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Terry Lichtor

Publications and source records attributed to Terry Lichtor.

17 recordsLinked to original sources
PubMed2006

Early experience from the application of a noninvasive magnetic resonance imaging-based measurement of intracranial pressure in hydrocephalus.

OBJECTIVE: The decision for surgical intervention in hydrocephalic patients presenting with symptoms suggesting raised intracranial pressure (ICP) is challenging because radiographic ventricular size often lacks the specificity to predict abnormal ICP. An early assessment of the potential clinical usefulness of a noninvasive magnetic resonance imaging-based measurement of ICP (MR-ICP) in symptomatic hydrocephalic patients is reported. METHODS: Twenty-seven symptomatic hydrocephalic patients (18 with shunts and 9 without shunts) underwent brain magnetic resonance imaging-based studies that included measurements of cerebrospinal fluid and blood flows to and from the cranial vault, from which measurements of ICP were derived using a previously described algorithm. The predictive values of the MR-ICP measurement were determined on the basis of whether or not the patient underwent a surgical treatment of a shunt placement or shunt revision within a 3-month period after the magnetic resonance imaging-based study. RESULTS: MR-ICP values in these patients spanned a much wider range than in healthy control subjects. However, the majority of the patients (20 out of 26 patients) had MR-ICP values within the normal range. The short-term follow-up of patients who had normal MR-ICP measurement reveals that only one of the 20 patients required surgery. Consequently, the MR-ICP measurement has a strong negative predictive value (95% for all patients and 100% for patients without a shunt). CONCLUSION: A finding of a normal MR-ICP value in hydrocephalic patients presenting with symptoms suggestive of abnormal ICP is a strong predictor for resolution of symptoms or stable outcome without surgical intervention.

Adult↗
PubMed2006

Antigenic Differences Between Normal and Malignant Cells as a Basis for Treatment of Intracerebral Neoplasms Using a DNA-Based Vaccine.

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient's neoplasm. Poorly immunogenic tumor antigens, characteristic of malignant cells, can become strongly antigenic if they are expressed by highly immunogenic cells. A DNA-based vaccine was prepared by transfer of genomic DNA from a breast cancer that arose spontaneously in a C3H/He mouse into a highly immunogenic mouse fibroblast cell line, where genes specifying tumor-antigens were expressed. The fibroblasts were modified in advance of DNA-transfer to secrete an immune augmenting cytokine and to express allogeneic MHC class I-determinants. In an animal model of breast cancer metastatic to the brain, introduction of the vaccine directly into the tumor bed stimulated a systemic cellular anti-tumor immune response measured by two independent in vitro assays and prolonged the lives of the tumor-bearing mice. Furthermore, using antibodies against the various T-cell subsets, it was determined that the systemic cellular anti-tumor immunity was mediated by CD8(+), CD4(+) and NK/LAK cells. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.

Journal Article↗
PubMed2006

Immunogene therapy as a treatment for malignant brain tumors in young mice.

OBJECT: New and innovative forms of effective treatments for malignant brain tumors in children are urgently needed. The authors have previously shown that intracerebral injection into the tumor bed of allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) results in prolongation of survival and an antitumor immunocytotoxic response in adult mice that harbor intracerebral gliomas. The first goal of this study was to determine if malignant gliomas (GI261) could be treated in mice (C57BL/6) in the pediatric age group (weanlings [2-3 weeks old] and adolescents [3-4 weeks old]). The second goal was to determine the effectiveness of using IL-2-secreting allogeneic fibroblasts as a protective vaccine to prevent the development of intracerebral gliomas in these young mice. METHODS: Using GI261 glioma cells derived from a spontaneously arising glioma in C57BL/6 immunocompetent mice, animals 2 to 4 weeks of age received an intracranial injection of 5 x 10(4) tumor cells into the right frontal lobe through a bur hole. The treatment vaccine consisted of 10(6) allogeneic IL-2-secreting fibroblasts, given at the time of tumor injection (treatment experiments) or at three weekly intervals prior to tumor injection (protection experiments). Control groups received either medium or nonsecreting allogeneic fibroblasts. The effects of this treatment on survival and long-term immunity were investigated. The results demonstrate a significant prolongation of survival in animals harboring intracerebral gliomas that were treated with intracerebral injections of IL-2-secreting allogeneic fibroblasts (p < 0.05). Morbidity and mortality rates did not increase as a result of intracerebral immunization. Compared with naive controls, long-term survivors demonstrated immune memory, as evidenced by prolongation of survival when they were rechallenged with tumor cells. The results of the protection experiment demonstrate a significant delay (p < 0.005) in the development of gliomas in the animals pretreated with either allogeneic nonsecreting or allogeneic IL-2-secreting fibroblasts prior to the introduction of tumor cells. In addition, in 78% of these animals a tumor did not develop when rechallenged. CONCLUSIONS: These results demonstrate the efficacy and safety of using intratumoral injection of IL-2-secreting allogeneic fibroblasts as a treatment or protective vaccine in young mice. It is hoped that these preclinical studies will lead to a clinical trial for the treatment of malignant brain tumors in children.

Age Factors↗
PubMed2006

Advantages of a unique DNA-based vaccine in comparison to paclitaxel in treatment of an established intracerebral breast cancer in mice.

In this study we compared the benefits of treating C3H/He mice with an established intracerebral breast carcinoma by immunization with a unique DNA-based vaccine to chemotherapy with paclitaxel. Prior studies revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. Here, C3H/He mice with an established intracerebral breast cancer were treated either by injection into the tumor bed through a unique cannula system with the cell based vaccine or with paclitaxel administered intraperitoneally. Both treatment strategies were effective in prolonging survival and stimulating a systemic anti-tumor immune response (p< 0.025). However, unlike mice treated with the vaccine, the animals that received paclitaxel alone displayed significant toxic side effects. No additional therapeutic advantage was detected when these two treatment strategies were combined. The vaccine tended to provide a somewhat better therapeutic and clearly better systemic immunologic effect based on two independent spleen cell assays in comparison to paclitaxel.

Journal Article↗
PubMed2005

Intratumoral injection of IL-secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells prolongs the survival of mice with intracerebral breast cancer.

Prior studies have revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. The rationale for this type of vaccine is that genes specifying an array of weakly immunogenic, unique tumor antigens associated with the malignant cells will be expressed in a highly immunogenic form by the transfected cells. Here, the immunotherapeutic properties of a vaccine prepared by transfection of mouse fibroblasts with DNA from a breast carcinoma (SB-5b) that arose spontaneously in a C3H/He mouse (H-2Kb) were tested in mice with intracerebral breast cancer. To augment their nonspecific immunogenic properties, before DNA transfer, the fibroblasts (of C3H/He mouse origin) were modified to express allogeneic MHC class I H-2Kb-determinants and to secrete IL-2, IL-18 or GM-CSF. The results indicate that C3H/He mice injected intracerebrally (i.c.) with the breast cancer cells and syngeneic/allogeneic-transfected fibroblasts modified to secrete IL-2 survived significantly longer (P < .005) than mice in various control groups, including mice injected i.c. with the breast cancer cells alone. The immunotherapeutic properties of transfected fibroblasts modified to secrete IL-18 or GM-CSF were less efficacious. The results of two independent in vitro cytotoxicity assays indicate that systemic cellular antitumor immunity was generated in mice injected i.c. with the transfected cells, and the immunity was mediated predominantly by CD8+ T cells.

Animals↗
PubMed2005

Magnetic resonance imaging-based measurements of cerebrospinal fluid and blood flow as indicators of intracranial compliance in patients with Chiari malformation.

OBJECT: The diagnosis of Chiari malformation (CM) is based on the degree of tonsilar herniation, although this finding does not necessarily correlate with the presence or absence of symptoms. Intracranial compliance (ICC) and local craniocervical hydrodynamic parameters derived using magnetic resonance (MR) imaging flow measurements were assessed in symptomatic patients and control volunteers to evaluate the role of these factors in the associated pathophysiology. METHODS: Seventeen healthy volunteers and 34 symptomatic patients with CM were studied using a 1.5-tesla MR imager. Cine phase-contrast images of blood and cerebrospinal fluid (CSF) flow to and from the cranium were used to quantify local hydrodynamic parameters (for example, cord displacement and systolic CSF velocity and flow rates) and ICC. The ICC was derived using a previously described method that measures the small, natural changes in intracranial volume and pressure with each cardiac cycle. Differences in the average cord displacement and systolic CSF velocity and flow, comparing healthy volunteers and patients with CM were not statistically significant. Note, however, that a statistically significant lower ICC (20%) was observed in patients compared with controls. CONCLUSIONS: Previous investigators have focused on CSF flow velocities and cord displacement to explain the pathogenesis of CM. Analysis of results have indicated that ICC is more sensitive than local hydrodynamic parameters to changes in the craniospinal biomechanical properties in symptomatic patients. The authors concluded that decreased ICC better explains CM pathophysiology than local hydrodynamic parameters such as cervical CSF velocities and cord displacement. Low ICC also better explains the onset of symptoms in adulthood given the decline in ICC with aging.

Adolescent↗
PubMed2004

Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-Abeta antibody into the third ventricle of TgCRND8 mice.

We have previously shown that anti beta-amyloid (Abeta) antibody injected into the third ventricle of mice is distributed throughout the brain within 24 hr and is completely washed out of brain within 36 hr after injection and that, in Tg2576 animals, a single injection of antibody reduces cerebral Abeta and restores presynaptic deficits 1 month after injection without producing hemorrhage or inflammation at an early plaque stage. Here we report the effects of a single ICV injection of anti-Abeta antibody on cerebral levels of immunoreactive Abeta and of microglial activation measured by immunoreactive interleukin-1beta (IL-1beta) at 1, 4, and 8 weeks after injections in TgCRND8 mice at two ages, 2 months (sparse plaques) and 8 months (abundant plaques). The data show that parenchymal amyloid accumulates before cerebral microvascular amyloid and that a single ICV injection reduces only parenchymal amyloid by about 70%, without affecting vascular amyloid, and reduces microglial activation by 46-60% at 1 week after injection. The reappearance of plaques after antibody injection takes 4-8 weeks, whereas plaque-associated focal microglial activation begins increasing between 1 and 4 weeks, suggesting that accumulation of nonfibrillar oligomeric Abeta may account for the earlier onset of microglial activation. No perivascular hemorrhage or inflammation was observed. These results suggest that periodic intraventricular administration of anti-Abeta is a potentially useful method for rapid reduction of both preexisting amyloid load and associated inflammation, providing a window of 4 weeks' duration for possible pharmacological cotreatment(s) to prevent de novo Abeta formation. This ICV method of passive immunization may be safer than active immunization, which has been known to produce encephalitis, or systemic passive immunization, which exposes amyloid-laden cerebral microvasculature to high levels of antibody in the blood and the potential of perivascular hemorrhages.

Age Factors↗
PubMed2004

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.

Adult↗
PubMed2003

Aging potentiates Abeta-induced depletion of SNAP-25 in mouse hippocampus.

UNLABELLED: Previously we showed that in Tg2576 mouse hippocampus, synaptosomal-associated protein 25 (SNAP-25) immunoreactivity (IR) is greatly reduced and intracerebroventricular injection of anti-Abeta reverses this depletion. 3- and 24-month-old wild-type mice received juxta-amygdala injection of Abeta42 and hippocampal sections were analyzed for glial fibrillary acidic protein (GFAP)- and SNAP-25-IR at intervals after injections. In young mice, SNAP-IR declined >95% at 1 week in DG-Smi and remained low until 8 weeks, while decreasing in SR, SL and hilum by 8-27% at 1 week and returning to baseline by 2 weeks. There was no change in DG-SMm. In old mice, DG-Smi was specifically depleted in SNAP-IR by >95% even before injection. At 2 weeks, SNAP-IR had declined in all layers by 30-39% of baseline values and by 8 weeks had returned to control values, except the DG-SMm which showed only a 10% reduction at 2 weeks. Baseline GFAP-IR was 10-fold higher in old than in young mice in the fimbria/IC but not appreciably changed in hippocampus. In young mice, the injections of Abeta caused 20-fold increases in GFAP-IR in the fimbria/IC and 2-fold increases in the hippocampal neuropil at 1 week, all of which values returned to baseline by 8 weeks. In old mice, Abeta injections caused relatively much larger increases in GFAP-IR in the hippocampal neuropil than in the fimbria/IC and the GFAP-IR remained greatly increased at 8 weeks. CONCLUSIONS: the Abeta effect on presynaptic SNAP-25 depletion is increased with age. DG-SMi shows the most severe changes and therefore may represent the most critical site in hippocampus for Abeta neurotoxicity.

Aging↗
PubMed2003

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 19200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192000; 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.

Algorithms↗
PubMed2003

Noninvasive intracranial compliance and pressure based on dynamic magnetic resonance imaging of blood flow and cerebrospinal fluid flow: review of principles, implementation, and other noninvasive approaches.

Current techniques for intracranial pressure (ICP) measurement are invasive. All require a surgical procedure for placement of a pressure probe in the central nervous system and, as such, are associated with risk and morbidity. These considerations have driven investigators to develop noninvasive techniques for pressure estimation. A recently developed magnetic resonance (MR) imaging-based method to measure intracranial compliance and pressure is described. In this method the small changes in intracranial volume and ICP that occur naturally with each cardiac cycle are considered. The pressure change during the cardiac cycle is derived from the cerebrospinal fluid (CSF) pressure gradient waveform calculated from the CSF velocities. The intracranial volume change is determined by the instantaneous differences between arterial blood inflow, venous blood outflow, and CSF volumetric flow rates into and out of the cranial vault. Elastance (the inverse of compliance) is derived from the ratio of the measured pressure and volume changes. A mean ICP value is then derived based on a linear relationship that exists between intracranial elastance and ICP. The method has been validated in baboons, flow phantoms, and computer simulations. To date studies in humans demonstrate good measurement reproducibility and reliability. Several other noninvasive approaches for ICP measurement, mostly nonimaging based, are also reviewed. Magnetic resonance imaging-based ICP measurement may prove valuable in the diagnosis and serial evaluation of patients with a variety of disorders associated with alterations in ICP.

Cerebrospinal Fluid↗
PubMed2003

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.

Animals↗
PubMed2002

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.

Brain Neoplasms↗
PubMed2002

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.

Animals↗
PubMedDate not supplied

Treatment with allogeneic interleukin-2 secreting fibroblasts protects against the development of malignant brain tumors.

We have reported that mice with an intracerebral (i.c.) malignant glioma or breast cancer treated with i.c. injection of allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) survived longer than mice in various control groups. The goal of the present study was to determine the effectiveness of utilizing IL-2 secreting allogeneic fibroblasts as a protective treatment to prevent the development of an i.c. glioma or breast carcinoma. Using an intracranial microcannula system that we developed, the animals received weekly injections of the cellular vaccine prior to the introduction of tumor cells via the cannula. The results demonstrate a significant delay (P < 0.005) in the development of glioma in the animals pre-treated with either allogeneic non-secreting or IL-2-secreting fibroblasts prior to introduction of tumor cells. In addition, 50% of the animals pre-treated with IL-2 secreting allogeneic fibroblasts injected subsequently with G1261 glioma cells did not develop a tumor, while all of the animals injected with glioma cells alone and 92% of those treated with non-secreting fibroblasts eventually died. The long-term survivors from the pre-treatment group were subsequently re-challenged with tumor and compared to naive controls. There was evidence that long-term immunity was established in the pre-treated animals, since there was a significant prolongation of survival (P < 0.01). In similar experiments using breast cancer cells, 62% of the animals pre-treated with non-secreting allogeneic fibroblasts and 75% of the animals pre-treated with allogeneic IL-2 secreting fibroblasts subsequently injected with SB-5b breast carcinoma cells did not develop tumors and had a significant prolongation of survival. These data suggest that i.c. injection of allogeneic IL-2 secreting fibroblasts are effective as a protective treatment in the prevention of the development of a brain tumor when the fibroblasts are introduced into the same site where the tumor is subsequently injected.

Adenocarcinoma↗