Thorsteinn Gunnarsson

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING NoNO Inc and Arbor Vita Corp.

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathway-driven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell–cell interaction between the CD133+ Hh receptor cells and the CD133− Hh-secreting cells.

FoxG1 Interacts with Bmi1 to Regulate Self‐Renewal and Tumorigenicity of Medulloblastoma Stem Cells

Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 (“non‐Shh/Wnt MBs”) are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor‐initiating cell (BTIC) self‐renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup‐specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString‐subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non‐Shh/Wnt MBs and showed these genes to mediate MB stem cell self‐renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self‐renewal mechanisms amenable to therapeutic targeting. STEM Cells2013;31:1266–1277

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.

Surgical exposure of the carotid artery for endovascular interventional procedures

BackgroundTransfemoral approach for endovascular interventions is not always possible in cases of unfavorable anatomy. We report our experience using a transcervical approach with carotid cut down and direct, controlled puncture of the carotid artery.MethodsFour patients underwent surgical exposure of the carotid artery for endovascular procedures. One patient had retrograde placement of a stent in the common carotid artery, and three patients had coiling of an intracranial aneurysm. After the endovascular procedure, the sheath was removed and the vessel was closed, under direct visualization.ResultsThe technique allowed access to extracranial and intracranial lesions. There were no access site complications. There were no access site-related cardiac, systemic, or neurologic events.ConclusionsTranscervical access with surgical exposure of the carotid artery for direct and controlled vascular puncture is an effective alternative for endovascular extracranial and intracranial procedures in patients in whom the femoral route cannot be used.

Combined staged endoscopic and microsurgical approach of a third ventricular choroid plexus papilloma in an infant.

BACKGROUND Choroid plexus papillomas of the third ventricle in newborn infants are quite rare and present a significant surgical challenge. This case report illustrates the utility of endoscopy in facilitating tumor resection. PATIENT A 6-week-old boy, born prematurely at a gestational age of 35 weeks, presented with hydrocephalus secondary to a choroid plexus papilloma in the third ventricle, extending to the aqueduct of Sylvius and into the fourth ventricle. On admission, he was found to have clinical signs of raised intracranial pressure. MRI revealed a homogeneously enhancing mass primarily in the third ventricle. The initial surgical procedure was insertion of a ventriculo-peritoneal shunt, followed by an endoscopic biopsy, which allowed the surgeons to mobilize the tumor into the right lateral ventricle. This facilitated a subsequent transcortical approach to completely remove the tumour. RESULT AND CONCLUSION The authors present a case of choroid plexus papilloma in an uncommon location with a unique surgical approach and a successful outcome with no neurological deficits. We detail our surgical approach and the complexity of approaching a tumor located in the third ventricle of an infant.

Timing of complications during and after elective endovascular intracranial aneurysm coiling

Objective To determine the time to complications during and after elective endovascular intracranial aneurysm coiling. Methods A retrospective chart review of patients undergoing elective endovascular aneurysm coiling between March 2006 and October 2013 in one large Eastern Canadian Neurointerventional Service was performed. Data regarding the incidence, time and type of complication related to the endovascular coiling procedure and clinical outcome at last follow-up were collected. Patient, aneurysm and operation factors were analyzed to determine any factors associated with complication occurrence. Results Of the 150 patient procedures analyzed, 16% experienced a coiling-related complication, although none resulted in death. 6.7% of patients experienced an intraoperative complication, of which thromboembolism was the most common type. The majority of the complications were detected in the first 6 hours after reversal of anesthesia, and a small proportion the next morning prior to discharge. Only 3.3% of patients had persistent neurological deficit after the procedure on last follow-up. Duration of the operation demonstrated a strong association with the occurrence of procedure-related complications. Conclusion This study demonstrates that coiling-related complications of elective endovascular coiling tend to occur either intraoperatively or are detected shortly after reversal of anesthesia. Further investigation with a larger cohort may help to guide important preoperative communication with patients and identify a select group of patients who may not necessarily require prolonged admission to hospital for observation.

Undifferentiated sarcoma in the cerebellopontine angle of an 11-year-old boy.

intracranial neoplasms in the adult population; by contrast, these lesions constitute only 1% of pediatric central nervous system (CNS) tumors1. In adults, the vast majority (approximately 80%) of CPA lesions are vestibular schwannomas (VSs), commonly known as acoustic neuromas. The remainder are largely meningiomas, primary cholesteatomas, schwannomas, epidermoid cysts, ependymomas, other primary tumors of the skull base and inner ear, and metastases. In children, arachnoid cysts, choroid plexus papillomas, gliomas, craniopharyngiomas, and central primitive neuroectodermal tumors (cPNETs) have also been reported in the CPA1. Neoplasms in this CNS region are most commonly of low histological grade. In fact, high-grade extra-axial tumors of the CPA are exceedingly rare and thus carry a substantial risk of being misdiagnosed as benign disease. A high-grade undifferentiated sarcoma involving the CPA has only been described in two previous reports in the literature, both in adult subjects2,3. To the authors’ knowledge, the present case report is the first to describe a high-grade undifferentiated sarcoma of the cerebellopontine angle affecting a pediatric patient, an 11-year-old boy.

An unexpected intracranial pressure crisis: infant brain abscess of unusual aetiology

BackgroundBrain abscess in infants is extremely rare in the developed world. Often, these children have a predisposing history and are infected with certain bacterial aetiology.Case historyA 3-month-old boy presented to the hospital emergently with an increased intracranial pressure crisis. All predisposing factors such as maternal history, family history or the infant’s medical history were entirely free of suggestive aetiological pathology. Neuroimaging revealed a complex mass lesion for which differential diagnosis included neoplasm and brain abscess. We will report on the surgical and medical intervention as well as patient outcome.DiscussionA focus will be placed on the rare pathology discovered and a short review of the literature on the aetiology of this child’s brain lesion will be included as well as support for the management steps taken.ConclusionsBrain abscess in infants is often extremely serious and overwhelming. Concluding topics will focus on contradictions to expected outcome as well as prognostic prospects for patients with this type of devastating disease.