1993年Kleihues等确定的WHO脑肿瘤组织学分类

（一）神经上皮组织肿瘤１－星形细胞来源的肿瘤（１）星形细胞瘤变异型：①纤维性星形细胞瘤;②原浆性星形细胞瘤;③肥胖性星形细胞瘤（２）间变性（恶性）星形细胞瘤（３）胶质母细胞瘤变异型：①巨细胞胶质母细胞瘤;②胶质肉瘤（４）毛细胞性星形细胞瘤（５）多形性黄色星形细胞瘤（６）室管膜下巨细胞星形细胞瘤（常伴结节性硬化）２－少突胶质细胞来源肿瘤（１）少突胶质细胞瘤（２）间变性（恶性）少突胶质细胞瘤３－室管膜细胞来源肿瘤（１）室管膜瘤变异型：细胞型、乳头型、透明细胞型（２）间变性（恶性）室管膜瘤（３）粘液乳…     

脑胶质瘤的分子靶向治疗

间变星形细胞瘤或间变少枝胶质细胞瘤与胶质母细胞瘤,统称为高级别胶质母细胞瘤。其中,恶性度最高的,即恶性多形性胶质母细胞瘤(简称:恶性胶母瘤),其发病率约占所有颅内肿瘤的12%～15%、占所有星形细胞肿瘤的50%～60%。恶性多     

人脑星形细胞瘤中肿瘤相关抗原RCAS1的表达

目的探讨表达于SiSo细胞系上的受体结合癌抗原(RCAS1)在星形细胞瘤中的表达情况,及其与肿瘤病理分级的关系.方法用免疫组织化学方法检测RCAS1的表达,研究对象为6例正常脑组织、13例毛细胞型星形细胞瘤、25例弥漫型星形细胞瘤、20例间变型星形细胞瘤、13例胶质母细胞瘤.结果 RCAS1在人脑星形细胞瘤中的总表达率为60.1%, RCAS1的表达与肿瘤级别呈正相关(P<0.001),间变型星形细胞瘤与胶质母细胞瘤之间的阳性表达细胞计分差异有显著性(P<0.01).结论 RCAS1是人脑星形细胞瘤的新的肿瘤相关抗原,其表达与胶质母细胞瘤的形成相关.     

影响恶性胶质瘤生存预后的临床因素分析

目的 探讨与大脑半球恶性胶质瘤生存预后相关的临床因素. 方法 选择中山大学附属第一医院神经外科自2004年1月至2009年12月收治的194例恶性胶质瘤患者,其中间变性星形细胞瘤120例,胶质母细胞瘤74例,随访其生存状况,Kaplan-Meier生存分析与Cox多元同归分析患者无进展生存时间与总生存时间的影响因素. 结果 间变性星形细胞瘤和胶质母细胞瘤患者的无进展生存时间分别为18、10个月,总生存时间分别为21、12个月;Kaplan-Meier生存分析法显示年轻、KPS评分高、肿瘤无强化、术前有抽搐症状及间变性星形细胞瘤患者无进展生存时间及总生存时间均较长,差异有统计学意义(P＜0.05); Cox多元回归分析显示患者年龄、KPS评分、有无抽搐、病理分级是无进展生存时间、总生存时间的影响因素,年轻、KPS评分较高、有抽搐症状、间变性星形细胞瘤患者无进展生存时间与总生存时间较长. 结论 年龄较小、高KPS评分、间变性星形细胞瘤及术前有抽搐症状被提示是恶性胶质瘤患者获得较长生存期的保护因素,而性别、肿瘤部位、大小和手术切除程度对预后无影响,肿瘤强化与预后的关系有待进一步研究证实.     

高级磁共振成像技术在脑星形细胞瘤分级诊断中的应用进展

<正>2016版WHO中枢神经系统肿瘤分类标准首次将分子遗传学标志物应用于中枢系神经统肿瘤的分类与分型,其中星形细胞肿瘤分为级弥漫性星形细胞瘤(WHO分级Ⅱ级)、间变性星形细胞瘤(WHO分级Ⅲ级)和原发性胶质母细胞瘤(WHO分级Ⅳ级),     

颅内胶质肉瘤（附15例报告）

胶质肉瘤是由恶性胶质成分和肉瘤成分组成的少见的原发中枢神经系统肿瘤。在临床上，胶质肉瘤和胶质母细胞瘤或间变性星形细胞的表现相似。本文报告了１５例胶质肉瘤，就其临床表现和病理与胶质母细胞瘤或间变性星形细胞瘤的主要不同点，结合文献进行讨论。     

后装192Ir间质内放射治疗复发性脑胶质瘤

资料与方法1 .临床资料　患者为复发性脑胶质瘤 ,分后装治疗组和放疗组。收集首次手术后复发的脑胶质瘤6 5例 ,其中后装治疗组 35例 ,男 2 1例 ,女 1 4例 ,年龄 8～ 6 8岁 ,平均 38.6岁 ;放疗组 30例 ,男 1 7例 ,女 1 3例 ;年龄 6～ 6 7岁 ,平均 39.8岁。所有病例均经手术后病理证实为脑胶质瘤 ,后装机组星形细胞瘤Ⅱ级 1 2例 ,间变型星形细胞瘤 1 4例 ,多形性胶质母细胞瘤 7例 ,少枝胶质细胞瘤 2例 ;放疗组星形细胞瘤Ⅱ级 (AⅡ ) 1 0例 ,间变型星形细胞瘤 (AA)1 3例 ,多形性胶质母细胞瘤 5例 ,少枝胶质细胞瘤 2例。术后均经CT、MRI证实…     

间变性星形细胞瘤

<正>间变性星形细胞瘤是弥漫性浸润的恶性星形细胞肿瘤,成人好发,发生于大脑半球,可能起源于WHOⅡ级弥漫性星形细胞瘤,亦可能原发,通常无低度恶性原始病变,具有进展为胶质母细胞瘤的倾向。组织学特征与弥漫性星形细胞瘤基本相似,但细胞密度、核异型性、染色质深染和核分裂象增加(图1)。局灶性或弥漫性高细胞密度是诊断依据,即使细胞密度不增加,存在足够的核分裂象亦可明确诊断。伴进行性间变者核多形性更加复杂,胞核大小、形态不一,染色质密集或分散,核仁明显、     

世界卫生组织中枢神经系统肿瘤分类(2007年)——神经上皮组织肿瘤

星形细胞肿瘤Astrocytic tumours毛细胞型星形细胞瘤Pilocytic astrocytoma(WHOⅠ级)毛细胞黏液型星形细胞瘤Pilomyxoid astrocytoma(WHOⅡ级)室管膜下巨细胞型星形细胞瘤Subependymal giant cell astrocytoma(WHOⅠ级)多形性黄色瘤型星形细胞瘤Pleomorphic xanthoastrocytoma(WHOⅡ级)弥漫性星形细胞瘤Diffuse astrocytoma(WHOⅡ级)纤维型Fibrillary(WHOⅡ级)肥胖细胞型Gemistocytic(WHOⅡ级)原浆型Protoplasmic(WHOⅡ级)间变性星形细胞瘤Anaplastic astrocytoma(WHOⅢ级)胶质母细胞瘤Glioblastoma(WHOⅣ级)巨细胞型胶质母细     

三苯氧胺联合化疗治疗恶性胶质瘤

目的探讨三苯氧胺联合化疗对恶性胶质瘤治疗的效果及毒副作用。方法29例经病理证实的恶性胶质瘤患者,间变性星形细胞瘤12例,多形性胶质母细胞瘤17例,所有患者治疗前均行外科手术及术后放射治疗。每例患者每日口服他莫昔芬40~60mg,分1~2次服用,连服6个月。并给予化疗,化疗方案为替尼泊甙,3周为1周期。传统治疗的21例恶性胶质瘤患者,间变性星形细胞瘤8例,多形性胶质母细胞瘤13例,手术及放射治疗后仅口服洛莫司汀,6~8周为1周期。两组化疗均给予2~4周期。结果29例联合应用三苯氧胺治疗及传统治疗的21例患者,治疗后总中位生存期分别为30.2个月、23.1个月(P<0.01),肿瘤进展期分别为21.3个月、16.5个月(P<0.05);其中间变性星形细胞瘤中位生存期为38.9个月、29.6个月(P<0.05),多形性胶质母细胞瘤为18.6个月、12.3个月(P<0.005);肿瘤进展期间变性星形细胞瘤为26.8个月、22.9个月(P>0.05),多形性胶质母细胞瘤为14.3个月、8.7个月(P<0.05)。结论三苯氧胺联合化疗较传统治疗方法有一定优势,无明显毒副作用,为恶性胶质瘤化疗提供了一种新的方案。     

Expression of cyclooxygenase (COX)-2 in astrocytic tumors and anti-tumor effects of selective COX-2 inhibitors]

Cyclooxygenase (COX)-2 of astrocytic tumors was studied by immunohistochemistry. COX-2 was expressed in 8 of 12 (75%) glioblastoma multiforme, 1 of 7 (14%) anaplastic astrocytoma, but none in astrocytoma. COX-2 was detected by an immnoblotting in 2 of 9 human glioblastoma cell lines (KNS42 and U138). In glioblastoma cell lines, NS398 and Etodolac inhibited cell proliferation and induced apoptosis. The result showed that COX-2 expression may be related with histological grades and COX-2 inhibitors will be one of promising therapeutic tools in human astrocytic tumors.     

微管相关蛋白LC3B-Ⅱ和自噬基因Beclin1在星形细胞肿瘤中的表达及其意义

目的 探讨微管相关蛋白1轻链3B(MAP1-LC3B)和自噬相关基因Beclin1在星形细胞肿瘤中的表达及其与星形细胞肿瘤病理和临床表现的相关性及意义.方法 选择上海长征医院神经外科2006年1月至2006年12月住院手术治疗的初发性星形细胞肿瘤患者62例,其中Ⅰ级(毛细胞性星形细胞瘤)4例,Ⅱ级(星形细胞瘤)23例,Ⅲ级(间变性星形细胞瘤)12例,Ⅳ级(胶母细胞瘤)23例.免疫组织化学染色检测肿瘤标本中Beclin 1的表达,免疫印迹法检测Beclin 1和MAP1-LC3B的表达并统计Beclin 1、MAP1-LC3B的表达与星形细胞肿瘤临床病理表现的关系.结果免疫组化显示Ⅰ～Ⅳ级星形细胞肿瘤中Beclin 1的表达随肿瘤级别的升高而降低,差异有统计学意义(P＜0.05).免疫印迹检测结果显示不同病理分级、生存期患者Beclin 1的表达差异有统计学意义(P＜0.05),不同病理分级患者MAP1-LC3B-Ⅱ表达的差异有统计学意义(P＜0.05);相关性分析显示MAP1-LC3B-Ⅱ、Beclin 1在星形细胞肿瘤中的表达与病理分级呈负相关关系(r=-0.334,P=0.007;r=-0.448,P=0.000),MAP1-LC3B-Ⅱ、Beclin 1在星形细胞肿瘤中的表达与生存时间呈正相关关系(r=0.285,P=0.027;r=0.359,P=0.005).MAP1-LC3B-Ⅱ和Beclin 1的表达之间也呈正相关关系(r=0.272,P=0.035).结论 MAP1-LC3B-Ⅱ和Beclin 1在胶母细胞瘤中的表达下调,自噬活性的改变可能与星形细胞肿瘤的发生、发展相关.

Abstract：

Objective To investigate the expressions of microtubule -associated protein 1 (MAP1) light chain 3B (LC3B) and autophagy-related gene Beclin1 in astrocytic tumors, and explore their correlations with the pathological features and clinical manifestations of astrocytic tumors to further reveal their roles in tumorigenesis and development of astrocytic tumors. Methods Sixty-two specimens with different-grade astrocytic tumors, including 4 with grade Ⅰ (pilocytic astrocytoma), 23 with grade Ⅱ (astrocytoma), 12 with grade Ⅲ (anaplastic astrocytoma) and 23 with grade Ⅳ (glioblastoma multiforme), were selected in our study. Immunohistochemistry was employed to detect the expression of Beclin1; the expressions of MAP 1-LC3B and Beclin1 were detected by Western blotting.The correlations between expressions of MAP 1-LC3B and Beclin 1 and both the pathological features and clinical manifestations of astrocytic tumors were analyzed. Results Immunohistochemistry showed decreased Beclin1 expression in the astrocytic tumors following the increase of tumor grades (P＜0.05).Western blotting indicated that the expressions of Beclin1 in tumors with different grades and these patients with different life cycles were significantly different (P＜0.05) and the average optical density ratio of Beclin1 in high-grade astrocytic tumors (grade Ⅲ/Ⅳ) was obviously lower than that in low-grade astrocytic tumors (grade Ⅰ/Ⅱ, P＜0.05). The expressions of LC3B-Ⅰ showed significant differences in different-grade astrocytic tumors, and the expression of LC3B-Ⅰ of grade Ⅳ tumor was statistically lower than that of grade Ⅰ, Ⅱ and Ⅲ tumors(P＜0.05). The expressions of LC3B-Ⅱ and Beclin 1 were negatively correlated to the pathological grade of the tumors (r=-0.334, P=0.007; r=-0.448, P=0.000), but positively correlated to the survival time(r=0.285, P=0.027; r=0.359, P=0.005). The expressions of LC3B-Ⅱ and Beclin 1 had a positive correlation (r=0.272, P=0.035). Conclusion Expressions of LC3B-Ⅱ and Beclin1 are down-regulated in glioblastoma multiforme; the decrease of autophagic capacity may relate to the tumorigenesis and development of astrocytic tumors.     

Altered cellular distribution and subcellular sorting of gamma-tubulin in diffuse astrocytic gliomas and human glioblastoma cell lines

Centrosome amplification is a pivotal mechanism underlying tumorigenesis but its role in gliomas is underinvestigated. The present study specifically examines the expression and distribution of the centrosome-associated cytoskeletal protein gamma-tubulin in 56 primary diffuse astrocytic gliomas (grades II-IV) and in 4 human glioblastoma cell lines (U87MG, U118MG, U138MG, and T98G). Monoclonal anti-peptide antibodies recognizing epitopes in C-terminal or N-terminal domains of the gamma-tubulin molecule were used in immunohistochemical, immunofluorescence, and immunoblotting studies. In tumors in adults (n = 46), varying degrees of localization were detected in all tumor grades, but immunoreactivity was significantly increased in high-grade anaplastic astrocytomas and glioblastomas multiforme as compared to low-grade diffuse astrocytomas (p = 0.0001). A similar trend was noted in diffuse gliomas in children but the sample of cases was too small as to be statistically meaningful. Two overlapping patterns of ectopic cellular localization were identified in both primary tumors and glioblastoma cell lines: A punctate pattern, in which gamma-tubulin was partially co-distributed with pericentrin in the pericentriolar region, and a diffuse pattern, independent of pericentrin staining, denoting a soluble pool of gamma-tubulin. Cellular gamma-tubulin was detected in both soluble and insoluble (nocodazole-resistant) fractions of glioblastoma cells. Divergent localizations of gamma-tubulin and pericentrin suggest a differential distribution of these 2 centrosome-associated proteins in glioblastoma cell lines. Our results indicate that overexpression and ectopic cellular distribution of gamma-tubulin in astrocytic gliomas may be significant in the context of centrosome protein amplification and may be linked to tumor progression and anaplastic potential.     

Biologic parameters that correlate with the prognosis of human gliomas

Much clinical and biologic data have been processed in the search for useful objective parameters to predict brain tumor behavior. Seventy cases of astrocytic glioma collected by a single clinical team were studied using a full complement of clinical procedures: follow up (7 years), histologic analysis, DNA content estimation, and cell kinetics by flow cytometry. Proliferating cell nuclear antigen (PCNA) was determined by immunocytochemical‐coupling flow cytometry (PFC) and also by counting under light microscopy (PIHC). A statistical evaluation was carried out to establish the usefulness of several parameters for glioma prognosis. The cases were histologically classified as 14 low‐grade astrocytomas, 20 anaplastic astrocytomas, and 36 glioblastomas multiforme. The survival curve showed significant differences between his‐tologic groups. Diploid populations were more frequent in low‐grade astrocytomas, and aneuploid tumors often had increased S‐phase and proliferative fractions. The PCNA‐labeled index (PCNA‐LI) increased with malignancy and correlated with histologic grading (P = 0.01). The PCNA‐LI and age segregated low‐ from high‐grade astrocytomas (including anaplastic astrocytoma and glioblastoma multiforme), but none of the variables considered differentiated anaplastic astrocytoma from glioblastoma multiforme. The Cox regression test displayed significant values for age, histologic diagnosis, and PCNA determinations when considered in tandem. Discriminant analysis obtained a function integrating age and specifically PIHC‐LI to help in the prognosis of doubtful cases. The results emphasize the importance of parameters integrating different variables in an attempt to provide an accurate prognosis, the most significant being age, histopathologic diagnosis, and the proliferative fraction determined by PCNA.     

Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression

Podoplanin (aggrus) is a mucin-like transmembrane sialoglycoprotein that is expressed on lymphatic endothelial cells. Podoplanin is putatively involved in cancer cell migration, invasion, metastasis, and malignant progression and may be involved in platelet aggregation. Previously, we showed upregulated expression of podoplanin in central nervous system (CNS) germinomas, but not in non-germinomatous germ cell tumors, except for parts of immature teratomas in limited numbers. However, little information exists about its role in CNS astrocytic tumors. In this study, 188 astrocytic tumors (30 diffuse astrocytomas, 43 anaplastic astrocytomas, and 115 glioblastomas) were investigated using immunohistochemistry with an anti-podoplanin antibody, YM-1. In 11 of 43 anaplastic astrocytomas (25.6%) and in 54 of 115 glioblastomas (47.0%), podoplanin was expressed on the surface of anaplastic astrocytoma cells and glioblastoma cells, especially around necrotic areas and proliferating endothelial cells. However, the surrounding brain parenchyma was not stained by YM-1. On the other hand, podoplanin expression was not observed in diffuse astrocytoma (0/30: 0%). Furthermore, we investigated the expression of podoplanin using quantitative real-time PCR and Western blot analysis in 54 frozen astrocytic tumors (6 diffuse astrocytomas, 14 anaplastic astrocytomas, and 34 glioblastomas). Podoplanin mRNA and protein expression were markedly higher in glioblastomas than in anaplastic astrocytomas. These data suggest that podoplanin expression might be associated with malignancy of astrocytic tumors.     

p53 protein alterations in adult astrocytic tumors and oligodendrogliomas

BACKGROUND: p53 is a tumor suppressor gene implicated in the genesis of a variety of malignancies including brain tumors. Overexpression of the p53 protein is often used as a surrogate indicator of alterations in the p53 gene. AIMS: In this study, data is presented on p53 protein expression in adult cases (>15 years of age) of astrocytic (n=152) and oligodendroglial (n=28) tumors of all grades. Of the astrocytic tumors, 86% were supratentorial in location while remaining 14% were located infratentorially - 8 in the the cerebellum and 13 in the brainstem. All the oligodendrogliomas were supratentorial. MATERIALS AND METHODS: p53 protein expression was evaluated on formalin-fixed paraffin-embedded sections using streptavidin biotin immunoperoxidase technique after high temperature antigen retrieval. RESULTS: Overall 52% of supratentorial astrocytic tumors showed p53 immunopositivity with no correlation to the histological grade. Thus, 58.8% of diffuse astrocytomas (WHO Grade II), 53.8% of anaplastic astrocytomas (WHO Grade III) and 50% of glioblastomas (WHO Grade IV) were p53 protein positive. In contrast, all the infratentorial tumors were p53 negative except for one brainstem glioblastoma. Similarly, pilocytic astrocytomas were uniformly p53 negative irrespective of the location. Among oligodendroglial tumors, the overall frequency of p53 immunopositivity was lower (only 28%), though a trend of positive correlation with the tumor grade was noted - 25% in Grade II and 31.5% in grade III (anaplastic oligodendroglioma). Interestingly, p53 labeling index (p53 LI) did not correlate with the histopathological grade in both astrocytic and oligodendroglial tumors. CONCLUSIONS: Thus, this study gives an insight into the genetic and hence biological heterogeneity of gliomas, not only between astrocytic tumors vs. oligodendrogliomas but also within astrocytic tumors with regard to their grade and location. With p53 gene therapy trials in progress, this will possibly have future therapeutic implications.     

J1‐31 protein expression in astrocytes and astrocytomas

J1‐31 is one of the astrocytic proteins, the expression of which has not been evaluated in astrocytomas. In the present study, we studied the expression of J1‐31 protein in astrocytes and astrocytomas in comparison with GFAP, p53 and Ki‐67. Materials consisted of formalin‐fixed paraffin‐embedded tissue specimens that included five cases of normal brain, 17 of gliosis, 15 of pilocytic astrocytoma (WHO grade I), 26 of low‐grade diffuse astrocytoma (WHO grade II), four of anaplastic astrocytoma (WHO grade III), and eight of glioblastoma (WHO grade IV). GFAP was highly expressed in all specimens examined. The anti‐J1‐31 antibody exhibited strong cytoplasmic staining of reactive gliosis in 17/17 (100%) cases with a higher intensity of staining than that observed in the adjacent normal astrocytes. The antibody showed reactivity with tumor cells in 12/15 (80%) cases of pilocytic astrocytoma, although intensity of staining was generally weaker and more focal than observed in reactive gliosis. J1‐31‐positive tumor cells were detected in only 9/26 (35%) cases of the low‐grade diffuse astrocytoma and none of the cases of anaplastic astrocytoma and glioblastoma. Increasing Ki‐67 indices paralleled advancing tumor grades. p53 protein was expressed more commonly in infiltrating astrocytomas compared to pilocytic astrocytoma. In conclusion, down‐regulation of J1‐31 expression correlates with advancing grade of astrocytomas. The result suggests this protein plays some role in astrocytes that is progressively lost in malignant progression. The anti‐J1‐31 antibody may help further our understanding of astrocytes in disease and may be useful as an aid in the pathologic diagnosis of astrocytic lesions.     

Immunohistochemical study of S-phase cells in human gliomas

Intermediate filament proteins are cytoskeletal components in most vertebrate eukaryotic cells and some of these proteins are recognized markers of cell differentiation. To investigate the expression of intermediate filament proteins of the S-phase cells in human glial tumors, we have examined fourteen patients with benign and malignant gliomas by immunohistochemical study using in vivo labeling with bromodeoxyuridine (BrdU). Five glioblastoma multiforme, five anaplastic astrocytoma, three fibrillary astrocytoma and one gemistocytic astrocytoma were studied. All patients were given intravenous infusion of BrdU (10 mg/kg) one hour before craniotomy for labeling the S-phase cells of the tumors. Surgical specimens were immersed in 70% ethanol, and embedded in paraffin. Four micron sections were immunostained with anti-BrdU monoclonal antibody (Mab) and anti-vimentin Mab by avidin-biotin complex (ABC) method, and anti-glial fibrillary acidic protein (GFAP) serum by peroxidase-antiperoxidase (PAP) method. All sections (except for case 4) were double-labeled with anti-BrdU Mab and anti-GFAP serum, or with anti-BrdU Mab and anti-vimentin Mab. The population of BrdU-labeled cells (i.e. S-phase cells), and double-labeled cells were analyzed. The proportions of BrdU-labeled cells ranged from 6.1% to 17.0% (average 11.1%) in glioblastoma multiforme, from 3.5% to 15.6% (average 8.8%) in anaplastic astrocytoma, and from 2.0% to 2.8% (average 2.5%) in fibrillary astrocytomas. One gemistocytic astrocytoma showed S-phase fraction of 1.7%. Two recurrent cases of anaplastic astrocytoma showed higher S-phase fractions than other non-recurrent cases of anaplastic astrocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival

Diffuse astrocytic gliomas are the most common human glial tumors with glioblastoma being the most malignant form. Epidermal growth factor receptor (EGFR) gene amplification is one of the most common genetic changes in glioblastoma and can lead to the activation of various downstream signaling molecules, including STAT3, MAPK, and AKT. In this study, we investigated the activation status of these 3 signaling molecules as well as wild-type (EGFRwt) and mutant (EGFRvIII) EGFR in 82 malignant astrocytic gliomas (55 glioblastomas and 27 anaplastic astrocytomas) using immunohistochemistry. The presence of EGFRwt, but not EGFRvIII, immunopositivity correlated significantly with prevalent EGFR gene amplification in glioblastomas. STAT3 and AKT activation correlated significantly with EGFR status, although the correlation for p-STAT3 was attributed exclusively to EGFRvIII. The distribution of these 3 activated molecules varied significantly with tumor grade; although activation of STAT3 was essentially identical between anaplastic astrocytomas and glioblastomas, an increase in the activation of MAPK and AKT appeared to correlate with the progression of anaplastic astrocytoma to glioblastoma. Finally, activated STAT3 and AKT were marginally predictive of improved and worse prognosis, respectively. Taken together, these findings begin to elucidate the interrelationship between these signaling pathways in astrocytic gliomas in vivo.     

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas

WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6-4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.