Quantitative tissue analysis reveals AK2, COL1A1, & PLG protein signatures: Targeted therapeutics for meningioma.

BACKGROUND: Meningioma is the most prevalent primary intracranial brain tumor and accounts for one-third of all CNS tumors. Meningioma is known to be the most common yet life-threatening brain tumor with a higher recurrence rate. Globally, there is an increase in the healthcare burden due to meningioma and hence in its research. The present clinical approach includes surgical resection, chemotherapy, and radiation therapies to which the malignancy does not seem to respond efficiently. Targeted therapies and molecular markers provide elite patient treatment and care for individuals suffering from meningiomas as compared to conventional measures. Although there is proteomic data on meningioma the knowledge of potential biomarkers differentiating the grades is scarce. To identify the best set of biomarkers, validation of reported markers in large and independent sample cohorts in the future is necessary. METHODS: A total of 12 samples, 3 each of control (which made pool 1) Meningioma grade I (which made 2 sets: pool 2 and pool 3), and Meningioma grade II (which made pool 4) were taken for LC-MS/MS. After this, the expression of three proteins was checked by immunocytochemistry, flow cytometry, and western blotting. RESULTS: Protein expression was analyzed using various techniques like mass spectrometry, immunocytochemistry, flow cytometry, and western blotting. Mass spectrometry is the most commonly used standard and reliable technique for identifying and quantifying protein expression. We got three highly upregulated proteins namely AK2, COL1A1, and PLG using this technique. The biomarker potential of these proteins was further checked by ICC, western blotting, and flow cytometry. Three important proteins were found to be upregulated namely AK2 (Adenylate Kinase 2), COL1A1 (Collagen 1A1), and PLG (Plasminogen). The order of increased protein expression was control < MG grade I < MG grade II according to mass spectrometry and western blotting. In immunocytochemistry, we found that COL1A1 expression increases significantly with grades in comparison to control. Similarly, AK2 and PLG also showed little increase but not as much as COL1A1. In flow cytometry, PLG showed higher upregulation in grades than control. While AK2 and COL1A1 showed little increase in expression in grades than control. All techniques, especially mass spectrometry and western blotting presented higher expression of these proteins in grades as compared to control. CONCLUSIONS: In the quest to find a suitable therapeutic marker, this study incorporates quantitative labeling and detection followed by flow cytometry, Immunocytochemistry, and western blotting for early diagnosis and treatment of meningioma. The article further explores the efficacy of some proteins namely AK2, COL1A1 & PLG to be the targeted molecules.

Cytochrome C as a potential clinical marker for diagnosis and treatment of glioma.

Gliomas are the most prevalent kind of malignant and severe brain cancer. Apoptosis regulating mechanisms are disturbed in malignant gliomas, as they are in added forms of malignancy. Understanding apoptosis and other associated processes are thought to be critical for understanding the origins of malignant tumors and designing anti-cancerous drugs for the treatment. The purpose of this study was to evaluate the variation in the expression level of several apoptotic proteins that are responsible for apoptosis in low to high-grade glioma. This suggests a significant change in the expression of five apoptotic proteins: Clusterin, HSP27, Catalase, Cytochrome C, and SMAC. Cytochrome C, one of the five substantially altered proteins, is a crucial component of the apoptotic cascade. The complex enzyme Cytochrome C is involved in metabolic pathways such as respiration and cell death. The results demonstrated that Cytochrome C expression levels are lower in glioma tissues than in normal tissues. What's more intriguing is that the expression level decreases with an increase in glioma grades. As a result, the discovery shows that Cytochrome C may be a target for glioma prognostic biomarkers.

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma.

Gliomas are the most common type of the malignant brain tumor, which arise from glial cells. They make up about 40% of all primary brain tumors and around 70% of all primary malignant brain tumors. They can occur anywhere in the central nervous system (CNS) and have a poor prognosis. The average survival of glioma patients is approximately 6-15 months with poor aspects of life. In this edge, identification of proteins secreted by cancer cells is of special interest because it may provide a better understanding of tumor progression and provide early diagnosis of the diseases. Extracellular vesicles (EVs) were isolated from pooled plasma of healthy controls (n=03) and patients with different grades of glioma (Grade I or II or III, n=03 each). Nanoparticle tracking analysis, western blot, and flow cytometry were performed to determine the size, morphology, the concentration of glioma-derived vesicles and EV marker, CD63. Further, iTRAQ-based LC-MS/MS analysis of EV protein was performed to determine the differential protein abundance in extracellular vesicles across different glioma grades. We further verified galectin-3 binding protein (LGALS3BP) by ELISA in individual blood plasma and plasma-derived vesicles from control and glioma patients (n=40 each). Analysis by Max Quant identified 123 proteins from the pooled patient exosomes, out of which 34, 21, and 14 proteins were found to be differentially abundant by more than 1.3-fold in the different grades of glioma grade I, pilocytic astrocytoma; grade II, diffuse astrocytoma; grade III, anaplastic astrocytoma, respectively, in comparison with the control samples. A total of seven proteins-namely, CRP, SAA2, SERPINA3, SAA1, C4A, LV211, and KV112-showed differential abundance in all the three grades. LGALS3BP was seen to be upregulated across the different grades, and ELISA analysis from individual blood plasma and plasma-derived extracellular vesicles confirmed the increased expression of LGALS3BP in glioma patients (p<0.001). The present study provides LGALS3BP as a potential biomarker for early detection of glioma and improve survival outcome of the patient. The present study further provides the information of progression and monitoring the tumor grades (grade 1, grade II, grade III).

Exploring the role of epidermal growth factor receptor variant III in meningeal tumors.

Meningioma is the second most common type of intracranial brain tumor. Immunohistochemical techniques have shown prodigious results in the role of epidermal growth factor receptor variant III (EGFR vIII) in glioma and other cancers. However, the role of EGFR vIII in meningioma is still in question. This study attempt the confer searches for the position attained by EGFR vIII in progression and expression of meningioma. Immunohistochemistry technique showed that EGFR vIII is highly expressed in benign tumors as compared to the atypical meningioma with a highly significant p-value (p<0.05). Further analysis by flow cytometry results supported these findings thus presented high intensity of EGFR vIII in low grades of meningioma. The study revealed that the significant Ki 67 values, to predictor marker for survival and prognosis of the patients. Higher expression of EGFR vIII in low grades meningiomas as compared to high-grade tumors indicate towards its oncogenic properties. To our knowledge, limited studies reported in literature expressing the EGFR vIII in meningioma tumors. Hence, Opinions regarding the role that EGFR vIII in tumorigenesis and tumor progression are clearly conflicting and, therefore, it is crucial not only to find out its mechanism of action, but also to definitely identify its role in meningioma.

Management of multiple tethering in spinal dysraphism.

INTRODUCTION: The most challenging component of spinal dysraphism is cord tethering. Tethering can occur due to single or multiple lesions within the same patient. It is imperative to aggressively identify and release all the tethering lesions in order to provide maximum benefit to the patient. With increasing number of tethering lesions, the clinical profile and outcome show significant differences, and this difference is significantly more when more than two tethering lesions coexist in the same patient. MATERIAL AND METHODS: Out of the 248 patients of spinal dysraphism who underwent surgical management at Sanjay Gandhi Institute of Medical Sciences, Lucknow, India, between 1997 and 2007, 160 were included in the study. Patients were classified into two groups based on the number of tethering lesions. The first group (Group A) comprised cases of spinal dysraphism with tethering demonstrable at one or two sites. The second group (Group B) comprised patients with radiological or intraoperative evidence of multiple tethering lesions (more than two). RESULTS: There were 119/160 patients in Group A, while 41/160 patients were in Group B (with more than two sites of tethering). The preoperative neurological examination revealed significant differences between the two study groups. The clinical profile and the surgical outcomes have shown significant differences in the two study groups. These differences are statistically significant. CONCLUSION: We strongly believe that the mere presence or absence of tethering is not a sufficient documentation to predict its effect on the cases of spinal dysraphism. Tethering is a complex entity that needs to be further classified in terms of the number of tethering lesions, which significantly affect the pre- and postoperative status of the patients. We would like to suggest the term "Spina Bifida Multiplex" for the cases where more than two lesions are found to be responsible for tethering.

Primary midbrain germinoma.

An 11-year-old boy presented with a 4-month history of progressive holocranial headache, intermittent vomiting and visual blurring. Later, he began walking unsteadily, with progressive bilateral visual and hearing loss. He had had two episodes of abnormal tonic posturing the day prior to admission. On examination, the patient was drowsy and did not respond to commands. Imaging showed an enhancing midbrain mass with an exophytic component with hydrocephalus. Emergency ventriculoperitoneal shunt was performed, following which there was neurological improvement. Later he underwent a midline suboccipital craniectomy with vermian splitting and decompression of the exophytic component of the tumor from the midbrain. Biopsy of the tumor revealed a germinoma. Post-operatively, the patient received chemotherapy followed by radiotherapy. Primary midbrain germinoma is an extremely rare entity and to the best of our knowledge only two cases to date have been reported in the literature.

Craniovertebral junction anomaly with atlas assimilation and reducible atlantoaxial dislocation: a rare constellation of bony abnormalities.

A rare case of craniovertebral junction anomaly with associated reducible C(1)-C(2) dislocation and assimilation of the atlas is reported. The patient presented with neck pain with spastic quadriparesis. A posterior stabilization utilizing a contour rod, sublaminar wire fixation and onlay bone grafts between the occiput, and C(3) and C(4) vertebrae was performed followed by symptomatic improvement.

Pediatric intracranial aneurysms: an institutional experience.

INTRODUCTION: Intracranial aneurysms are extremely uncommon in the pediatric population. Their epidemiology is poorly understood, and certain features make them unique. In our study we analyzed pediatric intracranial aneurysm patients to gain an insight into the epidemiology, clinicoradiological profile and outcome. MATERIAL AND METHODS: Out of 36 children (< or =18 years of age; male:female ratio = 1.076:1; mean age 13.19 +/- 3.72 years, age range 5-18 years) presenting with subarachnoid hemorrhage (SAH; n = 33; 91.67%) and mass effect (n = 3; 8.33%), 27 who were positive on digital subtraction angiography and treated for intracranial aneurysms between January 1991 and February 2007 were included in this study. RESULTS: At presentation, the majority (n = 21) of the pediatric intracranial patients showed a good grade, and 23 (85.18%) presented with SAH. Sudden severe headache (n = 19; 70.37%) and loss of consciousness (n = 14; 51.85%) were the most common symptoms, and meningeal signs (n = 18; 66.66%) most commonly elicitable. There were 7 patients with giant aneurysms and 8 patients with posterior circulation aneurysms. Internal carotid artery (ICA) bifurcations (n = 6; 18.18%) followed by middle cerebral artery (MCA) bifurcations (n = 4; 12.12%) were the most common sites. At a mean follow-up of 18.67 +/- 10.85 months (range 1-42 months), there were 21 (77.77%) patients with favorable outcome and 3 patients died. CONCLUSIONS: Intracranial aneurysms in children commonly present with SAH; there is a male predominance, and ICA bifurcations followed by MCA bifurcations are the most common sites. The incidence of posterior circulation aneurysms and giant aneurysms is higher as compared to adults. The pediatric patients present with better grades and have better overall surgical results.

Tubercular atlantoaxial dislocation in children: an institutional experience.

OBJECT: In this paper the authors analyzed the clinical and imaging-documented profile of pediatric patients with tubercular atlantoaxial dislocation (AAD). METHODS: Seventeen children 16 years of age or younger with tubercular AAD were included in the study. Patients with reducible AAD underwent direct posterior stabilization. All patients were treated with a four-drug antituberculosis therapy (ATT) regimen (10-20 mg/kg/day rifampicin, 10-20 mg/kg/day isoniazid, and 15 mg/kg/day ethambutol in a single daily dose; and pyrazinamide 20-35 mg/kg/day in two divided doses) for 3 months. The pyrazinamide was then discontinued after 3 months and the ethambutol after 1 year. The rifampicin and isoniazid were continued for 18 months. RESULTS: Most of the patients had irreducible AAD. There was a high incidence of long tract signs, and the restriction of neck movements, as well as neck pain, was also very common. There was a significant delay in seeking neurosurgical consultation. Most patients were assigned poor preoperative grades, but they experienced excellent improvement postoperatively. CONCLUSIONS: The presence of tubercular AAD in children can have subtle manifestations leading to delayed diagnosis. The successful management of tubercular AAD can be achieved after determining the extent of the disease process and the underlying instability. The goal of surgery is tissue diagnosis and relief of neural compression and stabilization. Medical treatment with ATT is an integral part of the treatment protocol.

Primary pineal malignant melanoma - illustrated review.

AIM: Primary pineal melanoma is a rare tumor. We herein review the histogenesis, pathology, radiology and therapeutic options of this rare tumor. MATERIAL AND METHODS: We conducted a PUBMED search using a combination of keywords such as "primary pineal melanoma", "CNS melanoma", and "pineal tumor" and identified 16 cases of primary pineal melanoma. Clinical features, pathologic characteristics and treatment details of these patients were noted from respective case reports. We also describe a case of a 45-year-old Indian woman with primary pineal melanoma treated with a combination of surgery and post-op radiation. RESULTS: The median age at presentation is 50 years. Median duration of symptoms is 6 weeks. Common symptoms at presentation include headache (58.8%), personality changes (41.2%), gait disturbance (35.3%) and Parinaud's syndrome (29.4%). Surgery, radiotherapy and chemotherapy have been used in 29.4%, 47.1% and 23.5% of patients respectively. Median overall survival is 56 weeks. Leptomeningeal dissemination and ventricular ependymal spread were noted in 70.6% and 35.3% patients, respectively. CONCLUSION: Combined modality treatment comprising maximal safe surgery and post-operative radiation should be preferred in patients with localized pineal melanoma without leptomeningeal dissemination. Taking a cue from other subsites of melanoma, chemotherapy can perhaps be deferred until recurrence.

Bilateral acute foot drop following lumbar disc herniation--a case report.

Cauda equina compression and acute unilateral foot drop are commonly described associations with prolapsed intervertebral lumbar disc. The bilateral acute foot drop however is a rare occurrence. A 45-year-old adult male labourer presented with 1 month history of low backache, with acute exacerbation 1 day later. He developed acute bilateral foot drop and urinary retention within 2 hours. An urgent magnetic resonance imaging (MRI) revealed large central disc prolapse at L3-L4 level with significant canal stenosis. He was operated on emergent basis following which he had progressive neurological improvement.

Hemangiopericytoma of thoracic spine: a rare bony tumor.

CASE REPORT: We report the case of a 16-year-old girl who developed hemangiopericytoma of the thoracic spine; the main clinical symptoms were of spastic paraparesis with sensory involvement and uro-fecal incontinence. She was initially put on antitubercular treatment keeping in mind the endemicity of tuberculosis in the region. When she deteriorated on conservative management, she was operated upon, and the histopathological report was suggestive of hemangiopericytoma. MATERIALS AND METHODS: Additional immunocytochemistry was performed in the paraffin-embedded tumor sections. CONCLUSIONS: An extremely rare case of primary epidural malignant hemangiopericytoma of the thoracic spinal column is described. It is a rare tumor, which is locally aggressive, and a potentially malignant tumor. The tumor is more commonly found in the cranium, and spinal involvement is rare, and only few case reports could be retrieved from the literature. We discuss the clinical profile, management, and outcome of spinal hemangiopericytomas along with pertinent review of the literature.

Lhermitte-Duclos disease.

BACKGROUND: Lhermitte-Duclos disease (LDD; dysplastic gangliocytoma of the cerebellum) is a rare hamartoma of the cerebellum. It was first described by Lhermitte and Duclos in 1920 as "Sur un ganglioneurome diffus du cortex du cervelet" (Lhermitte and Duclos [Bull Assoc Fr Etude Cancer 9:99-107, 1920]). Since then, due to its rarity and the variability of its presentation, the diagnosis is often missed. It is not only important for the neurosurgeon and the pathologist to be aware of this entity so as to differentiate from malignant lesions but also to distinguish it from other cerebellar malformations, which may be hypoplastic or dysplastic, focal or diffuse in nature, with brain stem and cerebral involvement, and varied natural course. ILLUSTRATIVE CASE: We report a case of LDD in a 16-year-old boy. This case exemplifies the rarity of the disease leading to lack of awareness with which the diagnosis was easily missed. We also take this opportunity to discuss the clinical presentation, neuroradiological appearance, and a brief summary of histopathological findings, pathogenetic considerations, and neurogenetical aspects.