Prognostic significance of serum p53 antibody according to KRAS status in metastatic colorectal cancer patients.
转移性结直肠癌患者血清 p53 抗体根据 KRAS 状态的预后意义。
- 作者列表："Daitoku N","Miyamoto Y","Sakamoto Y","Tokunaga R","Hiyoshi Y","Nagai Y","Iwatsuki M","Iwagami S","Yoshida N","Baba H
BACKGROUND:Serum anti-p53 antibody is used clinically as a tumor marker of colorectal cancer. However, its prognostic significance in patients with metastatic colorectal cancer (mCRC) remains unclear. KRAS status may influence the host immune response against tumor progression. In the present study, we investigated the prognostic significance of serum anti-p53 in mCRC patients with wild-type KRAS and mutant KRAS treated with systemic chemotherapy. METHODS:A retrospective study of 150 mCRC patients in whom serum anti-p53 antibody was measured before first-line chemotherapy was conducted. The patients were divided into two groups, high p53 and low p53, based on their serum anti-p53 antibody levels. Associations between serum anti-p53 level and clinical outcomes were evaluated in conjunction with KRAS status. RESULTS:There were 97 (64.7%) patients with wild-type KRAS and 53 (35.3%) with mutant KRAS. In an analysis of all patients, there was no significant difference in overall survival (OS) between the high p53 and low p53 groups. In patients with mutant KRAS, those in the high p53 group exhibited significantly longer OS than those in the low p53 group (p = 0.017, log-rank test). In the multivariate analysis, serum p53 antibody level was an independent predictor of OS in mCRC patients (high vs. normal; hazard ratio 0.438, 95% confidence interval 0.178-0.974, p < 0.05). CONCLUSIONS:Serum anti-p53 antibody level may be an independent predictor of OS in mCRC patients with KRAS mutant tumors.
背景: 血清 anti-p53 抗体作为结直肠癌的肿瘤标志物被临床应用。然而，其在转移性结直肠癌 (mCRC) 患者中的预后意义仍不清楚。KRAS 状态可能影响宿主对肿瘤进展的免疫反应。在本研究中，我们研究了野生型 KRAS 和突变型 KRAS 接受全身化疗的 mCRC 患者血清 anti-p53 的预后意义。 方法: 回顾性分析 150 例 mCRC 患者一线化疗前血清 anti-p53 抗体的检测结果。根据血清 anti-p53 抗体水平将患者分为高 p53 组和低 p53 组。结合 KRAS 状态评价血清 anti-p53 水平与临床结局的相关性。 结果: 野生型 KRAS 患者 97 例 (64.7%)，突变型 KRAS 患者 53 例 (35.3%)。在对所有患者的分析中，高 p53 组和低 p53 组之间的总生存期 (OS) 没有显著差异。在突变型 KRAS 患者中，高 p53 组的 OS 明显长于低 p53 组 (p = 0.017，log-rank 检验)。在多变量分析中，血清 p53 抗体水平是 mCRC 患者 OS 的独立预测因子 (高 vs.正常; 风险比 0.438，95% 置信区间 0.178-0.974，p <0.05)。 结论: 血清 anti-p53 抗体水平可能是 KRAS 突变肿瘤患者 OS 的独立预测因子。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.