- 作者列表："Hectors SJ","Lewis S","Besa C","King MJ","Said D","Putra J","Ward S","Higashi T","Thung S","Yao S","Laface I","Schwartz M","Gnjatic S","Merad M","Hoshida Y","Taouli B
OBJECTIVE:To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC). METHODS:This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months. RESULTS:Qualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929). CONCLUSIONS:MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation. KEY POINTS:• MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.
目的: 评估 MRI 影像组学定性和定量特征对肝细胞癌 (HCC) 免疫肿瘤学特征和预后的无创预测价值。 方法: 这项回顾性、 IRB 批准的研究包括 48 例 HCC 患者 (M/F 35/13，平均年龄 60y)，他们在腹部 MRI 检查 4 个月内接受了肝切除或移植。定性成像特征、定量非纹理相关和纹理特征在对比增强 T1-weighted 和扩散加权图像的指数病变中进行评估。使用二元 logistic 回归和相关分析评估影像学特征与免疫谱和基因组学特征的相关性。还采用二元 logistic 回归分析放射组学、组织病理学和基因组学特征与 12 个月时 HCC 放射学早期复发的相关性。 结果: 定性 (r =-0.41-0.40，p <0.042) 和定量 (r =-0.52-0.45，p <0.049) radiomics 特征与 T 细胞 (CD3) 、巨噬细胞 (CD68) 和内皮细胞 (CD31) 的免疫组织化学细胞类型标记相关。Radiomics 特征也与免疫治疗靶 PD-L1 在蛋白水平的表达相关 (r = 0.41-0.47，p <0.029) 以及 mRNA 表达水平的 PD1 和 CTLA4 (r =-0.48-0.47，p <0.037)。最后，放射学特征，包括肿瘤大小，对评估早期 HCC 复发显示出显著的诊断性能 (AUC 0.76-0.80，p <0.043),而免疫谱和基因组特征没有 (p = 0.098-0929)。 结论: MRI 影像组学特征可作为 HCC 免疫肿瘤学特征和肿瘤复发的无创预测因子，并可能有助于 HCC 患者的治疗分层。这些结果需要前瞻性验证。 要点: • MRI 影像组学特征显示与肝细胞癌的免疫表型和基因组学特征显著相关。•放射组学特征，包括肿瘤大小，显示与切除术后早期肝细胞癌复发显著相关。
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.