CD44 的表达与胶质瘤的生存: 一项荟萃分析。
- 作者列表："Wu G","Song X","Liu J","Li S","Gao W","Qiu M","Yang C","Ma Y","Chen Y
BACKGROUND:Higher tumor expression of CD44, a marker of cancer stem cells, is associated with poor overall survival (OS) in various cancers. However, the association between CD44 and poor OS remains inconsistent in glioma. We aimed to evaluate the potential predictive role of CD44 for prognosis of glioma patients in a meta-analysis. METHODS:Observational studies comparing OS of glioma patients according to the level of CD44 were identified through searching PubMed, Embase, and Cochrane's Library databases. Meta-analyses were performed with a random- or fixed-effect model according to the heterogeneity. Subgroup analyses were performed to evaluate the influences of study characteristics. RESULTS:Eleven retrospective cohort studies were included. Results showed that increased CD44 expression in tumor predicted poor OS in glioma patients (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.02 to 1.97, p = 0.04). Subgroup analyses showed that higher tumor CD44 expression significantly predicted poor OS in patients with WHO stages II-III glioma (HR: 2.99, 95% CI: 1.53 to 5.89, p = 0.002), but not in patients with glioblastoma (HR: 1.26, 95% CI: 0.76 to 2.08, p = 0.47; p for subgroup difference = 0.03). Results were not statistically different between subgroups according to patient ethnicity, sample size, CD44 detection method, CD44 cutoff, HR estimation, univariate or multivariate analysis, or median follow-up durations (p values for subgroup difference all >0.10). CONCLUSIONS:Higher tumor expression of CD44 may predict poor survival in patients with glioma, particularly in those with WHO stage II-III glioma.
背景: 肿瘤干细胞标志物 CD44 的高表达与各种癌症的总生存期 (OS) 差相关。然而，CD44 与胶质瘤中较差 OS 之间的关联仍然不一致。我们的目的是在一项荟萃分析中评价 CD44 对胶质瘤患者预后的潜在预测作用。 方法: 通过检索 PubMed 、 Embase 和 Cochrane 图书馆数据库，确定根据 CD44 水平比较胶质瘤患者 OS 的观察性研究。根据异质性采用随机或固定效应模型进行 Meta 分析。进行亚组分析以评价研究特征的影响。 结果: 共纳入 11 项回顾性队列研究。结果显示，肿瘤中 CD44 表达增加预示胶质瘤患者 OS 较差 (风险比 [HR]: 1.42，95% 置信区间 [CI]: 1.02 ~ 1.97，p = 0.04)。亚组分析显示，较高的肿瘤 CD44 表达显著预测 WHO ⅱ-ⅲ 期胶质瘤患者 OS 较差 (HR: 2.99，95% CI: 1.53 ~ 5.89，p = 0.002),但在胶质母细胞瘤患者中没有 (HR: 1.26，95% CI: 0.76 ~ 2.08，p = 0.47;亚组差异 p = 0.03)。结果根据患者种族、样本量、 CD44 检测方法、 CD44 截断值、 HR 估计、单变量或多变量分析，亚组间无统计学差异,或中位随访时间 (亚组差异的 p 值均> 0.10)。 结论: CD44 的高肿瘤表达可能预示胶质瘤患者的生存率较低，尤其是 WHO ⅱ-ⅲ 期胶质瘤患者。
METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.
METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.
METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.