Glioblastoma (GBM) is the most common primary malignant type of brain neoplasm in adults and carries a dismal prognosis. The current standard of care for GBM is surgical excision followed by radiation therapy (RT) with concurrent and adjuvant temozolomide-based chemotherapy (TMZ) by six additional cycles. In addition, antiangiogenic therapy with an antivascular endothelial growth factor (VEGF) agent has been used for recurrent glioblastoma. Over the last years, new posttreatment entities such as pseudoprogression and pseudoresponse have been recognized, apart from radiation necrosis. This review article focuses on the role of different imaging techniques such as conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), dynamic contrast enhancement (DCE-MRI) and dynamic susceptibility contrast (DSE-MRI) perfusion, magnetic resonance spectroscopy (MRS), and PET/SPECT in differentiation of such treatment-related changes from tumor recurrence.
Central and peripheral nervous system toxicity are frequent complications of most chemotherapy regimens, often leading to reduction of dosages or cessation of the responsible drugs. However, sometimes the afflicted toxicity may not be reversible, especially if it is not recognized early, further compromising the quality of life of the cancer patients. The most common chemotherapeutic agents that might cause CNS toxicity manifested as encephalopathy of various severities include methotrexate, vincristine, ifosfamide, cyclosporine, fludarabine, cytarabine, 5-fluorouracil, cisplatin and the interferons (alpha > beta). Involvement of the peripheral nervous system manifested as distal peripheral neuropathy results after therapy with cisplatin, vincristine, taxanes, suramin and thalidomide. Although several compounds have been proposed as neuroprotective agents, few have been shown to be active against the chemotherapy induced neurotoxicity.
We have previously demonstrated the effectiveness of adenovirus-mediated expression of antisense urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) in inhibiting tumor invasion in vitro and ex vivo. However, the therapeutic effect of the adenovirus-mediated antisense approach was shown to be transient and required potentially toxic, high viral doses. In contrast, RNA interference (RNAi)-mediated gene targeting may be superior to the traditional antisense approach, because the target mRNA is completely degraded and the molar ratio of siRNA required to degrade the target mRNA is very low. Here, we have examined the siRNA-mediated target RNA degradation of uPAR and MMP-9 in human glioma cell lines. Using RNAi directed toward uPAR and MMP-9, we achieved specific inhibition of uPAR and MMP-9. This bicistronic construct (pUM) inhibited the formation of capillary-like structures in both in vitro and in vivo models of angiogenesis. We demonstrated that blocking the expression of these genes results in significant inhibition of glioma tumor invasion in Matrigel and spheroid invasion assay models. RNAi for uPAR and MMP-9 inhibited cell proliferation, and significantly reduced the levels of phosphorylated forms of MAPK, ERK, and AKT signaling pathway molecules when compared with parental and empty vector/scrambled vector-transfected SNB19 cells. Furthermore, using RNAi to simultaneously target two proteases resulted in total regression of pre-established intracerebral tumor growth. Our results provide evidence that the use of hairpin siRNA expression vectors for uPAR and MMP-9 may provide an effective tool for cancer therapy. RNA interference (RNAi)1 is a sequence-specific, post-transcriptional gene silencing mechanism, which is triggered by double-stranded RNA and causes the degradation of mRNA homologous in sequence to the double-stranded RNA (1-3). This is an ancient and ubiquitous antiviral system used by organisms to maintain the integrity of the genome, to defend cells against viral infection, and to regulate expression of cellular genes (4). RNAi depends upon the formation of doublestrand RNA (double-stranded RNA) whose antisense strand is complementary to the transcript of a targeted gene. Recently, it has been shown that sequence-specific inhibition RNAi can also be induced in mammalian cells (4, 5). In one implementation of RNAi, selective degradation of target mRNAs in mammalian cells is achieved by transfection with double-stranded, short interfering RNAs (siRNAs), leading to rapid and efficient degradation of the target (4). These siRNAs were shown to avoid the well documented nonspecific effects triggered by longer double-stranded RNAs in mammalian cells.Glioblastoma multiforme is a highly malignant primary central nervous system neoplasm, which is extremely refractory to therapy. One property that makes glioblastoma resistant to treatment is the tendency of the tumor cells to invade normal brain tissue (6). Invasiveness is thus considered to be a major determinant of ...
Meningioma is a common intracranial tumor, originating from the meninges of the skull or spinal canal. Most meningiomas are benign tumors, however atypical or anaplastic tumors can be found in 6% of cases. Patients with asymptomatic small benign meningiomas can be followed without therapy, but in symptomatic patients complete surgical resection should be performed. For recurrent previously resected tumors re-resection is recommended followed by radiotherapy in selected cases. Antiprogesterone treatment can also be considered in recurrent benign meningiomas. Immunotherapy with interferon-alpha and chemotherapy should be reserved for all cases of recurrent meningiomas (benign, atypical, and malignant) when all the standard therapies have failed or contraindicated.
Purpose Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. Methods We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), 11C-methionine (MET), and 18F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. Results Twenty-three studies with a total of 994 participants were included in this meta-analysis. The pooled sensitivities of both MET PET and FET PET were found to be significantly higher than of FDG PET (94%, 88%, and 63% respectively, P < 0.001). The pooled specificity of FDG PET was found to be significantly greater compared with both MET PET and FET PET (89%, 55%, and 57%, respectively; P = 0.002). Fluorodeoxyglucose PET was superior in terms of higher positive likelihood ratio values compared with both FET PET and MET PET. Conclusions This meta-analysis indicated that both MET and FET were superior to FDG in terms of sensitivity for identifying glioma grade.
BackgroundPolymorphisms of the vitamin D receptor (VDR) gene have been linked to both multiple sclerosis (MS) and osteoporosis. We examined the frequency of the Taq-I and Bsm-I polymorphisms of the vitamin D receptor (VDR) gene in 69 patients with MS and 81 age and sex-matched healthy individuals. Genotyping of Taq-I (rs731236) and Bsm-I (rs1544410) was performed using TaqMan® SNP Genotyping Assay. All patients and controls had determination of body mass index (BMI), bone mineral density (BMD) and smoking history.ResultsThe mean age of patients was 39 ± 10.5 years compared to 38.7 ± 10.7 years of the controls (p = 0.86), the BMI was 24.8 ± 4.2 kg/m2 compared to 25.7 ± 4.8 kg/m2 of the controls (p = 0.23), the BMD in the lumbar spine 0.981 ± 0.15 compared to 1.025 ± 013 of the controls (p = 0.06) and the total hip BMD was 0.875 ± 0.14 compared to 0.969 ± 0.12 of the controls (p < 0.001). There were no differences of the Taq-I (TT, CT, CC) and Bsm-I genotypes (GG, GA, AA) and allelic frequencies between MS and control individuals. Multivariate analysis also failed to show any association of the Taq-I and Bsm-I polymorphisms and MS or sex, BMI, BMD and smoking history.ConclusionsThis study suggests that the Taq-I and Bsm-I polymorphisms of the VDR gene are not associated with MS risk, BMI or BMD in the Greek population studied.
Cerebral Aneurysms (CAs) are characterized by a pathological wall structure with internal elastic lamina and media disruption which leads to focal weakened pouches of the arterial wall. The prevalence of unruptured CAs is estimated to be 2-5% in the general population. During the past few decades, the pathophysiological mechanisms behind the formation, growth and rupture of CAs have been the focus of numerous research studies. In this review, the inflammatory pathways, genetics and risk factors for the formation, growth and rupture of CAs are summarized. In addition, the concepts of geometrical indices, flow patterns and fluid dynamics that govern CA development are discussed.
In gliomas, germline gene alterations play a significant role during malignant transformation of progenitor glial cells, at least for families with occurrence of multiple cancers or with specific hereditary cancer syndromes. Scientific evidence during the last few years has revealed several constitutive genetic abnormalities that may influence glioma formation. These germline abnormalities are manifested as either gene polymorphisms or hemizygous mutations of key regulatory genes that are involved either in DNA repair or in apoptosis. Such changes, among others, include hemizygous alterations of the neurofibromatosis 1 (NF1) and p53 genes that are involved in apoptotic pathways, and alterations in multiple DNA repair genes such as mismatch repair (MMR) genes, x-ray cross-complementary genes (XRCC), and O6-methylguanine-DNA methyltransferase (MGMT) genes. Subsequent cellular changes include somatic mutations in cell cycle regulatory genes and genes involved in angiogenesis and invasion, leading eventually to tumor formation in various stages. Future molecular diagnosis may identify new genomic regions that could harbor genes important for glioma predisposition and aid in the early diagnosis of these patients and genetic counseling of their families.
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