Difference in imaging biomarkers between transient and permanent neurological deficits after endovascular treatment of cerebrovascular aneurysms.
- 作者列表："Li Y","Kim J","Simpson D","Aagaard-Kienitz B","Niemann D","Esene IN","Ahmed A
OBJECTIVE:The literature suggests that blood-brain barrier disruption (BBBD) plays a significant role in the development of neurological events in patients with diffusion-weighted imaging (DWI) that is negative for lesions. In this prospective, single-center cohort study, the authors compared the imaging characteristics of patients suffering transient neurological events (TNEs) with those in patients suffering permanent neurological events (PNEs) after having undergone elective embolization of unruptured intracranial aneurysms. METHODS:This prospective cohort study was conducted between July 2016 and June 2019. Inclusion criteria were adults undergoing elective neuroendovascular procedures and the absence of contraindications to MRI. All subjects underwent brain MRI including postcontrast FLAIR (pcFLAIR) sequences for evaluation of BBBD within 24 hours postprocedure. RESULTS:In total, 128 patients harboring 133 unruptured aneurysms were enrolled, 109 of whom (85.2%) showed some degree of BBBD on pcFLAIR MRI and 50 of whom (39.1%) suffered an ischemic insult per DWI. In total, 23 patients (18%) suffered neurological complications, 16 of which (12.5%) were TNEs and 7 of which (5.5%) were PNEs. The median extent of BBBD was focal in asymptomatic patients as compared to hemispheric and lobar in the TNE and PNE groups, respectively (p < 0.001). The American Society of Anesthesiologists physical status classification predicted the extent of BBBD (p = 0.046).Lesions on DWI were noted in 34 asymptomatic patients (32.4%) compared to 9 patients (56.3%) with TNEs and all 7 patients (100%) with PNEs (p < 0.001). The median number of DWI lesions was 0 (range 0-18 lesions) in the asymptomatic group compared to 1.5 (range 0-8 lesions) and 8 (range 1-13 lesions) in the TNE and PNE groups, respectively (p < 0.001). Smoking (p = 0.008), older age (p = 0.002), and longer surgery (p = 0.006) were positively associated with the number of lesions on DWI.On multivariate analysis, intraarterial verapamil (p = 0.02, OR 8.01, 95% CI 1.35-47.43) and extent of BBBD (p < 0.001, OR 58.58, 95% CI 9.48-361.84) were positively associated with the development of TNEs, while intravenous infusion of midazolam during surgery (p = 0.02, OR 6.03, 95% CI 1.29-28.20) was negatively associated. An increased number of lesions on DWI was the only significant predictor for the development of PNEs (p < 0.001, OR 49.85, 95% CI 5.56-447.10). CONCLUSIONS:An increasing extent of BBBD was associated with the development of TNEs, whereas an increasing number of lesions on DWI was significantly associated with the development of PNEs. BBBD imaging using pcFLAIR may serve as a valuable biomarker for detecting subtle cerebral ischemia and stratifying the risk for ischemic events.
目的: 文献表明，在病灶阴性的弥散加权成像 (DWI) 患者中，血脑屏障破坏 (BBBD) 在神经系统事件的发展中起着重要作用。在这项前瞻性、单中心队列研究中，作者比较了短暂性神经系统事件 (TNEs) 患者与永久性神经系统事件 (PNEs) 患者的影像学特征接受选择性栓塞未破裂颅内动脉瘤后。 方法: 本前瞻性队列研究于 2016 年 7 月至 2019 年 6 月进行。纳入标准为接受择期神经血管内手术且无 MRI 禁忌症的成人。所有受试者均在术后 24 小时内接受包括对比后 FLAIR (pcFLAIR) 序列在内的脑 MRI 评估 BBBD。 结果: 总的来说，128 患者窝藏 133 未破裂动脉瘤患者，其中 109 (85.2%) 表现出一定程度的 BBBD 上 pcFLAIR 磁共振成像 (MRI) 和 50 名 (39.1%) 根据 DWI 遭受缺血损伤。共有 23 例 (18%) 患者发生神经系统并发症，其中 16 例 (12.5%) 为 TNEs，7 例 (5.5%) 为 PNEs。与 TNE 组和 PNE 组的半球和脑叶相比，无症状患者的 BBBD 中位范围为局灶性 (p <0.001)。美国麻醉医师协会身体状态分类预测 BBBD 的程度 (p = 0.046)。在 34 例无症状患者 (32.4%) 的 DWI 上观察到病灶，与 9 例 TNEs 患者 (56.3%) 和所有 7 例 PNEs 患者 (100%) 相比 (p <0.001)。无症状组 DWI 病灶的中位数为 0 (范围 0-18 个病灶)，而 1.5 (范围 0-8 个病灶) 和 8 (范围 1-13 个病灶)。分别在 TNE 和 PNE 组 (p <0.001)。吸烟 (p = 0.008) 、年龄较大 (p = 0.002) 和手术时间较长 (p = 0.006) 与 DWI 上的病灶数量呈正相关。在多变量分析中，动脉内维拉帕米 (p = 0.02，OR 8.01，95% CI 1.35-47.43) 和 BBBD 范围 (p <0.001，OR 58.58,95% CI 9.48-361.84) 与 TNEs 的发生呈正相关，而术中静脉输注咪达唑仑 (p = 0.02，OR 6.03，95% CI 1.29-28.20) 呈负相关。DWI 上病灶数量增加是 PNEs 发展的唯一显著预测因子 (p <0.001，OR 49.85，95% CI 5.56-447.10)。 结论: BBBD 的增加程度与 TNEs 的发展有关，而 DWI 上的病变数量增加与 PNEs 的发展显著相关。使用 pcFLAIR 的 BBBD 成像可能作为检测细微脑缺血和分层缺血事件风险的有价值的生物标志物。
METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.
METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.
METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.