History and Evolution of Radiosurgery in India: Strength to Strength.

Stereotactic radiosurgery (SRS) has been well received by the neurosurgical community since its introduction in India. Knowledgeable radiosurgeons and visionary neurosurgeons have contributed to its success. At present, we have five functional and busy gamma knife centers, one proton radiosurgery center, and seven CyberKnife centers in India. However, there is a need for more such centers and formal training facilities, especially in the unorganized private sector. Radiosurgery has expanded its horizon from its initial indications of vascular and benign disorders to functional ailments and metastasis. Here, we take a look at the seminal points in its development in India along with the centers of excellence that contributed to the same. While we have tried to cover all the facets of its development, it is natural to miss some undocumented events not available in public domain. Nonetheless, the future of radiosurgery seems promising in India with the assurance of minimally invasive, safe, and effective treatment delivery.

Nuclear respiratory factor 1 transcriptomic signatures as prognostic indicators of recurring aggressive mesenchymal glioblastoma and resistance to therapy in White American females.

PURPOSE: The mechanisms contributing to recurrence of glioblastoma (GBM), an aggressive neuroepithelial brain tumor, remain unknown. We have recently shown that nuclear respiratory factor 1 (NRF1) is an oncogenic transcription factor and its transcriptional activity is associated with the progression and prognosis of GBM. Herein, we extend our efforts to (1) identify influential NRF1-driven gene and microRNA (miRNA) expression for the aggressiveness of mesenchymal GBM; and (2) understand the molecular basis for its poor response to therapy. METHODS: Clinical data and RNA-Seq from four independent GBM cohorts were analyzed by Bayesian Network Inference with Java Objects (BANJO) and Markov chain Monte Carlo (MCMC)-based gene order to identify molecular drivers of mesenchymal GBM as well as prognostic indicators of poor response to radiation and chemotherapy. RESULTS: We are the first to report sex-specific NRF1 motif enriched gene signatures showing increased susceptibility to GBM. Risk estimates for GBM were increased by greater than 100-fold with the joint effect of NRF1-driven gene signatures-CDK4, DUSP6, MSH2, NRF1, and PARK7 in female GBM patients and CDK4, CASP2, H6PD, and NRF1 in male GBM patients. NRF1-driven causal Bayesian network genes were predictive of poor survival and resistance to chemoradiation in IDH1 wild-type mesenchymal GBM patients. NRF1-regulatable miRNAs were also associated with poor response to chemoradiation therapy in female IDH1 wild-type mesenchymal GBM. Stable overexpression of NRF1 reprogramed human astrocytes into neural stem cell-like cells expressing SOX2 and nestin. These cells differentiated into neurons and form tumorospheroids. CONCLUSIONS: In summary, our novel discovery shows that NRF1-driven causal genes and miRNAs involved in cancer cell stemness and mesenchymal features contribute to cancer aggressiveness and recurrence of aggressive therapy-resistant glioblastoma.

Nuclear Respiratory Factor 1 (NRF1) Transcriptional Activity-Driven Gene Signature Association with Severity of Astrocytoma and Poor Prognosis of Glioblastoma.

Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM. NRF1 has higher mRNA expression and transcription factor activity in astrocytoma compared to non-tumor brain tissue. NRF1 activity also correlated with the aggressiveness of cancer. Increased NRF1 TF activity coupled with overexpression of RHOG was associated with poor survival of GBM patients. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition and cell cycle progression. Overexpression of CDK4, AKT1, APAF1, HDAC1, NBN, TGFB1, & TNFRSF1A and downregulation of CASP3, IL7, STXBP1 and OPA1 predicted GBM malignancy in high expressors of NRF1 activity. Increased expression of the NRF1 motif containing genes, H6PD, NAT10, NBEAL2, and RNF19B predicted poor survival of IDH1 wild-type GBM patients. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets - LDHA, ZMAT3, NSUN2, ARMC5, NDEL1, CLPTM1L, ALKBH5, YIPF5, PPP2CA, and TFG. These findings suggest that aberrant NRF1 activity may contribute to the pathogenesis of GBM and severity of astrocytoma. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.

Surpass Flow Diverter in the Treatment of Ruptured Intracranial Aneurysms-A Single-Center Experience.

BACKGROUND: Use of a Surpass flow diverter (FD) device in the treatment of acutely ruptured aneurysm has not been well studied and reported in the literature. METHODS: We retrospectively reviewed patients with subarachnoid hemorrhage who were treated by Surpass FD placement at our hospital between June 2016 and March 2018. Detailed analysis of medical records was performed to obtain patient age, gender, clinical history, Hunt and Hess grade, Fisher grade, results of radiographic and procedural details including technical success and complication, clinical outcome, and follow-up angiographic results. RESULTS: Our search identified 16 patients with 16 aneurysms who were treated with Surpass FD, of which 13 aneurysms (81%) were in the anterior circulation and 3 (19%) were in the posterior circulation. Aneurysm size ranged from 1.1 to 16 mm, with a mean of 4 mm. The mean delay between subarachnoid hemorrhage and endovascular treatment was 5 days (range, 3-20 days). Only 1 Surpass FD was used in each patient, ranging in size from 3 × 25 mm to 4 × 50 mm. Fifteen patients (94%) achieved favorable clinical outcome (modified Rankin Scale score 0-1) at 3 months. One patient died of invasive fungal infection. Angiographic follow-up results were assessed by O'Kelly-Marotta grading scale in 15 surviving patients and showed a grade D result (no filling) in 13/15 aneurysms (87%) at 3 and 6 months. CONCLUSIONS: A Surpass FD device is a feasible option for the treatment of ruptured intracranial aneurysms that are difficult to treat by conventional clipping and coiling; however, larger and comparative studies with long-term follow-up are needed to confirm its safety and efficacy.

Are childhood and adult medulloblastomas different? A comparative study of clinicopathological features, proliferation index and apoptotic index.

Childhood medulloblastomas have been suspected to be biologically different from adult tumors, though comparative studies are sparse in the literature. The present study aims to establish any differences or nexus in the biological characteristics between childhood and adult medulloblastomas. A total of 181 medulloblastomas were studied with respect to clinical and histological characteristics, MIB-1 labeling index (MIB-1 LI), apoptotic index (AI), ratio of apoptotic to LI, p53 and Bcl-2 protein expressions. Two-thirds (112) of the 181 medulloblastomas occurred in children (< or = 15 years) and 69 in adults (> 15 years). Childhood tumors were more commonly of classical histology and midline location while the desmoplastic variant and lateral location occurred more frequently in adults. Adult medulloblastomas were biologically less aggressive, having lower growth rate parameters (mean MIB-1 LI 19.1 +/- 15.7; AI 3.73 +/- 2.71 and AI:LI 0.207 +/- 0.162) as compared to childhood tumors (mean MIB-1 LI 28.3 +/- 20.4; AI 2.86 +/- 2.14 and AI:LI 0.108 +/- 0.111). p53 and Bcl-2 protein expressions were infrequent in all groups of tumors. No difference was noted in any of the parameters when classical and desmoplastic medulloblastomas were compared as a whole. But when compared between the age groups, an interesting observation (hitherto unreported in English literature) was that both classical and desmoplastic variants of childhood medulloblastomas had higher LI, lower AI and lower AI:LI ratio than their counterparts in adults, indicating that differences in growth rates cannot be attributed to differences in the frequency of occurrence of the histological variants in the two age groups. Thus, this study conclusively shows that there is a biological difference between childhood and adult medulloblastomas which is independent of standard histology and appeared to be associated more with age-related factors. This also warrants less-aggressive therapy for adult medulloblastoma.