Radiotherapy-related Tiredness in Patients with Glioblastoma Multiforme (GBM)

Tiredness may be caused by the brain injury due to the tumor or the treatment in patients with glioblastomamultiforme (GBM). Some patients describe a sense of tiredness particularly after radiation or oral chemotherapy.To evaluate tiredness level of patients with GBM during preoperative, postoperative and radiotherapy we hereeamined a sample of 38 patients. Data were collected over six months in a neurosurgery clinic. Patients assignedto Group I were given a booklet and information about radiotherapy, oral temozolomide and tiredness. GroupII received only the booklet. The chi-squared test were used to determine differences in tiredness betweenGroup I and Group II, with Spearman’s correlation for post-radiotherapy results (3 and 6 months postoperative).In conclusion, the level of tiredness was assessed to be significantly better in Group I than in Group II. Levels oftiredness in patients with GBM were greatly affected by the radiotherapy and oral chemotherapy (temozolomide).     

Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis

Cytokines play a significant role in cancer diagnosis, prognosis and therapy. The immune system’s failure to recognize the malignant tumor cells and mount an effective response may be the result of tumor-associated cytokine deregulation. Glioblastoma Multiforme (GBM) has a characteristic cytokine expression pattern, and abnormalities in cytokine expression have been implicated in gliomagenesis. Within the heterogeneous GBM microenvironment, the tumor cells, normal brain cells, immune cells, and stem cells interact with each other through the complex cytokine network. This review summarizes the current understanding of the functions of key cytokines on GBM, and highlights potential therapeutic applications targeting these cytokines.     

Autophagy Inhibition Promotes Gambogic Acid-induced Suppression of Growth and Apoptosis in Glioblastoma Cells

Objective: To investigate the effects of gambogic acid (GA) on the growth of human malignant glioma cells.Methods: U251MG and U87MG human glioma cell lines were treated with GA and growth and proliferationwere investigated by MTT and colony formation assays. Cell apoptosis was analyzed by annexin V FITC/PI flowcytometry, mitochondrial membrane potential assays and DAPI nuclear staining. Monodansylcadaverine (MDC)staining and GFP-LC3 localisation were used to detect autophagy. Western blotting was used to investigate themolecular changes that occurred in the course of GA treatment. Results: GA treatment significantly suppressedcell proliferation and colony formation, induced apoptosis in U251 and U87MG glioblastoma cells in a timeanddose-dependent manner. GA treatment also lead to the accumulation of monodansylcadaverine (MDC)in autophagic vacuoles, upregulated expressions of Atg5, Beclin 1 and LC3-II, and the increase of punctatefluorescent signals in glioblastoma cells pre-transfected with GFP-tagged LC3 plasmid. After the combinationtreatment of autophagy inhitors and GA, GA mediated growth inhibition and apoptotic cell death was furtherpotentiated. Conclusion: Our results suggested that autophagic responses play roles as a self-protective mechanismin GA-treated glioblastoma cells, and autophagy inhibition could be a novel adjunctive strategy for enhancingchemotherapeutic effect of GA as an anti-malignant glioma agent.     

Glioblastoma multiforme with an abscess: case report and literature review

An intratumoral or peritumoral microbial intracranial abscess is an infrequent diagnosis. The development of this complication may not be preceded by apparent local or general infection in all cases. To identify this diagnosis by radiological (MRI) or laboratory investigations is very intricate. Nevertheless, the recommended life-saving strategy is early surgery with resolution of both the tumor and infection. If subsequent oncological treatment is required, it has to be adjusted for prevention of re-inflammation. The described patient suffered from an intracranial abscess superimposed on a Glioblastoma Multiforme. The confirmed etiological agent was Staphylococcus aureus. The suspected route of microbial migration and colonization in this tumor was bacteremia via agents from thrombophlebitis. The patient is in a good condition following surgery, antimicrobial treatment, and radiotherapy.     

Novel Derivatives of Tetrahydrobenzo (g) Imidazo[α-1,2] Quinoline Induce Apoptosis Via ROS Production in the Glioblastoma Multiforme Cells,U-87MG

Background: Despite newer therapeutic approaches against glioblastoma multiforme (GBM), the severely poor prognosis and treatment resistance are still disadvantages that slow down the patient’s recovery process. Consistent with the need to develop more effective and optimized therapies to control GBM cell growth, the effects of a new series of tetrahydrobenzo(g)imidazo[α-1,2]quinolone derivatives on GBM cell growth and the underlying mechanism is investigated in the current study. Methods: U-87MG cell line, glioblastoma multiforme and normal skin fibroblast cell line, AGO1522 were used to study the anticancer effects of 5 derivatives of tetrahydrobenzo(g)imidazo[α-1,2]quinolone and paclitaxel as a standard drug. The cytotoxic effect on cell growth was assessed using the MTT assay. Annexin V FITC staining and PI staining were applied to detect apoptosis and cell cycle distribution using flow cytometry. The extent of reactive oxygen species (ROS) formation was assessed using the fluorescent probe 7-dichlorofluorescin diacetate and caspase-3 activity using the colorimetric assay kit. Results: Among the 5 derivatives of tetrahydrobenzo(g)imidazo[α-1,2]quinolone, the 5c derivative (5-(6-bromo-2-chloroquinolin-3-yl)-9a-hydroxy-8,8-dimethyl-4-Nitro-2,3,5,5a,7,8,9,9a-octahydroimidazo[α-1,2]quinoline-6(1H)) showed the strongest cytotoxic effect on U-87MG cells in a time and Dose-dependent manner compared to the other derivatives and paclitaxel. The IC50 (11.91 M) of the 5c derivative induced apoptosis accompanied by a significant increase in sub-G1 and super-G2 phases of U-87MG cells. The increased level of cellular ROS and caspase 3 activity after treatment of U-87MG cells with 5c derivative was significant compared to untreated cells. Conclusion: Our data provide insights into the potent anticancer effects of the 5c-derivative of tetrahydrobenzo(g)imidazo[α-1,2]quinolone on GBM cells via the caspase-dependent apoptotic pathway, which may merit further attention.     

Targeting metabolic remodeling in glioblastoma multiforme

A key aberrant biological difference between tumor cells and normal differentiated cells is altered metabolism, whereby cancer cells acquire a number of stable genetic and epigenetic alterations to retain proliferation, survive under unfavorable microenvironments and invade into surrounding tissues. A classic biochemical adaptation is the metabolic shift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability, a phenomenon termed the "Warburg Effect". Aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and elevated production of lactate, is associated with a survival advantage as well as the generation of substrates such as fatty acids, amino acids and nucleotides necessary in rapidly proliferating cells. This review discusses the role of key metabolic enzymes and their association with aerobic glycolysis in Glioblastoma Multiforme (GBM), an aggressive, highly glycolytic and deadly brain tumor. Targeting key metabolic enzymes involved in modulating the "Warburg Effect" may provide a novel therapeutic approach either singularly or in combination with existing therapies in GBMs.     

Soluble c-Met Levels Correlated With Tissue c-Met Protein Expression in Patients With Advanced Non–Small-Cell Lung Cancer

Background

Immunohistochemistry (IHC) and fluorescent in situ hybridization are reliable methods for identifying c-Met protein expression or c-Met gene amplification. However, each technique requires a high-quality tissue sample, which might not be available. The aim of the present study was to investigate the correlation between the soluble c-Met level and tissue c-Met protein expression and the relationship between these markers and patient prognosis.

An analysis of dose-effect relationship in the radiotherapy of malignant gliomas.

The relationship between increasing survival and increasing doses of radiotherapy has been examined in 621 patients who were entered into three successive Brain Tumor Study Group protocols between 1966 and 1975. These patients were operated upon and had histologically proven malignant gliomas. The median survival of patients who received no radiotherapy was 18.0 weeks; for those who had ?4500 rad, it was 13.5 weeks (p = .346); those who received 5000 rad had a median survival of 28 weeks (p < .001), 5500 rad - 36.0 weeks (p < .001), and 6000 rad - 42.0 weeks (p < .001). The specific relationship between 5000 and 6000 rad indicates a 1.3 times increase in median life span associated with the higher dose (p = .004). A detailed analysis of specific factors which might have significantly biased results indicated that patients who received less than 4500 rad were not comparable to other groups of patients because they had a poorer initial performance status and a greater number died before completion of radiotherapy. Factors of importance including parameters of radiotherapy, pathology distribution, the influence of corticosteroids, and the effect of age, sex, and initial performance status were all comparable within the various other subgroups. No other treatment characteristics or selective factors which might have a direct effect on survival were identified. It was concluded that radiotherapy had a significant influence on the survival of patients with malignant glioma and that a clear-cut dose-effect relationship exists.     

Prognostic significance of plasma scatter factor/hepatocyte growth factor levels in patients with metastatic hormone- refractory prostate cancer: results from cancer and leukemia group B 150005/9480

Background

Scatter factor, also known as hepatocyte growth factor (SF/HGF), is a polypeptide growth factor thought to be important in the growth and spread of prostatic carcinoma.

Patients and Methods

Scatter factor/HGF levels in pretreatment plasma samples from 171 men with metastatic hormone-refractory prostate cancer enrolled in CALGB 9480 were quantified by solid-phase, enzyme-linked immunosorbent assay.

Results

The Cox proportional hazards model was used to assess the prognostic importance of SF/HGF with adjustment for established prognostic factors. Median SF/HGF was 991 pg/mL (range, 212-2733 pg/mL). In a univariate analysis, although plasma SF/HGF levels above versus below the median value did not reach statistical significance (P = 0.0862), the cutoff point of > 935 pg/mL was associated with a significant reduction in overall survival (P = 0.0334). Patients with SF/HGF levels > 935 pg/mL experienced a median survival of 15 months compared with 19 months for men with SF/HGF levels ≤ 935 pg/mL. In a multivariate analysis, adjusting for SF/HGF, prostatespecific antigen, lactate dehydrogenase, and performance status, only plasma alkaline phosphatase was significantly associated with overall survival (hazard ratio, 1.7; 95% confidence interval, 1.2-2.5; P = 0.0017).

Conclusion

Higher plasma levels of SF/HGF in men with hormonerefractory prostate cancer are associated with a decreased patient survival. Currently, SF/HGF levels do not appear to be of value as a contributor to multivariate models for prediction of outcome, but the association with decreased survival suggests that SF/HGF might be a potential target for therapy.     

多形性胶质母细胞瘤预后分级研究

目的总结成人多形性胶质母细胞瘤(GBM)的疗效,判定影响预后的相关因素,初步建立GBM预后的分级系统.方法回顾研究手术治疗的171例多形性胶质母细胞瘤患者的临床资料并根据随访,采用Kaplan-meier法计算生存率,绘出生存曲线;Logistic回归分析判定影响预后的因素.根据多因素分析结果,建立GBM预后的分级系统.结果 Logistic多因素回归分析显示病人的年龄、Karnofsky行为等级(KPS)评分、手术切除范围和术前影像学显示的肿瘤坏死程度等是多形性胶质母细胞瘤重要的预后不利因素.通过以上四种因素建立的GBM分级系统表明:分值越高,生存时间越短,分值与预后明显相关.结论初步建立的GBM分级系统对判定患者的预后有一定指导作用.     

Mouse models to interrogate the implications of the differentiation status in the ontogeny of gliomas

Glioblastoma multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors, with a median survival of 14-16 months despite optimal surgery, radiation and chemotherapy. A reason for this dismal prognosis is insufficient understanding of the ontogeny of GBMs, which are highly heterogeneous at a pathological level. This pathological diversity, between and within GBMs as well as varying grades of gliomas, has not been fully explained solely on the grounds of oncogenic stimulus. Interaction with the tumor microenvironment is likely a source of this pathological heterogeneity, as well as the inherent characteristics of the tumor cell of origin. Currently, controversy exists on whether the initial transformed cell is a differentiated astrocyte, progenitor or neural stem cell. Putative cancer stem cells (CSCs), which have features of normal stem cell plus the ability to recapitulate the tumor phenotype in vivo in small numbers, have been identified from a variety of solid human cancers, including GBMs. Evidence suggesting that regions harboring normal stem cells in the adult CNS, such as the subventricular zone and the dentate gyrus, are more prone to viral and chemical oncogenesis, is supportive of the hypothesis that brain tumors arise from stem cells. However, it is still to be determined whether the appearance of brain tumor stem cells (BTSC) is the cause or consequence of tumor initiation and progression. This review discusses emerging evidence highlighting the relevance of the state of differentiation and regional heterogeneity in the ontogeny of GBM. This is an area of high interest in cancer in general, with potential significant therapeutic and prognostic implications.     

No association of <Emphasis Type="Italic">MDM2</Emphasis> SNP309 with risk of glioblastoma and prognosis

The MDM2 SNP309 variant has been shown to increase MDM2 expression and to be associated with tumor formation. In glioblastomas, the P53/MDM2 pathway is of crucial importance and MDM2 amplification is related to poor prognosis. However, we show here that MDM2 SNP309 is not associated with glioblastoma risk, and is not a prognostic factor.     

GSTP-1基因遗传变异对术后接受替莫唑胺联合放疗的脑胶质瘤患者预后的影响

目的 探讨谷胱甘肽S-转移酶P-1（GSTP-1）基因遗传变异对术后接受替莫唑胺联合放疗的脑胶质瘤患者预后的影响。方法 收集患者外周血进行GSTP-1基因多态性位点基因分型。收集部分患者接受化疗前的新鲜外周血单核细胞提取RNA进行GSTP-1 mRNA表达实验。对多态性位点和其他变量进行相关性分析。结果 Ile105Val位点在研究人群中的分布频率为：G/G型68.00%（119例）,G/A型29.14%（51例）,A/A型2.86%（5例）,最小等位基因频率为0.17,该位点基因型分布频率符合Hardy-Weinberg平衡（P=0.868）。G/A+A/A型和G/G基因型患者的中位无进展生存期（PFS）分别为4.4和6.9月,差异有统计学意义（P=0.005）。G/A+A/A型和G/G基因型患者的中位总生存期（OS）分别为11.0和15.3月,差异有统计学意义（P<0.001）。G/A+A/A基因型对OS具有独立的影响意义（OR=1.68, P=0.011）。G/A+A/A基因型患者的GSTP-1 mRNA表达较G/G型高（P<0.001）。结论 GSTP-1基因Ile105Val位点可能通过影响GSTP-1基因mRNA表达进而影响接受替莫唑胺联合放疗的胶质瘤患者预后。     

Chk1在胶质母细胞瘤中的表达及其与肿瘤生物学行为和预后生存的关联性

目的 研究细胞周期检测点激酶1(Checkpoint kinase 1,Chk1)在胶质母细胞瘤细胞(Glioblastoma,GBM)中的表达及其与GBM细胞增殖、成瘤活性和预后生存的关联性。方法 利用TCGA数据库和脑肿瘤分子数据库(Rembrandt)选择和分析GBM中Chk1的表达,并采用Western blot和Real-time PCR等分子生物学技术检测GBM细胞中Chk1的表达水平;通过慢病毒转染siRNA沉默Chk1的表达以探究其对于GBM细胞增殖和成球能力的影响;同时利用免疫组化染色及Rembrandt数据库对Chk1与GBM患者的预后生存关系进行分析。结果 TCGA和Rembrandt数据库分析结果表明Chk1在GBM组织中呈现高表达,同样Western blot和Real-time PCR检测结果显示Chk1在GBM细胞中呈现高表达;慢病毒转染siRNA特异性沉默Chk1能够显著抑制U87细胞的生长(P＜0.01)和成球能力(P＜0.05);预后生存分析结果显示Chk1低表达GBM患者的临床预后显著优于高表达患者(P＜0.001)。结论 Chk1在GBM细胞中过量表达,表达上调能够促进GBM细胞的生长和增殖,并和GBM患者的不良预后相关。     

Multiple spinal metastases of cranial gliosarcoma: a case report and review of the literature

Gliosarcoma is a rare brain tumor that consists of both glial and mesenchymal components. We report the case of a 68-year-old female with cranial gliosarcoma metastatic to the spinal cord. Initially, the patient was diagnosed with cranial gliosarcoma and treated with surgical resection followed by radiotherapy. Four months after she completed treatment, she presented with a sudden onset of hemiplegia. MRI (Magnetic Resonance Imaging) scan demonstrated two masses at the thoracic spinal cord. Immediate surgery was performed and the lesions were resected. No further therapy was recommended due to the poor condition of the patient. The patient subsequently died 3 months after diagnosis of the spinal cord metastases. There are about 20 reported cases of metastatic gliosarcoma and most focus on systemic metastases of gliosarcoma. Spinal cord metastases are, however, very rare and here we report such a case. Available literature on metastatic gliosarcoma was also reviewed.