Purpose: Current methods of classification of astrocytoma based on histopathologic methods are often subjective and less accurate. Although patients with glioblastoma have grave prognosis, significant variability in patient outcome is observed. Therefore, the aim of this study was to identify glioblastoma diagnostic and prognostic markers through microarray analysis. Experimental Design: We carried out transcriptome analysis of 25 diffusely infiltrating astrocytoma samples [WHO grade IIödiffuse astrocytoma, grade IIIöanaplastic astrocytoma, and grade IVöglioblastoma (GBM)] using cDNA microarrays containing 18,981 genes. Several of the markers identified were also validated by real-time reverse transcription quantitative PCR and immunohistochemical analysis on an independent set of tumor samples (n = 100). Survival analysis was carried out for two markers on another independent set of retrospective cases (n = 51). Results: We identified several differentially regulated grade-specific genes. Independent validation by real-time reverse transcription quantitative PCR analysis found growth arrest and DNA-damage^inducible a (GADD45a) and follistatin-like 1 (FSTL1) to be up-regulated in most GBMs (both primary and secondary), whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1 were up-regulated in the majority of primary GBM. Further, identification of the grade-specific expression of GADD45a and FSTL1 by immunohistochemical staining reinforced our findings. Analysis of retrospective GBM cases with known survival data revealed that cytoplasmic overexpression of GADD45a conferred better survival while the coexpression of FSTL1with p53 was associated with poor survival. Conclusions: Our study reveals that GADD45a and FSTLI are GBM-specific whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1are primary GBM-specific diagnostic markers. Whereas GADD45a overexpression confers a favorable prognosis, FSTL1 overexpression is a hallmark of poor prognosis in GBM patients.
Malignant astrocytomas comprise anaplastic astrocytoma (AA; grade III) and Glioblastoma (GBM; grade IV). GBM is the most malignant with a median survival of 10-12 months in patients. Using cDNA microarray based expression profiling of different grades of astrocytomas, we identified several fold increased levels of PBEF1 transcripts in GBM samples. Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes Nicotinamide phosphoribosyltransferase (NAmPRTase), which catalyses the rate limiting step in the salvage pathway of NAD metabolism in mammalian cells. Further validation using real time RT-qPCR on an independent set of tumor samples (n = 91) and normal brain samples (n = 9), GBM specific higher expression of PBEF1 was confirmed. Immunohistochemical staining for PBEF1 on a subset of the above samples largely reinforced our finding. We carried out ELISA analysis on serum samples of astrocytoma patients to determine whether this protein levels would correlate with the presence of tumor and tumor grade. PBEF1 serum levels were substantially elevated in many of the AA and GBM patients. Statistical analysis of these data indicates that in patients with astrocytoma, serum PBEF1 levels correlate with tumor grade and is highest in GBM. Immunohistochemical analysis of an independent set of 51 retrospective GBM cases with known survival data revealed that PBEF1 expression in the tumor tissue along with its co-expression with p53 was associated with poor survival. Thus, we have identified PBEF1 as a potential malignant astrocytoma serum marker and prognostic indicator among GBMs.
Object Extraforaminal compression of the L-5 nerve encompasses multiple pathological entities and may result from disc herniations as well as bony (osteophytes or sacral ala) or ligamentous (sacroiliac ligament and lumbosacral band) compression. Several other factors, such as disc space collapse or coronal wedging, can also contribute to narrowing of the extraforaminal space. The extraforaminal space at L5–S1 has unique anatomical features compared with the upper lumbar levels, which makes surgical access to this region difficult. Minimally invasive techniques offer easier access to the region. The purpose of this study was to analyze the contributing factors for extraforaminal compression of the L-5 nerve and assess clinical outcome following surgical decompression. Methods Fifty-two consecutive patients who underwent a minimally invasive far-lateral approach for extraforaminal compression of the L-5 nerve were retrospectively analyzed for clinical data, outcomes, and imaging features (type of disc prolapse, coronal wedging, degree of disc and facet degeneration, facet tropism, foraminal stenosis, osteophytes, and adjacent-level disease). The authors describe the surgical technique used in this study. Results The mean age of the patient sample was 57 years. Sixteen patients each had an extraforaminal ruptured disc or contained protrusion, and the remaining 20 patients had disc protrusions extending into the foraminal region or the lateral recess. Associated foraminal stenosis was found in 38.5%, and adjacent-level stenosis was noted in 22 cases (42.3%) and spondylolisthesis in 4 (7.7%). Osteophytes were noted in 18 cases. A coronal wedging angle ≥ 3° was found in 46.2%, and the laterality of wedging corresponded to the symptomatic side in 91% of cases. Fifteen patients (28.8%) complained of postoperative dysesthesias, which completely resolved in all cases within 6 months. The incidence of dysesthesias was more common in the ruptured disc group. There were no differences in clinical outcome among the different types of disc prolapses. The mean preoperative and postoperative visual analog scale scores were 7.6 and 3.6, respectively. The mean preoperative and postoperative Japanese Orthopaedic Association (JOA) scores were 6.4 and 13.8, respectively. The mean JOA recovery rate was 86.1%. According to the Macnab functional grading system, 96% of the patients had excellent or good grades at follow-up. Conclusions A minimally invasive far-lateral approach to L5–S1 requires a good understanding of the regional anatomy and can provide good to excellent clinical results in properly selected cases. This approach is effective in decompressing the far-lateral and foraminal zones. Adequate preoperative diagnosis and tailoring the surgical procedure to address the relevant compressive element in each case is essential to achieving good clinical results.
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