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Ewing sarcoma is a pediatric bone cancer defined by a chromosomal translocation fusing one of the FET family members to an ETS transcription factor. There have been seven reported chromosomal translocations, with the most recent reported over a decade ago. We now report a novel FET/ETS translocation involving FUS and ETV4 detected in a patient with Ewing sarcoma. Here, we characterized FUS/ETV4 by performing genomic localization and transcriptional regulatory studies on numerous FET/ETS fusions in a Ewing sarcoma cellular model. Through this comparative analysis, we demonstrate significant similarities across these fusions, and in doing so, validate FUS/ETV4 as a bona fide Ewing sarcoma translocation. This study presents the first genomic comparison of Ewing sarcoma–associated translocations and reveals that the FET/ETS fusions share highly similar, but not identical, genomic localization and transcriptional regulation patterns. These data strengthen the notion that FET/ETS fusions are key drivers of, and thus pathognomonic for, Ewing sarcoma. Implications: Identification and initial characterization of the novel Ewing sarcoma fusion, FUS/ETV4, expands the family of Ewing fusions and extends the diagnostic possibilities for this aggressive tumor of adolescents and young adults.

Background Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI. Objective To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions. Methods A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted. Results Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (β = -0.58, 95% CI -0.111, -0.005, P = .033). Conclusion RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations.

Glioblastoma (GBM) is a malignant cerebral neoplasm carrying poor prognosis. The importance of extent of resection (EoR) in GBM patient outcomes has been argued in the literature. Previous studies included tumors in eloquent regions of the brain. This confounds the role of EoR by including patients with intrinsically worse outcomes but will be over-represented in the reduced EoR category. In a homogenous group of patients in whom GTR was considered achievable, we investigated the effect of increasing EoR on survival. A retrospective review of 51 patients was undertaken. Quantitative, volumetric analysis of pre-operative and post-operative magnetic resonance image was compared with corresponding clinical details. The primary outcome measured was post-operative overall survival. Median overall survival was 18.3 months for GTR patients compared to 11.6 months for non-GTR (p = 0.025). Median pre-operative contrast-enhancing tumor volume for GTR patients was 54.7 cm3 and 24.9 cm3 for non-GTR. Post-operative median residual tumor volume was 1.1 cm3 in the non-GTR cohort. In multivariate analyses, GTR (HR [95% CI] = 0.973 [0.954–0.994], p = 0.00559) and increasing EoR (HR [95% CI] = 0.964 [0.944–0.985], p = 0.000665) remained predictors of survival. Centile dichotomization of EoR revealed 74% (HR [95% CI] = 0.351 [0.128–0.958], p = 0.0409) as the lowest threshold conferring statistically significant survival benefit. Where technically feasible, both GTR and EoR remained as independent prognostic factors for survival. GTR remains the gold standard for surgical treatment of GBM in patients, 74% being the minimum EoR required to confer survival benefit.

Ewing sarcoma is an aggressive pediatric bone cancer defined by a chromosomal translocation fusing one of the FET family members to a member of the ETS transcription factor family. To date, there have been seven reported translocations, with the most recent translocation reported over a decade ago. We now report the first identification of a novel translocation occurring between the FUS gene and ETS family member ETV4 detected in a neonatal patient with Ewing sarcoma. Given its apparent rarity, we conducted an initial characterization of FUS/ETV4 function by performing genomic localization and transcriptional regulatory studies. We knocked down endogenous EWS/FLI in the A673 cell line, and expressed FUS/ETV4 in its stead, and performed CUT&Tag and RNA-sequencing analyses. We compared these data to similar “knock-down/rescue” analyses of other rare (non-EWS/FLI) Ewing sarcoma-associated translocation products. Through this comparative analysis in the same genetic background, we demonstrate significant similarities across these fusions, and in doing so, validate this novel FUS/ETV4 translocation as a bona fide Ewing sarcoma translocation. This study presents the first genomic comparisons of the rare Ewing sarcoma-associated translocation products, and reveals that the FET/ETS fusions share highly similar, but not identical, genomic localization and transcriptional regulation patterns. These data provide insights into the roles of both the FET and ETS sides of these fusions, and provide a generic strategy to provide further strength to the notion that FET/ETS fusions are key drivers of, and thus pathognomonic for, Ewing sarcoma.SignificanceIdentification and initial characterization of the novel Ewing sarcoma fusion, FUS/ETV4, expands the family of Ewing-fusions and extends the diagnostic possibilities for this aggressive tumor of adolescents and young adults.

New Zealand has one of the highest rates of melanoma in the world. In up to 10% of cases, the disease is metastatic at diagnosis. Cerebral metastatic involvement carries a particularly poor prognosis. 110 patients were included in the analysis. A retrospective consecutive series of patients treated surgically at Auckland City Hospital were studied, with parameters of demographics, tumour characteristics, surgery, pathology, systemic therapy and survival analysed. Mean age was 59.9 years (range 22-81 years). Median survival from date of surgery was 8.1 months (95% CI 6.9-9.4 months). Of the 58 patients tested for BRAF mutation, 28 were positive, similar to previously published data. This conferred a better prognosis with median overall survival of 12.3 months (95% CI 7.2-17.3 months) compared to 7.8 months (95% CI 5.6-10 months) for those who were negative (p 0.05). Survival correlated positively with extent of surgical resection. Both BRAF positive status and targeted and/or immunotherapy were significant predictors of improved survival. In this cohort, radiation therapy did not show a statistically significant improvement in overall survival. Survival from resection of cerebral metastases from melanoma is improving. Survival benefit is conferred by BRAF mutation, solitary metastasis and gross total resection of lesion.

Hydrocephalus is the single most common pediatric neurosurgical problem worldwide. Current treatment of this life-threatening disorder involves diverting excess fluid from the ventricles of the brain via a prosthetic shunt. While many hydrocephalus sufferers rely heavily on their ventriculo-distal shunt to maintain a healthy intracranial pressure, shunts carry a high risk of failure. Current methods of assessing shunt patency are performed within the hospital, and many patients and their families feel bound to remaining within close proximity of a hospital in order to receive timely medical intervention in the event of a shunt failure. There is a need for a system which can detect shunt malfunction, simply and reliably. We present a novel method of obtaining flow measurements from a piezoresistive pressure transducer. This builds on an earlier development of obtaining simultaneous temperature and pressure measurement from the single ultra-miniature solid-state transducer. The flow measurement system is capable of measurements in the range 0-35 ml/h, typical of the fluid flow rates through a hydrocephalus shunt. Within the flow range 0–14 ml/hour the resolution is 2 ml/hour. For flow rates greater than 16 ml/hour the resolution is 5 ml/hour. Employing a thermal flow sensing technique, the maximum heating of the local fluid is 0.65 ± 0.02 °C. The flow signal is independent of ambient temperature. The sensor would be implanted in the shunt to allow the detection of the flow rate of fluid through it, enabling the clinician to measure the patency of a shunt in real time.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Despite the current clinical management of surgical resection, followed by radiation and chemotherapy, the median survival time is still a dismal 15 months. This may be due to treatment-resistant GBM stem cells (GSCs) that survive and migrate, resulting in tumour recurrence. Therefore, elucidating the mechanisms of GSC migration and studying ways of limiting this process will be beneficial in the treatment of GBM. A key molecule of interest is polysialylated neural cell adhesion molecule (PSA-NCAM). During normal development and adult neurogenesis, its presence on the cell surface reduces interactions with the extracellular matrix and aids in cellular migration. However, it has also been associated with malignant brain tumours and with negative patient prognosis. METHODS: We investigated PSA-NCAM’s role in tumour recurrence by immunohistologically evaluating over 160 surgically resected brain tumour specimens for PSA-NCAM expression and correlating this with patient outcomes. We also utilized GSCs isolated from the same patient specimens to investigate the role of PSA-NCAM in tumour cell migration. RESULTS: Univariate and Cox proportional hazard analysis showed that PSA-NCAM expression was a strong predictor of rapid tumour progression, even more so than the cell proliferation marker Ki67, which is often used to assess tumour grade. In addition, high-content image analysis revealed that PSA-NCAM was highly expressed by migrating patient-derived GSCs in vitro, and drugs that limited their migration also decreased PSA-NCAM expression. This led to investigations that aimed to elucidate the effects of PSA-NCAM removal on GSC migration. SUMMARY: Our work highlights the potential role of PSA-NCAM in GSC migration and tumour progression. This opens up avenues to pharmacologically and genetically manipulate PSA-NCAM to reduce GBM cell migration and curb tumour recurrence.

Background Although hypothermia and barbiturates improve neurologic outcomes in animal temporary focal ischemia models, the clinical efficacy of these interventions during temporary occlusion of the cerebral vasculature during intracranial aneurysm surgery (temporary clipping) is not established. Methods A post hoc analysis of patients from the Intraoperative Hypothermia for Aneurysm Surgery Trial who underwent temporary clipping was performed. Univariate and multivariate logistic regression methods were used to test for associations between hypothermia, supplemental protective drug, and short- (24-h) and long-term (3-month) neurologic outcomes. An odds ratio more than 1 denotes better outcome. Results Patients undergoing temporary clipping (n = 441) were assigned to intraoperative hypothermia (33.3 degrees +/- 0.8 degrees C, n = 208) or normothermia (36.7 degrees +/- 0.5 degrees C, n = 233), with 178 patients also receiving supplemental protective drug (thiopental or etomidate) during temporary clipping. Three months after surgery, 278 patients (63%) had good outcome (Glasgow Outcome Score = 1). Neither hypothermia (P = 0.847; odds ratio = 1.043, 95% CI = 0.678-1.606) nor supplemental protective drug (P = 0.835; odds ratio = 1.048, 95% CI = 0.674-1.631) were associated with 3-month Glasgow Outcome Score. The effect of supplemental protective drug did not significantly vary with temperature. The effects of hypothermia and protective drug did not significantly vary with temporary clip duration. Similar findings were made for 24-h neurologic status and 3-month Neuropsychological Composite Score. Conclusion In the Intraoperative Hypothermia for Aneurysm Surgery Trial, neither systemic hypothermia nor supplemental protective drug affected short- or long-term neurologic outcomes of patients undergoing temporary clipping.

We report on a giant basilar tip aneurysm in a 48-year-old woman that could not be clipped despite temporary occlusion of the basilar trunk. Adenosine induced cardiac asystole reduced the aneurysm's wall tension and coupled with increased exposure resulting from brain relaxation allowed for the aneurysm to be satisfactorily occluded via an extended right pterional craniotomy. In difficult vascular cases, adenosine induced cardiac standstill is a useful technique which may allow for technical success when other methods such as temporary clipping fail. It acts to both reduce aneurysm wall tension and increase operative exposure by reducing vascular, and hence brain volume.

Non-traumatic separate simultaneous intracerebral haemorrhages (SSIHs) are rare. Relevant aetiologies are diverse and their diagnosis challenging. We report a unique case of SSIH in an 18-year-old male with a background of previously undiagnosed testicular choriocarcinoma and Klinefelter syndrome. The patient was admitted to Auckland City Hospital with headaches, drowsiness and vomiting. A CT scan revealed SSIH in a background of tumorous lesions. His β human chorionic gonadotropin titre was elevated at 355 000 IU/L. The SSIH and the associated tumorous lesions were acutely surgically resected and the patient started on bleomycin, etoposide and cisplatin combination chemotherapy with excellent results. In this article, we underline choriocarcinoma as a rare aetiology of SSIH and present an example of the clinical presentation, investigation and management of this very rare pathological entity.

We analysed 166 cases of paediatric central nervous system tumour presenting to Auckland City and Starship Children’s Hospital, New Zealand, between 1995 and 2004. The purpose of this study was to perform an audit of paediatric neurosurgical practice in the upper North Island of New Zealand with the objective of assessing patient presentation, demographics, and modality and efficacy of therapy. The overall incidence of central nervous system tumours was 3.42/100,000/year. The incidence rate of medulloblastoma for Maori was over double that for European New Zealanders. Tumour clearance was attempted in 81.3% of patients. Some type of adjunct therapy was received by 45.2% of patients. Overall, 60.8% of patients had satisfactory or good results. Survival rates for pilocytic astrocytoma and ependymoma were consistent with previous studies. Survival data for medulloblastoma demonstrate improved outcomes with complete resection of tumour and with a specialist paediatric neurosurgeon compared with general neurosurgeons. Recent management changes have led to improved outcomes.

✓ The purpose of this article is to raise awareness of spontaneous spinal hematomas that develop after administration of low-molecular-weight heparin therapy. The authors describe four patients in whom these hematomas developed without precipitating events while receiving a treatment dose of enoxaparin (Clexane) (∼1 mg/kg). Spontaneous spinal hematomas (not related to trauma, surgery, or lumbar puncture) are a rare clinical entity. Several causes have been identified, including acquired and congenital clotting abnormalities and underlying vascular lesions. Aspirin, warfarin, tissue plasminogen activator, and heparin have all been implicated in causing spinal hematomas. Concerns regarding the use of low-molecular-weight heparin agents in neuraxis anesthesia have been well documented. Their possible contribution to nontraumatic spinal hematomas has been less well described. The authors believe that low-molecular-weight heparin agents present a small but significant risk of spinal hematoma. This should be considered when prescribing therapy because such a complication may be catastrophic.

Knowledge of the force required to generate a subdural hematoma is important when considering the veracity of histories given by family members of young children. Traditional wisdom is that a substantial impact is required to cause an acute subdural hematoma. We present a case of acute subdural hematoma following a low-level fall in a 3-year-old patient. An antecedent head injury associated with normal CT scan might have had some bearing on this outcome.

A 34-year-old woman presented with a rapid onset of meningitic symptoms. Cerebrospinal fluid (CSF) from a lumbar puncture revealed a leucocytosis with a preponderance of monocytes, elevated protein and reduced glucose. Herpes simplex virus (HSV) type II was subsequently confirmed by polymerase chain reaction (PCR) of CSF. The patient's level of consciousness deteriorated and a CT scan revealed hydrocephalus. The patient required placement of an external ventricular drain for 5 days; however, she made a full recovery without specific antiviral therapy. This is the first reported case of hydrocephalus secondary to isolated HSV type II meningitis.

Background: Hydrocephalus patients are commonly treated by insertion of ventriculoperitoneal shunts, but these have high complication rates. Monitoring of shunt and patient condition can be achieved through measuring intracranial pressure (ICP). Significant zero drift has limited previous developments towards a long-term implantable ICP monitor. We present a new implantable solid-state pressure sensor system appropriate for chronic (lifetime) monitoring of ICP.

OBJECTIVE: We examined the incidence of perioperative fever and its relationship to outcome among patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial. METHODS: One thousand patients with initial World Federation of Neurological Surgeons grades of I to III undergoing clipping of intracranial aneurysms after subarachnoid hemorrhage were randomized to intraoperative normothermia (36 degrees C-37 degrees C) or hypothermia (32.5 degrees C-33.5 degrees C). Fever (> or =38.5 degrees C) and other complications (including infections) occurring between admission and discharge (or death) were recorded. Functional and neuropsychologic outcomes were assessed 3 months postoperatively. The primary outcome variable for the trial was dichotomized Glasgow Outcome Scale (good outcome versus all others). RESULTS: Fever was reported in 41% of patients. In 97% of these, fever occurred in the postoperative period. The median time from surgery to first fever was 3 days. All measures of outcome were worse in patients who developed fever, even in those without infections or who were World Federation of Neurological Surgeons grade I. Logistic regression analyses were performed to adjust for differences in preoperative factors (e.g., age, Fisher grade, initial neurological status). This demonstrated that fever continued to be significantly associated with most outcome measures, even when infection was added to the model. An alternative stepwise model selection process including all fever-related measures from the preoperative and intraoperative period (e.g., hydrocephalus, duration of surgery, intraoperative blood loss) resulted in the loss of significance for dichotomized Glasgow Outcome Scale, but significant associations between fever and several other outcome measures remained. After adding postoperative delayed ischemic neurological deficits to the model, only worsened National Institutes of Health Stroke Scale score, Barthel Activities of Daily Living index, and discharge destination (home versus other) remained independently associated with fever. CONCLUSION: These findings suggest that fever is associated with worsened outcome in surgical subarachnoid hemorrhage patients, although, because the association between fever and the primary outcome measure for the trial is dependent on the covariates used in the analysis (particularly operative events and delayed ischemic neurological deficits), we cannot rule out the possibility that fever is a marker for other events. Only a formal trial of fever treatment or prevention can address this issue.

Object The aims of this study were to determine whether contrast-enhanced ultrasonography (CEU) could be used for noninvasive evaluation of cerebral perfusion in patients with traumatic brain injury (TBI) and to assess the effect of decompressive surgery on cerebral perfusion as measured by CEU. Methods Contrast-enhanced ultrasonography with intravenous administration of a microbubble contrast agent was performed in six patients with TBI undergoing decompressive craniectomy. Contrast-enhanced ultrasonography was performed through a bur hole before craniectomy and through the calvarial defect immediately after craniectomy and on postoperative Days 1 and 2. For the latter two studies, patients were placed in the recumbent position and at a 35° incline to investigate changes in perfusion produced by modulation of intracranial pressure (ICP). Cerebral microvascular blood flow increased by almost threefold immediately after craniectomy, from a mean of 7.5 ± 6.9 (standard deviation [SD]) to 20.9 ± 11.6 (p < 0.05), and further improved on postoperative Day 1 (mean 37.1 ± 13.9 [SD], p < 0.05, compared with postcraniectomy microvascular blood flow) without subsequent change on Day 2. The change in microvascular perfusion correlated inversely with the initial ICP (p < 0.01), indicating less recovery of flow when preoperative ICP was markedly elevated. On postoperative Days 1 and 2, head-of-bed elevation produced an increase in microvascular perfusion on CEU (mean 37 ± 11 compared with 51 ± 20, p < 0.05) and a small decrease in ICP (mean 16 ± 5 mm Hg compared with 12 ± 4 mm Hg, p < 0.05). In patients with parenchymal hematoma, CEU provided spatial information on perfusion abnormalities in the hemorrhagic core and surrounding tissues. Conclusions Contrast-enhanced ultrasonography has potential for the intraoperative and bedside assessment of cerebral perfusion in patients with TBI. The technique may be appropriate for evaluating responses to therapies aimed at preventing secondary ischemia and for assessing regional perfusion abnormalities.

Background: Delays in patient transfer to definitive neurosurgical care after traumatic brain injury are important in determining neurological outcome. The efficiency of interhospital transfer of patients to Auckland City Hospital (ACH) was analysed and compared with international standards. Methods: The ACH Department of Critical Care Medicine database for the year 2002 was reviewed, with supplementary information obtained from transfer organizations, hospital notes, radiology archives, and operative logbooks. Results: Thirty-four adult patients with traumatic brain injury and no special reasons for delayed transfer were transported intubated from other hospitals in the North Island of New Zealand. The median time from injury to arrival at ACH was 6.5 h. It took a median 4.4 h for patients to get from initial computed tomographic imaging to ACH. For those requiring evacuation of haematomas, the mean time from arrival at ACH to the start of the operation was 1.4 h. Only 33% of patients from other metropolitan Auckland hospitals, and none from hospitals outside the city, arrived within 4 h from the time of injury. Conclusion: Transfer times for brain trauma patients are currently longer than recommended for optimal neurological outcome. Referring hospitals and transfer organizations should review their systems to identify areas for improvement. Direct admission to theatre needs to be expedited within ACH when required. Triage of all trauma patients in metropolitan Auckland with a Glasgow Coma Scale score of less than 14 to ACH would be likely to improve time to treatment. A mobile acute neurosurgical service based in Auckland that would support general surgeons initiating acute decompressive cranial operations would be likely to reduce time to surgery and improve outcomes for patients admitted to hospitals outside Auckland. The development of a mobile acute neurosurgery service which would complete decompressive procedures started by general surgeons would likely improve trauma outcomes for patients injured outside Auckland.

Results The patient was referred for neurosurgical opinion due to a 2-week history of gait instability on a background of progressive ataxia and urinary incontinence. MRI showed triventricular hydrocephalus due to a tectal plate mass with thalamic extension. On examination, his GCS was 15/15 and he demonstrated truncal ataxia, gait instability, and upper limb dysmetria. He was admitted for an endoscopic third ventriculostomy with biopsy. Operative approach: The patient was anaesthetised and placed supine. Incision and burr hole were over the left coronal suture. A third ventriculostomy was performed for hydrocephalus. The tumour was then approached through the cavum septum pellucidum. Septal fenestrations allowed easy access to the cavum. Internal cerebral veins were identified and the velum interpositum opened with sharp scissors. The opening was dilated and an endoscope advanced into the posterior third ventricle. The tumour was identified and biopsies obtained. He had a satisfactory recovery and was discharged 6 days later. Histology showed a low-grade glioma, which remained stable on follow-up MRI.