Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas

Abnormal signaling through the platelet-derived growth factor receptor (PDGFR) has been proposed as a possible mechanism of spinal cord glioma initiation and progression. However, the extent of PDGFR expression in human spinal cord gliomas remains unknown. In this study we perform immunohistochemical analysis of PDGFRα expression in a series of 33 primary intramedullary spinal cord gliomas of different types and grades. PDGFRα was seen to be expressed in a significant subset of these tumors across all major glioma types including ependymoma, oligodendroglioma, pilocytic astrocytoma, astrocytoma, and glioblastoma. These results support the hypothesis that growth factor signaling through the PDGFR may be important for the development of at least a subset of human spinal cord gliomas. Further studies investigating the prognostic significance of PDGFR expression as well as the role of PDGF signaling on the development of intramedullary spinal cord gliomas are warranted.     

FDG-PET as a Prognostic Factor in High-grade Astrocytoma

Background: The prognostic value of the metabolic status of cerebral gliomas determined by positron emission tomography with [¹⁸F]-fluoro-deoxy-D-glucose (FDG-PET) has been established in populations with a mixture of grades 2, 3 and 4 gliomas, but remains uncertain when only malignant gliomas are considered (grade 3 and 4). Methods: FDG-PET performed in 30 patients with anaplastic astrocytoma (grade III) and 61 patients with glioblastoma (grade 4) were classified according to a metabolic grading. The uptake of FDG was lower in the tumor compared to white matter (WM) in grade 1 (4 glioblastoma, 4 anaplastic astrocytoma), it was intermediate between WM and cortex in grade 2 (20 glioblastoma, 22 anaplastic astrocytoma), and it was superior to cortex in grade 3 (38 glioblastoma, 4 anaplastic astrocytoma). Results: Kaplan–Meier survival curves were similar in patient with grades 1 and 2, but were significantly worse (p = 0.007) in grade 3. In multivariate analysis considering age, pathological grade (anaplastic astrocytoma versus glioblastoma), and metabolic grades, the metabolic grade did not appear to be an independent prognostic factor. When anaplastic astrocytomas and glioblastomas were considered separately, metabolic grade is of predictive value only in the group of glioblastomas. Conclusion: In malignant gliomas, metabolic grading determined by FDG-PET was not superior to the pathological grading for survival prediction. Still, it remains of predictive value when applied to malignant gliomas histologically classified as glioblastoma.     

Towards a molecular classification of gliomas

Several molecular genetic alterations have been characterized in gliomas in the past years. Molecular profiles have been associated with specific histologic and prognostic tumor subgroups, contributing to improve the classification of gliomas. At least two alternative molecular pathways have been suggested in the astrocytoma progression involving TP53 inactivation (secondary glioblastomas) and EGFR amplification (de novo glioblastomas) respectively. Oligodendroglial tumors have demonstrated recurrent combined loss of chromosome 1p/19q, which represent a favorable prognosis marker and probably a predictor of a good chemosensitivity of the tumor. This review discusses recent molecular advances and clinical implications with special focus on oligodendroglial tumors.     

PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme

BACKGROUND: Survival of patients with anaplastic astrocytoma is highly variable. Prognostic markers would thus be useful to identify clinical subsets of such patients. Because specific genetic alterations have been associated with glioblastoma, we investigated whether similar genetic alterations could be detected in patients with anaplastic astrocytoma and used to identify those with particularly aggressive disease. METHODS: Tissue specimens were collected from 174 patients enrolled in Mayo Clinic Cancer Center and North Central Cancer Treatment Group clinical trials for newly diagnosed gliomas, including 63 with anaplastic astrocytoma and 111 with glioblastoma multiforme. Alterations of the EGFR, PTEN, and p53 genes and of chromosomes 7 and 10 were examined by fluorescence in situ hybridization, semiquantitative polymerase chain reaction, and DNA sequencing. All statistical tests were two-sided. RESULTS: Mutation of PTEN, amplification of EGFR, and loss of the q arm of chromosome 10 were statistically significantly less common in anaplastic astrocytoma than in glioblastoma multiforme (P =.033, P =.001, and P<.001, respectively), and mutation of p53 was statistically significantly more common (P<.001). Univariate survival analyses of patients with anaplastic astrocytoma identified PTEN (P =.002) and p53 (P =.012) mutations as statistically significantly associated with reduced and prolonged survival, respectively. Multivariate Cox analysis of patients with anaplastic astrocytoma showed that PTEN mutation remained a powerful prognostic factor after adjusting for patient age, on-study performance score, and extent of tumor resection (hazard ratio = 4.34; 95% confidence interval = 1.82 to 10.34). Multivariate classification and regression-tree analysis of all 174 patients identified EGFR amplification as an independent predictor of prolonged survival in patients with glioblastoma multiforme who were older than 60 years of age. CONCLUSION: PTEN mutation and EGFR amplification are important prognostic factors in patients with anaplastic astrocytoma and in older patients with glioblastoma multiforme, respectively.     

Novel immunotherapeutic approach

Malignant astrocytoma is the most common primary brain tumor in adults. The median survival time of patients with high-grade malignant astrocytoma is about 1 year, despite aggressive treatment with surgical resection, radiotherapy, and cytotoxic chemotherapy. Novel therapeutic approaches are therefore needed to prolong survival. Immunotherapy is one such novel approach that has been investigated for application with different types of tumors, including brain tumors. The author reviews immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. A number of potentially targetable antigens have been identified in gliomas. Both tenascin and epidermal growth factor receptor (EGFR) have been studied extensively as targets for direct immune attack via specific antibodies. As a novel target, interleukin 13 receptor alpha 2-chain (IL-13 R alpha 2) has been identified. IL-13 R alpha 2 is abundantly and specifically overexpressed in glioblastoma multiforme, and recently a MHC class I-restricted CTL epitope has been identified. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that have a unique potency for activating T cells. DCs have been investigated in several clinical trials in patients with malignant tumors including malignant gliomas. So far, seven papers concerning immunotherapy with DCs against malignant gliomas have been published. These reports demonstrate that immunotherapy with DCs induces immune responses and clinically antitumor effects in some patients with malignant glioma. In addition, none of these studies reported evidence of autoimmune neurotoxicity.     

Elevated expression of macrophage migration inhibitory factor correlates with tumor recurrence and poor prognosis of patients with gliomas

Macrophage migration inhibitory factor (MIF) plays a critical role in tumorigenesis. We aim to examine the association of MIF with tumor recurrence and survival of gliomas, and to determine whether MIF is a valuable prognostic predictor for glioma patients. The expression of MIF and interleukin 8 (IL-8) was evaluated in 36 high-grade gliomas (20 glioblastoma multiforme, 13 anaplastic astrocytoma, and 3 anaplastic oligoastrocytoma) and 32 low-grade gliomas (18 fibrillary astrocytoma, 5 pilocytic astrocytoma, 5 oligodendroglioma, 3 ependymoma and 1 pleomorphic xanthoastrocytoma) by immunostaining. Intratumoral microvessel density (IMD) of tumors in relation to immunostainings and clinicopathological factors were analyzed statistically as well as the follow-up data of patients. High expression of both MIF (58.8%) and IL-8 (52.9%) was significantly associated with high-grade gliomas and increased microvessels in tumors, but only high expression of MIF was closely related to tumor recurrence (P = 0.001). High expression of IL-8 exhibited a close correlation with high expression of MIF in tumors (P = 0.001). Histological grading, high expression of MIF and IL-8 correlated with patients’ overall survival in univariate analysis. However, only histological grading and MIF expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis; the hazard ratios were 28.012 (P = 0.001) and 11.782 (P = 0.001), respectively. Elevated production of MIF in glioma tumor cells may contribute to tumor recurrence and a worse prognosis. MIF may serve as an independent predictive factor for prognosis of glioma patients.     

Treatment modalities for malignant gliomas with reference to their pathophysiology

The histological classification, pathophysiology, and treatment modalities of malignant gliomas (glioblastoma, malignant astrocytoma) were reviewed with reference to the WHO classification of primary brain tumors and the recent progress made in glioma biology. Patients with glioblastoma and malignant astrocytoma showed, respectively, 10.6% and 22.2 of the five-year survival rate according to the All Japan Brain Tumor Registry. In order to improve the prognosis of malignant glioma patients, many clinical trials have been conducted throughout the world. Malignant gliomas that grow in and invade the brain parenchyma cannot be cured by surgical resection. One should treat the residual tumor with irradiation, chemotherapy and immunotherapy. Radiation therapy alone and radiation therapy plus chemotherapy using nitrosoureas or procarbazine have been proved statistically to be more effective for malignant gliomas than supportive care and radiation therapy alone, respectively. Prospective clinical trials support the view that malignant gliomas should be treated vigorously using a multimodal approach that includes surgical resection, high-dose radiation therapy, and prolonged maintenance chemotherapy.     

Prognostic significance of histological grading,p53 status,YKL-40 expression,and <Emphasis Type="Italic">IDH1</Emphasis> mutations in pediatric high-grade gliomas

The objective of this study was to evaluate, in a series of 43 pediatric high-grade gliomas (21 anaplastic astrocytoma WHO grade III and 22 glioblastoma WHO grade IV), the prognostic value of histological grading and expression of p53 and YKL-40. Moreover, mutational screening for TP53 and IDH1 was performed in 27 of 43 cases. The prognostic stratification for histological grading showed no difference in overall (OS) and progression-free survival (PFS) between glioblastomas and anaplastic astrocytomas. Overexpression of YKL40 was detected in 25 of 43 (58%) cases, but YKL-40 expression was not prognostic in terms of OS and PFS. p53 protein expression was observed in 13 of 43 (31%) cases but was not prognostic. TP53 mutations were detected in five of 27 (18%) cases (four glioblastomas and one anaplastic astrocytoma). Patients with TP53 mutation had a shorter median OS (9 months) and PFS (8 months) than those without mutations (OS, 17 months; PFS, 16 months), although this trend did not reach statistical significance (p = 0.07). IDH1 mutations were not detected in any of the cases analyzed. Our results suggest that in pediatric high-grade gliomas: (i) histological grading does not have strong prognostic significance, (ii) YKL-40 overexpression is less frequent than adult high-grade gliomas and does not correlate with a more aggressive behavior, (iii) TP53 mutations but not p53 expression may correlate with a more aggressive behavior, and (iv) IDH1 mutations are absent. These observations support the concept that, despite identical histological features, the biology of high-grade gliomas in children differs from that in adults, and therefore different prognostic factors are needed.     

Prognostic significance of the immunohistochemical staining of cleaved caspase-3, an activated form of caspase-3, in gliomas.

PURPOSE: Gliomas are common tumors of the central nervous system, and the majority of patients with gliomas have a poor prognosis. The prediction of prognosis is very important in selecting treatment. In the present study, we retrospectively examined the immunohistochemical staining of cleaved caspase-3 (CC3), an activated form of caspase-3 that acts as a lethal protease at the most distal stage of the apoptosis pathway, in gliomas, and the correlation between the prognosis of patients and caspase-3 activation to find useful prognostic indicators. EXPERIMENTAL DESIGN: Immunohistochemical staining of CC3 was done in 65 patients with gliomas. The percentage of CC3 staining-positive cells was defined as the CC3 immunoreactivity score (IRS). Survival analysis between CC3 IRS of glioma patients and survival time was carried out using the Kaplan-Meier method with the log-rank test and the Cox proportional hazards regression model. RESULTS: CC3 IRS was statistically analyzed to designate the best provisional cutoff point, and when detected in >10% of glioma cells, it was considered positive. The Kaplan-Meier method with the log-rank test revealed that patients with CC3 IRS-positive tumors had significantly greater survival than those with CC3 IRS-negative tumors among three grades, 2, 3, and 4 (P = 0.0061), and within grade 3 of anaplastic astrocytoma (P = 0.0458). After adjustment for known clinical prognostic factors, such as age, WHO grade, and performance status, the hazard ratio for CC3 IRS-positive was 0.39 with 95% confidence interval between 0.19 and 0.85 (P = 0.0187). Within high grades, including grades 3 and 4, the hazard ratio was 0.40 with 95% confidence interval between 0.20 and 0.86 (P = 0.0192). CONCLUSIONS: CC3 IRS could be useful as a good prognostic indicator for glioma patients.     

Prognostic factors and survival in patients with spinal cord gliomas after radiation therapy.

The purpose of this study was to determine the impact of various prognostic factors on survival in spinal cord gliomas treated with radiation. Fifty-three patients with spinal cord gliomas irradiated at three major institutions were studied. Fifty-one patients were classified as having ependymoma, astrocytoma, or both. Two patients were classified as having gliomas (otherwise unspecified). Eleven patients had complete resection of their tumor. Biopsy or partial resection was done in the remaining patients. All patients received external beam radiation. Information on these patients was placed in a central database file and analyzed for the effect of several prognostic factors on survival. Overall survival of the entire group was 76.9% and 61.5% at 5 and 10 years, respectively. Pathologic status significantly affected survival (p = 0.03). Patients with ependymomas had a 5-year survival of 93.8% and a 10-year survival of 67.5%. Patients with astrocytoma had a 5-year survival of 64.2% and a 10-year survival of 54%. Univariate analysis showed pathology and the presence of cysts (p = 0.038) to significantly affect survival. Age, sex, location of the primary, extent of surgery radiation dose, and number of involved segments did not affect survival. On multivariate analysis, astrocytic pathology, involvement of more than five segments, male sex, and the absence of cysts (in or adjacent to the tumor) were associated with a significantly inferior survival. This study confirms the importance of pathology and number of segments involved in determining outcome or survival. The presence of cysts adjacent to or within the tumor was found to be associated with an improvement in survival.     

Rare mutations of the DMBT1 gene in human astrocytic gliomas

The Deleted in Malignant Brain Tumors 1 gene (DMBT1) has been proposed as a tumor suppressor gene candidate in human brain tumors, based on the observation of homozygous deletions affecting the DMBT1 region or part of the gene. In order to support this hypothesis, we performed a mutational analysis of the entire coding region of DMBT1, employing SSCP analysis and direct DNA sequencing in a series of 79 astrocytic gliomas. Five somatic mutations were detected. Two mutations, one of which resulted in an amino acid exchange, occurred in glioblastomas. One pilocytic astrocytoma carried two missense mutations and another pilocytic astrocytoma contained a somatic mutation, not affecting the presumed protein. In addition, 21 of the 27 single nucleotide polymorphisms identified in this study have not been recognized previously. The data indicate, that small mutations are not a frequent finding in gliomas.     

Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications

A total of 1440 malignant astrocytic gliomas from three Phase III trials of the National Brain Tumor Study Group were studied to document the clinical usefulness of subclassifying these lesions as either an anaplastic astrocytoma or a glioblastoma multiforme. As defined by a previous "blind" pathology review, the two groups of patients were compared as to mean age, mean duration of preoperative symptoms, and postrandomization survival. In addition, 10 histologic variables were studied in 150 patients with the anaplastic astrocytoma to establish internal correlations, and to relate specific histologic variables to patient age and postrandomization survival. There were highly significant differences in the age, duration of preoperative symptoms, and post randomization survival between the two groups. Internal correlations between histologic variables in the anaplastic astrocytoma disclosed statistically significant associations between the presence of lymphocytes and gemistocytic astrocytes. It is concluded that the subclassification of malignant gliomas into the anaplastic astrocytoma and the glioblastoma multiforme defines groups of patients that are significantly different in regard to age, duration of symptoms, and length of survival. The problems of tissue sampling are recognized, however, the assignment, by a blind pathology review, to two such different groups indicates that the classification has utility for large randomized clinical trials. The analysis of histologic variables in the anaplastic astrocytomas confirms previous suggestions that lymphocytes and gemistocytes frequently coexist in malignant gliomas, but in this study these inflammatory cells did not appear to influence survival. The study reemphasizes the association between advancing age and shorter survivals in patients with malignant gliomas.     

Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases

Eighty-eight adult patients with histologically verified cerebral low grade gliomas (grades 1 and 2) treated with post-operative radiotherapy at the Royal Marsden Hospital between 1960 and 1985 were reviewed. Survival of oligodendroglioma patients was greater than those with astrocytoma (64% vs 36% at 5 years) but the difference was less marked in the long term (35% vs 26% at 10 years). Previous studies have identified prognostic factors important in these tumors: age, extent of surgery, grade, performance status, and duration of symptoms. In this study of low grade astrocytomas and oligodendrogliomas, age (highly significant in the former and significant in the latter), extent of surgery (oligodendrogliomas), and performance status have been demonstrated as factors influencing outcome. The precise role of radiotherapy including the optimal radiation dose and timing of treatment remains unclear. The information, given by a retrospective analysis such as this, helps in the design of prospective, randomized studies looking at radiation dose and time of surgical and radiotherapeutic interventions, always with careful assessment needed of quality of life and treatment morbidity.     

Supratentorial astrocytomas and oligodendrogliomas treated in the MRI era.

BACKGROUND: There is at present no consensus on the policy for the treatment of patients with low-grade gliomas (LGGs). METHODS: This report is a retrospective multi-institutional study of 100 patients (ages 16-65 years) with astrocytoma (grade II), oligodendroglioma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma of the supratentorial areas which were treated with surgery and postoperative radiotherapy at five university hospitals in northern Japan between 1990 and 1997 when MRI was routinely used to determine the target volume. Most patients were irradiated with 50-60 Gy. The target volume usually covered the areas with T2 prolongation of MRI with a margin of 2 cm. RESULTS: The disease-specific 5-year survival rate was 87.4% for patients with oligodendroglioma and 75.3% for patients with astrocytoma. Survival for patients with astrocytoma in the MRI era appears to be improved compared with historical controls in the literature. Patients with astrocytoma aged 40 years and under had a significantly better disease-specific survival rate than those over 40 years (P < 0.05) and patients with oligodendroglioma and oligoastrocytoma showed a similar tendency. Patients with astrocytoma who had over 50% of their tumor removed had a significantly better survival rate than those who had less than 50% removed (P < 0.05). Chemotherapy appeared to improve the disease-specific survival rate of patients with oligodendroglioma but not that of patients with astrocytoma. CONCLUSION: Oligodendroglioma has a more protracted course of disease progression than astrocytoma. This particular feature and the sensitivity of LGGs to chemotherapy as well as their relevant prognostic factors, such as age, histopathology and amount of tumor removal, should be taken into account before any decision on treatment methods for LGGs is made.     

Molecular biology of malignant gliomas

Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oligodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10–15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made (table 1). Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies. Supported by an unrestricted educational grant by Bristol-Myers Squibb.     

Prognostic factors for anaplastic astrocytomas

Anaplastic astrocytomas (WHO grade III) constitute about 10% of all gliomas. Definitive data on predictive and prognostic factors are lacking for these neoplasms that are considered the most enigmatic entity among the whole spectrum of astrocytic tumors because of their unclear biologic behavior and variable clinical outcome. Currently, only few factors have been identified as useful for prognosis of anaplastic astrocytoma: age and Karnofsky Performance Status. Attempts have been made to identify biological prognostic factors for response to therapy and clinical outcome, as well as potential targets for new therapies. Potential prognostic biomarkers concern tumor suppressor genes on chromosome 9q that are involved in the RB1 pathway; PTEN, the PI3k/Akt/p70s6k cascade, survivin gene, Formylpeptide receptor, minichromosome maintenance protein 3 and genes on chromosome 7. Furthermore, some angiogenic factors (e.g. hypoxia-inducible factor-1α, vascular endothelial growth factor and scatter factor/hepatocyte growth factor) and the methylation status of O6-methylguanine-DNA methyltransferase gene (one of the main effectors of DNA repair system) are emerging novel putative determinants of prognosis. Moreover, recent studies on magnetic resonance imaging characteristics give prognostic significance to the presence of necrosis and enhancement. The state of the art pictured here underlie the recent interest on gene expression profile to identify aberrations useful to understand the biologic behavior of astrocytic tumors. Our knowledge in this field is still limited, and remains an issue of great concern.     

Prognostic Factors in Malignant Gliomas with Special Reference to Intra-Arterial Chemotherapy

Survival was analyzed in 173 patients with malignant gliomas to study the importance of possible pretreatment prognostic factors. Seventy-nine of these patients received preirradiation intra-arterial chemotherapy with BCNU combined with vincristine intravenously and procarbazine orally; the others received only postoperative whole-brain irradiation. To judge by univariate and multivariate analyses the most important pretreatment prognostic factors were histology, corticosteroid dependency, pretreatment performance status and frontal lobe location of the tumors. Patients with anaplastic astrocytoma, not corticosteroid-dependent, with pretreatment performance status of 0-2 and with a frontal lobe location of the tumor seemed to benefit most from preirradiation chemotherapy.     

Advances in genetic and epigenetic analyses of gliomas: a neuropathological perspective

Gliomas, the most common malignant primary brain tumors, are universally fatal once they progress from low-grade into high-grade neoplasms. In recent years, we have accumulated unprecedented data about the genetic and epigenetic abnormalities in gliomas; yet, our appreciation of how these deadly tumors arise is still rudimentary. One of the major deterrents in understanding gliomagenesis is the remarkably complex and heterogeneous molecular composition of gliomas, as well as their ability to change phenotypically as they progress and recur. In the past decade, several monumental studies have begun to define better glioma heterogeneity. Four distinct molecular subgroups have emerged: proneural, classical, mesenchymal, and neural; which have unique gene expression signatures and prognostic significance. Of these, gliomas of the proneural subtype, which encompass most grade II/III diffuse gliomas and secondary glioblastomas and often carry isocitrate dehydrogenase (IDH) mutations, have emerged as a distinct tumor subclass with a notably superior prognosis. Important molecular markers with prognostic relevance, such as mutant IDH1/2, have already been incorporated into clinical neuropathological practice. The recent molecular discoveries in gliomas have also emphasized the intimate link between epigenetics and genetics in gliomagenesis. Several of the novel genetic mutations described are responsible for distinct epigenetic remodeling in gliomas, the mechanisms of which are currently being elucidated. Importantly, these epigenetic and genomic alterations represent new and exciting drug targets for future therapeutic interventions in our continuous fight with this fatal malignancy.