or zonisamide was 13, 10 and 11 days, respectively, which was not a statistically significant difference. Phenobarbital and valproate did not affect either IFN-gamma production or their survival rate. In addition, immunohistochemistry showed a reduction in tumor-infiltrating lymphocytes containing CD4 and CD8 antigens in the mice treated with phenytoin and zonisamide. Two anticonvulsants, phenytoin and zonisamide, showed a significant inhibitory effect on IFN-gamma production by CLN lymphocytes in murine glioma models, although there was no statistically significant difference in MST between controls and the anticonvulsant-treated mice. These drugs might have some detrimental influence on the prognosis of brain tumor patients when combined with the latent immune dysfunction accompanying the tumor-bearing state.

Monoclonal antibody ONS-M21 recognizes integrin alpha3 in gliomas and medulloblastomas.

The monoclonal antibody ONS-M21 recognizes an antigen found on the surface of glioma and medulloblastoma cells but does not react with the antigens of normal brain tissue. We purified and identified the 140-kDa protein by means of an antibody-binding affinity column. This 140-kDa antigen has sequences homologous to the amino-terminal region and five parts of the internal domain of integrin alpha3. When the integrin alpha3-related sequences was amplified and used to analyse the mRNA of glioma and medulloblastoma surgical specimens, the transcription level of integrin alpha3 mRNA appeared to be quantitatively correlated with the grade of malignancy. These findings suggest that the ONS-M21 antibody, which reacts with integrin alpha3, might be useful in the diagnosis of gliomas and medulloblastomas.

Systemic interleukin 12 displays anti-tumour activity in the mouse central nervous system.

In various systemic cancers, interleukin 12 (IL-12) induces anti-tumour immunity mediated by T lymphocytes and natural killer cells. To determine whether IL-12 has anti-tumour activity against malignant gliomas in the central nervous system (CNS), which is considered to be an immunologically privileged site, we treated mice with meningeal gliomatosis by intraperitoneal (i.p.) or intrathecal (i.t.) administration of recombinant murine IL-12. Although untreated mice revealed symptoms, such as body weight loss or paraplegia as a result of the meningeal gliomatosis within 8 days after tumour inoculation, 80% of the mice treated with IL-12 at 0.5 microg i.p. were cured. Many lymphocytes, mostly CD4+ and CD8+ cells, infiltrated to the tumours of IL-12-treated mice. The numbers of these cells increased in the cervical lymph nodes, into which the cerebrospinal fluid drains, and there they secreted a considerable amount of interferon-gamma. Mice cured by IL-12 rejected subcutaneous or i.t. rechallenge with their original glioma cells, but the same mice were not able to reject other syngeneic tumour cells. These results indicate that the immune system recognizes malignant glioma cells in the subarachnoid space of the CNS and that systemic IL-12 may produce effective anti-tumour activity and long-lasting tumour-specific immunity.

Internalization with high targeting potential of mouse monoclonal antibody ONS-M21 recognizing human malignant glioma antigen.

In order to evaluate the targeting potential of mouse monoclonal antibody ONS-M21 recognizing a human astrocytoma- and medulloblastoma-associated antigen, the internalization ability of this antibody and the selective cytotoxicity in the toxin-conjugated form were examined. Internalization assay with 125I-labeled ONS-M21 showed that about 20% of the total radioactivities was detected in the cellular fraction of human medulloblastoma cell line ONS-76 cells and that the reaction reached a plateau level in 30 min. To examine the selective delivery capacity of a high molecular substance in place of 125I, an immunotoxin was prepared with ricin A chain and ONS-M21 via disulfide bonds. A cytotoxic effect against ONS-76 cells was found with [3H]thymidine incorporation assay using the immunotoxin, but not against antigen-negative HuH-7 and SW480 cells. These results suggest that ONS-M21 could effectively deliver toxins, chemotherapeutic agents or radionuclei to malignant glioma specifically.

Microvascular permeability of the non-heart-beating rabbit lung after warm ischemia and reperfusion: role of neutrophil elastase.

BACKGROUND: The duration of warm ischemia and reperfusion injury is a major limiting factor in the setting of lung transplantation with non-heart-beating donors (NHBD). We hypothesized that reperfusion with neutrophil elastase inhibitor or leukocyte-depleted blood has an inhibitory effect on the ischemia-reperfusion injury of NHBD rabbit lungs. METHODS: To assess the lung injury, we used a perfused rabbit lung model and measured the hemodynamic parameters and filtration coefficient. The rabbit lungs after hypoxic cardiac arrest for 30, 50, and 60 minutes were harvested at room temperature, and ventilated lungs were reperfused for 1 hour at a constant flow (120 mL/min). The group with 60 minutes of warm ischemia and hypoxia was further divided into three groups to determine the effects of leukocyte-depleted reperfusion or neutrophil elastase inhibitor, (1) no other special treatment, (2) reperfusion with leukocyte-depleted blood, and (3) administration of 10 mg of specific neutrophil elastase inhibitor. The lungs reperfused immediately after harvest from the heart-beating donor were regarded as the control. RESULTS: Sixty minutes of warm ischemia and hypoxia resulted in an increase in filtration coefficient (0.68+/-0.20 g x min(-1) x cm H2O(-1) per 100 g) compared with the control values of 0.13+/-0.03 g x min(-1) x cm H2O(-1) per 100 g. The increase in filtration coefficient after 60 minutes of warm ischemia and hypoxia in NHBD was remarkably suppressed by leukocyte depletion (0.23+/-0.07) and by neutrophil elastase inhibitor (0.21+/-0.08). The shunt fraction and histology results were also near normal. CONCLUSIONS: These results suggested that leukocyte depletion or treatment with neutrophil elastase inhibitor during reperfusion reduces alveolar-capillary damage caused by lung ischemia-reperfusion injury in the NHBD lung transplantation setting. This effect might be mediated by inhibition of neutrophil elastase activity or sequestration, and thus may lead to the increased availability of NHBD lungs.

Possible common origin of alpha-fetoprotein- and human chorionic gonadotropin--secreting cells in intracranial germ cell tumor. Case report.

A primary intracranial germ cell tumor in a 16-year-old boy secreted both alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). The tumor, located in the right thalamus, contained germinomatous, trophoblastic, and endodermal sinus components. To identify AFP- and HCG-secreting cells, germ cells from the surgical specimen were cultured in vitro. These cultured cells secreted AFP and HCG for 10 weeks, and immunohistochemical studies showed that some of the cells secreted both AFP and HCG. These findings suggest that multipotential germ cells migrate to the encephalic region and may become germ cell tumors containing various types of tissue.

A humanized single-chain Fv fragment with high targeting potential against human malignant gliomas.

A humanized ONS-M21 antibody (hM21) against human medulloblastoma and glioma cells was engineered as a single-chain Fv fragment (scFv), and its ability to internalize into tumor cells was evaluated by conjugation with ricin A. The scFv of hM21 (schM21) was easily purified from E.coli by one-step affinity column chromatography. Purified schM21 bound to a medulloblastoma ONS-76 cell with almost equal antigen-binding activity of hM21-Fab fragment. Furthermore, the schM21-ricin A conjugate inhibited the growth of ONS-76 cells, but not that of antigen-negative hepatoma HuH-7 cells, suggesting that the schM21 can be internalized after binding to antigen-positive cells. Thus, schM21 could be expected to act as a novel carrier of diagnostic and therapeutic agents for brain tumors.

Transduction of glioma cells using a high-titer retroviral vector system and their subsequent migration in brain tumors.

The intracranial migration of transduced glioma cells was investigated in order to improve the treatment of malignant glioma by gene therapy using retroviral vectors. In this study, about half the volume of the tumor mass could be transduced in 14 days after only a single implantation of 3 x 10(5) retrovirus-producing cells into a tumor mass with a diameter of 5 mm. Moreover, we were able to follow the migration of glioma cells transduced by the lacZ-harboring retroviruses originating from the high-titer retrovirus-producing cells. Besides the importance of using a high-titer retroviral vector system, our results also indicate that the implantation site of the virus-producing cells and the interval between the implantation of the virus-producing cells and the subsequent administration of ganciclovir are important factors for the efficient killing of glioma cells.