动态增强MRI纹理特征对胶质瘤级别及异柠檬酸脱氢酶基因表型的判断价值

目的 探讨动态增强磁共振成像(DCE-MRI)纹理特征对胶质瘤级别及异柠檬酸脱氢酶(IDH)基因表型的判断价值。方法 回顾性分析2016年1月至2020年12月于南京医科大学第一附属医院病理确诊为胶质瘤患者(36例)的临床资料,其中低级别胶质瘤(WHOⅠ～Ⅱ级,LGG组)13例,高级别胶质瘤(WHOⅢ～Ⅳ级,HGG组)23例;IDH突变型20例、野生型16例。应用DCE-MRI检查,扫描序列主要包括轴面T1WI及T2WI平扫、轴面DCE和轴面、矢状面、冠状面T1WI增强和磁共振成像液体衰减反转恢复序列(FLAIR)。比较不同级别及IDH基因表型胶质瘤的DCE-MRI纹理特征,利用血流动力学双室模型对感兴趣区(ROI)行渗透性定量分析,得到血浆容积分数(Vp)、血管外细胞外容积分数(Ve)、速率常数(Kep)、双室模型计算生成全脑的容积转运常数(Ktrans)及信号强度-时间曲线下面积(AUC)参数图。基于灰度共生矩阵法,提取能量(Ene)、熵(Ent)及逆差矩(IDM)等纹理特征,获取EneKtrans, EneKep, EneVe, EneVp, EneAUC、EntKtrans、E...     

磁敏感加权成像在评估胶质瘤级别中的价值

目的 探讨磁敏感加权成像(SWI)的特点与评估胶质瘤级别的作用.方法 45例经手术病理证实的脑胶质瘤患者术前行平扫磁共振成像(MRI)、增强MRI和SWI检查.采用双盲法对T1WI、T2WI、增强T1WI、SWI、增强SWI等方法对肿瘤、瘤周水肿、肿瘤出血及肿瘤静脉显示上进行评分,利用测量软件对肿瘤低信号区进行体积测量...     

IDH1突变在胶质瘤中的研究进展

脑胶质瘤是一种常见的颅内原发恶性肿瘤,起源于神经胶质细胞,严重影响人类的健康。随着神经肿瘤分子的发展,异柠檬酸脱氢酶-1（isocitrate dehydrogenase,IDH1）已经成为目前胶质瘤分子标志物的研究热点。IDH1的突变引起2-羟基戊二酸（2-hydroxyglutaric acid,2-HG）异常增高,进一步导致DNA和组蛋白高甲基化,目前已经成为研究的潜在靶点,这一发现能够使胶质瘤的临床治疗获益。本文概述了突变型IDH1的功能,以及目前IDH1突变在胶质瘤发生机制中的作用。此外,还讨论了IDH1突变的胶质瘤的靶向治疗、免疫治疗及临床预后。     

异柠檬酸脱氢酶基因突变在脑胶质瘤中的研究进展

异柠檬酸脱氢酶1（IDH1）基因突变在神经胶质瘤中的研究备受关注。IDH1突变导致酶原有活性下降,同时获得将α-酮戊二酸转化为2-羟戊二酸的新功能,并改变了胶质瘤的表观遗传学特征,使胶质瘤代谢重编程,破坏胶质瘤氧化还原稳态。本文简述了IDH1突变在胶质瘤中的机制、诊断价值、预后判断和靶向治疗的国内外研究进展,为IDH1突变深入研究、进一步了解胶质瘤病因及干预措施打下基础,亦为胶质瘤分子水平分类和治疗提供新思路。     

63例高级别胶质瘤中IDH1和TERT突变状态的预后价值

目的:探讨异柠檬酸脱氢酶-1（IDH1）和端粒酶逆转录酶（TERT）启动子突变对高级别胶质瘤患者的预后价值。方法:选取2014年9月至2017年6月于我院行手术切除且术后病理提示为高级别胶质瘤的患者63例（WHO Ⅲ级27例，Ⅳ级36例），完善临床资料、随访资料、分子检测结果。应用Sanger测序法检测样本中IDH1和TERT启动子突变情况，根据结果将患者分为不同亚组，通过比较其生存期的差异，分析基因突变与患者预后的关系。结果:63例高级别胶质瘤中，IDH1突变型和野生型患者的中位生存期分别为24和10个月，差异有统计学意义（P＜0.01）；TERT突变型和野生型的中位生存期无明显差异（P＞0.05）。IDH1突变为高级别胶质瘤患者预后良好的因素，TERT突变不能单独提示预后，二者联合分析提示:IDH1突变／TERT突变组预后最好，IDH1野生／TERT突变组预后最差，IDH1突变／TERT野生组预后稍好于IDH1野生／TERT野生组，四组间预后有明显差异。结论:IDH1突变的高级别胶质瘤患者有较好的临床预后，在此基础上，TERT启动子突变检测有助于进一步划分其预后分层。     

人异柠檬酸脱氢酶1（IDH1）R132 H突变型脑胶质瘤细胞的原代培养及鉴定

目的：建立简单、方便、高效的异柠檬酸脱氢酶1（IDH1）突变型胶质瘤原代细胞体外培养方法,为研究IDH1突变型脑胶质瘤提供细胞模型。方法：样本组织取自低级别脑胶质瘤手术患者,采用组织块法行原代细胞培养,倒置显微镜下观察细胞形态特点;瘤组织应用苏木精－伊红染色法（HE ）和免疫组织化学染色确定胶质瘤病理类型以及级别;原代细胞提取基因组行碱基序列测序以鉴定IDH1突变类型;采用MTT法绘制生长曲线,检测IDH1突变型细胞的体外增殖特性。结果：成功建立WHOⅡ级IDH1 R132H突变型人脑星形胶质细胞瘤细胞株,并可传代。结论：应用合适的方法以及培养液,可以培养出IDH1 R132H突变型人脑胶质瘤原代细胞。     

异柠檬酸脱氢酶1突变在胶质瘤发生中的 作用

0 引言 癌症是一种由于基因突变或染色体结构变异造成细胞恶性增殖的疾病,因此癌症发生相关基因的鉴定及生物学功能研究成为该领域的重点之一[1],至今已鉴定出大量的癌基因和抑癌基因,这些基因功能广泛,可作为生长因子、受体、激酶以及转录因子等发挥生物学活性[2],科学家估计可能还有更多相关基因未被发现,因此启动了癌症基因组计划,以寻找癌症发生的新线索.     

MGMT启动子甲基化状态与IDH1及1p/19q对脑胶质瘤患者假性进展的诊断价值

脑胶质瘤是中枢神经系统中最常见的恶性肿瘤,起源于神经上皮细胞。术后联合放化疗已成为其标准治疗的组成部分,而MRI检查是随访颅内病变的常规手段。随访中出现的影像学变化,需进行真假进展的鉴别,由于二者的临床决策不同,因此真假进展的识别极为重要,但目前尚缺乏有效的鉴别手段。MGMT启动子、异柠檬酸脱氢酶-1（IDH1）及1p/19q分子标记物与假性进展相关,分子状态与影像学结合用于真假进展的鉴别,可能成为新的探索方向。本研究将对研究现状进行梳理,分析MGMT启动子、IDH1及1p/19q分子标记物在区分真假进展中的作用,为临床鉴别及精准医疗提供新参考。      

SWI、3D-ASL及IVIM在各级脑胶质瘤分级中的价值

目的:评价磁敏感加权成像(susceptibility weighted imaging,SWI)、三维动脉自旋标记(three-dimensional arterial spin labeling,3D-ASL)成像及体素内不相干运动(intravoxel incoherent motion,IVIM)成像在鉴别II级/III级/IV级胶质瘤中的价值。方法:纳入92例脑胶质瘤患者（II级:35例,III级:13例,IV级:44例）,所有患者术前均接受SWI、3D-ASL和IVIM扫描,然后进行肿瘤内敏感性信号强度（intratumoral susceptibility signal intensity,ITSS）评分,测量肿瘤最大血流量（TBFmax）、快速表观扩散系数（fast apparent difficious,fast ADC）、慢速表观扩散系数（slow ADC）和灌注分数（perfusion fraction,f）,并将TBFmax与对侧正常白质、对侧正常灰质和镜像区的脑血流量进行对比,取相对值r1、r2和r3。探究这些参数在II级与III级、III级与IV级以及II级与IV级肿瘤之间的差异。利用受试者工作特性（receiver operating characteristic,ROC）曲线分析评估这些参数的诊断效能。结果:ITSS评分在鉴别II级与III级、III级与IV级、II级与IV级肿瘤之间有统计学差异,并且较高级别的脑胶质瘤显示出较高的ITSS评分（P<0.05）。fast ADC、slow ADC和f值在鉴别II级与III级、II级与IV级肿瘤之间有统计学差异（P<0.05）,但是TBFmax、r1、r2和r3只在鉴别II级与IV级胶质瘤中有统计学差异（P<0.05）。其中slow ADC为鉴别II级和III级提供了最高的AUC值（0.94）,ITSS评分为鉴别II级和IV级提供了最高的AUC值（0.96）,而ITSS值在鉴别III级与IV级胶质瘤中的AUC值为0.72。结论:SWI、3D-ASL和IVIM的参数可用于鉴别各级脑胶质瘤。     

IDH1 mutation detection by droplet digital PCR in glioma

Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation.     

IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma

The current World Health Organization (WHO) classification of human gliomas is mainly based on morphology. However, it has limitations in prognostic prediction. We examined whether combining isocitrate dehydrogenase (IDH) 1/2 mutation status with the Ki-67 labeling index would improve the definition of prognostically distinct entities. We investigated the correlation of Ki-67 expression with IDH1/2 mutation status and their impact on clinical outcome in 703 gliomas. Low Ki-67 expression closely overlapped with IDH1/2 mutation in our cohort (P < 0.0001). Patients with IDH1/2 mutation survived significantly longer than patients with wild-type IDH1/2 did (P < 0.0001); higher Ki-67 expression was associated with shorter progression-free survival and overall survival (OS) (P < 0.0001). IDH1/2 combined with Ki-67 was used to re-classify glioma patients into five groups. IDH1/2 mutant patients with low and moderate Ki-67 expression (Group1) had the best prognosis, whereas patients with wild-type IDH1/2 and high Ki-67 expression (Group5) had the worst prognosis (Median OS = 1527 vs. 355 days, P < 0.0001). To summarize, our new classification model distinguishes biologically distinct subgroups and provides prognostic information regardless of the conventional WHO grade. Classification based on IDH1/2 mutation status and Ki-67 expression level could be more convenient for clinical application and guide personalized treatment in malignant gliomas.     

全氟己烷脂质体纳米粒在超声造影方面价值的实验研究

目的:研究并评价基于全氟己烷的新型纳米超声造影剂的可行性。方法:本实验首先设计并成功制备了一种全新的全氟己烷（PFH）-光敏剂（IR780）脂质体纳米粒［LIP(PFH+IR780)］。该纳米粒可在近红外光激发下,由IR780产热升温,触发PFH气化产生大量微泡。对LIP(PFH+IR780)进行粒径测定、光镜成像,明确性质。并在体外及体内对该纳米粒子进行超声成像,验证LIP(PFH+IR780)的超声增强效果。结果:通过体外表征,证实该纳米粒粒径为250 nm左右。经过体外超声实验发现,LIP(PFH+IR780)较对照组使得超声回声明显增强。荷瘤小鼠体内实验发现,LIP(PFH+IR780)可以有效蓄积在肿瘤部位,并且同样使得超声图像得到显著增强。结论:LIP(PFH+IR780)纳米粒子在超声造影成像上具有一定的应用价值。     

Fully automated hybrid approach to predict the IDH mutation status of gliomas via deep learning and radiomics

BackgroundGlioma prognosis depends on isocitrate dehydrogenase (IDH) mutation status. We aimed to predict the IDH status of gliomas from preoperative MR images using a fully automated hybrid approach with convolutional neural networks (CNNs) and radiomics.MethodsWe reviewed 1166 preoperative MR images of gliomas (grades II–IV) from Severance Hospital (n = 856), Seoul National University Hospital (SNUH; n = 107), and The Cancer Imaging Archive (TCIA; n = 203). The Severance set was subdivided into the development (n = 727) and internal test (n = 129) sets. Based on T1 postcontrast, T2, and fluid-attenuated inversion recovery images, a fully automated model was developed that comprised a CNN for tumor segmentation (Model 1) and CNN-based classifier for IDH status prediction (Model 2) that uses a hybrid approach based on 2D tumor images and radiomic features from 3D tumor shape and loci guided by Model 1. The trained model was tested on internal (a subset of the Severance set) and external (SNUH and TCIA) test sets.ResultsThe CNN for tumor segmentation (Model 1) achieved a dice coefficient of 0.86–0.92 across datasets. Our hybrid model achieved accuracies of 93.8%, 87.9%, and 78.8%, with areas under the receiver operating characteristic curves of 0.96, 0.94, and 0.86 and areas under the precision-recall curves of 0.88, 0.82, and 0.81 in the internal test, SNUH, and TCIA sets, respectively.ConclusionsOur fully automated hybrid model demonstrated the potential to be a highly reproducible and generalizable tool across different datasets for the noninvasive prediction of the IDH status of gliomas.     

MSH6基因对胶质瘤易感性、耐药性和进展的影响

MutS同源物6（MutS homolog 6,MSH6）基因是一种错配修复（mismatch repair,MMR）基因,其编码的MSH6蛋白主要参与识别、修复碱基取代和单碱基插入/缺失错配。MSH6基因种系突变增加胶质瘤的肿瘤易感性,体细胞MSH6基因突变可致烷化剂的获得性耐药和胶质瘤复发,MSH6突变可导致基因组的超突变从而促进胶质瘤的进展。最新研究亦发现MSH6基因存在致癌作用,其上调将导致预后不佳。     

术前预后营养指数在脑胶质瘤患者术后预后评估中的应用

目的:探讨术前预后营养指数(prognostic nutrition index,PNI)在脑胶质瘤患者术后临床预后中的应用。方法:收集2011年1月至2017年6月四川省大邑县人民医院神经外科手术治疗且经术后病理确诊的131例初发脑胶质瘤患者的临床资料及术后生存资料,采用ROC曲线分析获得PNI的最佳临界值,依据该最佳临界值将患者分为高PNI值组及低PNI值组,采用卡方检验比较两组临床病理学特征,采用Cox比例风险回归模型分析PNI与胶质瘤患者术后临床预后的关系。结果:131例脑胶质瘤患者术后中位总生存时间（overall survival,OS）为23个月,95%CI:9.736~36.264个月,术后1年、2年、3年、5年生存率分别为76.3%、52.0%、43.0%、33.5%。ROC曲线分析,PNI的最佳临界值为48.5。低PNI值组中年龄≥45岁、行非全切手术和较低级别肿瘤分级所占的比例较高PNI值组更高(P＜0.05)。多因素Cox回归分析显示,肿瘤分级、PNI值是影响脑胶质瘤患者术后预后的独立影响因素。结论:PNI值为脑胶质瘤患者预后的独立危险因素,较低的PNI水平预示着较差的预后。PNI值可用于初步判断脑胶质瘤患者的预后。     

MR diffusion tensor and perfusion-weighted imaging in preoperative grading of supratentorial nonenhancing gliomas

We evaluate the value of MR diffusion tensor imaging (DTI) and dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted imaging (PWI) in preoperative grading of supratentorial nonenhancing gliomas. This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study involved 52 patients: 37 with low-grade gliomas (LGGs) and 15 with high-grade gliomas (HGGs). The mean trace apparent diffusion coefficient (ADC), minimal ADC, mean fractional anisotropy (FA), maximal FA, and maximal relative cerebral blood volume (rCBV) ratio of the lesions were measured and compared between LGG and HGG. The efficacy of the above parameters in grading supratentorial nonenhancing gliomas was evaluated. There was no significant difference in rCBV ratio, minimal ADC, and mean ADC between LGG and HGG (p > 0.05). The mean and maximal FA values of LGG were significantly lower than the values of HGG (p < 0.001). The receiver operating characteristic analysis showed that the mean FA with a cutoff value of 0.129 and the maximal FA with a cutoff value of 0.219 could differentiate between LGG and HGG with specificity of 69.2% and 76.9%, respectively, and sensitivity of 93.3% and 100.0%, respectively. The combination of mean FA and maximal FA based on the linear discriminant analysis improved the diagnostic accuracy with specificity of 92.3% and sensitivity of 86.7%. These findings were better than maximal rCBV ratio, mean ADC, and minimum ADC. The mean FA and maximal FA, used individually or combined, may be useful in preoperative grading of supratentorial nonenhancing gliomas.