手术联合化疗及放疗治疗儿童中枢性原始神经外胚瘤的疗效及预后分析

目的分析手术联合化疗及放疗治疗儿童中枢性原始神经外胚瘤(cPNET)的疗效,并对其预后危险因素进行探讨。方法收集2012年6月至2018年9月诊断为cPNET的42例患儿的临床资料并进行回顾性分析。结果 42例患儿的中位总生存(OS)期为2.0年,中位无事件生存(EFS)期为1.3年;1、3、5年OS率分别为76.2%±6.6%、41.4%±8.7%、37.3%±8.8%,1、3、5年EFS率分别为64.3%±7.4%、32.7%±8.0%、28.0%±8.1%。单因素分析结果显示,不同手术切除方式、化疗次数、危险度分级患儿OS率、EFS率比较差异均有统计学意义(P<0.05),是否放疗患儿的OS率比较差异亦有统计学意义(P<0.05)。多因素Cox回归分析结果显示,化疗次数、危险度分级是cPNET患儿OS率及EFS率的独立影响因素(P<0.05),化疗次数越多,危险度越低,EFS率及OS率越高。结论手术、化疗及放疗联合的综合治疗是目前治疗儿童cPNET的有效方法,早期发现早期治疗及尽量延长、坚持化疗有助于提高EFS率及OS率。

Gene expression profiling reveals Ki-67 associated proliferation signature in human glioblastoma

Background Everlasting cellular proliferation is the fundamental feature during gliomagenesis and Ki-67 is one of the classical proliferation markers in human glioblastoma multiforme （GBM）. However, the driver genes or core pathways for cellular proliferation in GBM have not been elucidated systematically. Methods We evaluated by immunohistochemistry the prognostic value of Ki-67 expression in the clinical outcome of 156 Chinese patients with GBM and a total of 64 GBM samples were selected for further Agilent genome-wide microarray analysis. On the basis of the microarray data from Tiantan （n--64） and The Cancer Genome Atlas （TCGA） （n=202） database, differentially expressed genes between the GBM subgroups with high or low level of Ki-67 expression were identified using Significance Analysis of Microarrays （SAM）. Gene Ontology （GO） and KEGG Pathway analyses were then undertaken for the Ki-67 associated genes to identify the most significant biological processes and signaling pathways. Results We confirmed that Ki-67 was an independent prognostic indicator in the largest Chinese patient cohort of 156 GBM samples via immunohistochemical staining. Survival analysis of Ki-67 over-expression revealed a highly significant association with a worse clinical outcome （P=0.010 for progression-free survival; P=0.007 for overall survival）. Comparative and integrated analysis between -Iqantan and TCGA database identified a 247-gene ＂proliferation signature＂ （205 up-regulated and 42 down-regulated genes） that distinguished Ki-67 expression phenotypes. GO and KEGG Pathway analyses further indicated that Ki-67 expression phenotype was associated with distinct changes in gene expression associated with the regulation of cellular growth and proliferation. Conclusions Proliferation marker Ki-67 is an independent prognostic indicator in Chinese GBM patients. And Ki-67 associated proliferation signature identified through genome-wide microarray analysis may provide potential targets for anti-proliferation therapy in GBM.

Prognostic factors influencing clinical outcomes of glioblastoma multiforme

Background Glioblastoma multiforme （GBM） is the most malignant kind of astrocytic tumors and is associated with a poor prognosis. In this retrospective study, we assessed the clinical, radiological, genetic molecular and treatment factors that influence clinical outcomes of patients with GBM. Methods A total of 116 patients with GBM who received surgery and radiation between January 2006 and December 2007 were included in this study. Kaplan-Meier survival analysis and Cox regression analysis were used to find the factors independently influencing patients＇ progression free survival （PFS） time and overall survival （OS） time. Results Age, preoperative Karnofsky Performance Scale （KPS） score, KPS score change at 2 weeks after operation, neurological deficit symptoms, tumor resection extent, maximal tumor diameter, involvement of eloquent cortex or deep structure, involvement of brain lobe, Ki-67 expression level and adjuvant chemotherapy were statistically significant factors （P 〈0.05） for both PFS and OS in the univariate analysis. Cox proportional hazards modeling revealed that age 〈50 years, preoperative KPS score 〉80, KPS score change after operation 〉0, involvement of single frontal lobe, non-eloquent area or deep structure involvement, low Ki-67 expression and adjuvant chemotherapy were independent favorable factors （P 〈0.05） for patients＇ clinical outcomes. Conclusions Age at diagnosis, preoperative KPS score, KPS score change at 2 weeks postoperation, involvement of brain lobe, involvement of eloquent cortex or deep structure, Ki-67 expression level and adjuvant chemotherapy correlate significantly with the prognosis of patients with GBM.

Antiangiogenic therapy with bevacizumab in recurrent malignant gliomas： analysis of the response and core pathway aberrations

Background Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown promising activity in recurrent malignant gliomas. We reported the treatment response for the combination of bevacizumab and chemotherapy in a series of six patients with recurrent malignant glioma and investigated the molecular alterations in cancer pathways using the surgical biopsies from these patients. Methods Standard therapy with primary resection followed by adjuvant chemoradiotherapy had failed in all patients. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks. Concomitantly, four patients received temozolomide （50 mg·m^-2·d^-1）, one patient irinotecan （125 mg/m^2 every 2 weeks） and one patient topotecan （1.2 mg·m^-2·d^-1）. Response to therapy was mainly determined by magnetic resonance imaging. The expression of Ras, phosphorylated mitogen activated protein kinase （p-MAPK）, phosphorylated AKT （p-AKT）, phosphorylated mammalian target of rapamycin （p-mTOR） and phosphorylated signal transducer and activator of transcription 3 （p-STAT3） were semiquantitatively assessed by immunohistochemistry using surgical biopsies before the initial treatment. Results Five of the six patients had a radiographic response. Three were complete response, and two were partial response. Only one patient had progressive disease. The 6-month progession-free survival （PFS） was 33% and the median PFS was 15 weeks, with a range of 6 to more than 60 weeks. Of the three core pathways analyzed in this study, the Ras/MAPK and phosphatidylinositol-3-kinase （PI3K）/AKT/mTOR pathways were more likely to be associated with the treatment response to bevacizumab. In two younger patients （ages 〈50） with complete response, simultaneous overexpression of p-MAPK, p-AKT and p-mTOR might be the crucial feature. Conclusions Bevacizumab in combination with chemotherapeutic agents may be an effective strategy for patients with recurrent malignant glioma. Activated MAPK and AKT might be possible biomarkers for selecting suitable patients for this targeted therapy.

Effect of intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy on clinical outcomes in patients with glioblastoma multiforme

Background Few studies were reported on the comparison of clinical outcomes between intensity-modulated radiotherapy （IMRT） and three-dimensional conformal radiotherapy （3D-CRT） in the treatment of glioblastoma multiforme （GBM）.This study aimed to determine whether IMRT improves clinical outcomes compared with 3D-CRT in patients with GBM.Methods The records of 54 patients with newly-diagnosed GBM from July 2009 to December 2010 were reviewed.The patients underwent postoperative IMRT or 3D-CRT with concurrent and adjuvant temozolomide.Kaplan-Meier method and log rank test were used to estimate differences of patients＇ survival.Results The median follow-up was 13 months.Of the 54 patients,fifty （92.6%） completed the combined modality treatment.The 1-year overall survival rate （OS） was 79.6%.The pattern of failure was predominantly local.A comparative analysis revealed that no statistical difference was observed between the IMRT group （n=21） and the 3D-CRT group （n=33） for 1-year OS （89.6% vs.75.8%,P=0.795）,or 1-year progression-free survival （PFS） （61.0% vs.45.5%,P=0.867）.In dosimetric comparison,IMRT seemed to allow better sparing of organs at risk than 3D-CRT did （P=0.050,P=0.055）.However,there was no significant difference for toxicities of irradiation between the IMRT group and the 3D-CRT group.Conclusions Our preliminary results suggested that delivering standard radiation doses by IMRT is unlikely to improve local control or overall survival for GBM compared with 3D-CRT.Given this lack of survival benefit and increased costs of IMRT,the utilization of IMRT treatment for GBM needs to be carefully rationalized.

Increase of plasma IgE during treatment correlates with better outcome of patients with glioblastoma

Background Previous studies have shown that glioma patients have lower blood IgE levels than controls. To evaluate its potential as a surrogate biomarker for glioma, we measured plasma IgE levels in glioma patients and healthy controls,and correlated them with clinicopathological factors and the patients＇ outcome.Methods We used enzyme-linked immunosorbant assay （ELISA） to determine the plasma IgE levels of 25 normal subjects and 252 glioma patients （85 patients with grade Ⅱ glioma, 46 patients with grade Ⅲ glioma, and 121 patients with glioblastoma）. We also collected longitudinal plasma samples from glioblastoma patients and compared the plasma IgE levels before operation, one week after operation, in the middle of radiotherapy, after two cycles of chemotherapy, and after recurrence. The correlations between plasma IgE levels and the outcomes of the patients were determined.Results Plasma IgE levels were significantly lower in glioma patients （P=0.004）; patients with low-grade glioma have lower IgE levels than patients with high-grade glioma do （P=0.029）. In 24 patients with both preoperative plasma and two-cycle chemotherapy plasma samples, IgE levels increased after successful removal of the tumor （P=0.021）, and the increase correlated with the patients＇ survival （increase 〉100 ng/ml vs. 〈100 ng/ml, 127.5 weeks vs. 62.3 weeks. P=0.012,log-rank）. Plasma IgE level increase of 〉100 ng/ml has a specificity of 80% and a sensitivity of 78% to predict the patients＇ long survival （〉18 months）.Conclusions Our results suggest that plasma IgE level correlates with clinical and pathological factors in glioma patients. It has the potential to be a biomarker for glioma patients.

An initial exploration of surgery following radiotherapy for the treatment of gliomatosis cerebri

Gliomatosis cerebri （GC） is a diffuse glial tumor that infiltrates the brain extensively. The optimaltherapeutic strategy for this tumor has not yet been established. Radiotherapy, temozolomide and other chemotherapeutic modalities have been used to treat GC.2 Despite aggressive and often multimodal therapeutic intervention, survival rates for adult and pediatric patients with GC are extremely poor. Here we report two cases of GC in which we initially explored a new therapeutic strategy for this disease.