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Macrophages plasticity is a key feature in cancer progression. Neoplastic cells can alter their immune functions and orient them into a pro-tumoral phenotype. In this context, we developed a new therapeutic strategy to switch macrophages phenotype and reactivate their anti-tumoral functions. We showed a dual activity of a proprotein convertases inhibitor as anti-glioma drug and anti-tumoral macrophages’ reactivation drug. Proprotein convertases are proteases that cleave proteins into functional proteins. Several of their substrates are involved in tumorigenesis and immunosuppression. We combine here proprotein convertases inhibitor with Poly (I:C), a TLR3 ligand, to increase the anti-tumoral activity of macrophages. With mass spectrometry-based proteomics, system biology, combined with biological assays, we established that a stimulation of macrophages with Poly (I:C) increased their secretion of pro-inflammatory cytokines and anti-tumoral factors. 3D invasion assay showed the efficacy of these anti-tumoral factors against mixed glioma cells and macrophages spheroids. Besides, immunofluorescence and proliferation assays showed an additive effect of the proprotein convertases inhibitor and the anti-tumoral factors secreted by Poly (I:C)-treated macrophages on both anti-glioma activity and macrophages anti-tumoral orientation directly in tumor microenvironment, leading to an innovative glioma therapy.

In the era of molecular diagnostic testing, mixed gliomas are very rarely reported tumors. They can be grade 2 or grade 3 tumors and should be managed similar to their pure counterparts of astrocytoma or oligodendroglioma. This chapter gives an overview of mixed gliomas.

The most common mixed glioma encountered in routine surgical practice is oligoastrocytoma (OA); however, its is currently considered a vanishing entity. The 2016 classification of the World Health Organization (WHO) discourages the diagnosis of tumors as mixed glioma. The recommendations are that diffuse gliomas, including those with mixed or ambiguous histological features, should be subjected to molecular testing. Dual-genotype OAs are not yet a distinct entity or variant in the classification. We report a case of mixed glioma: a pleomorphic xanthoastrocytoma (PXA) mixed with an oligodendroglioma. The immunohistochemistry (IHC) pattern of isocitrate dehydrogenase 1 (IDH1) negativity with retained nuclear expression of the alpha-thalassemia x-linked intellectual disability syndrome (ATRX) protein, and 1p19q co-deletion negativity in both the components enabled its identification as a mixed glioma rather than a collision tumor. To the best of our knowledge, the case herein presented is the fourth case of PXA with oligodendroglioma. Out of the other three reported cases, only one was of a collision tumor with a dual genotype, and the other two showed similar molecular signatures in both components. The present article discusses the histological, immunohistochemical and molecular features of the aforementioned case.

The aim of this report was to describe the magnetic resonance imaging (MRI) and pathological features of a canine mixed glioma. A 12-year-old boxer male dog was presented for necropsy along with data from an MRI evaluation conducted ante-mortem. The images were examined and showed a poorly demarcated prosencephalic lesion, hyperintense on T2W images, hypointense on T1W images and heterogeneously hyperintense on T2W FLAIR images. There was mild nonuniform contrast enhancement, apparent midline shift, moderate perilesional edema and marked distortion of the adjacent lateral ventricle. The brain was evaluated macroscopically, microscopically and immunohistochemically. Grossly, there was a poorly demarcated soft mass, with areas of hemorrhage, within the left parietal and temporal lobes. Histologically, there was a densely cellular mass composed of two geographically distinct populations of neoplastic cells. The first population was composed of small and round cells organized in a honeycomb pattern. The second population constituted of intermingled streams and bundles of neoplastic cells that were strongly immunolabeled for glial fibrillary acidic protein (GFAP). The diagnosis of a mixed glioma was based on MRI findings, and mainly on histological and immunohistochemical findings.

Background Mixed gliomas, such as oligoastrocytomas (OA), anaplastic oligoastrocytomas, and glioblastomas (GBMs) with an oligodendroglial component (GBMO) are defined as tumors composed of a mixture of two distinct neoplastic cell types, astrocytic and oligodendroglial. Recently, mutations ATRX and TP53, and codeletion of 1p/19q are shown to be genetic hallmarks of astrocytic and oligodendroglial tumors, respectively. Subsequent molecular analyses of mixed gliomas preferred the reclassification to either oligodendroglioma or astrocytoma. This study was designed to apply genetically integrated diagnostic criteria to mixed gliomas and determine usefulness and prognostic value of new classification in Korean patients. Methods Fifty-eight cases of mixed OAs and GBMOs were retrieved from the pathology archives of Seoul National University Hospital from 2004 to 2015. Reclassification was performed according to genetic and immunohistochemical properties. Clinicopathological characteristics of each subgroup were evaluated. Overall survival was assessed and compared between subgroups. Results We could reclassify all mixed OAs and GBMOs into either astrocytic or oligodendroglial tumors. Notably, 29 GBMOs could be reclassified into 11 cases of GBM, IDH-mutant, 16 cases of GBM, IDH-wildtype, and two cases of anaplastic oligodendroglioma, IDH mutant. Overall survival was significantly different among these new groups (p

BACKGROUND Low and high grade gliomas, are the most common pediatric central nervous system (CNS) tumors and they show an extremely broad range of clinical behavior. Pediatric glioma is distinct from its adult counterpart with different genetic/epigenetic profile and biological features. Recently, several studies have shown the involvement of voltage-gated Na+ channels (VGSC) in different types of cancer, including gliomas. VGSC are multimeric transmembrane complexes, responsible for membrane depolarization in excitable cells playing an important role also in cell proliferation, migration, apoptosis and differentiation. VGSC are therapeutic targets in cardiovascular and neurological disorders and, in cancers, they could be a novel target for the development of promising anticancer therapy MATERIAL AND METHODS Firstly, we explored the genetic background of 9 pediatric glioblastomas (1–9 pGBMs), through whole-exome sequencing (WES) using HiSeq1000 platform (Illumina) with paired-end approach. On the basis of our results, we extended our study in another group of 16 epileptogenic mixed neuronal-glial tumors of pediatric age, (WHO grade I and II), through an amplicon approach (TSCA) using MiniSeq System platform (Illumina) RESULTS We identified variants in SCN1A gene in 3/9 pGBMs: case 3 had c.5782C>G in tumor and blood; case 5 showed c.2278G>T and two mosaic variants (c.5933C>T, 22% and c.4942C>T, 14%); case 6 showed c.667G>T variant only in tumor, and not in other non tumoral tissues (blood, urine and buccal swab). No variants in SCN1A were identified in a group of 16 pediatric mixed gliomas CONCLUSION In this study, we explore the genetic background of two groups of pediatric neuroepithelial brain tumors, through Next generation sequencing approach. We identified only in pGBMs variants in SCN1A gene that encoded for VGSCs and is involved in a spectrum of early-onset epileptic encephalopathies. None of our mutated patients showed history of epilepsy. Now, it is not clear the significance of these variants in pGBMs but interestingly, these variants are present in pGBM and not in mixed gliomas. Further studies on a big cohort of patients are needed to establish if they could play a role in pGBMs aggressiveness, migration and progression. Moreover, VGSCs could be a pharmacological target in pGBMs treatment

Gliomas are the most common type of pediatric brain tumor and include a wide variety of histologies and biologic behaviors. This heterogeneous group of tumors can arise throughout the central nervous system (CNS) but most frequently occur in the supratentorial compartment [1]. Gliomas can be broadly divided into low- and high-grade lesions as defined by WHO classification grades I–IV. Low-grade gliomas (LGG) occur as WHO grades I and II, and high-grade gliomas (HGG) occur as WHO grades III and IV. Glioma describes a variety of histologic groups including astrocytoma, ependymoma, oligodendroglioma, mixed glioma, dysembryoplastic neuroepithelial tumors, and glioblastoma, as well as some more rare histologies.

The 2016 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri” was held in San Diego, California, at the Society of Toxicologic Pathology’s (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers’ talks, along with select images that were used by the audience for voting and discussion. Some lesions and topics covered during the symposium included malignant glioma and histiocytic sarcoma in the rodent brain; a new statistical method designed for histopathology data evaluation; uterine stromal/glandular polyp in a rat; malignant plasma cell tumor in a mouse brain; Schwann cell proliferative lesions in rat hearts; axillary schwannoma in a cat; necrosis and granulomatous inflammation in a rat brain; adenoma/carcinoma in a rat adrenal gland; hepatocyte maturation defect and liver/spleen hematopoietic defects in an embryonic mouse; distinguishing malignant glioma, malignant mixed glioma and malignant oligodendroglioma in the rat; comparison of mammary gland whole mounts and histopathology from mice; and discussion of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) collaborations.

The aim of this report was to describe the magnetic resonance imaging (MRI) and pathological features of a canine mixed glioma. A 12-year-old boxer male dog was presented for necropsy along with data from an MRI evaluation conducted ante-mortem. The images were examined and showed a poorly demarcated prosencephalic lesion, hyperintense on T2W images, hypointense on T1W images and heterogeneously hyperintense on T2W FLAIR images. There was mild nonuniform contrast enhancement, apparent midline shift, moderate perilesional edema and marked distortion of the adjacent lateral ventricle. The brain was evaluated macroscopically, microscopically and immunohistochemically. Grossly, there was a poorly demarcated soft mass, with areas of hemorrhage, within the left parietal and temporal lobes. Histologically, there was a densely cellular mass composed of two geographically distinct populations of neoplastic cells. The first population was composed of small and round cells organized in a honeycomb pattern. The second population constituted of intermingled streams and bundles of neoplastic cells that were strongly immunolabeled for glial fibrillary acidic protein (GFAP). The diagnosis of a mixed glioma was based on MRI findings, and mainly on histological and immunohistochemical findings. RESUMO O objetivo deste relato foi descrever as características patológicas e das imagens de ressonância magnética de um glioma misto canino. Um cão de 12 anos de idade da raça Boxer foi submetido à necropsia. As imagens obtidas ante mortem por ressonância magnética foram analisadas, e nelas se observou uma lesão prosencefálica com contornos pouco definidos, sinal hiperintenso nas imagens ponderadas em T2, hipointenso nas imagens ponderadas em T1, e heterogeneamente hiperintenso em T2-FLAIR. Havia discreto realce desuniforme ao contraste, evidente desvio da linha média, edema perilesional moderado e marcada distorção do ventrículo lateral adjacente. O encéfalo foi avaliado macroscopicamente, microscopicamente e imuno-histoquimicamente. Macroscopicamente, havia uma massa pobremente demarcada, com áreas de hemorragia, nos lobos parietal e temporal esquerdos. Histologicamente, havia uma massa densamente celular, composta por duas populações de células neoplásicas distintas separadas geograficamente. A primeira população era composta por células pequenas e redondas, organizadas com aspecto de favo de mel. A segunda população era constituída por feixes entrelaçados de células neoplásicas fortemente imunomarcadas para a proteína fibrilar ácida glial (GFAP). O diagnóstico de glioma misto foi obtido com base nos achados imaginológicos e, principalmente, em suas características histológicas e imuno-histoquímicas.

The aim of this report was to describe the magnetic resonance imaging (MRI) and pathological features of a canine mixed glioma. A 12-year-old boxer male dog was presented for necropsy along with data from an MRI evaluation conducted ante-mortem. The images were examined and showed a poorly demarcated prosencephalic lesion, hyperintense on T2W images, hypointense on T1W images and heterogeneously hyperintense on T2W FLAIR images. There was mild nonuniform contrast enhancement, apparent midline shift, moderate perilesional edema and marked distortion of the adjacent lateral ventricle. The brain was evaluated macroscopically, microscopically and immunohistochemically. Grossly, there was a poorly demarcated soft mass, with areas of hemorrhage, within the left parietal and temporal lobes. Histologically, there was a densely cellular mass composed of two geographically distinct populations of neoplastic cells. The first population was composed of small and round cells organized in a honeycomb pattern. The second population constituted of intermingled streams and bundles of neoplastic cells that were strongly immunolabeled for glial fibrillary acidic protein (GFAP). The diagnosis of a mixed glioma was based on MRI findings, and mainly on histological and immunohistochemical findings.

Contains fulltext : 153542.pdf (Publisher’s version ) (Open Access) For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of 'canonical oligodendroglioma'. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of 'canonical oligodendrogliomas' should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients.

Automatic segmentation of tumor abnormality is a very difficult task for the radiologist. In this research, we proposed a located brain tumor with automatic seed point localization and no need to initially select the location of the region which is to be infected. Estimation of the abnormalities for initial bounding box after this, we proposed the segmentation of tumor called automatic level set minimization function with a new technique that is localization based energy minimization of MRI brain tumor. The performance of localization is evaluated using based on the level of detection and radiologist analytical results. Total 100 FLAIR, T1, and T2-weighted MRI brain tumor images (Astrocytoma (22), Ganglioglioma (6), Glioblastoma (23), Epidermoide (3), Mixed Glioma (5) and Meningnet (41)) (5type of tumors) were used for the experiment. Experimental results show that the method has successfully localized the brain tumors with 97% accuracy.

Gliomas represent the most frequent form of primary brain tumors in adults, the prognosis of which remains extremely poor. Inactivating mutations on the tumor suppressor TP53 were proposed as a key etiological trigger of glioma development. p53 has been recently identified as a transcriptional target of parkin. Interestingly, somatic mutations on parkin have also been linked to glioma genesis. We examined the possibility that a disruption of a functional interaction between p53 and parkin could contribute to glioma development in samples devoid of somatic parkin mutations or genetic allele deletion. We show here that parkin levels inversely correlate to brain tumor grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas. We demonstrate that p53 levels negatively and positively correlate to bax and Bcl2 respectively, underlying a loss of p53 transcriptional activity in all types of glial tumors. Using various cell models lacking p53 or harboring either transcriptionally inactive or dominant negative p53, as well as in p53 knockout mice brain, we establish that p53 controls parkin promoter transactivation, mRNA and protein levels. Furthermore, we document an increase of parkin expression in mice brain after p53-bearing viral infection. Finally, both cancer-related p53 inactivating mutations and deletion of a consensus p53 binding sequence located on parkin promoter abolish p53-mediated control of parkin transcription, demonstrating that p53 regulates parkin transcription via its DNA binding properties. In conclusion, our work delineates a functional interplay between mutated p53 and parkin in glioma genesis that is disrupted by cancer-linked pathogenic mutations. It also allows envisioning parkin as a novel biomarker of glioma biopsies enabling to follow the progression of this type of cancers.

Astrocytomas are the most common intramedullary spinal cord tumors in pediatric and adolescent patients and the incidence decreases with age. Spinal oligoastrocytoma, which is a mixed glioma with distinct astrocytic and oligodendroglial components, is an extremely rare pathology of the spinal cord. To authors' best of knowledge, there are only 7 spinal oligoastrocytomas reported in the English literature. Here, the authors report a patient of a pathologically confirmed spinal oligoastrocytoma, who presented with severe left leg pain and numbness. This patient reminds us of the rarity of spinal oligoastrocytoma, and the treatment and prognosis were also investigated and reviewed.

Low-grade gliomas (LGG) comprise nearly 15-20 % of all central nervous system glial tumors. Several factors have been recognized as playing role in LGG malignant transformation (MT). A breakthrough analysis of a multidisciplinary group pointed that temozolomide may play a role in MT of LGGs. We analyzed the prevalence of MT in LGG patients submitted to adjuvant therapy (AT). We analyzed the medical charts of 43 patients with LGG submitted to surgery or biopsy and attending at Hospital do Servidor Publico Estadual de Sao Paulo (Sao Paulo, Brazil), consecutively diagnosed from 1995 to 2013. 43 patients (24 women and 19 men) were evaluated, with mean age of 45.3 years. According to histology, 30 were astrocytomas (70 %), 12 (27 %) were oligodendrogliomas, and 1 (3 %) were mixed glioma. Mean follow-up time was 4.2 years with the standard deviation of 2.1. Twenty-eight patients did not receive adjuvant therapy and 15 received adjuvant therapy. From 43 patients with complete follow-up, 21 (48 %) experienced malignant transformation. Among such patients, nine were users of AT. Forty-eight percent of patients presented MT, being 60 % in the AT group and 42.8 % without AT. Our analysis revealed a high prevalence of MT in patients undergoing AT, higher than in patients without AT.

It is generally said that neoplastic cells are immunohistochemically negative for glial fibrillary acidic protein (GFAP) in rat spontaneous astrocytomas, and there are no reports describing the existence of GFAP-positive neoplastic astrocytes in rat spontaneous oligodendrogliomas and mixed gliomas which contain neoplastic astrocytes. In the present study, to clarify whether GFAP-positive neoplastic astrocytes exist in rat spontaneous oligodendrogliomas and mixed gliomas or not, immunohistochemical examination was performed on spontaneous oligodendrogliomas (26 cases) and mixed gliomas (5 cases) collected from the carcinogenicity studies and short-term toxicity studies. The neoplastic cells that constitute oligodendrogliomas and mixed gliomas were morphologically classified into five types: round A, round B, round C, spindle, and bizarre. The cells of round A, B, and C types were thought to be neoplastic oligodendrocytes because of their positive immunostainability for Olig2. The origin of bizarre cells was obscure because they were negative for Olig2, GFAP, and nestin. The spindle cells were considered to be neoplastic astrocytes, because some of them were positive for GFAP or nestin, and GFAP-positive spindle cells could be morphologically distinguished from reactive astrocytes. In conclusion, the present study clarified for the first time that GFAP-positive neoplastic astrocytes exist in rat spontaneous gliomas.

Twenty-eight spontaneously occurring glial tumors (previously diagnosed as astrocytomas, oligodendrogliomas, and gliomas) and eleven granular cell tumors (GCTs) were selected for evaluation using a panel of immunohistochemistry (IHC) stains ( Ricinus communis agglutinin type 1 [RCA-1], ionized calcium-binding adapter molecule 1 [Iba-1], OX-6/major immunohistocompatibility complex class II, oligodendrocytes transcription factor 2 [Olig2], glial fibrillary acidic protein [GFAP], S100 beta, glutamine synthetase, neurofilament, proliferating cell nuclear antigen). In addition, nine brain tumors from a 2-year drinking water study for acrylonitrile were obtained from the Acrylonitrile Group, Inc. Based on IHC staining characteristics, Olig2+ oligodendrogliomas were the most commonly diagnosed spontaneous tumor in these animals. Many of the spontaneous tumors previously diagnosed as astrocytomas were RCA-1+, Iba-1+ and negative for GFAP, S100beta, and glutamine synthetase; the diagnosis of malignant microglial tumor is proposed for these neoplasms. Three mixed tumors were identified with Olig2+ (oligodendrocytes) and Iba-1+ (macrophage/microglia) cell populations. The term mixed glioma is not recommended for these tumors, as it is generally used to refer to oligoastrocytomas, which were not observed in this study. GCT were positive for RCA-1 and Iba-1. All acrylonitrile tumors were identified as malignant microglial tumors. These results may indicate that oligodendrogliomas are more common as spontaneous tumors, while acrylonitrile-induced neoplasms are microglial/histiocytic in origin. No astrocytomas (GFAP, S100 beta, and/or glutamine synthetase-positive neoplasms) were observed.

With the exception of oligoastrocytoma, mixed gliomas are rarely encountered, and the astrocytic component of mixed oligoastrocytoma is almost always fibrillary and diffusely infiltrative. Pleomorphic xanthoastrocytoma (PXA) has occasionally been described in conjunction with ganglioglioma, as well as in 1 case of oligodendroglioma. In this latter case, described by Perry et al., 1p/19q codeletions were not detected. The authors report on a 25-year-old woman with a combined PXA/oligodendroglioma in which concurrent 1p/19q codeletions were detected in the oligodendroglial component only. The patient presented with a 1-month history of headaches. Neuroimaging revealed a heterogeneous left temporal mass with focal enhancement, cystic changes, hemorrhage, and left-to-right midline shift. The patient underwent a craniotomy and gross-total resection. Pathological examination revealed a glial tumor composed of 2 apparently distinct components. The largest component exhibited a prominent fascicular, reticulin-rich, spindle cell arrangement admixed with areas of highly pleomorphic cells, with bizarre cytological features reminiscent of PXA. A smaller component was composed of cellular sheets and lobules of oligodendroglial cells. Both components were characterized by anaplastic features. Dual-color fluorescence in situ hybridization for 1p/19q codeletions was performed. Only the oligodendroglial component showed the combined 1p/19q deletions. This case represents the first instance in which PXA has been reported in conjunction with an oligodendroglioma exhibiting the “molecular signature” characteristic of oligodendroglial neoplasms. The different genetic alterations seen in the 2 components of this neoplasm argue in favor of a “collision tumor” rather than a mixed glioma of the same genotype.

The overarching goal of the International Low Grade Glioma (LGG) Registry is to allow for focused study of LGG (defined as adult grade II astrocytoma, mixed glioma, or oligodendroglioma), including quality of life (QOL). To date, enrollment is completed for 234 patients from 21 states and nine countries (US, France, United Kingdom, Canada, Australia, Hong Kong, New Zealand, Belarus and Spain). Pilot data on QOL (MOS SF-36 scale, measured from 0–100 with higher scores suggesting better QOL) are available for 112 LGG patients for whom we have confirmed treatment via medical record review. Enrolled LGG patients were predominantly White (91.2%), female (56.3%), generally otherwise healthy with only 5% reporting a co-morbid condition) and had a mean age of 36.9 years. A wide range of symptoms were reported by patients: 23.4% reported being unable to drive, 32.4% reported trouble thinking, and 35.1% reported difficulty with getting words out. To date, fifty-two percent of patients have received radiation (XRT): patients not treated with XRT at diagnosis report significantly better physical functioning than do those who received XRT, with persons receiving XRT at time of diagnosis reporting the lowest scores (p=0.003). Interestingly, patients not treated with XRT reported lower emotional and mental health scores than did those receiving XRT (p=0.02). Interpretation of these findings is limited at this point given the small sample and possible selection bias; possibilities include that the no XRT group may be more depressed/anxious for unrelated reasons, or, the absence of treatment may leave them feeling uneasy. When compared to study subjects from our prior meningioma case/control study of QOL, these results suggest significant reduction in QOL for LGG patients and possible variation by XRT treatment and thus the need to better understand these differences.

Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas. However, histological and molecular classifications do not always correspond as many alterations are shared by high-grade tumors, whatever their histological type. Besides, few molecular alterations have a prognostic value. Among them combined 1p19q loss is associated with a better prognosis and response to treatment for oligodendrogliomas. Another promising marker is MGMT, a DNA repairing enzyme. If inactivated (by methylation of the promoter of the gene) a better sensitivity is observed with nitrosoure agents. However, some concerns exist for the method of detection of this abnormality. Quality control for molecular techniques is also required before using them for therapeutic strategy. In the future, studies of gene expression profiles by cDNA-microarray as well as works in the field of neural progenitor cells will probably provide new insights in gliomagenesis.

Background: We hypothesized that the incidences of oligodendrogliomas, anaplastic oligodendrogliomas, and mixed gliomas have significantly increased from the early 1990s forward, while the incidences of anaplastic and grade II astrocytic tumors have significantly decreased. Methods: Data for the years 1973–2004 from the Surveillance, Epidemiology and End Results (SEER) public-use data and for 1985–2004 from six collaborating registries of the Central Brain Tumor Registry of the US (CBTRUS) were obtained. SEER*Stat was used to estimate age-adjusted incidence trends and annual percent change (APC) for selected histologies. Joinpoint regression was used to identify sharp changes in incidences occurring over time. Results: Using CBTRUS data, the incidences (per 100,000 person-years) of oligodendrogliomas (APC = 4.7), mixed gliomas (APC = 3.9) and anaplastic oligodendrogliomas (APC = 12.5) have all increased over time, while the incidences of astrocytoma not otherwise specified (APC = –8.1) and fibrillary astrocytoma (APC = –2.1) have decreased. Restricting the analyses to later years (1992–2004) using SEER data shows the incidence of oligodendrogliomas leveling off (APC = 0.5), while joinpoint analyses demonstrate a decreasing trend after 1998. Conclusions: This study has demonstrated that increases in oligodendroglial tumor incidence correspond to decreases in astrocytic tumor incidence over the same time period. Minimizing misclassification of glial tumors will be essential for accurately assessing incidence, survival, and mortality rates, as well as for identifying homogeneous subgroups for epidemiologic and treatment studies.

OBJECTIVE: The objective of this study was to investigate the histological correlate of 11 C-methionine (MET) PET uptake of brain gliomas by image fusion for navigated surgery. METHODS: Twenty-seven patients (18 male, 9 female; mean age 42 years; range 11-77 years; 8 low-grade and 11 high-grade astrocytomas or mixed gliomas, 8 oligodendrogliomas) underwent MET PET studies preoperatively. RESULTS: MET PET tumor uptake was detected in 26 of 27 patients (96.3%). The quantitative MET tumor standardized uptake value (SUV) ratio was significantly higher in malignant gliomas and oligodendrogliomas than in low-grade gliomas (2.76/2.62 vs. 1.67, p=0.03). Generally, qualitative visual grading of MET uptake revealed 2 main patterns: focal MET uptake in 12 and uniform global MET uptake in 11 patients. Focal uptake corresponded to malignant glioma histology in 66.7%, and uniform global uptake to oligodendroglial histology in 72.7%. In oligodendrogliomas, global MET uptake constituted 81.5% (range 53.8-135%) of the MRI T 1 tumor volume on average and was limited to the MRI FLAIR tumor volume in 86% (7/8) of patients. Tissue samples of focal MET uptake areas correlated with histological anaplasia in 66.6% (8/12 glioma patients), although 62.5% (5/8 patients) lacked MRI contrast enhancement. CONCLUSION: MET PET image fusion may facilitate the targeting of anaplastic foci in homogeneous MRI non-enhancing gliomas for biopsy, may identify oligodendroglial histology preoperatively as well as characterize biologically active tumor volumes within MRI T 1 /FLAIR tumor areas of candidate patients for resection.

Nogo or reticulon-4 (RTN4), also known as neurite outgrowth inhibitor, is a member of the reticulon family of genes. Nogo-A, one of the three isoforms, is enriched in the central nervous system (CNS). The extracellular domain of Nogo-A, Nogo-66, has neurite growth inhibitory activity that is specific for neurons and is mediated by the Nogo receptor. However, most of its functions are not known yet. We investigated whether Nogo-A modulates the migration and invasion of a glioblastoma cell line, as well as the factors that have an effect on Nogo-A. The expression of Nogo-A was evaluated using western blotting and immunohistochemistry in human brain tumor specimens. U87MG cells were transfected with a sense-Nogo-A cDNA construct (U87-Nogo-A cells expressing Nogo-A) and an empty vector (U87MG-E cells not expressing Nogo-A). The migration and invasion abilities of these cells were investigated using simple scratch and Matrigel invasion assays. Morphologic and cytoskeletal changes were documented by confocal microscopy. The proliferation rate was estimated using doubling time assay. The effects of Nogo-A on Rho activity and phosphorylated cofilin were determined by a Rho activity assay and western blotting. Among primary brain tumors, Nogo-A expression was found in a higher percentage of oligodendrogliomas (90.0%) compared with the percentage in the glioblastomas (68.4%). In addition, the percentage in mixed gliomas was 42.9%, while it was not expressed in pituitary adenomas or schwannomas. The migration and invasion abilities of the U87-Nogo-A cells were decreased compared with the control. In the U87-Nogo-A cell line, Rho activity and phosphorylated cofilin expression were also decreased and morphology became more flat in comparison with the U87MG-E cell line. Nogo-A may inhibit the migration and invasion of human malignant glioma cells via the downregulation of RhoA-cofilin signaling.

We report a novel case of a mixed choroid plexus papilloma (CPP) and ependymoma with cartilaginous differentiation. This kind of mixed tumor has not been previously reported in the English literature. The patient was a 5-year-old girl, who presented with a 1-week history of fever and numbness of the right lower limb. Magnetic resonance imaging of the brain with gadolinium revealed a heterogeneously enhancing mass in the occipital horn of the left lateral ventricle. Histologically, the tumor showed an intermixed CPP area and a low-grade papillary ependymoma-like area, which was studded with cartilage islands and psammoma bodies. In many foci, direct transition of CPP and ependymoma was observed, but there were no high-grade features. We report this novel case, describe the unique microscopic and immunohistochemical features, and speculate on the pathogenesis.

To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas. Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m2 carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men). Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%). Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.

Diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas (mixed gliomas) WHO grade II, pleomorphic xanthoastrocytomas (PXAs), pilocytic astrocytomas, and subependymal giant cell astrocytomas (SEGAs) are often referred to as low-grade gliomas. WHO grade II astrocytomas, oligodendrogliomas, and mixed gliomas are characterized by their infiltrative growth, frequent tumor recurrence and a more than 50 % risk for malignant progression. In contrast, pilocytic astrocytomas and SEGAs are circumscribed tumors amenable to a (radio)surgical cure. There are few universally accepted guidelines for the treatment of low-grade gliomas. In this review, three neurosurgeons, a neurologist, a neuropathologist, and a radiation oncologist discuss some of the difficult issues surrounding the diagnosis and treatment of low-grade gliomas from their individual points of view (i. e., classification and neuropathology, MR imaging, stereotactic biopsy, microsurgery, interstitial radiotherapy/brachytherapy, radiotherapy, wait and see strategy).