Fluorescence lifetime technique for intraoperative identification of IDH mutations in brain cancer

荧光寿命技术用于术中识别脑癌 IDH 突变

• 批准号: 10044980
• 负责人: Orin Bloch
• 金额: $ 38.66万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044980
• 关键词: Address; Area; Basic Cancer Research; Biopsy; Brain; Brain Neoplasms; Cancer Patient; Characteristics; Classification; Clinical; Clinical Research; Complex; Consumption; Correlative Study; Craniotomy; Data; Data Collection; Data Display; Databases; Detection; Discriminant Analysis; Ensure; Excision; Fluorescence; Fluorescence Spectroscopy; Gene Mutation; Genes; Genomics; Glioblastoma; Glioma; Global Change; Goals; Harvest; Image-Guided Surgery; Imaging Techniques; Immunohistochemistry; Impairment; Isocitrate Dehydrogenase; Isocitrates; Malignant neoplasm of brain; Measurement; Measures; Metabolism; Methods; Morbidity - disease rate; Mutate; Mutation; NADP; Nervous System Trauma; Neurosurgical Procedures; Normal tissue morphology; Operative Surgical Procedures; Optics; Oxidation-Reduction; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Phase; Phenotype; Predictive Value; Primary Brain Neoplasms; Procedures; Prognostic Factor; Prognostic Marker; Property; Radio; Research; Risk; Specimen; Statistical Data Interpretation; Surgeon; Surgically-Created Resection Cavity; Techniques; Time; Tissues; Validation; Variant; Visual; alpha ketoglutarate; base; brain tissue; chemotherapy; clinically relevant; data acquisition; flexibility; fluorescence lifetime imaging; imaging detection; imaging system; improved; in vivo; interest; mutant; mutational status; neoplastic cell; neurosurgery; novel; optical imaging; response; surgery outcome; temporal measurement; tumor

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to demonstrate that brain tumors which harbor isocitrate dehydrogenases (IDH) gene mutations can be distinguished from IDH wild-type (WT) tumors intraoperatively and in real-time, based on their autofluorescence emission properties. Mutation of the IDH1/2 genes is common in low-grade gliomas (LGG) and occur infrequently in glioblastoma multiforme (GBM). The presence of IDH mutations is the greatest prognostic marker for GBM patients. Patients with IDH mutant gliomas have improved survival compared to their grade matched, WT counterparts. Importantly, recent studies suggest that the benefit of aggressive surgical resection differs between IDH-WT and IDH-mutant tumors; thus, intraoperative identification of IDH mutations will change the operative goals. Subsequently, there is a considerable interest in developing rapid, intraoperative methods to identify IDH mutations. IDH mutations cause global changes in cellular metabolism by impairing the conversion alpha-ketoglutarate (αKG) to isocitrate, which normally reduces NADP+ to NADPH. Instead, αKG is converted to 2-hydroxyglutarate, consuming NADPH to produce NADP+. Brain autofluorescence properties are highly interlinked with changes in cellular metabolism. In particular, the variation in autofluorescence emission intensity of brain tissue has been attributed to differences in NAD(P)H concentration and redox state. Also, differences in the lifetime (or decay) of autofluorescent intensities between glioma and normal brain tissues have been attributed to disparities between free- and bound-NAD(P)H. Therefore, we hypothesize that optical parameters derived from autofluorescence lifetime measurements of gliomas can be correlated to changes in cellular metabolism caused by IDH mutations. This proposal will build on previous clinical studies that demonstrate gliomas of distinct phenotypes have distinct fluorescence lifetime characteristics and our expertise with moving fluorescence lifetime imaging (FLIm) techniques into clinical settings. To accomplish our goal, we propose 2 specific aims. Aim 1: Conduct FLIm intraoperative measurements in LLG and HGG patients (N=80) undergoing conventional neurosurgical procedures. This will provide an extensive database of FLIm parameters (retrieved from both in vivo and ex vivo measurements) correlated with tissue pathology including IDH mutation status. Aim 2: Validate the utilization of FLIm as a means for real-time detection of IDH mutations. This will demonstrate the predictive value of FLIm for detection of IDH mutation status and for potential guidance during brain tumor surgery. In summary, this study will demonstrate the clinical utility of FLIm for intraoperative, real-time assessment of IDH mutation status to improve surgical outcomes. Since the FLIm apparatus is characterized by simple, fast and flexible data acquisition and display, and allows for seamless integration with existing imaging techniques used in neurosurgery, the findings are immediately translational. For GBM patients, identification of IDH mutations during surgery will alter goals concerning the extent of resection, leading to less aggressive tissue removal and decreased morbidity while ensuring limited impact on survival. For LGG patients, where extent of resection has been associated with a near doubling in overall survival, identification of IDH mutant tissue in real-time will allow differentiation between tumor and normal brain, thereby maximizing the extent of resection while decreasing the risk of neurologic injury.

项目总结/摘要 这项研究的目的是证明携带异柠檬酸脱氢酶（IDH）基因的脑肿瘤 基于其突变，可以在术中和实时将IDH野生型（WT）肿瘤与IDH突变区分开。 自发荧光发射特性。IDH 1/2基因突变在低级别胶质瘤（LGG）中很常见， 在多形性胶质母细胞瘤（GBM）中很少发生。IDH突变的存在是最大的预后 GBM患者的标志物。IDH突变型胶质瘤患者的生存率与其分级相比有所改善 匹配的WT对应物。重要的是，最近的研究表明，积极的手术切除的好处， IDH-WT和IDH突变型肿瘤之间存在差异;因此，IDH突变的术中鉴定将发生变化， 行动目标。随后，有相当大的兴趣，发展快速，术中方法 来鉴定IDH突变。 IDH突变通过损害α-酮戊二酸转化导致细胞代谢的整体变化 （αKG）转化为异柠檬酸，后者通常将NADP+还原为NADPH。相反，αKG转化为2-羟基戊二酸， 消耗NADPH产生NADP+。大脑自发荧光特性与大脑中 细胞代谢特别地，已经研究了脑组织的自发荧光发射强度的变化。 这归因于NAD（P）H浓度和氧化还原状态的差异。此外，寿命（或衰变）的差异 胶质瘤和正常脑组织之间的自体荧光强度归因于 游离和结合态NAD（P）H。因此，我们假设来自自发荧光的光学参数 神经胶质瘤的寿命测量可以与IDH突变引起的细胞代谢变化相关。 这项建议将建立在先前的临床研究基础上，这些研究表明不同表型的胶质瘤具有不同的 荧光寿命特性和我们在移动荧光寿命成像（FLIm）方面的专业知识 技术应用于临床。为了实现我们的目标，我们提出了两个具体目标。目标1：进行FLIm 接受传统神经外科手术的LLG和HGG患者（N=80）的术中测量值 程序.这将提供FLIm参数的广泛数据库（从体内和体外检索 测量值）与包括IDH突变状态的组织病理学相关。目标2：提高利用率 FLIm作为IDH突变实时检测的手段。这将证明FLIm的预测价值， IDH突变状态的检测和脑肿瘤手术期间的潜在指导。 总之，本研究将证明FLIm用于IDH术中实时评估的临床实用性 突变状态，以改善手术结果。由于FLIm设备的特征在于简单、快速和高效。 灵活的数据采集和显示，并允许与现有成像技术无缝集成 在神经外科中，这些发现是立即转化的。对于GBM患者，IDH突变的鉴定 在手术过程中，将改变有关切除范围的目标，从而减少侵袭性组织切除， 降低发病率，同时确保对生存的影响有限。对于LGG患者，切除范围 与总生存率几乎翻倍相关，实时鉴定IDH突变组织将允许 肿瘤和正常脑之间的差异，从而最大限度地扩大切除范围，同时减少 神经损伤的风险。

项目成果

Mesoscopic fluorescence lifetime imaging: Fundamental principles, clinical applications and future directions.

• DOI: 10.1002/jbio.202000472
• 发表时间: 2021-06
• 期刊: Journal of biophotonics
• 影响因子: 2.8
• 作者: Alfonso-Garcia A;Bec J;Weyers B;Marsden M;Zhou X;Li C;Marcu L
• 通讯作者: Marcu L

Intraoperative detection of IDH-mutant glioma using fluorescence lifetime imaging.

• DOI: 10.1002/jbio.202200291
• 发表时间: 2023-04
• 期刊: JOURNAL OF BIOPHOTONICS
• 影响因子: 2.8
• 作者: Noble Anbunesan, Silvia;Alfonso-Garcia, Alba;Zhou, Xiangnan;Bec, Julien;Lee, Han Sung;Jin, Lee-Way;Bloch, Orin;Marcu, Laura
• 通讯作者: Marcu, Laura

First in patient assessment of brain tumor infiltrative margins using simultaneous time-resolved measurements of 5-ALA-induced PpIX fluorescence and tissue autofluorescence.

• DOI: 10.1117/1.jbo.27.2.020501
• 发表时间: 2022-03
• 期刊: Journal of biomedical optics
• 影响因子: 3.5
• 作者: Alfonso-García A;Zhou X;Bec J;Anbunesan SN;Fereidouni F;Jin LW;Lee HS;Bloch O;Marcu L
• 通讯作者: Marcu L