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 神经外科切除术，然后进行放射治疗（RT）和替莫唑胺（TMZ）化疗。虽然 放疗是治疗这种侵袭性疾病最有效的疗法之一，尝试使用放疗剂量来提高生存率 TMZ 时代之前的升级基本上不成功。在一项研究中，GBM 患者接受了以下任一治疗： 标准剂量辐射 (60 Gy) 或一系列递增剂量（最高相当于 75 Gy），以及 TMZ， 复发或生存率没有显着差异；然而，这可能是通过剂量递增来解释的 仅限于标准磁共振成像 (MRI) 中肿瘤的对比度增强部分，这 可能无法准确预测复发风险高的肿瘤。我们假设辐射剂量增加可能 如果可以识别并靶向所有高风险肿瘤区域，那么这将是有益的。我们建议补充标准 质子能谱磁共振成像 (sMRI) 是一种用于测量的特殊技术 无需注射造影剂即可确定特定体积组织内的内源代谢物水平。我们 通过将全脑 sMRI 代谢图谱与手术 规划 MRI 并导入神经导航系统以指导 GBM 患者的组织采样。样品 在大块切除之前以类似活检的方式从代谢异常的区域收集。纸巾 对样本进行神经胶质瘤标记物 (SOX2) 免疫染色，并进行分析以量化染色细胞的密度 使用自动化数字病理图像分析工具。 sMRI 标记物与 SOX2 密度之间的相关性 进行了评估。 sMRI 生物标志物与 SOX2 阳性细胞密度显着相关。胆碱至 N-乙酰天冬氨酸 (Cho/NAA) 比率与每个定量标记物显着相关 (ρ = 0.82, p < 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负相关，这一结果发表在最近的 Neuro- 肿瘤学（Cordova 等人，2016）。由于它可以识别肿瘤浸润和复发高风险区域，sMRI 可以补充传统 MRI 以改善 GBM 患者的局部控制。其他几份报告还 证明高 Cho/NAA 比率与高肿瘤细胞密度区域相关，并且在治疗后， 专门针对肿瘤复发。因此，sMRI 可以帮助确定最佳治疗体积，以进行更高、 杀肿瘤辐射剂量。我们最先进的 sMRI 可通过 3D 全脑以高分辨率快速进行 覆盖范围。我们的成像对于放射肿瘤学家选择最佳目标区域具有重要价值 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.