Spectroscopic MRI to guide radiation dose escalation for glioblastoma patients

胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤。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最有效的方法之一，试图通过RT剂量来提高生存率 TMZ时代之前的升级基本上是不成功的。在一项研究中，GBM患者接受 标准剂量辐射（60戈伊）或一系列递增剂量（高达相当于75戈伊），沿着TMZ， 在复发或生存率方面无显著差异;然而，这可能是剂量递增所致 局限于标准磁共振成像（MRI）中肿瘤的对比度增强部分， 可能无法准确预测复发高风险的肿瘤。我们假设辐射剂量的增加可能 如果所有高风险肿瘤区域都能被识别和靶向，这将是有益的。我们建议补充标准 MRI与质子光谱磁共振成像（sMRI），一种特殊的技术进行测量 在不注射造影剂的情况下，确定的组织体积内的内源性代谢物水平。我们 进行了一项临床试验（R21 CA 186169），将全脑sMRI代谢物图谱与手术 计划MRI并导入神经导航系统，以指导GBM患者的组织取样。样品 在大块切除前以活检样方式从代谢异常区域收集。组织 对样本进行神经胶质瘤标记物（SOX 2）的免疫染色并分析以定量染色细胞的密度 使用自动数字病理学图像分析工具。sMRI标记物与SOX 2密度的相关性 进行了评估。sMRI生物标志物表现出与SOX 2阳性细胞密度的显著相关性。胆碱， N-乙酰天冬氨酸（Cho/NAA）比值与各定量指标均呈显著相关（ρ = 0.82，p <0.01）。 0.001）。有趣的是，sMRI代谢异常早于肿瘤复发部位的对比增强 并与无进展生存期呈反比关系，这一结果发表在最近的《神经学》杂志上， 肿瘤学（Cordova et al，2016）。由于它可以识别肿瘤浸润和复发的高风险区域， 可以补充常规MRI，以改善GBM患者的局部控制。其他几份报告也 表明高Cho/NAA比值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可以帮助确定最佳体积， 杀死肿瘤的辐射剂量我们最先进的sMRI以高分辨率快速执行3D全脑 覆盖我们的成像将是非常有价值的放射肿瘤学家在选择最佳区域的目标 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.