Confirmatory Analysis of QUARTZ Study Results: Survival Prolongation After Whole-brain Radiotherapy.
- 作者列表："Nieder C","Dalhaug A","Pawinski A
BACKGROUND/AIM:The aim of this study was to analyze the survival of patients with brain metastases treated with best supportive care or additional whole-brain radiotherapy (WBRT), in order to confirm results from the prospective randomized QUARTZ study, which suggested prolonged survival after WBRT (5 fractions of 4 Gy) if favorable prognostic factors were present (age younger than 60 years, graded prognostic assessment score 2.5-3 points). PATIENTS AND METHODS:We performed a retrospective single institution analysis of 76 patients with favorable prognosis. In contrast to the QUARTZ trial, inclusion was not limited to patients with non-small cell lung cancer (NSCLC). Furthermore, a cohort treated with higher total doses of WBRT was included (10 fractions of 3 Gy). RESULTS:All patients were younger than 60 years or had a graded prognostic assessment score of 2.5-3. The median survival was significantly shorter after best supportive care (1.2 months; 3.2 months after WBRT with 5 fractions of 4 Gy and 3.9 months after 10 fractions of 3 Gy). Also, in multivariate analyses, survival was significantly better after WBRT. Further favorable prognostic factors included better performance status, no or limited extracranial metastases and primary tumor other than gastrointestinal. CONCLUSION:In line with the QUARTZ trial results, WBRT prolonged survival in patients with favorable prognostic features.
背景/目的: 本研究的目的是分析接受最佳支持治疗或额外全脑放疗 (WBRT) 治疗的脑转移患者的生存情况。为了证实前瞻性随机QUARTZ研究的结果，该研究提示如果存在良好的预后因素，WBRT后生存期延长 (4 Gy的 5 个分数)(年龄小于 60 岁，分级预后评估评分 2.5-3 分)。 患者和方法: 我们对 76 例预后良好的患者进行了回顾性单机构分析。与QUARTZ试验相反，纳入不限于患有非小细胞肺癌 (NSCLC) 的患者。此外，包括用较高总剂量的WBRT治疗的队列 (3 Gy的 10 个分数)。 结果: 所有患者年龄均小于 60 岁或分级预后评估评分为 2.5-3 分。最佳支持治疗后，中位生存期显著缩短 (1.2 个月; WBRT后 3.2 个月，4 Gy的 5 个分数，3 Gy的 10 个分数后 3.9 个月)。此外，在多变量分析中，WBRT后生存率显著提高。进一步有利的预后因素包括更好的性能状态，没有或有限的颅外转移和胃肠道以外的原发肿瘤。 结论: 与QUARTZ试验结果一致，WBRT延长了具有良好预后特征的患者的生存期。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.