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We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTPmu) and that the more invasive astrocytomas, glioblastoma multiforme (GBM), downregulate full-length PTPmu expression. Loss of PTPmu expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTPmicro. Here, we identify that a cleaved extracellular fragment containing the domains required for PTPmicro-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTPmu fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTPmu peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTPmu peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTPmu extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease.

Background: The transoral approach provides the most direct exposure to extradural lesions of the ventral craniovertebral junction. Lesions that extend beyond the exposure provided by the standard transoral approach require an extended transoral modification. The exposure can be expanded in the sagittal and axial planes by adding mandibulotomy, mandibuloglossotomy, palatotomy, and transmaxillary approaches to the standard transoral approach. Extended transoral approaches increase the surgical complexity and the risk of cosmetic and functional complications. Until recently, selection of an extended approach has been arbitrary and dependent on the surgeon's familiarity with the surgical approach., Objective: We review the literature of extended transoral approaches and analyze the different modifications in terms of the technical aspects, added exposure, and complications., Methods: Classic approaches and recently published morphometric studies that objectively document the gain in exposure provided by several modifications were analyzed and tabulated to outline the limits of exposure and risk of complications associated with the various modifications., Results: Transmaxillary approaches expand the exposure to include the sphenoid sinus and upper lateral clivus. To expand the exposure more inferiorly to C4-C5, mandibulotomy or mandibuloglossotomy can be applied. Mandibuloglossotomy increases the rostral exposure as well to the upper third of the clivus. Palatotomy increases rostral exposure without requiring a facial incision or perioperative tracheostomy, but is associated with a significant risk of velopharyngeal insufficiency., Conclusion: Surgical decisions can be based on comprehensive preoperative evaluation of anatomy, pathology, and radiographic studies to maximize exposure while minimizing complications.

The cell-surface receptor protein tyrosine phosphatase mu (PTPmu) is a homophilic cell adhesion molecule expressed in CNS neurons and glia. Glioblastomas (GBMs) are the highest grade of primary brain tumors with astrocytic similarity and are characterized by marked dispersal of tumor cells. PTPmu expression was examined in human GBM, low-grade astrocytoma, and normal brain tissue. These studies revealed a striking loss of PTPmu protein expression in highly dispersive GBMs compared to less dispersive low-grade astrocytomas and normal brain. We hypothesized that PTPmu contributes to contact inhibition of glial cell migration by transducing signals in response to cell adhesion. Therefore, loss of PTPmu may contribute to the extensive dispersal of GBMs. The migration of brain tumor cells was assessed in vitro using a scratch wound assay. Parental U-87 MG cells express PTPmu and exhibited limited migration. However, short-hairpin RNA (shRNA)-mediated knockdown of PTPmu induced a morphological change and increased migration. Next, a brain slice assay replicating the three-dimensional environment of the brain was used. To assess migration, labeled U-87 MG glioma cells were injected into adult rat brain slices, and their movement was followed over time. Parental U-87 MG cells demonstrated limited dispersal in this assay. However, PTPmu shRNA induced migration and dispersal of U-87 MG cells in the brain slice. Finally, in a mouse xenograft model of intracranially injected U-87 MG cells, PTPmu shRNA induced morphological heterogeneity in these xenografts. Together, these data suggest that loss of PTPmu in human GBMs contributes to tumor cell migration and dispersal, implicating loss of PTPmu in glioma progression.

Glioblastoma multiforme (GBM), the most common malignant primary brain tumor, represents a significant disease burden. GBM tumor cells disperse extensively throughout the brain parenchyma, and the need for tumor-specific drug targets and pharmacologic agents to inhibit cell migration and dispersal is great. The receptor protein tyrosine phosphatase mu (PTPmu) is a homophilic cell adhesion molecule. The full-length form of PTPmu is down-regulated in human glioblastoma. In this article, overexpression of full-length PTPmu is shown to suppress migration and survival of glioblastoma cells. Additionally, proteolytic cleavage is shown to be the mechanism of PTPmu down-regulation in glioblastoma cells. Proteolysis of PTPmu generates a series of proteolytic fragments, including a soluble catalytic intracellular domain fragment that translocates to the nucleus. Only proteolyzed PTPmu fragments are detected in human glioblastomas. Short hairpin RNA-mediated down-regulation of PTPmu fragments decreases glioblastoma cell migration and survival. A peptide inhibitor of PTPmu function blocks fragment-induced glioblastoma cell migration, which may prove to be of therapeutic value in GBM treatment. These data suggest that loss of cell surface PTPmu by proteolysis generates catalytically active PTPmu fragments that contribute to migration and survival of glioblastoma cells.

Both pro- and antioncogenic properties have been attributed to EphA2 kinase. We report that a possible cause for this apparent paradox is diametrically opposite roles of EphA2 in regulating cell migration and invasion. While activation of EphA2 with its ligand ephrin-A1 inhibited chemotactic migration of glioma and prostate cancer cells, EphA2 overexpression promoted migration in a ligand-independent manner. Surprisingly, the latter effects required phosphorylation of EphA2 on serine 897 by Akt, and S897A mutation abolished ligand-independent promotion of cell motility. Ephrin-A1 stimulation of EphA2 negated Akt activation by growth factors and caused EphA2 dephosphorylation on S897. In human astrocytoma, S897 phosphorylation was correlated with tumor grades and Akt activation, suggesting that the Akt-EphA2 crosstalk may contribute to brain tumor progression.

Background: Brain metastasis is common in patients with malignant melanoma and represents a significant cause of morbidity and mortality. Nearly 37% of patients with malignant melanoma eventually develop brain metastasis, and autopsy reports show that 75% of those who died of this disease developed brain metastasis., Methods: We review the level I and level II evidence that guides indications for treatment with surgery, stereotactic radiosurgery, chemotherapy, and immunotherapy for patients with melanoma brain metastasis., Results: Level I evidence supports the role of whole brain radiotherapy, microsurgery, and radiosurgery alone or in combination for the treatment of patients with melanoma brain metastasis. Chemotherapy has been ineffective. Ongoing studies continue to assess the effects of immunotherapy and agents in development., Conclusions: Brain metastasis is a common and formidable challenge in patients with malignant melanoma. Although there have been no randomized controlled trials exclusively in patients with melanoma brain metastasis, care can be guided by the application of level I evidence for the treatment of brain metastasis in general and phase II studies focusing specifically on melanoma brain metastasis. Promising new agents and approaches are needed and will hopefully be identified in the near future.

The role of neural stem cells in gliomagenesis remains controversial. The aim of this study was to determine the anatomic relationship of human gliomas to the lining of the ventricular walls, known as the subventricular zone, an area replete with neural stem cells. We performed a retrospective radiographic analysis of 100 consecutive patients with gliomas and sought to determine the relationship of the lesions to the ventricular walls as seen on their MRI scans. Our results indicated that in 93% of cases the lesions contacted at least one region of the lateral ventricular wall. Contact with the ventricular wall was independent of the glioma size or mass effect. These findings were correlated to cytoarchitectural studies of the human subventricular zone. Our findings lend further support that there is an intimate association between gliomas and the subventricular zone.

Mutations in TP53 and RB1 have been shown to participate in the development of malignant brain tumors. Emerging evidence shows that mutations are involved in LGI1 in brain tumor progression. Herein we present data from the sequencing of a series of high- and low-grade gliomas with matched normal DNA. We report on 35 unique missense mutations in TP53, RB1 and LGI1 genes and use available information for each mutation in order to classify them as likely to be 'driver' or 'passenger' mutations. The identification of putatively deleterious mutations in LGI1 supports the notion that this locus may play a role in brain cancer development.

Object: This study was undertaken to evaluate the association between age at diagnosis, patterns of care, and outcome among elderly individuals with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Methods Using the Surveillance, Epidemiology and End Results database, the authors identified 1753 individuals with primary GBM and 205 individuals with primary AA (diagnosed between June 1991 and December 1999) who were 66 years and older and whose records were linked to Medicare information. To facilitate gathering of prediagnosis comorbidity and postdiagnosis treatment information, only those individuals were included who had the same Medicare coverage for 6 months before and 12 months after diagnosis. The odds of undergoing various combinations of treatments and the associations with outcome were calculated by tumor type and age and adjusted by various predictors., Results: Age was not associated with treatment differences in individuals with AA. Very elderly individuals (>or= 75 years old) with GBM were more likely to have biopsy only (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.78-3.59), surgery only (OR 1.47, 95% CI 1.15-1.87), or biopsy and radiation (OR 1.39, 95% CI 1.07-1.82) and were less likely to receive multimodal therapy. Regardless of patient age or lesion histological characteristics, survival was decreased in patients treated with biopsy only. Individuals with GBM who had surgery only or biopsy and radiation had worse outcomes than individuals treated with surgery and radiation. There were no differences in survival by lesion histological characteristics. Very elderly individuals with malignant astrocytomas were more likely to receive limited treatment (most pronounced in individuals with GBM). Survival variation correlated with treatment combinations., Conclusions: These findings suggest that in clinical neurooncology patient age is associated with not receiving effective therapies and hence worse prognosis.

Objective: This study was designed to more precisely characterize the changes in exposure achieved by modifying the standard transoral approach by sequential mandibulotomy and mandibuloglossotomy with or without palatotomy., Methods: A series of cadaveric dissections was performed and the operative distance and angle of exposure in both axial and sagittal planes was evaluated for each approach, with and without palatotomy. Intraoperative measurements were made in patients undergoing transoral approaches to assess the validity of the anatomic model. The use of this model was then assessed by a retrospective analysis of a group of 19 patients operated on through transoral approaches between 1991 and 2006., Results: The simple transoral approach exposed the region from the lower third of the clivus to the middle of the C2 vertebral body at an operative distance of 12.9 +/- 1.0 cm from the dura. The axial and sagittal angles of exposure were 39.4 +/- 3.5 degrees and 36.8 +/- 3.5 degrees, respectively. Mandibulotomy significantly increased the sagittal exposure to 59.0 +/- 1.0 degrees (P < 0.001), exposing the area from the midclivus to the C2-C3 interspace while simultaneously increasing the axial angle of exposure to 51.9 +/- 7.4 degrees (P < 0.01) and decreasing the operative distance to the dura to 10.7 +/- 1.7 cm (P < 0.05). Mandibuloglossotomy augmented sagittal exposure to 85.3 +/- 0.3 degrees (P < 0.001), revealing the region between the upper one-third of the clivus and the C4-C5 interspace (P < 0.001) while decreasing the operative distance to the dura to 8.7 +/- 0.3 cm (P < 0.05). Palatotomy significantly increased the rostral exposure achieved by each approach by 8.5 to 12.3 degrees (P < 0.01) without altering caudal or axial exposure or the operative distance., Conclusion: The cadaveric data correlated well with intraoperative measurements and the need for modifications of the transoral approach in 15 of the 16 adult patients (93.8%). Pediatric patients, patients with limited mouth opening, elevated craniovertebral junctions, and particularly deep lesions required more extensive exposure. This analysis may be useful for determining the optimal approach for patients undergoing transoral surgery.

Background: Few studies have assessed racial/ethnic differences in survival after primary glioblastoma diagnosis. We investigate these differences, incorporating information on White, Hispanics and Asians, as well as White, non-Hispanics and Blacks, among elderly individuals with a primary glioblastoma utilizing the population-based Surveillance, Epidemiology and End Results (SEER) Program-Medicare linked database., Methods: A total of 1,530 individuals diagnosed > = 66 years of age from 6/1/91 to 12/31/99 in the SEER data were linked with Medicare information from 1/1/91 to 12/31/01. All individuals had Medicare Parts A and B and were non-HMO for 6 months before and 12 months after diagnosis to gather pre-diagnosis co-morbidities and post-diagnosis first course of treatment. Survival differences by race/ethnicity and by race/ethnicity stratified by treatment type and/or median household income were examined using Kaplan-Meier and multivariable Cox proportional hazards models., Results: Significant racial/ethnic differences existed between White, non-Hispanics and Blacks in marital status, income and SEER registry region for the entire US. In analysis limited to the West region, significant racial/ethnic differences existed for income only. Overall there were no differences in survival between White, non-Hispanics and Blacks, however, in analysis limited to the West region, Asians had a lower risk of death compared to White, non-Hispanics [HR = 0.67, 95% CI (0.43, 1.03)]. Asians who had multiple treatments also had a lower risk of death compared to White, non-Hispanics [HR = 0.65, 95% CI (0.41, 1.01)]., Conclusions: Racial/ethnic differences in survival after primary glioblastoma diagnosis exist and may be partially explained by racial/ethnic differences in treatment and income.

Gliosarcoma is a rare malignant neoplasm of the central nervous system with a propensity for metastasis. There are fewer than 20 reported cases of extracranial metastases of gliosarcoma with the majority of cases reflecting a tendency for hematogenous dissemination. Here we describe the case of a 47-year-old man who developed pervasive extracranial metastases from a temporal gliosarcoma following radio- and chemotherapy for a primary glioblastoma. The patient initially presented with progressively worsening headaches, left-sided weakness and numbness associated with right temporo-parietal mass for which he underwent craniotomy with stereotactic gross-total excision. Two months postoperatively, interstitial brachytherapy and external beam radiotherapy were initiated. The patient initially declined chemotherapy. The tumor recurred twice and the patient underwent re-operation and multiple courses of chemotherapy; histopathological diagnosis remained glioblastoma multiforme. Nineteen months following initial resection the patient's clinical status deteriorated and CT scan demonstrated multiple intrathoracic, hepatic and splenic lesions. Postmortem examination revealed widespread, infiltrating gliosarcoma with intravascular gliomatosis and extensive visceral metastases. This is the first report of pervasive extracranial metastases to numerous sites, several of which have not been previously reported. The histogenesis and the potential role of therapeutic irradiation in the development of gliosarcoma are briefly reviewed.

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modal treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis remains dismal for patients diagnosed with these tumors. With the discovery of RNA interference (RNAi) for target-specific gene silencing via small interfering RNA (siRNA), a novel method to target malignant gliomas has been exposed, an endeavor that is aggressively being carried out in numerous laboratories. However, practical difficulties in tissue- or organ-specific targeting of therapeutic quantities of siRNA still preclude its applicability in a clinical setting. MicroRNA (miRNA), an endogenously expressed form of siRNA, not only presents an alternate method to induce RNAi in a given diseased tissue or organ, but also exposes a unique set of diagnostic markers that can be used to identify, and then differentiate between tumor grades. Thus, miRNA can be considered the cells' answer to siRNA. Discovered over a decade ago, miRNA is fast becoming recognized as crucial in regulating gene expression in cancers. Therein lies the therapeutic potential of miRNA, as it may now be possible to induce or inhibit RNAi in a given diseased cell population by controlling the cells' miRNA expression profile. This review outlines the potential of miRNA as a therapeutic strategy against high-grade gliomas, and also the technological hurdles that need to be addressed before this promising technique can be administered in a clinical setting.

Immunotherapy is an appealing therapeutic modality for malignant gliomas because of its potential to selectively target residual tumor cells that have invaded the normal brain. Most immunotherapeutic studies are designed to exploit the capacity of dendritic cells for inducing cell-mediated effects as well as immune memory responses for destroying residual tumor cells and preventing recurrence. Although initial clinical studies on dendritic cell-based immunotherapy resulted in very limited success, they have prompted many new studies on exploring strategies to induce a more robust antitumor immune response by using novel adjuvants for maturation and activation of dendritic cells. More studies have focused on the mechanisms of immune suppression by tumor cells and the role of regulatory T cells in tumor growth and progression. In this article, the authors review the evolution of dendritic cell-based immunotherapeutic strategies for adjuvant treatment of malignant gliomas. The authors also discuss how new knowledge on tumor-intrinsic mechanisms of tolerance induction and immunosuppression are likely to shape the future of immunotherapy for high-grade gliomas.

During the past 25 years, radiosurgery has evolved as a primary treatment modality for certain meningiomas when resection would be associated with high patient morbidity. In addition, radiosurgery is now routinely used as an adjunctive therapy for residual or recurrent meningiomas after surgical removal. In this review the authors summarize the vascular complications that occur after radiosurgery for meningiomas as well as experimental study data that give insight into the pathogenesis of this complication. These data may be useful when discussing with patients the risk/benefit ratio of choosing among conservative management, radiosurgery, and surgery.

Concurrent temozolomide (TMZ) and radiotherapy is the new standard of care for patients with newly diagnosed glioblastoma. In 51 consecutive patients treated according to this regimen, 7 patients (14%) manifested surgically confirmed early necrosis without evidence of recurrent tumor. This observation suggests that daily TMZ may represent a potent radiosensitizing regimen.

Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors. Primarily the result of altered isozyme expression, these adaptations enhance the survival and proliferation of the tumor at the expense of surrounding normal tissue. Consequently, they also expose a unique set of targets for tumor destruction while sparing healthy tissues. Despite this fact, development of drugs to directly target such altered metabolic pathways of malignant tumors has been under-investigated until recently. One such target is the ultimate step of glycolysis, which, as expected, presents itself as a metabolic aberration in most malignant tumors. Termed "aerobic glycolysis" due to abnormal conversion of pyruvic acid to lactic acid even under normoxia, the altered metabolism requires these tumors to rapidly efflux lactic acid to the microenvironment in order to prevent poisoning themselves. Thus, exposed is a prime "choke-point" to target these highly malignant, frequently chemo- and radio- resistant tumors. This review will focus on current outcomes in targeting lactate efflux in such tumors using glioma as a model, an ongoing project in our laboratory for the past half-decade, as well as supporting evidence from recent studies by others on targeting this "tail-end" of glycolysis in other tumor models.

Spinal tumors constitute 15% of all CNS neoplasms. Radiation therapy can be administered for palliation of pain and spinal cord compression. However, the amount of radiation that can be administered is often limited by the tolerance of the spinal cord, especially in cases where prior radiation therapy has been given. Stereotactic radiosurgery and radiotherapy allow the delivery of a higher dose of radiation to spinal lesions, while limiting the spinal cord dose to below the tolerance level. These are technically demanding procedures and should be performed only when proper equipment and expertise are available. Data on spinal stereotactic radiosurgery and radiotherapy have emerged in recent years. This review summarizes the clinical applications of stereotactic radiosurgery and radiotherapy for spinal tumors.

Objective: To investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death., Methods: We inhibited lactate transport in U87-MG gliomas with alpha-cyano-4-hydroxycinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays., Results: MRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death., Conclusion: Inhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radio- and chemotherapeutic regimen.

Purpose: To evaluate the diagnostic value of susceptibility-weighted imaging (SWI) for studying brain masses., Materials and Methods: SWI is a high-resolution, three-dimensional, fully velocity-compensated gradient-echo sequence that uses both magnitude and phase data. Custom postprocessing is applied to enhance the contrast in the magnitude images between tissues with different susceptibilities. This sequence was applied to 44 patients (24 males and 20 females, 15-89 years old, mean age = 50.3 years) with brain masses, pre- and/or postcontrast, and compared with conventional sequences (T1, T1 postcontrast, T2, proton density (PD), fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) at 1.5T). Correlation with pathology was obtained in 12 cases. All images were reviewed independently by three radiologists., Results: In the evaluation of tumor visibility, boundary definition, blood products, venous vasculature, architecture, and edema, SWI gave better information than the standard T1-weighted postcontrast images in 11%, 14%, 71%, 73%, 63%, and 75% of the data, respectively, in a subgroup of 38 patients. This demonstrates that the information presented by SWI is complementary in nature to that available from conventional methods. On the whole, SWI was much more sensitive for showing blood products and venous vasculature. SWI showed a useful FLAIR-like contrast and complemented the information obtained by conventional T1 postcontrast sequences regarding the internal architecture of the lesions. Good pathologic correlations were found for blood products as predicted by SWI., Conclusion: SWI should prove useful for tumor characterization because of its ability to better highlight blood products and venous vasculature and reveal new internal architecture., ((c) 2006 Wiley-Liss, Inc.)

RNA interference (RNAi) is a recently discovered, powerful molecular mechanism that can be harnessed to engineer gene-specific silencing in mammalian tissues. A mechanism, where short double-stranded RNA (dsRNA) molecules, when introduced into cells elicit specific "knock-down" of gene expression via degradation of targeted messenger RNA, has lately become the technique of choice for analysis of gene function in oncology research. Thus, RNAi is currently being extensively evaluated as a potential therapeutic strategy against malignant gliomas, since surgical, radiological, and chemotherapeutic interventions during the past few decades have done little to improve the poor prognosis rate for patients with these dreaded tumors. This review summarizes the pre-clinical studies that are currently underway to test the validity of RNAi as a potential therapeutic strategy against malignant gliomas, and discusses the potential technical hurdles that remain to be overcome before the technique can become a promising clinical therapy to combat this frequently lethal disease.

Ependymoma accounts for 5-10% of all childhood CNS tumors and less than 5% of intracranial tumors in adults. Ependymomas typically have a sharp tumor-brain parenchyma interface and this characteristic lends itself well to stereotactic radiation delivery. Data on the use of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for ependymoma in various settings have emerged over the past 10 years. SRS has been used in recurrent disease and as a boost after external beam radiation therapy. FSRT has been used in pediatric brain tumors and can potentially limit the long-term toxicities associated with radiation therapy by reducing the amount of normal brain parenchyma treated. Long-term follow-up is needed to determine the long-term efficacy and toxicities associated with these treatment modalities.

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. alpha-[(11)C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD') and the metabolic rate constant (k(3)') were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood-brain barrier, while k(3)' values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k(3)'. In contrast, oligodendrogliomas showed high VD' values but lower k(3)' as compared with normal cortex. In astrocytic tumors, low grade was associated with high k(3)' and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Background: Racial differences in survival for children with brain tumors have not been well studied, particularly in Hispanics and Asians. The objective of this study was to assess racial differences in survival of children with brain tumors, focusing on Hispanics, African Americans and Asians compared to Non-Hispanics., Methods: Subjects identified through the SEER Program were 2799 children, < or =19 years old at diagnosis, newly diagnosed between 1973 and 1996 with primary, malignant brain tumors. Chi-square tests were used to evaluate prognostic variables by race. Kaplan-Meier models and Cox proportional hazards models were used to assess racial differences in overall survival and in survival by histological type of tumor., Results: The distribution histological type of tumor varied significantly by race. Overall survival was similar for Hispanics, African Americans, Asians compared to Non-Hispanics, although trends of increased risk of death for the minority groups were noted when stratifying by histological type of tumor., Conclusions: Racial differences in survival could exist by histological type of tumor, but further work is necessary for a more complete understanding of these differences.

Objective: Dependence on glycolysis is a hallmark of malignant tumors. As a consequence, these tumors generate more lactate, which is effluxed from cells by monocarboxylate transporters (MCTs). We hypothesized that 1) MCT expression in malignant tumors may differ from normal tissue in quantity, isoform, or both; and 2) silencing MCT expression would induce intracellular acidification, resulting in decreased proliferation and/or increased cell death., Methods: We quantified expression of MCT isoforms in human glioblastoma multiforme and glioma-derived cells lines by Western blot analysis. MCTs that were abundant or specific to glioma then were targeted in the model U-87 MG glioma cell line via small interfering ribonucleic acid-mediated gene silencing and tested for inhibition of lactate efflux, intracellular pH changes, reduced proliferation, and/or induction of cell death., Results: MCT 1 and 2 were the primary isoforms expressed in human glioblastoma multiforme and glioma-derived cell lines. In contrast, MCT 3 was the predominantly expressed isoform in normal brain. Small interfering ribonucleic acid specific for MCT 1 and 2 reduced expression of these isoforms in U-87 MG cells to barely detectable levels and reduced lactate efflux by 30% individually and 85% in combination, with a concomitant decrease of intracellular pH by 0.6 units (a fourfold increase in intracellular H(+)). Prolonged silencing of both MCTs reduced viability by 75% individually and 92% in combination, as measured by both phenotypic and flow cytometric analyses., Conclusion: MCT targeting significantly reduced the viability of U-87 MG cells mediated by both apoptosis and necrosis. This indicates that the strategy may be a useful therapeutic avenue for treatment of patients with malignant glioma.

Objective: To compare the efficacy of various immunotherapeutic strategies of loading dendritic cells (DCs) with whole-glioma cell antigens and characterize the effector responses induced., Methods: DCs were either fused with major histocompatibility complex (MHC)-matched glioma cells (Fusion) or pulsed with apoptotic tumor cells (DC/Apo), total tumor ribonucleic acid (RNA) (DC/RNA), or tumor lysate (DC/Lys). These tumor-DC preparations were then assessed for their phenotype, cytokine profile, and capacity to stimulate autologous peripheral blood mononuclear cells (PBMCs) in vitro. Phenotype and tumor-specific cytolytic activities of various effector cell populations were characterized and compared., Results: The various tumor-DC preparations exhibited similar phenotype and cytokine profiles irrespective of the method of loading tumor-cell antigens. However, the fusion, DC/Apo, and DC/RNA induced superior tumor cytolytic activities in PBMCs compared with DC/Lys or DC and tumor controls. DC/Apo induced the greatest expansion of tumor-specific lymphocytes, as detected by trypan blue exclusion and thymidine incorporation assays. Flow cytometric analyses also revealed the highest relative percentages of T helper cells (CD3+CD4+), cytotoxic T lymphocytes (CTLs) (CD3+CD8+), and natural killer (NK)-like T cells (CD3+CD56+) in the DC/Apo group among all the groups studied, indicating that DC/Apo induced expansion of PBMCs bearing multiple T and NK cell markers. Interestingly, isolated NK-like T cells demonstrated significantly higher tumor cytotoxicity compared with CTLs isolated from the same groups and was also non-MHC-restricted., Conclusion: Apoptotic tumor cells may be an optimal source of whole-tumor-cell antigen for immunotherapy of gliomas. The study also demonstrates for the first time that both CTLs and NK-like T cells are expanded and stimulated by mature, tumor-pulsed DCs.

Purpose: Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer., Patients and Methods: Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs., Results: Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites., Conclusion: Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.

The failure of conventional treatment modalities for gliomas, in spite of tremendous progress in research in the past two decades, has led to increasing interest in alternative treatment strategies, including immunotherapy. It has become evident that vaccination with dendritic cells (DC), designed to express tumor antigens, is a potent strategy to elicit anti-tumor immune response in both pre-clinical and clinical settings. Various methods have been applied in order to induce DC to express tumor antigens including: pulsing with isolated tumor peptides or whole tumor lysate; fusion with tumor cells; and pulsing with apoptotic tumor cells. Herein, we review the recent progress in DC biology with regard to tumor immunity and discuss current DC-based strategies and future prospects in immunotherapy for malignant gliomas.

Object: The purpose of this study was to examine patterns of diagnosis and relative survival rates in individuals in whom a primary malignant brain tumor was diagnosed between 1973 and 1997; follow-up review of these patients continued through the end of 1999., Methods: The study population was composed of 21,493 patients with primary malignant brain tumors that were diagnosed between 1973 and 1997. Data on these patients were obtained from the population-based Surveillance, Epidemiology, and End Results Program. The study population was divided into three cohorts based on the year of diagnosis, and these groups were compared with respect to variables of interest by performing chi-square tests and relative survival analysis with the life table method. Over time, there were consistently more men, more Caucasians, more patients undergoing surgery, and more individuals 70 years and older who received the diagnosis of primary malignant brain tumor. An examination of proportions of individuals with astrocytoma, other; oligodendroglioma, other; and oligodendroglioma Grade III showed significant temporal changes with frontal and temporal lobe tumors occurring most often. The diagnosis was obtained at an earlier age in African-American than in Caucasian patients. Caucasians had higher proportions of glioblastoma multiforme (GBM), which was associated with decreased survival times, and of oligodendroglioma, other, whereas African Americans had higher proportions of astrocytoma, other; ependymoma Grade II or III; and medulloblastoma, all of which were associated with increased survival times. The relative survival case demonstrated a continuous improvement over time, although older patients, those who underwent biopsy only, and those with GBMs continue to have the poorest survival times. The relative survival rates of African Americans consistently were similar or worse than those of Caucasians when the groups were stratified by prognostic factors., Conclusions: Over time, the relative survival rate of individuals with primary malignant brain tumor has improved and differences in survival are seen by examining the race of the patients.

Gliomas are the most common primary neoplasm of the central nervous system. The failure of conventional treatment modalities to improve outcome over the last two decades has led to interest in alternative treatment modalities. Dendritic cell (DC)-based immunotherapy has utilized DC pulsed with tumor lysate or peptide to induce an antitumor immune response mediated largely by CD8 T cells. While this has been effective in preclinical studies, clinical efficacy remains unproven. Recently, hybrid cells produced by fusions of tumor and autologous DC have demonstrated remarkable efficacy for stimulating an anti-tumor immune response in both preclinical and clinical studies of extra-cranial neoplasms. The advantage of generating such hybrid cells is that the entire cellular material of the tumor is processed and presented in both endogenous and exogenous pathways. This leads to activation of both MHC class I restricted CD8 cells as well as MHC class II restricted CD4 T cells. Here, we examined in vitro T cell stimulatory capacity of autologous human DC-glioma fusion in comparison to DC loaded with apoptotic glioma. DC fused with autologous tumor or loaded with apoptotic tumor cells (DC/apo) were first used to stimulate autologous non-adherent peripheral blood mononuclear cells (PBMC), in vitro. The PBMC were then examined for phenotype (CD3, CD4, CD8) and intracellular IFN-gamma using flow cytometry. Lymphocyte proliferation and cytolytic responses were also assessed. Lymphocytes stimulated in vitro with fusion or DC/apo cells showed significantly enhanced cytotoxicity and proliferation against autologous tumor cells compared with PBMC stimulated with tumor cells or DC alone. Both strategies had similar efficacy. Tumor-cytolytic responses were enhanced by the addition of CD40 ligand (CD40L), and partially blocked by anti-MHC class I antibody. Flow cytometric analysis detected CD3+ CD8+ T cells, which also stained positive for intracellular IFN-gamma. The study suggests that DC/glioma fusion and DC/apo have comparable efficacy for stimulation of CTL with cytolytic and proliferative activity against human malignant gliomas. These findings may have implications for future studies of DC-based immunotherapy in malignant gliomas.

Background: Previous studies have shown that the overall incidence of primary malignant brain tumor is greatest in Caucasians, although survival is better in African Americans. The objective of this study was to examine racial differences in survival after diagnosis with primary malignant brain tumor in a population-based sample of patients while adjusting for prognostic variables that differ by race., Methods: The authors analyzed 21,493 patients (20,493 Caucasians and 1000 African Americans) who were diagnosed with primary malignant brain tumors from 1973 to 1997 (with follow-up through 1999) from the population-based Surveillance, Epidemiology, and End Results (SEER) Program. Chi-square tests were used to determine statistical significance of prognostic variables and race (using two-sided P values). Kaplan-Meier and Cox proportional hazards models were used to assess survival differences by race., Results: The univariable model for race showed no survival difference by race. The multivariable model demonstrated that African American patients were at a 13% increased risk of death from any cause compared with Caucasian patients. The racial difference was explained further by an interaction between race and surgery type in which there was an increased risk of death for African American patients who underwent subtotal resections or surgery not otherwise specified compared with Caucasian patients who underwent the same procedures., Conclusions: There was a significant difference in the risk of death due to any cause for Caucasian patients and African American patients who were diagnosed with first primary brain tumors., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11534)

Treatment of patients having malignancy near or within the spinal cord can be more challenging or limited than in patients with brain tumors. This is largely because of the near total lack of noneloquent neural tissue associated with the spinal cord and/or intimately associated peripheral nerves. The adverse effects of surgery, radiation therapy, and chemotherapy or multimodality therapy can be acute or chronic, insidious, and often permanent in nature. Because cancer therapies (particularly combination therapies) have become more effective with regard to tumor control, the potential impact of each modality on spine and peripheral nerve injury has become even more significant. Similarly, with increasing survival, the likelihood of observing long-term injury is likely to increase. Thus, the expression of acute and long-term spine and peripheral nerve injury is becoming a more important factor in the management of patients with spine malignancies. This review presents current management and investigations associated with these modality-related injuries.

Radiation, surgery, and chemotherapy, singly or combined, are modalities that are frequently used for the treatment of primary brain malignancies and metastases that secondarily spread to the brain. Each of the 3 modalities continues to improve with time; likewise the efficacy in management of malignant brain tumors has gradually improved. As cancer therapies become more effective with regard to disease control and survival, the potential impact of each modality on brain injury, either alone or when combined, becomes even more significant. In addition, with increasing survival, the likelihood of observing long-term injury is likely to increase. Thus, the expression of acute and long-term brain injury is becoming a more important factor in the management of patients with brain malignancies. This review presents current management and investigations associated with these modality-related injuries.

Object: In many new clinical trials of patients with malignant gliomas surgical intervention is incorporated as an integral part of tumor-directed interstitial therapies such as gene therapy, biodegradable wafer placement, and immunotherapy. Assessment of toxicity is a major component of evaluating these novel therapeutic interventions, but this must be done in light of known complication rates of craniotomy for tumor resection. Factors predicting neurological outcome would also be helpful for patient selection for surgically based clinical trials., Methods: The Glioma Outcome Project is a prospectively compiled database containing information on 788 patients with malignant gliomas that captured clinical practice patterns and patient outcomes. Patients in this series who underwent their first or second craniotomy were analyzed separately for presenting symptoms, tumor and patient characteristics, and perioperative complications. Preoperative and intraoperative factors possibly related to neurological outcome were evaluated. There were 408 patients who underwent first craniotomies (C1 group) and 91 patients who underwent second ones (C2 group). Both groups had similar patient and tumor characteristics except for their median age (55 years in the C1 group compared with 50 years in the C2 group; p = 0.006). Headache was more common at presentation in the C1 group, whereas papilledema and an altered level of consciousness were more common at presentation in patients undergoing second surgeries. Perioperative complications occurred in 24% of patients in the C1 group and 33% of patients in the C2 group (p = 0.1). Most patients were the same or better neurologically after surgery, but more patients in the C2 group (18%) displayed a worsened neurological status than those in the C1 group (8%; p = 0.007). The Karnofsky Performance Scale score and, in patients in the C2 group, tumor size were important neurological outcome predictors. Regional complications occurred at similar rates in both groups. Systemic infections occurred more frequently in the C2 group (4.4 compared with 0%; p < 0.0001) as did depression (20 compared with 11%; p = 0.02). The perioperative mortality rate was 1.5% for the C1 group and 2.2% for the C2 group (p = not significant). The median length of the hospital stay was 4 days in each group., Conclusions: Perioperative complications occur slightly more often following a second craniotomy for malignant glioma than after the first craniotomy. This should be considered when evaluating toxicities from intraoperative local therapies requiring craniotomy. Nevertheless, most patients are neurologically stable or improved after either their first or second craniotomy. This data set may serve as a benchmark for neurosurgeons and others in a discussion of operative risks in patients with malignant gliomas.

Object: Recent studies have suggested a high incidence of cognitive deficits in patients undergoing high-dose chemotherapy, which appears to be dose related. Whole-brain radiotherapy (WBRT) has previously been associated with cognitive impairment. The authors attempted to use gamma knife radiosurgery (GKS) to delay or avoid WBRT in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) in whom brain metastases were diagnosed., Methods: A retrospective review of our experience from 1996 to 2001 was performed to identify patients who underwent HDC/ABMT for advanced breast cancer and brain metastasis. They were able to conduct GKS as initial management to avoid or delay WBRT in 12 patients following HDC/ABMT. All patients were women. The median age was 48 years (range 30-58 years). The Karnofsky Performance Scale score was 70 (range 60-90). All lesions were treated with a median prescription dose of 17 Gy (range 15-18 Gy) prescribed to the 50% isodose. Median survival was 11.5 months. Five patients (42%) had no evidence of central nervous system disease progression and no further treatment was given. Four patients were retreated with GKS and three of them eventually received WBRT as well. Two patients were treated with WBRT as the primary salvage therapy. The median time to retreatment with WBRT was 8 months after the initial GKS., Conclusions: Gamma knife radiosurgery can be effectively used for the initial management of brain metastases to avoid or delay WBRT in patients treated previously with HDC, with acceptable survival and preserved cognitive function.

Background: SAGE (serial analysis of gene expression) is a recently developed technique for systematic analysis of eukaryotic transcriptomes. The most critical step in the SAGE method is large scale amplification of ditags which are then are concatemerized for the construction of representative SAGE libraries. Here, we report a protocol for purifying these ditags via an 'in situ' PAGE purification method. This generates ditags free of linker contaminations, making library construction simpler and more efficient., Results: Ditags used to generate SAGE libraries were demarcated 'in situ' on preparative polyacrylamide gels using XC and BPB dyes, which precisely straddle the ditag band when a 16% PAGE gel (19:1 acrylamide:bis, 5% cross linker) is used to resolve the DNA bands. Here, the ditag DNA was directly excised from gel without visualization via EtBr or fluorescent dye staining, resulting in highly purified ditag DNA free of contaminating linkers. These ditags could be rapidly self ligated even at 4 degrees C to generate concatemers in a controlled manner, which in turn enabled us to generate highly efficient SAGE libraries. This reduced the labor and time necessary, as well as the cost., Conclusions: This approach greatly simplified the ditag purification procedure for constructing SAGE libraries. Since the traditional post-run staining with EtBr or fluorescent dyes routinely results in cross contamination of a DNA band of interest by other DNA in the gel, the dry gel DNA excision method described here may also be amenable to other molecular biology techniques in which DNA purity is critically important.

Background: Patient participation in well-designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi-institutional registry of patients with malignant glioma., Methods: Data were examined from 708 patients who underwent first or second surgery for a malignant glioma who were enrolled in the Glioma Outcomes Project, which is a prospective observational data base that captures clinical practice patterns. The frequency of clinical trial participation and the variables that may have been associated with trial participation were evaluated. These variables included age, gender, race, household income, educational level, first versus second craniotomy, histology, and whether the patient was treated at an academic institution., Results: One hundred fifty-one of 708 patients (21.3%) participated in a clinical trial, which was higher than the participation reported typically for patients with other types of primary malignancies. In univariate analysis, race, histology, and first craniotomy were significant between the two groups, with Caucasian patients and patients with glioblastoma histology showing higher participation rates. In a multivariate logistic regression model, significant predictors included young age and glioblastoma multiforme histology., Conclusions: The authors present information on factors that may influence clinical trial participation among patients with malignant glioma and compare their data with information described previously on patients with other types of malignant disease. The percent of participation among the patients in the current study was greater than among patients with other primary tumor sites. Strategies should be implemented to improve recruitment to neuro-oncology trials, especially in elderly and minority populations.