Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma

Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaete-scute complex-like 1 (Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM

Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis

Background: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM). Methods: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins. Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients. Results: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs. RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes. With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues. Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot. GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 0.0001). Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis. Conclusions: Several novel potential serum biomarkers of GBM are identified and validated. High serum OPN level is found as a poor prognostic indicator in GBMs. Impact: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis

Tube-assisted Minimally Invasive versus Open Posterior Decompression for Multilevel Degenerative Cervical Myelopathy: A Prospective Comparative Study

Objective There have been several reports of minimally invasive decompression for cervical canal stenosis and degenerative myelopathy. Most of these reports are for less than 4 levels and there have not been any comparative studies between Open and MIS cervical decompression for multilevel (≥4) degenerative cervical myelopathy. Methods Twenty consecutive patients were allotted to undergo either ‘Open’ cervical laminectomy (n=10) or MIS posterior cervical decompression (n=10). All patients were evaluated for 1. Clinical, (JOA, MDI, NDI, Nurick grade, Blood loss, Duration of surgery); 2. Radiological (CSA of dural sac and Spinal cord, Muscle edema on post-op T2W MRI); 3. Laboratory (TLC, CRP, ESR, CPK) and 4. Physical (Isometric neck extensor muscle strength). Differences between Open and MIS groups were calculated with respect to above parameters. Results The mean number of levels decompressed was 4.4 (range, 4–6). MIS group had significantly longer duration of surgery and lesser blood loss as compared to open group. The patients in open group were more disabled than MIS group pre-operatively, as evidenced by higher MDI and NDI. However, proportionate improvements were seen in both groups post-operatively in terms of all clinical parameters. Postoperative increase in CSA of spinal cord was also identical in both groups. Elevations in CRP and ESR were significantly higher in Open group post-operatively as compared to MIS group. Post-operative extensor neck muscle strength improved to a higher extent in MIS group as compared to open group though this was not statistically significant. No patient had any major post-operative complications. Conclusion MIS posterior cervical decompression is safe and effective, can achieve similar extent of decompression and degree of clinical improvement as compared to open surgery. MIS has definite advantages of lesser blood loss, reduced tissue injury and better improvement in post-operative neck muscle strength as compared to open surgery

Trigeminal Neuralgia Due to a Small Meckel's Cave Epidermoid Tumor: Surgery Using an Extradural Corridor

Tumors at the petrous apex are associated with a variety of symptoms, which most often involve the trigeminal nerve. The authors present a rare case of a small epidermoid tumor in Meckel's cave that caused medically refractory trigeminal neuralgia. The surgical challenge associated with approaches to such lesions is discussed. The skull base tumor was excised completely through a small temporal craniotomy. The practicality of neuronavigation in reaching the petrous apex using a small extradural window is presented

Can bradycardia pose as a “red herring” in neurosurgery? Surgical stress exposes an asymptomatic sick sinus syndrome: Diagnostic and management dilemmas

Bradycardia in neurosurgery is almost always assumed to be secondary to intracranial conditions, specifically raised intracranial pressure causing Cushing’s reflex, the trigemino-cardiac reflex or brainstem lesions. We present a case of posterior fossa surgery in which persistent bradycardia developed in the postoperative period. A cardiac cause was initially overlooked since hydrocephalus was present preoperatively, which was initially assumed to be the cause of the bradycardia. The baseline pulse rate prior to surgery was 66 beats/minute. Only when repeated imaging revealed complete resolution of the hydrocephalus was a cardiology work up done and diagnosis of sick sinus syndrome established. The authors present an interesting case which demonstrates the need for a high degree of suspicion for such rare co-existing conditions. The diagnostic and management dilemmas are further discussed

Can bradycardia pose as a "red herring" in neurosurgery? Surgical stress exposes an asymptomatic sick sinus syndrome: Diagnostic and management dilemmas

Bradycardia in neurosurgery is almost always assumed to be secondary to intracranial conditions, specifically raised intracranial pressure causing Cushing\u2032s reflex, the trigemino-cardiac reflex or brainstem lesions. We present a case of posterior fossa surgery in which persistent bradycardia developed in the postoperative period. A cardiac cause was initially overlooked since hydrocephalus was present preoperatively, which was initially assumed to be the cause of the bradycardia. The baseline pulse rate prior to surgery was 66 beats/minute. Only when repeated imaging revealed complete resolution of the hydrocephalus was a cardiology work up done and diagnosis of sick sinus syndrome established. The authors present an interesting case which demonstrates the need for a high degree of suspicion for such rare co-existing conditions. The diagnostic and management dilemmas are further discussed

Automated detection of epileptic seizures using successive decomposition index and support vector machine classifier in long-term EEG

Epilepsy is a commonly observed long-term neurological disorder that impairs nerve cell activity in the brain and has a severe impact on people's daily lives. Accurate seizure detection in the long-term electroencephalogram (EEG) signals has gained vital importance in the diagnosis of patients with epilepsy. Visual interpretation and detection of epileptic seizures in long-term EEG is a time-consuming and burdensome task for neurologists. Therefore, in this study, we propose a computationally efficient automated seizure detection model using a novel feature called successive decomposition index (SDI). We observed that the SDI feature was significantly higher during the epileptic seizure as compared to normal EEG. The performance of the proposed method was evaluated using three databases, namely the Ramaiah Medical College and Hospital (DB1), CHB-MIT (DB2) and the Temple University Hospital (DB3) consisting of 58 h, 884 h, and 408 h of EEG, respectively. Experimental results revealed the sensitivity--false detection rate--median detection delay of 97.53%--0.4/h--1.5 s, 97.28%--0.57/h--1.7 s, and 95.80%--0.49/h--1.5 s for DB1, DB2, and DB3, respectively, using the support vector machine classifier. The proposed method significantly outperformed previously presented methods (wavelets and other feature extraction methods) while being computationally more efficient. Further, to the best of the author's knowledge, present study is the first study that was tested on three different EEG databases and showed consistent results leading to the generalization and robustness of the algorithm. Hence, the proposed method is an efficient tool for neurologists to detect epileptic seizures in long-term EEG