Clinical diagnosis and management of multiple cerebral ring-enhancing lesions-study of 50 patients at a tertiary healthcare center.

AIM OF THE STUDY: Multiple ring-enhancing lesions are commonly experienced group of brain pathologies which we come across in day-to-day practice. Clinical symptoms in these lesions are quite non-specific, and hence, it is difficult to reach a final diagnosis. However, these lesions have a varied group of differential diagnosis and it is sometimes difficult to have an accurate diagnosis on conventional MRI. This article was written with the objective of discussing the demographical study and etiology, clinical diagnosis and management for these patients. MATERIALS AND METHODS: It is a prospective study carried out at the Department of Neurosurgery, Dr. D Y Patil Medical College and Hospital, Pune, from September 2019 to August 2022 and included 50 patients who presented to us multiple ring-enhancing brain lesions. RESULTS: In our study, 50 patients between age (1-70 years) with multiple ring-enhancing lesions were analyzed. Majority of the patients were between age group 30-39 years. Males (76%) were majority in our study than females (24%). Most common pathology was primary neoplasm (glioma) and metastasis, followed by nine patients of pyogenic abscess and tuberculosis each. Neurocysticercosis was seen in eight patients and three patients were diagnosed with CNS lymphoma. Most of our patients presented with headache (38 patients) and a subset of patients had associated seizures (28 patients). Two patients with primary neoplasm were diagnosed to have WHO grade 3 glioma and seven patients were diagnosed to have WHO grade 4 glioma. Glioblastoma multiforme presented as multifocal and multicentric lesions. Among the patients with primary neoplasm, three patients underwent stereotactic biopsy for diagnosis and the rest of seven patients underwent maximum safe resection followed by chemotherapy and radiotherapy. Ten patients were diagnosed with metastatic lesions, among them six patients underwent stereotactic biopsy for histopathological diagnosis and immunohistochemistry, and rest of the patients were managed on the basis of the primary lesion. Five patients were immune-compromised, among them two patients presented with abscess and three patients presented with primary neoplastic lesion. Thirty-six patients underwent biopsy, among them seven patients underwent frameless, seven patients underwent frame stereotactic biopsy, and the rest 22 patients underwent excision biopsy. CONCLUSION: Multiple ring-enhancing lesions of brain pose a challenge in terms of achieving an accurate diagnosis and planning further treatment. It is of utmost importance to have a diagnosis in mind based on radiological investigations, so that surgical intervention can be planned accordingly be it by invasive or minimal invasive techniques. An idea toward the diagnosis also helps in prognosticating these patients which could avoid costly whole-body scans and unnecessary surgical intervention.

Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells.

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.

The role of transforaminal percutaneous endoscopic discectomy in lumbar disc herniations.

OBJECTIVES: To study 1)the efficacy of transforaminal percutaneous endoscopic lumbar discectomy in lumbar disc herniations.2) limitations and advantages of the surgical procedure. 3)morbidity and complications associated with the procedure. MATERIALS AND METHODS: This study was carried out on 120 patients who had single level herniated disc Pre-operative assessment of VAS and MSS scoring systems were documented one day prior to surgery. Post operative results were determined by MacNab criteria and by modified Suezawa and Schreiber clinical scoring system (MSS score). RESULTS: Maximum patients were in the age group of 31 to 40 years and 83.43% of the patients were males. 80% patients had lumbar disc herniation at L4-L5 level, The mean operative time of endoscopic discectomy was 52.28 minutes and the mean hospital stay was 2.1days.8 cases of L5-S I were abandoned due to high iliac bone and hence their disc could not be accessed. Out of 112 patients who underwent operation, 2 patients developed discitis and 1 was found to have dysesthesia. Also recurrent prolapsed intervertebral disc was seen in 6 cases The mean preoperative and 6 months follow-up VAS score was 8.4 and 1.89 respectively. Mean preoperative and 6 months follow-up Modified Suezawa And Schreiber Clinical Scoring System(MSS Score) was 3.47 and 7.92 respectively. MSS score showed excellent and good outcome in 82.12% patients and Modified Macnab Criteria showed excellent and good outcome in 89.3% patients at 6months follow-up. CONCLUSION: TPELD can be a reasonable alternative to conventional microscopic discectomy for the treatment of patients with LDH. We also conclude that TPELD is not an effective procedure for L5-S 1 disc and an open procedure should be opted for better outcomes.

Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling.

Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1ß suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.

Oncostatin-M differentially regulates mesenchymal and proneural signature genes in gliomas via STAT3 signaling.

Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention.

Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death.

Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)-4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par-4 induces apoptosis in cancer cells, its potential in drug-resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi-drug resistance and serve as ideal experimental models. We investigated the role of Par-4 in Tamoxifen (TAM)-induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par-4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par-4 expression, high level of chemo-resistance genes and were resistant to TAM-induced cytotoxicity. In monolayer cells, TAM-induced cytotoxicity was associated with enhanced expression of Par-4 and was alleviated by silencing of Par-4 using specific siRNA. TAM effectively induced secretory Par-4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM-induced cell death by exposure to conditioned medium (CM)-containing Par-4 (derived from TAM-treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par-4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par-4 induces apoptosis by binding to membrane GRP78, secretory Par-4 is an attractive candidate for potentially overcoming therapy-resistance not only in malignant glioma but in broad spectrum of cancers.

Expression and regulation of prostate apoptosis response-4 (Par-4) in human glioma stem cells in drug-induced apoptosis.

Gliomas are the most common and aggressive of brain tumors in adults. Cancer stem cells (CSC) contribute to chemoresistance in many solid tumors including gliomas. The function of prostate apoptosis response-4 (Par-4) as a pro-apoptotic protein is well documented in many cancers; however, its role in CSC remains obscure. In this study, we aimed to explore the role of Par-4 in drug-induced cytotoxicity using human glioma stem cell line--HNGC-2 and primary culture (G1) derived from high grade glioma. We show that among the panel of drugs- lomustine, carmustine, UCN-01, oxaliplatin, temozolomide and tamoxifen (TAM) screened, only TAM induced cell death and up-regulated Par-4 levels significantly. TAM-induced apoptosis was confirmed by PARP cleavage, Annexin V and propidium iodide staining and caspase-3 activity. Knock down of Par-4 by siRNA inhibited cell death by TAM, suggesting the role of Par-4 in induction of apoptosis. We also demonstrate that the mechanism involves break down of mitochondrial membrane potential, down regulation of Bcl-2 and reduced activation of Akt and ERK 42/44. Secretory Par-4 and GRP-78 were significantly expressed in HNGC-2 cells on exposure to TAM and specific antibodies to these molecules inhibited cell death suggesting that extrinsic Par-4 is important in TAM-induced apoptosis. Interestingly, TAM decreased the expression of neural stem cell markers--Nestin, Bmi1, Vimentin, Sox2, and Musashi in HNGC-2 cell line and G1 cells implicating its potential as a stemness inhibiting drug. Based on these data and our findings that enhanced levels of Par-4 sensitize the resistant glioma stem cells to drug-induced apoptosis, we propose that Par-4 may be explored for evaluating anti-tumor agents in CSC.

Giant intradural intramedullary epidermoid cyst Report of two cases with varied presentations.

We report two cases with giant intramedullary epidermoid cysts in the thoracolumbosacral and lumbosacral regions with varied presentations. Magnetic resonance (MR) imaging of the thoraco lumbar spine in case 1revealed an intramedullary elongated mass extending from T10 to S2 level causing significant widening of the spinal canal while MR imaging of lumbosacral spine in case 2 showed straightening of the lumbar spine and spina bifida at L5 level with conus at L3 and a lobulated long segment intramedullary solid cystic lesion extending from L2 to S2 veterbrae. The lesion was surgically resected and the pathology revealed an epidermoid cyst. Epidermoid cysts of the spinal cord are rare tumours in the adult population which may be congenital or acquired. Symptoms arising from epidermoid cysts vary with the level of involvement. The treatment of epidermoid cysts is surgical and if possible, complete removal is the goal.