Imaging as a Biomarker for Diffuse Intrinsic Brainstem Gliomas

理想的无创监测脑干生物或代谢活动的方法尚未建立。现有的评估脑组织的方法（例如PET）在应用于脑干时存在局限性。目前正在研究新的无创成像方法。我们将采用动态敏感性对比MR灌注、动态增强MRI、质子核磁共振波谱成像、FDG PET等方法进一步探讨脑桥胶质瘤的影像学特征。该项目目前正在进行四项临床试验。几乎所有患有中枢神经系统肿瘤的儿童患者都至少在其中一项研究中接受了广泛的影像学检查。在过去的几年里，我们已经证明了在临床试验中使用标准MRI来定义反应的困难，并根据这些结果提出了这些患者临床获益的新定义。对治疗的反应以及因此产生的新药物的疗效通常采用按照世卫组织标准或最近使用RECIST标准进行的二维肿瘤测量来测量。RECIST标准尚未被证实用于儿童中枢神经系统肿瘤的测量，二维测量仍然是联合试验的标准。我们通过四个独立的盲法阅读器比较弥漫性内禀脑桥胶质瘤的1D、2D和3D测量结果。结果表明，所有测量结果都存在显著的可变性（0-197%），因此肿瘤大小的变化不能作为临床试验反应的良好指标。我们还对全国的儿科肿瘤学家和神经肿瘤学家进行了电子调查，以确定肿瘤测量的标准做法。我们的结果表明，没有标准的测量方法被用于测量这些病变。我们发表了一份报告，建议使用FLAIR图像来测量DIPG，并将其与研究中的最佳反应扫描进行比较。图像应该并排比较。还建议对涉及DIPG的临床试验进行中心综述。我们正在继续评估其他MR序列的实用性，包括灌注和光谱成像，试图确定特定成像技术（如光谱、PET）在这些患者中的作用。最近，我们利用质子光谱成像证明了CHO:NAA比值随时间的变化是预后的预测指标。该研究已在国际儿科神经肿瘤学会发表，并已提交了一份手稿。此外，我们证明在任何时间点灌注增加是一个不良的预后因素。这也在ISPNO（2010年维也纳）和辛辛那提DIPG会议上提出。

The ideal method for non-invasive monitoring of biological or metabolic activity in the brainstem has not yet been established. Existing methods for evaluating cerebral tissue (e.g. PET) have limitations when applied to the brainstem. New noninvasive imaging methods are currently being studied. We are using dynamic susceptibility contrast MR perfusion, dynamic enhanced MRI, proton nuclear magnetic spectroscopic imaging, and FDG PET to further investigate the imaging characteristics of pontine gliomas. There are four clinical trials which currently fall under this project. Nearly all pediatric patients with CNS tumors undergo extensive imaging on at least one of these studies. Over the past several years, we have demonstrated the difficulty in using standard MRI for definition of response in clinical trials and have proposed a new definition of clinical benefit for these patients based on these results. Response to treatment and therefore efficacy of new gents is typically measured using two-dimensional tumor measurements following WHO criteria, or more recently, using RECIST criteria. RECIST criteria have not been validated for the measurement of pediatric CNS tumors and two-dimensional measurements continue to be the standard in consortium trials. We compared the 1D, 2D and 3D measurements of diffuse intrinsic pontine gliomas by four separate blinded readers. The results show that there is significant variability (0-197%) in all measurements and change in tumor size is therefore a poor indicator of response for clinical trials. We have also electronically surveyed pediatric oncologists and neuro-oncologists across the country to determine the standard practice of tumor measurement. Our results show that there is no standard measurement method being used in the measurement of these lesions. We have published a report recommending the use of FLAIR images to measure DIPG and comparing these with the best response scans on study. Images should be compared side by side. Central review was also recommended for clinical trials involving DIPG.We are continuing to evaluate the utility of additional MR sequences, including perfusion and spectroscopic imaging in an attempt to define the role of specific imaging techniques (e.g. spectroscopy, PET) in these patients. Recently, we have demonstrated that changes in maximum CHO:NAA ratios over time using proton spectroscopic imaging were prognostic of outcome. This was presented at the International Society of Pediatric Neuro-Oncology and a manuscript has been submitted. In addition, we demonstrated that increased perfusion at any time point was a poor prognostic factor. This was also presented at ISPNO (Viena 2010) and the DIPG Conference in Cincinnati.