Spectroscopic MRI to guide radiation dose escalation for glioblastoma patients

胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤。护理标准包括 神经外科手术切除，然后进行放射治疗(RT)和替莫唑胺(TMZ)化疗。虽然 RT是治疗这种侵袭性疾病的最有效的疗法之一，试图通过RT剂量来提高存活率 在TMZ时代之前，升级基本上是不成功的。在一项研究中，GBM患者接受了任何一种治疗 标准剂量辐射(60GY)或一系列逐步增加的剂量(最高相当于75GY)，以及TMZ， 在复发率或存活率方面没有显著差异；然而，这可能是由于剂量的增加。 在标准磁共振成像(MRI)中仅限于肿瘤的对比度增强部分， 可能无法准确预测复发风险较高的肿瘤。我们假设辐射剂量的增加可能 如果所有肿瘤高危区域都能被识别和靶向，这将是有益的。我们建议补充标准 使用质子光谱磁共振成像(SMRI)的核磁共振成像，这是一种特殊的测量技术 在规定的组织体积内的内源性代谢物水平，而不必注射造影剂。我们 进行了一项临床试验(R21 CA186169)，通过将全脑sMRI代谢物图与外科手术共同注册 计划MRI并导入神经导航系统，以指导GBM患者的组织采样。样本 在大块切除前，以活检法从代谢异常区域收集。组织 对样本进行胶质瘤标志物(SOX2)免疫组织化学染色，并分析染色细胞的密度 使用自动数字病理图像分析工具。SMRI标志物与SOX2浓度的相关性 都进行了评估。SMRI生物标志物与SOX2阳性细胞密度显著相关。胆碱能 N-乙酰天冬氨酸(Cho/NAA)比值与各定量指标均呈显著正相关(ρ=0.82，p&lt； 0.001)。有趣的是，在肿瘤复发部位，sMRI代谢异常先于对比剂增强 并与无进展存活率呈负相关，这项研究发表在最近的《神经学》杂志上。 肿瘤学(Cordova等人，2016)。因为它确定了肿瘤的渗透和复发的高危区域，sMRI 可作为常规MRI的补充，提高GBM患者的局部控制率。其他几份报告也 研究表明，高Cho/NAA比率与高肿瘤细胞密度区域相关，治疗后 对肿瘤复发有特异性。因此，sMRI可以帮助定义治疗HIGH、 杀瘤辐射剂量。我们最先进的sMRI以高分辨率和3D全脑快速执行 覆盖范围。我们的成像将对放射肿瘤学家选择最佳靶区具有重要价值 用于剂量递增。

Glioblastoma (GBM) is the most common primary brain tumor in adults. Standard of care includes neurosurgical resection, followed by radiation therapy (RT) and temozolomide (TMZ) chemotherapy. Although RT is one the most effective therapies for this aggressive disease, attempts to improve survival using RT dose escalation prior to the TMZ era have been largely unsuccessful. In one study, GBM patients treated with either standard dose radiation (60 Gy) or a range of escalated doses (up to the equivalent of 75 Gy), along with TMZ, showed no significant differences in recurrence or survival; however, this might be explained by dose escalation being limited to contrast-enhancing portions of the tumors in standard magnetic resonance imaging (MRI), which may not accurately predict tumor at high risk for recurrence. We hypothesize that radiation dose escalation may be beneficial, if all regions at high risk tumor can be identified and targeted. We propose to supplement standard MRI with proton spectroscopic magnetic resonance imaging (sMRI), a special technique performed to measure endogenous metabolite levels within defined volumes of tissue without having to inject a contrast agent. We conducted a clinical trial (R21 CA186169) by co-registering whole-brain sMRI metabolite maps with surgical planning MRI and imported into a neuronavigation system to guide tissue sampling in GBM patients. Samples were collected from regions with metabolic abnormalities in a biopsy-like fashion before bulk resection. Tissue samples were immunostained for glioma marker (SOX2) and analyzed to quantify the density of staining cells using an automated digital pathology image analysis tool. Correlations between sMRI markers and SOX2 density were evaluated. sMRI biomarkers exhibit significant correlations with SOX2-positive cell density. The choline to N-acetylaspartate (Cho/NAA) ratio showed significant associations with each quantitative marker (ρ = 0.82, p < 0.001). Intriguingly, sMRI metabolic abnormalities predated contrast-enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free survival, which was published in recent Neuro- Oncology (Cordova et al, 2016). As it identifies tumor infiltration and regions at high-risk for recurrence, sMRI could complement conventional MRI to improve local control in GBM patients. Several other reports also demonstrated that a high Cho/NAA ratio correlated with areas of high tumor cell density and, after treatment, is specific for tumor recurrence. As such, sMRI could assist in defining the optimal volume to treat with higher, tumoricidal radiation doses. Our state-of-the-art sMRI is performed rapidly at high-resolution with 3D whole brain coverage. Our imaging would be of great value to radiation oncologists in choosing the optimal regions to target for dose escalation.