脑胶质瘤组织CMTM1、ME2表达与临床病理特征和复发的关系研究

摘要 目的：探讨脑胶质瘤组织含CKLF样MARVEL跨膜结构域的蛋白1（CMTM1）、苹果酸酶2（ME2）表达与临床病理特征和复发的关系。方法：选取2018年1月～2021年1月徐州医科大学附属医院接受切除手术的92例脑胶质瘤患者，根据术后是否复发分为复发组和未复发组。采用免疫组化法检测脑胶质瘤组织和瘤旁组织CMTM1、ME2表达，分析二者与临床病理特征的关系，采用多因素Logistic回归分析脑胶质瘤患者术后复发的影响因素。结果：与瘤旁组织比较，脑胶质瘤组织中CMTM1、ME2阳性表达率升高（P＜0.05）。不同分化程度、世界卫生组织（WHO）中枢神经系统肿瘤分类脑胶质瘤组织中CMTM1、ME2阳性表达率比较，差异有统计学意义（P＜0.05）。随访2年，92例脑胶质瘤患者术后复发率为47.83%（44/92）。多因素Logistic回归分析显示，低分化、WHO中枢神经系统肿瘤分类Ⅲ～Ⅳ级、部分切除和CMTM1、ME2阳性表达为脑胶质瘤患者术后复发的独立危险因素（P＜0.05）。结论：脑胶质瘤组织中CMTM1、ME2阳性表达率升高，与分化程度、WHO中枢神经系统肿瘤分类等级和术后复发有关，可能成为脑胶质瘤患者术后复发的辅助评估指标。     

miR-324-5p、miR-605-3p在脑胶质瘤组织的表达及与临床病理参数和预后的关系

摘要 目的：探讨微小核糖核酸（miRNA）-324-5p、miR-605-3p在脑胶质瘤组织的表达及与临床病理参数和预后的关系。方法：选取2018年1月～2019年12月徐州医科大学附属医院收治的90例脑胶质瘤患者。收集术中部分瘤组织和瘤旁组织,采用实时荧光定量聚合酶链式反应（qRT-PCR）检测miR-324-5p、miR-605-3p表达。根据脑胶质瘤组织中miR-324-5p、miR-605-3p表达的平均值分为高表达组和低表达组,采用Kaplan-Meier法分析不同miR-324-5p、miR-605-3p表达脑胶质瘤患者生存情况,采用多因素Cox回归分析脑胶质瘤患者预后的影响因素。结果：与瘤旁组织比较,脑胶质瘤组织中miR-324-5p、miR-605-3p表达降低（P＜0.05）。不同分化程度、淋巴结转移、世界卫生组织（WHO）中枢神经系统肿瘤分类的脑胶质瘤患者miR-324-5p、miR-605-3p表达比较有差异（P＜0.05）。90例脑胶质瘤患者3年总生存率为36.67%（33/90）。Kaplan-Meier生存曲线分析显示,miR-324-5p高表达组、miR-605-3p高表达组总生存率高于miR-324-5p低表达组、miR-605-3p低表达组（P＜0.05）。多因素Cox回归分析显示,低分化、淋巴结转移和WHO中枢神经系统肿瘤分类Ⅲ～Ⅳ级为脑胶质瘤患者死亡的独立危险因素,miR-324-5p和miR-605-3p升高为独立保护因素（P＜0.05）。结论：脑胶质瘤组织中miR-324-5p、miR-605-3p呈低表达,与分化程度、淋巴结转移、WHO中枢神经系统肿瘤分类有关,miR-324-5p、miR-605-3p低表达还可导致不良预后。     

胶质母细胞瘤组织转录因子叉头框 C1、D1的表达及其临床意义

摘要 目的：研究胶质母细胞瘤（GBM）组织转录因子叉头框C1（FOXC1）、叉头框D1（FOXD1）的表达及临床意义。方法：选取自2018年2月至2021年10月期间广西壮族自治区人民医院诊治的98例GBM患者,取胶质瘤组织作为研究样本（GBM组）,以同期因颅脑损伤接受内减压术切除的40例患者,取正常脑组织样本作为对照组。采用免疫组化法检测GBM组及对照组中FOXC1、FOXD1的表达。Kaplan-Meier生存分析（Log-Rank检验）不同FOXC1,FOXD1表达的GBM患者生存预后的差异。单因素及多因素Cox比例回归风险模型分析影响GBM患者生存预后的因素。结果：GBM组中FOXC1,FOXD1蛋白主要定位于细胞核。GBM组中FOXC1,FOXD1蛋白阳性表达率为67.35%,65.31%,明显高于对照组的12.50%,10.00%（均P＜0.05）。GBM 组中FOXC1,FOXD1的表达与肿瘤直径及WHO中枢神经系统肿瘤分级有关（P＜0.05）。随访1年,死亡60例,1年总生存率为38.78%。FOXC1阳性组和FOXC1阴性组1年总生存率分别为27.27%,62.50%。FOXD1阳性组和FOXD1阴性组1年总生存率分别为26.56%,61.76%。Kaplan-Meier生存分析显示,FOXC1阳性组累积总生存率明显低于FOXC1阴性组,FOXD1阳性组累积总生存率明显低于FOXD1阴性组（均P＜0.05）。经多因素Cox回归分析结果显示术前KPS评分<80分、WHO中枢神经系统肿瘤分级Ⅲ～Ⅳ级、无术后放疗、无术后替莫唑胺化疗、FOXC1阳性、FOXD1阳性是GBM患者不良生存预后的独立危险因素。结论：GBM组织FOXC1,FOXD1阳性表达升高,两者与肿瘤直径及WHO中枢神经系统肿瘤分级有关,是GBM患者不良预后的独立危险因素。     

脑胶质瘤组织miR-211、miR-374、miR-510表达水平与临床病理特征及预后的关系研究

摘要 目的：探讨脑胶质瘤组织微小RNA（miR）-211、miR-374、miR-510表达水平与临床病理特征及预后的关系。方法：选择2013年8月至2015年8月我院诊治的83例脑胶质瘤患者作为研究对象,选择同期由于脑外伤在我院行内减压术切除的正常脑组织样本31份作为对照样本。采用荧光定量PCR检测miR-211、miR-374、miR-510表达水平,生存分析采用Kaplan-Meier法,应用Cox比例风险回归模型分析预后的影响因素。结果：与正常脑组织相比,脑胶质瘤组织中miR-211、miR-374表达水平明显下降,miR-510表达水平明显升高（P<0.05）。脑胶质瘤组织miR-211、miR-374、miR-510表达均与WHO分级和卡氏功能状态量表(KPS)评分有关（P<0.05）。miR-211、miR-374低表达患者的5年总生存率明显低于高表达患者,miR-510低表达患者的5年总生存率明显高于高表达患者（P<0.05）。WHO分级、KPS评分、miR-211、miR-374和miR-510表达是脑胶质瘤患者预后的影响因素（P<0.05）。结论：脑胶质瘤组织中miR-211和miR-374表达下调,而miR-510表达上调,miR-211、miR-374和miR-510表达均与WHO分级、KPS评分和预后相关,检测miR-211、miR-374和miR-51在脑胶质瘤患者的诊断和治疗中具有一定临床意义。     

WBSCR22在脑胶质瘤中的表达与临床病理特征及预后关系

摘要 目的：探索WBSCR22在脑胶质瘤中的表达及与临床病理特征和预后的关系。方法：通过生物信息学数据库,分析WBSCR22表达与脑胶质瘤生存的关系、在不同种族脑胶质瘤表达差异。通过免疫组织化学法检测WBSCR22在171例脑胶质瘤组织芯片中的表达,分析其与脑胶质瘤患者临床病理特征及总生存期的关系。结果：生物信息学分析显示脑胶质瘤WBSCR22表达高的患者生存期较表达低的患者短（P<0.05）。亚洲人群脑胶质瘤中WBSCR22表达较高加索人、非洲人种表达升高（P<0.05）。组织芯片学结果显示：不同肿瘤分级、复发与否的脑胶质瘤患者WBSCR22的表达存在差异,差异具有统计学意义（P<0.05）。不同性别、年龄患者脑胶质瘤细胞 WBSCR22表达率比较,差异无统计学意义（P＞0.05）WBSCR22高表达患者的总生存期明显短于WBSCR22低表达患者的总生存期（P<0.01）。结论：WBSCR22在亚洲人群脑胶质瘤中表达较高,其表达水平与肿瘤分级相关,且脑胶质瘤细胞WBSCR22表达水平越高,总生存期越短。     

脑胶质瘤组织长链非编码RNA FTX、RHPN1-AS1表达与预后的关系

摘要 目的：探讨脑胶质瘤组织长链非编码核糖核酸(LncRNA) FTX、RHPN1-AS1表达与预后的关系。方法：选取我院105例脑胶质瘤患者手术切除的癌组织和癌旁组织（距离肿瘤边缘3~5 cm）。采用实时荧光定量PCR（qRT-PCR）检测组织中LncRNA FTX、RHPN1-AS1表达。分析LncRNA FTX、RHPN1-AS1表达与脑胶质瘤患者临床病理特征的关系。K-M法绘制不同LncRNA FTX、RHPN1-AS1表达脑胶质瘤患者术后5年无进展生存期和总生存期曲线。Cox回归分析脑胶质瘤患者预后不良的影响因素。结果：脑胶质瘤组织中LncRNA FTX、RHPN1-AS1表达水平高于癌旁组织(P＜0.05)。LncRNA FTX、RHPN1-AS1表达与脑胶质瘤患者卡氏体力状态(KPS)评分和世界卫生组织(WHO)分级相关(P＜0.05)。LncRNA FTX、RHPN1-AS1高表达组无进展生存期和总生存期均短于低表达组(P＜0.05)。KPS评分(HR=2.621,95%CI：1.284～5.348)、WHO分级(HR=2.264,95%CI：1.152～4.449)、LncRNA FTX(HR=1.997,95%CI：1.017～3.922)、LncRNA RHPN1-AS1(HR=2.431,95%CI：1.257～4.701)均是脑胶质瘤患者预后不良的影响因素(P＜0.05)。结论：脑胶质瘤组织中LncRNA FTX、RHPN1-AS1表达水平升高,且二者与KPS评分、WHO分级均是患者预后不良的影响因素,可用于脑胶质瘤患者预后评估。     

脑胶质瘤患者血清VTN、IGFBP、UBE2C水平与临床病理特征和预后的关系研究

摘要 目的：研究脑胶质瘤患者血清玻连蛋白（VTN）、类胰岛素样生长因子结合蛋白（IGFBP）、泛素耦联酶2C（UBE2C）水平与临床病理特征和预后的关系。方法：将新疆医科大学第一附属医院从2019年1月～2020年1月收治的97例脑胶质瘤患者纳入研究,记作研究组,另取同期于本院进行体检的健康志愿者90例作为对照组。此外,对所有研究组人员均进行为期1年的随访,将其按照随访结局的差异分作死亡组40例和存活组57例。检测并比较各组血清VTN、IGFBP、UBE2C水平,分析血清VTN、IGFBP、UBE2C水平与脑胶质瘤患者临床病理特征和预后的关系,并以受试者工作特征（ROC）曲线分析血清VTN、IGFBP、UBE2C水平预测脑胶质瘤患者死亡的效能。结果：研究组血清VTN、IGFBP及UBE2C水平均高于对照组（均P＜0.05）。肿瘤大小≥5 cm、世界卫生组织（WHO）分级为Ⅲ～Ⅳ级、Karnofsky功能状态（KPS）＜70分脑胶质瘤患者的血清VTN、IGFBP水平均高于肿瘤大小＜5 cm、WHO分级为Ⅰ～Ⅱ级、KPS评分≥70分的脑胶质瘤患者（均P＜0.05）;WHO分级为Ⅲ～Ⅳ级、KPS评分＜70分脑胶质瘤患者的血清UBE2C水平高于WHO分级为Ⅰ～Ⅱ级、KPS评分≥70分的脑胶质瘤患者（均P＜0.05）。死亡组血清VTN、IGFBP、UBE2C水平均高于存活组（均P＜0.05）。经ROC曲线分析发现：血清VTN、IGFBP、UBE2C水平联合检测预测脑胶质瘤患者死亡的曲线下面积、灵敏度、特异度及约登指数均高于上述三项指标单独检测。结论：脑胶质瘤患者血清VTN、IGFBP、UBE2C水平均存在异常高表达,且与肿瘤恶性进展相关,联合检测可能有利于预测患者的预后。     

胶质瘤中CT联合MR动态扫描的诊断价值及其表观弥散系数的定量研究

摘要 目的：探讨胶质瘤中电子计算机断层扫描（CT）联合核磁共振（MR）动态扫描的诊断价值及其表观弥散系数（ADC）定量价值,以促进胶质瘤的有效早期诊断。方法：2017年4月到2021年3月选择在本院进行诊治的颅内肿瘤患者68例作为研究对象,所有患者均给予CT联合MR动态扫描,记录ADC值并判断诊断价值。结果：在68例患者中,病理诊断为胶质瘤38例（胶质瘤组）,非胶质瘤30例（非胶质瘤组）。胶质瘤组的CT出血、水肿、跨中线、界限不清等特征与非胶质瘤组对比差异有统计学意义（P<0.05）。胶质瘤组多表现为T1WI低信号、T2WI高信号,非胶质瘤组多表现为T1WI等信号或低信号、T2WI高信号,对比差异有统计学意义（P<0.05）。胶质瘤组的MR ADCmax、ADCmedian、ADCmin都低于非胶质瘤组（P<0.05）。胶质瘤中CT联合MR动态扫描诊断为胶质瘤37例,非胶质瘤31例,CT联合MR动态扫描诊断胶质瘤的敏感性与特异性为97.4 %（37/38）和100.0 %（30/30）。结论：CT联合MR动态扫描诊断胶质瘤具有很好的敏感性与特异性,ADC值能有效反映病灶组织的病理特征,为临床上提供了一种较为安全、有效的胶质瘤影像检查方法。     

成人胶质瘤诊断的分子遗传学研究进展

胶质瘤是目前中枢神经系统中常见的恶性肿瘤,由于脑组织的特殊性,胶质瘤呈弥漫浸润性生长,恶性程度高,手术难以完整切除且易复发。2007年(第四版)WHO中枢神经系统肿瘤病理学和遗传学对胶质瘤进行了详细的组织学分类,但是循证医学发现依靠组织学的病理诊断标准并不能对胶质瘤的临床表现和预后评估作出精准的判断。近年来全世界都在开展胶质瘤相关的遗传学研究,许多遗传学分子改变被发现,如异柠檬酸脱氢酶(IDH)突变、染色体1p/19q缺失、TP53突变、ATRX突变和TERT启动子突变等,组织学诊断受到了挑战。因此更多的病理科和神经外科医生结合组织形态和遗传学改变对胶质瘤作出"综合性"诊断,使得病理诊断更接近胶质瘤的生物学本质,以便更精准的指导临床治疗。     

脑胶质瘤患者术后睡眠障碍的影响因素分析及对认知功能、心理状态和康复进程的影响

摘要 目的：分析脑胶质瘤患者术后睡眠障碍的影响因素,并探讨术后睡眠障碍对机体认知功能、心理状态和康复进程的影响。方法：选择2019年4月~2021年12月期间中国医科大学附属第一医院收治的260例脑胶质瘤患者。根据病例资料收集并记录患者基本信息,采用单因素和多因素Logistic回归分析脑胶质瘤患者术后睡眠障碍的影响因素。以匹茨堡睡眠质量指数量表（PSQI）评估所有患者的睡眠质量;以简易智力状态检查量表（MMSE）、蒙特利尔认知评估量表（MoCA）评估所有患者的认知功能;以焦虑自评量表（SAS）评分和抑郁自评量表（SDS）评估所有患者的心理状态。观察睡眠障碍对机体认知功能、心理状态和康复进程的影响。结果：260例脑胶质瘤患者中,出现睡眠障碍的有98例,睡眠障碍发生率为37.69%。根据是否发生睡眠障碍将患者分为睡眠障碍组（n=98）和无睡眠障碍组（n=162）。单因素分析结果显示：脑胶质瘤患者术后睡眠障碍与性别、肿瘤部位、脑胶质瘤病理分级、肿瘤直径、合并疾病数量、术后疼痛评分有关（P<0.05）,而与年龄、体质量指数、文化程度、家庭人均月收入、手术时间、术中出血量、肿瘤占位症状、吸烟史、饮酒史、术前卡式功能状态（KPS）评分无关（P>0.05）。多因素Logistic回归分析结果显示：性别为女、合并疾病数量2种及其以上、术后疼痛评分偏高、肿瘤部位为多个脑叶、脑胶质瘤病理分级为Ⅲ级是脑胶质瘤患者术后睡眠障碍的危险因素（P<0.05）。睡眠障碍组的MoCA、MMSE评分均低于无睡眠障碍组（P<0.05）。睡眠障碍组的SAS、SDS评分均高于无睡眠障碍组（P<0.05）。睡眠障碍组的术后恢复进食时间、首次下床活动时间、尿管拔除时间、术后住院时间均长于无睡眠障碍组（P<0.05）。结论：脑胶质瘤患者术后睡眠障碍的发生率较高,性别、术后疼痛评分、合并疾病数量、脑胶质瘤病理分级、肿瘤部位均是睡眠障碍的影响因素,睡眠障碍会影响患者的认知功能,增加抑郁焦虑程度,影响康复进程。     

Glioma-derived mutations in isocitrate dehydrogenase 2 beneficial to traditional chemotherapy

Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. In the present study, we report that mutations of IDH1 and IDH2 are not detected in the rat C6 glioma cell line model, which suggests that these mutations are not required for the development of glioblastoma induced by N,N′-nitroso-methylurea. The effects of IDH2 and IDH2^R172G on C6 cells proliferation and sensitivity to chemotherapy and the possible mechanism are analyzed at the cellular level. IDH1 and IDH2 mutations lead to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2HG), respectively, and result in lowering NADPH levels even further. The low NADPH levels can sensitize tumors to chemotherapy, and account for the prolonged survival of patients harboring the mutations. Our data extrapolate potential importance of the in vitro rat C6 glioma cell model, show that the IDH2^R172G mutation in gliomas may give a benefit to traditional chemotherapy of this cancer and serve as an important complement to existing research on this topic.     

The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma

BackgroundMalignant gliomas have disproportionally high morbidity and mortality. Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1^R132H requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, loss of IDH1^R132H heterozygosity is associated with glioma progression in an IDH1-wildtype-like phenotype. Although previous studies have reported that transgenic IDH1^R132H induces the expression of nestin—a neural stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with better outcome of IDH1^R132H glioma because of a negative association of nestin with overall survival.MethodsGene expression was compared between IDH1^R132H-hemizygous and IDH1^R132H-heterozygous glioma cells under adherent and spheroid growth conditions. The results were validated for (D)-2-hydroxyglutarate responsiveness by pharmacologic agents, associations with DNA methylation by bioinformatic analysis, and associations with overall survival. Bisulfite DNA sequencing, chromatin immunoprecipitation, and pharmacological approach were used.FindingsNeural stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in IDH-mutant gliomas and IDH1^R132H-heterozygous spheroid growth compared respectively with IDH-wildtype gliomas and IDH1^R132H-hemizygous spheroid growth, in agreement with their negative associations with patient outcome. In contrast, CD24 is specifically upregulated and apparently associated with better survival. CD24 and NES expression respond differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in the downregulated genes.InterpretationThe better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of neural stem-cell marker genes.     

Mutation Analysis of IDH1 in Paired Gliomas Revealed IDH1 Mutation Was Not Associated with Malignant Progression but Predicted Longer Survival

Recurrence and progression to higher grade lesions are characteristic behaviorsof gliomas. Though IDH1 mutation frequently occurs and is considered as an early event in gliomagenesis, little is known about its role in the recurrence and progression of gliomas. We therefore analysed IDH1 and IDH2 statusat codon 132 of IDH1 and codon 172 of IDH2 by direct sequencing and anti-IDH1-R132H immunohistochemistry in 53 paired samples and their recurrences, including 29 low- grade gliomas, 16 anaplastic gliomas and 8 Glioblastomas. IDH1/IDH2 mutation was detected in 32 primarytumors, with 25 low- grade gliomas and 6 anaplastic gliomas harboring IDH1 mutation and 1 low- grade glioma harboring IDH2 mutation. All of the paired tumors showed consistent IDH1 and IDH2 status. Patients were analyzed according to IDH1 status and tumor-related factors. Malignant progression at recurrence was noted in 22 gliomas and was not associated with IDH1 mutation. Survival analysis revealed patients with IDH1 mutated gliomas had a significantly longer progression-free survival (PFS) and overall survival (OS). In conclusion, this study demonstrated a strong tendency of IDH1/IDH2 status being consistent during progression of glioma. IDH1 mutation was not a predictive marker for malignant progression and it was a potential prognostic marker for gliomas of Chinese patients.     

神经胶质瘤生物标志物研究进展

神经胶质瘤(glioma)是最常见的原发性脑肿瘤,占颅内肿瘤的81%。神经胶质瘤的诊断手段与预后评估主要以影像学为主,但因神经胶质瘤的浸润性生长特点,影像学不能完全作为诊断及预后评估依据。因此,发现和鉴定全新生物标志物对神经胶质瘤的诊断、治疗和预后评估显得尤为重要。最新研究结果表明,在神经胶质瘤患者组织和血液中,多种生物标志物可用于神经胶质瘤的辅助诊断和预后评估。其中,诊断标志物包括IDH1/2基因突变、BRAF基因突变与融合、p53基因突变、端粒酶活性增加、循环肿瘤细胞和非编码RNA等。预后标志物包括1p/19p共缺失、MGMT基因启动子甲基化及基质金属蛋白酶-28、胰岛素样生长因子结合蛋白-2和CD26的表达上调和Smad4的表达下调。本文重点介绍了上述神经胶质瘤生物标志物在诊断和预后评估方面的最新研究进展。     

IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis

Background

Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.

Methodology and Principal Findings

An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.

Conclusion

Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.     

Autocrine BMP4 Signaling Enhances Tumor Aggressiveness via Promoting Wnt/β-Catenin Signaling in IDH1-mutant Gliomas

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1^Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1^Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1^Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.     

Glioma-derived mutations in IDH: From mechanism to potential therapy

Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. Heterozygous mutations in the IDH1 occur in the majority of grade II and grade III gliomas and secondary glioblastomas and change the structure of the enzyme, which diminishes its ability to convert isocitrate (ICT) to α-ketoglutarate (α-KG) and provides it with a newly acquired ability to convert α-KG to R(-)-2-hydroxyglutarate [R(-)-2HG]. The IDH1 and IDH2 mutations are relevant to the progression of gliomas, the prognosis and treatment of the patients with gliomas harboring the mutation. In this paper, we reviewed these recent findings which were essential for the further exploration of human glioma cancer and might be responsible for developing a newer and more effective therapeutic approach in clinical treatment of this cancer.     

磁共振灌注加权成像与弥散加权成像在脑胶质瘤分级诊断中的应用

目的:探讨磁共振灌注加权成像(perfusion weighted imaging,PWI)与弥散加权成像(diffusion weighted imaging,DWI)在脑胶质瘤分级诊断中的应用价值。方法:选取2012年1月-2017年6月在我院就诊并经病理证实为脑胶质瘤患者100例,其中高、低级别胶质瘤患者各44、56例。对所有患者行PWI、DWI检查,比较肿瘤不同区域表观扩散系数(apparent diffusion coefficient,ADC)、局部脑血流量(regional cerebral blood flow,rCBF),不同级别肿瘤实质区、瘤周水肿区rADC、rrCBF,根据ROC曲线分析rADC、rrCBF对不同级别胶质瘤的诊断阈值、敏感性、特异性。结果:与对侧相应正常脑实质比较,瘤周水肿区及肿瘤实质区ADC、rCBF均显著升高(P0.05);与瘤周水肿区比较,肿瘤实质区ADC、rCBF均显著升高(P0.05)。高级别肿瘤实质区rADC显著低于低级别肿瘤实质区(P0.05),rrCBF显著高于肿瘤实质区(P0.05)。高级别瘤周水肿区与低级别瘤周水肿区rADC间无显著差异(P0.05),高级别瘤周水肿区rrCBF显著高于低级别瘤周水肿区(P0.05)。在对高、低级别脑胶质瘤的分级中,rADC、rrCBF的曲线下面积(under the receiver operating characteristic curve,AUC)分别为0.957、0.978,均0.9。rADC诊断不同分级胶质瘤的敏感度是90.12%,特异度是95.26%,诊断阈值是13.12;rrCBF诊断不同分级胶质瘤的敏感度是92.31%,特异度是98.57%,诊断阈值是2.62。rADC与rrCBF诊断不同分级胶质瘤敏感度、特异度间无显著差异(P0.05)。结论:PWI、DWI能够为脑胶质瘤的分级诊断提供参考依据。