The AANS/CNS Section on Tumors: a summary of 40 years of advocacy to advance the care of patients with brain and spine tumors.

The AANS/CNS Section on Tumors was founded 40 years ago in 1984 to assist in the education of neurosurgeons interested in neuro-oncology, and serves as a resource for other national organizations regarding the clinical treatment of nervous system tumors. The Section on Tumors was the first national physicians' professional organization dedicated to the study and treatment of patients with brain and spine tumors. Over the past 40 years, the Section on Tumors has built solid foundations, including establishing the tumor section satellite meetings, founding the Journal of Neuro-Oncology (the first medical journal dedicated to brain and spine surgical oncology), advancing surgical neuro-oncology education and research, promoting neurosurgical involvement in neuro-oncology clinical trials, and advocating for patients with brain and spine tumors. This review provides a synopsis of the Section on Tumors' history, its challenges, and its opportunities, drawing on the section's archives and input from the 17 section chairs who led it during its first 40 years.

Identification of reversible causes of minority inequity in stroke: severity related to race and socio-economic status.

OBJECTIVES: Previous reports of a higher incidence and risk of stroke in minorities were associated primarily with race and ethnicity, yet the relationship between socio-economic status (SES) and racial disparities in stroke is less well known. We have investigated the effects of SES on the incidence of stroke type and its severity in minorities. METHODS: The clinical and demographic data on 140 patients diagnosed with a stroke in the North Lawndale neighbourhood of Chicago, one of the city's poorest communities, were collected prospectively over a 13-month period and then were retrospectively analysed. RESULTS: Overall, haemorrhagic stroke occurred in 31% of cases, differing from the previously reported haemorrhagic stroke incidence of 15%. When accounting for SES, the incidence of haemorrhagic stroke in the uninsured versus the privately or Medicaid-insured increased to 50%. Uninsured African-American patients experienced even higher rates of haemorrhagic stroke at 55%. CONCLUSIONS: Patients who are uninsured minorities may be at an increased risk for severe strokes. This increase in risk appears to be related to the increased incidence of risk factors and lack of treatment. The lack of funds, care access, and limited education in these patients may be related to their increase in risk factors. This paper identifies potentially reversible environmental and societal factors that can lead to improved outcomes in indigent minority patients.

The First Neurosurgery Boot Camp in Southeast Asia: Evaluating Impact on Knowledge and Regional Collaboration in Yangon, Myanmar.

BACKGROUND: For the first time in Southeast Asia, a Fundamentals of Neurosurgery Boot Camp was held at the University of Medicine 1 in Yangon, Myanmar, February 24-26, 2017. The aim of this course was to teach and train fundamental skills to neurosurgery residents. METHODS: The Myanmar Neurosurgical Society, Foundation for International Education in Neurosurgery, Society for Neurological Surgeons, The University of Medicine 1 in Yangon, Myanmar, and the Henry Ford Department of Neurosurgery developed a 2-day resident training course. Day 1 activities consisted of lectures by faculty, small group case discussions, and industry-supported demonstrations of surgical techniques. Day 2 activities consisted of hands-on skill stations for common neurosurgical procedures with each station supervised by attending faculty. Written evaluations were distributed before the meeting, immediately after the meeting, and 6 months after the meeting. RESULTS: Boot camp attendees included 40 residents and 24 neurosurgical faculty from Myanmar, Cambodia, Nepal, Singapore, South Korea, Thailand, and Vietnam. There were 35 evaluations completed before the boot camp, 34 completed immediately after boot camp, and 20 completed 6 months after boot camp. Knowledge of participants improved from 62.75% before boot camp to 71.50% 6 months after boot camp (P = 0.046). CONCLUSIONS: Boot camps provide fundamental didactic and technical exposure to trainees in developed and developing countries and help standardize training in basic neurosurgical competencies, while exposing local faculty to important teaching methods. This model provides a sustainable solution to educational needs and demonstrates to local neurosurgeons how they can take ownership of the educational process.

Planning and Executing the Neurosurgery Boot Camp: The Bolivia Experience.

BACKGROUND: The neurosurgical boot camp has been fully incorporated into U.S. postgraduate education. This is the first implementation of the neurosurgical boot in a developing country. To advance neurosurgical education, we developed a similar boot camp program, in collaboration with Bolivian neurosurgeons, to determine its feasibility and effectiveness in an international setting. METHODS: In a collective effort, the Bolivian Society for Neurosurgery, Foundation for International Education in Neurological Surgery, Solidarity Bridge, and University of Massachusetts organized and executed the first South American neurosurgical boot camp in Bolivia in 2015. Both U.S. and Bolivian faculty led didactic lectures followed by a practicum day using mannequins and simulators. South American residents and faculty were surveyed after the course to determine levels of enthusiasm and their perceived improvement in fund of knowledge and course effectiveness. RESULTS: Twenty-four neurosurgery residents from 5 South American countries participated. Average survey scores ranged between 4.2 and 4.9 out of 5. Five Bolivian neurosurgeons completed the survey with average scores of 4.5-5. This event allowed for Bolivian leaders in the field to unify around education, resulting in the formation of an institute to continue similar initiatives. Total cost was estimated at $40 000 USD; however, significant faculty, industry, and donor support helped offset this amount. CONCLUSION: The first South American neurosurgical boot camp had significant value and was well received in Bolivia. This humanitarian model provides a sustainable solution to education needs and should be expanded to other regions as a means for standardizing the core competencies in neurosurgery.

Variability in quantitative expression of receptors in nonfunctioning pituitary macroadenomas--an opportunity for targeted medical therapy.

OBJECTIVE: The surgical removal of a nonfunctioning pituitary macroadenoma (NFP-Mac) is often incomplete. The appropriate treatment of recurrent/residual NFP-Macs is not well established. Our objective was to detect and quantify receptors that may serve as potential targets for medical therapy for NFP-Macs with postsurgical residuals. METHODS: Several classes of pituitary receptors were analyzed by quantitative reverse transcriptase-polymerase chain reaction in 17 adult NFP-Mac patients who underwent surgery. RESULTS: The median age was 50 years, and 76% of patients were male. On magnetic resonance imaging, the mean NFP-Mac diameter was 3.3 ± 1.02 cm. Somatostatin receptor (SSTR) and dopamine receptor (DR) subtypes were found in almost all tumors. Based on previous studies, we postulated a cutoff of ≥ 2,000 receptor copies at which a response to therapy may occur. This cutoff was found in SSTR3 in 3 patients, SSTR2 in 2 patients, SSTR1 and SSTR5 in 1 patient each, DR(2_total) in 13 patients, DR(2_short) (considered the most responsive to dopamine agonists) in 10 patients, and DR(2_long), DR5, DR4, and DR1 in 7, 3, 2, and 1 patient, respectively. Tumor size, invasiveness score, immunochemistry, gender, age, clinical symptoms, and postoperative residual tumor growth did not correlate with the type or copy number of receptor mRNAs. CONCLUSION: NFP-Macs with significant postsurgical tumor residuals contain several DR and SSTR subtypes, some with high copy numbers. The receptor composition of NFP-Macs may guide future clinical research into targeted treatment strategies to reduce residual tumor volume. Such studies would determine the potential threshold of receptor levels for response to therapy for existing dopaminergic agonists and somatostatin analogs.

Beneficial actions of the anti-inflammatory dimethyl fumarate in glioblastomas.

BACKGROUND: Dimethylfumarate (DMF), a drug used in the treatment of psoriasis and multiple sclerosis, has been shown to limit the growth of melanoma cells. The ability of DMF to inhibit the Rel protein has been used to explain the antioncogenic properties of this drug. Studies analyzing the effect of DMF in gliomas are limited. Therefore, we investigated the potential antitumor effects of DMF by assessing its effects on proliferation, cell death, and differentiation in gliomas in several glioma models. METHODS: Mouse glioma Gl261, human glioblastoma A172 and human glioblastoma cells from patients were exposed to DMF at therapeutic concentrations (100 µM) and supratherapeutic concentrations (300 µM) and studies to assess proliferation, cellular lysis, and differentiation undertaken. The 5-bromo-2'-deoxyuridine (BRDU) proliferation assay and lactate dehydrogenase LDH cell lysis assay were used. Immunocytochemistry was used to assess differentiation: CD133 (stem cell marker), Nestin (progenitor marker), Sox2 (progenitor marker), ß-tubulin III (neuronal marker), glial fibrillary acidic protein (astrocytic marker), and myelin basic protein (oligodendrocytic marker). We also assessed cellular expression of nuclear factor kappa B (NF-κB) via immunocytochemistry. RESULTS: Proliferation significantly decreased and tumor cell lysis significantly increased in all tumor cell lines after exposure to DMF. The human glioblastoma cells expressed the Neuronal Stem Cell marker CD133, Progenitor Cell markers, Neuronal and Astrocytic Cell Markers in vitro. When exposed to DMF, a drastic decline in CD133 expression was observed in addition to a decrease in the expression of NF-κB. CONCLUSION: DMF appears to have a promising role in the treatment of malignant brain neoplasms. DMF reduced proliferation rate, generated cell lysis, decreased the expression of NF-κB, and restricted the growth of CD133 cells in gliomas. This suggests that DMF may be considered for further antitumor studies, and provide a new treatment modality for brain tumors.

Immunogene therapy.

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 antitumor 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 antitumor immunity was mediated by CD8+, CD4+ and NK/LAK cells. In addition an enrichment strategy has also been developed to increase the proportion of immunotherapeutic cells in the vaccine which has resulted in the development of enhanced antitumor immunity. Finally regulatory T cells (CD4+CD25+Fox p3+-positive) were found to be relatively deficient in the spleen cells from the tumor-bearing mice injected intracerebrally with the enriched vaccine. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.

Initial observations of combination barbiturate coma and decompressive craniectomy for the management of severe pediatric traumatic brain injury.

OBJECTIVE: In the pediatric population, treatment of severely injured children presenting with low Glasgow Coma Score (GCS) and fixed and dilated pupils is controversial. The combination of barbiturate coma and decompressive craniectomy as an aggressive means of controlling intracranial pressure is limited to few studies. In the present series, we report our experience with aggressive combination therapy resulting in good outcomes in pediatric patients with severe traumatic brain injury (TBI). PATIENTS AND METHODS: Six TBI patients, aged <18 years, either presented with or deteriorated to a GCS <5 with fixed and dilated pupils and CT evidence of surgical lesions with brain edema. Despite hyperventilation, anesthesia, and mannitol, intracranial pressures remained elevated and all patients underwent decompressive craniectomy and external ventricular drainage and were subsequently placed into barbiturate coma for 72 h. RESULTS: One patient died and 1 patient remained vegetative. Two patients had excellent recoveries (GOS 5/Rankin 1 or 0, no cognitive deficits) and 2 patients had good recoveries (GOS 4/Rankin 1, mild cognitive deficits). CONCLUSIONS: Combination of barbiturate coma with decompressive craniectomy and external ventricular drainage led to good outcomes in a small group of pediatric patients with severe TBI. Based on this series we recommend further investigation into aggressive combination management.

Investigation of immunosuppressive mechanisms in a mouse glioma model.

The development of an immune competent mouse model for the study of immunosuppressive mechanisms is important for improving the efficacy of brain tumor immunotherapy. In the present study we investigated regulatory T cells (Tregs), TGF-beta1 and other putative immunosuppressive cytokines using GL261 mouse glioma in C57BL mice. We explored whether tumor growth factor-beta1 (TGF-beta1) is expressed and secreted by glioma cells constitutively or in response to a T-cell mediated immunity (simulated by conditioned media from T cells (TCM) activated by anti-CD3 antibody). We also investigated TGF-beta1's role in Treg mediated immunosuppression by quantifying TGF-beta1secretion from T regulatory cells (Tregs) co-incubated with GL261 cells as compared to Tregs alone. Finally, we studied other newly identified cytokines that were secreted preferentially by glioma cells in response to CD3 activated TCM versus cytokines secreted by glioma cells in absence of T-cell activation (naïve TCM). TGF-beta1expression was studied using RT-PCR and secretion was quantified using ELISA. A 308 protein cytokine array was used to identify and quantify cytokine expression. TGF-beta1expression and secretion from glioma cells was found to be up-regulated by conditioned media from CD3-activated T cells, suggesting that this immunosuppressive cytokine is not secreted constitutively but in response to immunity. TGF-beta1 was not found to be differentially secreted by Tregs co-incubated with glioma cells as compared to Tregs alone. This data suggest that TGF-beta1immunosupppression may not be a Treg dependent mechanism in this glioma model. Finally, the cytokine array elucidated several other cytokines which were up-regulated or down-regulated by CD3-activated TCM. These results have several implications for enhancing immunotherapy treatment, including the potential benefit of TGF-beta1inhibition in conjunction with immunotherapy, as well as the illumination of several other potential cytokine targets to be explored as shown by the cytokine array.

A rare case of hemangioma of infancy presenting as intraspinal hemorrhage.

Hemangiomas of infancy (HOIs) are among the most common benign tumors of childhood and classically appear as a vascular stain or small vascular papule at birth. They are unique tumors due to their propensity to proliferate, involute, and finally regress. These lesions can be associated with visceral malformations that have been shown to affect mainly the liver and the gastrointestinal tract, but rarely the spinal cord. The authors report a rare case of a spinal HOI in a 2-month-old infant presenting with quadriplegia due to intratumoral hemorrhage. Following resection of the lesion, the child regained function. This first reported case of spinal HOI suggests another location for hemangiomatosis. Spinal HOI should be included in the differential diagnosis of acute intraspinal hemorrhage in infants.

Relationship between ventricular morphology and aqueductal cerebrospinal fluid flow in healthy and communicating hydrocephalus.

OBJECTIVES: Differences in the magnitude of cerebrospinal fluid (CSF) volumetric flow through the cerebral aqueduct between healthy and hydrocephalic patients have been previously reported. However it is not clear whether this is directly related to the pathophysiology or secondary to altered ventricular morphology and hydrodynamics. This work aims to determine the role of anatomic and hydrodynamic factors in modulating the magnitude of CSF flow through the aqueduct. MATERIALS AND METHODS: Twenty subjects (10 healthy and 10 patients with communicating hydrocephalus of different causes) were studied by MRI. Scans included T1-weighted 3D anatomic imaging and velocity-encoded cine phase-contrast scans of transcranial blood and CSF flows as well as CSF flow through the aqueduct. Anatomic MR data were used for quantitation of ventricular volumes, third ventricular width, and gray and white brain tissue volumes. Velocity-encoded imaging was used for quantitation of aqueductal and cervical CSF stroke volumes (SV), aqueductal lumen area, and systolic maximal intracranial volume change. Because data from normal and hydrocephalic patients were aggregated, a battery of statistical methods that accounted for the group effects were used. Partial correlation was used to determine which of these parameters were most significantly associated with aqueductal stroke volume (ASV). Multiple linear regression analyses were employed to identify anatomic and hydrodynamic models with the least amount of variables that are significant predictors of ASV. Finally, the association between the magnitude of ASV and the aqueductal lumen area, and its implication on the CSF flow dynamic characteristics and aqueductal pressure difference was established. RESULTS: Using partial correlations, 5 of the 6 anatomic parameters and none of the hydrodynamic parameters and brain tissue volume were found to be statistically significant. The highest partial correlations were with the total ventricular volume (r = 0.838) and third ventricle width (r = 0.811). These parameters were also found to be significant predictors of ASV in the multiple linear regression analyses with third ventricle volume and group effects as insignificant predictors (F = 28.08, P < 0.0001, R = 0.85). On the other hand, both cervical CSF SV and maximal ICVC were found to be weak predictors of ASV with group effects as the only significant variable of the hydrodynamic model (F = 4.18, P = 0.023, R = 0.33). A combined anatomic-hydrodynamic model including the predictive variables of the anatomic model and the ICVC provides the strongest coefficient of determination (R = 0.873). Pearson correlation analysis revealed a very strong relationship between ASV and the aqueductal lumen area (r = 0.947). CONCLUSIONS: Aqueductal CSF flow is strongly correlated with ventricular morphology, especially with the total ventricular volume and the third ventricle width, but not with the tested hydrodynamic parameters. In addition, ASV is linearly correlated with aqueductal lumen area, suggesting that the aqueductal CSF flow characteristics can be explained by oscillating pressure differences on the order of less than 0.01 mmHg. These findings may explain why a standalone ASV is a poor diagnostic marker and an insensitive indicator of shunt outcome in idiopathic normal pressure hydrocephalus.

PPAR-gamma Thiazolidinedione Agonists and Immunotherapy in the Treatment of Brain Tumors.

Thiazolidinediones (TZDs) are selective agonists of the peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor belonging to the superfamily of nuclear hormone receptors. Although activation of PPARgamma by TZDs has been best characterized by its ability to regulate expression of genes associated with lipid metabolism, PPARgamma agonists have other physiological effects including modulating pro- and anti-inflammatory gene expression and inducing apoptosis in several cell types including glioma cells and cell lines. Immunotherapeutic approaches to reducing brain tumors are focused on means to reduce the immunosuppressive responses of tumors which dampen the ability of cytotoxic T-lymphocytes to kill tumors. Initial studies from our lab show that combination of an immunotherapeutic strategy with TZD treatment provides synergistic benefit in animals with implanted tumors. The potential of this combined approach for treatment of brain tumors is reviewed in this report.

Enhanced immunity to intracerebral breast cancer in mice immunized with a cDNA-based vaccine enriched for immunotherapeutic cells.

Structural differences between malignant and nonmalignant cells of the same individual form the basis of clinical immunotherapeutic strategies. Previously, we reported the therapeutic properties of a vaccine prepared by transfer of a cDNA-expression library from breast cancer cells into a highly immunogenic allogeneic fibroblast cell line where genes specifying an array of breast cancer antigens were expressed. Here, we report the application of this cell-based vaccination strategy for breast cancer metastatic to the brain. As relatively few cells in the vaccine were expected to have incorporated cDNA fragments specifying breast cancer antigens (most specify normal cellular constituents), an enrichment strategy was employed to increase the proportion of immunotherapeutic cells. Enhanced immunity to the neoplasm mediated predominantly by CD4+, CD8+, and NK/LAK cells was generated in the spleens of mice injected intracerebrally into the tumor bed with cells from the enriched vaccine, which translated into prolonged survival. Regulatory T cells (CD4+CD25+Foxp3+-positive) were relatively deficient in the spleen cells from tumor-bearing mice injected intracerebrally with the enriched vaccine.

Prolonged survival of mice with established intracerebral glioma receiving combined treatment with peroxisome proliferator-activated receptor-gamma thiazolidinedione agonists and interleukin-2-secreting syngeneic/allogeneic fibroblasts.

OBJECT: In this study the authors explored the benefits of treating C57B1/6 mice with an established intracerebral glioma by combining immunotherapy with interleukin (IL)-2-secreting syngeneic/allogeneic fibroblasts administered into the tumor bed along with the chemotherapeutic agent pioglitazone, a thiazolidinedione (TZD). The TZDs are agonists of the peroxisome proliferator-activated receptor-gamma. They have been found to exert antiproliferative effects on several transformed cell lines. Data from prior studies by these authors have revealed the immunotherapeutic properties of the IL-2-secreting fibroblasts in treating intracerebral gliomas in mice. METHODS: The sensitivity of GL261 glioma cells and primary astrocytes to pioglitazone was determined in vitro by incubating the cells with increasing amounts of the drug. Viability was assessed by measuring lactate dehydrogenase release, and effects on metabolism were determined by measuring superoxide production and levels of superoxide dismutase. The GL261 cells were injected intracerebrally into C57B1/6 mice, followed by treatment with pioglitazone either orally or intracerebrally into the tumor bed. The effect of the combined therapy was determined by injecting C57B1/6 mice with an established intracerebral GL261 glioma with IL-2-secreting allogeneic fibroblasts and pioglitazone directly into the tumor bed through a unique cannula system. Pioglitazone was found to induce cell death in GL261 glioma cells grown in vitro while causing only modest damage to astrocytes. The application of pioglitazone also resulted in a significantly greater induction of cellular superoxide in glioma cells than in astrocytes, which can activate apoptotic pathways. Pioglitazone administered intracerebrally (p < 0.05) but not orally was found to prolong survival in mice harboring an intracerebral glioma. Synergistic effects of combination therapy on prolonging survival were found in mice receiving both pioglitazone and IL-2-secreting fibroblasts (p < 0.005, compared with untreated animals). Pioglitazone induces metabolic and oxidative stresses that are tolerated by astrocytes but not glioma cells, which could account for selective vulnerability and increased sensitivity to IL-2, suggesting potential for the use of this Food and Drug Administration-approved drug in the treatment of brain tumors. CONCLUSIONS: The data indicate the beneficial effects of combination therapy using pioglitazone and immunotherapy in mice harboring intracerebral glioma.

Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes.

Recent studies show that thiazolinediones (TZDs), agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), induce apoptosis in glioma and glioblastoma cells. Here we compared the effects of troglitazone (Trog), a TZD with low affinity for binding to PPARgamma but with potent metabolic effects, on survival and metabolism in GL261 glioma cells versus primary astrocytes. Trog dose-dependently induced cell death in GL261 cells (with over 90% death at 30 microM) but did not cause any toxicity in astrocytes at the same doses. Measurements of glucose and lactate levels after incubation with Trog (30 microM) indicated an overall increase of glucose consumption and lactate production in both cell types. In astrocytes the ratio of lactate produced to glucose utilized was not significantly altered by Trog, while in glioma cells this ratio was decreased by about 40%. Trog dose-dependently reduced mitochondrial membrane potential (DeltaPsi(m)) in both cell types; and the loss of DeltaPsi(m) was greater in the tumor cells (90% loss at 20 microM) than in astrocytes (70% loss at 20 microM). These results suggest that differences in metabolic responses could contribute to the selective resistance of astrocytes to cytotoxic effects of Trog. TZDs such as Trog should therefore be considered for testing in treatment of gliomas.

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.

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.

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.

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.