Project 3: Direct & Repeated Measurement of pO2 in Deep-seated Tumors using EPR O

通过富氧气体或调节肿瘤来提高肿瘤含氧量的若干策略 血管系统(如雅康、阿瓦斯丁)在临床试验中未能显示出有效性，尽管在临床前很有希望 结果。这些研究中的一个主要警告是缺乏监测肿瘤和 因此，目前尚不清楚该疗法是否确实有效地减少了肿瘤的缺氧。监测势在必行 肿瘤pO2以了解未来临床试验中的治疗反应。 在项目3中，我们将实施一种新的植入式深层组织氧传感器方法，并提高其通用性。 适用于距离患者皮肤10毫米深处的肿瘤。此方法将使用OxyChip(项目 2)，但增加了一根细的(&lt；0.2 mm线规)非磁线来传递微波能量 从深层组织到获取EPR光谱的光谱仪。植入式深部组织氧 核磁共振成像显示，传感器经过了严格的设计和测试，可同时在2-4个地点进行氧分压测量 实验动物模型的亲和性和生物相容性。我们将首先执行一个安全和可行的 在患者中进行研究，然后继续进行两个机构(达特茅斯和埃默里)的研究以测量氧气 基线水平、时间波动和对二氧化碳(2%二氧化碳+98%O2)高氧的反应 呼吸。重要的是，我们将测量正在接受抗血管生成药物治疗的复发性胶质瘤的氧气水平。 阿瓦斯丁探员。这项研究将有助于我们了解阿瓦斯丁对患者肿瘤PO2的影响 并确定如何在放射治疗的同时最好地给予阿瓦斯丁，以改善治疗结果。这些 研究将提供一种在治疗期间测量肿瘤含氧量的范例，并将是 向更广泛的放射肿瘤学社区传播这项技术。 我们提出以下具体目标，以实现本项目的目标和项目小组的总体目标： (1)建立植入式深层组织氧传感器的有效性和安全性，并调查治疗前的情况 深部头颈、肉瘤和脑肿瘤患者的氧谱；(2)确定 高氧和抗血管生成治疗对肿瘤组织氧分压的反应和变化 以及(3)在同时进行放射治疗期间测定肿瘤氧气水平，并随后评估 放射治疗中氧修饰干预的效果。项目3将满足未得到满足的需求 监测深层肿瘤的氧分压，这将为临床医生提供关键的诊断、治疗和 提供预后信息以改善患者的治疗结果。

A number of strategies to improve oxygen levels in tumors by oxygen enriched gases or modulation of tumor vasculature (e.g. ARCON, avastin) have failed to show efficacy in clinical trials despite promising pre-clinical results. A major caveat in these studies is the lack of techniques for monitoring oxygen levels in the tumors and therefore it is not known if the therapy indeed was effective in reducing tumor hypoxia. It is imperative to monitor tumor pO2 to understand treatment responses in future clinical trials. In project 3, we will implement a novel implantable deep-tissue oxygen sensor approach with improved versatility to be used in tumors located at depths > 10 mm from the patient's skin. This approach will use OxyChip (Project 2), but with the addition of a thin (<0.2 mm wire gauge) non-magnetic wire to transduce the microwave energy from deep-tissue to the spectrometer for the acquisition of EPR spectra. The implantable deep-tissue oxygen sensors has been designed and rigorously tested for pO2 measurements at 2-4 sites simultaneously, MRI compatibility, and biocompatibility in experimental animal models. We will first perform a safety and feasibility study in patients, and then proceed with a two institutional (Dartmouth and Emory) study to measure oxygen levels at baseline, temporal fluctuations and response to hyperoxygenation with carbogen (2% CO2 + 98% O2) breathing. Importantly, we will measure oxygen levels in recurrent gliomas being treated with an anti-angiogenic agent, avastin. This study will contribute to our understanding of the effect of avastin on tumor pO2 in patients and determine how best to administer avastin with radiation therapy for improving treatment outcomes. These studies will provide a paradigm to measure tumor oxygen levels during therapy and will be the first step in disseminating this technology to the broader radiation oncology community. We propose the following specific aims to meet the objective of this project and the overall goals of the PPG: (1) Establish the efficacy and safety of implantable deep-tissue oxygen sensors and investigate pre-treatment oxygen profiles of patients with deep-seated head and neck, sarcoma and brain tumors; (2) Determine the response and change in pO2 induced by hyperoxygenation and anti-angiogenic treatment in human tumors, and (3) Determine tumor oxygen levels during concurrent treatment with radiation and subsequently evaluate the effects of oxygen-modifying interventions during radiotherapy. Project 3 will fulfill the unmet need for monitoring pO2 in deep-seated tumors, which will provide clinicians crucial diagnostic, therapeutic, and prognostic information to improve the treatment outcome of patients.