胶质瘤中端粒酶逆转录酶启动子区突变分析及其预后意义

目的:探讨端粒酶逆转录酶(TERT)启动子区突变与胶质瘤患者临床病理指标的关系及其对预后的影响。方法:应用Sanger测序技术检测78例脑胶质瘤组织中TERT启动子区C228T和C250T位点的突变情况,分析TERT启动子区突变与临床病理指标的关系及其对预后的影响。结果:TERT启动子区突变在脑胶质瘤中的发生率为32.1%,在低级别(Ⅰ~Ⅱ)和高级别(Ⅲ~Ⅳ)胶质瘤中突变分别占28.0%和34.0%。其中少突星形细胞瘤中突变占57.1%,胶质母细胞瘤中突变占44.4%,低级别星形细胞瘤和少突胶质细胞瘤中突变分别占28.6%和23.1%。TERT启动子区突变与胶质瘤患者术后生存时间显著相关,突变型术后生存时间显著短于野生型(P=0.001)。按低级别和高级别分组独立分析后发现,TERT启动子区突变在低级别组和高级别组中均与不良预后相关(P值分别为0.019和0.018)。Cox回归分析表明,TERT启动子区突变和术后放化疗是独立的预后影响因素(P=0.002,HR=3.486,95%CI: 1.591 ~7.637;P=0.004,HR=0.331,95%CI:0.156～0.699)。结论:TERT启动子区突变频繁发生于脑胶质瘤中,突变型胶质瘤患者预后不良。     

DH1基因突变及MGMT基因启动子

摘 要：［目的］ 探讨IDH1基因突变及MGMT基因启动子甲基化状态在指导胶质瘤患者临床化疗和预后判断的意义。［方法］ 运用PCR测序和焦磷酸测序方法对190例胶质瘤患者的肿瘤标本分别进行IDH1基因突变和MGMT基因启动子甲基化状态分析;分析两者与胶质瘤患者临床病理特征及预后的关系。［结果］ 胶质瘤中IDH1基因突变在不同年龄（P=0.026）、病理分级（P=0.020）、KPS评分（P=0.004）组间分布差异有统计学意义;而在不同性别（P=0.900）、p53表达（P=0.878）、肿瘤幕上幕下位置（P=0.106）组间分布差异无统计学意义。MGMT基因启动子甲基化在不同年龄（P=0.488）、性别（P=0.447）、病理分级（P=0.287）、KPS评分（P=0.077）、p53表达（P=0.970）及肿瘤幕上与幕下位置不同（P=0.915）。IDH1基因突变型组与野生型组30个月总生存期差异有统计学意义（P=0.002）,高级别胶质瘤术后化疗患者MGMT基因启动子甲基化组与非甲基化组30个月总生存期差异有统计学意义（P=0.049）。［结论］ IDH1基因突变可作为判断胶质瘤患者预后的指标,而MGMT基因启动子甲基化可作为指导化疗的重要指标。     

基于IDH1基因检测联合体外药敏试验的恶性脑胶质瘤个体化综合治疗的疗效评价

目的:研究恶性脑胶质瘤患者异柠檬酸脱氢酶-1（isocitrate dehydrogenase-1，IDH1）突变状态与体外药敏试验结果相关性，以及基于二者的恶性脑胶质瘤患者个体化综合治疗的疗效评价。方法:选择术后病理确诊为恶性脑胶质瘤的患者67例，用Sanger测序法检测IDH1基因突变状态，并取其新鲜标本采用胶滴肿瘤药敏检测技术（CD-DST法）进行体外药敏试验，分析二者之间关联性。根据是否按照体外药敏实验结果进行规范疗程的化疗，将患者分为个体化治疗组和非个体化治疗组，比较两组患者临床疗效。结果:67例患者中，IDH1基因突变者14例，未突变者53例，IDH1基因突变患者卡莫司汀（BCUN）、依托泊苷（VP-16）、替莫唑胺（TMZ）体外药敏试验敏感性高于IDH1野生型患者，差异具有统计学意义（P<0.05）。IDH1基因突变患者中位生存期为30个月，IDH1野生型患者为14个月，差异具有统计学意义（P<0.05）。个体化治疗组患者中位生存时间为22个月，非个体化治疗组患者中位生存时间为14个月，差异具有统计学意义（P<0.05）。IDH1基因突变并行个体化治疗亚组中位生存时间为32个月，明显长于其他亚组，差异具有统计学意义（P<0.05）。结论:IDH1基因检测联合体外药敏试验指导恶性脑胶质瘤患者的个体化综合治疗能获得较好的临床疗效。     

胶质瘤中异柠檬酸脱氢酶的检测及其临床意义

目的 分析异柠檬酸脱氢酶(IDH)在胶质瘤中的突变情况,探讨IDH基因突变对胶质瘤的诊断和预后意义.方法 通过Sanger DNA测序法检测胶质瘤中IDH基因突变情况,同时比较分析IDH突变在不同人群中的突变频率以及对预后的影响.结果 20例胶质瘤患者中发现IDH突变7例,均为IDH1 R132H(C.395G＞ A)突变,突变率为35.0％;存在IDH突变的胶质瘤患者无进展生存期和总生存期优于IDH野生型患者.结论 IDH突变对胶质瘤的辅助诊断和预后判断具有重要的临床意义.     

磁共振动态磁敏感对比增强成像在术前脑胶质瘤分级诊断及IDH突变状态评估中的应用价值

目的:探讨动态磁敏感对比增强磁共振成像在胶质瘤术前分级诊断及IDH突变状态评估中的应用价值。 方法:纳入我院经病理确诊脑胶质瘤71例［30例低级别胶质瘤（low-grade glioma，LGG），41例高级别胶质瘤（high-grade glioma，HGG）,41例IDH突变型（isocitrate dehydrogenase mutant），30例IDH野生型（IDH wild type）］。术前均行常规MR平扫、增强、DWI及DSC-MRI，运用后处理工作站对各MR图像进行分析，分别测量肿瘤实质区、瘤周水肿区及对侧正常脑白质区的相对脑血容量（relative cerebral blood volume，rCBV）、相对脑血流量（relative cerebral blood flow，rCBF）、平均通过时间（mean transit time，MTT）以及达峰时间（time to peak，TTP），并计算规范化（肿瘤实质区/对侧正常脑白质区）肿瘤实质区的各参数值。所得数据经统计软件进行组间比较，并与病理分级及IDH突变状态进行相关性以及各参数诊断效能的分析。 结果:肿瘤实质区，LGG的规范化rCBF和rCBV值低于HGG（P<0.05），IDH突变型的规范化rCBF和rCBV值低于IDH野生型（P<0.05）。规范化的rCBF，rCBV值与高、低肿瘤级别间呈正相关（P<0.01），与IDH突变状态呈负相关（P<0.01）。对高、低级别胶质瘤的诊断，以rCBV值的曲线下面积最大（0.849），诊断阈值为2.2 mL/100 g，敏感性为87.8%，特异性为76.7%。对IDH突变状态的评估，以rCBV值的曲线下面积最大（0.741），诊断阈值为3.6 mL/100 g，敏感性为62.2%，特异性为90.9%。DSC预测高、低级别胶质瘤分级诊断的准确性为81.7%，预测IDH突变状态的准确性为80.0%。 结论:DSC是脑胶质瘤术前无创分级诊断及评估IDH突变状态的有效影像学技术，可在术前检测胶质瘤灌注信息判断其级别及IDH突变状态，为患者的精确诊治提供帮助。     

DH1基因检测联合CD-DST药敏指导胶质瘤术后辅助化疗的临床应用分析

摘 要：［目的］ 研究胶质瘤中异柠檬酸脱氢酶1（isocitrate dehydrogenases 1,IDH1）突变和胶滴肿瘤药敏检测技术（CD-DST）结果的关联性及指导术后辅助化疗方案的疗效分析。［方法］收集手术切除并经病理证实的高级别脑胶质瘤组织57例,新鲜标本分别对替莫唑胺等5种化疗药物进行CD-DST检测指导治疗方案,同时采用直接测序法检测肿瘤组织中IDH1基因突变情况,分析两者相关性。以CD-DST检测结果为指导治疗患者57例,比较16例行指导规范治疗与未行指导规范治疗患者的生存情况。［结果］ 57例高级别脑胶质瘤患者中IDH1突变13例（22.8%）,IDH1突变患者中位总生存时间显著性优于IDH1未突变患者（12.0个月 vs 7.5个月,P=0.002）。IDH1突变患者的替莫唑胺、Vp-16、卡铂和卡莫司汀的体外敏感率高于无IDH1突变的患者,而顺铂敏感性在有无突变组差异无统计学意义。CD-DST指导的行规范治疗与未行规范治疗患者的中位总生存时间分别为12个月和8个月,差异无统计学意义（P>0.05）。IDH1突变联合CD-DST敏感指导规范治疗患者的中位总生存时间为14个月,显著性优于其他组别(P=0.019)。［结论］ IDH1基因检测联合CD-DST技术对于高级别脑胶质瘤术后辅助化疗方案具有一定的临床指导价值。     

多发高级别胶质瘤的病理特征及复发模式

目的:探讨多发高级别胶质瘤（multiple high-grade gliomas,M-HGGs）的病理特征及复发模式。方法:回顾性分析2020年08月至2022年04月于我院放射治疗科诊疗的26例M-HGGs患者，分析其病理特征、影像特征、治疗方式及复发模式。结果:本组26例患者均行手术治疗，术后病理示IDH野生型24例，IDH突变型2例，8例（30.8%）患者伴有MGMT启动子甲基化，免疫组化显示25例p53过表达，1例阴性；Ki-67均值为（40.19±6.99）%。24例患者术后行辅助治疗，2例行保守治疗。随访时间3~20个月，19例患者复发，14例（73.7%）局部复发，5例脑部远地部位复发；复发时间1~14个月，中位无进展生存期（progression-free survival，PFS）6个月。Kaplan-Meier生存分析显示手术切除程度及术后辅助治疗与较好的PFS相关（P=0.001，P=0.000）；多变量分析同样提示手术切除程度及术后辅助治疗是改善PFS的预后因素（P=0.006，P=0.031）。结论:M-HGGs多为IDH野生型，且伴有p53过表达和高Ki-67增殖指数等不良预后指标；局部复发仍是M-HGGs最常见的复发模式，手术切除程度和术后辅助治疗可能影响M-HGGs患者的预后。     

EGFR基因突变型与野生型非小细胞肺癌脑转移预后的病例对照研究

目的：探讨表皮生长因子受体（epidermal growth factor receptor，EGFR）基因突变与非小细胞肺癌（non-small cell lung cancer，NSCLC）伴脑转移患者预后的相关性，为改善NSCLC合并脑转移患者预后、指导个体化治疗提供临床依据。方法：回顾性分析福建省立医院2013年1月1日至2018年9月30日期间收治的88例NSCLC合并脑转移患者的临床资料，随访取得患者的死亡时间，随访截止日期为2019年10月31日。收集和分析的临床资料包括性别、年龄、吸烟史、病理类型、基因检测、治疗情况、无进展生存期（progression free survival，PFS）、总生存期（overall survival，OS）等。运用生存分析（Kaplan-Meier生存时间曲线）评价EGFR突变型患者的预后，以单因素分析（log-rank检验）预测影响EGFR-TKI治疗效果的因素。结果：88例NSCLC脑转移患者有57例为EGFR突变型，其中位PFS（MPFS）为13.0个月（95%CI：11.951~14.049），明显高于EGFR野生型患者（P=0.003），患者中位生存期（median survival time，MST）为29.0个月（95%CI：20.531~37.468），明显高于EGFR野生型（P=0.001）。EGFR突变型中，Exon19-del突变组患者较Exon21 L858R突变组患者OS有延长趋势（P=0.05），Exon19-del+Exon20T790M突变组患者OS较Exon21 L858R突变组有延长趋势（P=0.077）。结论：EGFR突变组较野生型组NSCLC脑转移患者预后相对好些，且携带19外显子单一缺失突变的患者预后最好。     

高级别胶质瘤手术联合术后辅助放化疗的疗效分析（附56例）

目的:探讨高级别胶质瘤的手术和术后放化疗的治疗效果。方法:回顾性分析56例高级别胶质瘤患者的临床资料,均采用手术、术后同步放化疗及6个周期以上的替莫唑胺化疗,对其治疗效果和不良反应进行评价分析。结果:56例患者手术全切除10例（17.9%）,次全切除35例（62.5%）,部分切除11例（19.6%）。分子病理提示IDH1132H突变19例;MGMT基因启动子甲基化20例。随访过程中13例未见明显复发;35例复发;1例出现脊髓的多发转移灶;7例出现放射性脑损伤,其中3例再次手术减压,4例保守治疗。12个月、24个月和36个月总生存率分别为66.1%、50.0%和32.1%;无进展生存率分别为57.1%、39.3%和25.0%。结论:高级别胶质瘤预后不佳,术后残留、复发、转移和放射性损伤是治疗的重点和难点;MGMT基因启动子甲基化患者总体生存率和无进展生存率高于MGMT启动子未甲基化患者。     

No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas

Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 70-80 % of astrocytomas and oligodendrogliomas of WHO grades II and III, and in secondary glioblastomas. In addition, a low incidence of IDH2 mutations has been detected in these tumors, and the occurence of IDH1 and IDH2 mutations is mutually exclusive. For patients with anaplastic gliomas and glioblastomas with IDH1 mutations, overall survival was significantly longer than for patients with wild-type tumours. However, the prognostic value of IDH1 in low-grade gliomas remains ambiguous. IDH1 codon 132 and IDH2 codon 172 mutation status were determined by direct sequencing for a retrospective series of 100 patients with histologically diagnosed Astrocytomas WHO Grad II (A II), and investigated for association with patient outcome. For the patient cohort analysed, median progression-free survival (PFS) was 44.6 months (95 %-CI 1.0-267.0), time to progression (median time to malignant progression (TtMP) was 74.9 months (95 %-CI 1.6-236.2), and median overall survival (OS) was 81.4 months (95 %-CI 5.5-274.8). IDH1 mutations were identified in 79 % of the patients. IDH2 mutations were not observed. Univariate and multivariate analysis revealed no association between IDH1 mutation status and PFS, TtMP, and OS. Furthermore, there were no significant differences regarding PFS, TtMP, and OS between patients with and without IDH1 mutations who did not receive adjuvant treatment. The prognostic value of IDH1 mutations in low-grade astrocytomas is rather low compared with that in high-grade gliomas.     

Combining two biomarkers, IDH1/2 mutations and 1p/19q codeletion, to stratify anaplastic oligodendroglioma in three groups: a single-center experience

IDH1/2 mutations and 1p/19q codeletion occur frequently in anaplastic gliomas and are prognostic factors. We combined these two biomarkers to stratify patients treated for anaplastic oligodendroglioma (AO). 43 consecutive WHO AO were selected. We combined immunohistochemistry (IHC) with the monoclonal antibody mIDH1R132H and DNA sequencing of IDH1 and IDH2 genes. Fluorescence in situ hybridization was carried out to evaluate 1p/19q codeletion. These biomarkers were correlated with progression-free survival (PFS) and overall survival (OS). IDH1/IDH2 mutations occurred in 23/43 (54 %) patients: 20/43 IDH1-R132H mutation in IHC, 2/43 IDH1-R132G mutation and 1/43 IDH2-R172K mutation identified by DNA sequencing. 1p/19q codeletion was detected for 23/43 patients. With median follow-up of 19 months (range 1.4–128), median PFS and OS were 22 and 35 months respectively. IDH1/IDH2 mutations were strongly associated with improved PFS and OS: 5-year PFS was 86 versus 6 % and 5-year OS was 91 versus 9 % for patients with IDH1/IDH2 mutations versus wild-type IDH respectively. In multivariate analyses, IDH1/IDH2 mutations and 1p/19q loss were independent prognostic factors. Three groups with distinct prognostic features were identified: patients with IDH1/2 mutations and 1p/19q loss (median PFS, median OS not reached), patients with IDH1/2 mutations or 1p/19q loss (median PFS: 22 months, median OS: 30 months), and patients without IDH1/2 mutations nor 1p/19q loss with a bad prognosis (median PFS: 8.6 months, median OS: 9.9 months). Combining two biomarkers, IDH1/2 and 1p/19q codeletion, makes it possible to stratify AO in three groups with very distinct prognostic features.     

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.     

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.     

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

Mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) appear to occur frequently and selectively in gliomas. Our aim was to assess whether IDH mutations are common in Chinese glioma patients and whether the mutations predict good response to concomitant chemoradiotherapy. In this study IDH1 and IDH2 mutations were detected in a series of 203 gliomas. IDH1 mutations were present in 75 of the 203 cases (36.9%) while IDH2 mutations in 5 of the 203 cases (2.5%). No tumor was mutated in both IDH1 and IDH2. IDH1/2 mutations were associated with prolonged overall survival in the whole series of patients exclusive of pilocytic astrocytoma (P<0.001), WHO grade Ⅱ patients who received no adjuvant therapy after surgery (P=0.014) and WHO grade Ⅲ patients who received concomitant chemoradiotherapy (standard schedule) after surgery (P=0.033). Furthermore, there was no correlation between IDH1/2 mutations and reponse to concomitant chemoradiotherapy in anaplastic gliomas. Our results suggest that IDH1 mutations also occur freuqently in Chinese glioma patients but the frequency of IDH1 mutations is below the findings reported by North American and European groups. Furthermore, we confirm the prognostic significance of IDH1/2 mutations in gliomas, but the mutations cannot predict a favorable response to concomitant chemoradiotherapy in anaplastic gliomas.     

Occupational exposure to metals and risk of meningioma: a multinational case-control study

The prognosis of patients with WHO grade III gliomas is highly dependent on their genomic status such as the isocitrate dehydrogenase (IDH) 1/2 mutation and1p/19q co-deletion. However, difficulties have been associated with determining which tumors have certain genomic profiles by preoperative radiographical modalities, and the role of surgical resection in achieving better outcomes remains unclear. This retrospective study included 124 consecutive patients with newly diagnosed grade III gliomas. The genomic status of IDH1/2 and 1p/19q was analyzed in these patients. Tumors were then divided into 3 subgroups based on their genomic status; the IDH 1/2 mutation with the 1p/19q co-deletion (1p/19q co-del), the IDH 1/2 mutation without the 1p/19q co-deletion (non-1p/19q co-del), and the IDH 1/2 wild type (IDH wt). Survival times were compared between patients who underwent gross total resection and those who did not (GTR versus non-GTR). The relationships between genomic statuses and MR imaging characteristics such as ring-like or nodular enhancements by gadolinium, and very low intensity on T1-weighted images with blurry enhancements (T1VL) were also examined. Among all patients with grade III gliomas, GTR patients had longer median survival and progression-free times than those of non-GTR patients (undefined versus 87 months, p?=?0.097, and 124 versus 34 months, p?=?0.059, respectively). No significant differences were observed in survival between GTR and non-GTR patients in the 1p/19q co-del group (p?=?0.14), or between GTR and non-GTR patients in the IDH wt group (26 and 27 months, p?=?0.29). On the other hand, in non-1p/19q co-del group, survival was significantly longer in GTR patients than in non-GTR patients (undefined versus 77 months, p?=?0.005). Radiographically, T1VL was detected in most tumors in the non-1p/19q co-del group (78.2?%), but only 6 (21.4?%) and 17 (41.5?%) tumors in the 1p/19q co-del and IDH wt groups, respectively. A correlation was not found between other genomic subgroups and MR imaging findings. Strict surgical removal is important to improve the prognosis of patients with grade III gliomas, especially for tumors with the IDH 1/2 mutation without the 1p/19q co-deletion. The MR finding of T1VL can be used to select candidates for more radical resection.     

Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.     

2-Hydroxyglutarate concentration in serum from patients with gliomas does not correlate with IDH1/2 mutation status or tumor size

IDH1/2 mutations occur at high frequency in diffusely infiltrating gliomas of the WHO grades II and III and were identified as a strong prognostic marker in all WHO grades of gliomas. Mutated IDH1 or IDH2 protein leads to the generation of excessive amounts of the metabolite 2-hydroxyglutarate (2HG) in tumor cells. Here, we evaluated whether 2HG levels in preoperative serum samples from patients with gliomas correlate with the IDH1/2 mutation status and whether there is an association between 2HG levels and glioma size. In contrast to the strong accumulation of 2HG in the serum of patients with IDH1/2 mutated acute myeloid leukaemia, no accumulation was observed in this series of IDH1/2 mutated gliomas. Furthermore, we found no association between glioma size measured by magnetic resonance imaging and 2HG levels. We conclude that 2HG levels in preoperative sera from patients with diffusely infiltrating gliomas of the WHO grades II and III cannot be used as a marker to differentiate between tumors with versus without IDH1/2 mutation. Furthermore, the observation that there is no correlation between 2HG levels and tumor volume may indicate that 2HG cannot be utilized as marker to monitor tumor growth in gliomas.     

IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas

This study investigated the prognostic and predictive significance of IDH1 and IDH2 mutations in low-grade astrocytomas (LGA). The presence and consistency of IDH mutations during the progression of LGA to secondary high-grade gliomas (sHGG) were detected. Samples of patients with LGA and sHGG were investigated. The genomic regions around IDH1 codon 132 and IDH2 codon 172 were PCR amplified and directly sequenced. Furthermore, the MGMT promoter status was provided using the methylation-specific PCR. Our population comprised 71 patients with a total of 45 pairs of LGA and their consecutive sHGG. Median follow-up was 9.6 years. IDH mutations were found in 36/45 LGA (80%) and their sHGG without changes in the mutation status. A total of 71 patients with LGA were analyzed according to clinical and molecular tumor-related factors: 56/71 patients (78.8%) had an IDH mutation without significant influence on the progression-free or overall survival (OS), and 22/71 (31%) of the patients received postoperative radiotherapy (RT) after diagnosis of LGA. Patients with early RT but without IDH mutations had the shortest survival. Our study shows that IDH mutation status is stable during the progression course of LGA to sHGG. The presence of IDH mutations fails to demonstrate a significant influence on survival in the multivariate analysis of LGA patients. Early RT appears to be beneficial only LGA patients with IDH-mutations.