VRK2 identifies a subgroup of primary high-grade astrocytomas with a better prognosis.

BACKGROUND: Malignant astrocytomas are the most common primary brain tumors and one of the most lethal among human cancers despite optimal treatment. Therefore, the characterization of molecular alterations underlying the aggressive behavior of these tumors and the identification of new markers are thus an important step towards a better patient stratification and management. METHODS AND RESULTS: VRK1 and VRK2 (Vaccinia-related kinase-1, -2) expression, as well as proliferation markers, were determined in a tissue microarray containing 105 primary astrocytoma biopsies. Kaplan Meier and Cox models were used to find clinical and/or molecular parameters related to overall survival. The effects of VRK protein levels on proliferation were determined in astrocytoma cell lines. High levels of both protein kinases, VRK1 or VRK2, correlated with proliferation markers, p63 or ki67. There was no correlation with p53, reflecting the disruption of the VRK-p53-DRAM autoregulatory loop as a consequence of p53 mutations. High VRK2 protein levels identified a subgroup of astrocytomas that had a significant improvement in survival. The potential effect of VRK2 was studied by analyzing the growth characteristics of astrocytoma cell lines with different EGFR/VRK2 protein ratios. CONCLUSION: High levels of VRK2 resulted in a lower growth rate suggesting these cells are more indolent. In high-grade astrocytomas, VRK2 expression constitutes a good prognostic marker for patient survival.

Integration of global spectral karyotyping, CGH arrays, and expression arrays reveals important genes in the pathogenesis of glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. METHODS: We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). RESULTS: By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). CONCLUSIONS: We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM.

Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas.

BACKGROUND: Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs) are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM. METHODS: Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA; RESULTS: Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders). Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups of samples: those discriminated by tumour location and, the most importantly, the group discriminated by their proliferative potential; CONCLUSIONS: Primary glioblastomas could be sub-classified according to the properties of their CD133+ cells. The molecular characterization of these potential stem cell populations could be critical to find new therapeutic targets and to develop an effective therapy for these tumours with very dismal prognosis.

Posterior lumbar interbody fusion with instrumented posterolateral fusion in adult spondylolisthesis: description and association of clinico-surgical variables with prognosis in a series of 36 cases.

BACKGROUND: We present our experience in the treatment of patients with isthmic or degenerative spondylolisthesis, by means of a posterior lumbar interbody fusion (PLIF) and instrumented posterolateral fusion (IPLF), and we compare them with those published in the literature. We analyse whether there exists any statistical association between the clinical characteristics of the patient, radiological characteristics of the disease and our surgical technique, with the complications and the clinical-radiological prognosis of the cases. METHOD: We designed a prospective study. A total of 36 cases were operated. The patients included were 14 men and 22 women, with an average age of 57.17±27.32 years. Our technique consists of PLIF+IPLF, using local bone for the fusion. The clinical results were evaluated with the Visual Analogical Scale (VAS) and the Kirkaldy-Willis criteria. The radiological evaluation followed the Bratingan (PLIF) and Lenke (IPLF) methodology. A total of 42 variables were statistically analysed by means of SPSS18. We used the Paired Student's T-test, logistic regression and Pearson's Chi-square-test. RESULTS: The spondylolisthesis was isthmic in 15 cases and degenerative in 21 cases. The postoperative evaluations had excellent or good results in 94.5% (n = 34), with a statistically significant improvement in the back pain and sciatica (p < 0.01). The rate of circumferential fusion reached was approximately 92%. We had 13.88% of transitory morbility and 0% of mortality associated with our technique. A greater age, degree of listhesis or length of illness before the intervention, weakly correlated with worse clinical results (p< -0.2). In our series, the logistical regression showed that the clinical characteristics of the patient, radiological characteristics of the lesion and our surgical technique were not associated with greater postoperative complications. CONCLUSION: Although a higher level of training is necessary, we believe that the described technique is a very effective decision in cases of spondylolisthesis, isthmic or degenerative, refractory to conservative treatment, for the obtaining the best clinical results and rates of fusion, with similar risks to those of the other published techniques. Our statistical analysis could contribute to improve outcomes after surgery.