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，但临床医生没有 TBI的神经保护治疗选择。此外，调查人员的先验预测能力有限， TBI后死亡率雌二醇（E2）和孕酮（PRO）因其神经保护作用而闻名 当在临床前TBI模型中研究时。然而，我们的独立临床数据表明， 内源性激素在TBI后发生，其来源于性腺外来源，并且是以下因素的结果： 放大芳构化途径。这些途径利用TNF α产生E2，并与死亡率有关， 可怜的结果。文献表明，E2的积累可能反映了对损伤的复杂的全身反应 由交感神经系统（SNS）引发并由SNS诱导的炎症持续， 导致E2产生增加，这与全身性损害、非神经器官损害、 功能障碍（NNOD）和增加的死亡率和不良结局风险。我们的工作显示了E2和它的额外- 性腺基因组转录因子TNF α是TBI后重要的死亡率预测因子， 导致不良结局的全身性并发症。动物研究和第三阶段之间的二分法 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亚群的可行神经保护治疗选择， 了解E2和TNF α水平是否/如何预测PRO治疗的治疗效果异质性（HTE）。 我们的中心假设是，血清E2和TNF-α，反映全身反应TBI，是新的指标， 基线死亡率/不良结局风险，是可变PRO效应的敏感指标。E2和TNF α 可能有效地表征那些具有非常高/低风险的人（无论治疗如何）以及那些 可能会受益于PRO或受到PRO的伤害。使用ProTECT III研究和BioProTECT的数据和样本 试验，我们有一个独特的机会来描述生物异质性和其他贡献者的空 治疗结果。这些队列提供了一个严格开发的临床研究平台， 检验全身性E2和TNF-α反映了全身对TBI的反应，并可作为TBI的一个指标的假设。 HTE至PRO治疗的指标。在学习结束时，我们将了解如何1）有效地计算 中/重度TBI后基线死亡率和不良结局风险的异质性，2）表征如何 PRO治疗的异质性降低了基线风险，并促成了独特但可变的PRO应答 3）确定随机化后生物标志物是否/如何受到治疗应答中PRO的影响 第4组）生成一个简约的基线风险计算器，以在其他TBI人群中进行测试， 在未来RCT中进行有效的随机化前患者选择。这项工作结合了基线风险 异质性和HTE是告知PRO治疗反应的精确医学方法的关键特征 在TBI后和急性RCT TBI患者选择中更普遍。

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.