Naresh Murty

Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis

IMPORTANCE Endovascular intervention for acute ischemic stroke improves revascularization. But trials examining endovascular therapy yielded variable functional outcomes, and the effect of endovascular intervention among subgroups needs better definition. OBJECTIVE To examine the association between endovascular mechanical thrombectomy and clinical outcomes among patients with acute ischemic stroke. DATA SOURCES We systematically searched MEDLINE, EMBASE, CINAHL, Google Scholar, and the Cochrane Library without language restriction through August 2015. STUDY SELECTION Eligible studies were randomized clinical trials of endovascular therapy with mechanical thrombectomy vs standard medical care, which includes the use of intravenous tissue plasminogen activator (tPA). DATA EXTRACTION AND SYNTHESIS Independent reviewers evaluated the quality of studies and abstracted the data. We calculated odds ratios (ORs) and 95% CIs for all outcomes using random-effects meta-analyses and performed subgroup and sensitivity analyses to examine whether certain imaging, patient, treatment, or study characteristics were associated with improved functional outcome. The strength of the evidence was examined for all outcomes using the GRADE method. MAIN OUTCOMES AND MEASURES Ordinal improvement across modified Rankin scale (mRS) scores at 90 days, functional independence (mRS score, 0-2), angiographic revascularization at 24 hours, symptomatic intracranial hemorrhage within 90 days, and all-cause mortality at 90 days. RESULTS Data were included from 8 trials involving 2423 patients (mean [SD] age, 67.4 [14.4] years; 1131 [46.7%] women), including 1313 who underwent endovascular thrombectomy and 1110 who received standard medical care with tPA. In a meta-analysis of these trials, endovascular therapy was associated with a significant proportional treatment benefit across mRS scores (OR, 1.56; 95% CI, 1.14-2.13; P = .005). Functional independence at 90 days (mRS score, 0-2) occurred among 557 of 1293 patients (44.6%; 95% CI, 36.6%-52.8%) in the endovascular therapy group vs 351 of 1094 patients (31.8%; 95% CI, 24.6%-40.0%) in the standard medical care group (risk difference, 12%; 95% CI, 3.8%-20.3%; OR, 1.71; 95% CI, 1.18-2.49; P = .005). Compared with standard medical care, endovascular thrombectomy was associated with significantly higher rates of angiographic revascularization at 24 hours (75.8% vs 34.1%; OR, 6.49; 95% CI, 4.79-8.79; P < .001) but no significant difference in rates of symptomatic intracranial hemorrhage within 90 days (70 events [5.7%] vs 53 events [5.1%]; OR, 1.12; 95% CI, 0.77-1.63; P = .56) or all-cause mortality at 90 days (218 deaths [15.8%] vs 201 deaths [17.8%]; OR, 0.87; 95% CI, 0.68-1.12; P = .27). CONCLUSIONS AND RELEVANCE Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days.

Chronic Subdural Hematoma Management: A Systematic Review and Meta-analysis of 34829 Patients

Objective:To compare the efficacy and safety of multiple treatment modalities for the management of chronic subdural hematoma (CSDH) patients. Background:Current management strategies of CSDHs remain widely controversial. Treatment options vary from medical therapy and bedside procedures to major operative techniques. Methods:We searched MEDLINE (PubMed and Ovid), EMBASE, CINAHL, Google scholar, and the Cochrane library from January 1970 through February 2013 for randomized and observational studies reporting one or more outcome following the management of symptomatic patients with CSDH. Independent reviewers evaluated the quality of studies and abstracted the data on the safety and efficacy of percutaneous bedside twist-drill drainage, single or multiple operating room burr holes, craniotomy, corticosteroids as a main or adjuvant therapy, use of drains, irrigation of the hematoma cavity, bed rest, and treatment of recurrences following CSDH management. Mortality, morbidity, cure, and recurrence rates were examined for each management option. Randomized, prospective, retrospective, and overall observational studies were analyzed separately. Pooled estimates, confidence intervals (CIs), and relative risks (RRs) were calculated for all outcomes using a random-effects model. Results:A total of 34,829 patients from 250 studies met our eligibility criteria. Sixteen trials were randomized, and the remaining 234 were observational. We included our unpublished single center series of 834 patients. When comparing percutaneous bedside drainage to operating room burr hole evacuation, there was no significant difference in mortality (RR, 0.69; 95% CI, 0.46–1.05; P = 0.09), morbidity (RR, 0.45; 95% CI, 0.2–1.01; P = 0.05), cure (RR, 1.05; 95% CI, 0.98–1.11; P = 0.15), and recurrence rates (RR, 1; 95% CI, 0.66–1.52; P = 0.99). Higher morbidity was associated with the adjuvant use of corticosteroids (RR, 1.97; 95% CI, 1.54–2.45; P = 0.005), with no significant improvement in recurrence and cure rates. The use of drains following CSDH drainage resulted in a significant decrease in recurrences (RR, 0.46; 95% CI, 0.27–0.76; P = 0.002). Craniotomy was associated with higher complication rates if considered initially (RR, 1.39; 95% CI, 1.04–1.74; P = 0.01); however, craniotomy was superior to minimally invasive procedures in the management of recurrences (RR, 0.22; 95% CI, 0.05–0.85; P = 0.003). Conclusions:Percutaneous bedside twist-drill drainage is a relatively safe and effective first-line management option. These findings may result in potential health cost savings and eliminate perioperative risks related to general anesthetic.

Minimally invasive approach for the resection of spinal neoplasm.

Study Design. Retrospective Case Series. Objective. To determine if extradural, intradural extramedullary, and intramedullary spinal neoplasms can be safely resected through a minimally invasive corridor. Summary of Background Data. The use of minimally invasive approaches for resection of spinal neoplasms has been described for intradural schwannomas and ependymomas. We demonstrate that this approach can be extended to the resection of a variety of extradural, intradural and intramedullary spinal tumors. Methods. We undertook a retrospective review of all patients presenting with clinical and radiographic evidence of spinal neoplasm that subsequently underwent a minimally invasive approach for resection of the tumor using the METRx MAST QUADRANT Retractor System (Medtronics, Memphis, TN). Primary endpoints analyzed include completeness of resection, postoperative neurologic status, operative time, blood loss, postoperative pain, length of hospital stay, and operative complications. Results. Two cervical, seven thoracic and 13 lumbar neoplasms were identified in 20 patients operated on between September 2005 and May 2009. Mean intraoperative time was 210 minutes, blood loss 428 mL and average length of hospital stay was 3 days. Four patients required postoperative patient-controlled analgesia for pain control and an average of 5.8 doses of narcotic were given per patient. Two patients developed postoperative complications. Fifteen of 22 tumors (68%) were completely resected, with only one patient requiring repeat operation for residual tumor. All but one patient were improved from preoperative status at 6 months. Conclusion. Intramedullary, intradural and extradural spinal neoplasms can be resected through a minimally invasive approach without increased risk for adverse neurologic outcome. This technique may be an appropriate alternative to the open approach for well-circumscribed extramedullary lesions spanning one or two spinal levels. With increasing experience, reduced operative time, blood loss, complications, length of hospital stay, postoperative pain, and spinal instability may be seen.

Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis

BACKGROUND Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. METHODS We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. RESULTS A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14-5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58-14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45-3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12-0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46-1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26-5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91-8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13-3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05-5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18-1.49, P = .223). CONCLUSIONS Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs.

A Cancer Stem Cell Model for Studying Brain Metastases From Primary Lung Cancer

BACKGROUND Brain metastases are most common in adults with lung cancer, predicting uniformly poor patient outcome, with a median survival of only months. Despite their frequency and severity, very little is known about tumorigenesis in brain metastases. METHODS We applied previously developed primary solid tumor-initiating cell models to the study of brain metastases from the lung to evaluate the presence of a cancer stem cell population. Patient-derived brain metastases (n = 20) and the NCI-H1915 cell line were cultured as stem-enriching tumorspheres. We used in vitro limiting-dilution and sphere-forming assays, as well as intracranial human-mouse xenograft models. To determine genes overexpressed in brain metastasis tumorspheres, we performed comparative transcriptome analysis. All statistical analyses were two-sided. RESULTS Patient-derived brain metastasis tumorspheres had a mean sphere-forming capacity of 33 spheres/2000 cells (SD = 33.40) and median stem-cell frequency of 1/60 (range = 0-1/141), comparable to that of primary brain tumorspheres (P = .53 and P = .20, respectively). Brain metastases also expressed CD15 and CD133, markers suggestive of a stemlike population. Through intracranial xenotransplantation, brain metastasis tumorspheres were found to recapitulate the original patient tumor heterogeneity. We also identified several genes overexpressed in brain metastasis tumorspheres as statistically significant predictors of poor survival in primary lung cancer. CONCLUSIONS For the first time, we demonstrate the presence of a stemlike population in brain metastases from the lung. We also show that NCI-H1915 tumorspheres could be useful in studying self-renewal and tumor initiation in brain metastases. Our candidate genes may be essential to metastatic stem cell populations, where pathway interference may be able to transform a uniformly fatal disease into a more localized and treatable one.

Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells

The master regulatory gene Bmi1 modulates key stem cell properties in neural precursor cells (NPCs), and has been implicated in brain tumorigenesis. We previously identified a population of CD133+ brain tumor cells possessing stem cell properties, known as brain tumor initiating cells (BTICs). Here, we characterize the expression and role of Bmi1 in primary minimally cultured human glioblastoma (GBM) patient isolates in CD133+ and CD133- sorted populations. We find that Bmi1 expression is increased in CD133- cells, and Bmi1 protein and transcript expression are highest during intermediate stages of differentiation as CD133+ BTICs lose their CD133 expression. Furthermore, in vitro stem cell assays and Bmi1 knockdown show that Bmi1 contributes to self-renewal in CD133+ populations, but regulates proliferation and cell fate determination in CD133- populations. Finally, we test if our in vitro stem cell assays and Bmi1 expression in BTIC patient isolates are predictive of clinical outcome for GBM patients. Bmi1 expression profiles show a marked elevation in the proneural GBM subtype, and stem cell frequency as assessed by tumor sphere assays correlates with patient outcome.

The value of scheduled repeat cranial computed tomography after mild head injury: single-center series and meta-analysis.

BACKGROUND After an initial computed tomography (CT) scan revealing intracranial hemorrhage resulting from traumatic brain injury, a standard of care in many trauma centers is to schedule a repeat CT scan to rule out possible progression of bleed. OBJECTIVE To evaluate the utility of routine follow-up CT in changing the management of mild head injury patients despite clinical stability, although repeat imaging is indicated to assess a deteriorating patient. METHODS The trauma database at our institution was retrospectively reviewed and the literature was searched to identify patients after mild head injury with positive initial CT finding and scheduled repeat scan. Patients were divided into 2 groups for comparison. Group A included patients who had intervention based on neurological examination changes. Group B comprised patients requiring a change in management according to CT results exclusively. The meta-analysis of the present cohort and included articles was performed with a random-effects model. RESULTS Overall, 15 studies and 445 patients met our eligibility criteria, totaling 2693 patients. Intervention rates of groups A and B were 2.7% (95% confidence interval, 1.7-3.9; P = .003) and 0.6% (95% confidence interval, 0.3-1; P = .21), respectively. The statistical difference between both intervention rates was clinically significant with P < .001. CONCLUSION The available evidence indicates that it is unnecessary to schedule a repeat CT scan after mild head injury when patients are unchanged or improving neurologically. In the absence of supporting data, we question the value of routine follow-up imaging given the associated accumulative increase in cost and risks.

Endoscopic Transnasal Approach to the Craniocervical Junction

Anterior access to the craniocervical junction has traditionally been through a transoral approach. With the advent of newer techniques, recent literature suggests a possible role for a transnasal endoscopic approach to the craniocervical junction. A review of the literature primarily consists of case reports and three anatomic cadaveric studies demonstrating the feasibility of an endonasal approach. In this retrospective review, we report our experience with four patients who underwent an endoscopic transnasal approach to the C1-C2 region. The surgical technique using a binasal endoscopic approach is described. The results indicate that the procedure is well tolerated with no significant deleterious sequelae. Although the use of this technique is in its early stages, the transnasal approach may offer a safe and effective alternative with minimal morbidity. Larger clinical studies are necessary to further explore the risks and benefits of this procedure.

Pyrvinium Targets CD133 in Human Glioblastoma Brain Tumor–Initiating Cells

Purpose: Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133+ treatment-refractory population. Experimental Design: Using gain/loss-of-function studies for CD133 we assessed the in vitro self-renewal and in vivo tumor formation capabilities of patient-derived glioblastoma cells. We generated a CD133 signature combined with an in silico screen to find compounds that target GICs. Self-renewal and proliferation assays on CD133-sorted samples were performed to identify the preferential action of hit compounds. In vivo efficacy of the lead compound pyrvinium was assessed in intracranial GIC xenografts and survival studies. Lastly, microarray analysis was performed on pyrvinium-treated GICs to discover core signaling events involved. Results: We discovered pyrvinium, a small-molecule inhibitor of GIC self-renewal in vitro and in vivo, in part through inhibition of Wnt/β-catenin signaling and other essential stem cell regulatory pathways. We provide a therapeutically tractable strategy to target self-renewing, chemoradioresistant, and functionally important CD133+ stem cells that drive glioblastoma relapse and mortality. Conclusions: Our study provides an integrated approach for the eradication of clonal populations responsible for cancer progression, and may apply to other aggressive and heterogeneous cancers. Clin Cancer Res; 21(23); 5324–37. ©2015 AACR.

Cervical Spine Clearance in Obtunded Patients After Blunt Traumatic Injury: A Systematic Review

Cervical spine trauma is a major public health problem and a common reason for admission to trauma wards and intensive care units. The cervical spine is injured in 2.3% to 4.3% (14) of blunt traumas. Resultant neurologic impairment is encountered in 33% to 54% (57) of patients with cervical spine trauma. In fact, more than 50% of all acute spinal cord injuries affect the cervical spine (8, 9). Unfortunately, these injuries have poor functional outcomes. Mortality after traumatic cervical spinal cord injury may exceed 20% (1013), and survivors often face lifelong physical disability, along with the associated emotional, psychological, and social burdens (6, 8, 14, 15). The economic costs of spinal cord injury are enormous. In the United States, the total annual direct cost of spinal cord injuries approaches