Walter C. Jean

Reperfusion injury after focal cerebral ischemia: The role of inflammation and the therapeutic horizon

Recent evidence indicates that thrombolysis may be an effective therapy for the treatment of acute ischemic stroke. However, the reperfusion of ischemic brain comes with a price. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion. We have reviewed the existing data indicating that an inflammatory response occurring after the reestablishment of circulation has a causative role in this reperfusion injury. The recruitment of neutrophils to the area of ischemia, the first step to inflammation, involves the coordinated appearance of multiple proteins. Intercellular adhesion molecule-1 and integrins are adhesion molecules that are up-regulated in endothelial cells and leukocytes. Tumor necrosis factor-alpha, interleukin-1, and platelet-activating factor also participate in leukocyte accumulation and subsequent activation. Therapies that interfere with the functions of these factors have shown promise in reducing reperfusion injury and infarct extension in the experimental setting. They may prove to be useful adjuncts to thrombolytic therapy in the treatment of acute ischemic stroke.

Immunization with Dendritic Cells Pulsed with Tumor Extract Increases Survival of Mice Bearing Intracranial Gliomas

The purpose of this study is to investigate the efficacy of dendritic cell-mediated immunotherapy against intracranial gliomas. Cloned DC2.4 dendritic cells originating from C57BL/6 mice were pulsed with glioma GL261 cell extracts and administered i.p. to C57BL/6 mice with intracranial GL261 gliomas. The survival of mice with and without pulsed dendritic cells was monitored after intracranial implantation of the GL261 glioma cells. Fluorescence activated cell sorting (FACS) analysis showed that DC2.4 cells express high levels of MHC class I and class II molecules, costimulatory molecules B7-l and B7-2, and the cell adhesion molecule ICAM-l. Antigen-presenting capabilities in these dendritic cells were initially characterized in vitro by a mixed lymphocyte reaction, showing that Balb/c CD4+ and CD8+ T cells were able to generate allogeneic responses to DC2.4 cells. Tumor extract-pulsed DC2.4 dendritic cells were then used for the treatment of C57BL/6 mice with syngeneic GL261 gliomas. Animals with intracranial GL261 gliomas and vaccinated i.p. with pulsed DC2.4 dendritic cells exhibited significantly enhanced survival, relative to animals treated with saline or non-pulsed DC2.4 cells alone. In addition, cured animals showed an increased delayed-type hypersensitivity response to GL261 cells and survived when rechallenged with intracranial GL261 gliomas. In summary these results indicate that dendritic cells pulsed with tumor extract can enhance immune responses to tumor antigen and therefore represent a potential immunotherapeutic approach for treating patients with intracranial gliomas.

Interleukin-12-based immunotherapy against rat 9L glioma

OBJECTIVE Interleukin-12 (IL-12) may be useful for immunotherapy against gliomas because it can reverse the glioma-induced suppression of T-cell proliferation and interferon-gamma production. We postulated that peripheral infusion of IL-12 along with irradiated tumor cells can lead to immunological rejection of 9L glioma. METHODS 9L gliosarcoma flank tumors were established in syngeneic Fischer 344 rats. Osmotic minipumps delivered IL-12 subcutaneously, and irradiated 9L cells were injected on Days 0, 3, 7, 14, and 21. Tumor volumes were measured by a blinded observer. For tumor rechallenge, animals initially cured of 9L flank tumors received either another implantation of flank tumor or a stereotactic injection of 10(6) 9L cells into the right striatum. Delayed-type hypersensitivity was measured after injecting 10(6) irradiated 9L tumor cells into the right pinnae. RESULTS Tumor growth curves were significantly different between treated and control animals. Among the animals that received 1 ng per day of IL-12, 40% did not develop any measurable tumors at all. A combination of irradiated 9L cells and IL-12 was necessary for optimal effect. Cured animals rejected future flank tumors. All animals rechallenged with intraparenchymal brain tumors survived, whereas control animals all died by Day 22. Delayed-type hypersensitivity measurements showed a specific and long-lasting response against 9L cells. CONCLUSION Continuous administration of the lymphokine IL-12, in the presence of irradiated tumor cells for antigen presentation, circumvents the need for gene transfection for generating tumor cell vaccines. We have demonstrated that the combination of IL-12 and irradiated tumor cells can lead to regression of 9L flank tumors and resistance to future flank and central nervous system tumor challenges.

Multiple Intracranial Aneurysms as Delayed Complications of an Atrial Myxoma: Case Report

OBJECTIVE AND IMPORTANCE Atrial myxomas are rare cardiac tumors that may cause neurological complications; however, delayed neurological events after total tumor resection are rare. In this report, we present a patient who developed transient cerebral ischemic attacks and was found to have multiple intracranial aneurysms 5 years after successful resection of her atrial myxoma. At the time of myxoma resection, there were no neurological symptoms; at the time of presentation with transient ischemic attacks, there was no evidence of atrial recurrence. CLINICAL PRESENTATION A 32-year-old woman presented with five episodes of right arm and face paresthesia, each lasting 15 to 20 minutes, 5 years after successful resection of her atrial myxoma. Clopidogrel bisulfate therapy was initiated, with resolution of her symptoms. Angiography revealed multiple, peripherally located, fusiform cerebral aneurysms. INTERVENTIONA left frontal craniotomy for resection and biopsy of one of the aneurysms was performed, to establish the diagnosis. Pathological analysis of the biopsied aneurysm provided evidence of direct atrial myxoma invasion and occlusion of the cerebral blood vessel. CONCLUSIONNeurological symptoms may accompany or lead to the diagnosis of atrial myxoma. Rarely, as in this case, myxomatous aneurysms may develop years after definitive treatment of the primary tumor. Patients who have undergone successful resection of a left atrial myxoma may be at risk for delayed cerebral ischemia associated with aneurysm development, and this phenomenon must be considered for patients with neurological symptoms who present even years after myxoma removal. The natural history, pathophysiological features, and treatment dilemma of these aneurysms are discussed.

Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat.

Cytokines play a major role in the regulation of the immune system. Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate dendritic cells to present tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies have shown that each of these cytokines alone can induce the regression of tumor cells. In the present study we postulated that peripheral infusion of GM-CSF along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased survival from 9L brain tumors. 9L gliosarcoma cells (106) were implanted in the brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12. Irradiated 9L cells were injected subcutaneously at various time points during treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis were used to further characterize the anti-tumor response. Treatment with GM-CSF and irradiated tumor cells led to an increase in survival rate in rats with intracranial 9L tumors when compared to untreated animals. The addition of IL-2 or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These results suggest that the combined infusion of GM-CSF and other cytokines may be effective adjuvants in treating brain tumors.

Reperfusion Injury after Focal Cerebral Ischemia: The Role Inflammation and the The rapeutic Horizon

Recent evidence indicates that thrombolysis may be an effective therapy for the treatment of acute ischemic stroke. However, the reperfusion of ischemic brain comes with a price. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion. We have reviewed the existing data indicating that an inflammatory response occurring after the reestablishment of circulation has a causative role in this reperfusion injury. The recruitment of neutrophils to the area of ischemia, the first step to inflammation, involves the coordinated appearance of multiple proteins. Intercellular adhesion molecule-1 and integrins are adhesion molecules that are up-regulated in endothelial cells and leukocytes. Tumor necrosis factor-alpha, interleukin-1, and platelet-activating factor also participate in leukocyte accumulation and subsequent activation. Therapies that interfere with the functions of these factors have shown promise in reducing reperfusion injury and infarct extension in the experimental setting. They may prove to be useful adjuncts to thrombolytic therapy in the treatment of acute ischemic stroke.

Cervical arachnoid cysts after craniocervical decompression for Chiari II malformations: Report of three cases

OBJECTIVE AND IMPORTANCE We describe three cases in which ventrally situated cervical arachnoid cysts led to spinal cord or cervicomedullary compression after repeat craniocervical decompression for Chiari II malformations. CLINICAL PRESENTATION All three patients underwent craniocervical decompression when their Chiari malformations became symptomatic. The first patient developed chronic vertiginous spells and headache and was treated with repeated craniocervical decompression procedures during several years. Seven months after undergoing her third decompression procedure, she developed severe dizzy spells, which were determined to be of brain stem origin. The second patient had a small, asymptomatic arachnoid cyst anterior to the brain stem discovered at age 6 years. After undergoing repeat craniocervical decompression for headaches 8 years after undergoing his first procedure, the patient developed severe neck pain and acute quadraparesis. A third patient underwent repeat craniocervical decompression at age 14 years for cranial nerve dysfunction. Postoperatively, he acutely developed paresis of extraocular movements and incoordination of the upper extremities. All three patients were found to have anteriorly situated arachnoid cysts compressing the brain stem and/or cervical spinal cord. INTERVENTION AND TECHNIQUE Fenestration of the arachnoid cyst or drainage with cystoperitoneal shunting adequately treated acute brain stem or cervical spinal cord compression. All three patients had achieved satisfactory relief from their acute symptoms of neural compression at their follow-up examinations. CONCLUSION An association between spinal arachnoid cysts and neural tube defects has previously been reported. However, the development of previously undetected spinal arachnoid cysts after craniocervical decompression was unexpected. We hypothesize that extensive craniocervical decompression may alter the cerebrospinal fluid pressure dynamics in such a way that the anterior subarachnoid space, previously compressed, may dilate. Occasionally, because of perimedullary arachnoiditis, the cerebrospinal fluid may become loculated and act as a mass. Direct fenestration or shunting may successfully treat this problem, and less extensive craniocervical decompression may avoid it.