Development of an Integer-based Risk Score to Predict 90-Day Mortality After Hepatectomy in Patients With Hepatocellular Carcinoma.
开发基于整数的风险评分来预测肝细胞癌患者肝切除术后 90 天的死亡率。
- 作者列表："Qi Y","LeVan TD","Haynatzki G","Are C","Farazi PA
BACKGROUND:The incidence of liver cancer has more than tripled since 1980. Hepatectomy represents the major curative treatment for liver cancer. The risk factors associated with 90-day mortality after hepatectomy are not well understood and there are currently no good prediction models for this outcome. The objectives of the current study were to identify risk factors of 90-day mortality after hepatectomy in patients with hepatocellular carcinoma and to develop an integer-based risk score using the National Cancer Database. METHODS:Hepatectomies recorded in the National Cancer Database during 2004-2012 were reviewed for 90-day mortality. Risk factors were identified by multivariate logistic regression models. An integer-based risk score was developed using the β coefficients derived from the logistic regression model and tested for discriminatory ability. According to the total risk score, patients were grouped into 4 risk groups. RESULTS:The overall 90-day mortality was 10.2%. Ten risk factors were identified, which included sex, age, race/ethnicity, insurance status, education, annual hospital volume, stage, tumor grade, Charlson-Deyo Score, and surgical procedure. The risk of 90-day mortality was stratified into 4 groups. The calculated 90-day mortality rates were 2.47%, 5.88%, 12.58%, and 24.67% for low-risk, medium-risk, high-risk, and excessive-risk groups, respectively. An area under the receiver operating characteristic curve of 0.69 was obtained for model discrimination. CONCLUSIONS:The integer-based risk score we developed could easily quantify each patient's risk level and predict 90-day mortality after hepatectomy. The stratified risk score could be a useful addition to perioperative risk management and a tool to improve 90-day mortality after hepatectomy.
背景: 自 1980 年以来，肝癌的发病率增加了两倍多。肝切除术是肝癌的主要治愈性治疗方法。与肝切除术后 90 天死亡率相关的危险因素尚不十分清楚，目前尚无良好的预测模型。本研究的目的是确定肝细胞癌患者肝切除术后 90 天死亡率的危险因素，并使用国家癌症数据库制定基于整数的风险评分。 方法: 回顾了 2004-2012 年间国家癌症数据库中记录的肝切除术的 90 天死亡率。通过多因素 logistic 回归模型确定危险因素。使用 logistic 回归模型得出的 β 系数制定基于整数的风险评分，并进行区分能力测试。根据总风险评分将患者分为 4 个风险组。 结果: 总的 90 天死亡率为 10.2%。确定了 10 个危险因素，包括性别、年龄、种族/民族、保险状况、教育程度、年住院量、分期、肿瘤分级、 Charlson-Deyo 评分和手术操作。将 90 天死亡率的风险分为 4 组。低危组、中危组、高危组和高危组的 90 天死亡率分别为 2.47% 、 5.88% 、 12.58% 和 24.67%。获得了 0.69 的受试者工作特征曲线下面积，用于模型判别。 结论: 我们开发的基于整数的风险评分可以很容易地量化每个患者的风险水平，并预测肝切除术后 90 天的死亡率。分层风险评分可能是围手术期风险管理的有用补充，也是改善肝切除术后 90 天死亡率的工具。
METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.
METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.
METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.