Terry Lichtor

Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis.

OBJECTIVE Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient’s prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. METHODS On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. RESULTS One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. CONCLUSION A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.

Evaluating the effect of decompression surgery on cerebrospinal fluid flow and intracranial compliance in patients with chiari malformation with magnetic resonance imaging flow studies.

OBJECTIVE:To quantify the effect of decompression surgery on craniocervical junction hydrodynamics and on global intracranial compliance (ICC) in patients with Chiari I malformation by use of magnetic resonance measurements of cerebrospinal fluid and blood flow. Studying the effect of decompression surgery may improve our understanding of the pathophysiological characteristics of Chiari I malformation and aid in identifying patients who will benefit from the procedure. METHODS:Twelve patients were studied with a 1.5-T magnetic resonance imaging scanner before and after decompression surgery. Cine phase contrast magnetic resonance images were used to quantify maximum cord displacement, maximum systolic cerebrospinal fluid velocity and volumetric flow rate, and overall ICC. ICC was derived by use of a previously reported method that measures small changes in intracranial volume and pressure that occur naturally with each cardiac cycle. RESULTS:After surgery, changes were documented both in the local hydrodynamic parameters and in ICC. However, only the change in ICC, an average increase of more than 60%, was statistically significant. Increased ICC, which was associated with improved outcome, was measured in 10 of the 12 patients, no significant change was documented in 1 patient, and decreased ICC was measured in 1 patient whose symptoms persisted after surgery. CONCLUSION:An increase in the overall compliance of the intracranial compartment is the most significant and consistent change measured after decompression surgery. Changes in cord displacement, cerebrospinal fluid velocities, and flow in the craniospinal junction were less consistent and less affected by the operation. Thus, ICC may play an important role in the outcome of decompression surgery related to improving symptoms and restoring normal neurological hydrodynamics in patients with Chiari I malformations.

Application of interleukin-2-secreting syngeneic/allogeneic fibroblasts in the treatment of primary and metastatic brain tumors.

We found previously that mice injected intracerebrally (i.c.) with a mixture of malignant cells and allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) survived longer than mice in various control groups. The primary goal of this study was to determine if an established i.c. glioma (Gl261) or breast carcinoma (SB-5b) could be treated by injection of IL-2–secreting allogeneic fibroblasts into the tumor region. As an additional objective, these results were compared with the effectiveness of injecting IL-2–secreting allogeneic fibroblasts prior to the introduction of the tumor cells as a means of preventing the development of an i.c. glioma or breast carcinoma. The results demonstrated that treatment of mice bearing an established i.c. glioma or breast carcinoma with IL-2–secreting allogeneic fibroblasts resulted in a prolonged survival. Furthermore, the results demonstrate a significant delay (P<.005) in the development of glioma in the animals treated with either allogeneic nonsecreting or IL-2–secreting fibroblasts prior to introduction of tumor cells. In addition, 50% of the animals pretreated with IL-2–secreting allogeneic fibroblasts injected subsequently with Gl261 glioma cells did not develop a tumor, whereas all of the animals injected with glioma cells alone and 92% of those treated with nonsecreting fibroblasts eventually died. Evidence also exists that long-term immunity was established in the treated animals because there was a significant prolongation of survival in comparison to naïve controls (P<.01) for those animals without evidence of glioma that previously had been immunized with treatment cells when challenged again with tumor cells. In a parallel experiment, 62% of the animals pretreated with nonsecreting allogeneic fibroblasts and 75% of the animals pretreated with allogeneic IL-2–secreting fibroblasts subsequently injected with SB-5b breast carcinoma cells did not develop tumors. The results indicate that IL-2–secreting allogeneic fibroblasts can be effective in the treatment of an established brain tumor. These data also suggest that i.c. injection of allogeneic IL-2–secreting fibroblasts is effective in prevention of the development of a brain tumor when the fibroblasts are introduced into the same site where the tumor is subsequently injected.

Distribution of intraventricularly administered antiamyloid-beta peptide (Aβ) antibody in the mouse brain †

There is considerable interest in utilizing the intracerebroventricular (icv) route of administration of antibodies in the brain for various studies and for the therapy of malignancies, but very little is known about the anatomic extent of distribution of the antibody in brain after injection into the third ventricle. To explore the potential for icv administration of antiamyloid‐beta peptide (Aβ) in reducing Aβ toxicity in brain in Alzheimers disease, we first mapped the time course and path of transit of horseradish peroxidase (HRP)‐labeled antibody. The results show that, after a single injection into the mouse third venticle, the HRP‐labeled antibody is localized within the microvasculature, first that of the corticohippocampal region close to the site of injection at 3 hr. By 24 hr, the antibody is distributed throughout the hippocampus and frontoparietal cortex close to the injection site, as well as in the deep and outer cerebral cortex and cerebellar cortex remote from the injection site. The injected antibody is almost entirely removed by 4 days. Therefore, the antibody had diffused throughout all the brain by 24 hr, showing the feasibility of small quantities of anti‐Aβ antibody infused into the third ventricle to reach extracellular epitopes throughout the brain parenchyma rapidly. J. Neurosci. Res. 66:231–235, 2001. Published 2001 Wiley‐Liss, Inc.

From Cerebrospinal Fluid Pulsation to Noninvasive Intracranial Compliance and Pressure Measured by MRI Flow Studies

The pulsation of the cerebrospinal fluid (CSF) has fascinated investigators of the intracranial physiology since it was first documented by invasive CSF pressure measurements. Advances in dynamic Magnetic Resonance Imaging (MRI) now enable visualization of and quantitation the CSF flow dynamics and has contributed to our understanding of the origin of CSF pulsation and its relation to the pulsatile blood flow. This, in turn, has led to the development of a noninvasive method for measurement of intracranial compliance and pressure by MRI. This article reviews the neurophysiologic and hydrodynamic principles that are the basis of the method, it describes the implementation of the method and validation studies to date with a non-human primate animal model, computer simulations, healthy human subjects and patients. The article further reviews the application of this method to study the effect of body posture on the cerebral physiology in humans through the relationships between blood and CSF flow dynamics. Finally, recent results from the application of the method in Chiari Malformations (CM) are briefly presented as an example of a potential clinical application of this methodology. The application to CM provided, for the first time, evidence of the important role intracranial compliance plays in the pathophysiology of this poorly understood disorder. The potential diagnostic value of an MRI-based measurement of ICP for other neurological problems is discussed.

Intradural thoracic disc herniation

Study Design. Patients with intradural herniation of an intervertebral disc were identified and managed surgically. Objectives. Illustrative cases of patients with intradural herniated discs at the mid‐thoracic level are presented, the literature is reviewed, and the management of these patients is discussed. Summary of Background Data. Intradural herniation of an intervertebral disc is rare and most common at the lumbar level, but isolated cases have been reported at other levels. Cases reports of this entity have been published, but the surgical details have not been adequately addressed. Methods. In this report, two patients with calcified intradural herniated discs at the mid‐thoracic level are presented. Results. Both patients had progressive paraparesis and had calcified disc material in the mid‐thoracic canal. Both were treated successfully with a posterolateral extracavitary costotransversectomy and hemilaminotomy using intraoperative ultrasound and somatosensory‐evoked potential monitoring. Conclusions. This entity should be suspected when a calcified disc within the spinal canal is being treated. The optimal exposure is a posterolateral extracavitary costotransversectomy with a hemilaminotomy. Alternative approaches to a typical thoracic disc would be problematic in managing these patients. [Key words: intradural disc herniation, intravertebral disc herniation, spinal cord compression, thoracic disc] Spine 1994;19: 1281–1284

Genomic Expression Discovery Predicts Pathways and Opposing Functions behind Phenotypes

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19,200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192,000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems.

Cytokine Immuno-Gene Therapy for Treatment of Brain Tumors

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory involving the use of allogeneic cells genetically modified to secrete cytokines. In our studies, mice with an i.c. glioma, melanoma or breast carcinoma treated solely by intratumoral injections with allogeneic cells genetically modified to secrete interleukin-2 (IL-2) were found to survive significantly longer than mice in various control groups. The anti-tumor response was mediated predominantly by T-cell subsets (CD8+ and NK/LAK cells). The injections resulted in the killing of only the neoplastic cells; non-neoplastic cells were unaffected. Experiments involving treatment of animals with i.c. tumor using subcutaneous injections of cytokine-secreting allogeneic cells in the presence of tumor antigens demonstrated no effect in prolonging survival in spite of the development of a vigorous systemic anti-tumor immune response. Of special interest, mice injected intracerebrally with the cytokine-secreting allogeneic cells alone exhibited no neurologic defect and there were no adverse effects on survival. The injection of cytokine-secreting allogeneic cells into the microenvironment of an i.c. tumor is hypothesized to induce an anti-tumor immune response capable of prolonging survival. This pre-clinical animal data directly translates into clinical treatments for patients with a malignant i.c. tumor.

Cavernous angioma of the upper cervical spinal cord : a case report

Study Design The treatment of a patient with progressive neurologic deficit secondary to a cavernous angioma located in the dorsal midline of the upper-most cervical spinal cord was described. Objectives An illustrative case of a patient with an exophytic cavernous angioma of the cervical spinal cord near the cervicomedullary junction was presented, the literature reviewed, and the treatment of these patients discussed. Summary of Background Data Cavernous angiomas of the spinal cord were rarely seen, and only more recently appreciated with the advent of MRI scanning. These lesions were usually intramedullary in location. Intradural extramedullary cavernous angiomas, or intramedullary lesions with exophytic extramedullary extension, were particularly rare and usually occurred at the cauda equina. Methods The surgical treatment of a patient with an exophytic cavernous angioma of the upper carvical spinal cord was presented. Results This patient underwent surgery after a hemorrhage that occurred after the patient was treated conservatively for sevaral years. The entire lesion was resected with standard microsurgical technique, and the neurologic symptoms subsequently resolved. Conclusions This entity should be suspected in the differential diagnosis of patients with progressive and step-wise deterloration of spinal cord function. Although these patients can be treated conservatively, those with progressive neurologic deficits should undergo microsurgical resection to avert subsequent lesion enlargement or repeated hemorrhage.

Mathematical modeling of noise and discovery of genetic expression classes in gliomas.

The microarray array experimental system generates noisy data that require validation by other experimental methods for measuring gene expression. Here we present an algebraic modeling of noise that extracts expression measurements true to a high degree of confidence. This work profiles the expression of 19 200 cDNAs in 35 human gliomas; the experiments are designed to generate four replicate spots/gene with switching of probes. The validity of the extracted measurements is confirmed by: (1) cluster analysis that generates a molecular classification differentiating glioblastoma from lower-grade tumors and radiation necrosis; (2) By what other investigators have reported in gliomas using paradigms for assaying molecular expression other than gene profiling; and (3) Real-time RT–PCR. The results yield a genetic analysis of gliomas and identify classes of genetic expression that link novel genes to the biology of gliomas.