Predictive Biomarkers & Models Assessing Systemic Response to Injury after Moderate-to-Severe TBI

摘要 尽管对创伤性脑损伤 (TBI) 患者的护理有所改善，但临床医生仍无法 TBI 的神经保护治疗选择。此外，调查人员先验预测的能力有限 TBI 后的死亡率。雌二醇 (E2) 和黄体酮 (PRO) 因其神经保护作用而闻名 在临床前 TBI 模型中进行研究时。然而，我们的独立临床数据表明， TBI 后出现内源性激素，这些激素源自性腺外，是以下因素的结果 放大的芳构化途径。这些途径使用 TNFα 产生 E2，并与死亡率和死亡率相关。 结果不佳。文献表明 E2 积累可能反映了对损伤的复杂系统反应 由交感神经系统 (SNS) 发起并通过 SNS 诱导的炎症持续存在， 导致 E2 产生放大，与系统性损害、非神经器官相关 功能障碍（NNOD）以及死亡率增加和不良结果风险。我们的工作主体展示了 E2 及其额外内容 性腺基因组转录因子 TNFα 是 TBI 后重要的死亡率预测因子，并且与 导致不良结果的全身并发症。动物研究和 III 期研究之间的二分法 PRO 的随机临床试验 (RCT) 特别说明了需要进一步研究的重要问题 协调 PRO 是否/如何成为 TBI 亚人群可行的神经保护治疗选择，并 了解 E2 和 TNFα 水平是否/如何可以预测 PRO 治疗的治疗效果 (HTE) 的异质性。 我们的中心假设是血清 E2 和 TNF-α 反映了对 TBI 的全身反应，是新的指标 死亡率/不良结果的基线风险，并且是可变 PRO 效应的敏感指标。 E2 & 肿瘤坏死因子α 可能可以有效地描述那些具有非常高/低风险（无论治疗如何）以及那些 可能会因 PRO 受益或受到损害。使用 ProTECT III 研究和 BioProTECT 的数据和样本 试验中，我们有一个独特的机会来描述生物异质性和零的其他贡献者 发现治疗结果。这些队列提供了严格开发的临床研究平台 检验以下假设：全身 E2 和 TNF-α 反映了对 TBI 的全身反应，并且可以作为 HTE 至 PRO 治疗的指标。在研究结论中，我们将了解如何 1) 有效计算 中度/重度 TBI 后基线死亡率和不良结果风险的异质性，2) 描述了如何 PRO 治疗中的异质性会缓和基线风险，并导致不同但可变的 PRO 反应 组，3) 确定治疗反应中 PRO 是否/如何影响随机化后的生物标志物 4) 生成一个简约的基线风险计算器，在其他 TBI 人群中进行测试，以支持 在未来的随机对照试验中进行有效的预随机化患者选择。这项工作共同纳入了基线风险 异质性和 HTE 作为精准医学方法的关键特征，以告知 PRO 治疗反应 TBI 后和急性 RCT TBI 患者的选择更为普遍。

ABSTRACT Despite improvements in care for individuals with traumatic brain injury (TBI), clinicians have no neuroprotective treatment options for TBI. Moreover, investigators have limited ability a priori to predict mortality after TBI. Estradiol (E2) and progesterone (PRO) are well known for their neuroprotective qualities when studied in pre-clinical TBI models. However, our independent clinical data suggest relative increases in endogenous sex hormones occur after TBI that are derived from extra-gonadal sources and are the result of amplified aromatization pathways. These pathways use TNFα to produce E2 and are linked with mortality and poor outcome. The literature indicates that E2 accumulation may reflect a complex systemic response to injury that is initiated by the sympathetic nervous system (SNS) and perpetuated by SNS-induced inflammation, leading to amplified E2 production that is associated with systemic compromise, non-neurological organ dysfunction (NNOD) and increased mortality and poor outcome risk. Our body of work shows E2 and its extra- gonadal genomic transcription factor TNFα are important mortality predictors post-TBI and are associated with systemic complications that contribute to poor outcome. The dichotomy between animal studies and phase III randomized clinical trials (RCTs) for PRO specifically illustrate important questions requiring further study to reconcile if/how PRO might be a viable neuroprotective treatment option for subpopulations with TBI and to understand if/how E2 & TNFα levels can predict heterogeneity of treatment effects (HTE) with PRO therapy. Our central hypothesis is that serum E2 & TNF-α, reflect the systemic response to TBI, are novel indicators of baseline risk for mortality/poor outcome, and are sensitive indicators of variable PRO effects. E2 & TNFα may be effective in characterizing those with very high/low risk (regardless of treatment) as well as those who might benefit or be harmed by PRO. Using data and samples from the ProTECT III study and the BioProTECT trial, we have a unique opportunity to delineate biological heterogeneity and other contributors to the null findings treatment result. These cohorts provide a rigorously developed clinical research platform from which to test the hypothesis that systemic E2, & TNF-α, reflect the systemic response to TBI and can serve as an indicator of HTE to PRO therapy. At study conclusion, we will understand how to 1) effectively calculate heterogeneity in baseline mortality and poor outcome risk after moderate/severe TBI, 2) characterize how heterogeneity in PRO treatment moderates baseline risk and contributes to distinct, yet variable PRO response groups, 3) identify if/how post-randomization biomarkers are affected by PRO among treatment response groups 4) generate a parsimonious baseline risk calculator to test in other TBI populations in support of effective pre-randomization patient selection in future RCTs. Together this work incorporates baseline risk heterogeneity and HTE as key features in a precision medicine approach to informing PRO treatment response after TBI and for acute RCT TBI patient selection more generally.