Malignant Glial Tumors Research Articles

Anti-angiogenic therapy in glioma

There has been great interest in developing anti-angiogenic therapies for the treatment of patients with high-grade gliomas. In fact, some anti-angiogenic agents are now routinely used for the treatment of patients with glioblastoma. However, the use of these agents is largely based on trials which indicate an initial radiographic response, while it remains unclear whether any anti-angiogenic therapies tested to date have improved the overall survival of patients with malignant glial tumours. This manuscript reviews the landscape of anti-angiogenic therapy in glioma, with a focus on GBM, and demonstrates that further innovation is needed to determine the true utility of anti-angiogenic therapy.

CyberKnife Stereotactic Radiosurgery for Intracranial Neoplasms, with a Focus on Malignant Tumors

Stereotactic radiosurgery is well established as a means of managing intracranial tumors, both as an adjuvant to surgical resection, and also as a primary treatment modality for those tumors that are considered unresectable by conventional surgical means. Of particular concern during radiosurgery of brain tumors is the risk of radiation damage to otherwise healthy tissue, potentially resulting in cognitive impairment. The conformality and precise targeting of the CyberKnife radiation beam enables this risk to be minimized to a greater extent than hitherto possible, which may allow treatment to be completed in a small number of fractions, thereby improving the quality of life for patients. The CyberKnife has proven particularly valuable in the treatment of metastases, which represent the great majority of brain tumors, though its role in the management of malignant glial tumors remains a subject of controversy. This article reviews the published studies on the efficacy of CyberKnife radiosurgery for brain tumors of both glial and metastatic origin, and considers its future role in the management of such lesions.

Molecular Pathogenesis of Malignant Glial Tumors

Malignant glial tumors are the most aggressive and difficult to treat neoplasms arising in the brain. More than 22,000 people in the United States are diagnosed with a malignant glioma annually, and most will die within the first two years from diagnosis. Traditionally, gliomas have been categorized based solely on tumor histological features. However, expression studies have found that molecular signatures can be used to categorize these tumors into subclasses that more effectively predict patient outcome. The heterogeneity between tumors as well as within individual tumors makes understanding the molecular aspects of tumorigenesis extremely important. Several genetically engineered mouse models (GEMMs) of glioma have been developed that recapitulate the molecular alterations observed in the human disease. GEMMs of glioma have allowed researchers to more closely study the role of cancer stem cells (CSC) in gliomagenesis as well as the relevance of signaling within the CSC microenvironment. Knowledge of the underlying molecular signatures of malignant glial tumors coupled with the existence of a variety of human disease-relevant GEMMs of this tumor type provide researchers and clinicians with valuable resources for the discovery of new drug targets.

Isolated extracranial recurrence of anaplastic ependymoma

Anaplastic ependymoma is a malignant glial tumor thought to arise from radial glial cells of the ventricular zone. Because ependymoma is frequently encountered within ventricular spaces, they are prone to leptomeningeal dissemination. Metastatic extracranial ependymoma has been reported, but in the context of progressive intracranial disease. We report on a boy who developed isolated extracranial recurrence of his anaplastic ependymoma, initially at the scalp and later metastases to cervical lymph nodes. The location of tumor recurrence proximate to the surgical site suggested surgical seeding. This case demonstrates an unusual site of recurrence of anaplastic ependymoma and highlights a previously underappreciated surgical complication.

Nonanastomotic Indirect Bypass Surgery In The Surgical Treatment Of Malignant Glial Tumors

Nonanastomotic Indirect Bypass Surgery In The Surgical Treatment Of Malignant Glial Tumors

Transformation of intracranial anaplastic astrocytoma associated with neurofibromatosis type I into gliosarcoma: Case report

Gliosarcoma is an uncommon malignant brain tumor composed of distinct sarcomatous and malignant glial cell elements. These tumors are defined as a variant of glioblastoma, and it can be developed by progression of the malignant glial cell tumors or primary tumors. We report a rare case with gliosarcomatous recurrence of anaplastic astrocytoma with neurofibromatosis type 1 (NF-1) followed by chemoradiation therapy. A 26-year-old male patient was presented with headache. Five years before admission, he had been diagnosed with NF-1. Magnetic resonance imaging (MRI) showed a well-demarcated, enhanced lesion in the right frontal lobe and multiple enhanced lesions in the scalp, lower cervical, thoracic, and upper lumbar regions. He underwent an osteoplastic craniotomy with total tumor resection. Histopathology of the tumor showed findings corresponding with anaplastic astrocytoma. He was followed by radiotherapy and chemotherapy postoperatively. A month later, his spinal lesion was also resected and confirmed pathologically as plexiform neurofibroma. The subsequent follow-up period of 27 months was uneventful until he developed a generalized tonic-clonic seizure. MRI showed tumor recurrence in the original site of the tumor. Re-exploration was carried out. Pathological examination displayed a biphasic pattern of the glial and sarcomatous components suggesting gliosarcoma.

Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival

Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival

Serum proteomics of glioma: methods and applications

The prognosis of patients with glioblastoma, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies in order to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. Serum biomarkers have the potential to revolutionize the process of cancer diagnosis, grading, prognostication and treatment response monitoring. Besides having the advantage that serum can be obtained through a less invasive procedure, it contains molecules at an extraordinary dynamic range of ten orders of magnitude in terms of their concentrations. While the conventional methods, such as 2DE, have been in use for many years, the ability to identify the proteins through mass spectrometry techniques such as MALDI-TOF led to an explosion of interest in proteomics. Relatively new high-throughput proteomics methods such as SELDI-TOF and protein microarrays are expected to hasten the process of serum biomarker discovery. This review will highlight the recent advances in the proteomics platform in discovering serum biomarkers and the current status of glioma serum markers. We aim to provide the principles and potential of the latest proteomic approaches and their applications in the biomarker discovery process. Besides providing a comprehensive list of available serum biomarkers of glioma, we will also propose how these markers will revolutionize the clinical management of glioma patients.

Extracranial Relapse of an Anaplastic Oligodendroglioma in an Adolescent: Case Report and Review of the Literature

Oligodendroglioma is an uncommon childhood tumor and is more chemosensitive than other malignant glial neoplasms. Treatment involves gross total resection, and if anaplastic, radiation and chemotherapy. Distinct genetic alterations are associated with improved prognosis. We report a child with a low-grade oligodendroglioma that recurred as a high-grade oligodendroglioma and ultimately as extraneural systemic relapse. It was initially responsive to temozolomide, cyclophosphamide, etoposide, and carboplatin, perhaps predicted by combined loss of heterozygosity at 1p and 19q. This chemotherapy may be promising in treating malignant oligodendroglioma. However, he succumbed to progressive systemic disease. Positron emission spectroscopy scan was useful in sequentially assessing his disease.

Gliomas and venous thromboembolism: how common?

Physicians who routinely care for patients with malignant glial tumors know that a venous thromboembolism (VTE) and its dire consequence of pulmonary embolism, can be a concern. Multiple studies over the last two decades have addressed this risk and the potential treatment and prophylaxis of VTE. The combination of a major neurosurgical procedure, postoperative immobility, use of prothrombotic steroid agents, pharmacological-based dehydration, and the prothrombotic nature of gliomas has been widely argued as a possible etiological factor for the high incidence of this morbid condition. A number of studies and reviews have addressed this issue, albeit with relatively small patient numbers (in the 100s) and single-site experience. In this issue of the Journal of Neurosurgery, Semrad and colleagues present a 6-year comprehensive epidemiological study of the incidence of VTE in patients with malignant glioma. This is the largest published study to date, comprising 9489 patients with a diagnosis of glioma identified retrospectively by the authors from the cancer registry of the state of California for 1993 through 1995 and 1997 through 1999. Using the California Patient Discharge Data Set, they were then able to link medical discharge diagnoses (such as VTE and pulmonary embolism) to each patient. The authors found that the 2-year cumulative incidence for VTE was 7.5% (715 cases) and that 391 VTEs occurred within 61 days of major neurosurgery. This relatively high incidence becomes even more striking when compared with the 2-year incidence of patients with other types of cancer. In fact, the cancer with the second highest association with VTE after glioma turns out to be pancreatic, with a reported 2-year incidence of 5.7%. What more does the study from Semrad and colleagues teach? Not surprisingly, the risk for VTE was associated with older age (. 45 years), male sex, the presence of one

Expression of WT1 Protein and Correlation With Cellular Proliferation in Glial Tumors

The expression of Wilms' tumor gene WT1 protein was investigated immunohistochemically in 73 glial tumors, including 60 astrocytic tumors, eight oligodendroglial tumors, and five ependymal tumors. WT1 protein was detected in 70 of the 73 glial tumors (95.9%) examined. Almost all glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, and anaplastic oligodendrogliomas expressed high levels of WT1 protein. A significant (p < 0.001) correlation was found between WT1 protein expression and MIB-1 staining index. Histological examination found that WT1 protein was strongly expressed in the anaplastic portions and areas with perivascular proliferation and high cellularity, implying that WT1 gene might be important in glial tumor cell proliferation. WT1 gene is overexpressed in various types of solid tumors and WT1 protein is a target antigen for cancer immunotherapy. This study indicates that many malignant glial tumors are good candidates for cancer immunotherapy targeting WT1 protein and that WT1 protein expression could be used as a proliferation marker in glial tumors.

Recent advances in the medical therapy of high-grade gliomas

Malignant glial neoplasms, including glioblastoma, are amongst the most devastating and intractable of solid tumors. Until recently the standard of care for newly diagnosed glioblastoma was surgical resection to the extent feasible followed by conventional fractionated radiotherapy. When administered for disease progression, chemotherapy had modest benefit and its use in the adjuvant setting was controversial. Temozolomide, an oral alkylating chemotherapeutic agent, has now been demonstrated to increase survival time in patients with newly diagnosed glioblastoma when used concurrently with radiotherapy and as adjuvant or maintenance treatment for six cycles thereafter. Correlative molecular studies suggested that the benefit of temozolomide is largely restricted to patients whose tumor has silenced the gene for methylguanine methyltransferase, a repair enzyme implicated in resistance to alkylator chemotherapy. Use of temozolomide chemotherapy upfront in the management of glioblastoma is now considered the standard of care. This significant advance has also stimulated development of therapeutic strategies that incorporate temozolomide, and other agents, in the initial management of most high-grade gliomas. Furthermore, our increased understanding of the molecular derangements that underlie gliomagenesis has identified a number of putative molecular targets against which novel therapeutics have been tested with encouraging preliminary results. Finally, the challenges presented by the blood–brain barrier to adequate drug delivery have stimulated the development of unique locoregional delivery techniques that are currently undergoing clinical evaluation. This review summarizes these recent advances, and speculates on how the field is likely to evolve in the near future.

Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P

Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Activity of lysosomal exoglycosidases in human gliomas

There is a lot of data suggesting that modifications of cell glycoconjugates may be important in progression of cancer. In the present work we studied activities of lysosomal exoglycosidases: beta-hexosaminidase and its isoenzymes A and B, beta-galactosidase and alpha-mannosidase, in human gliomas. Enzyme activity was determined spectrophotometrically based on the release of p-nitrophenol from p-nitrophenyl-derivative of appropriate sugars. The activities of the exoglycosidases tested were significantly higher in malignant glial tumors than in control tissue (normal brain tissue) and non-glial tumors. The highest activities of exoglycosidases were observed in high-grade gliomas, and a positive correlation of enzyme activities and degree of malignancy was noted. Our results suggest that lysosomal exoglycosidases may participate in the progression and dynamical development of glial tumors.

Identification of oligodendroglioma specific chromosomal copy number changes in the glioblastoma MI-4 cell line by array-CGH and FISH analyses

Glioblastomas, the most frequent and malignant glial tumors, are known to be phenotypically heterogeneous. A low fraction of glioblastomas is associated with specific chromosomal losses at 1p and 19q, which are commonly found in oligodendrogliomas and are generally considered to be a primary event in the development of these tumors. Subsequent progression of oligodendroglial tumors appears to be triggered by additional molecular features underlying the transition to anaplastic oligodendroglioma and glioblastoma multiforme (GBM) such as deletions of 9p and 10q, and alterations of CDKN2A (p16), which is located at 9p21. These findings strengthen the view that GBM on rare occasions may develop from oligodendroglial differentiated cells. In the present study, we evaluated the newly established MI-4 glioblastoma cell line, which displays 1p and 19q specific alterations targeting preferential regions of allelic loss in glial neoplasms, by array-CGH and fluorescence in situ hybridization (FISH) analyses that were combined to obtain a high resolution map of targeted chromosome rearrangements and copy number changes throughout the genome. Genome-wide and chromosome 19 full coverage array-CGH analysis of the MI-4 cell line revealed that in this particular cell line, 1p-specific loss, including the CDKN2 (p18) gene, is not accompanied by loss of the previously described 19q13.3 tumor suppressor candidate region. Interestingly, the array-CGH (CGHa) profile showed an increase in copy number along most of 19q including the AKT2 oncogene and the KLKs gene family, which have previously been shown to be amplified in pancreatic carcinomas and upregulated in several tumors, respectively. The concomitant 1p partial loss and chromosome 19 alterations, with the +7 and −10-specific GBM markers associated with homozygous deletion of 9p21.3 including CDKN2A (p16), are distinct features of the glioblastoma MI-4 cell line, illustrating its origin from an olidodendroglial tumor. Based on these results, we conclude that the MI-4 glioblastoma cell line might function as a model system for investigations into the behavior of a defined oligodendroglioma subtype.

Dendritic cell-based immunotherapy for malignant gliomas

Despite dramatic advances in surgical techniques, imaging and adjuvant radiotherapy or chemotherapy, the prognosis for patients with malignant glial tumors remains dismal. Based on the current knowledge regarding immune responses in the healthy CNS and glioma-bearing hosts, this review discusses dendritic cell-based immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. It is now recognized that the CNS is not an immunologically tolerated site and clearance of arising glioma cells is a routine physiologic function of the normal, noncompromised immune system. To escape from immune surveillance, however, clinically apparent gliomas develop complex mechanisms that suppress tumoricidal immune responses. Although the use of dendritic cells for the treatment of glioma patients may be the most appropriate approach, an effective treatment paradigm for these tumors may eventually require the use of several types of treatment. Additionally, given the heterogeneity of this disease process and an immune-refractory tumor cell population, the series use of rational multiple modalities that target disparate tumor characteristics may be the most effective therapeutic strategy to treat malignant gliomas.

TMZ and PCV in unresectable high grade gliomas: a retrospective comparison between two common schedules

1580 Backgrond: Treatment of unresectable high grade gliomas still remains a controversal item. After surgery and radiotherapy, chemotherapy is the only chance for these patients (pts) even though benefits are unclear in spite of significant side effects. In this retrospective study we compared in terms of response rate, toxicity, time to progression and survival two regimens commonly used in this setting. Methods: We evaluated 52 pts, 31 male and 18 female; median age was 46 years (range 21–71). Sixteen of them had histologic diagnosis of anaplastic astrocytoma (AA), 14 of glioblastoma multiforme (GM) and 19 of oligodendroglioma (ODG). PS ECOG was 0 to 3. Thirtyone pts received temozolomide (TMZ) p.o. 200 mg/m2, days 1 to 5 every 28; 18 received chemotherapy according to PCV schedule (Lomustine 110 mg/m2 p.o. day 1, Procarbazine 60 mg/m2 p.o. days 2 to 8, Vincristine 1,4 mg/m2 i.v. days 8 and 29). Treatment was interrupted in case of disease progression or unacceptable toxicity. Results: We observed no complete responses; partial responses were 7 (22,6%) and 3 (16,7%), stable disease 13 (42%) and 10 (55,5%), progressions 11 (35,6%) and 5 (27,8%) in the TMZ and PCV groups, respectively. Hematological toxicity was generally mild in the TMZ group in comparison with the PCV population (grade III-IV NCI-CTC neutropenia and thrombocitopenia were observed in 3,8% and 12,1% of cycles, respectively). Median overall survival and time to progression were 10 and 8 months in the TMZ group and 18 and 9,5 in the PCV group, respectively. Conclusions: PCV seems to be more effective and more toxic than PCV. However, the histological stratification revealed a prevalence of ODG (better prognosis than other malignant glial tumors) in the PCV group. Re-evaluating our results on this basis, differences between the two groups in terms of efficacy disappeared. TMZ still showed a better profile in terms of safety. No significant financial relationships to disclose.

Expression of the Aquaporin-1 Water Channel in Human Glial Tumors

Malignant glial tumors are associated with cerebral edema. The aquaporins (AQPs) are a family of membrane proteins that provide a major pathway for water transport in mammals. In the central nervous system, AQP1 is selectively expressed in the choroid plexus and thought to participate in cerebrospinal fluid production. Prior studies have suggested that AQP1 may be up-regulated in glial tumors, potentially contributing to tumor-associated edema. The objective of this study was to investigate the expression of AQP1 in a large series of human glial tumors. Thirty-six human glial tumors were obtained from the University of California, San Francisco Neurosurgery Tissue Bank. AQP1 expression was evaluated by reverse transcriptase polymerase chain reaction, complementary deoxyribonucleic acid gene array, Western blot analysis, and immunohistochemical analyses. AQP1, normally restricted to choroid epithelia, was highly expressed in glioblastomas. Complementary deoxyribonucleic acid array, Western blot analysis, and immunohistochemical analysis revealed intense up-regulation of AQP1 expression in all glioblastomas studied. The abnormal up-regulation of AQP1 in glial tumors suggests a potential pathological role for this membrane water channel and raises the possibility that selective AQP1 inhibition might offer a new therapeutic target for treatment of tumor-associated edema.

Intraoperative ultrasonographic characteristics of malignant intracranial lesions

The aim of this study was to evaluate the capability of intraoperative ultrasonography (IOUSG) in identifying malignant intraparenchymal tumors during surgical intervention. Forty patients with intrinsic malignant tumors were evaluated by using IOUSG. A real-time ultrasound scanner with a 3- or 5-MHz transducer was used for this study in all cases. The tip of the ultrasound probe was placed on the intact cranial dura mater and then moved in the sagittal and coronal planes. Nineteen of forty patients had lesions that were primary malignant glial tumors. Five of them had previous surgery and radiotherapy. The remaining twenty-one had metastatic tumors. All lesions were well localized and malignant characteristics were well defined by IOUSG. Radiation-induced changes in five lesions in the surrounding brain and tumor parenchyma were described. In conclusion, IOUSG is not only helpful in localizing lesions but it can also be used in determining the malignant characteristics of lesions.

T cell immunity in patients with malignant glioma: recent progress in dendritic cell-based immunotherapeutic approaches

Despite dramatic advances in surgical technique, imaging, and adjuvant radiotherapy or chemotherapy, the prognosis for patients with malignant glial tumors remains dismal. Based on the current knowledge regarding immune responses in the healthy central nervous system (CNS) and glioma-bearing hosts, we discuss dendritic cell (DC)-based immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. It is now recognized that the CNS is not an immunologically tolerated site, and clearance of arising glioma cells is a routine physiological function of the normal, non-compromised immune system. To escape from immune surveillance, however, clinically apparent gliomas develop complex mechanisms that suppress tumoricidal immune responses. Although the use of DCs for the treatment of glioma patients may be the most appropriate approach, an effective treatment paradigm for these tumors may eventually require the use of several types of treatment. Additionally, given the heterogeneity of this disease process and an immune-refractory tumor cell population, the series use of rational multiple modalities that target different tumor characteristics may be the most effective therapeutic strategy to treat malignant gliomas.